key: cord- -voi gu l authors: xuan, huiyu; xu, lida; li, lu title: a ca-based epidemic model for hiv/aids transmission with heterogeneity date: - - journal: ann oper res doi: . /s - - - sha: doc_id: cord_uid: voi gu l the complex dynamics of hiv transmission and subsequent progression to aids make the mathematical analysis untraceable and problematic. in this paper, we develop an extended ca simulation model to study the dynamical behaviors of hiv/aids transmission. the model incorporates heterogeneity into agents’ behaviors. agents have various attributes such as infectivity and susceptibility, varying degrees of influence on their neighbors and different mobilities. additional, we divide the post-infection process of aids disease into several sub-stages in order to facilitate the study of the dynamics in different development stages of epidemics. these features make the dynamics more complicated. we find that the epidemic in our model can generally end up in one of the two states: extinction and persistence, which is consistent with other researchers’ work. higher population density, higher mobility, higher number of infection source, and greater neighborhood are more likely to result in high levels of infections and in persistence. finally, we show in four-class agent scenario, variation in susceptibility (or infectivity) and various fractions of four classes also complicates the dynamics, and some of the results are contradictory and needed for further research. focus on hiv/aids transmission among human groups in order to better understand its dynamical behavior. in epidemic modeling (see, e.g., bailey ; anderson and may ; murray ) , there are two frequently used methodologies: mathematical and simulation methods. for mathematical approaches, a cohort of people is often classified into susceptibles, infectives, and recovereds with (without) immunity (see, e.g., kermack and mckendrick ) . systems of differential equations are used to describe the linear (nonlinear) dynamics of epidemics. macroscopically, mathematical models can reveal the relationship among primary factors and describe their effects to epidemic spreading under certain assumptions. as to hiv/aids epidemic, many models have been proposed (may and anderson ; hyman et al. ; brauer and driessche ; wu and tan , etc.) . however, mathematical approaches have some serious drawbacks due to its intractability and the complexity of epidemics. moreover, the complicated nature of hiv/aids transmission makes it even harder to obtain analytical solutions and difficult to study them. in the early s, some researchers started to apply simulation approaches to this field. there is a large literature that addresses the computer simulation of epidemic dynamics (see, e.g., leslie and brunham ; atkinson ; rhodes and anderson ; rhodes and anderson ; ahmed and agiza ; benyoussef et al. ; tarwater and martin ) . particularly, cellular automata (ca) method (some literature refers to this as a lattice-based method) has been widely used in modeling complex adaptive systems. despite of its simple structure, ca is well suited to describing the propagation phenomena, such as rumor spreading, particle percolation, innovation propagation, and disease spreading. for instance, in epidemic modeling, fuentes and kuperman ( ) propose two ca models corresponding to the classical mathematical sis model and sis model respectively. ahmed and agiza ( ) develop a ca model that takes into consideration the latency and incubation period of epidemics and allow each individual (agent) to have distinctive susceptibility. gao et al. ( ) put forward a ca model for sars spreading which takes account of social influence. more recently, other methods such as agent-based modeling and system dynamics are introduced to this field (see, e.g., gordan ; bagni et al. ) . our paper contributes to this filed by developing an extended ca simulation model. we then use the new ca model to investigate some issues in hiv/aids epidemics. most models, including the foregoing ca models, have some limitations that fail to consider the peculiarities of hiv/aids epidemics and are thereby incapable of describing the epidemic accurately and completely (see frauenthal for more discussion). first, most of the models assume that there is no latent (or incubation) period. however, for some epidemics, especially aids, there are variously lasting periods of latency and incubation as well as behavior-varying infectivity (or susceptibility) during these periods. in fact, the development of aids involves a few stages in which an infected individual can exhibit different behaviors. those diversified behaviors, in turn, have some ignorable effects on the dynamics of hiv/aids. in light of this, we extend the conventional division of epidemic process (i.e., susceptible, infection, and removed) by dividing the infection period into three sub-stages, each corresponding to the clinical stage occurring in the course of aids development. due to the inability of classical ca approaches to accommodate those newly added state transitions events, we also borrow some ideas from discrete-event simulation techniques and make one agent's stage transitions being time-triggered instead of using some state-based transition rules. secondly, it is commonly assumed that individuals in the population are homogenous in the sense that they have equal infectivity and susceptibility, or they can exert the same influence on each other, etc. this assumption may be satisfied in commonly observed epidemics but not consistent with the hiv/aids epidemic. as we know, susceptibility and infectivity heavily depends on individuals' behavior. for examples, safe sex practices such as the use of condom could dramatically reduce the chance of infection. also, the way of hiv/aids transmission for one to another is various, depending on the interactions between people, and thus the probability of getting infected is determined in part by transmission routes and can be quite different between infected-male/susceptible-female and susceptible-male/infectedfemale interactions. under this assumption, the models that are confined to a single high-risk human group are not suitable in overall population cases. new models are needed to explicitly consider the complexity. therefore, we make an extension to the traditional ca model by introducing the extended definition of neighborhood and attaching some attributes to each agent such as infectivity and resistibility. we also define four types of agents that are characterized by different infectivity (and susceptibility) and various forms of neighborhood to represent four types of people in real life. in doing so, we will be able to investigate the dynamics of hiv/aids with heterogeneous groups in a realistic way. thirdly, classical ca models assume that agents in the grid are spatially fixed, that is, once an agent is placed in a cell, it does not move into another cell. this assumption is problematical because people in the real world are migratory. for instance, in china, millions of rural people leave their hometowns and seek jobs in the cities. the migration of population is a driving force for the spread of hiv/aids. ignoring the mobility of agents in epidemic models would jeopardize the creditability of the results obtained. considering this point, we incorporate agents' mobility into their behaviors. in our model, each agent is allowed to move randomly into one of its adjoined and unoccupied cells at random time intervals. recently, agent-based modeling is used in various fields to solve plenty of problems (see, e.g. zhang and bhattacharyya ; luo et al. ) . some reader might notice that our improved ca model have features that usually found in agent-based methodology. as a matter of fact, our method borrows much from agent-based simulation modeling. to make things simple, we prefer to view this model as being a ca models. this paper is organized as follows. in the next section, we present our extended ca simulation model. section gives a detailed description of simulation results and analyzes some influential factors that affect the dynamical behavior of the model. section concludes and points out some possible extensions and directions for future research. cellular automata have been extensively used as tools for modeling complex adaptive systems such as traffic flow, financial markets, chemical systems, biological groups, and other social systems (see e.g. gerhard and schuster ; gerhardt et al. ; weimar et al. ; karafyllidis and thanailakis ; karafyllidis ) . usually, a typical ca model consists of a regular two-dimension grid with a certain boundary condition and a swarm of agents living in the grid. the neighborhood of an agent is defined to some (or all) of the immediately adjacent cells and the agents who inhabit in the neighborhood are called neighbors. agents are restricted to local neighborhood interaction and hence are unable to communicate globally. there are several states agents can be in at each time and an agent's state at time t + is determined based on its neighbors' states at time t . the rules used in the determination of next-time states can be written as a mapping: where s is the set of states and t denotes simulation time. the mathematical properties of cellular automata have been studied in martin et al. ( ) . in our model, we consider a population of size n(t) at time t randomly distributed in a two-dimension w × w lattice. population growth rate r is fixed throughout the simulation. at each time, new agents are added to the model, and the dead removed. simulation time advances in a discrete way. the time interval (t, t + ) is specified to represent one week in real life. this assumption makes the simulations run reasonably fast (with respect to the whole progress of epidemics) without losing any time-specific clinical properties associated with hiv/aids. explicitly modeling the post-infection progression to aids is one feature of our model compared with conventional ca models. classical epidemic models divide the closed population into three subgroups: susceptible, infective, and recovered (removed). this simplified classification is not consistent with the epidemics in real life. particularly, it is well established that an individual, once infected with hiv, undergoes roughly three clinical phrases towards the full-blown aids: ( ) infected, not yet infectious, ( ) infectious, not yet asymptomatical, and, ( ) symptomatical (may and anderson ; may et al. ) . the lifetime of an individual should cover not only the process from health to infection, but also the sub-stages after infection. thus, we assume that each agent can go through the following states: • s : healthy state, initially, each agent is set to be in s state. healthy agents have no risk of being infected. when a healthy agent moves into the neighborhood of an infectious one or an infectious agent approaches him, the healthy agent's state will change from s to s because contacts with infectives incur the danger of infection. as for an agent in s state, it can transit in two directions: one direction is to change from s back to s , after all its infectious neighbors move away (or its dead neighbors are removed from the grid) or he leaves the neighborhoods of its infectious neighbors; the other direction is to change from s to s if he unluckily get infected. note that we assume infection is instantaneous, i.e., instantaneous transmission from an infected individual to a susceptible. a newly infected agent is unable to transmit hiv virus until seroconversion. the s state corresponds to the early stages of hiv infection. let t denote the duration of this period. empirical works have been done to estimate the parameter. , anderson and medley ( ) report t to lie between and days in transfusion-induced aids cases. in our model we assume that t is a random variable following a normal distribution with the mean μ and the variance σ . after t , the infected agent enters s state: infectious state. medically, the duration during which an infected is infectious but not yet symptomatic is called incubation period. we let t donate the period. empirical work suggests an average incubation period of around to around years (medley et al. . a weibull distribution are commonly used to describe this incubation period (see, e.g., anderson ; anderson and medley ) . furthermore, , anderson and medley ( ) estimated t with a weibull distribution (with a mean of . years and a median of . year) based on transfusioninduced aids cases. for simplicity, we take t as a real number drawn from a normal distribution with the mean μ and the variance σ rather than a weibull distribution. it should be pointed out that the simulation results generated with the normal distribution here are proved to have little, if any, difference compared with those generated when a weibull distribution is employed. during the t period, hiv viruses in the victim's body are constantly cloning themselves and eventually the immunity system collapses. at this point, the victim starts to show some symptoms and thus transit to s state: symptomatic stage. as usually, let t denote the duration of this period. rothenberg et al. ( ) report - year survival rates among idus (intravenous drug user) in new york city and find a median time of survival of days. chang et al. ( ) report a median survival time of . months. empirical work shows that almost all hiv infectives, excluding those who die from other causes, will inevitably develop aids and die of it (may and anderson ) . similarly, we assume t follows a normal distribution with the mean μ and the variance σ . eventually, the ill agent enters s state after t passes by agents in s state will be removed from the population at the beginning of the next time and all of their uninfected neighbors will be released from s state, back to s state. generally, these state transitions take place in the order of s , s , s , s , s , and s . it is impossible for an agent to return from s state to s or s state. this backward transition s to s , demonstrated by a dashed line in fig. , is due to the disappearance of threats posed by infectious agents. moreover, although the transitions among s , s , and s state are not relevant to the propagation process, this process is closely related to hiv/aids transmission. taking account of this procession is essential for a better understanding of hiv/aids transmission. in the model, all the events triggering transitions could be divided into two categories. one category is a rule-based, such as healthy-to-dangerous, dangerous-to-infected, and dangerous-to-healthy state-transition events. these events occur according to the ca transition rules: an agent's state at time t + is based not only on its own state but also on the states of its neighbors at time t . the other category is time-based, meaning that these events are scheduled at pre-specified times. for instance, an agent entering s state will be assigned a time indicating when to change to s state. after that amount of time elapse, the transition occurs spontaneously. despite the distinction between these two categories, the subtlety of implementing the two event-triggering mechanisms is very trivial and leaves no further elaboration necessary. actually, these six states can be divided into three "super" classes in terms of the taxonomy used in the classical mathematical models: s and s states correspond to the susceptible state; s , s , and s states belongs to the infection state, and s state is the removed state. obviously, s and s state could be treated as one single state without changing any results. the reason why we divide this into two sub-states is that this makes our model easily implemented and our logic decent and legible. hiv/aids epidemic differs from other epidemics in that its dynamics is heavily affected by individual's behavioral patterns and the interactions between them. for example, careful sex practices and sanitization measures in drug taking will make individuals less likely to be infected. behavioral patterns and interactions are mostly determined by individual's life styles, personalities, social networks, etc. however, the majority of models fail to take account of the heterogeneity in agents' behaviors. to capture this, we extend classical ca models by allowing each agent to have its own attributes such as mobility, infectivity, resistibility (susceptibility) and different extent of neighborhood. assume that each cell in the grid can be occupied by at most one agent at a time. at time t , agent i can move from one cell into one of its adjacent cells with probability p m i . here, p m i is a measurement of agent i's activity level. it is a fixed real number, drawn from a uniform distribution (p m min , p m max ) ( ≤ p m min ≤ p m max ≤ ). when p m min = p m max , the activity level across agents is equal and therefore agents have the same inclination to move around. one extreme case is p m min = p m max = , which corresponds to the situation in which agents stay in their initial places during simulation, whilst p m min = p m max = means that each agent will move into one empty neighboring cell at almost each time (he could get stocked and not move anywhere if it's neighborhood is occupied). it is easy to induce that the average time per move is calculated as /p m i . intuitively, high level of activity leads to speedy spreading. our simulation results verify this. besides the heterogeneity in agents' activity, another kind of heterogeneity is introduced when we assign various levels of infectivity and susceptibility to agents. let f i denote the infectivity level of agent i. f i is a real number drawn uniformly from the interval ( , ). it measures the possibility that agent i transmits hiv viruses to others when they meets. evidently, greater values of f i indicate higher infectiousness of agent i. suppose also that each agent has resistance to being infected. we denote this resistibility as r i for agent i. similarly, r i is also a real number drawn uniformly from the interval ( , ) and has the property that the greater the resistibility, the less is the chance of getting infected. note that the infectivity of an agent need not be a constant. an agent can have different level of infectivity, depending both on its state as well as on its behavior. it is widely believed that infectives experience two periods of high infectivity (see e.g. may and anderson ; may et al. ), one shortly after being infected and the other at the late stage of his illness. another example is that a patient might have high infectivity during the incubation period and low infectivity owing to good health care during the symptomatic period. although our model allow for various infectivity at different stages for a single agent, we adopt the fixed infectivity for each agent. in doing so, we can focus our attention on some significant issues. we leave various infectivity scenarios for future work. conventional ca models define two types of neighborhoods: moore neighborhood and von neumann neighborhood. in this paper, we extend the concept of ca neighborhood in order to better describe various situations encountered in agent-based modeling. figure illustrates the definition. as we can see in fig. b shows the classical moore neighborhood, and fig. d classical von neumann neighborhood. figure c represents an extended moore neighborhood with the order of × , and fig. e an extended × von neumann neighborhood. specially, fig. a can be simply viewed as an extended × moore (or von neumann) neighborhood. note that fig. b , f-i have the neighborhoods with one direction. this directional structure is able to capture the biases or preferences embedded in individuals' behavioral patterns and we can use different directions to represent variable ways of interactions. it is easy to see that the greater is the neighborhood, the larger extent to which an agent can exert its influence to its neighbors. given the above neighborhood definition, a concept of distance is naturally induced. let a pair of integer numbers (x, y) represent an agent's coordinates in the grid. the distance between agent i and j is thus given as ( ) next, we specify that the influence indicator m i,j of agent i and j satisfies the following condition: that is to say, the influence intensity is inversely proportional to the distance between them if the influence can be exerted, and zero otherwise. therefore, the infective impact i i,j of agent i on agent j can be expressed as and the probability of an agent infected by one of its neighbors is defined as: where p(·) is a function satisfying the conditions: ( ) p(·) is a real-valued function with the value between zero and one; ( ) p(·) is increased in i i,j and decreased in r i . in this model, we assume p(·) takes the form of the following equation: here, p(i i,j , r i ) is interpreted as the probability of agent i being infected by its neighbor j . denoted by b i the set of all its neighbors, agent i's overall probability of infection is thus given by it indicates that this overall probability is determined by the most influential neighbor. such specification makes sense in most cases. the model developed in sect. is implemented using java programming language with the repast software package. detailedly commented source code is available from the authors upon request. next, we begin our analysis by considering first a typical simulation run as a benchmark case. . benchmark case table lists the input parameters chosen for the benchmark case. in this case, the grid consists of × sites (w = ). the population size n is set to with the initial infected ratio α = . . all agents are homogeneous in terms of having the same infectivity f i = . , resistibility r i = . , and × moore neighborhood. they are uniformly distributed in the grid. the total simulation time t for each run is set to . figure shows a snapshot of the spatial distribution of the population at some time in a typical simulation. it is commonly believed that as the epidemic develops, its spread ends up with two typical situations: extinction or prevalence. figure depicts these two situations. in fig. a , the number of infections climbs early in the process. after about time t = , the infection level starts to drop slowly until it reaches zero at time t = , while in fig. b , the number of infections increases slowly and reaches an equilibrium level after t = . the intuition . the spatial distribution of the population at time t = behind is that in the first case, newly infected continuously enter the pool of infectives at a fairly low rate in early stages. after the lengthy incubation period, these infectives begin to develop aids and eventually die. the total number of them drops when the infection rate is very low with regard to the rate at which infectives leave the pool for some reason (dead in the model). while in the second case, healthy agents get infected at a relatively high rate in early stages. the infection level continues to increases because the number of removed agents is relatively small in later stages. thus high infection rate often leads to prevalence as demonstrated in fig. b . these two results can be found in real-world situations. notice that fig. the infections vs. time result in two simulations in the parameters setting, the growth rate r is almost zero (r = . ). in next subsection, we will explore the effects of various factors, such as population density, initial infection ratio, and infectivity, on the epidemic. now we keep other parameters constant as before and let the population density β vary to see how β (β = n/w ) affects the dynamics of hiv/aids transmission. tarwater and martin ( ) investigate this issue when studying the outbreaks of measles or measles-like infectious diseases. as one would expect, many common infectious diseases spread more rapidly at a high population density than at a low population density. figure illustrates the time series of the mean numbers of infectives for different population sizes n = , , , , and . we can see that when population density is relatively low (n = , ) , the infection levels are relatively low during the entire simulation and decline slowly in the later stages. this suggests that the epidemic died out eventually. in the and at last. for n = and , the infection numbers reach to a very high level and then drop rapidly. the collapse is because that so many infectives are removed from the model that the pool of infectives shrinks. for clarity, we also plot the fractions of infectives in the population vs. time in fig. . clearly, in late stages of the epidemic, the fractions are greater when β is great than when β is small. in summary, hiv/aids infection is more likely to persist at higher population densities. this is due to that with the population density increasing, the population contact rate rise, leading to increases in the probability of infection. early work (see, e.g., rhodes and anderson ) suggests that there is a threshold below which the epidemic would eventually dies out and above which it would persist. due to the limitation of ca methods, it is diffi- fig. mean number of infections vs. time for different initial infected ratios cult to pin down its exact value. however, with many simulation runs, we still can give an approximate interval in which the threshold lies. an interesting question one may ask is how epidemic spreading is affected by initial configurations of susceptibles and infectives, or whether the multiple infection sources will make the disease more likely to become endemic. with other parameters fixed as before, we run the simulations with α = . , . , . , and . , respectively. figure presents the result. clearly, as α increase, the infection level shifts upwards. in the case of α = . , the infection level reach at time t = , higher than in the case of α = . . by contrast, the level in the case of α = . climb to around at time t = and drops slightly to at time t = . the maximum infection is reached in the case of α = . at time t = , which is more than . spatially, more sources of infection imply greater chance of being infected within a certain area, letting hiv/aids epidemics to be more likely to spread out and persist. statistically speaking, an individual's probability of infection is generally proportional to the number of infectious sources. intuitively, the more migratory the population, the more likely that an epidemic is to spread. suppose an agents' activity can be measured by the number of contacts it makes with others within a unit of period of time. as a result, our model assumes that individuals' activity is measured by mobility. later stages. this is, in the case of p m max = . , the level is above and in the case p m max = . , the level is in the range ( , ). in the last case of p m max = . , the infection level fluctuates above , higher than those of other cases. so we conclude that mobility plays a significant role in the dynamics. it could explain why chinese government took rather strong measures to control the migratory people and quarantine the infectives or the suspects during the outbreak of sars in the spring of . as to our model, if agents are configured with higher mobilities, it is more likely that the hiv/aids infection can persist in the population, whilst if configured with lower mobilities, the infection would gradually diminish and eventually die out. next, we are to examine how neighborhood forms affect hiv/aids epidemic dynamics. the parameter sets are kept the same as in benchmark case, except for the adoption of different neighborhood forms. figure illustrates the simulation results generated in two cases: one with × von neumann neighborhood and the other with × moore neighborhood. in the case where the von neumann neighborhood is used, the level of infection goes up to about . it is clearly greater than that of the case with × moore neighborhood in which the level only reach about . such result suggests that with wider neighborhood, an agent is more likely to get influenced by its neighbors and therefore the likelihood of getting infected increases accordingly. it is easy to induce that the infection level rises with the order of neighborhood. this result also suggests that hiv/aids epidemic dynamics is significantly affected by strong interactions between agents. we now turn to examine heterogeneous mixing, i.e., different at-risk groups coexist. usually, heterogeneous mixing will make the dynamics more complicated and unpredictable. in the following, we assume the whole population is divided into four different groups as shown in table . as shown in table , class p has very low infectivity, low susceptibility, and × von neumann neighborhood. it can represents children and (or) elders in the population who hardly infect others and are easy to be infected. class pl refers to ordinary people who have relatively low infectivity and high resistibility (therefore low susceptibility). in our model, this class amounts to a large fraction of the whole population. class ph and class ph+ can represent the two high-risk groups observed in real life. agents of class ph have high infectivity and low resistibility duo to their high-risk behaviors like incautious sex without protection, needle sharing, unhygienic blood transfusion and so on. the biased × (or × ) von neumann neighborhood captures their potential oriented or biased behaviors. in contrast, agents of class ph+ with both higher infectivity and higher susceptibility represent those who are, although being in the minority, the most dangerous and malevolent group. such group does exist in real life. for instance, some crimes were reported in china in recent years that a few aids infectives intentionally have sex with innocent people or shot people with contaminated syringes in public places. they blame their infection on the society and the government for not being able to provide necessary health service and compensating too little. the × moore neighborhood indicates their intensive influence on others. we distinguish class ph+ from class ph in order to see whether such malevolent behaviors have significant impacts on the spread of hiv/aids and to what extent. while such rough classification may be incorrect or even erroneous, it surely is reasonable and well supported by our extended ca model. table gives the values of f i and r i used in the following simulations. as we will see later, the results generated with this classification are fairly consistent with those obtained through empirical work. figure gives a typical simulation result in the four-class scenario. the fractions of four classes here are: n p = . , n pl = . , n ph = . , and n ph+ = . . the infection curve in fig. is quite similar to that obtained in the single-class scenarios except that its level is fairly higher. in this section, we will investigate the effect of agents' susceptibility on the dynamics of hiv/aids. given n p = . , n pl = . , n ph = . , n ph+ = . and others as before, let r ph+ vary. figure gives the infection levels when r ph+ is set to be . , . , . , and . , respectively. as we can see, these equilibrium infections are almost at the same level, which is inconsistent with our expectation. the differences are so small that we cannot assure with confidence whether changes in susceptibility have impact on the epidemic dynamics. the possible reasons, we believe, are twofold: first, the role played by susceptibility may be not as decisive as the above factors. second, we may describe susceptibility in the wrong way and make it an inessential factor in our model. future work will reconsider this issue and find the better way to describe susceptibility. at last, we will examine whether changes in the fractions of some classes can affect epidemic behaviors. given n p = . , n pl = . and other parameters as before, we take n ph = . (n ph+ = . ), . ( . ), . ( . ), . ( . ), . ( . ), respectively. figure shows the infection levels in these five combinations. as observed from fig. , we obtained very similar results, compared with those in the foregoing analysis. with n ph+ decreasing, infection level declines. recall that ph+ has more influence on its neighbors than ph, thus leading to greater transmission to others and larger infection rate. this finding suggests the government should pay more attention to those who have high-risk life styles and revengeful behaviors. this makes it the essential issue of how highly infectious and malevolent individuals are restricted and controlled. the focus of the paper is on the modeling of the entire course of hiv/acid epidemics and heterogeneity in agents' behaviors. even though classical ca models are capable of describing the spread of common epidemics but fail to represent the complicated epidemics like hiv/aids disease. the ignorance of heterogeneity gives rise to unacceptable errors in the prediction of the development trends. in addition, components of a conventional ca system such as topological forms of grid, the definition of neighborhood, and state transition rules are simple and unchanged over time. this makes the modeling of complicated dynamics such as hiv/aids transmission difficult and uncontrollable. in this paper, we have developed an extended ca model to capture key epidemiological and clinical features of hiv/aids epidemic. first, we explicitly models and simulates the whole progression of hiv/aids disease (i.e., infected but not infectious, infectious but asymptomatic, symptomatic, and deceased). such improvement can give us a better understanding of the dynamics during the entire hiv/aids epidemics. in order to examine various degrees of influence between agents, we have introduced an extended definition of neighborhood to represent the intensity and bias of influence. this lets us gain insight into how various degrees of interactions affects the hiv/aids epidemics. another type of heterogeneity in disease-related attributes such as susceptibility, infectivity and durations of epidemic phrases is also taken into consideration. moreover, we also consider the effect of agents' mobility on epidemics dynamics. given all the improvements, we have obtained richer simulation results similar to those usually found in the mathematical models or other classical simulation models. we have identified some influential factors that greatly affect the hiv/aids epidemic dynamics. the main findings are that ) hiv/aids epidemic can end up in the two regimes: extinction and persistence; ) with these factors such as agents' mobility, population density, initial infection ratio, and the extent of neighborhood increasing, the infection level get higher. after crossing some critical point, the regime generated could change from dying-out to persistence at some point. this result is robust across many of the tested parameter combinations; ) in four-class scenarios, the great fraction of 'super' infectives (the ph+ class in our model) can also produce higher level of infection. however, our simulation study above is still preliminary. there are some issues needed to be addressed. first, as said before, we should redefine susceptibility in a better way to check its role in the dynamics of hiv/aids epidemic. second, most models posit that a virus carrier's infectivity is constant during the progress of a disease. however, this is not the case for hiv/aids epidemic. various infectivity at different stages could have substantial impact on the dynamics of hiv/aids transmission. this problem needs special attention. additional, further developments of our model, e.g. by adding age-related structure (griffiths et al. ) , different subgroup classification, and other heterogeneity, would greatly add to the appeal of this model. with these additions, a better understanding of hiv/aids and thorough empirical work are required. finally, a natural extension of the model is to include the assessment of various control policies and managerial strategies, and this will be a firm support for the decision-making in prevention programs against hiv/aids. on modeling epidemics. including latency, incubation and variable susceptibility the epidemiology of hiv infection: variable incubation plus infectious periods and heterogeneity in sexual activity infectious diseases of humans: dynamics and control possible demographic consequences of aids in developing countries epidemiology of hiv infection and aids: incubation and infectious periods, survival and vertical transmission a simulation model of the dynamics of hiv transmission in intravenous drug users a comparison of simulation models applied to epidemics the mathematical theory of infectious diseases and its applications dynamics of hiv infection on d cellular automata models for transmission of disease with immigration of infectives survival and mortality patterns of an acquired immunodeficiency syndrome (aids) cohort in new york state mathematical modeling in epidemiology cellular automata and epidemiological models with spatial dependence a heterogeneous cellular automata model for sars transmission a cellular automaton describing the formation of spatially ordered structures in chemical systems a cellular automaton model of excitable media a simple agent model of an epidemic an age-structured model for the aids epidemic the differential infectivity and staged progression models for the transmission of hiv a model for the influence of the greenhouse effect on insect and microorganism geographical distribution and population dynamics a model for predicting forest fire using cellular automata. ecological modelling a contribution to the mathematical theory of epidemics the dynamics of hiv spread: a computer simulation model flood decision support system on agent grid: method and implementation algebraic properties of cellular automata transmission dynamics of hiv infection the transmission dynamics of human immunodeficiency virus (hiv) [and discussion incubation period of aids in patients infected via blood transfusion the distribution of the incubation period for the acquired immunodeficiency syndrome (aids) mathematical biology i experiences creating three implementations of the repast agent modeling toolkit persistence and dynamics in lattice models of epidemic spread epidemic thresholds and vaccination in a lattice model of disease spread survival with the acquired immunodeficiency syndrome. experience with cases in new york city effects of population density on the spread of disease diffusion and wave propagation in cellular automaton models of excitable media modelling the hiv epidemic: a state-space approach effectiveness of q-learning as a tool for calibrating agent-based supply network models we would like to express our gratitude to the many people in xi'an jiaotong university who have participated in planning, data collection, and presenting the results. without their efforts, this simulation modeling would not have been possible. this work is supported by nsfc under contract . we are grateful to ting zhang and jie huang for excellent research assistance and the referees for many helpful comments that greatly improved the presentation. key: cord- -en taikk authors: nagy, nathalie; remmelink, myriam; van vooren, j. p.; salmon, isabelle title: infections gastro-intestinales chez le patient immunocompromis date: journal: acta endoscopica doi: . /bf sha: doc_id: cord_uid: en taikk the gastrointestinal tract is frequently involved in immunocompromised hosts. the most common digestive manifestations are dysphagia, odynophagia and diarrhea. these diseases are more frequent in patients with acquired immunodeficiency virus (aids). these gi diseases are of several categories: hiv related inflammatory conditions (hiv related enteropathy, idiopathic esophageal ulceration), infections due to germs also commonly present in immunocompetent patients (salmonellosis, shigellosis,…), opportunistic infections (cmv, mucormycosis,cryptosporidium, mycobacterium, isospora belli,…). the prevalence, pathogenesis, clinical manifestation, gross pathological findings and microscopic features are discussed for each entity. muqueuse, l'absence quasi complete de lymphocytes cd + au niveau intra- pith ial et de mani~re concomitante une diminution des lymphocytes cdll+ intra- pith iaux du gr~le et du rectum. le rapport t /t de la lamina propria est identique h celui observ dans le sang p riph rique. le nombre et la fonction rdduits des cd rdsultent en une diminution du nombre de plasmocytes ig a s~crdtant au sein de la muqueuse. ii existe dgalement une rdduction de la s~cr~tion acide gastrique, probablement lide gt la presence d'anticorps anti cellules paridtales, ainsi qu'une diminution de la motilitd intestinale rdsultant d'une ddnervation autonomique. la combinaison de tous ces facteurs permet une colonisation aisle de l'intestin grgle par une flore anadrobie, source de diarrhdes pr~cddant trds souvent des infections opportunistes [ ] . dans les pays industrialis s, % des patients hiv ou sida d veloppent des diarrh es persistantes ; ce chiffre atteint % dans les pays en voie de d veloppement. dans % des cas, ces diarrhdes sont imputables ~ des ent ropathog~nes dont la coccioidose est la plus fr quente [ ] . une malabsorption, des anomalies de la muqueuse gr~le en l'absence d'agent pathog ne a pour la premiere fois t d crite en . le virus hiv a t d tect dans la muqueuse intestihale, suscitant l'hypothbse qu'il soit lui-m me responsable, du moins en partie, des sions observdes. n anmoins, cette hypoth se n'a pas t formellement confirm e et certains auteurs sceptiques sugg rent que ces diarrh es seraient dues ?a des agents opportunistes non d tectables par les techniques usuelles ou inconnus. enfin, les facteurs alimentaires tels que le r gime pauvre en prot ines, le d ficit en acide folique ou en vitamine a peuvent galement affecter l'int grit de l' pithflium intestinal. approximativement ?a % des patients hiv pr senteront durant le d cours de la maladie une atteinte cesophagienne. l'agent pathog ne le plus fr quemment isol est le candida albicans survenant dans plus ou moins % des cas, suivi des infections herp tiques et cmv, estimdes h - % [ , ] . n anmoins, lorsque toutes les causes tiologiques causant des ulc rations oesophagiennes ont t imi-n es, a % des patients hiv pr sentent des ulc rations idiopathiques. au sein du tissu de granulation, la prot ine hivp core a t d tect e, sugg rant une participation active dans le processus d'ulc ration en l'absence d'autre agent pathog ne. ces ulc rations surviennent le plus souvent lorsque le taux de cd est bas. les sympt mes en sont gdn ralement de l'odynophagie, l'aspect endoscopique mimant les ulc~res her-p tiques et ~ cmv. ces ulcbres sont souvent difficile h gu rir ; une instillation intral sionnelle de corticoides de m me que le thalidomide semblent donner de bons r sultats. dans les proctocolites li es au virus hiv, les marqueurs de l'inflammation sont non sp cifiques, tels que l'augmentation du nombre de granules lysosomiaux au sein des lymphocytes intra- pith iaux, la pr sence de cellules pith iales apoptotiques, la pr sence de structures r ticulaires au sein des cellules endoth iales, des lymphocytes ou des monocytes. le degr d'inflammation semble corr er avec le taux d'antig~ne p d cel dans la muqueuse ainsi qu'avec l'importance des sympt mes cliniques, sug-g rant un rfle tiologique du virus hiv [ ] . l'ent rocolite neutrop nique est une condition inflammatoire non li e au virus hiv ou aux infections opportunistes, galement appel e typhlite. celle-ci est caract ris e par une inflammation aigue affectant essentiellement le caecum, l'appendice et parfois l'il on terminal. d'abord d crite chez l'enfant leuc mique et s v~rement neutrop nique, l'affection se rencontre actuellement chez les patients souffrant d'h mopathies malignes ou de cancers. la neutrop nie associ e aux effets de la chimioth rapie permettent aux baet ries intraluminales d'envahir et d'endommager la muqueuse. une septic mie, le plus souvent causee par des bacilles gram n gatifs, survient chez % des patients. au niveau histologique, des h morragies, un ~ed~me marqu , une inflammation focale pauvre en cellules inflammatoires sont observ s. parfois, une zone ndcrotique r sultant d'un ulc re bien ddlimit , provoque une perforation. focalement, des colonies bact riennes intramurales et des kystes gazeux sousmuqueux peuvent tre vus. les infections opportunistes representent la majo-rit des infections rencontrees chez l'hete immunocompromis, la plupart d'entre elles se rencontrant au niveau du tractus gastro-intestinal. le spectre de celles-ci s'est rapidement elargi. lors d'etudes anterieures ( ) , % des causes d'enteropathies associees ~ des diarrhees chroniques taient inconnues. une etude ans plus tard n'en revelait plus que %, r sultant de l'identification de nouveaux patho-g~nes [ ] . les affections opportunistes varient egalement en fonction du sexe, du groupe h risque, de la localisation et de la periode etudiee. par exemple, la candidose eesophagienne, atteinte gastro-intestinale la plus frequente chez le patient hiv aux etats-unis et en europe, affecte plus particulierement les femmes. de m~me, les infections ~ cmv ou les cryptosporidioses surviennent plus frequemment chez tes homosexuels que chez les patients sida ayant contracte la maladie par drogues intraveineuses. l'isosporiase affectant % des patients sida haitiens est pratiquement absente aux usa. lorsque les traitements sont efficaces et que la survie des patients augmente, l'epidemiologie des infections opportunistes se modifie. par exemple, les pneumonies resultant du pneumocystis carinii ont largement diminue depuis , alors que les infections herpetiques et ~ cmv ont particuli~rement progress surtout chez les hommes homosexuels. dans h % des patients sida presentant une enteropathie due ~un ou plusieurs agents pathogenes concomitant, des symptemes gastro-intestinaux sont retrouves. le diagnostic d'infections opportunistes est en general base sur une combinaison de culture de selles, examen direct des selles ~ la recherche d'ceufs ou de larves, et d'une biopsie endoscopique. les symptemes gastro-intestinaux sont plus frdquents chez les patients africains que chez les europeens et les nord americains. les deux plaintes majeures sont l'odynophagie et les diarrhees. l'atteinte ~esophagienne survient chez ~ % des patients ; l'incidence des diarrhees est plus elevee atteignant % particulierement chez les patients sevbrement immunocompromis. les infections virales se rencontrent chez tous les groupes de patients immunocompromis. l'infection cmv est le pathog~ne gastro-intestinal le plus frequent. l'infection herpetique semble tre plus frequente chez le patient hiv que chez les autres patients immunodeprimes. dans une importante etude prospective r alisee sur patients hiv pr sentant une cesophagite her-petique, le virus hsv n'a te identifi que darts % des cas alors que la prevalence du virus cmv atteignait % [ ] . les infections herpetiques chez l'hete immunocompromis semblent representer une reactivation d'une infection latente contractee plus tet dans la vie, et son incidence augmente lorsque l'immunodepression gagne du terrain. des anticorps igg specifiques diriges eontre l'anti-g~ne herpetique ont te documentes chez plus de % des hommes homosexuels. chez le patient hiv, la reactivation du virus hsv survient lorsque le taux de cd diminue au-dessous de /ram . l'infection herpetique infecte essentiellement la muqueuse malpighienne ; d~s lors la muqueuse peri-anale et l'cesophage sont les muqueuses les plus frequemment tou-chees. l'oesophagite herpetique peut parfois, dans des formes severes, se compliquer d'une necrose transmurale associee ~ une fistule tracheo-~esophagienne. les une atteinte gastrique s'accompagne en g n ral d'une atteinte diss min e dans le tube digestif. les colites ~ cmv prddominent dans le caecum et le c lon droit ; la muqueuse peut paraitre normale mais en g n ral on y observe de profondes ulcdrations. dans certaines atteintes s vhres, une n crose de la paroi avec perforation peut s'observer comme dans les m gac ons toxiques. l'aspect histologique des cellules infectdes par le virus est caract ristique ; on retrouve au sein du cytoplasme ou du noyau des inclusions virales ; les cellules semblent ballonis es. les inclusions nucl aires sont acidophiles et fr quemment entour es d'un halo ; les inclusions cytoplasmiques sont souvent multiples, granulaires et basophiles (fig. ) . le cmv infecte plusieurs types cellulaires, essentiellement les cellules endoth iales, mais aussi les cellules musculaires lisses, les fibroblastes, et les cellules ganglionnaires. les cellules glandulaires sont nettement moins infect~es que les cellules malpighiennes. le diagnostic est r alis par endoscopie et biopsies [ ] . les immunomarquages et l'hybridation in situ sont des m thodes plus sensibles que i'he ; la pcr repr sente la technique diagnostique la plus sensible. le r sultat du traitement par gancyclovir peut ~tre monitor par un grading histologique sur les sp cimens biopsiques [ ] . certains auteurs ont d velopp un syst~me de gradation simple ddfini en trois grades selon le hombre de cellules infectdes visualis es : grade i = de ~ cellules infect es, grade ii = de ~ , grade lii= plus de . les patients sida prdsentent plus fr quemment des sympt mes li s/t ces organismes, ainsi que des infections prolong es par rapport fi la population g n rale. la salmonellose r sultant d'une infection ~ partir de salmonella typhimurium est fois plus frequente chez les patients sida. la shigellose est souvent isolde des coprocultures chez ces patients sida; dans cette population, l'infection est potentiellement fatale. les infections ~ campylobacter ont t identifi es dans approximativement % des coprocultures des patients sida, qu'ils souffrent ou non de diarrh es ; ces patients, pr sentant une incidence d'infection, sont fois plus importants que dans la population g n rale. les femmes sont plus fr quemment infect es que les hommes. le clostridium difficile affecte la plupart des types de patients immunocompromis et est li essentiellement h la prise d'antibiotiques et aux hospitalisations prolong es ou r p t es [ ] . la tuberculose gastro-intestinale reste rare malgr une atteinte pulmonaire fr quente atteignant % des patients sida ; celle-ci ne survient que dans ~ % des cas, chiffre comparable fi ceux retrouv s dans la population gdn rale ( %). le tractus gastro-intestinal semble ~tre la porte d'entr e de la mycobact rie et son atteinte est deux fois plus fr quente que la forme pulmonaire. bien que tousles segments du tractus digestif puissent ~tre entrepris, c'est la portion intestinale qui est le site primaire le plus fr quent, le foie et la rate rant les sites les plus fr quents de dissdmination [ ] . le diagnostic est r alis ~i partir de coprocultures ou de biopsies. au niveau histologique, la lamina propria de la muqueuse intestinale est diffus ment infiltrde d'histiocytes, comblant les villosit s et s parant les cryptes. lorsque cette infiltration est massive, celle-ci est aisdment reconnuc aux colorations de routine d'he ; cependant, la coloration de ziehl facilite le diagnostic. cette coloration permet en effet de visua-liser les nombreux baciues au sein des macrophages mais aussi en extra-cellulaire. le diagnostic diff rentiel se pose avec la maladie de whipple au sein de laquelle les macrophages sont fortement color s par le pas et n gatifs pour la coloration de ziehl. une culture sanguine positive tablit le diagnostic de mac diss min e, mais pas celui d'une infection active au niveau digestif. une coproculture positive sugg~re mais ne prouve pas une infection digestive. les cultures sanguines peuvent ~tre n gatives n cessitant des cultures r p -t es, des biopsies de moelle osseuse ou des traitements empiriques. r cemment, un nouveau type de mycobact rie a merg , il s'agit de la mycobactorie genovense. mycobactdrie gordonae est galement une cause rare d'atteinte digestive. la spiroch tose survient relativement frdquemment chez les mgles homosexuels ; l'affection touche galement environ % de la population gdndrale, et % des homosexuels ne pr sentent pas de tableau d'immunod ficience. la spiroch tose ne s'accompagne d'aucune sion macroscopiquement ou endoscopiquement visible. au niveau histologique, les spirochbtes adh rent h la surface de la muqueuse ot~ ils apparaissent comme un tapis chevelu bleut . ils se r v~lent aux colorations de pas et de warthin-starry [ ] . une majorit d' tudes indique que la pr valence des infections ~ hp est plus faible chez les patients sida que clans la population g n rale pour des cohortes appari es pour le sexe, l'fige et les symp-t mes. la pr valence est certainement plus faible lorsque le taux de cd est inf rieur ?a . ceci sugg~re un r e des cd et une fonction immune ndcessaire aux infections a hp et aux ulc~res peptiques r sultant de l'hp. cependant, lorsque les patients sida sont infect s, la maladie peut tre particuli~rement virulente et la charge d'organismes, importante [ ] . les candidoses gastro-intestinales surviennent dans une grande cat gorie des patients immunocompromis mais affecte particuli~rement les patients sida. la candidose est l'affection gastro-intestinale la plus fr quente chez le patient sida ( %). l'~esophage est l'organe cible. une co-infection avec le virus cmv est frdquente. chez les patients neutrop niques, la candidose intestinale est une importante source de diss mination h matog ne. le candida albicans est l'espbce la plus fr quemment isolde. chez les patients sida, la flore orale dif-f~re de celle de la population g n rale par une diver-sit appauvrie; la pathogen~se de la candidose oesophagienne d bute done par un remplacement de la flore orale par une flore moins complexe progressant vers l'oropharynx lorsque le nombre de cd diminue sous /mm , r sultant en une infection eesophagienne invasive lorsque le taux de cd est > /ram [ ] . le diagnostic final se fait g partir de l'identification des filaments myc iens et des spores h partir de sp cimens biopsiques ou des brossages cesophagiens. au niveau histologique, la candidose invasive implique la pr sence de filaments myc iens p ndtrant au sein d'une muqueuse intacte, alors que la colonisation se caract rise par la pr sence de filaments et de spores au niveau de zones ulcdr es ou n crotiques. les filaments peuvent ~tre ddtectds aux colorations de routine d'he mais sont mieux identifiables aux colorations de pas ou de grocott. une histoplasmose colique a galement t d crite en association avec le syndrome de job. l'identification de l'agent pathog~ne sur mat riel biopsique est primordiale tant donn que les mises en culture peuvent prendre plusieurs semaines [ ] . la cryptoccocose digestive a t identifi e dans % des autopsies or) celle-ci se prdsentait sous sa forme diss min e. on la rencontre chez les patients sida mais aussi chez les patients souffrant d'h mopathies malignes ou b n ficiant de corticoth rapie au long court [ ] . au niveau digestif, ce sont l'eesophage et le c on qui sont le plus souvent affect s. l'aspergillus infecte rarement le tractus digestif, l'cesophage reste le site pr f rentiel. l'aspergillose invasive se rencontre surtout chez les patients sdv~rement immunod primds (fig. ) la mucormycose est une affection rare et souvent fatale rencontr e chez les h tes immunocompromis. les facteurs de risque principaux incluent le diabbte, l'acidoc tose, les neutrop nies s v res, les leuc mies et les traitements immunosuppresseurs. seuls quelques cas ont t rapport s chez les patients sida. le tractus gastro-intestinal est rarement affect , repr sentant seulement % de tousles cas [ ] . l'infection initiale du tractus digestif r sulte probablement de l'ingestion de spores. % des infections digestives surviennent au niveau gastrique ; les perforations sont fr quentes. le c on ( %), le grole ( %) et l'cesophage ( %) peuvent galement tre infect s. la caraet ristique histologique principale est l'invasion locale des vaisseaux sanguins par les filaments, induisant des vasculites aigu~s, la formation de thrombi et de n crose isch mique du tissu adjacent. les filaments sont peu sept s, branch s de manibre irr gulibre ~ ~ peu color s par i'he. la plupart des filament sont pais et atteignent ~ microns de diam tre. certains filaments pr sentent galement un aspect torsad . les diarrh es sont le sympt me gastro-intestinal le plus frdquemment rencontr chez les patients sida, affectant h % des individus pr sentant un taux de cd rdduit. les protozoaires sont actuellement reconnus comme les principaux agents pathog nes des diar-rh es infectieuses, les deux organismes les plus fr quemment identifi s tant le cryptosporidium et le comme les virus et les mycoses, c'est principalemerit l'intestin gr~le qui est affect en premier. ii existe certaines variations g ographiques, surtout chez les patients sida, l'ispora belli est par exemple frdquemment rencontr ~ haiti, alors que le cryptosporidium est le pathog ne le plus souvent responsable de diarrh es h washington. une pneumocystose extra-pulmonaire a t identi-fi e chez , % des patients sida/~ new york, avec une atteinte digestive de %. l'affection digestive r~sulte en g~n ral soit d'une diss mination h partir des ganglions ou de la voie h matog~ne suivant une infection pulmonaire soit par r activation d'une infection gastrique latente. approximativement % des patients prdsentant une forme extra-pulmonaire ont bdn fici d'un traitement ~ la pentamidine, r duisant le risque de la forme pulmonaire mais ne pr venant pas la forme diss min e. la forme diss min e est typiquement un v nement survenant tardivement dans le ddcours de la maladie, lorsque le taux de cd est infdrieur /mm . l'atteinte par pneumocystis a tout d'abord t d crite au niveau ~esophagien et duod nal chez un patient vivant en ; depuis lors, des infections gastriques, coliques et gr es ont galement t identi-fi es. au niveau histologique, il existe de nombreux organismes et macrophages spumeux dans la lamina propria [ ] . le cryptosporidium est devenu l'agent pathog~ne le plus fr quemment responsable des diarrh es ren-contr es chez les patients sida. identifi en comme agent responsable d'ent rites chez l'humain, l'affection reste limit e chez les h tes immunocom-p tents mais peut ~tre s vbre chez les sujets immunocompromis. la cryptosporidiose survient chez /a % des patients sida, quel que soit le groupe ~ risque mais est plus fr quente chez les homosexuels. l'infection se rencontre surtout chez les hiv pr sentant des diarrh es chroniques. lorsque le taux de cd est inf rieur ~ /mm , l'infection est souvent dramatique. d'autres maladies li es au sida pr -c~dent le d veloppement de la cryptosporidiose dans % des cas [ ] . l'organisme infecte le plus souvent le j junum, mais se rencontre galement ailleurs dans le tube digestif ou darts les voies biliaires. le c on est le deuxi~me site le plus fr quemment infect , suivi de l'estomac et de l'~esophage. le diagnostic repose sur l'identification de l'organisme soit dans les aspirations duod nales, soit sur mat riel biopsique. les protozoaires sont clairement visualis s aux colorations de routine d'he, mais sont mieux observ s la coloration de giemsa. ils se caract risent par des organismes sph riques, basophiles, mesurant entre et microns de diambtre et sont attach s aux microvillosit s formant la bordure des cellules pith iales (fig. ) . le sommet ainsi que les bords lat raux des villosit s comptent le plus grand nombre d'organismes au nlveau de la muqueuse gr~le; alors qu'au niveau colique, les cryptes et l' pith ium de surface sont infect s de mani~re gale. la variabilit de taille des organismes correspond aux diff rentes ~tapes du cycle de vie [ , ] . le diagnostic peut galement tre tabli par identification des oocystes dans les selles, en utilisant une coloration de ziehl ou une immunofluorescence. les formes tissulaires sont elles ndgatives pour la coloration de ziehl ou les colorations du mucus. les microsporidium sont un groupe h t rog~ne de protozoaires, pr sentant un cycle obligatoirement intra-cellulaires. identifi s pour la premibre fois chez l'humain en , ils peuvent se rencontrer dans le tractus digestif et les voies biliaires, la v sicule biliaire et l'arbre respiratoire. l'incidence des diarrh es ~ microsporidium identitides chez les patients sida varie de , a %, mais m me les patients asymptomatiques peuvent ~tre porteurs de l'organisme dans l'intestin gr~le. les ces agents pathog~nes sont difficiles ~ identifier en microscopie optique, la microscopie ectronique est souvent n cessaire. ils peuvent ~tre mis en vidence dans les aspirations j junales et les selles en utilisant une coloration acid-fast afin de d tecter les oocytes, qui sont autofluorescents bleu lorsqu'ils sont examin s en microscopie, en pifluorescence ultra-violette. la pr sentation clinique est similaire a celle obser-v e dans les infections dues au cryptosporidium parvum [ ] . entomoeba histolytica est consid r comme un agent commensal non pathog~ne chez les patients homosexuels. l'infection peut survenir lors d'ingestion de kystes par la voie oro-faecale. les patients hiv ne semblent pas pr senter de susceptibilit particulibre ~ amoebae. cependant une colonisation m me par des agents non pathog nes peut tre responsable d'affections s vhres chez les patients immunocompromis [ ] . giardia lamblia peut occasionnellement provoquer une diarrh e chez les patients sida. comme c'est le cas pour les entomoeba, le patient hiv ne pr sente pas de susceptibilit particuli re. la microscopie optique d tecte largement les giardia, et moins fr quemment les trophozoites, et constitue la m thode diagnostique de choix. bien avant les pid mies de sida, le toxoplasme tait reconnu comme protozoaire responsable d'infections opportunistes chez les patients immunocompromis. l'atteinte digestive r sulte en g n ral d'une toxoplasmose diss min e et s'observe darts % des autopsies. chez les patients sida, l'atteinte digestive peut otre g n ralis e ou n'affecter qu'un seul segment, et peut exceptionnellement tre diagnostiqu e du vivant du patient [ ] . c'est un protozoaire obligatoirement intra-cellulaire, qui peut se d velopper darts n'importe quel type cellulaire, ~ l'exception des globules rouges. certaines tudes rapportent des strongyloidoses diss min es chez des patients immunocompromis. le d nominateur commun semble tre une corticothdrapie. on ne remarque pas d'incidence plus ev e chez les patients sida. la leishmaniose visc rale est une maladie s vhre, acquise en g n ral au niveau du bassin m diterran en, se ddveloppant le plus souvent chez les h tes immunocompromis lors de voyages dans les zones end miques. l'infection s'aequihre par morsure de la femelle de la mouche des sables, transfusions sanguines, infections g nitales et rapports sexuels. les infections visc rales sont major es chez les patients hiv et les atteintes digestives sont fr quentes; certaines tudes rapportent % d'atteinte gastro-intestinale [ ] . le diagnostic est r alis par identification des amastigotes de la leishmania, dans les frottis ou les sp cimens biopsiques. les biopsies j junales pr sentent des alt rations villositaires telles que des villosit s massu es, dues h l'infiltration massive de la lamina propria par des histiocytes gorg s de leishmania. les ent rocytes bordant les cryptes et les villositds ne comprennent pas d'organisme. ceux-ci apparaissent bleut s h la coloration de giemsa. chez les patients immuno-comp tents, des granulomes peuvent tre observ s dans la lamina propria ; ils sont en g ndral absents ou peu form s chez les immunocompromis. dans une tude, le blastocystis homminis tait le troisihme organisme le plus fr quemment identifi aprss le cryptosporidium et le cmv chez les patients hiv. ils se rencontrent toujours lorsque l'immunosuppression est sdv re dans un contexte de diarrh es chroniques. les biopsies en gdndral apparaissent normales; lorsqu'elles sont anormales, elles exhibent des alt rations non sp cifiques. although gastrointestinal infections occur in all groups of immunocompromised patients, the frequency is highest in patients with acquired immunodeficiency syndrome (aids). the reduced number and the reduced function of the cd + cells affect the terminal differentiation of ig a-bearing to ig a-secreting b cells, resulting in a decreased number of mucosal iga-bearing plasma cells. there is also a reduction in gastric acid production, probably related to parietal cell antibodies and a decrease in intestinal motility resulting from autonomic denervation. the combination of all these factors promotes colonisation of the small bowel by anaerobic bacteria, which commonly causes diarrhea preceding opportunistic infections [ ] . % in some developing countries. at least % of cases of chronic diarrhoea can be attributed to specific enteropathogens among which coccidial parasites are the most frequent [ ] . malabsorption and mucosal abnormalities of the small bowel in the absence of detectable pathogens were first described in . hiv has been detected within the intestinal mucosa and it has been proposed that the virus itself might be responsible, at least in part, for the enteropathy. however, no direct evidence of this theory has been produced so far and sceptics favour the suggestion that diarrhoea is actually due to opportunistic infection which has failed to be detected or to unrecognised pathogens. approximately - % of patients with hiv will have oesophageal disease some time during their illness. candida albicans is the most frequently isolated pathogen, accounting for - % of cases, followed by cmv and hsv in that order, accounting for to % [ , ] . however, after all known aetiologies of hiv-related oesophageal ulceration are excluded, to % of patients have idiopathic oesophageal ulceration. hiv p core protein has been detected in the granulation tissue. these findings suggest that hiv is capable of producing ulcers in the absence of other pathogens. these ulcers occur mostly when the patients have a low cd count. these ulcers can be very difficult to treat, intralesional injection of steroids has shown some therapeutic potential as well as thalidomide. in hiv-related proctocolitis non specific markers of inflammation are seen such as an increased number of lysosomal granules in intraepithelial lymphocytes, focal crypt epithelial cell apoptosis, and tubuloreticular structures in endothelial cells, lymphocytes and monocytes. the degree of inflammation appears to correlate with the mucosal level of p antigen and clinical symptoms, suggesting an aetiologic role of hiv [ . first described in children with leukaemia and severe neutropenia, this condition is now known in immunocompromised patients suffering from lymphoma, anaplastic anaemia and cancer. the combined effects of neutropenia and chemotherapy allows luminal bacteria to invade and injure the bowel wall. septicaemia, mostly caused by gram-negative bacilli, occurs in more than % of patients. histologically, haemorrhage, marked edema, and patchy inflammation with a paucity of inflammatory cells are seen. sometimes necrosis results in well demarcated ulcers that may perforate. focally, intramural bacterial colonies and submucosal gas cysts may be seen. in a large prospective study of hiv-infected patients with ulcerative oesophagitis, hsv was identified in only % of cases, whereas the prevalence of cmv was almost % [ ] . [ , ] . pneumocystis carinii. cmv infections typically occur when immunodeficiency is severe (cd + < lo /mm ) and also represents reactivation of a latent virus conversely, persistent cmv infection itself may promote the decline of immune function. the infection may involve any part of the gi tract, and the risk of involvement of a given segment varies with the type of immunosuppression. in patients with aids, the colon is mostly affected; and in the upper gi tract, oesophageal disease is more common. in immunocompromised patients without aids, the lower and upper gi tract is equally affected and gastroduodenal disease is more common than oesophageal. in the oesophagus cmv preferentially affects the distal segment. gastric involvement is usually associated with involvement elsewhere in the gi tract. in cmv colitis', predominantly seen in the caecum and the right colon, the mucosa may appear normal but usually deep ulcerations are seen. severe cases may manifest as necrotising colitis or toxic megacolon with perforation. nuclear inclusion are acidophilic and often surrounded by a halo, cytoplasmic inclusion bodies are multiple, granular and often basophilic (fig. ) . the diagnosis is made by endoscopy and biopsy [ ] . immunohistochemistry and in situ hybridisation are more sensitive than he; pcr represents the most sensitive technique. results of treatment with ganciclovir can be monitored by means of histological grading of cmv in biopsy specimen. some autors developed a simple grading system that defines grade i as one to four, grade h as five to nine, and grade iii as ten or more cmv-infected cells per biopsy specimen [ ] . clostridium difficile affects individuals with variable types of immunosuppression and related to the prevalence of antibiotic use and frequent hospitalisation [ ] . these infections include mycobacterium tuberculosis, mycobacterium avium complex or intracellulare and other atypical mycobacteria. tuberculosis, despite extrapulmonary tuberculosis being common in aids patients (occurring in to %), rarely involves the gi tract ( % to %), and not significantly more frequently than in general population ( %). oesophageal, small bowel and colonic tuberculosis have been described. oesophageal involvement may develop after mediastinal lymph node tuberculosis and can result in a tracheo-oesophageal fistula. [ , ] . the gi tract appears to be the most common portal entry and gi involvement is twice as common as the respiratory tract. although segments of the gi tract may be implicated, the intestine is the most common primary site and liver and spleen are the most common sites for dissemination [ ] . [ ] . the majority of studies indicate that the prevalence of hp in aids patients is significantly lower than in age, sex, and symptom-matched hiv patients. the prevalence is certainly lower when the cd count is lesser than . this suggests a role of cd cell and immune function in sustaining hp infections and hp-related peptic ulcer disease. nevertheless, when aids patients become infected, the d&ease may exhibit particularly aggressive lesions and large number of organisms [ ] . candidiasis is the most frequent aids-defining gi disease ( %). the oesophagus is the prime target organ. co-infection with cmv is frequent. in neutropenic patients, gi candidiasis is an important source of haematogenous dissemination. candida albicans is the species most commonly isolated. in aids patients the oral flora differs from that of the general population by a low level of genetic diversity; the pathogenesis of oesophageal candidiasis begins thus with the replacement of the normal oral flora with a less complex flora and progresses to oropharyngeal candidiasis as the number of cd + decreases below /mm and results in invasive oesophageal disease when the cd + are < /mm [ ] . the definitive diagnosis rests on the identification of typical yeast forms in endoscopic mucosal biopsies or oesophageal brushings. histopathologically, invasive candidiasis implies hypheal penetration into intact mucosa as opposed to colonisation, which implies the presence of yeasts on an intact mucosa surface or in necrotic tissue. candida can be seen on he stains but is better visualised by a pas stain or grocott methenamine silver (gms). other species than c. albicans have been found in aids patients in % to % including c. parapsilosis, c. krusei, c. tropicalis and torulopsis glabrata. disseminated histoplasmosis develops in approximately % of patients with aids in the midwest of the usa where histoplasmosis is endemic. colonic histoplasmosis has also been described in association with job's syndrome. recognition of the organism in biopsy specimen is crucial because culture may take several weeks [ ] . cryptococcal gi disease has been identified at autopsy in % of patients with disseminated cryptoccoccosis, including patients with aids and haematological malignancies as well as those receiving corticosteroid therapy. the oesophagus and colon are mostly involved [ ] . aspergillosis rarely affects the gi tract, but the target site is the oesophagus. invasive aspergillosis affects severely debilitated patients (fig. ) [ ] . [ ] . the organism infects the jejunum most heavily, but it can be found throughout the gi tract including the biliary tract. the colon is the second more common location, followed by the stomach and finally the oesophagus. the diagnosis is made by identification of the organism in either duodenal aspirates, stool, or tissue samples. the protozoan can be clearly observed on he stain, but is best seen with giemsa stain as rows or clusters of basophilic spherical structures to mm in diameter attached to the microvillous border of the epithelial cells (fig. ) . tips and lateral aspects of villi show the greatest number of organisms in the small bowel whereas in the colon crypt and surface epithelial involvement appears equal. the variation of the size of the organisms corresponds to different stages of the life cycle [ , ] . the diagnosis can also be made by identification of the oocysts in stools using acid-fast or irnmunofluorescent stains. however, tissue forms do not stain with acid-fast stains, and are mucous stain negative. microsporidia are a heterogeneous group of obligate intracellular spore-forming (coccidian) protozoa. first described in the human in , they can be found in the gi tract, in the biliary tract, the gallbladder and in the respiratory tract. the reported incidence of microsporidium in aids patients with diarrhoea ranges between . % and %, but even patients without symptoms may harbour the organism in the small bowel. microsporidiosis resulting from infection with enterocytozoon bieneusi affects exclusively the small intestine and the enterocytes, while septata intestinalis, first described in , may disseminate and infect other organs like kidney and gallbladder parasites are then localised in macrophages, fibroblasts and endothelial cells. although electron microscopy of small bowel biopsies is considered to be the best method, the examination of a biopsy specimen stained with he, giemsa or a modified trichrome method, has sensitivities of %- % and specificities approaching % [ , ] . diagnosis can also be made by identification of microsporidial spores in stools and duodenal aspirates. microsporidium is mostly identified in the jejunum as an intracellular parasite seen in the villous enterocytes from just above the mouths of the crypts to the tips of the villi where they are more numerous. parasites are to mm in diameter, supranuclear, either paler or darker than the surrounding cytoplasm, and contain prominent clefts. spores are less frequent than the parasite, but are supranuclear, clustered, dark, and refractile. the cytoplasm of the enterocyte becomes progressively vacuolated, and the nucleus is hyperchromatic. taking into account that albendazole is highly effective for e. intestinalis but largely ineffective for e. bienusi, it is important to make a specific diagnosis [ ] . enteritis resulting from isospora belli has been observed in a number of settings of immunosuppres-sion, including aids, alpha-chain disease, lymphoblastic leukaemia and t-cell lymphoma. isospora is common in haitian and african patients with aids ( % to %), but is rare in the usa ( % to %). the symptoms are similar to those of cryptosporidiosis, but eosinophilia may be present. the diagnosis is made by identification of the oocysts in stool specimens using acid-fast stain, or by biopsy; the diagnosis is of importance because specific therapy is available. isospora can be recognised on he stains of small bowel specimens, the intracellular protozoon is larger than microsporidium and measures between and pro in diameter the common merozoite is bananashaped and found at all levels of the enterocyte cytoplasm. although poorly stained and pale, the central nucleus, large nucleolus, perinuclear halo, and location within a parasitophorous vacuole give it a characteristic appearance. the infection produces mucosal atrophy and tissue eosinophilia. cyclospora [ , ] . these pathogens are difficult to appreciate on optical microscopy, although electron microscopy is often diagnostic. they can be identified in jejunal aspirates and in stool specimens using acid-fast stain to detect oocysts which are autofluorescent blue when examined with ultraviolet epifluorescence microscopy. the clinical presentation is quite similar to that of cryptosporidium parvum [ ] . entamoeba histolytica is often a non-pathogenic commensal in homosexual men. infection can occur by ingesting cysts through oral-anal contact. hiv patients do not appear to have an increased susceptibility to amoebae. as expected, colonisation, even with non-pathogenic strains, may cause significant disease in immunocompromised patients [ ] . giardia lamblia can occasionally cause diarrhoea in aids patients. as in the case of amoebae, hiv patients do not appear to have an increased susceptibility to giardia. light microscopic detection of giardia cysts and, less frequently, trophozoites, continues to be the mainstay of diagnosis. even before the aids epidemic toxoplasmosis was well known as a protozoal opportunistic infection of a variety of immunocompromised patients. disseminated toxoplasmosis resulting in gi involvement, was observed at autopsy in % of cases. aids-related gi toxoplasmosis may involve the entire gi tract or only one segment and may exceptionally be diagnosed antemortem by endoscopic biopsy [ ] . it is an obligatory intracellular protozoan, that lives in any type of cells with the exception of red blood cells. trophozoites appear round to slightly oval and to pm in diameter in he-stained section. a central or eccentric haematoxylinophylic dot, representing the nucleus surrounded by pale cytoplasm, is seen in trophozoites. pas stains confirm the presence of glycogen-containing bradyzoites and true cysts. some studies report the cases of disseminated strongyloidiasis in a variety of clinical settings of immunosuppression. the common denominator appears to be corticosteroid therapy. visceral leishmaniasis is a severe disease, usually acquired (mediterranean countries) and usually developing in immunocompromised patients, by travel to an endemic region. the infection is acquired through bites of infected female sand flies, blood transfusion, genital infections and sexual contact. visceral infection is increasingly reported in hiv patients, and gi tact involvement is very frequent, some studies reporting an involvement of lo % of cases [ ] . in one study blastocystis hominis was the third most common organism isolated after cryptosporidiosis and cmv in hlv patients. it is always recovered from severely immunosuppressed patients with chronic diarrhea. biopsies often appear normal; when abnormal, they only exhibit mild non specific abnormalities. gastrointestinal pathology, an atlas and text gastrointestinal disease in the immunocompromised patient. human pathol -review article : the therapy of gastrointestinal infections associated with the acquired immunodeficiency syndrome -aids and the gut recently recognised microbial enteropathies and hiv infection -gastrointestinal manifestations of aids in children c --idiopathic esophageal ulceration in acquired immunodeficieney syndrome : successful treatment with misoprostol and viscous lidocain -lower helicobacter priori infection and peptic ulcer disease prevalence in patients with aids and suppressed cd counts e --aids and the gastrointestinal tract. postgraduate medicine key: cord- -dqqcajjd authors: smith?, robert j; gordon, richard title: the optaids project: towards global halting of hiv/aids date: - - journal: bmc public health doi: . / - - -s -s sha: doc_id: cord_uid: dqqcajjd nan we face a unique, transitory opportunity in the history of the hiv/aids epidemic, because we have collectively pooled money faster than the epidemic has grown [ ] . can we then seize the moment and halt this epidemic now? most scenarios for the future of hiv/aids project modest reductions spread out over decades [ ] . the very timescale of such projections, beyond the persistence time of all models, makes them unreliable [ ] . can we do better, quicker? the optaids project was conceived as a means to address this issue. its implementation thus far has been twofold: a workshop held in july and this supplement on the eradication of aids. the aims of the project are to address two questions: . can we optimally spend our way out of the hiv/aids epidemic? . can we work together to build a world halting aids model (wham) that would permit us to estimate the quickest way to halt hiv/aids, monitor our success, and adjust our strategy as we go? the optaids project grew out of a frustration with existing attempts to tackle the disease. aids exceptionalism means that hiv/aids is handled differently from other public-health epidemics, which has likely been detrimental [ , ] . consequently, much of the funding of hiv/aids efforts has been for qualitative observations of the expanding epidemic rather than quantitatively effective intervention. although fund accumulation has recently outpaced the epidemic, we argue that plans to spend donor money are too long range in the face of a growing epidemic [ ] . longrange scenarios have no reality to them, so that only shortterm solutions -those that fall within the persistence time of their models -have any possibility of being realistic [ ] . furthermore, disease is a global problem that is only tackled locally [ ] ; epidemics cross borders, whereas we fund mostly local or national "solutions". the optaids project was an outgrowth of the stop afghan aids project [ ] . this project was led by mathematical modellers planning to continuously adapt their models to new data and predicting what data should be collected. the stop afghan aids project showed how it should be possible to intervene quantitatively in an epidemic. the usefulness of modelling in complex systems is not new. mathematical models of the economy tell us whether a decrease in income tax will result in an increase in investment or an increase in imported consumer goods. mathematical models of the atmosphere tell us what the effects of carbon dioxide emissions or of nuclear wars may be. mathematical modelling is used routinely in such things as aircraft design and the design of traffic systems [ ] . so too, epidemics are quantitative creatures with predictable thresholds. models that can be adapted to new results and to changes in control policy have been identified as an integral part of disease-control programs [ ] . modelling-led interventions were instrumental in halting the foot and mouth outbreak in the uk [ ] . a mathematical model of the dynamics of measles in new zealand developed in successfully predicted an epidemic in and was instrumental in the decision to carry out an intensive immunisation campaign in that year. while the epidemic began some months earlier than anticipated, it was rapidly brought under control, and its impact on the population was much reduced [ ] . the west african onchocerciasis (river blindness) control program successfully used modeling to supplement intervention programs [ ] . by using clearly delineated endpoints, these models helped convince donors and the scientific community that the aims of the program were achievable [ ] . as a result, mathematical models have retained a role in subsequent policy discussions [ ] . insights from mathematical models during the sars epidemic helped determine how serious the epidemic might become, as well as the impact of proposed control measures. these models provided important guidance to public-health authorities at a critical time when little other information was available. insights from the models showed that, if unchecked, the virus could cause a significant epidemic, but that basic epidemiological control measures -patient isolation, contact tracing, etc -could have a substantial impact on the extent of the epidemic. subsequently, these control measures played a major role in limiting the spread of the epidemic [ ] . weather prediction models provide a workable analogy. such models consist of continually updatable inputs, that must adapt to an enormous array of incoming data [ ] . short-term predictions, especially those associated with discrete, extreme weather events such as floods and hurricanes, have proven useful in supporting emergency management strategies, unlike events such as earthquakes or acid rain, which have longer lead times [ ] . complex mediating models which themselves have explanatory power and which embody techniques of modeling can be refined and passed down to successor models [ ] . the virtue of mathematics in such a context is that it forces clarity and precision upon the conjecture, thus enabling meaningful comparison between the consequences of basic assumptions and the empirical facts [ ] . existing scenarios for hiv control have typically been spread out over two or more decades [ ] , which means that the reliability of their predictions is low. the basic concept of optaids is to spend more money up front, effectively, based on the best models and their parameters we can formulate, with the goal being a rapid halt to the epidemic with the fewest additional cases. this means that models can be shorter term and therefore more relia-ble, because we stay within the models' persistence time. optaids emphasises continuous monitoring to check the accuracy and adjust the parameters of the global model. mathematically, this is an optimal halting problem. the optaids workshop was the first of its kind: a scientific meeting held simultaneously in both a real world location and also second life ® http://secondlife.com, a virtual landscape that allows real-time communication. the broad topic was the eradication of aids using optimal spending models, but this encompasses an enormous number of issues surrounding the aids epidemic. topics covered included the impact of circumcision, the effect of traditional medicine, prevention strategies for countries with nascent epidemics and the difficulties of developing an hiv vaccine. mitacs http://www.mitacs.ca gave us a can$ , workshop grant for this meeting, which was held on july , . given that this amount would only cover a few airfares, we decided to allow people to participate via second life ® . second life ® allows the creation of avatars [ ] , so that users can participate in the world. within the virtual world, you can talk to other people's avatars, upload powerpoint slides and manipulate objects within the environment. twenty-two people convened over the day in toronto (figure ) , including ten presenters. the traffic count during the day indicated avatar arrivals in second life ® , four of whom were presenters. the workshop was advertised to pertinent groups in second life ® and open to the avatar public. the second life ® building includes a location where the original slide presentations can be viewed ( figure ). two screens were used in toronto, showing the slides and the audience (represented by avatars), while second life ® participants could lecture by having their avatar stand near a virtual screen in second life ® . everyone could hear everyone else. a second virtual screen showed a live camera view of the audience in toronto (figure ) . the all-day meeting had only a few short interruptions for technical reasons. a summary and follow-up discussion was presented at the annual meeting of the society for mathematical biology shortly afterwards. the four speakers presenting via second life ® were located in poland, seattle, denmark and los angeles. the technology allowed for interactive discussion, so speakers in toronto faced questions from second life ® participants all around the world, while second life ® speakers had their powerpoint presentations shown on a screen in toronto (operated by their avatars in second life ® and simultaneously by the organisers in toronto), and faced questions from toronto and other second life ® participants. the size of the turnout in second life ® demonstrated the effectiveness of virtual conferencing; many more people were able to attend the conference than would have been feasible otherwise. the event was covered by the national post, which reported on the innovative use of second life ® in an academic setting. all the presentations remain in second life ® http://slurl.com/secondlife/silver bog/ / / as posters that can be clicked on by anyone interested. speakers can be asked to show up personally as avatars to go over the slides. the aim of this supplement is to discuss aids as a global phenomenon and address issues surrounding its eradica-tion. due to the scale of the epidemic, a great number of sub-issues arise. in thinking of aids as a global pandemic, we need to tackle the disease from as many directions as possible. some of the articles involve mathematical models, others involve a thorough examination of the state of resources, or an understanding of the effect of the disease on society. this supplement comprises fifteen articles (including this introduction), divided into six themes: . history . resources . demographics . in-host models . computation . spending our way out of the epidemic theme comprises an introduction and overview of mathematical modeling [ ] , as well as a history of aids in africa and its effects on human development [ ] . theme is concerned with the various resources that comprise our intervention arsenal: the allocation of resources [ ] , cost-effectiveness of prevention [ ] , antiretroviral pricing [ ] , the effects of migration upon availability of health professionals [ ] , and the relation- ship between mathematical models and resource allocation [ ] . theme looks at the effects of demographic changes in china on hiv [ ] and the spread of hiv among men who have sex with men [ ] . theme examines in-host modeling -a crucial element in tackling the disease, often overlooked by epidemiologists -by proposing new methods for evaluating the efficacy of antiretroviral treatment [ ] and examining antioxidant supplementation as hiv therapy, with a focus on injecting drug users [ ] . theme looks at using virtual epidemics to understand real ones [ ] and develops an epidemic simulator of an agent-based, data-driven disease model [ ] . finally, theme examines the question at the core of the optaids project: spending our way out of the aids epidemic [ ] . the collection of articles in this supplement run the gamut of topics related to hiv/aids. they examine the disease from a global perspective, in an attempt to untangle many of the problems associated with the epidemic. however, we view this as a starting point: the next step is for policymakers and the donor community to embrace the idea of global eradication. only by working together can we combat this disease. aids is the fourth worst infectious disease of all time, resulting in more deaths per day over the past years than occurred on / / [ ] . over million adults are now infected with hiv, many in the developing world, where resources are scarce and infrastructure is struggling under the weight of this burgeoning epidemic. the hiv/ aids epidemic is often spoken of in terms of "reducing the spread" [ ] , or achieving "sustainable financing" [ ] however, this special issue demonstrates that, despite the immensity of the epidemic, eradication is not only possible, it is feasible. the time has come to stop thinking locally and to start acting globally. global health--the gates-buffett effect the case for expanding access to highly active antiretroviral therapy to curb the growth of the hiv epidemic useless arithmetic: why environmental scientists can't predict the future aids and the arrows of pestilence hiv testing, human rights, and global aids policy: exceptionalism and its discontents can we spend our way out of the aids epidemic? a world halting aids model why rich countries should care about the world's least healthy people aids , xvi international aids conference - mathematical models: questions of trustworthiness epidemiological modeling for onchocerciasis control. parasitology today the uk foot-and-mouth disease outbreak -the aftermath predicting and preventing measles epidemics in new zealand: application of a mathematical model the role of mathematical modeling in evidence-based malaria control neglected tropical diseases: infection, modelling and control final report of the conference on the eradicability of onchocerciasis the geographic spread of infectious diseases: models and applications princeton university press representing model uncertainty in weather and climate prediction prediction in science and policy uses and abuses of mathematics in biology aids in africa: three scenarios to avatars: exploring and building virtual worlds on the internet berkeley mathematical epidemiology is not an oxymoron the impact of hiv/aids on human development in african countries the past, present and future of hiv, aids and resource allocation hiv prevention cost effectiveness: a review of the literature factors influencing global antiretroviral procurement prices addressing the migration of health professionals: the role of working conditions and educational placements recommendations for increasing the use of hiv/aids resource allocation models population profiling in china by gender and age: implication for hiv incidences a sex-role preference model for hiv transmission among msm population quantifying the treatment efficacy of reverse transcriptase inhibitors: new analyses of clinical data based on within-host modeling reconciling conflicting clinical studies of antioxidant supplementation as hiv therapy: a mathematical approach halting hiv/aids with avatars and havatars: a virtual world approach to modelling epidemics epidemic modeling with discrete-space scheduled walkers: extensions and research opportunities reducing the spread of hiv infection in sub-saharan africa: some demographic and economic implications sixtieth session, agenda item . follow-up to the outcome of the twenty-sixth special session: implementation of the declaration of commitment on hiv/aids. scaling up hiv prevention, treatment, care and support we would like to thank natalie k. björklund- gordon the authors declare that they have no competing interests. rjs wrote the introduction, overview of the supplement and the conclusion. rg set the theme in the first draft and wrote the start of the introduction and the section on the workshop. both authors proofread and approved the final manuscript. key: cord- - c t an authors: frankish, helen title: new who chief promises greater commitment to hiv/aids date: - - journal: lancet doi: . /s - ( ) -x sha: doc_id: cord_uid: c t an nan w ith a pledge to give greater priority to hiv/aids and achieving results in poor countries, south korea's jong-wook lee took office as the new director-general of who on july . "we must scale up an integrated global hiv/aids strategy linking prevention, care, and treatment, prioritising poor and underserved areas", said lee in his inaugural address to about who staff at the organisation's geneva headquarters. "i am, therefore, constituting an hiv/aids leadership team to ensure that who, working with local, national, and international partners, will be at the forefront of this effort." to promote synergy in combating infectious diseases, the who department in charge of tackling hiv/aids will be brought into one group together with tuberculosis and malaria. taken together, the three diseases are responsible for about % of all deaths worldwide each year. lee named american jack chow, former special representative for hiv/aids to us secretary of state colin powell, as the new head of the hiv/aids, tuberculosis, and malaria cluster. in the long term, lee said, who's goal would be to provide antiretroviral drugs to million people in developing countries by the end of -the so-called "three-by-five" target. "by dec this year, world aids day, who's hiv/aids department, working with partners, will produce a global plan for reaching the three-by-five target", lee said. "together with partners such as unaids, who will use all available tools of advocacy to mobilise the political will and the additional resources needed to put this plan into action." the three-by-five target will guide much of who's work on hiv/aids, he said, but patterns of resistance to antiretroviral drugs would also be closely monitored through a global network in collaboration with who's partners. lee, a communicable diseases expert and former head of who's stop tb programme, also vowed to improve notification and monitoring systems to help tackle contagious diseases such as severe acute respiratory syndrome (sars). "the sars crisis illustrated who's essential role in coordinating the international response to infectious disease outbreaks", he said. but he conceded that the sars epidemic also revealed weaknesses in global disease surveillance. "we will work with our partners in the global outbreak alert and response network, and with bilateral and multilateral donors, to reinforce national and regional surveillance systems." on his first day in office, the new director-general also reinforced who's commitment to achieving the millennium development goals, targets that world leaders agreed on at the millennium summit years ago. "we see the millennium goals as milestones on the road to health for all", he asserted. in his address, lee admitted that in recent years, who's resources have become increasingly concentrated in geneva, and that there has been "a gradual drift" towards programmes driven by headquarters' priorities, rather than towards programmes based on countries' individual needs. to ensure that who's resources are aimed at producing results where they are needed most, lee pledged to increase funds at country level over the coming months and years, adding that the organisation would ensure that country offices have the resources and authority they need to work more effectively in responding to national and local health needs. lee asked the newly appointed assistant directors-general (see panel, p ) to analyse the work of their respective areas and to propose specific steps for moving resources from headquarters to the various regions. "i will begin by deploying additional resources to priority country offices for building up capacity in hiv/aids control and health systems", he said. rights were not granted to include this image in electronic media. please refer to the printed journal. le gales-camus, a former scientific adviser to the director-general of health in france, as head of non-communicable diseases. yach, meanwhile, has been appointed to design a plan to strengthen who's response to non-communicable diseases. david nabarro, from the uk, will be replaced by germany's kerstin leitner, undp's resident representative in china, as head of the sustainable development and healthy environments cluster. nabarro will now lead who's health action in crises programme. and botswana's minister of health, joy phumaphi, will take over from tomris türmen, from turkey, as assistant director-general for family and community health, while türmen will now lead a team charged with developing policy recommendations regarding the health implications of intellectual property rights structures. concluding his address, lee called for the continued commitment of who's staff, the member states, and its national and international partners in order to meet who's goals in the years ahead. "who's founding vision, its achievements, its partners and, above all, its people create a solid foundation. guided by our principles of loyalty, transparency, and commitment to excellence, we will move forward towards the goal of health for all. together, learning from the past, we can change the future of global health." lee also pledged to tackle the shortage of skilled health-care staff worldwide, which will slow progress towards goals such as the three-by-five target and has hindered the millennium development goals. "our cooperation with other countries on this issue must intensify. together, we must build the health workforce using innovative methods of training, development, and supervision of allied and community health workers. community mobilisation is a key to success", he said. lee also outlined ways in which who could directly contribute to strengthening human resources within the health sector. in early , he announced, who would launch the health leadership programme, an initiative to recruit promising young health workers from around the world, and provide them with the opportunity to work within who-at country level, in regional offices, and at who's headquarters in geneva. "mentored by senior who staff, these young professionals will form part of the next generation of international health leaders", he said. notably, lee also marked his takeover from the outgoing director-general, gro harlem brundtland, by replacing many of her most senior staff with a new team of assistant directors-general (see panel). david heymann, executive director of communicable diseases, who led the who's efforts earlier this year to control the sars outbreak, will now take charge of the drive to eradicate polio worldwide. ghanaian anarfi asamoa-baah, a who official who has been working for the agency since , will take over from heymann as assistant director-general of communicable diseases. and south african derek yach, who spearheaded who's framework convention on tobacco control -adopted in may by the world health assembly after a -year negotiation period-will be replaced by catherine gro harlem brundtland hands over to jong-wook lee ap lee's newly appointed team of assistant directors-general uk), formerly chef de cabinet, will become director of the director-general's office anarfi asamoa-baah (ghana), currently executive director for health technology and pharmaceuticals, will lead the communicable diseases cluster director of the eastern mediterranean liaison office, will head the external relations and governing bodies cluster special representative of the us secretary of state for hiv/aids, will take charge of the hiv/aids, tuberculosis, and malaria cluster director of health equity at the rockefeller foundation in new york, will lead the evidence and information for policy cluster catherine le gales-camus (france), most recently scientific adviser to france's director-general of health will take leadership of the non-communicable diseases and mental health cluster un resident coordinator and undp resident representative in china, will be responsible for the sustainable development and healthy environments cluster russia), most recently the head of the department of general and clinical pharmacology at the russian university of people's friendship, will take responsibility for the health technology and pharmaceuticals cluster head of the health division at the swedish international development cooperation agency, will take control of the general management cluster joy phumaphi (botswana), minister of health in botswana and hiv/aids commissioner appointed by the un secretary-general key: cord- - fu s c authors: hage, chadi a.; knox, kenneth s.; sarosi, george a. title: endemic mycosis date: journal: tropical and parasitic infections in the intensive care unit doi: . / - - - _ sha: doc_id: cord_uid: fu s c nan histoplasmosis, blastomycosis, and coccidioidomycosis are the three major endemic fungi in north america. although histoplasmosis is found in all continents except antarctica, coccidioidomycosis in south america, and blastomycosis in africa, only in north america are these illnesses common. these three fungal diseases share many characteristics. the causative agents are mycelial soil organisms. illness is acquired by inhaling aerosolized spores. in the infected host, the organisms change their form, a characteristic called dimorphism. histoplasma capsulatum and blastomyces dermatitidis convert to a yeast form at degrees c (thermal dimorphism), whereas coccidioides immitis converts in tissue to a spherule that replicates by forming endospores (tissue dimorphism). the endemic areas are large. most of the midwest and south central united states is endemic for both histoplasmosis [ ] and blastomycosis [ ] , and a large area in the southwest united states and an adjacent area of mexico are endemic for coccidioidomycosis [ ] . all three illnesses occur in normal hosts, although histoplasmosis and coccidioidomycosis are also major opportunistic mycoses in patients with depressed cell-mediated immunity, and especially in patients with acquired immunodeficiency syndrome (aids) [ ] , [ ] . histoplasmosis, blastomycosis and coccidioidomycosis are major t-cell opportunistic infections, as demonstrated by the very aggressive course seen in patients with aids, in whom t-cell deficiency is most severe. in the united states h. capsulatum var. capsulatum is responsible for the majority of the cases of histoplasmosis. h. capsulatum var. duboisii is predominantly found in south africa and europe ( ). the spectrum of disease ranges from the asymptomatic acquisition of a positive histoplasmin skin test reaction to a rapidly fatal pulmonary or disseminated illness. it is the balance between the net immune status of the subject and the load of the infecting inoculum that determines the severity of the illness. during the past two decades, histoplasmosis has emerged as a common opportunistic infection in patients with aids especially those residing in endemic areas. most of our current knowledge about this disease is derived from outbreak investigation in the midwestern united states. histoplasma is a thermally dimorphic fungus. it has two forms; a mycelia phase and a yeast phase. mycelia are the forms found in the environment, they are considered to be the infectious form. mycelia display macro-and micro-conidia. yeasts are what are found in the infected individuals. in the laboratory these two forms are inter-convertible by altering the temperatures and nutrients of the growth medium. the disease is highly endemic in the midwestern and southeastern parts of the us. it is estimated that - % of people living in the ohio and mississippi river valleys have evidence of remote infection with histoplasma [ ] human and animal infections occurred after inhalation of aerosolized micro-conidia, the infecting particle, which can reach the alveolar space due to its very small size of to mm. extensive skin test surveys suggest that as many as million people in the united states have been infected by h. capsulatum and that there are up to , new infections yearly [ ] . for decades most outbreaks have occurred in urban settings. most are associated with construction projects that disturbed contaminated soil. the most recent (and largest ever) outbreak occurred in indianapolis, indiana [ ] , associated with downtown construction of a swimming pool complex. mini-outbreaks also still occur. activities such as cutting up fallen trees or cleaning large bushes have been linked to smaller outbreaks. histoplasmosis occurs in to % of patients with aids who reside in endemic areas and up to % in selected areas during periods of outbreaks [ ] . pathogenesis. the lung is the portal of entry in almost every case. due to their small size, microconidia can reach the alveolar space where they convert to the yeast form, a key step in the pathogenesis. the initial tissue response to the organism is predominantly neutrophilic, followed by an increase in alveolar macrophages [ ] . after being phagocytosed, yeast survive and actually proliferate inside the macrophages, which serve then as a carrier throughout the reticuloendothelial system. shortly after infection the yeast forms can be identified in the mediastinal lymph nodes. the fungus then gains access to the circulation. it is likely that transient self-limited fungemia occurs in most, if not all, patients. later the yeast disseminates throughout the body to establish foci of infection in many organs, such as the liver, spleen and the adrenal glands [ ] . about two weeks after infection, specific cellular immunity begins to develop. activated lymphocytes secrete cytokines that stimulate macrophages in an attempt to boost their fungicidal activity. in mice, interleukin- is an important signal, leading to increased interferongamma production that confers protection against primary infection [ ] , [ ] , [ ] . tumor necrosis factor-alpha seems to be an important element in this scheme. inhibition of has been shown to alter the adaptive immune response to histoplasma infection and may predispose patients disseminated infection [ ] , [ ] , [ ] . with the advent of t-lymphocyte-mediated cellular immunity, fungal replication is checked and granuloma formation begins. healing of these lesions is accompanied by peripheral fibrosis. central areas of encapsulated, necrotic material frequently calcify. these calcified foci manifest on chest roentgenogram as single or multiple calcified nodules. calcified lesions are often seen in the liver and the spleen [ ] . if the cell-mediated immune response is poor, the yeast continues to multiply. more macrophages are recruited, which in turn become parasitized and eventually disrupted, perpetuating the cycle [ ] . a severe systemic illness develops, which invariably leads to death unless treated promptly and aggressively. clinical manifestations. most normal persons who are infected by the fungus remain asymptomatic. when present, symptoms vary widely from brief periods of malaise to severe, life-threatening illness. it is classically a flu-like illness with abrupt onset of fever, chills, and substernal chest discomfort. a harsh, nonproductive cough develops along with headache, arthralgias, and myalgias. in immunocompetent individuals severe pulmonary illness develops rarely, only when the infective dose is unusually high. it may progress rapidly to the acute respiratory distress syndrome, and may lead to death from respiratory insufficiency if not treated promptly [ ] . immunocompromised individuals are more likely to progress to disseminated disease even after an infection with a smaller inoculum. the vast majority of progressive disseminated histoplasmosis is seen in patients with advanced aids with cd counts below cells/ml [ ]. most patients with progressive disseminated histoplasmosis present with fever, chills, weight loss, cough and progressive dyspnea [ ] . on physical examination, patients are febrile and acutely ill. hepatosplenomegaly may be present. laboratory evaluation shows anemia, leukopenia, and thrombocytopenia. in extremely ill patients the syndrome of disseminated intravascular coagulation may be seen. up to % of patients present with severe septic shock, respiratory failure and progress to multi-organ failure. this syndrome represents an advanced stage of the illness and is usually seen when diagnosis and appropriate therapy were delayed. mortality is very high with this scenario. the chest roentgenographic findings are variable, ranging from normal to diffusely abnormal, with reticulonodular pattern being the most frequently reported finding. pleural effusions are rarely seen [ ] . the radiographic findings are very similar to those seen with pneumocystis carinii pneumonia [ ] ( figure ). chest x-ray of a hiv + patient with progress disseminated histoplasmosis. peripheral blood smear may show phagocytoses yeast in some of patients with severe disease. biopsy material from the bone marrow and other involved tissue shows collections of macrophages full of intracellular yeast or, in the most severe instances, widespread necrosis with large numbers of organisms lying loose in the extracellular debris. there is little, if any, evidence of granuloma formation [ ] . virtually all patients with this form of the illness have some degree of t-cell defect. before the modern era of widespread use of cytotoxic agents and glucocorticoids, many patients had underlying hodgkin's disease, a well-known example of naturally occurring t-cell immune deficiency [ ] , [ ] . the most severe form of progressive disseminated histoplasmosis (pdh) occurs in patients with aids with profound t-cell dysfunction [ ] . in fact, most cases of pdh now occur in aids patients, and most occur in highly endemic areas [ ] , [ ] . newer biological therapies for rheumatoid arthritis and other auto-immune disorders have added a new pool of immunosuppressed patients at risk for tuberculosis and also histoplasmosis and other t-cell opportunistic fungal infections. in most instances, exposure of an immunosuppressed person to an infected aerosol is the antecedent event preceding pdh. in the recent large outbreak in indianapolis, most patients who were immunocompromised when they developed primary histoplasmosis progressed to pdh [ ] . in particular, patients with aids nearly always progressed to pdh [ ] . in other cases, the onset of pdh is temporally related to intense immunosuppression, most commonly progression of aids or therapy with high doses of glucocorticoids. in some of these cases, reactivation of dormant histoplasmosis may be the mechanism of infection [ ] . patients with aids who develop pdh after long residence in new york city or san francisco are clear examples of such endogenous reactivation because primary infections are never seen in these cities. some patients with pdh present with a subacute to chronic illness. they may have a chronic wasting disease with anorexia, weight loss, and lowgrade fever. mucosal and mucocutaneous junction ulcers may occur in the mouth, oral pharynx, rectum, and glans penis. adrenal involvement may cause addison's disease [ ] . biopsy material from involved tissues shows well-formed epithelioid granulomas, and only a diligent search will reveal rare organisms. demonstration of organisms almost always requires special stains [ ] , [ ] . the disease may be systemic or involve only one organ. this more chronic form of pdh generally occurs in patients who are less immunosuppressed than the patients who develop more fulminant pdh. central nervous system histoplasmosis is rare and may present as chronic meningitis or intracranial histoplasmoma [ ] . endocarditis can also occur, involving either the aortic or mitral valves. vegetations are usually large, and emboli are common. endocarditis may occur on prosthetic or previously normal valves. recently, histoplasma involvement of abdominal aortic aneurysms has been reported in a few patients with the chronic form of pdh [ ] . the gold standard of diagnosis is culture of the fungus from biologic material. cultures are time consuming and one cannot wait for them in the management of cases with severe pdh. delay in diagnosis while awaiting results of fungal cultures may lead to a fatal outcome in more severe cases isolation of h. capsulatum may occur within week in a minority of patients but usually takes several weeks. serologic studies of histoplasmosis are seldom useful in the management of pdh. positive serology does not predict development of pdh in patients undergoing bone marrow transplantation [ ] . the complement fixation test is negative in up to % of patients with pdh. immunodiffusion fails to identify up to % of patients with acute histoplasmosis and usually does not reach maximum positivity for to weeks after exposure [ ] . their main drawbacks are imperfect sensitivity and lack of timeliness. several weeks must pass before they become positive. by that time, most patients have either recovered or have required other more invasive methods of diagnosis because of rapidly worsening disease there are two ways to make a rapid diagnosis of pdh, sampling and examination of likely infected tissue with the use of special stains and the use of the ultrasensitive assay for fungal antigens. bronchoscopy is an important diagnostic tool, especially for pdh. specimens obtained from bronchoscopy have a high but poorly defined yield in severe primary histoplasmosis with progressive ards and especially in pdh in aids, when diffuse infiltrates are one of the clinical features. in highly selected series the diagnostic yield of bronchoscopy for diagnosis of histoplasmosis in an endemic area is about % in patients with infiltrates [ ] . in a strictly aids population in indianapolis, indiana, fungal stains performed on bronchoalveolar lavage fluid provided a rapid diagnosis in % of patients; diagnostic yield increased to % when culture results were included. in that series, % of patients had co-infections or alternative diagnoses that were detected by bal and would not have been detected if histoplasma antigen testing had been the sole diagnostic test [ ] . use of cytologic examination without special fungal staining (silver, pas) may explain the lower yield of bal reported in series from non-endemic areas [ ] . it is likely best to do a battery of stains including a silver stain. although transbronchial biopsy is not mandatory at the time of bronchoscopy and bal, histopathology does appear to enhance the diagnostic yield [ ] . the fungus is difficult to see on standard hematoxylin and eosin stains; special stains (usually a silver stain) are needed. special stains are particularly important when well-formed granulomas are present because of the paucity of organisms in such cases. in patients with suspected pdh, sampling of the reticuloendothelial system is often effective for diagnosis. bone marrow biopsy is likely the best and safest method [ ] . in heavily parasitized samples, a direct smear of the bone marrow, stained with a supravital stain such as the giemsa stain, usually gives a rapid diagnosis ( figure ). on permanent histologic sections, the fungus is difficult to see on standard slides prepared with hematoxylin and eosin stain. it is best to go directly to special stains, usually one of several modifications of the silver stain or the pas stain. recently, the role of blood cultures in diagnosis of pdh has expanded. the lysis-centrifugation system increases sensitivity. in aids patients with pdh, the density of organisms is higher than in other immunosuppressed patients, and blood cultures are particularly useful, yielding a diagnosis in up to % of cases. in fact, in aids patients with pdh typical intracellular organisms can be seen directly on peripheral blood smears (buffy coat preparations) up to % of the time. bronchoalveolar lavage also has a very high yield, both by direct smear and by culture in aids patients with high burden of organisms. bronchoalveolar lavage offers the additional advantage of ready diagnosis of other opportunistic infections that are usually in the differential diagnosis, including p. carinii pneumonia. antigen detection. another approach to diagnosis of fungal infections is the use of the ultrasensitive assays for fungal antigens. this test is very useful when the burden of the infection is high. detection of the histoplasma antigen in body fluids permits rapid diagnosis of pdh. the specificity of antigen detection is greater than %. there is, however, known cross reactivity with the other endemic fungi such as african histoplasmosis, blastomycosis, paracoccidioidomycosis, and penicillium marneffii infection [ ] . sensitivity is lower in patients who are moderately immunosuppressed. however, the high density of organisms in aids patients with pdh makes antigen testing extremely useful in that setting. antigen testing is more sensitive on urine than serum. it is positive in either urine or serum in up to % of patients with pdh complicating aids [ ] . levels of histoplasma polysaccharide antigen in urine and serum also are useful for following the course of treatment and for predicting relapses [ ] , [ ] . the test is done reliably in a single reference laboratory in indianapolis, which makes it a "send out" for many institutions. severe cases of pdh in non-aids patients are best treated promptly and aggressively with amphotericin b to a total dose of mg/kg. itraconazole ( mg/day in a single daily dose) can be used successfully for patients with mild to moderate disease [ ] . sequential therapy for severely ill patients with amphotericin b to clinical improvement followed by months of itraconazole is also being used but is not well studied. aids patients are treated differently from other pdh cases. relapse is expected if treatment is stopped. all patients require induction therapy to control symptoms and then maintenance therapy. amphotericin b is used initially for all moderately and severely ill patients. after clinical response, treatment is changed to itraconazole ( mg daily for or more weeks, then mg daily until sustained recovery of the immune system) [ ], [ ] . there is emerging data that support the discontinuation of maintenance itraconazole in patients with hiv who recover their immune system [ ] . itraconazole can be used from onset for mild cases [ ] . other maintenance strategies for those intolerant of itraconazole include weekly amphotericin b infusions or fluconazole at doses of at least mg/day. ketoconazole therapy is ineffective for maintenance therapy, and fluconazole even at high daily doses ( to mg) is less effective than itraconazole [ ] . in a recent double blind, randomized trial liposomal amphotericin b (l-amb) was somewhat more effective than amb in both time of response and survival, although the differences were not statistically significant [ ] . in this study both types of amb were used for fourteen days before switching to oral itraconazole therapy. blastomycosis is an illness caused by the thermal dimorphic fungus blastomyces dermatitidis. the spectrum of disease ranges from the asymptomatic acquisition of the fungus to a rapidly progressive and lifethreatening respiratory or disseminated illness. blastomycosis is most common in the central and south-central united states [ ] . the proposed endemic area includes much of the central, south central, and southeastern united states, beginning near the minnesota-north dakota border and extending eastward and southward. the southeastern limit extends to south carolina but not to florida. this area overlaps most of the endemic area of histoplasmosis [ ]. the northern limit, however, extends further. northern minnesota and northern wisconsin and also the adjacent canadian provinces of ontario and manitoba are endemic for blastomycosis but are free of histoplasmosis [ ] , [ ] . similar to h. capsulatum, b. dermatitidis is a soil-dwelling fungus. infection occurs by inhalation of airborne spores. infected individuals develop a positive blastomycin skin test reaction or the in vitro correlate of delayed hypersensitivity. as with histoplasmosis, isolated microfoci of high infectivity exist in a large endemic area. outbreaks often occur during activities such as hunting, camping, or canoeing in wooded or swampy environments [ ]; these are most common when soil temperatures have been increasing for several days and when there is rain on the day of exposure. for sporadic cases, residence close to water in a highly endemic area and recent excavation activity are risk factors [ ] . dogs are also susceptible to blastomycosis. canine blastomycosis is a well-recognized entity in veterinary practice in the endemic areas. the recognition of canine cases in a community should alert physicians that human blastomycosis may be present in their geographic area [ ] . at ambient temperatures, the fungus grows as an aerial mycelium. when foci of actively growing blastomyces are disturbed, small -to spores become airborne and an infective aerosol is formed. these infecting particles then may be inhaled by humans or by other mammals disturbing the site. some spores may escape the nonspecific defenses of the lung and reach the alveoli. the initial inflammatory response is neutrophilic. as the organism converts to the parasitic yeast form and begins to multiply, large numbers of yeast are seen, surrounded by neutrophils. following this macrophages increase in number. eventually, as specific cellular immunity develops, there are giant cells and well-formed epithelioid granulomas. in contrast to histoplasmosis, the neutrophilic component of the inflammatory response does not disappear completely, and the histopathologic examination often shows a mixed pyogenic and granulomatous response, even in chronic cases [ ] . it would be misleading, however, to think that there is a "characteristic" tissue response in blastomycosis. occasionally, the neutrophilic component is minimal and the granulomas are noncaseating, producing a picture similar to that of sarcoidosis. in contrast, granulomas are sometimes entirely absent in overwhelming infections. the entire inflammatory reaction consists of neutrophils, and the histopathologic picture mimics that of bacterial infection. the histopathologic response in cutaneous blastomycosis is striking. the stratified squamous epithelium becomes markedly hyperplastic, with exaggerated downgrowth of the rate pegs. within these fingerlike projections are a number of microabscesses. the same hypertrophic tissue response is seen when the disease involves the oropharynx or the larynx. the histopathologic appearance may superficially resemble carcinoma. the characteristic organisms, seen best with special stains, provide a diagnosis. the initial inflammatory and immune response may confine the infection to the lungs and the hilar lymph nodes. it is likely (but not proven) that selflimited early fungemia does not occur as often as it does in histoplasmosis. in some instances, however, the organism spreads beyond lung and the hilar nodes. dissemination is usually to skin, bones, prostate, and meninges but can be seen in any organ [ ], [ ] . the incubation time for blastomycosis is longer than for histoplasmosis and more variable. in the eagle river outbreak, in which time of exposure was short and precisely defined, the median incubation period was days, with a range of to days [ ], [ ] . the portal of entry is almost always the lung, and the primary illness is a lower respiratory infection. some patients have an acute illness that resembles bacterial pneumonia, in contrast to acute pulmonary histoplasmosis, which more closely mimics influenza. the onset of symptoms is abrupt, with high fever and chills, followed by cough that rapidly becomes productive of large amounts of mucopurulent sputum. pleuritic chest pain may occur. this acute onset is common in an outbreak setting, but also may be seen in sporadic cases. in most sporadic cases, however, the onset of clinical symptoms is more gradual. the patient presents with a low-grade fever, productive cough, and weight loss [ ] [ ] . lung cancer or tuberculosis are highest in the differential diagnosis, rather than bacterial pneumonia, depending on the roentgenographic findings. physical examination is usually unremarkable except for fever. auscultation of the chest in patients who have segmental or lobar infiltrates may show crackles and focal consolidation; more often the physical examination is negative. skin lesions are highly variable in appearance, ranging from subcutaneous nodules and abscesses to papules to ulcers with heaped up borders mimicking squamous cell cancers. perhaps the most characteristic lesion has irregular borders and a crusted surface, varying in size from to or more centimeters. skin lesions may be single or multiple and may occur in crops of several new lesions daily or every few days if the disease is rapidly disseminating. routine laboratory tests are seldom helpful. in cases resembling acute bacterial pneumonia, the white blood cell count is elevated, and frequently there is a shift to the left toward earlier forms in the granulocyte series. there is no "characteristic" chest roentgenographic pattern in blastomycosis [ ] . lesions may vary from single or multiple round densities throughout both lung fields to segmental or lobar consolidation. severe pulmonary infections can present with diffuse infiltrates, nodular, interstitial, or even alveolar (figure ) . the diffuse alveolar infiltrates are identical to acute lung injury (as in acute respiratory distress syndrome) of diverse cause. mass-like perihilar infiltrates, especially on the right side, are common and are often misinterpreted as neoplastic. on the lateral chest roentgenogram, the mass-like infiltrate is usually behind the hilum, in the apical-posterior segment of the lower lobe. hilar lymph node involvement may occur but is not nearly as common as in histoplasmosis. cavities may occur during the acute phase of the illness and usually close during successful treatment. unlike histoplasmosis, calcification due to healed blastomycosis is rare. figure year old man who failed antibiotic therapy for a community acquired pneumonia, presenting with a rapidly progressive respiratory failure. bronchoalveolar lavage recovered blastomyces dermatitidis. extrapulmonary spread of the fungus may occur during the acute, symptomatic phase of the illness. in some instances, only the distant lesion (usually skin or bone) is symptomatic. the skin and the bony skeleton are the most common sites of symptomatic extrapulmonary spread. the prostate gland, meninges, oral pharynx, larynx, and abdominal viscera, including the liver and the adrenal glands, are involved less frequently [ ] . blastomycosis can present as a progressive infection in patients with t-cell defects, including organ transplant recipients and other patients being treated with high-dose glucocorticoids and other immunosuppressive therapy for malignant and nonmalignant disorders. as with histoplasmosis, the disease can often be cured with amphotericin b in patients with intermediate degrees of immunosuppression. blastomycosis is much less common in aids and other t-cell-deficient conditions than are histoplasmosis and coccidioidomycosis. this is probably because exposure to this fungus, while immunosuppressed, is less common and because there is a smaller reservoir of patients with remote healed infection waiting to relapse should t-cell function markedly decline [ ] . blastomycosis can also occur in aids, usually with a cd count below infection is particularly severe, and cure is not likely. maintenance therapy is required for those who respond to initial treatment. patients with aids are likely to progress with widespread dissemination of the infection with multi-organ involvement. patients may present with sepsis like picture. meningitis or brain abscess are common in this setting and it is associated with a high early mortality [ ]. the easiest and most rapid method of diagnosis is examination of expectorated sputum or aspirated pus after % potassium hydroxide digestion [ ] . the characteristic large ( -to organism is easily identified. the yeast is single budding, with a broad neck of attachment between the parent and the daughter cells. the wall is thick and is double refractile, and there are multiple nuclei. other direct fungal stains including periodic acid schiff (pas), calcoflour white, and silver stains are more sensitive. another sensitive technique for rapid diagnosis of blastomycosis on direct sputum smears is cytologic analysis with the standard papanicolaou stain (figure ) . the direct techniques are probably complementary and examining multiple sputum samples increases diagnostic yield [ ] . papanicolaou stain of a sputum specimen from a patient with rapidly progressive respiratory failure after a community acquired pneumonia, showing the large budding yeast with broad neck of blastomyses. bronchoscopy is useful when patients are unable to expectorate adequate sputum, and when urgent diagnosis is needed because of rapid pace of the illness. in one study, bronchoscopy (specimens obtained included bronchoalveolar lavage (bal) in % and bronchial washings in all) was diagnostic in % of patients when culture results were included in the final analysis [ ] . for patients who are acutely ill or have an ards-like picture, rapid diagnosis is crucial and can only be achieved by direct examination of respiratory secretions. if direct sputum smears are negative or not possible, then bronchoscopy should be done urgently with bal and bronchial washings sent for both direct fungal stains (some combination of koh, calcofluor white, silver stain, pas and cytology preparation) and for culture [ ] . the cytology laboratory should be informed whenever there is high clinical suspicion of infection. cellblocks of concentrated bal fluid can be done to maximize the yield of the submitted specimens. histopathologic examination of biopsy material is also an excellent way to establish the diagnosis. the decision whether or not to perform transbronchial biopsies at the time of initial bronchoscopy will likely depend on contraindications in any given patient that give added risk beyond risk of bal. this is particularly true in critically ill patients. if blastomycosis is being considered in this setting, bronchoscopy with bal can be the initial procedure, reserving transbronchial biopsy for cases with no diagnosis from a safer and easier first procedure. standard hematoxylin and eosin stains do not stain the fungus and special stains are required. the periodic acid-schiff stain preserves morphological detail, but silver stains are more commonly used and likely have better sensitivity. identification of the fungus by culture is not difficult, but it is slower. growth may occur as early as to days but often takes several weeks. exoantigen testing can provide positive identification as soon as good growth is established. formerly, positive identification required conversion of the mycelial culture to the yeast phase of growth, adding or more weeks of delay. serologic testing is of limited value in diagnosis of blastomycosis. they are positive in about a quarter of cases. most cases of blastomycosis are diagnosed by smear, culture, and histopathology rather than by serological tests. severely ill patients with pulmonary blastomycosis require immediate and aggressive treatment with amphotericin b. itraconazole is highly effective for blastomycosis and is the treatment of choice for most patients with pulmonary and nonmeningeal disseminated disease; oral therapy with mg/day for months successfully treats most patients with mild to moderate pulmonary disease, skin disease, and bone disease. amphotericin b (dosing as described for histoplasmosis; total cumulative dose mg) is preferred for a small minority of severely ill patients, including all patients with diffuse infiltrates and severe gas exchange abnormalities. patients with edematous lobar pneumonia (bulging fissures), extremely toxic patients, and patients who are rapidly disseminating should all receive amb. for these severe infections, sequential therapy with amb to clinical improvement (usually to mg total dose) followed by months of oral itraconazole is often used and is effective though not well studied. this approach is also used for aids patients. patients with aids and blastomycosis are not permanently cured. life-long maintenance therapy is needed after induction therapy to improve symptoms. meningeal blastomycosis is always treated with systemic amphotericin b therapy in standard doses. l-amb achieves higher brain tissue levels in animals and may be preferred. fluconazole is overall less potent for blastomycocis than itraconazole but penetrates cns much better. high dose fluconazole (often in combination with l-amb) has been used for central nervous system blastomycosis. voriconazole is theoretically attractive but has not been studied. intracisternal amphotericin b has been used anecdotally in addition to systemic therapy for selected patients, but it is uncertain whether there is additional benefit [ ], [ ] . intracisternal therapy is used less often now that there is a wider range of therapy. coccidioidomycosis is the illness caused by the tissue-dimorphic fungus coccidioides immitis. although most infections are mild and self-limited, the spectrum of illness includes life-threatening pulmonary disease and widely disseminated systemic disease with a high mortality rate. differences between it and histoplasmosis and blastomycosis include different endemic areas, higher frequency of meningeal infections, and poorer response to all antifungal therapy, including amphotericin b. the endemic area for coccidioidomycosis in north america is the southwestern united states and the contiguous areas of northern mexico. the endemic area of the united states includes central and southern california and extends eastward to arizona, new mexico, and western texas. in nature, the fungus grows as an aerial mycelium with septate hyphae. alternating cells form thick-walled barrel-shaped structures called arthroconidia, with empty cells in between. when a natural site is disturbed, the mature arthrospores easily detach and become airborne, producing an infective aerosol. the risk of infection is greatest during the hot dry summers. strong winds can carry the arthrospores for long distances. a huge wind storm that blew north from the san joaquin valley in caused a major outbreak of coccidioidomycosis in sacramento, far north of the usual endemic area [ ] . not surprisingly, occupations and activities with exposure to the soil carry the greatest risk for infection, including construction work, farm labor, and working on archeological digs [ ]. after inhalation, some arthrospores evade the nonspecific lung defenses and reach the alveoli, where germination begins. the arthrospores develop into spherules, the tissue phase of the fungus. spherules are large, round, thick-walled structures that vary in diameter between and reproduction of the fungus occurs within the spherule. the cytoplasm of the spherule undergoes progressive cleavage, forming numerous endospores within the spherule. once a spherule matures, it bursts and releases the endospores into the surrounding tissues. each endospore can become a new spherule and thus repeat the process. the initial inflammatory response to inhaled arthrospores is neutrophilic. resident alveolar macrophages also phagocytose the arthrospores and prime specific t lymphocytes, which multiply, recruit more macrophages, and arm the macrophages, engaging specific cell-mediated immunity. even though many well-formed granulomas are seen, the neutrophilic inflammatory exudate does not disappear. histopathologically, there is a mixed granulomatous and suppurative reaction more similar to blastomycosis than to histoplasmosis [ ] . granuloma formation is important for successful limitation of the infection. good outcome correlates with preponderance of well-formed granulomas. most primary infections are asymptomatic or relatively mild. the fungus usually remains localized to the lung and hilar lymph nodes. dissemination occurs in less than % of patients. hematogenous spread can affect many tissues, including the skin, bones, lymph nodes, visceral organs, and meninges [ ] . meningitis is the most feared clinical syndrome with an ominous prognosis [ ] . except for rare instances of inoculation coccidioidomycosis, the portal of entry is the lung. about % of individuals with primary pulmonary infection remain totally asymptomatic. in the remaining %, the spectrum of disease ranges from a mild, influenza-like respiratory illness to a severe, life-threatening pneumonia [ ] . the clinical symptoms and their severity are variable. common symptoms include cough, fever, and pleuritic chest pain. cough may be nonproductive, or there may be small amounts of mucopurulent sputum. true rigors are not common. headache, common during the acute phase of the illness, is nonspecific. severe headache is always worrisome, however, because coccidioidal meningitis often becomes clinically apparent during the early part of the illness. if meningitis is suspected, a lumbar puncture should be performed immediately. several dermatologic aspects of acute coccidioidomycosis are important. a mild nonspecific so-called toxic rash occurs in many patients [ ], [ ] . it is an erythematous macular rash that occurs early during the illness, before the skin test turns positive. erythema nodosum and erythema multiforme are other skin manifestations of primary coccidioidal infection. together with fever and arthralgias, these skin lesions are part of a variable symptom complex first recognized by locals in the san joaquin valley of south central california and labeled "valley fever". more than % of patients with primary coccidioidomycosis have an abnormal chest roentgenogram. the most common roentgenographic abnormality is a single or multiple areas of patchy pneumonitis. the ipsilateral hilar nodes are enlarged in about % of patients [ ] . hilar adenopathy may also be seen without recognizable parenchymal disease ( figure ). this primary complex usually heals rapidly. necrosis in the center of a pneumonic lesion may produce cavitation [ ] . this is often accompanied by minor hemoptysis, which may be alarming but is seldom lifethreatening. hemoptysis as a late complication is uncommon but can be life-threatening, in contrast to the minimal bleeding that is often seen as the cavity forms. another complication is rupture of the cavity with development of a pyopneumothorax. in rare instances, primary pulmonary coccidioidomycosis is not self-limited but progresses within the lung. symptoms are fever, cough, and weight loss. the chest roentgenogram shows progression of the infiltrate and variable involvement of the hilar nodes [ ] . this form of pulmonary coccidioidomycosis is dangerous and augers impending dissemination. most of the patients with progressive pulmonary disease are either immunosuppressed or belong to groups at high risk for dissemination. the primary pulmonary infection usually either resolves completely or stabilizes. rarely does a patient die when the disease is restricted to the lung. in some individuals, however, the fungus spreads widely throughout the body, resulting in a systemic infection known as disseminated coccidioidomycosis. patients receiving glucocorticoid or cytotoxic or newer immune modulating therapy for malignant or nonmalignant diseases are at risk of dissemination. this is especially true for recipients of renal and other organ transplant and patients with aids [ ], [ ] . the excess risk of coccidiodomycosis in organ transplant recipients in highly endemic areas has led to targeted prophylaxis to prevent re-activation whenever there is a history of coccidiodal infection or positive serologic results on pretransplant screening [ ] . there are other well-recognized risk factors for dissemination. race and ethnicity are important. disseminated coccidioidomycosis is more likely in blacks, filipinos, and native americans than in whites. male gender is also a risk factor, as is diabetes mellitus. the very young and the very old are more likely to have dissemination [ ] . there is much anecdotal information suggesting that coccidioidomycosis during the third trimester of pregnancy may be a severe illness with rapid dissemination. dissemination from the primary pulmonary focus tends to occur early, usually within a few months after a symptomatic pulmonary infection. in some patients, however, the findings of disseminated disease are the first manifestations of coccidioidomycosis, presumably because the preceding pulmonary infection was sub-clinical. dissemination may involve any organ in the body. the skin is one of the most common sites of dissemination and is involved in most patients some time in the course of the disease. involvement of the bones is the next most common manifestation of disseminated coccidioidomycosis. osteomyelitis may be either the sole evidence of extrapulmonary spread or part of a more widespread dissemination. bone disease is usually restricted to one or two sites, but occasionally as many as eight separate lesions may be present. meningitis is the most dreaded complication of coccidioidal dissemination. between one third and one half of all patients with disseminated disease have meningitis, frequently as the only obvious extrapulmonary site. the onset of meningitis may be subtle, with only mild headache and minimal alteration of mental functions. striking boardlike nuchal rigidity, as in purulent meningitis, is seldom seen [ ] . in fact, the findings of meningitis can be so minimal that all patients with dissemination at other sites should have a diagnostic lumbar puncture to exclude meningitis. involvement of the base of the brain is characteristic. as the disease progresses, an exudate frequently obstructs the aqueduct of sylvius and the foramina of the fourth ventricle, producing hydrocephalus. when obstruction occurs, the patient's clinical condition suddenly worsens, with diminished level of consciousness and the development of papilledema. the cerebrospinal fluid shows characteristics of chronic meningitis: predominantly mononuclear cell pleocytosis, increased protein, and decreased glucose. occasionally, eosinophils are present in the cerebrospinal fluid. if present, they are a valuable clue to the possible coccidioidal nature of the chronic meningitis. when coccidioidomycosis complicates hiv infection, the severity depends on the residual immune competence of the host. with near-normal cd lymphocyte counts, coccidioidomycosis is not significantly different from the disease seen in normal hosts. when the cd count falls below cells/ml, disseminated disease tends to be severe and rapidly progressive. patients usually have high fever, complain of dyspnea, and are hypoxemic; chest roentgenograms often show diffuse reticulonodular infiltrates with nodules mm or greater in diameter ( figure ). diffuse macronodular pulmonary infiltrates are present in less than one per cent of non-aids patients with disseminated coccidioidomycosis, but in up to % of advanced aids patients with this condition. meningeal disease is present in up to % of the patients [ ], [ ] . mycologic studies. direct examination of sputum and other respiratory specimens (or pus from a non-pulmonary site) may reveal the diagnostic spherules. direct smears have highest utility in patients who produce copious sputum or have multi-lobar infiltrates [ ] . bronchoscopy is often performed in selected cases. in one study bronchoscopy was diagnostic in % of patients (compared to % for sputum stains and cultures) when patients with solitary pulmonary nodules on chest radiograph were excluded from analysis [ ] . this study also showed usefulness of a postbronchoscopy sputum and equivalent sensitivity for papanicolaou and silver staining. the airway can be examined at the time of bronchoscopy and may be abnormal, providing clues to the diagnosis [ ]. bronchoscopy is typically performed in patients who are immunosuppressed and severely ill, especially if they have diffuse infiltrates on chest radiograph. multiple infections often co-exist, adding additional value to diagnostic bronchoscopy early in the course of illness [ ] , [ ] . bronchial washings and bronchoalveolar lavage fluid should be sent for cytology, fungal stains, and culture. in a recent study of an aids patient in phoenix, arizona, the papanicolaou stain was the most useful direct test (when compared to koh and calcofluor white) for rapid diagnosis of pulmonary coccidioidomycosis and was even positive in two patients with negative cultures [ ] . histopathologic examination of biopsy material is extremely helpful. when mature spherules (visible on standard hematoxylin and eosin stained tissue sections) are seen, the diagnosis is secure. more commonly, only endospores, immature spherules or spherule fragments are present. therefore fungal stains such as a silver stain should always be used in addition to hematoxylin and eosin staining. in one study, transbronchial biopsy yielded a specific tissue diagnosis of coccidioidomycosis in eight of eight patients. cultural identification of the fungus is not difficult but is hazardous to laboratory personnel. isolation should be attempted only under rigid biohazard protection. traditional laboratory methods for identifying culture isolates require conversion of mycelial-phase cultures to the tissue phase either by animal inoculation or directly by the use of slide cultures. now immunodiffusion tests are performed directly on the supernatants of liquid mycelial-phase cultures. this method of identification (called exoantigen testing) is safer, simpler, and faster [ ] . positive identification of a coccidioidal isolate can sometimes be made by day , although it usually takes longer. because cultural identification is slow and even somewhat dangerous, serologic tests have been developed that facilitate rapid diagnosis [ ] [ ] . a tube precipitin tests for detection of ig m antibodies is positive in % of patients by the third week (negative only in very mild infections). because the test usually reverts to negative within months, it is quite specific for recent infection [ ] . currently, an immunodiffusion test for igm has largely replaced the tube precipitin test. the immunodiffusion test measures the same antibodies, but it is easier to perform. the most important serodiagnostic test is the complement fixation (cf) test. cf antibodies are of the igg class and appear later than igm antibodies. in most symptomatic patients, the cf test is positive by months and remains positive for several months or longer [ ] . the test is highly specific but is not sensitive. most asymptomatic skin test converters never have cf titers over : , which is the threshold for a positive result. most symptomatic patients have titers of : or : . titers of : or higher are generally associated with more severe infections and poorer prognosis. in the classic studies of smith and colleagues [ ], many patients with these high titers either had already undergone or were about to undergo dissemination. however, other patients with disseminated coccidioidomycosis did not have high titers. also the cutoff of a : cf titer as a harbinger of dissemination never transferred perfectly to other laboratories that did not use the same method or the same antigen. a single cf titer, no matter how high, should never be used to make a diagnosis of disseminated coccidioidomycosis. nonetheless, a steadily rising titer should raise the suspicion of disseminated coccidioidomycosis and prompt further tests (including bone scan, spinal tap, or both when appropriate) to better define the extent of disease. because dissemination is more likely in immunosuppressed patients, in diabetics, and in certain racial and ethnic groups, it may be prudent to treat patients in high-risk groups during the primary infection, before dissemination takes place. in the past some authorities recommended a treatment course to a total dose of to mg of amphotericin b [ ] . similarly, many experts believed that all patients with pulmonary disease that is severe or persists beyond a few weeks should receive amphotericin b to approximately the same total dose to prevent local pulmonary progression and to prevent dissemination. in current practice, many such patients (and also less symptomatic patients with pulmonary coccidioidomycosis of shorter duration) are often given fluconazole for - months, reserving amb for patients with diffuse infiltrates and women in the third trimester of pregnancy. these recommendations are based on expert opinion and observational studies. amphotericin b is likely the best treatment for persistent pulmonary coccidioidomycosis. because of their lesser toxicity, oral azoles are often tried. about two thirds of patients have clinical improvement with azole therapy, but many relapse when the course of treatment is finished. ketoconazole was used first. currently fluconazole and itraconazole are being used. voriconazole will likely be evaluated in the future. disseminated coccidioidomycosis requires prompt and aggressive treatment. unfortunately, amphotericin b is not as effective for disseminated coccidioidomycosis as it is for disseminated histoplasmosis or blastomycosis. the standard dose of amphotericin b is to mg given over many weeks or months. if necessary, much larger total doses may be given [ ] . daily doses of amphotericin b (usually to mg) are given while the patient is acutely ill. when the patient stabilizes, frequency should be reduced to three times weekly. currently disseminated disease without cns involvement should be treated with fluconazole or itraconazole first, especially in mild to moderate cases. amb should be reserved for severe disease or treatment failure. fluconazole and itraconazole are now azoles of choice for nonmeningeal disseminated coccidioidomycosis. neither is perfect for difficult cases for which even amphotericin b is often only suppressive. long-term therapy is often required, extending to years or even indefinitely. fluconazole has the advantage of better absorption, less gastrointestinal upset, and better penetration of the central nervous system. in a recently published randomized controlled trial, oral fluconazole and itraconazole were compared for treatment of non-meningeal coccidioidomycosis. soft tissue dissemination responded best. overall, itraconazole was somewhat more effective than fluconazole, producing response in % of the patients vs. % response in fluconazole treated patients (p = . ). among patients with skeletal infections, itraconazole was clearly superior, (p= . ) [ ] . some difficult cases of bone, lymph node, and soft-tissue coccidioidomycosis may be best managed with surgical drainage of focal abscesses, a to mg course of amphotericin b, and a prolonged course of itraconazole or fluconazole. as might be expected, the treatment of disseminated coccidioidomycosis in aids is particularly difficult. because of the rapid tempo of the disease, amphotericin b should be used initially, especially if the patient is severely ill. if the clinical course stabilizes, it is reasonable to switch to fluconazole for long-term suppression. prognosis is poor. even with prompt diagnosis and treatment, up to % of severely immunosuppressed patients die during the initial hospitalization. other patients, usually with lesser degrees of immunosuppression, respond well to treatment[ ], [ ] . meningeal coccidioidomycosis is a major therapeutic challenge. the standard therapy in the past included a course of to mg systemic amphotericin therapy plus intensive and lengthy intrathecal (by lumbar or cisternal route) amb therapy [ ] . intrathecal (or, less commonly, intraventricular via surgically placed reservoir [ ] ) amb in doses between . and mg was injected two to three times weekly until symptoms and cerebrospinal fluid pleocytosis resolve. even after the patient had apparently recovered fully and cerebrospinal fluid pleocytosis had resolved, most authorities recommended continued injections of amphotericin to prevent relapse, first weekly and then at longer intervals. relapses were common, but, with careful management, lengthy remissions could be obtained. because of the toxicity of this once standard approach to coccidioidomycotic meningitis, fluconazole has been evaluated as primary therapy for stable patients and as suppressive therapy after initial response to amphotericin b for more severely ill patients. most patients respond favorably to fluconazole and maintain good clinical function. dosage is to mg/daily or even higher. therapy has to be continued long term, likely indefinitely [ ] . recently anecdotal reports have shown favorable response to voriconazole and this agent will undoubtedly be tried in various forms of coccidioidomycosis, including meningitis. a drug with potency and wide spectrum of itraconazole but with tissue penetration like fluconazole seems especially attractive for an treatment resistant illness with high incidence of meningeal spread. however clinical data is sparse. severely ill patients with both nonmeningeal and meningeal disease were previously treated with intravenous and intrathecal amphotericin b. now they are sometimes treated with intravenous amphotericin b for faster, more effective initial therapy of the nonmeningeal disease and with fluconazole to control the central nervous system infection. amphotericin b is continued to clinical improvement and fluconazole indefinitely. newer antifungal agents are being developed; their potential role in coccidioidomycosis is uncertain. as mentioned voriconazole has some promise because it has better cns penetration than itraconazole -and yet may retain the potency advantage of itraconazole over fluconazole which has been demonstrated in non-meningeal disseminated disease. state of the art: histoplasmosis disseminated histoplasmosis in immunologically suppressed patients. occurrence in a nonendemic area disseminated histoplasmosis: clinical and pathologic correlations histoplasmosis capsulati and duboisii in europe: the impact of the hiv pandemic, travel and immigration an atlas of sensitivity to tuberculin, ppd-b, and histoplasmin in the united states the incidence of hospitalized cases of systemic mycotic infections a large urban outbreak of histoplasmosis: clinical features disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. medicine (baltimore) early pathogenesis of experimental histoplasmosis factors involved in regulating primary and secondary immunity to infection with histoplasma capsulatum: tnf-alpha plays a critical role in maintaining secondary immunity in the absence of ifngamma modulation of immune responses in murine pulmonary histoplasmosis complex requirements for nascent and memory immunity in pulmonary histoplasmosis intrapulmonary response to histoplasma capsulatum in gamma interferon knockout mice histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy the healed primary complex in histoplasmosis experience during outbreaks in indianapolis and review of the literature disseminated histoplasmosis in aids: findings on chest radiographs trephine biopsy of the bone marrow in disseminated histoplasmosis histoplasmosis in the acquired immune deficiency syndrome clinical review: progressive disseminated histoplasmosis in the aids patient risk factors for disseminated or fatal histoplasmosis disseminated histoplasmosis: results of long-term followup. a center for disease control cooperative mycoses study histoplasma capsulatum infections of the central nervous system. a clinical review. medicine (baltimore) progressive disseminated histoplasmosis; favorable response to ketoconazole incidence of histoplasmosis following allogeneic bone marrow transplant or solid organ transplant in a hyperendemic area serodiagnosis of histoplasmosis bronchoscopy in the diagnosis of pulmonary histoplasmosis diagnosis of histoplasmosis in patients with the acquired immunodeficiency syndrome by detection of histoplasma capsulatum polysaccharide antigen in bronchoalveolar lavage fluid histoplasmosis in patients at risk for the acquired immunodeficiency syndrome in a nonendemic setting cross-reactivity in histoplasma capsulatum variety capsulatum antigen assays of urine samples from patients with endemic mycoses histoplasmosis relapse in patients with aids: detection using histoplasma capsulatum variety capsulatum antigen levels effect of successful treatment with amphotericin b on histoplasma capsulatum variety capsulatum polysaccharide antigen levels in patients with aids and histoplasmosis itraconazole therapy for blastomycosis and histoplasmosis. niaid mycoses study group prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome. the national institute of allergy and infectious diseases clinical trials and mycoses study group collaborators itraconazole maintenance treatment for histoplasmosis in aids: a prospective, multicenter trial safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy: aids clinical trials group study a itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. aids clinical trial group treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. national institute of allergy and infectious diseases acquired immunodeficiency syndrome clinical trials group and mycoses study group safety and efficacy of liposomal amphotericin b compared with conventional amphotericin b for induction therapy of histoplasmosis in patients with aids prevalence and incidence studies of human and canine blastomycosis. . cases in the united states north american blastomycosis in central canada. a review of cases a common source epidemic of north american blastomycosis serious waterborne and wilderness infections epidemiology of human blastomycosis in canine blastomycosis as a harbinger of human disease north american blastomycosis: a study of patients. medicine (baltimore) isolation of blastomyces dermatitidis in soil associated with a large outbreak of blastomycosis in wisconsin epidemiologic aspects of blastomycosis, the enigmatic systemic mycosis clinical manifestations of pulmonary blastomycosis the radiological appearance of pulmonary blastomycosis clinical manifestations and management of blastomycosis in the compromised patient blastomycosis in patients with the acquired immunodeficiency syndrome the cytological diagnosis of pulmonary blastomycosis pulmonary blastomycosis: an appraisal of diagnostic techniques blastomycosis: organ involvement and etiologic diagnosis. a review of patients from mississippi the spectrum of primary blastomycotic meningitis: a review of central nervous system blastomycosis chronic blastomycotic meningitis an unusual outbreak of windborne coccidioidomycosis an epidemic of coccidioidomycosis among archeology students in northern california coccidioidal meningitis. an analysis of thirty-one cases and review of the literature. medicine (baltimore) unusual syndromes of coccidioidomycosis: diagnostic and therapeutic considerations; a report of cases and review of the english literature fungal pneumonias; pulmonary coccidioidal syndromes (part i). primary and progressive primary coccidioidal pneumonias --diagnostic, therapeutic, and prognostic considerations a long term study of patients with cavitary-abscess lesions of the lung of coccidioidal origin. an analytical study with special reference to treatment coccidioidomycosis in potentially compromised hosts: the effect of immunosuppressive therapy in dissemination coccidioidomycosis in renal replacement therapy early results of targeted prophylaxis for coccidioidomycosis in patients undergoing orthotopic liver transplantation within an endemic area coccidioidomycosis in the acquired immunodeficiency syndrome coccidioidomycosis during human immunodeficiency virus infection. a review of patients. medicine (baltimore) rapid diagnosis of pulmonary coccidioidomycosis. cytologic v potassium hydroxide preparations flexible fiberoptic bronchoscopy for diagnosing pulmonary coccidioidomycosis airway coccidioidomycosis--report of cases and review unrecognized coccidioidomycosis complicating pneumocystis carinii pneumonia in patients infected with the human immunodeficiency virus and treated with corticosteroids. a report of two cases detection of fungi and other pathogens in immunocompromised patients by bronchoalveolar lavage in an area endemic for coccidioidomycosis rapid diagnostic evaluation of bronchial washings in patients with suspected coccidioidomycosis immunological procedure for the rapid and specific identification of coccidioides immitis cultures pattern of , serologic tests in coccidioidomycosis practice guideline for the treatment of coccidioidomycosis chemotherapy of systemic mycoses (first of two parts) comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. a randomized, double-blind trial. mycoses study group a subcutaneous reservoir for intrathecal therapy of fungal meningitis is it ever safe to stop azole therapy for coccidioides immitis meningitis key: cord- -naromr a authors: mcleish, caitriona title: evolving biosecurity frameworks date: - - journal: the palgrave handbook of security, risk and intelligence doi: . / - - - - _ sha: doc_id: cord_uid: naromr a the relationship between infectious disease and security concerns has undergone an evolution since the end of the cold war. what was previously seen as two separate domains – public health and national security – have, through various events and disease outbreaks in the last years, become intertwined and as a result biosecurity policies now need to address a spectrum of disease threats that encompass natural outbreaks, accidental releases and the deliberate use of disease as weapons. in the last decade of the twentieth century, particular concern began to be expressed that globalisation was facilitating the spread of infectious disease. in for example the us institute of medicine issued a report which warned "some infectious diseases that now affect people in other parts of the world represent potential threats to the united states because of global interdependence, modern transportation, trade and changing social and cultural patterns" (lederberg et al, , pv) . framing infectious disease in this way was part of a growing appreciation that a series of new security challenges, such as terrorism, drug trafficking, and environmental degradation, were supplanting the more traditional state centric national security concerns of the cold war era. (brower and chalk, ) as remarked upon by james woolsey during his nomination hearing for director of the central intelligence agency in : "in many ways today's threats are harder to observe and understand . . . yes, we have slain a large dragon, but now find ourselves living in a jungle with a bewildering number of poisonous snakes" (woolsey, , p ) . the intelligence community had first taken up the issue of the threat posed by infectious disease in the s in relation to hiv/aids (cia, ) . however a declassified national intelligence estimate from january expanded the scope of diseases that might pose security concerns. the report noted, for example, that since at least thirty previously unknown diseases had been identified and at least twenty older infectious diseases had re-emerged or spread geographically over the same period frequently in drug resistant form. the authors of the report believed that "the spread of infectious diseases results as much from changes in human behaviourincluding lifestyles and land use patterns, increased trade and travel, and inappropriate use of antibiotic drugs-as from mutations in pathogens" and suggested that, new and re-emerging infectious diseases will pose a rising global health threat and will complicate us and global security over the next years. these diseases will endanger us citizens at home and abroad, threaten us armed forces deployed overseas, and exacerbate social and political instability in key countries and regions in which the united states has significant interests. (nic, ) what prompted the release of this national intelligence estimate was the announcement by the then us secretary of state madeline albright that the first un security council session of the new millennium would be devoted exclusively to the threat to africa from hiv/aids. whilst this session is often remarked upon for ultimately leading to resolution on the responsibility of the security council in the maintenance of international peace and security: hiv/aids and international peace-keeping operations, it was the discussions within the session that did much to characterise the evolving nature of the relationship between infectious disease and security concerns. un secretary general kofi annan, for example, noted that the impact of aids in africa was "no less destructive than that of warfare itself and by some measures it was far worse" and went on: nowhere else had aids become a threat to economic, social and political stability on the scale that it now was in southern and eastern africa . . . in already unstable societies . . . that cocktail of disasters was a sure recipe for more conflict. and conflict, in turn, provided fertile ground for further infections. the breakdown of health and education services, the obstruction of humanitarian assistance, the displacement of whole populations and a high infection rate among soldiers . . . all ensured that the epidemic spread ever further and faster. (unsc, ) as president of the security council during this session, us vice-president al gore noted that the links being articulated between hiv/aids and insecurity presented an opportunity to recast the work of the security council for the new century. with echoes of woolsey's comments at his nomination hearing for cia director seven years earlier, gore is reported to have said that for the past years the security council: had dealt with a classic security agenda built upon common efforts to resist aggression, and to stop armed conflict. but while the old threats still faced the global community, there were new forces that now or soon would challenge the international order, raising issues of peace and war . . . includ[ing] the challenges of: the environment; drugs and corruption; terror; and new pandemics. (ibid) three months later, in april , president clinton took the unprecedented step of designating an infectious disease (aids) a threat to us national security (gellman, , pa ) taken together, these actions signalled a "securitization" (buzan et al, ) of infectious disease that resulted in greater political interest and access to larger economic resources so as to tackle to issue on a global scale. in line with the "securitization" thesis, political interest in hiv/ aids has remained high and superior financial resources have indeed been accessed. this included us president george w. bush promising $ billion over five years to international hiv/aids programmes in his state of the union speech. however, selgelid and enemark ( ) note that hiv/ aids is a disease of attrition, meaning that "the effects of these diseases are relatively familiar and slow-acting, they do not concentrate the minds of people and politicians as readily as an unfamiliar and sudden outbreak crisis." consequently it was growing anxiety over a perceived new type of terrorist that may deliberately use infectious disease to further their aims which gave further salience to the relationship between infectious disease and security concerns. the attacks on the world trade center and the pentagon on / fundamentally altered perceived societal vulnerability towards terrorist use of infectious disease. though the events themselves were quite unrelated to biological weapons (i.e. the hostile use of disease), the idea that non state actors, including terrorists, might seek to employ biological weapons to further their aims was lifted from (arguably) a niche concern to a mainstream security issue. calling it niche is not to say that bioterrorism had not been considered a security threat prior to many commentators had noted the potential (see for example stern, ; tucker, tucker, , moodie and roberts, ; smithson and levy, ) ; table top exercises had been conducted, domestic preparedness programmes initiated (guillemin, , p ) , and in countries such as the us, policy directives had been crafted that gave the highest priority to "developing effective capabilities to detect, prevent, defeat and manage the consequences of nuclear, biological or chemical materials or weapons use by terrorists" (united states, ) . however what the / attacks did was alter the global frame of reference about what terrorists writ large might now be prepared to undertake. the attacks appeared to suggest that what had been considered previously as restraining factors on terrorist actions, such as limiting casualties so as not to "risk of alienating the public especially their own supporters" were no longer valid (butler, , p ) . instead this new breed of terrorist and extremist appeared to want to cause casualties on a massive scale, and appeared undeterred by the fear of alienating the public, their own supporters, or indeed by considerations of personal survival. after the sheer destructiveness of / tucker ( ) notes that it was a logical next step for government officials to voice "fears that terrorists might unleash a devastating epidemic" as part of a second wave of attacks and in early october this hypothetical bioterrorism threat became a reality with the first death from inhalational anthrax in the us since . twenty-one others went on to be diagnosed with either inhalational or cutaneous forms of anthrax and five more people died. the source of the exposure was five letters containing anthrax spores anonymously posted to media outlets and members of the senate. coming so soon after the / attacks, these letters created a near hysterical atmosphere. tucker writes: cable news networks hyped the bioterrorism threat with apocalyptic scenarios; postal workers sorted mail wearing rubber gloves and surgical masks; thousands of senate staff members were put on prophylactic antibiotics; and letters addressed to government officials were irradiated with electron beams to kill lingering spores, delaying mail for weeks. meanwhile, tens of thousands of ordinary americans stockpiled ciprofloxacin (a potent antibiotic with potentially dangerous side effects), snapped up gas masks of questionable effectiveness from army supply stores and hoarded canned food and bottled water in anticipation of spreading epidemics and quarantines. (tucker, , p ) although the letters were only posted in the us, the anthrax letter attacks had global impact particularly because of the cognitive link that was made between biological weapons and the perpetrators of the / attacks. in europe for example, civil protection and security forces were put on alert, and public health systems had to deal with numerous items of mail containing powders suspected of being contaminated with anthrax. and at the political level, european countries acted at both the community level and national level. in october for example, the heads of state and government asked for a european level programme to be prepared to improve the cooperation between member states for the evaluation of risks, alerts, and intervention, and the collaboration in the field of research. at the national level many european countries re-examined their preparedness plans and strengthened or implemented new measures designed to prevent the misuse of the biological sciences. this included placing restrictions on physical access to, and work performed with, certain pathogens labelled as "dangerous." european states were not alone in re-examining their preparedness programmes: in the us for example, at least three new pieces of legislation were enacted in quick succession aimed at preventing the misuse of disease and they significantly increased their investment in bio-defences, including medical countermeasures. at the international level, the threat from the deliberate spreading of disease slotted neatly into the global "war on terror" that president bush had launched in the days following / . addressing the united nations general assembly in november bush described terrorists as searching for weapons of mass destruction, the tools to turn their hatred into holocaust. they can be expected to use chemical, biological and nuclear weapons the moment they are capable of doing so. no hint of conscience would prevent it. this threat cannot be ignored. this threat cannot be appeased. civilization, itself, the civilization we share, is threatened. (bush, ) consequently the global community also acted together to combat the threat from bioterrorism. this included a range of activities including "operational" initiatives such as the proliferation security initiative, the g global partnership against the spread of weapons and materials of mass destruction and the global health security initiative as well as broadening the mandate of international organisations such as the world health organisation such that they now had a role in responding to the "natural occurrence, accidental release or deliberate use of biological and chemical agents or radionuclear material that affect health." (wha, ) at the diplomatic level, the work of the biological weapons convention (bwc) now became focused on a broadened understanding of the threat posed by biological weapons, including the possibility of terrorist use of biological agents. the focus prior to had been state level adherence to the norms of the bwc. however if properly implemented at the national level, the convention addresses potential terrorist use by transferring the obligations that states agree tonot to develop, produce, manufacture or stockpile biological and toxin weapons or methods of delivery of such weaponsonto individuals in their territory or under their jurisdiction anywhere. when tabling a number of proposals for future work in late the us delegation noted that "many of these ideas will bear little resemblance to the traditional arms control measures of the past" including the negotiation of a legally binding verification protocol which had recently failed (us department of state, ). these alternative proposals eventually initiated an "intersessional process" where states parties to the bwc meet twice yearly to discuss, promote common understanding and achieve effective action on a number of topics related to this broadened understanding of biological threats. viewed within the bioterrorism/war on terror framing, the political significance of mitigating naturally occurring disease outbreaks was elevated by linking global health engagement with set of efforts to counter violent extremism and bring stability to conflict-prone areas (chreiten, ) . consequently, much of the engagement that took place was therefore focused on africa as home to a number of fragile states with porous borders and groups linked to al qaeda. concurrent with this terrorism-focused framing of the threats posed by infectious disease, another more human security focused framing of disease was forwarded in documents such as the united nations high level panel on threats challenges and change where the challenges of disease were presented as follows: the security of the most affluent state can be held hostage to the ability of the poorest state to contain an emerging disease. because international flight times are shorter than the incubation periods for many infectious diseases, any one of million international airline passengers every year can be an unwitting global disease-carrier. (anan, p ) part of the stimulus for framing of the threats from infectious disease as "without borders" came from the experiences of the severe acute respiratory syndrome (sars) outbreak. the sudden appearance of sars had, by the time the world health organisation (who) declared the outbreak contained in july , spread to countries on all continents, infected more than people and presented an % lethality rate. (who, ) unlike the apocalyptic "dread risk" scenarios for bioterrorism attacks in the same period, sars was a "dread reality": evidence showed sars to be a fast spreading disease that did not require a vector; symptoms appeared to begin an average of four days after exposure to an infected person and mimicked many common diseaseshigh fever, a dry cough and shortness of breath (who, ) and the disease showed no particular geographical affinity. indeed on this last point an association was made early on between sars and travel on commercial airlines (see for example olsen et al, ) which resulted in guidelines being issued regarding travel to and from areas affected by sars that focused on hand hygiene and specified that anyone suspected of having sars should wear a facemask. however, public perception of the risk of becoming infected with sars led to widespread use of facemasks whether on a flight or not (see for example hesketh, . fear of infection was therefore a potent ingredient in the sars epidemic: in toronto, canada, there were reports of "public bus drivers using face masks on routes near chinese communities and empty seats surrounding chinese university students" (schram, , p ) and at the height of the epidemic, despite only eight people in the us having laboratory evidence of sars, eichelberger ( ) notes that % of americans reported avoiding asian businesses. indeed across the us "restaurants, travel agencies and other businesses from new york to san francisco [reported] customer traffic is down by % or more" (hopkins, ) . as with the anthrax letters then, the effects of the sars epidemic were not confined to ill health, or to those countries directly affected. indeed, it was the economic repercussions of the outbreak that came to define the disease. one assessment for example, estimated the total cost of the epidemic to the asian regional economy at us$ billion in gross domestic product for , "that is, over us$ million per person infected by sars," with gross expenditure and business losses being estimated as high as us$ billion (rossi and walker, p - ) the authors also note that this was a shared economic burden whether the country reported infections or not because of the association between airline travel and infection. this is because as elbe ( ) notes the travel and tourism sectors in the region were heavily affected with "room and airline seat bookings to [the region] down in several cases by more than per cent compared to previous years." any lingering doubts about whether the trans-border spread of infectious diseases created security issues were removed by the sars outbreak. sars also drew attention to potential security implications of a wider set of emerging and re-emerging infectious diseases that could no longer be ignored. indeed quickly on the heels of sars epidemic, concern began to be expressed over the pandemic potential of h n avian influenza. sensitised to the potential of an influenza a type pandemic by the outbreak of h n , or "bird flu," fear was now being expressed that h n could mutate or combine with a human influenza virus to form a new virus, capable of sustained human-tohuman transmission (see for example lee and fidler, and who, ). writing in the new york times members of the senate committee on foreign relations, barak obama and richard lugar, framed the relationship between national security and an influenza pandemic as follows: when we think of major threats to our national security the first to come to mind are nuclear proliferation, rogue states and global terrorism. but another kind of threat lurks beyond our shores, one from nature not humansan avian flu pandemic. an outbreak could cause millions of deaths, destablize southeast asia . . . and threaten the security of governments around the world (obama and lugar, ) what h n did, elbe ( ) notes, was render the mere possibility of a future outbreak a sufficient condition for considering an infectious disease as a threat to security and so requiring investment and proactive pandemic preparedness. indeed in january , the international community pledged us$ . billion to fight avian influenza and prepare for a possible human pandemic (beijing declaration, ) . the un high level panel report quoted above also alludes to another vulnerability that was exposed during the sars outbreak, namely the deficiencies in the contemporary reporting system for infectious disease outbreaks. at the time, the who was prevented from responding to an outbreak until it had received official reports from governments (heymann, ) . in the case of sars, there was a three-month delay from onset until the who received official reports from the chinese ministry of health by which time there were over cases and the disease had spread to five countries. part of the inadequacy of that reporting system was the mismatch between the framework under which the who had to work, the international health regulations, and the tools that the who had at its disposal in . for example the who were unable to act despite having "epidemic intelligence networks" such as the global outbreak alert and response network (goarn) in place at the time of the sars outbreak that had picked up on an outbreak prior to the official notification. this intelligence had been gathered by goarn's early warning element which collects and verifies reports and rumours of epidemics from a wide variety of unofficial sources, including nongovernmental organisations, news media, electronic discussion groups such as the program for monitoring emerging diseases, and other official surveillance networks. when the who was eventually able to act, the response side of goarn was activated and within a period of weeks after the first recognised case, a virtual network of eleven leading infectious disease laboratories in nine countries had been established. connected by a secure website and daily teleconferences, the laboratories collaborated to identify the causative agent of sars and to develop a diagnostic test; similar groups were also created to pool clinical knowledge and compare epidemiological data on sars (knobler et al, ) . the who used this information to make recommendations on patient management which included issuing travel recommendations in an attempt to curb, and eventually stop, the international spread of this newly recognised virus (heymann, ) . perhaps the most important legacy of the sars epidemic, and to a lesser extent the h n outbreak, was the sense of urgency it gave to finalising the updates to the international health regulations (ihrs). begun in the mid- s, the revision process had two primary goals: to make use of modern communication technologies to understand where diseases were occurring and had the potential to spread, and to change the international norm for reporting infectious disease outbreaks so that countries were not only expected to report outbreaks, but also respected for doing so (heymann, ) the updates were completed in and went into effect in . amongst the many updates, the establishment of a global surveillance system for public health emergencies was critical. surveillance is defined in the revised ihrs as "the systematic on-going collection, collation and analysis of data for public health purposes and the timely dissemination of public health information for assessment and public health response as necessary" (who, ). the surveillance system operates from the local to the global level. at the national level each state party is now required to notify who of "all events which may constitute a public health emergency of international concern" including any unexpected or unusual public health event regardless of its origin or source and also requires state parties, as far as is practicable, to inform the who of public health risks identified outside their territories that may cause international disease spread. to assist in compliance with this obligation, the ihrs defines a public health emergency of international concern (pheic) as an extraordinary event which is determined [by the who director-general] . . . (i) to constitute a public health risk to other states through the international spread of disease and (ii) to potentially require a coordinated international response. (ibid) and defines disease as an illness or medical condition irrespective of origin or source, that presents or could present significant harm to humans that does or could threaten human health. (ibid) a decision-tree to assist state parties in defining whether a health related event is a pheic is included, so too a list of diseases for which a single case may constitute a pheic and so must be reported to the who immediately. this list consists of smallpox, poliomyelitis, human influenza caused by new subtypes, and sars. arguably, as a direct result of perceived reluctance on the part of the chinese authorities to be transparent in the early stages of the sars outbreak, the revised ihrs state that the who can collect, analyse and use information "other than notifications or consultations" including from intergovernmental organisations, nongovernmental organisations and actors, and the internet. furthermore the who can now act upon the information gathered by requesting "verification from the state party in whose territory the event is allegedly occurring." when so requested, the state party has hours to give an initial reply to the who, or acknowledge the request from them, and if possible provide the who with available information on the status of the event referred to in the request. this is done through the newly required national focal point for the ihrs, a role established to ease communication between the who and the state party. in permitting the who to act upon that information and requiring states to perform some form of action within hours of that request, the principle of national sovereignty became subordinate to the collective interests of global disease surveillance. this had stalled the revision process, but as katz and fischer ( ) note the "sudden fear of the consequences of a single nation's failure to report an emerging infectionwhether due to lack of will or capacityovercame many of the concerns about sovereignty." although nowhere in the revised ihrs is the word "intentional" or "deliberate" used the scope of the definition of disease within the revised ihrs and the newly expanded role of the who with regard to deliberate disease outbreaks mean that the ihrs do encompass communicable and non-communicable disease events, whether naturally occurring, accidentally caused, or intentionally created. in part, this is because whether deliberate, accidental or naturally occurring, the initial response to the outbreak would be the same, meaning that early warning systems, indeed in general strong public health systems, serve multiple purposes. at the time of writing the ihrs have been in force for nine years and there have been four declared public health emergencies of international concern, including the ebola virus outbreak in west africa, declared a pheic on august . between march , when the outbreak was first reported, and march when the the who director-general declared the pheic at an end the total number of reported cases in the three worst affected countries (guinea, liberia and sierra leone) was , . a small number of cases were also reported in nigeria and mali and a single case reported in senegal; however, these cases were contained, with no further spread in these countries. in addition there were a small number of exported cases in spain ( case); the united states ( cases); the united kingdom ( case) and italy ( case). a review of who's response to this ebola outbreak characterised it as "the most complex outbreak on record . . . [which] devastated families and communities, compromised essential civic and health services, weakened economies . . . isolated affected populations . . . [and] put enormous strain on national and international response capacities, including who's outbreak and emergency response structures" (who, ) . indeed, the strain was such that the international response to the outbreak included the establishment of the first ever united nations emergency health mission, the united nations mission for emergency ebola response or unmeer, after the unanimous adoption of general assembly resolutions / and / , and the adoption of security council resolution ( ) on the ebola outbreak. whilst the idea that health issues and security are linked was by now firmly embedded within the international political consciousness and that response to outbreaks were considered both a national and international responsibility, the ebola outbreak served to highlight a significant mismatch between those ideas and practical realities. the review of the who's response noted above was extremely critical of the response effort on a number of levels. regarding the actions of the who itself, the panel's assessment regarded there to have been "significant and unjustifiable delays" in declaring the ebola outbreak a public health emergency of international concern, despite early warnings about the outbreak from its own staff and from non governmental organisations such as médecins sans frontières, and that the "who does not currently possess the capacity or organizational culture to deliver a full emergency public health response" (who, , p ) . part of the reason for this is that there are no core funds for emergency response and the panel recommended the immediate creation of a contingency fund in support of outbreak response as well as the establishment of a who centre for emergency preparedness and response which would develop the necessary new structures and procedures to achieve full preparedness and response capacity. considering the outbreak in terms of the revised ihrs, the panel also noted that nearly a quarter of who's member states "in violation of the regulations," instituted travel bans and other additional measures not called for by who, "which significantly interfered with international travel, causing negative political, economic and social consequences for the affected countries" (ibid, p ). the panel went on to say that they consider the situation "in which the global community does not take seriously its obligations under the international health regulations ( )a legally binding documentto be untenable" (ibid). implementation statistics for the revised ihrs do indeed demonstrate that many states have had difficulties in implementing what is required of them in this new system. all states were to have the new national core surveillance capabilities in place by june ; however, by that deadline less than % of the who member statesthat is statesreported they had achieved the core capacities; countries requested and obtained an additional two year extension and countries neither submitted an extension request nor indicated that they are in compliance (katz and fischer, , p ) . at the end of the second two-year extension period the who executive board noted that only an additional states ( nations in total) reported that they had fully implemented the revised ihrs (world health organisation, ) . in part to redress these implementation difficulties, the us in partnership with about other countries, ios, ngos and public/private enterprises launched the global health security agenda (ghsa) in february . the ghsa has discrete action packages under the three cluster heading of "prevent, detect and respond" covering issue areas such as antimicrobial resistance, zoonotic diseases, real time surveillance and reporting. eight of these packages relate in whole to the revised ihrs and a package is also specifically dedicated to improving biosafety and biosecurity systems and preventing bioterrorism. the spectrum of issues being addressed by the global health security agenda reflects the evolution of biosecurity issues since the end of the cold war. what had previously been considered as two separate domainspublic health and national securityhave now become merged to create a spectrum of biosecurity issues that encompasses naturally occurring incidents, accidental outbreaks and deliberate use of infectious disease. this intertwining is reflected in both domains: in the public health domain, the who for example had its mandate extended to include responding to deliberate use of biological agents and in the traditional arms control arena, states parties to the biological weapons convention are creating synergistic relations with public health organisations to further their aims of mitigating the effects of a deliberate use should it occur. in addition, the global health security agenda also reflects a change in views regarding responsibility for responding to this spectrum of biosecurity issues: whereas in the security council viewed hiv/aids as posing a threat to a geographically defined area, the sars outbreak in and the potential of an influenza pandemic shortly thereafter illustrated the truly global interconnected nature of the threat and so the shared international responsibility of responding to them. to use an argument put forward by andrew lakoff and stephan collier ( ) , the issue for the future is not whether a disease outbreak can be characterised as a biosecurity threat which requires attention but what kind of biosecurity problem does it present, what kind of techniques are used to assess them and what is the most appropriate kinds of responses. notes . on this see for example central intelligence agency, unclassified report to congress on the acquisition of technology relating to weapons of mass destruction, st july- st december . available at https://www.cia.gov/ library/reports/archived-reports- /july_dec .htm#chemical. . for example: in the uk, the anti-terrorism crime and security act, created a list of "dangerous" pathogens which required additional security requirements and access restrictions. in addition, the secretary of state now had to be informed of any premises where any dangerous substances was kept and used. . in addition to political action, the scientific community also responded to the perceived heightened vulnerability, especially addressing what actions they might take to support national efforts to prepare against deliberate attacks using disease and what actions they needed to take to prevent their work from being deliberately misused and contributing to the development of biological weapons. for more on this see mcleish c ( ) "science and censorship in an age of bioweapons threat" science and culture : , - ; mcleish c and p nightingale ( ) "biosecurity, bioterrorism and the governance of science: the increasing convergence of science and security policy", research policy ( ) - . . for more information on these initiatives see http://www.psi-online.info; http:// www.nti.org/treaties-and-regimes/global-partnership-against-spread-weaponsand-materials-mass-destruction- -plus- -over- -program/ and http://www. ghsi.ca/english/index.asp. . at the time of writing three such intersessional processes have been completed which have focused on topics as diverse as strengthening national implementation of the convention; assistance and cooperation in the events of a biological weapons attack; reviewing relevant developments in science and technology; and awareness efforts amongst scientists. for more information on the biological weapons convention and the intersessional process see www part of the reason for the unprecedented scale of the outbreak was its spread to urban centres including the capital cities of the three worst affected countries foreword' a more secure world: our shared responsibility united nations high level panel on threats challenges and change interrogating bio-insecurities' the global threat of new and re-emerging infectious diseases: reconciling us national security and public health policy review of intelligence on weapons of mass destruction security a new framework for analysis us military global health engagement since / : seeking stability through health the global aids disaster unclassified report to congress on the acquisition of technology relating to weapons of mass destruction sars and new york's chinatown: the politics of risk and blame during an epidemic of fear pandemic security federal agency biodefense funding aids is declared threat to security: white house fears epidemic could destabilize world china in the grip of sars the international response to the outbreak of sars in communicating disease risk: then and now sars scare hurts business in chinatowns international pledging conference on avian and human pandemic influenza the revised international health regulations: a framework for global pandemic response moving forward to the public health response to sars, institute of medicine, forum on microbial threats biosecurity interventions: global health and security in question emerging infections: microbial threats to health in the united states, committee on emerging microbial threats to health, division, institute of medicine avian and pandemic influenza: progress and problems with global health governance science and censorship in an age of bio-weapons threat biosecurity, bioterrorism and the governance of science: the increasing convergence of science and security policy terrorism with chemical and biological weapons: calibrating risks and responses, alexandria, va: chemical and biological arms control institute. national intelligence council ( ) the global infectious disease threat and its implications for the united states grounding a pandemic transmission of the severe acute respiratory syndrome on aircraft assessing the economic impact and costs of flu pandemics originating in asia how popular perceptions of risk from sars are fermenting discrimination hiv/aids, security and ethics ataxia: the chemical and biological terrorism threat and the will terrorists turn to poison? chemical/biological terrorism: coping with a new threat toxic terror: assessing terrorist use of chemical and biological weapons scourge: the once and future threat of smallpox united nations general assembly resolution / ( ) measures to contain and combat the recent ebola outbreak in west africa united nations mission for ebola emergency response un security council holds debate on impact of aids on peace and security in africa on the responsibility of the security council in the maintenance of international peace and security: hiv/aids and international peace-keeping operations united nations security council resolution ( ) peace and security in africa united states department of state ( ) new ways to strengthen the inter-national regime against biological weapons global public health response to natural occurrence, accidental release or deliberate use of biological and chemical agents or radio nuclear material that affect health summary of probable sars cases with onset of illness from pandemic influenza preparedness and response: a who guidance document report of the ebola interim assessment panel world health organization executive board ( ) implementation of the international health regulations originally trained as an historian and philosopher of science, her work focuses on issues relating to governance of dual use technologies and the design of effective mechanisms to prevent misuse of legitimate science and technology key: cord- -p py wau authors: winter, harland; chang, tien-lan title: gastrointestinal and nutritional problems in children with immunodeficiency and aids date: - - journal: pediatr clin north am doi: . /s - ( ) - sha: doc_id: cord_uid: p py wau nan harland winter, md, and tien-lan chang, md children acquire human immunodeficiency virus (hiv) either perinatally from an infected mother (vertical transmission) or from infected blood or blood products. the number of children infected following a blood transfusion has dropped markedly following the institution of rigorous screening protocols for blood donors in the mid- s. by the early s, more than % of newly diagnosed hiv-infected children acquired the disease via vertical infection.= the world health organization estimates that more than million people throughout the world are infected with hiv (table ) . three million of these individuals are women, most of whom are fewer than years of age, whereas , of them are children. thus, heterosexual transmission of hiv is the most common means of acquiring the infection when viewed from a worldwide perspective. hiv, a single-stranded rna lentivirus, infects cells that express a receptor capable of binding to the envelope glycoprotein (gp), gp . t lymphocytes and monocytes or macrophages that are cd -positive are the primary targets of the virus, but reports suggesting that other cells in the gastrointestinal tract can be infected have led investigators to data from world health organization: the hiv-aids pandemic: overview. geneva: who/ gpngnp . , . speculate that gastrointestinal symptoms may be related to epithelial cell infection with hiv- . fox and colleagues reported that hiv- infection of the gastrointestinal tract was limited to the lymphoid elements of the lamina propria; other investigators believe that, because intestinal epithelial cell line cultures became infected in the laboratory, y epithelial cells were infected in vivo in hiv-infected adults.'o, the characteristics of the mucosal immune system most likely have a significant role in the pathobiology of hiv- disease in children; however, mucosal immune function has not been studied specifically in hiv-infected children and, thus, pediatricians are left to speculate that observations made in the adult hiv-infected population are relevant to children. table summarizes gastrointestinal mucosal immunologic changes that occur in hivinfected individuals. vertical transmission occurs in approximately % of hiv-infected pregnant women who do not take antiretroviral therapy during pregnancy. the observations that transmission is increased in women who were symptomatic or who had more advanced aids and that zidovudine therapy given during pregnancy reduces perinatal transmission suggest that viral burden is an important factor in vertical transmission; however, the effects of maternal nutritional status, micronutrient deficiency, or acute infection on viral replication are difficult to evaluate. in addition, most hiv-infected women in africa, asia, and south america breast-feed their infants. this additional means by which infants can possibly become infected complicates assessment of factors contributing to transmission. in africa, the percentage of postnatal transmission is approximately y .~~ nevertheless, the morbidity and mortality caused by formula feeding in countries where potable water is a premium and safe infant formula is not readily available seem to be greater than the risk of acquiring hiv- from breast milk. the current recommendation is for the hiv-exposed infant to have formula feeding if and only if safe the deterioration of the immune system and mucosal immune systems results in cellular and humoral immunoregulatory deficiencies. in the gastrointestinal tract, hiv-infected lymphocytes could migrate from the lymphoid aggregates through the mesenteric nodes, the thoracic duct, and into the circulation. following selection by receptors on high endothelial venules, these infected cells then migrate home to the lamina propria, whereby in situ hybridization isolated hiv-infected cells can be identified (fig. ). most evidence 'supports the hypothesis that deterioration of mucosal immune function results in bacterial overgrowth; increased production of bacterial products, such as endotoxin; activation of mucosal lymphocytes with increased cytokine production; and probable interaction between immunoregulatory elements and epithelial cell function (fig. ) . although the reasons for early development of lactose intolerance and malabsorption are not known, substances involved in immune regulation also may interact with intestinal epithe-lial cells, resulting in dysfunction. hiv also may have a role in the genesis of intestinal dysfunction, but data are not available. clearly, enteric infections begin to occur at the time when immune function is deteriorating (fig. ) . the contribution of chronic intestinal infection to immune dysfunction, malabsorption, and malnutrition suggests that all of these factors are interrelated (fig. ) . one of the more important determinants of survival for the hivinfected child is the health status of the mother. in studies from africa, if an hiv-infected mother is symptomatic or dies, her hiv-infected infant is at increased risk for chronic diarrhea partially because of the resulting reliance on formula. chronic diarrhea in the hiv-infected child is an important prognostic variable for predicting malnutrition and death. because of the availability of safe formula in north america and europe, the relationship between maternal health and infant survival is not as obvious. nevertheless, a chronically ill mother has an obvious negative impact on infant growth and development, particularly if no additional support is available, such as respite and day care programs designed to enrich infants' psychosocial development and nutritional status. in hiv-infected children, nausea and vomiting can be caused by infectious diseases, such as helicobacter pylori or cytomegalovirus, medications, or central nervous system disorders. in a child with nausea, anorexia may be the presenting manifestation because she or he is not able to verbalize the sensation. in these individuals, refusal to chew or eat may be caused by gingival disease or painful lesions of candida in the mouth. in many children, an identifiable agent or pathogen may not be found despite a thorough search. some of the therapeutic agents that have been implicated as causes of nausea and vomiting are as follows: altered mental status or developmental delay should alert the clinician to the possibility of central nervous system disease, such as encephalopathy caused by hiv, or pathogens, such as toxoplasmosis. lymphoproliferative disorders in the central nervous system are rare in the pediatric population; however, lymphoma of the gastrointestinal tract can cause splenomegaly resulting in compression of the stomach and early satiety. evaluation of hiv-infected children with anorexia, nausea, or vomiting should begin with a careful history, social history, physical examination, and neurologic evaluation. an upper gastrointestinal radiograph is not reliable enough to establish or rule out mucosal disease. for this reason, endoscopic evaluation is frequently necessary in children with persistent symptoms and normal hepatobiliary and pancreatic tests. mucosal biopsies may identify an enteric pathogen or inflammation that can be treated with a specific agent. if no cause can be found, symptoms can be managed with phenothiazine derivatives, such as triethylperazine maleate (torecan), prochlorperazine (compazine), or promethazine (phenergan). other agents for which anecdotal treatment experience exists in children include: benzquinamide (emete-con); trimethobenzamide hydrochloride (tigan); hydroxyzine (vistaril or atarax); metoclopramide (reglan); cisapride (propulsid); and scopolamine (transdermscop); dronabinal (marinol). if treatment fails to relieve the symptoms, re-evaluation should be considered. difficulty in swallowing (dysphagia) or pain with swallowing (odynophagia) in children can be caused by oral lesions that can be identified by careful inspection of the mouth. stomatitis caused by ', '-dideoxycytidine '-triphosphate (ddc), herpes simplex or candida is treatable if the diagnosis is established. when oral lesions are present, coexistent esophagitis should be suspected. in contrast, if the mouth is free of lesions, esophagitis cannot be ruled out. candida and cytomegalovirus are the most common infectious agents causing esophagitis. dysphagia and odynophagia in hiv-infected children are more commonly associated with candida than with cytomegalovirus. children who are taking h, antagonists seem to be at increased risk for developing candida esophagitis. medications, such as zidovudine, have been reported to cause esophageal ulceration if, when swallowed, they do not reach the stomach. treatment for specific causes of oral or esophageal lesions is summarized in table . although enteric pathogens are frequently identified as the cause the incidence of of diarrhea and weight loss in hiv-infected enteric infection in hiv-infected children seems to be lower, o and the relationship between diarrhea, enteric pathogens, and growth retardation is not as clearly understood. in figure , the interrelationship between malabsorption, malnutrition, immune deficiency, and enteric infection is depicted. enteric infection results in intestinal injury and malabsorption, which, if not compensated by additional nutrient support, results in nutritional deficiency. the development of malnutrition causes immune deficiency, which is characterized by a defect in t-cell function that is similar to the defect caused by hiv disease. defective t-cell function results in increased susceptibility to enteric infection, and the circle is completed. hiv can interact at any of the stages of this cycle. in theory, intestinal absorption can be altered by modifying enterocyte function through immune modulators. by increasing apoptosis, hiv could cause premature senescence of enterocytes and decrease brushborder expression of disaccharidases and peptidases. some of these same agents, such as the cytokine, tumor necrosis factor-a), are upregulated by hiv infection, affect intermediate metabolism, and cause malnutrition by increasing nutrient requirements. the effects of hiv on the immune system are well known and result in immunocompromise and increased susceptibility to opportunistic infection. similar immunoregulatory abnormalities probably occur in the mucosal immune system, resulting in enteric infection. thus, hiv interacts at many levels to potentiate the development of malabsorption, malnutrition, immune deficiency, and enteric infection. giardia zarnbzia causes watery diarrhea, abdominal distention, and crampy abdominal pain. , , metronidazole or furazolidone is effective therapy and eradicates the organism in more than % of infected individuals. giardia zambzia does not occur more frequently in hivinfected children than in the general population, but retreatment may be necessary in the immunocompromised host. crypfosporidium parvum causes an acute, self-limited diarrheal illness in the immunocompetent host, but in the immunodeficient child with hiv disease, the infection causes a secretory diarrhea that is chronic and debilitating. the organism usually can be identified in the stool by immunofluorescent techniques or by kinyoun carbolfuchsin stain. in hiv-infected children in the united states, the incidence of cryptosporidiosis is lower than that reported in africa and south america. , , crypfosporidium can infect the small intestine, colon, gallbladder, biliary tract, and pancreatic duct. no therapy is consistently effective in eradicating the organism, but octreotide is reported to decrease stool reports of the beneficial effects of hyperimmune bovine colostrum suggest that this form of passive immunotherapy may be effective in hiv-infected individual^.^^ other enteric parasitic infections, including isospora bezzi and microsporidium, are rarely identified in hiv-infected children; however, blastocysfis hominis, a protozoan whose role as an enteric pathogen is still debated, may be more prevalent in hiv-infected children with diarrhea than in hiv-negative ~h i l d r e n .~ bacteria are an important cause of diarrhea throughout the world and for this reason contribute to the list of identifiable pathogens found in hiv-infected children. in africa, pathogenic strains of escherickia coli were identified in over three fourths of hiv-infected children. the risk for other bacterial enteric infections is not known for hiv-infected children, but the incidence of salmonella, skigella, campylobacter, yersinia, and clostridium difficile do not seem to be increased in hiv-infected children. the incidence of helicobacter pylori may be decreased in hivinfected chi dren.l the most serious enteric bacterial infection is mycobacterium avium-intrace lulare, which causes a multisystemic infection involving the lungs, liver, mesenteric lymph nodes, gastrointestinal tract, and bone marrow in the most severely immunocompromised hosts with cd counts less than cells/mm . acidfast bacilli can be identified in the jejunal mucosa or grown from stool or blood. the most common gastrointestinal symptoms of m avium-intracellulare are abdominal pain and diarrhea, and neither responds dramatically to therapeutic intervention. combinations of medications chosen from clarithromycin, ethambutol, ciprofloxacin, amikacin, rifampin, clofazamine, and azithromycin have been tried. rotavirus is the viral agent that most frequently causes chronic diarrhea. in the immunocompromised child, rotaviral diarrhea can be severe, persistent, and difficult to distinguish from other agents causing secretory diarrhea. diagnosis is established by identification of rotavirus in the stool using an enzyme-linked immunoassay. enterally administered serum immunoglobulin is effective therapy,i but little published data exist on the treatment for rotavirus in hiv-infected children. other viral pathogens, such as adenoviruses, can cause diarrhea but also are associated with systemic infection and fulminant hepatitis. cytomegalovirus usually causes an asymptomatic enteric infection, but some individuals develop focal ulcerations in the colon or jejunum and present with bloody diarrhea and abdominal pain. gastrointestinal bleeding is unusual in hiv-infected children, but, when present, it may be caused by focal ulcerations in the colon, stomach, small intestine, or esophagus from cytomegalovirus-induced disease. merely culturing cytomegalovirus from the intestinal mucosa does not establish a link between diarrhea and the infection. histologic evidence of mucosal injury is necessary. ganciclovir and foscarnet are used to treat cytomegalovirus-induced intestinal disease in children with active symptoms. bone marrow suppression is the main serious side effect. many children with hiv disease develop lactose intolerance earlier than predicted by genetic predisp~sition.'~ nevertheless, these lactoseintolerant children do not seem to have an increased probability for growth retardation or diarrheal disease. the impact of lactose malabsorption on the nutritional health of hiv-infected children is unclear; however, children who have decreased absorption of the carbohydrate d-xylose have an increased incidence of harboring an enteric pathogen. to evaluate hiv-infected children with chronic, nonbloody diarrhea, stool analysis for bacterial, viral, and parasitic infection should be performed. blood and polymorphonuclear leukocytes in the stool are indicative of colitis and should prompt evaluation of the colonic mucosa. if no enteric pathogen is identified, functional tests, such as lactose breath hydrogen and d-xylose absorption, may be useful in guiding nutritional therapy. the most beneficial diagnostic test is an upper endoscopy with biopsy. in addition to routine histology, mucosal biopsies of any focal lesions should be tested for bacterial, fungal, and viral culture and analyzed via electron microscopy. because mycobacterium and cytomegalovirus may not be detectable during endoscopic evaluation, surveillance biopsies of the jejunum should be evaluated by electron microscopy and culture. despite these diagnostic studies, enteric pathogens frequently are not identified in many hiv-infected children with diarrhea. hiv-infected children with abdominal pain should be evaluated for enteric infection, especially if they have diarrhea. fever and abdominal pain are symptoms that can indicate the presence of mycobacterium. association of these symptoms with the ingestion of milk should alert the clinician to the possibility of lactose intolerance, but for many children with lactase deficiency, the relationship is not evident. in addition, pancreatitis in the hiv-infected child is a serious and debilitating illness. not only do these children experience crampy abdominal pain, but the association with meals results in decreased caloric intake and increases the potential for malnutrition. lipase seems to be an early and sensitive marker for pancreatitis in the pediatric population. medications such as ddi and ddc are associated with pancreatitis, which may develop following many manths of therapy. other medications including pentamidine, trimethoprim-sulfamethoxazole, and dapsone have been implicated as causes of pancreatitis in children. the development of pancreatitis is an ominous event, and in one published study, the mean survival of children with pancreatitis was months following the diagnosis.ls because of the guarded outcome, decisions to perform additional diagnostic tests should be made after much discussion with the health care team. if a dilated pancreatic duct is identified by ultrasonography, the indication for endoscopic retrograde cholangiopancreatography should be based on quality-of-life issues. although strictures of the pancreatic duct could contribute to the symptoms, if therapeutic intervention is not feasible, invasive diagnostic studies should not be performed. although the majority of hiv-infected children have hepatomegaly, few experience severe hepatocellular dysfunction; fibrosis; or cirrhosis that results in coagulopathy, ascites, varices, or hepatic failure. many of the medications used to treat complications of hiv disease cause hepatocellular injury or cholestasis; however, infectious agents, such as hepatitis b, that cause hepatocellular injury by immune mechanisms have milder clinical courses in immunodeficient hosts.z preservation of immune function in hiv-infected children could account for the apparent increase in chronic active hepatitis in the pediatric population compared with the incidence in although abnormalities in liver function tests are not diagnostic, they are beneficial as screening procedures. elevated transaminases are caused by infectious agents, medications, or nutritional deficiency and malnutrition. when the transaminases exceed four times normal, viral disease or a drug-induced hepatitis should be suspected. m avium in tracellulare, hepatic pneumocysfis carinii, fungal-induced hepatitis, cytomegalovirus, or extrahepatic biliary tract obstruction cause elevation of alkaline phosphatase. liver biopsy is necessary to identify hepatic pathogens and should be considered in a child presenting with either fever and elevated liver function tests or a focal hepatic lesion. therapeutic intervention is available for some of the viral agents that cause hepatitis, but most infectious disorders in immunodeficient hosts do not respond favorably to treatment. wasting of body mass is one of the more serious manifestations of hiv disease. in adults, the decline in lean body mass correlates with decreased quality of life and eventual death.s, l in children with aids, growth failure and failure to thrive have been recognized symptoms from the beginning of the epidemic. infants born to hiv-infected mothers seem to weigh less by months of life and to be shorter by months of life when compared with hiv-exposed, but noninfected infants. in long-term survivors more than years of age, lean body mass wasting and short stature are common clinical features. the etiology of these derangements in growth is multifactorial, possibly including deranged metabolism, malabsorption, or decreased nutrient intake. the mechanism for the catabolic process is not known, but futile cycling of energy substrates, protein wasting, or hypermetabolism mediated by cytokines such as tnf, interleukin ( l)- , il- , and the interferons may contribute to the problem. the initial assessment of hiv-infected children with failure to thrive is directed at determination of caloric intake, nutrient losses, and metabolic requirements. if caloric intake is diminished, the reason for anorexia should be determined. nausea, abdominal pain, oral lesions, depression, despair, or lack of access to food need to be evaluated by the health care team. nutrient losses caused by diarrhea and malabsorption may contribute to increased nutrient requirements. enhanced metabolic requirements from febrile illnesses, recurrent infection, or from hiv replication may result in weight loss. anti-retroviral therapy can result in weight gain shortly after starting therapy. counseling and oral supplements are the first steps in nutritional treatment for children with weight loss or decreased lean body mass. providing increased calories and protein may reverse the loss, but most children require additional measures of support. although nasogastric tube feeding is simple and effective for short-term management, the adverse effect on quality of life and the increased possibility of sinus disease are limiting factors. in children requiring nutritional supplementation lasting greater than weeks, endoscopic placement of a gastrostomy tube button increases compliance and tolerance. as many as % recommended daily allowance for calories may be required to achieve weight gain in hiv-infected children. newly developed one-step gastrostomy buttons permit endoscopic insertion of devices that do not limit activity and provide access for nutritional support. despite providing sufficient nutrition to gain weight, enteral supplementation and gastrostomy tube feedings" do not increase lean body mass in hiv-infected children. similarly, appetite stimulants, such as megestrol acetate, a progesterone derivative, and dronabinol, a tetrahydrocannabinol derivative, do not increase lean body mass in adults infected with hiv. promising data in adults suggest that mammalian cell-derived recombinant human growth hormone therapy results in weight gain and anabolism as measured by stool nitrogen, urine nitrogen, and potassium excretion. if valid in the pediatric population, growth hormone could prove to be an effective treatment for failure to thrive by increasing lean body mass. anecdotal experience implicates specific vitamin deficiencies as contributing to the nutritional problems of hiv-infected children. in regions in which vitamin deficiency is endemic, it is not surprising to see the problem amplified in hiv-infected children. decreased vitamin a causes diminished t-cell response to mitogens and antigens, atrophy of lymphoid tissue, ° and is associated with increased maternal-child transmission.z supplementation of vitamin a seems to increase cd + cells, boost antibody response, and decrease morbidity and mortality from other infectious diseases. the effect of vitamin a supplementation on the health of hiv-infected children in the united states is not known. other vitamins, including vitamins d, e, , (thiamine), b (riboflavin), niacin, b , bi , folic acid, c, and carnitine, have been evaluated in various populations of hiv-infected individuals, and although abnormalities can be demonstrated for some vitamins, deficiencies related to the generalized state of malnutrition and not specifically to hiv-induced disease are difficult to prove beyond a reasonable doubt. similarly, deficiencies of iron, zinc, and selenium have been described in hiv-infected individuals. although these minerals have an important role in immunoregula- the redundancy of the immune system to provide protection against infection suggests that by the time the system begins to fail, no single cause can be found to correct the problem. for this reason, supplementation with a single therapeutic nutrient intervention can improve laboratory phenomena, but rarely impacts on a patient's quality of life or immunoregulatory defects. patients with primary immunodeficiency disorders frequently experience gastrointestinal problems in association with other clinical manifestations of systemic disease. the respiratory and gastrointestinal tracts are exposed to the environment and, in response, have developed complex systems to protect their mucosal surfaces from pathogens. antibody production, cell-mediated immune function, complement, and phagocytic function act together to prevent infection and uncontrolled inflammation. in the gastrointestinal tract, enteric pathogens and chronic inflammatory bowel disease are the two major clinical aspects of primary immune deficiency. surprisingly, individuals with identical deficiencies may not experience similar gastrointestinal symptoms. for example, children with immunoglobulin a deficiency may be asymptomatic or may have chronic diarrhea associated with chronic intestinal inflammation disease. in general, children with t-cell defects seem to have a higher incidence of chronic gastrointestinal problems compared with children with antibody defiqiency syndromes, complement defects, or disorders of phagocytic function. table lists the common primary immunodeficiencies together with the gastrointestinal manifestations commonly associated with each disorder. immunodeficient children pose a challenge to clinicians because of the interrelationship between infectious disease, metabolism, gastrointestinal tract function, psychosocial problems, and immune function. the interplay between these factors is not always clear, and frequently the best course of therapy is obscured because of an inability to determine which factors have the greatest impact on child health. to optimize therapeutic intervention, a multidisciplinary health care team must be involved with the management of children and their families. heiicobacter pylari in children with acquired immunodeficiency syndrome disseminated histoplasmosis as the acquired immunodeficiency syndrome-defining illness in an infant intestinal parasites and hiv infection in tanzanian children with chronic diarrhea centers for disease control: zidovudine for the prevention of hiv transmission from mother to infant significance of altered nutritional status in acquired immune deficiency syndrome (aids) esophageal ulceration induced by zidovudine aids, zinc deficiency and thymic hormone failure et a vitamin a supplementation and child mortality: a meta-analysis detection of hiv- rna in the lamina propria of patients with aids and gastrointestinal disease human immunodeficiency virus infection of enterocytes and mononuclear cells in human jejunal tissue effect of enteral tube feeding on growth of children with symptomatic human immunodeficiency virus infection italian multicentre study: epidemiology and clinical features of pediatric hjv infection: results from an italian multicentric study on children bosy composition studies in patients with the acquired immunodeficiency syndrome recommendations on prophylaxis and therapy for disseminated mycobacterium avium complex disease in patients infected with the human immunodeficiency virus benefit of oral immune globulin therapy in patients with immunodeficiency and chronic diarrhea growth and body composition in children infected with the human immunodeficiency virus- malnutrition and carbohydrate malabsorption in children with vertically transmitted human immunodeficiency virus infection et a pancreatitis in pediatric human immunodeficiency virus infection hiv replication and persistence in human gastrointestinal cells cultured in vitro anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection human immunodeficiency virus detection in bowel epithelium from patients with gastrointestinal symptoms diarrhea among african children born to human immunodeficiency virus-infected mothers: clinical, microbiologic and epidemiologic features effect of continuous intravenous infusion of zidovudine (azt) in chldren with symptomatic hiv infection hepatic involvement in patients with human immunodeficiency virus infection: discrepancies between aids patients and those with earlier stages of infection pediatric acquired immunodeficiency syndrome: special considerations for developing nations efficacy of octreotide in the management of chronic diarrhea in aids perinatal transmission of the human immunodeficiency virus type to infants of seropositive women in zaire survival in children with perinatally acquired human immunodeficiency virus type infection chlehanaw j d maternal vitamin a deficiency and mother-tochild transmission of hiv- altered t cell subset proportions in vitamin a deficient children a prospective study of diarrhea and hiv- infection among zairian infants chronic active hepatitis in a child with human immunodeficiency virus infection survival experience of children with acquired immunodeficiency syndrome gastrointestinal symptoms in patients infected with human immunodeficiency virus: relevance of infective agents isolated from gastrointestinal tract et a cessation of cryptosporidium-associated diarrhea in an acquired immunodeficiency syndrome patient after treatment with hyperimmune bovine colostrum postnatal transmission of human immunodeficiency virus type from mother to infant. a prospective cohort study in kigali, rwanda statement on breast feeding and hiv. who/ unicef consultative meeting of world health organization: the hiv/aids pandemic: overview. geneva: who/ gpa/cnp/ long-term toxicity/activity profile of ', '-dideoxyinosine in aids or aids-related complex gastrointestinal dysfunction and disaccharide intolerance in children infected with human immunodeficiency virus key: cord- - prvgmvt authors: darbyshire, philip title: nursing heroism in the (st )century' date: - - journal: bmc nurs doi: . / - - - sha: doc_id: cord_uid: prvgmvt background: the vivian bullwinkel oration honours the life and work of an extraordinary nurse. given her story and that of her world war ii colleagues, the topic of nursing heroism in the (st )century could not be more germane. discussion: is heroism a legitimate part of nursing, or are nurses simply 'just doing their job' even when facing extreme personal danger? in this paper i explore the place and relevance of heroism in contemporary nursing. i propose that nursing heroism deserves a broader appreciation and that within the term lie many hidden, 'unsung' or 'unrecorded' heroisms. i also challenge the critiques of heroism that would condemn it as part of a 'militarisation' of nursing. finally, i argue that nursing needs to be more open in celebrating our heroes and the transformative power of nursing achievements. summary: the language of heroism may sound quaint by (st )century standards but nursing heroism is alive and well in the best of our contemporary nursing ethos and practice. today's nursing heroism first, the more traditional concept of heroism as courage and providing service to others in the face of extreme personal danger is undoubtedly alive and well in nursing and in other human services. firemen still enter burning buildings to save their occupants and nurses still join their health care colleagues in providing care to the hungry, the fearful, the injured and the dying in both natural disaster areas and man made conflict zones. haitian nursing students and faculty from the episcopal university of haiti, were setting up first aid stations to help the victims of their city minutes after that country's massive earthquake [ ] . military nurses and nurses from voluntary organisations such as red cross and medicine sans frontiers are found in every war zone, every famine-blighted country, every dictatorial wasteland, every manifestation of 'hell on earth'. we fervently wish that the circumstances that draw them away from their own families and homes to these places did not exist, but they do, and thankfully, these nurses continue to respond. consider also, nurses' responses to the fear and danger surrounding the emergence of infectious outbreaks such as hiv/aids in the s and sars in . in the early s when first reports were emerging of young gay men in the usa dying of seemingly systemic immune system failure, we could not have realised that this thing called 'grid' was the start of the aids pandemic that has claimed the lives of more than million people worldwide and has left approximately . million people living with hiv/aids [ ] . during these times we saw the best and worst of nursing and health care. in an oral history project: "the aids epidemic in san francisco: the response of the nursing profession, - [ , ] " we hear from nurses involved that some nursing and medical staff held the same fears and prejudices that were so widespread in the broader community. they would refuse to care for the aids patients and stigmatise them along with the other so-called " h patients -homosexuals, haitians, hemophiliacs and heroin users" [ ] . helen miramontes, who later became one of the world's leading nurse advocates, specialists and educators in hiv/aids was then a clinician. she said that: "there was a lot of fear among health care providers about contagion, but there was also significant prejudice and discriminatory behavior because the new disease was identified in a population that was stigmatized by the larger society. identification of the disease in people of color, especially african americans and injection drug users, only exacerbated the biases, prejudices, and discriminatory behavior. many nurses demonstrated the same attitudes, beliefs, and behaviors seen in the larger society. i was a critical care nurse working in an intensive care unit (icu) in a large teaching facility. in the early years of the epidemic, it was not unusual to have two to three patients with pneumocystis carinii pneumonia on ventilators in the icu at any one time. because some nurses avoided taking care of these patients, several of us volunteered to care for them on a regular basis. there were frequent breaches in confidentiality, not only among nurses but also among other health care workers" [ ] . gary carr, who was a nurse practitioner at the aids clinic at san francisco general hospital, described the perverse ambivalence of a wider community that lauds and praises nurses for their 'heroic efforts' in the face of such public health crises. gary says: "i have no memories of being afraid or being brave. i just wasn't afraid. i just said to myself, this is what i want to do. this is important. the community needs this, and it's what i want to do. i remember there were people who stopped speaking to me. my mother for years didn't tell anybody what i did. my relatives for years thought i still worked in the trauma unit" [ ] . when, two decades later, sars emerged as a potentially lethal viral infection, nurses and health care staff again faced considerable dangers as they strove to treat patients and protect their communities. dr dessmon tai, who led the singapore efforts against sars, wrote that: "no other disease had such a phenomenal impact on healthcare workers." [ ] but it seems that something in our professional ethos had changed over these two decades. there had been a rediscovery or reaffirmation of our professional ethic and mission as nurses, doctors and health professionals. in hanoi, during the initial outbreak, rather than look for an 'opt-out' clause in their professional codes, doctors and nurses locked themselves into the hospital in isolation rather than risk spreading the disease [ ] . as emmanuel notes: "more than half of the first reported cases of sars involved health care workers who had come into contact with sars patients. indeed, apart from the very first case, all of the people who died in vietnam were doctors and nurses. nearly a quarter of all patients with sars in hong kong were health care workers. in canada, of the probable cases of sars diagnosed between february and may , ( %) involved health care workers. despite deadly peril, physicians and nurses tirelessly cared for patients with sars". [ ] however, the social stigma that surrounded hiv/aids twenty years earlier and the associated ambivalence of the community towards health care professionals was not so easily repressed. in toronto, canada, hall and colleagues reported that: "children of nurses were barred from school trips and families were shunned by their neighbours. other incidents included husbands of nurses being sent home from work, children of nurses shunned at school, nurses refused rides by taxi drivers, and singleparent nurses unable to get babysitters". [ ] similarly, in singapore, nursing staff were reportedly shunned in public spaces, forbidden to use the lifts in their apartments, found that buses and taxis would not stop for them and as one review reported, "at any packed food court, there would always be a seat for a tan tock seng hospital nurse. queue lines would quickly shorten when a nurse joined that queue". [ ] these personal travails were compounded by what many saw as the unavoidable violence done to some of the best traditions of the nurse-patient relationship by the nature of the sars virus and its containment. nurses working with sars patients were often isolated from collegial support, asked to eat meals alone and prohibited from attending meetings. rigorous isolation and anti-infection procedures saw nurses, effectively in spacesuits, caring for patients in enforced cubicle isolation. if this was a terrible way to be ill, it was an even more solitary and disconnected way to die. yet despite these dangers and demands, nurses and our health care colleagues exemplified the best of who we are and what we do. they worked in a cauldron of contagion, initially unaware of what they were fighting, how the infection spread, how it killed or how it could be treated. as one french doctor commented, "we were not playing with fire. it was playing with us" [ ] . was this heroism and heroic actions on their part, or were they 'just doing their job'? if we accept that heroism is "providing service to others in the face of extreme personal danger", then i have no qualms in considering these nurses as exemplars of st century nursing heroism. heroism and 'militarism': what's in a word? let me sidetrack slightly at this point to address a concern about the very legitimacy and appropriateness of the term heroism in nursing. for some critics, the very mention of 'wars against disease', 'defeating illness', 'the battle against sars', or 'nursing heroism', is tainted. the concern is related to the militaristic or combative nature of such language and how this might shape not only our understandings of illness and disease but also our understanding of nursing itself and indeed the content and foci of our education, research and services. the concerns are not new, having been articulated most forcefully and influentially by the late american essayist, critic and author, susan sontag in both her books: 'illness as a metaphor' and 'aids and its metaphors' [ ] . sontag was deeply critical of the metaphorical language that scaffolds our understandings of, in these cases, cancer and aids. she rejects metaphors of battle, war, magic bullets, invasion, surrender, attack etc and with aids is even more scathing of its damning metaphorical encumbrances around divine retribution, plague, sexual contagion and societal decay. "the body is not a battlefield" says sontag [ ] , but when faced with illness or injury, i suspect that it may become one, if for no other reason that nurses, people and patients need something to fight against. people will often accept the most devastating of diagnoses with almost a gratitude that seems completely misplaced, until they explain to us that the previous uncertainty or not knowing had been far, far worse. author and doctor, peter goldsworthy depicts this phenomenon beautifully in his celebrated novella, 'jesus wants me for a sunbeam' which describes how a family reacts when their young daughter develops leukaemia: "for rick and linda there was also, at the end of that terrible week of waiting and worry, an odd feeling of relief that it had happened to them, and theirs. anything was better than uncertainty; the waiting had been intolerable, the fear of the unmentionable had almost come to be a desire for the unmentionable; its certainty, its mention, was at least a resolution. to finally hear the word (leukaemia) spoken aloud provided a focus for worry, a definite enemy that they could now face, and fight, together, as a family." [ ] before leaving the subject of language, let me touch on a recently articulated concern about the language and discourses of militarism and how these may influence nursing. in a new paper this year on the politics of nursing knowledge, perron and her colleagues [ ] criticise what they call the 'militarization of nursing', claiming that: "many accounts provide angelic portrayals of nurses faced with the devastating effects of war. such nurses are described as loyal, beautiful, peaceful, healing, comforting, reliable, devoted, and courageous in the face of hardship. these romantic descriptions stand in sharp contrast to the organized killing and destruction of warmaking." [ ] i would argue that what perron and her colleagues have almost studiously overlooked are that these allegedly 'romantic descriptions' also stand in sharp contrast to any respectable historical account of the experiences of military nurses [ ] . in such histories, and in particular the growing collection of oral histories of nurses' wartime and conflict zone experiences [ , [ ] [ ] [ ] [ ] [ ] , we will find not saccharine, sentimentalized, spin-doctoring but vivid recollections and narratives from nurses, who, in addition to thankfully being 'loyal, comforting, devoted, healing, reliable and courageous', are also intelligent, skillful, determined, demanding, creative and resourceful. heather höpfl, a professor of management, takes a quite different, and i believe more coherent and enabling view of women's heroism than perron and her colleagues. she argues that: "the heroines of history are not impotent women. quite the contrary, they are women who refuse to be put in their place. the stories of heroines offer a picture of women who were far from meek and far from conciliated into male reality definitions. they were real women not mythological constructions. they shared values rather than common backgrounds and they are, to use an unfashionable term 'indomitable'. (...) the stories of the heroines of years ago and more are stories of recusancy. they are stories of opposition. they are in almost every case stories of gender politics. we are deceived when we are told they are stories of female oppression. (...) these women faced enormous obstacles but squared themselves off against them and responded with integrity and courage." [ ] of other 'quiet' and 'unrecorded' heroisms let me now speak of other heroisms, for i believe heroism in nursing to be a broad church, a continuum of courage rather than a zero-sum game. the nurse exhibiting what i might call, after dickens' character, sydney carton, a "quiet heroism", or what patricia benner calls "unrecorded heroism" [ ] , continues to be part of the fabric of health care today. nursing may not be among the first occupations that springs to mind when the word 'danger' is mentioned but a recent forbes magazine feature in the usa did identify nurses and nurses' aides as one of the top two groups experiencing among the highest rates of injury at work, albeit usually from lifting and handling incidents [ ] . in addition, hall and colleagues in the us reported that: "nursing assistants working in long-term care facilities have the highest incidence of workplace violence of any american worker". [ ] nurses in our emergency departments experience perhaps even more severe episodes of violence. in scotland, we used to joke that any particularly rough place was: "like casualty on a friday night", but it is no joke now. in a recent australian survey from wa, rose chapman and colleagues found that: "the majority ( %) of nurses said they had been verbally abused, % had been physically threatened and % had been physically assaulted". "only % of the nurses completed an official incident report. reasons for not reporting included the view that work place violence is just part of the job, and the perception that management would not be responsive". [ ] would emergency department nurses see themselves as 'heroes'? almost certainly not, as they seem to have internalized a workplace culture where abuse and violence is not an aberration but simply something that "comes with the job" [ ] and where reporting such abuse is scarcely worth the trouble. perhaps if we return to the definition of heroism as 'providing service in the face of extreme personal danger', then our emergency department nurses should allow themselves to feel, at least somewhat heroic. when we define heroism as providing service in the face of personal danger, that danger is not always the danger of illness, injury or death. sometimes, that danger emanates from inside the very organisations that we serve and what is under threat is not nurses' bodily integrity but their professional and personal integrity. i refer of course to the phenomena of whistleblowing in nursing and health care. nursing's official pronouncements, policy directives, mission and vision statements, strategic plans, nursing philosophies and the like invariably proclaim our commitment to the highest standards (indeed to excellence), to patient safety, to quality care, to collegiality, to mutual respect, to 'patient-centredness', to patient advocacy and more. but for many nurses, there is not merely a gap between these aspirations and clinical reality, there is a katherine gorge. debra jackson and her research team in sydney have done some of the best australian research in this area and it does not make for happy reading. as debra notes: "currently, whistleblowing represents a professional dilemma and a personal disaster." [ ] this observation does not only apply to nursing. medical whistleblowers fare equally badly at the hands of their own profession [ ] . indeed in all of the whistleblowing literature, it is difficult, if not impossible to find even one person whose principled actions have not resulted in huge personal and professional costs. and yet we know that nurses are not only vital because of our numbers but because we are patient care, safety and quality where the rubber hits the runway. nursing is not just some inert 'silo', needing to be dismantled. if a hospital or health authority does not understand the difference between nursing as a silo and nursing as a sentinel, they are in more trouble than they can possibly imagine. we are the world's best adverse patient experience early warning detection system. we are like the canaries down the mine or the frogs in the ecosystem. if nurses are metaphorically not singing or not croaking, if they are falling off the perch or disappearing from the ponds, then 'huston -we have a problem"! this problem is a phenomena that blighted not only bundaberg hospital [ ] , but other hospitals and health organisations across the world. this virulent, vocational virus -i'll call it: mrsa ('management resistance to staff alerts'), has been implicated in almost every hospital 'scandal' and health system failure inquiry in recent years. this strain of 'mrsa' seems endemic in health care systems and is as dangerous to staff and patients as any hospital acquired infection. in a nutshell, health organisations and their leaders are not only failing to listen to their front line nursing staff, but in the worst cases, they are actively and forcefully trying to silence them. at bundaberg hospital, what stopped dr jayant patel was not a new computer system, it was not an updated reporting mechanism, it was not visits from external regulators, it was not another reorganization, it was not a new management theory. it was the bulldog advocacy and persistence of icu nurse toni hoffmann in the face of managerial inactivity and intimidation [ ] . toni was recognised for her role with an australian local hero award in and an order of australia in . is toni hoffmann a st century nurse hero? without a shadow of doubt. what of the other contemporary meaning of heroism and heroes? who are our nursing heroes? who are the nursing giants upon whose shoulders we have stood and who continue to inspire us today? who are the nursing heroes that we tell our students about so that they can understand the best of nursing's history? who are they to emulate if they want to be the best nurse possible? our hardwired and often confused sense of egalitarianism makes us uncomfortable in even talking in such a way. when i ask nurses to tell me something wonderful that they did recently that made a real difference to a patient, client or family, their embarrassment and discomfort is almost immediately palpable. 'i didn't really do anything', 'it was the team', 'i'm just a nurse', 'i don't like to 'big note' (brag about) myself', 'all i did was..., 'i don't know what you mean'.... please, let us be more open and unabashed in celebrating our nursing heroes. if these were sportsmen or sportswomen, if they were musicians or actors, if they were business people: we would be lauding their finest performances, dissecting their latest work with relish and handing out awards and trophies by the cabinetful. i thought of my heroes for this paper, the nurses who have inspired me and who continue to do so. so let me celebrate, in no particular order of merit: possibly the most lucid and coherent writer on nursing ever. i read her little or page book, 'basic principles of nursing care' as a young student nurse and could recite her definition of nursing, even at parties after a few drinks, as if it were a catechism. it is no exaggeration to say that i understood nursing in a completely different light after virginia henderson. as a new phd student grappling with philosophy, phenomenology, qualitative research approaches and new understandings of practice, reading 'the primacy of caring', followed by 'novice to expert' was to have the scales fall from one's eyes and to see and understand the world anew. the quality of patricia benner's thinking and scholarship is matched only by her graciousness and generosity of spirit. margaret was dean and head of school when i took up my first post-phd lecturing position at glasgow caledonian university and was simply the dean from heaven. her standards and expectations were exhilaratingly exacting and her work rate would have shamed a chilean mine rescuer. her enthusiasm for nursing, for education, for research and for innovation and creativity was boundless. her guiding philosophy seemed to be: 'the answer's yes, now what's the question'. how could you fail to thrive and develop as a new faculty member under such inspiring and utterly humane leadership? linda aiken is undoubtedly the doyenne of contemporary nursing research and one of the most powerful voices in nursing, in that when linda aiken's research speaks, the world of healthcare listens. and so it should. her exemplary international research programme at the center for health outcomes and policy research at the university of pennsylvania demonstrates clearly that nursing is not simply one of many factors involved in improving health outcomes and patient safety, it is the key factor. get nursing right and you improve safety, quality and patient care. no ifs, no buts. dodie bryce was an enrolled nurse at the intellectual disability hospital where i trained as a new nurse in the s. these institutions could be grim places but dodie bryce's calm, humane, compassion and exemplary human caring skills made her truly, a light in the darkness. she was not just a great nurse but a presence. older and wiser, i now understand the difference. was a ward sister at the sick children's hospital in edinburgh when i trained in pediatrics. i was simply in awe of her. she managed, as the sole charge nurse, a bed surgical ward, the attached neonatal unit of around - cots and an attached bed cardiothoracic surgery unit. she knew every child, everything about their condition and its care and seemingly all of their families as well. she was unflappable in any crisis and utterly respected and listened to by every doctor and health professional. that she managed to take time and trouble to help students on the ward like myself made her even more remarkable. is south australia' first nurse practitioner and heads our pediatric palliative care service. she was also my first clinical research collaborator when i took up my joint chair position at women's & children's hospital. sara is a human dynamo, possessed with vision, drive and absolute determination. give a hospital half a dozen saras in clinical leadership positions and they could rule the world. debra was my phd student and the phd student of every supervisor's dreams. debra has a fierce intelligence matched only by her unstinting work ethic. when you combine these with a heart and personality that draws the best out of everyone around her, you can see why she now heads what is easily one of australia's best research centers. who are the heroes on your list and why? the business of nursing? we are told constantly that health care is a business and that nursing should follow more business-like principles. as a health service or hospital is indeed a multi-million dollar organisation that needs to be well managed, there are no arguments from me on that score. if we are in business however, then let us be absolutely clear about the nature of our business as nurses. we are in the transformation business and the 'making a difference' business. nurses don't just make the tea and coffee they make decisions. we need to appreciate the importance of processes and structures, but more importantly, we need a laser focus and a near-reverence for tangible and valued outcomes that improve patients' experiences. we are in the transformation business. as a clinician, you are not in the injections business or the dressingchanging business or the putting up ivs business or the bathing business. instead, as kerfoot notes, we transform [ ] "we transform a frightened -year-old girl in the emergency room into a little person who now feels she has some measure of control and can stop crying. we transform a -year-old father with out-of-control diabetes into a person who has the confidence to manage his condition. and we transform the frightening and painful experience of childbirth into a beautiful memory of ecstasy for a family that has created a new person. when life ends, we transform those final moments of life into sacred, beautiful transitions of passage for families to complete the circle of life." as a nurse educator, you are not in the business of 'lecturing', 'marking', 'supporting students', or 'writing curricula'. you are in the transformation business. [ ] we transform students into safe, skilled and self-confident practitioners. we transform apathy and cynicism into enthusiasm and robust idealism. we transform clinical, interpersonal and ethical problems from potential career-ending setbacks, into opportunities for deep learning and personal and professional mastery. we transform patient and client experiences from everyday anecdote into the bedrock of clinical judgement and service quality. we foster and build confidence and self-belief where this been eroded, damaged or has never developed while also challenging an equally dangerous overconfidence, arrogance or narcissism. as a nurse researcher, you are not in the business of interviewing, administering surveys or managing data. we transform the glib stereotype of the 'ivory-tower' academic by our meaningful, productive and mutually advantageous collaborations with clinical colleagues and service areas. we challenge the prejudice that academics and their research has little relevance or use in the 'real world' of health policy and politics by our focus on knowledge translation, transfer and research impact and by the demonstrable profile and presence that our work has in numerous key areas of health policy and politics. we are in the transformation business and the 'making a difference' business. all over the world, nurses are making rhetorical notions of 'the patient experience', quality & safety and improved outcomes very, very real: somewhere a nurse is helping a struggling and despairing new mum to learn all of the messages and nuances that her new baby is signalling, somewhere a nurse is bearing witness to another mother's dying, and comforting her during her last moments on this earth, somewhere a nurse is inserting a child's iv and helping them and their family begin their journey into the world of chemotherapy, somewhere a nurse is listening to an alzheimer's patient tell a story and trying to help them piece together who they really are, somewhere a nurse is helping a new student learn from a patient encounter and is passing on the wisdom of our art, somewhere a nurse is turning a hunch or a problem into a question that will eventually be researched and provide new knowledge and understanding, somewhere a nurse is managing a service with the passion and enthusiasm that enables her staff to thrive and to appreciate why they wanted to become nurses in the first place, and somewhere a nurse is working in a war zone, helping service personnel and villagers alike. these 'quiet' or 'unrecorded' heroisms surely deserve our acknowledgement and appreciation. at the end of her classic novel 'middlemarch' [ ] , george eliot writes an epitaph for her heroine dorothea: "but we insignificant people with our daily words and acts are preparing the lives of many dorotheas...her finely-touched spirit had still its fine issues, though they were not widely visible. her full nature, like that river of which cyrus broke the strength, spent itself in channels which had no great name on the earth. but the effect of her being on those around her was incalculably diffusive: for the growing good of the world is partly dependent on unhistoric acts; and that things are not so ill with you and me as they might have been, is half owing to the number who lived faithfully a hidden life, and rest in unvisited tombs." so too, the health, wellbeing, safety and experiences of patients, clients and families are dependent upon the often invisible and overlooked caring practices of nurses. today in the st century, they are worthy of sharing the term 'heroism' and i like to think that sister vivian bullwinkel would agree. author's position: director the story of the australian nurses after the fall of an australian heroine sole survivor of the massacre of australian nurses nurse heroes in haiti nurse practitioner at the aids clinic, san francisco general hospital," an oral history conducted in and by sally smith hughes in the aids epidemic in san francisco: the response of the nursing profession for the san francisco aids oral history series. regional oral history office the lessons of sars duty of care or medical heroism? annals of the academy of medicine heroes and heroines of the war on sars media portrayal of nurses' perspectives and concerns in the sars crisis in toronto illness as a metaphor and aids and its metaphors jesus wants me for a sunbeam sydney: flamingo/harper collins the politics of nursing knowledge and education: critical pedagogy in the face of the militarization of nursing in the war on terror the wartime experience of australian army nurses in vietnam review of: 'and if i perish: frontline u.s. army nurses in world war ii'. by evelyn m. monahan and rosemary neidel-greenlee vietnam memories: australian army nurses, the vietnam war, and oral history the australian nursing and midwifery history project: military nursing willingly into the fray: one hundred years of australian army nursing the death of the heroine the wisdom of our practice the most dangerous jobs in america nursing home violence: occurrence, risks, and interventions examining the characteristics of workplace violence in one non-tertiary hospital violence against nurses working in us emergency departments editorial: what becomes of the whistleblowers three australian whistleblowing sagas: lessons for internal and external regulation sick to death sydney: allen & unwin it's transformation, not patient care the section referenced here is cited from this editorial with the permission of nurse education today pre-publication history the pre-publication history for this paper can be accessed here cite this article as: darbyshire: nursing heroism in the st century authors' contributions pd is responsible for all aspects of this paper. the author declares that they have no competing interests. key: cord- -iodfgzjf authors: kaufmann, stefan h e; mcmichael, andrew j title: annulling a dangerous liaison: vaccination strategies against aids and tuberculosis date: - - journal: nat med doi: . /nm sha: doc_id: cord_uid: iodfgzjf human immunodeficiency virus (hiv) and mycobacterium tuberculosis annually cause million and million deaths, respectively. last year, , individuals, doubly infected with hiv and m. tuberculosis, died. since world war i, approximately million people have succumbed to these two infections—more total deaths than in all wars in the last , years. although the perceived threats of new infections such as sars, new variant creutzfeldt-jakob disease and anthrax are real, these outbreaks have caused less than , deaths globally, a death toll aids and tuberculosis exact every h. in , million people were infected with hiv, billion with m. tuberculosis, and million with both. last year, million and million were newly infected with hiv or m. tuberculosis, respectively, with million new double infections. better control measures are urgently needed. immunodeficiency. with new antiretroviral drugs, hiv infection can be controlled, but not eradicated. treatment, however, is expensive and less than % of individuals infected with hiv in developing countries have access to effective treatment. anti-hiv drugs target hiv reverse transcriptase, protease, integrase or the coiled coil domain of gp . used in combinations of three or more, they are very effective at treating hiv infection: patients with advanced aids have shown dramatic albeit incomplete recovery of cd + t cell counts and immune function, though sometimes the revitalized immune response causes severe problems by reacting to previously silent infecting pathogens. yet even when virus loads have become undetectable for several years, cessation of drugs results in rapid rebound of virus and return to the pretreatment levels . this implies that patients need to take these drugs for life. but because of serious side effects and expense, indefinite treatment is not possible for most of the world. drug resistance by virus mutation is well described and although triple therapy reduces the risk substantially, imperfect adherence to treatment regimes may result in selection of resistant virus. as is the case for tuberculosis, this could limit treatment options in the near future. transmission, however, can be reduced by 'safer sex' practices. such behavior changes may account for the reduction in prevalence of hiv- infection from > % to % in uganda over years . in south africa, more than % of the million inhabitants are infected with hiv and more than % suffer from active tuberculosis. in this country, more than half of all individuals with tuberculosis have concurrent hiv infection. immunodeficiency caused by hiv infection increases the risk of developing tuberculosis dramatically- % of double-infected individuals will develop active tuberculosis within a year of coinfection, as compared to the % lifelong risk in individuals infected with m. tuberculosis alone. despite the availability of effective chemotherapy to cure tuberculosis and the successful development of antiretroviral drugs that control hiv, vaccines provide the only realistic hope of effective prevention. tuberculosis most frequently develops in the lung (fig. ) . once tubercle bacilli have reached the lung alveoli, they are taken up by alveolar macrophages and probably dendritic cells (dcs) in the lung interstitium (fig. ) . m. tuberculosis is protected by a recalcitrant cell wall rich in waxes and other glycolipids , which is responsible for the unique staining characteristics of these microbes and contributes significantly to resistance against host defense. infected macrophages and dcs, therefore, do not destroy their bacterial prey and thus serve as a mobile habitat, transporting the microbes to the lung parenchyma and eventually to the draining lymph nodes , . infected macrophages attract monocytes and a lesion develops. dcs in the lymph nodes present mycobacterial antigens to t cells. at this early stage of infection, secreted proteins such as early secreted antigen for t cells (esat- ) and antigen (ag ) presumably serve as dominant antigens for cd + t cells, which accumulate in great numbers in lesions early after infection. at later stages of infection, cd + t cells also become stimulated . in addition, unconventional t cells are activated, including t cells expressing a γδ t cell receptor with specificity for small phosphorylated ligands and t cells with specificity for glycolipids, which are presented by major histocompatibility complex (mhc) class i-like molecules of the cd family [ ] [ ] [ ] [ ] . studies in nonhuman primates support a role for γδ t cells in protective immunity against tuberculosis . the cd -restricted t cells presumably evolved as a result of the evolutionary cross-talk between mycobacteria and the mammalian host, as they are specific for glycolipids abundant in mycobacteria but not found in other microbial pathogens . antigen-specific t cells induce the formation of a granuloma around infected macrophages, primarily composed of monocytederived macrophages (some of which transform into multinucleated giant cells), cd + t cells and an outer ring of cd + t cells. at later stages, the granuloma is surrounded by a fibrotic wall and lymphoid follicular structures develop in the vicinity, probably orchestrating the local immune response . (i) immediate eradication of m. tuberculosis by the pulmonary immune system. this alternative is rare to absent. (ii) infection transforms into tuberculosis. this frequently occurs in immunodeficient individuals, with the notable example of hiv infection increasing the risk of developing tuberculosis -fold. (iii) infection does not transform into disease because m. tuberculosis is contained inside granulomas. in the diseased individual, m. tuberculosis is no longer contained because caseation of the lesion results in dissemination and transmission of m. tuberculosis. after inhalation, m. tuberculosis is engulfed by alveolar macrophages and dcs. in draining lymph nodes, these cells present mycobacterial antigens to different t cell populations. antigen presentation probably involves cross-priming, allowing transfer of mycobacterial antigens from infected macrophages to dendritic cells. antigen-specific cd + t cells, cd + t cells, γδt cells and cd -restricted t cells participate in protection. most importantly, macrophages are activated by ifn-γ and tnf-α. in addition, t cells may kill mycobacteria present in macrophages by means of perforin and granulysin. in the granulomatous lesion, macrophages are activated by t lymphocytes through production of type i cytokines, notably interferon (ifn)-γ and tumor necrosis factor (tnf)-α . ifn-γ activates the capacity to control m. tuberculosis in macrophages , . moreover, ifn-γ and tnf-α are instrumental in walling off m. tuberculosis inside granulomatous lesions. the importance of these cytokines in the containment of mycobacteria is well illustrated by the observation that individuals with deficient ifn-γ signaling suffer from rapid onset of mycobacterial diseases, and that treatment with antibodies that neutralize tnf-α in individuals with rheumatoid arthritis reactivates tuberculosis in those with latent infection . the granuloma persists for years and efficiently contains tubercle bacilli as long as the individual remains immunocompetent. the granuloma deprives the arrested mycobacteria of oxygen and nutrients and as a direct consequence, the microbes survive, probably in a state of dormancy [ ] [ ] [ ] [ ] . the gene expression profile of m. tuberculosis is altered in response to the restricted growth conditions in the granulomatous lesion. it is highly probable that some of these dormancy-related gene products serve as the major antigens of dormant m. tuberculosis and hence represent promising candidate antigens for a postexposure vaccine aimed at preventing reactivation tuberculosis. the best-known dormancy antigen is the α-crystallin, a small heat-shock protein (hsp) also termed hspx . the mechanisms that determine latency and disease outbreak in tuberculosis remain elusive. although the risk of reactivation is understood to be determined by both host and microbial factors in addition to environmental components, virtually nothing is known about the responsible genes. increasing epidemiologic evidence that strains of the m. tuberculosis beijing/w genotype family, many of which are of the mdr type, are spreading throughout the world suggests that this family of m. tuberculosis evolved against the evolutionary pressure of bcg vaccination and chemotherapy , . a careful histologic analysis of lung autopsy material performed from cadavers more than years ago in zürich showed almost % m. tuberculosis infection in individuals over years of age, who had died of unrelated reasons . we can assume similarly high incidences nowadays for individuals living in tuberculosis 'hot spots' (e.g., prisons in some countries) and infection rates between % and % in areas with high m. tuberculosis incidences. how and why disease outbreak occurs after a period of latency are unclear , . increased risk of tuberculosis as a result of unique environmental and behavioral factors such as alcohol abuse or dietary iron overload emphasizes the importance of these components, but again provides little explanation of specific control mechanisms . a considerable proportion of individuals with tuberculosis develop disease within the first year after infection. moreover, superinfection as well as reinfection after successful tuberculosis chemotherapy have been described . it is probable that these individuals develop an insufficient immune response against natural infection with m. tuberculosis because of genetic host susceptibility, immune suppression by the pathogen or both. elucidation of the genetic mechanisms underlying susceptibility and protective immune mechanisms in resistant individuals that prevent disease outbreak in face of ongoing infection, as well as identification of the pathogen genes that promote transformation of latent infection into active tuberculosis, will facilitate rational design of a postexposure vaccine , , . of equal importance will be the careful analysis of the efficacy of bcg vaccination. bcg was found to protect against adult tuberculosis in the uk and against leprosy in malawi, but did not provide any protection in the world health organization trial in south india . overall, a % protective efficacy has been estimated for bcg . although environmental factors, notably frequent infection with atypical mycobacteria, probably have a role, contribution of genetic host factors should be assessed more carefully. it is possible that a small proportion of bcgvaccinated individuals develops a long-lasting immune response against tuberculosis, whereas the majority does not. because any new vaccine has to protect individuals who do not mount an appropriate immune response to natural infection with m. tuberculosis or to vaccination with bcg, the susceptible and resistant target populations and the criteria that distinguish them from each other need to be defined carefully. vaccination strategies against tuberculosis subunit vaccines given alone or in addition to bcg. new subunit vaccines against m. tuberculosis comprise antigen-adjuvant formulations, naked dna vaccine constructs or recombinant carriers expressing antigen ( table ) . they are mainly based on protein antigens. unfortunately, reliable rules for defining protective antigens for t cells do not exist. most vaccine antigens investigated thus far are early produced secreted antigens such as ag , a shared antigen with bcg, and esat- , which is an antigen unique to m. tuberculosis (fig. ) , . such antigens are probably adequate for pre-exposure vaccination. for individuals latently infected with m. tuberculosis, a postexposure vaccine composed of dormancyrelated antigens such as hspx seems more suitable (fig. ) [ ] [ ] [ ] . a recent screen has assessed the protective efficacy in mice of more than antigens that are differentially expressed in the proteomes of m. tuberculosis versus bcg . from these, only one antigen was identified that induced a robust protection similar to that of bcg, arguing against a unique role in protection of proteins exclusively present in the proteome of m. tuberculosis. although proteins will constitute the major antigens of subunit vaccines, glycolipid antigens can be included in these vaccine formulations. such glycolipids could serve both as antigen in the context of cd and as adjuvant for toll-like receptors (tlrs) . generally, subunit vaccines crucially depend on appropriate adjuvants that stimulate t helper type (t h ) immune responses by the different t cell populations required for protection against tuberculosis. naked dna constructs can stimulate cd + and cd + t cells. although they have proven their high immunogenicity in small-rodent animal models, human studies are thus far mostly disappointing. but new carrier systems such as polylactide glycolyde microparticles may facilitate application of naked dna vaccines in humans . recombinant bacterial and recombinant viral carriers expressing defined mycobacterial antigens have been constructed and their vaccine efficacy against tuberculosis have been determined in experimental animal models. these vectors induce potent cd + and cd + t h responses. the most advanced vaccine of this type is recombinant modified vaccinia virus ankara (r-mva) expressing ag , which has already entered phase clinical trials , . vaccination with mtb f protein in as a adjuvant or in the form of naked dna induces protective immunity in both mice and guinea pigs f-as a vaccine formulation has now entered a phase clinical trial in healthy m. tuberculosis-uninfected volunteers ( table ) . another protein-based vaccine comprising a fusion protein of esat- and ag in a mixture of oligodeoxynucleotides and a polycationic peptide (ic ) as an adjuvant has shown promising results in experimental animals and hence is aimed at entering a phase clinical trial later in ( table ) . generally heterologous prime-boost schemes are composed of a relatively simple first component (e.g., dna) that primes a focused immune response, and a second boost vaccine that induces an inflammatory response (e.g., using a recombinant virus) to magnify the initial response. to achieve a proper prime-boost effect, shared antigens are required for the subunit boost vaccination. in tuberculosis, however, heterologous prime-boost vaccination schemes starting with a bcg prime followed by a subunit boost are considered most promising, not only for scientific reasons but also because bcg vaccination of newborns cannot be given up prematurely. the recently discovered antigen rv is encoded in the bcg genome but is undetectable in its proteome . the increased protection seen in bcg-primed mice after boost vaccination with naked dna encoding rv indicates that this protein is an important antigen of m. tuberculosis that is suboptimally expressed in bcg. similarly, boost with mtb f in as a adjuvant increased protection induced by bcg prime . the r-mva expressing ag induced substantial protection both when given alone or as booster vaccination on top of bcg prime . a recent clinical phase trial showed that r-mva-ag induced ag -specific ifn-γ-secreting t cells ( table ) . more profound effects were observed in the bcg prime-r-mva-ag boost group, underlining the importance of heterologous prime-boost vaccination in the rational delineation of future tuberculosis vaccination strategies. vaccine efficacy data of mutant m. tuberculosis are still limited. during the early stage of infection, m. tuberculosis replicates actively. accordingly, m. tuberculosis knockout mutants, in which synthesis of essential amino acids is prohibited, will not grow in lungs of experimentally infected mice. typically, these are auxotrophic mutants that die of starvation in the absence of the required nutrients ( table ) , . a second group of m. tuberculosis knockout mutants show reduced growth in lungs of experimentally infected mice, but persist at a lower level than wild-type microorganisms. these mutations include deficient regulatory proteins, such as the phop/phoq two-component regulatory system and a variety of mutants with deficient lipid metabolism or transport , . although genes of this group include virulence factors, it is also possible that the gene products are needed for persistence rather than harming the host directly. m. tuberculosis knockout mutants deficient in genes expressed during dormancy replicate in the lungs of experimental mice in an unconstrained manner early after infection, but cease to grow at later stages because of their impaired dormancy gene program. one of the best described genes of this group is that which encodes isocitrate lyase . m. tuberculosis knockout mutants, which grow as well as wild-type microorganisms but induce weaker pathology, lack true virulence factors. some knockout mutants behave like wild-type m. tuberculosis in the lung but do not disseminate to other organs. the heparin-binding hemagglutinin adhesion molecule seems to participate in the dissemination of m. tuberculosis to extrapulmonary sites and hence qualifies as a member of this group . factors that facilitate dissemination to other tissues should be deleted in a viable vaccine in order to focus the response on the lymph nodes. a recently defined group of m. tuberculosis knockout mutants comprises strains that grow as well as wild-type microorganisms in normal mice, but do not persist in mouse knockout mutants with defined immunodeficiency . vaccine candidates based on m. tuberculosis knockout mutants will probably face strong objections against use in human clinical trials largely because of the genetic stability of the mutants. reversion is best prevented by having two independent chromosomal gene deletions. the advantage of m. tuberculosis knockout mutants is their profound stimulation of all t cell populations relevant to protective immunity. on the other hand, m. tuberculosis is known to impair the host immune response. therefore, it is probably not sufficient to reduce the virulence of m. tuberculosis knockout mutants. additional genetic modifications improving the immune response and reducing pathology will be required. although these vaccines will have a long way to go, a rationally designed m. tuberculosis mutant lacking a defined set of virulence genes in the long run could have great potential as a tuberculosis vaccine. as compared to m. tuberculosis, the current vaccine bcg lacks approximately genes that are clustered in regions of difference (rd) and are at least in part involved in pathogenicity and persistence. reintroduction of selected genes may increase immunogenicity, antigenicity or both of bcg without reverting it to a pathogen ( table ) . improved immunogenicity results in the stimulation of a profound immune response. antigenicity can be improved by introduction of additional antigens or by overexpression of antigens expressed at suboptimal level. pym et al. have introduced the entire rd region of m. tuberculosis into bcg, comprising at least genes . although it remains to be clarified whether the recombinant bcg (r-bcg) expressing rd genes is endowed with improved immunogenicity, antigenicity or both, it was claimed that this vaccine candidate provided slightly better protection than parental bcg in mice. not unexpectedly, however, this r-bcg candidate showed higher virulence in immunocompromised mice as compared to wild-type bcg. reintroduction of genes missing in bcg that do not confer virulence might increase vaccine efficacy of bcg without decreasing its safety. horwitz et al. introduced the gene encoding ag into bcg, an abundant secreted protein in m. tuberculosis . although the gene is also expressed in bcg, it was assumed that overexpression of this immunodominant antigen would increase protective immune responses. indeed, in guinea pigs, r-bcg expressing ag induced substantially higher protection than parental bcg against tuberculosis. this vaccine was at least as safe as bcg and has recently entered a phase clinical trial ( table ) . the r-bcg vaccine candidates with higher immunogenicity comprise strains that express human cytokines such as ifn-γ, ifn-α, interleukin (il)- , il- and granulocyte macrophage colony stimulating factor (gm-csf) [ ] [ ] [ ] . however, these cytokine-secreting r-bcg have yet to prove superior protection in animal models against tuberculosis, as they have not yet been compared to parental strains. another approach to improving immunogenicity of bcg takes advantage of the biological activity of listeriolysin (hly) . in its natural host, listeria monocytogenes, this cytolysin forms pores in the phagosomal membrane, promoting listerial egression into the cytosol . in the cytosol, listerial antigens are readily introduced into the mhc class i pathway, causing preferential stimulation of cd + t cells. compelling evidence suggests that bcg is insufficiently equipped for stimulating cd + t cells, whereas cd + t cell stimulation is satisfactory , the gene encoding hly was introduced into bcg to improve cd + t cell stimulation. indeed, such vaccine constructs induced better protection than parental bcg in mice (grode, l. et al; unpublished data). production of this vaccine under good manufacturing practices (gmp) conditions has been initiated and this candidate is aimed at entering a phase clinical trial in ( table ) . the use of subunit vaccines is based on the assumption that one or a few protective antigens and t cell clones will suffice for efficacious protection . in contrast, attenuated viable vaccines utilize the whole spectrum of expressed antigens to stimulate an optimal combination of t cell subtypes. genetically engineered viable vaccines are therefore best suited as replacements for bcg. despite previous reluctance, a recent expert group meeting has strongly advocated development of viable recombinant vaccines against tuberculosis because they are the most potent stimulators of protective immune responses that perform better than bcg in experimental animal models . as an essential requirement, any new viable vaccine should be at least as safe as bcg in immunocompetent and safer than bcg in immunocompromised individuals. cross-reactive immune responses against atypical mycobacteria might prematurely eradicate an improved r-bcg or attenuated recombinant m. tuberculosis and thereby impair efficacy of genetically engineered viable vaccines. although subunit vaccines are probably not affected by the preexisting cross-reactive immunity to environmental bacteria, generally immunity induced by subunit vaccines is short-lived. given the complementary strength of both types of new vaccine candidates, a heterologous prime-boost regimen comprising a prime with a viable vaccine candidate superior to bcg and a boost with a subunit vaccine candidate will probably be the most promising combination to ensure long-lasting efficacy. hiv is a member of the lentivirus subgroup of the retrovirus family, so named because of a long period of clinical latency after infection. its envelope is derived from cell membrane and expresses the glycoproteins gp (responsible for virus attachment to cells) and gp (responsible for membrane fusion). internally, matrix (gag p ) and capsid (gag p ) proteins enclose the viral rna. other viral proteins include the reverse transcriptase, protease, integrase and regulatory proteins nef, tat, rev, vif, vpr and vpu. the virus infects by attaching gp to the cd molecule and either the chemokine receptor ccr or cxcr present on t cells . gp mediates fusion and in the cytosol the rna is reverse transcribed and the preintegration complex moves to the nucleus, where the cdna is integrated as provirus into host dna in activated cells. gene expression is normally immediate; first regulatory and then structural proteins are made, regulated by tat and rev proteins. new virus particles bud from the surface of infected cells about h after infection. virus is shed for a further day or so before the cell dies . neutralizing antibodies eventually appear, although too late to prevent infection, and are easily evaded by viral mutation. t cell immunity seems to control the infection over several years but with a dynamic process of immune selection and escape occurring . cd + t cells are both deleted and functionally impaired early , with hiv-specific t cells preferentially infected and depleted . however, in some cells (e.g., long-lived memory t cells and macrophages), gene expression is delayed and the infection becomes latent. the progressive loss of cd + t cells leads to clinical immunodeficiency, which is manifested by opportunistic infections and, often, reactivation of tuberculosis. these infections rapidly cause death if untreated. hiv infects cd + t cells and monocytes and macrophages. the virus is cytopathic in activated t cells, but less so in macrophages, and not at all in latently infected cells with integrated provirus. these different forms of infection present problems for vaccines. those that stimulate and maintain high levels of neutralizing antibodies could prevent initial infection, but once that has occurred, it is almost impossible to eliminate hiv. under prolonged antiretroviral drug therapy, virus is eliminated from the activated t cells that express the enzymes targeted by the drugs, but not from cells in which virus turns over slowly or is latent . thus if an hiv vaccine does not prevent infection, it is unlikely to eliminate the virus but may be able to control the ongoing infection and prevent disease. there is no known protective immunity against hiv, in the sense that virus is never eradicated from those infected so that it is impossible to find people protected by previous infection, as is the case for many other viruses, such as measles, mumps and influenza. this poses serious problems for vaccine development, although it is not unique (epstein-barr virus is another such example). adult monkeys infected with attenuated siv (e.g., with deletions in nef) do not become sick, and are protected from challenge with pathogenic siv . this protection is probably, but not certainly, immunological . some highly hiv-exposed individuals resist hiv infection; others develop t cell responses to hiv but not serum antibodies, and their immunity depends on continuing exposure to the virus . this may represent immune resistance, although it is hard to prove. another clue may come from the rarity of superinfection in people infected with hiv who are repeatedly exposed to further infection. although there are elegant studies of superinfection , it is suspected that it is rare; if so, its rarity probably reflects immune protection. the spread of hiv- infection around the world in years has been alarming. the worst epidemics are in sub-saharan africa, where more than % of young adults are infected. mortality from hiv infection without drug treatment is close to %, although infected people usually survive from to years before developing aids. the introduction of effective antiretroviral drugs in high-income countries has reduced mortality without reducing infection. hiv is the most variable virus known. there are six major subtypes, a, bc, d, e, f and g, which are 'ancient' (in the hiv context of - years) and have distinct geographical distribution (fig. ) . the complexity is even greater because of recombinations between subtypes and within subtypes. each subtype differs by > % in amino-acid sequence, so that t cells specific for one subtype are unlikely to cross-react substantially with the others; each epitope of - amino acids will probably have two or more mutations, and this level of variability is known to adversely affect t cell recognition . although there are a few cross-reactive t cell epitopes, as well as conserved segments of hiv, it may be necessary to match any virus subtype with that of the circulating viruses in the population to be vaccinated. it is less certain that subtype-specific vaccines will be necessary for stimulating neutralizing antibodies, although sequence variability is known to be a major problem. a further complication is the variability within each subtype and within each individual. it is clear that both antibodies and cd + t cells are very effective at selecting virus escape mutants [ ] [ ] [ ] [ ] . as human leukocyte antigen (hla) type controls the epitopes recognized by t cells, it is not surprising that hla type influences virus sequence in individuals as a consequence of t cell-driven escape . however, the mutant virus may be less fit and the escape can offer advantages to the host. the constraints on the virus probably account for the overall conservation of virus sequence in primary infection, before the immune response evolves. therefore, vaccines that focus on conserved consensus sequences may have the best chance, at minimum selecting slightly less fit viruses during primary infection. a t cell vaccine that permits infection and induces selection of escape mutants could undermine vaccine effectiveness, as has been seen in macaques . but selection of less fit virus has also been observed in macaques in whom siv infection remains controlled, so this could favor the host . challenges. for hiv there are two major challenges: to find (i) immunogens that can stimulate broadly cross-reacting neutralizing antibodies and (ii) immunogens that stimulate high levels of persisting cd + and cd + t cells. both humoral and cellular immunity may be needed, but they require different types of immunogens; eventually vaccines could be mixed to achieve both (fig. ) . a prophylactic vaccine will be given months or years before exposure and, hopefully, prevent or ameliorate infection. an antibody-inducing vaccine could prevent infection , but as indicated above, a vaccine that stimulates t cell immunity cannot stop virus infecting cells. the latter vaccination might enable the host to suppress the infection for long periods and prevent disease. thus, macaques vaccinated to stimulate t cell immunity against siv became infected when challenged with virus, but had very low virus loads and experienced little effect on their health as compared to unvaccinated controls [ ] [ ] [ ] . because it is almost impossible to eliminate hiv infection, this may be the best that can be achieved. however, many chronic virus infections as well as latent m. tuberculosis infection are controlled effectively in the long term by cellular immunity without causing disease. hiv- does not cause disease in more than % of those infected in west africa , suggesting that the immune response and the virus are in balance in the infected but healthy individual. at present there is no realistic candidate hiv vaccine. it was thought that gp preparations would stimulate neutralizing antibodies, and they do against tissue culture-adapted hiv strains. however, all such vaccines have failed to neutralize primary virus isolates and one tested in two large efficacy trials failed to protect (nam, http://www.aidsmap.com/). now the aim is to design hiv envelope protein immunogens that will stimulate protective antibodies. unfortunately the dice are loaded against this: (i) the envelope is heavily glycosylated, making it largely nonimmunogenic; (ii) it is conformationally variable, so that the most sensitive site, the chemokine receptor binding site, is not exposed unless cd + has bound; (iii) the cd + binding site is deeply recessed and hard to access by antibodies; (iv) besides the carbohydrates, crucial parts of the gp surface are protected by hypervariable loops, which can and do vary by mutation at no cost to the virus, thereby escaping neutralizing antibodies , . real novelty in immunogen design is needed to get around these problems. as an alternative, much effort is being made to create vaccines that stimulate t cell immunity, particularly cd + t cells. in mice, several approaches comprising plasmid dna and various recombinant viruses and recombinant bacteria have given promising results [ ] [ ] [ ] . also particulate proteins and peptide-pulsed dcs can efficiently stimulate cd + t cells , . but these findings are not easily transferable to primates. dna vaccines stimulate only weak responses in humans and recombinant viruses give mixed results. the poxviruses (canary pox, the attenuated vaccinia virus (nyvac) and mva) induce weak primary responses , , possibly because the recombinant immunogen is swamped by more than poxvirus proteins. also, these viruses may be too attenuated, with little or no proliferation after infection. however, they may be better at boosting t cell responses that have already been primed (e.g., bcg; table ). the most promising results to date come from recombinant adenovirus , which has stimulated strong and sustained t cell responses, but its applicability is constrained by the high frequency of antibodies to this virus in most human populations. alternate candidates in trial include other strains of adenovirus, adeno-associated virus, alphaviruses and r-bcg as vectors for hiv. as for tuberculosis, heterologous prime-boost regimes offer enhanced t cell immune responses , and have been observed in macaques and humans . it seems that in humans, recombinant adenoviruses are good at both priming and boosting, whereas recombinant poxviruses such as mva are better at boosting than priming (mcmichael, a.j., goonetilleke, n., guimaeres-walker, a., dorrell, l., yan, h., hanke, t., unpublished data). vaccine-induced t cell responses should include both cd + and cd + t cells, even though the former are targets for the virus. cd + t cell help is important for optimal cd + t cell responses - -an issue of particular importance to hiv vaccine development because natural infection results in impaired cd + t cell immunity. protein immunogens typically elicit antibody responses and t helper cell responses, but the latter may be of the t h type, especially when alum is used as an adjuvant ; t h responses have little or no antiviral activity. live intracellular infections generally elicit t h responses and cd + t cell responses, hence the use of live attenuated vectors to mimic a virus infection. these deliver the required immunogen into the cytosol, from which it can enter the mhc class i antigen presentation pathway directly, or indirectly when the cell dies and virus protein is taken up by dcs for 'cross-priming' of cd + t cells [ ] [ ] [ ] [ ] . people who are homozygous for the δ variant of ccr do not express an intact chemokine receptor and are resistant to hiv infection . immune resistance is suspected for people who are highly exposed, yet uninfected. many generate cd + and/or cd + t cell responses, but without any serum antibody . it is not certain that the t cell responses are responsible for resistance. if they are, it is encouraging because the levels of t cell response seen in current vaccine trials could be sufficient. hiv enters the host through (usually genital) mucosa. hiv infects, or attaches to, mucosal langerhans cells first and then migrates to local lymphoid sites an hiv vaccine should stimulate b and t cell as well as mucosal and innate immunity. live attenuated hiv probably provokes all of these, but because it will set up a persistent infection, there are insoluble safety issues that render its use unlikely in humans. therefore, it may be necessary to build a set of vaccines to stimulate each component separately and administer them in combination. if control equivalent to that of chronic epstein-barr virus or cytomegalovirus or latent m. tuberculosis infection could be achieved for hiv, with reduced or negligible further transmission, it would represent a considerable advance. measuring the efficacy of the vaccine would be problematic, being dependent on reduced virus load at set point, the time at around months after primary infection when virus level stabilizes. the set-point level is inversely correlated with time of survival. only neutralizing antibodies, stimulated by vaccines, offer any real chance of sterile immunity and such vaccines are a long way off. a prophylactic vaccine for hiv is badly needed. unless current trials of vaginal microbicides are unexpectedly successful, there is no other way of controlling the infection and both antibody-and t cell-inducing vaccines need a total rethink. the most advanced of these vaccines is the merck recombinant adenovirus (ad ) vaccine that is about to enter clinical trials. but even if successful, a different vector will be needed to deal with the problem of pre-existing antibody immunity to ad . the merck trial may, however, indicate whether vaccines that stimulate t cell immunity offer any benefit, and that type of news is to be welcomed. could aids and tuberculosis vaccines be given together? probably, but this may be decades away. in parts of africa, bcg is given at birth. combining bcg with an aids vaccine, with a boost at puberty, may be feasible in the distant future. preclinical studies: tuberculosis and aids vaccine testing. most tuberculosis vaccine candidates have been tested in mice or guinea pigs. studies in mice take advantage of the in-depth knowledge of the mouse immune system, whereas guinea pigs have the advantage of developing a pathology that highly resembles human tuberculosis. these experimental animal studies form the starting point of the tedious pipeline leading to a new vaccine candidate . the us national institutes of health, through their preclinical tuberculosis screening program, and the european union, through its tbvac integrated project in the framework program , sponsor vaccine testing in experimental animals under standardized conditions. thus far, the two programs utilize different screening procedures, which need to be harmonized in order to achieve comparability of different vaccine candidates. however animal models cannot unequivocally predict the efficacy of a vaccine candidate against tuberculosis or hiv and immunogenicity results in mice often do not predict responses in humans. although nonhuman primate studies can be bypassed before phase and phase clinical trials, they may become necessary before embarking on phase trials. phase and phase clinical trials should also be exploited for determination of immunological correlates of protection (i.e., markers that unequivocally predict protective efficacy of a vaccine candidate). currently, ifn-γ produced by t cells with specificity for defined antigens is probably the best marker of protection for tuberculosis, but this is much less clear for hiv. in the most impressive vaccine protections studies, using attenuated siv as a vaccine it is not known what confers protection , and the ifn-γ elispot assay for t cells does not correlate with protection in vaccine-protected macaques . additional markers are required. the siv challenge model in macaques has been very useful for hiv vaccine development , but there are limitations. in these experiments, the virus challenge dose is always large, compared to repeated lowdose exposures in humans. in addition, the vaccine is nearly always homologous to the challenge virus, giving good chances of success that are unrealistic in humans. attempts are being made to introduce more representative challenges . finally the siv or siv-hiv hybrid (shiv) challenges may be slightly misleading; it seems easier to protect against the aggressive hybrid virus shiv . p compared to the less virulent siv mac . it is unclear which will be closer to an hiv exposure in humans. despite these problems, the existing data suggest vaccineinduced protection is possible. therapeutic vaccination for hiv is rarely discussed, but must be considered as recent studies in macaques and humans [ ] [ ] [ ] give it some credibility. in humans, therapeutic vaccination would probably be used to stimulate t cell responses in hiv-infected people whose virus was well controlled by antiretroviral drugs, with the aim of terminating antiretroviral therapy (art) once the t cell levels were boosted. the rationale is that t cells, particularly cd + t cells, are known to be effective in long-term control of the virus in the absence of drug treatment, but t cell responses decline in patients on effective art . when art is stopped, virus rebounds to pretreatment levels . if the t cell levels were already boosted, this might lead to lower virus levels at the new set point. at its best, this treatment could enable withdrawal of art for prolonged periods and offer new options in low-income countries in particular. patients whose virus was controlled in this way might also be less likely to transmit virus. clinical trials. the earliest vaccine trials are small and are concerned with vaccine safety and immunogenicity. then immunogenicity is optimized by finding the best vaccine dose and route of delivery. finally, the vaccine efficacy trials involve several thousand volunteers who are at high risk for infection. translation of vaccine candidates from bench science into clinical trials is relatively straightforward scientifically but complicated logistically and extremely expensive (box ). phase trials can be done in the country of origin of the vaccine, but increasingly good sites are being established in developing countries and several countries have hiv vaccine trial experience. in contrast, experience with tuberculosis vaccine trials is marginal and currently only a few phase trials have been initiated. two phase trials of vaxgen gp in , people showed clearly that the aids vaccine candidate offered no protection (e.g., reported at http://www.hivandhepatitis.com/ vaccines/ a.html). a phase b trial has now been proposed before . here, between , and , high-risk volunteers are given placebo or vaccine and all are followed for evidence of infection. once trial participants are infected, a detailed analysis of the relationship between infection and immunity is made. in the case of aids, virus load, subtype and t cell and humoral immune responses are determined and correlated and the degree of protection ascertained. it is arguable that such an approach might have obtained a result for the vaxgen trial in a shorter time at lower cost. it would be worthwhile to consider a similar strategy for tuberculosis vaccine efficacy trials. vaccine recipients for phase trials are volunteers who are at negligible risk of infection. nevertheless, they have to be counseled about the implications of testing, which adds some burden to all parties. it has proved relatively easy to recruit such volunteers in the uk and in kenya and uganda for aids vaccine testing. for efficacy trials, phase b and phase , it will be necessary to work with individuals with high risk for hiv infection. sex-worker cohorts are usually too small and follow up can be difficult. in a high-risk region in africa, the annual incidence may be - %, but the implementation of trials inevitably raises awareness and the best possible advice must be given to volunteers, particularly concerning condom use. therefore, it should be expected that incidence might decrease by half. this is important to realize in determining statistical powers before embarking on the trial. the population of high-risk volunteers is less well circumscribed for tuberculosis than for aids. there are major ethical issues in efficacy trials. double blinding and placebo controls are essential, but a difficult question is what to offer in terms of chemotherapy to trial participants in low-income countries such as africa. it is now generally agreed that the best possible (rather than best regional) therapy should be offered to all trial participants who become infected; the unresolved questions are for how long and when, given that drugs may not be required for - years. although it is desirable to insist on the highest safety standards for any vaccine candidate as defined by the fda and the emea it may be worthwhile to carefully assess whether risk-benefit relationships differ for countries with low or high tuberculosis or aids prevalence. side effects of new vaccine candidates may be tolerable for a vaccine that can prevent tuberculosis or aids mortality and morbidity in countries where incidences are skyrocketing, but not for countries with low tuberculosis or aids prevalence . hiv and tuberculosis vaccine trials will probably need multiple sites. a trial involving , volunteers with detailed prescreening, individual counseling and careful follow up will probably necessitate at least sites. although in theory such sites would have the infrastructure and could also conduct trials for both tuberculosis and hiv, it is unlikely that this would be possible at the same time because of high cost, a requirement for multiple vaccine groups and complicated data analysis. aids and tuberculosis rampage most freely in low-income countries where the total annual budget for public health is below us $ per capita [ ] [ ] [ ] [ ] . currently available therapeutic regimes exceed such budgets by several fold. similarly, vaccine development from the bench to the field consumes huge amounts of financial resources. consequently development of vaccines against tuberculosis and aids will be most successful as joint public-private enterprise with support from governmental and nongovernmental funding organizations and philanthropic foundations. such a consortium would be best equipped to bring forward vaccine development by a combination of 'push' and 'pull' programs. although support for preclinical research will be best directed by classical push programs, incentives should be made available for alternative approaches . the removal of roadblocks serves as a good example for a support strategy emphasizing innovation and not restrictive in the experimental approach. unconventional research areas, such as therapeutic hiv- and tuberculosis vaccination, could be further stimulated by pull programs rewarding a vaccine candidate that proves successful figure the major components of the immune response can be stimulated by different types of vaccine. inactivated vaccine t cell immunity innate immunity • intellectual property. for regulatory and manufacturing reasons, vaccines that go forward into trials must be protected as intellectual property. this ensures that sponsors, indemnifiers, gmp producers, etc. know what they are dealing with and that others will not be working unlicensed with the same product. • gmp production. preparation of a vaccine to 'good manufacturing practice' quality is essential for the regulators and ensures that each batch is identical and can be tracked. this is expensive (e.g., $ , - , for mva) and requires outsourcing. the manufacturer provides detailed documentation of processes and purity. • toxicity testing. this is required before submission to the us food and drug administration (fda) or the european medicines agency (emea). normally this requires acute toxicity and studies of distribution and persistence of vaccine at distant and critical sites after immunization. dose schedules should be the same as used for the trial, even though the animals are smaller and a detailed report is needed. • regulatory submission to the national or international authority (fda, emea, medicines and healthcare products regulatory agency, etc.). these follow standard procedures but require very detailed information including full protocols, standard operating procedures of assays, details of safety monitoring, definition of endpoints, statistical calculations, details of data handling. • ethical approval. this connects to regulatory submission. besides all protocols, details of informed consent, explanation to volunteers, details of volunteer recruiting and letters to family doctor explaining the trials are required. • other approvals may be needed from the gene therapy advisory committee (in the uk) and local and national safety committees for handling recombinant organisms. in preclinical studies. at the transition from the preclinical to the clinical phase, pull programs providing incentives for the market-ready final product would be most appropriate . these include tax reduction for vaccine production, secured future markets in developing countries, a tiered price system, and reduced interest rates or debt release by the world bank for vaccine purchase and distribution. in the absence of such incentives, even the best vaccine candidate may fail to reach the desired goal of unrestricted distribution in countries affected most by aids and tuberculosis. lack of financial incentive may provide some unique opportunities for vaccine development against aids and tuberculosis. notably, lowto-absent competition for financial profits can promote comparative clinical trials under the umbrella of governmental, nongovernmental or philanthropic organizations either alone or together with the aim first to select the most promising candidates, and second to proceed by 'learning by doing' (i.e., continuous vaccine improvement of candidates in iterative clinical trial processes). analysis of the immune responses of vaccine trial participants may provide new information that can be further explored in experimental animal models and help to define the next clinical trial step. strong efforts are required to harmonize vaccine trials and accompanying vaccine efficacy testing. it is rewarding that several major organizations including the us national institutes of health though their intramural and extramural programs, the bill and melinda gates foundation through aeras for tuberculosis and their vaccine enterprise for aids as well as the european union through their european & developing countries clinical trials partnerships program have committed themselves to bring vaccines against aids and tuberculosis from the bench to the field. vaccination strategies against these two diseases need to be integrated as soon as possible, considering the intimate interdependence of the two deadly pathogens and the consequences of their liaison. obviously, numerous hurdles need to be overcome. yet, even if only partially protective vaccines can be developed, return on investment will be enormous. this is not only true for the most impoverished countries, for which a rapid solution is vital, but also for industrialized countries, which may suffer significantly from global economic and social regressions and further weakening of unstable states. global tuberculosis control: surveillance, planning, financing (world health organization is the development of a new tuberculosis vaccine possible? die schutzimpfung gegen tuberkulose mit "bcg immune control of hiv- after early treatment of acute infection guidelines for using antiretroviral agents among hiv-infected adults and adolescents can population differences explain the contrasting results of the mwanza, rakai, and masaka hiv/sexually transmitted disease intervention trials?: a modeling study a waxy tale by mycobacterium tuberculosis intracelluar models of mycobacterium tuberculosis infection mycobacterium tuberculosis: the indigestible microbe cd t cells in tuberculosis cd and tuberculosis gamma/delta and other unconventional t lymphocytes: what do they see and what do they do? adaptive immune response of v gamma v delta (+) t cells during mycobacterial infections mycobacterial phosphatidylinositol mannoside is a natural antigen for cd d-restricted t cells human tuberculous granulomas induce peripheral lymphoid folliclelike structures to orchestrate local host defence in the lung how can immunology contribute to the control of tuberculosis? disseminated tuberculosis in interferon gamma gene-disrupted mice an essential role for interferon gamma in resistance to mycobacterium tuberculosis infection infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase iii trial. attract study group the immunological aspects of latency in tuberculosis mycobacterium bovis bcg response regulator essential for hypoxic dormancy inhibition of respiration by nitric oxide induces a mycobacterium tuberculosis dormancy program regulation of the mycobacterium tuberculosis hypoxic response gene encoding alpha -crystallin global dissemination of the mycobacterium tuberculosis w-beijing family strains worldwide occurrence of beijing/w strains of mycobacterium tuberculosis: a systematic review localisation und ausheilung der tuberculose. archiv für pathologische anatomie und genetic dissection of immunity to mycobacteria: the human model genetics of susceptibility to human infectious disease iron and microbial infection exogenous reinfection as a cause of recurrent tuberculosis after curative treatment survival perspectives from the world's most successful pathogen, mycobacterium tuberculosis the bcg story -lessons from the past and implications for the future efficacy of bcg vaccine in the prevention of tuberculosis. metaanalysis of the published literature selecting the components for a safe and efficient tuberculosis subunit vaccine-recent progress and post-genomic insights immunogenicity and protective efficacy of a tuberculosis dna vaccine protection of mice with a tuberculosis subunit vaccine based on a fusion protein of antigen b and esat- application of mycobacterial proteomics to vaccine design: improved protection by mycobacterium bovis bcg prime-rv dna boost vaccination against tuberculosis novel vaccination strategies microparticles as vaccine adjuvants and delivery systems recombinant modified vaccinia virus ankara expressing antigen a boosts bcg-primed and naturally acquired antimycobacterial immunity in humans enhanced immunogenicity of cd (+) t-cell responses and protective efficacy of a dna-modified vaccinia virus ankara prime-boost vaccination regimen for murine tuberculosis differential immune responses and protective efficacy induced by components of a tuberculosis polyprotein vaccine, mtb f, delivered as naked dna or recombinant protein the protective effect of the mycobacterium bovis bcg vaccine is increased by coadministration with the mycobacterium tuberculosis -kilodalton fusion polyprotein mtb f in m. tuberculosis-infected guinea pigs auxotrophic vaccines for tuberculosis characterization of auxotrophic mutants of mycobacterium tuberculosis and their potential as vaccine candidates an essential role for phop in mycobacterium tuberculosis virulence complex lipid determine tissue specific replication of mycobacterium tuberculosis in mice persistence of mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase the heparin-binding haemagglutinin of m. tuberculosis is required for extrapulmonary dissemination identification of mycobacterium tuberculosis counterimmune (cim) mutants in immunodeficient mice by differential screening comparative genomics of bcg vaccines by whole-genome dna microarray recombinant bcg exporting esat- confers enhanced protection against tuberculosis recombinant bacillus calmette-guerin (bcg) vaccines expressing the mycobacterium tuberculosis -kda major secretory protein induce greater protective immunity against tuberculosis than conventional bcg vaccines in a highly susceptible animal model manipulation and potentiation of antimycobacterial immunity using recombinant bacille calmette-guerin strains that secrete cytokines bacille calmette-guerin (bcg)-associated inflammation and fibrosis: modulation by recombinant bcg expressing interferon-gamma (ifn-gamma) recombinant bacille calmette-guerin (bcg) expressing human interferon-alpha b demonstrates enhanced immunogenicity mycobacterium bovis bacille calmette-guerin strains secreting listeriolysin of listeria monocytogenes molecular determinants of listeria monocytogenes pathogenesis improved protection by recombinant bcg. microbes infect new live mycobacterial vaccines: the geneva consensus on essential steps towards clinical development recent advances in understanding the molecular mechanisms of hiv- entry and fusion: revisiting current targets and considering new options for therapeutic intervention hiv- dynamics in vivo: implications for therapy escape of human immunodeficiency virus from immune control hiv- viremia prevents the establishment of interleukin -producing hiv-specific memory cd + t cells endowed with proliferative capacity hiv preferentially infects hiv-specific cd + t cells the challenge of viral reservoirs in hiv- infection protective effects of a live attenuated siv vaccine with a deletion in the nef gene prospects for an aids vaccine cytotoxic t cell responses to multiple conserved hiv epitopes in hiv-resistant prostitutes in nairobi late seroconversion in hiv-resistant nairobi prostitutes despite preexisting hiv-specific cd + responses hiv- superinfection despite broad cd + t-cell responses containing replication of the primary virus timing the ancestor of the hiv- pandemic strains t cell cross-reactivity and conformational changes during tcr engagement hiv escape: there and back again envelope-constrained neutralization-sensitive hiv- after heterosexual transmission hiv and siv ctl escape: implications for vaccine design rapid evolution of the neutralizing antibody response to hiv type infection evidence of hiv- adaptation to hla-restricted immune responses at a population level eventual aids vaccine failure in a rhesus monkey by viral escape from cytotoxic t lymphocytes reversion of ctl escape-variant immunodeficiency viruses in vivo transfer of neutralizing igg to macaques h but not h after shiv infection confers sterilizing protection: implications for hiv- vaccine development control of a mucosal challenge and prevention of aids by a multiprotein dna/mva vaccine control of viremia and prevention of clinical aids in rhesus monkeys by cytokine-augmented dna vaccination replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity plasma viral load, cd cell percentage, hla and survival of hiv- , hiv- , and dually infected gambian patients hiv vaccine design and the neutralizing antibody problem the antigenic structure of the hiv gp envelope glycoprotein humoral and cell-mediated immune responses to live recombinant bcg-hiv vaccines vaccine developments a recombinant vector derived from the host range-restricted and highly attenuated mva strain of vaccinia virus stimulates protective immunity in mice to influenza virus priming of human immunodeficiency virus type (hiv- )-specific cd + t cell responses by dendritic cells loaded with hiv- proteins hiv vaccine strategies safety and immune responses to a dna-based human immunodeficiency virus (hiv) type i env/rev vaccine in hiv-infected recipients: follow-up data enhanced t-cell immunogenicity of plasmid dna vaccines boosted by recombinant modified vaccinia virus ankara in humans hla class i serotypes and cytotoxic t-lymphocyte responses among human immunodeficiency virus- -uninfected thai volunteers immunized with alvac-hiv in combination with monomeric gp or oligomeric gp protein boosting enhancement of mhc class i-restricted peptide-specific t cell induction by a dna prime/mva boost vaccination regime enhanced immunogenicity for cd + t cell induction and complete protective efficacy of malaria dna vaccination by boosting with modified vaccinia virus ankara cd + t cells are required for the maintenance, not programming, of memory cd + t cells after acute infection requirement for cd t cell help in generating functional cd t cell memory a conditioned dendritic cell can be a temporal bridge between a cd + t-helper and a t-killer cell reduced functional capacity of cd + t cells expanded by post-exposure vaccination of gamma-herpesvirusinfected cd -deficient mice in interleukin- -deficient mice, alum not only generates t helper responses equivalent to freund's complete adjuvant, but continues to induce t helper cytokine production cd + t cell cross-priming via transfer of proteasome substrates antigen bias in t cell cross-priming type i interferons promote cross-priming: more functions for old cytokines cross-priming of cd + t cells stimulated by virus-induced type i interferon homozygous defect in hiv- coreceptor accounts for resistance of some multiply-exposed individuals to hiv- infection the pathogenesis of sexual mucosal transmission and early stages of infection: obstacles and a narrow window of opportunity for prevention cd + t cell depletion during all stages of hiv disease occurs predominantly in the gastrointestinal tract tuberculosis and the tubercle bacillus interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review mechanisms of protection induced by attenuated simian immunodeficiency virus repeated low-dose mucosal simian immunodeficiency virus sivmac challenge results in the same viral and immunological kinetics as high-dose challenge: a model for the evaluation of vaccine efficacy in nonhuman primates viremia control following antiretroviral treatment and therapeutic immunization during primary siv infection of macaques therapeutic dendritic-cell vaccine for chronic hiv- infection vaccination of macaques with long-standing sivmac infection lowers the viral set point after cessation of antiretroviral therapy decay kinetics of human immunodeficiency virus-specific effector cytotoxic t lymphocytes after combination antiretroviral therapy creating incentives for pharmaceutical research on neglected diseases world health organization. global atlas of infectious diseases report on the global aids epidemic world health organization. the world health report -changing history hiv- /aids and the control of other infectious diseases in africa methylation-dependent t cell immunity to mycobacterium tuberculosis heparin-binding hemagglutinin therapy of tuberculosis in mice by dna vaccination boosting vaccine for tuberculosis the authors declare that they have no competing financial interests. volume the sentence "in south africa, more than % of the million inhabitants are infected with hiv and more than % suffer from active tuberculosis" should read "more than . % suffer from active tuberculosis."in table two sentences in this article appeared incorrectly. on page , in the eighth paragraph, the third sentence should read "to the u -transplanted scid mice, mg of either sg/ , yn or vehicle was injected intravenously, and mg of either arac or normal saline was injected intraperitoneally on day of transplantation." on page , in the eighth paragraph, the fourth sentence should read "to nod-scid mice transplanted with patients' leukemic cells, mg of either sg/ or yn was injected intravenously, and mg of either arac or normal saline was injected intraperioneally on days and of transplantation." key: cord- -v vwu authors: thoden, j.; potthoff, a.; bogner, j. r.; brockmeyer, n. h.; esser, s.; grabmeier-pfistershammer, k.; haas, b.; hahn, k.; härter, g.; hartmann, m.; herzmann, c.; hutterer, j.; jordan, a. r.; lange, c.; mauss, s.; meyer-olson, d.; mosthaf, f.; oette, m.; reuter, s.; rieger, a.; rosenkranz, t.; ruhnke, m.; schaaf, b.; schwarze, s.; stellbrink, h. j.; stocker, h.; stoehr, a.; stoll, m.; träder, c.; vogel, m.; wagner, d.; wyen, c.; hoffmann, c. title: therapy and prophylaxis of opportunistic infections in hiv-infected patients: a guideline by the german and austrian aids societies (daig/Öag) (awmf / ) date: - - journal: infection doi: . /s - - - sha: doc_id: cord_uid: v vwu introduction: there was a growing need for practical guidelines for the most common ois in germany and austria under consideration of the local epidemiological conditions. materials and methods: the german and austrian aids societies developed these guidelines between march and november . a structured medline research was performed for diseases, namely immune reconstitution inflammatory syndrome, pneumocystis jiroveci pneumonia, cerebral toxoplasmosis, cytomegalovirus manifestations, candidiasis, herpes simplex virus infections, varizella zoster virus infections, progressive multifocal leucencephalopathy, cryptosporidiosis, cryptococcosis, nontuberculosis mycobacteria infections and tuberculosis. due to the lack of evidence by randomized controlled trials, part of the guidelines reflects expert opinions. the german version was accepted by the german and austrian aids societies and was previously published by the arbeitsgemeinschaft der wissenschaftlichen medizinischen fachgesellschaften (awmf; german association of the scientific medical societies). conclusion: the review presented here is a translation of a short version of the german–austrian guidelines of opportunistic infections in hiv patients. these guidelines are well-accepted in a clinical setting in both germany and austria. they lead to a similar treatment of a heterogeneous group of patients in these countries. although opportunistic infections (ois) in human immunodeficiency virus (hiv)-infected patients have become rare in industrialized countries [ ] , patients continue to present with advanced hiv disease and hiv-related ois. patients (so-called ''late presenters'') are often unaware of their hiv infection or have not received antiretroviral treatment. they present at a late stage and when their overall health status is already poor [ ] . diagnosis and therapy of these ois remain a challenge. the aim of the recommendations presented here is to develop general and practical guidelines for the treatment and prophylaxis of the most common ois in germany within the framework of local epidemiological conditions. the tables in the different sections of the guidelines represent a summary of the therapeutic guidelines. with regard to diagnosis, the authors refer to the appropriate literature. at the time the guidelines were approved some articles were only available as congress abstracts; if these were published as peer-reviewed article at a later date, the published articles were cited. the kaad (clinical aids working group germany) guidelines conform to the international guidelines of the u.s. centers for disease control and prevention (cdc) (http:// www.cdc.gov/mmwr) [ ] and guidelines formulated by the awmf (association of the scientific medical societies in germany) in the overlapping fields dermatology and neurology (http://www.uni-duesseldorf.de/awmf/ll/). members of other medical societies and the austrian aids society have also participated and have been consulted (see appendix). some of the following recommendations go beyond the approved use of drugs. in many cases, data from randomized controlled trials (rcts) are missing, and evidence is based on practical and clinical experiences not presented in published studies (expert opinion). in addition, we advise always checking interactions and toxicities of the applied drugs as these factors cannot be described in detail within the scope of this guideline. for the treatment of bacterial pneumonia, which is similar in hiv-positive and hiv-negative patients, the appropriate guidelines should be referred to. the indication for antiretroviral therapy (art) in germany is based on the guidelines by the german and austrian aids societies (daig and Ö ag, respectively). however, general recommendations regarding when to start art with mostly art-naïve patients in the setting of an (acute) oi cannot be given. in the case of candidiasis, herpes virus infections or, for example, cryptosporidiosis, the immediate start of art is uncomplicated; in the case of progressive multifocal leukoencephalopathy (pml) it is even necessary and recommended. the situation is more difficult in cases of pneumocystis jiroveci pneumonia (pcp), cerebral toxoplasmosis, cytomegalovirus (cmv)-retinitis, tuberculosis (tb), atypical mycobacteriosis, and cryptococcosis. we refer to the corresponding sections of these guidelines. the recommendations given here represent the consensus of the guideline consensus group. the recommendations referring to medical therapies might involve off-label therapies that have not been officially approved. this is due to the lack of data from rcts on hiv-infected patients with oi. in such cases, the recommendation often refers to data on hiv-negative persons or personal experience (expert opinion). it should also be noted that drug-drug interactions or toxicities need to be excluded in each single case. the kaad was given the task to develop guidelines for the treatment and prophylaxis of oi by the daig in march . the members of the daig, Ö ag, and other german medical societies (in total societies represented; see appendix) were asked to participate in the consensus process. the members formed small interest groups (n = - members) covering the different chapters of these guidelines. a first version was sent out in march based on the corresponding chapters of the digital version (http://www.hivbook.com). the different groups were free to base their chapters on this proposal after review of the relevant literature or to create new chapters. via an email system these new chapters were put together until the groups reached a consensus on a final draft. four weeks before a consensus conference in cologne on june , these drafts for all chapters were sent out to all members of all groups and to all daig members with the request for suggestions for changes. the submitted suggestions for changes which were received were then sent out to the members prior to the meeting. during the consensus conference all suggestions were discussed and voted on separately. finally, each single chapter and the whole guideline proposal were voted on separately. there was an agreement of % on the whole proposal between all members of the guideline group. in a third step the cologne proposal was sent out via email to all members of the daig four weeks prior to a daig member assembly in munich ( march ) for comment. only minor revisions were asked for. the guidelines were again put to vote during the meeting. during the final vote the guidelines received positive unanimous votes and were agreed on in the current version as the daig/kaad oi guidelines. the german version (long version) of these guidelines was submitted to the awmf on august and was published online on november (http://www.awmf. org/leitlinien/detail/ll/ - .html). Ö ag approved these guidelines on november . immune reconstitution inflammatory syndrome the immune system is expected to recover following initiation of art. some patients, however, show a paradoxical reaction. with widely varying symptoms, this pattern of disease is defined as immune reconstitution disease, immune reconstitution syndrome, or immune reconstitution inflammatory syndrome (iris) [ ] [ ] [ ] [ ] . different clinical case definitions exist [ , ] manifestations of iris are diverse and range from unspecific symptoms, ois to autoimmune diseases, and malignomas [ ] . regarding ois, the physician must differentiate between symptomatic relapse of a prior infection (paradoxical iris) and infections first appearing on art (unmasking iris). data on the incidence of iris vary widely, ranging between and % of all patients at initiation of an art [ ] [ ] [ ] [ ] . a prospective study showed an incidence rate in germany of . % [ ] . an international meta-analysis showed a total incident rate of . % for iris, with the highest rates for iris uveitis, followed by tb, cryptococcal meningitis, pml, and rarer cases of kaposi's sarcoma or varizella zoster virus (vzv) infections [ ] . the greatest risk factor would appear to be a low cd t-cell count of \ cells/ll [ , ] . patients starting an art with a cd t-cell count of \ cells/ll and especially those who have a high viral load require close monitoring. patients with\ cd t-cells/ll should also be tested for a latent mycobacterial infection (by culture). a large prospective trial [ ] showed no difference for the development of an iris when art was initiated immediately after patients had started an oi therapy (patients with tb were excluded from the trial). in this study, corticosteroids were often given on initiation of art in a high number of pcp cases, which possibly suppressed some iris cases. for tb and cryptococcosis, however, several studies showed an higher incidence of an iris when art was initiated early [ ] [ ] [ ] . corticosteroids are useful in cases of tb-iris [ ] . steroid therapy for - weeks is recommended for cryptococcal-iris (increase of intracerebral pressure). the use of non-steroidal anti-inflammatory drugs (nsaids) and thalidomide was recommended in some studies, but a general recommendation can not be given for these agents [ ] . art should only be interrupted in very severe cases. results of the swiss hiv cohort study prove that consequent isoniazid (inh)-prophylaxis in hiv patients with latent tb significantly reduces the risk of a relapse [ ] . in general, prognosis for an iris is good and the mortality rate is not higher than that for patients without an iris [ ] . pneumocystis jiroveci pneumonia is the most frequent oi in germany and appears predominantly in hiv-infected patients with advanced immunodeficiency (cd t cells \ /ll). if there clinical-radiological findings suggest pcp, therapy should be initiated immediately without awaiting results of a bronchoalveolar lavage. a mild pcp [bga: partial pressure of oxgen (po ) [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] can be treated in outpatient medical care. if ventilation becomes necessary, non-invasive methods (continuous positive airway pressure) are beneficial if applied at an early stage [ ] . with respect to the treatment of artnaïve patients, several experts believe that the initiation of art can be delayed until acute treatment is completed. however, one rct has shown advantages of an early start [ ] . acute therapy should be given at least for days, if necessary longer. the treatment of choice is a combination of trimethoprim and sulfamethoxazole (tmp/smx, cotrimoxazole). oral application of tmp/smx is only recommended in mild cases, but this therapy can be also considered after initial improvement during intravenous therapy. positive effects with lower doses of tmp/smx have been observed in some case reports, but data from controlled trials are missing [ ] . all severe cases should be treated intravenously in hospital. in cases of respiratory insufficiency [po \ mmhg or alveolar-arterial oxygen tension difference (aado ) c mmhg on room air], most experts recommend ( )- days of adjuvant administration of prednisolone [approx. mg/kg body weight as a single dose or split dose twice daily (bid)]. with prednisolone, mortality risk of severe pcp can be reduced by half and significantly fewer patients require mechanical ventilation [ ] . compared to tmp/smx, all alternative therapies are less effective. in the event of intolerance or sulfonamide allergy, intravenous pentamidine ( mg/kg once daily (qd) for - days is recommended as a second choice; this agent is however more toxic and the dose may therefore have to be reduced after days ( mg/kg). treatment with inhaled pentamidine can be attempted in mild cases of pcp [ , ] ; however, reports on experience with this approach are conflicting [ ] [ ] [ ] . instead of pentamidine, the administration of atovaquone suspension or a combination of trimethoprime and dapsone or clindamycin and primaquine is possible [test for glucose- -phosphate dehydrogenase (g pd) deficiency!]. data are only available for mild to moderate pcp [ ] [ ] [ ] . primaquine is no longer approved for use in germany, but it is available through international pharmacies. it can only be applied if there are no other alternatives and requires increased efforts in educating patients. according to a meta-analysis, the combination of clindamycin plus primaquine is the most successful therapy if cotrimoxazole therapy fails [ ] ; this combination appears to be more effective than pentamidine alone [ ] . patients with \ cd t-cells/ll (or \ % of total lymphocytic count) or a previous pcp require prophylaxis. the therapy of choice is tmp/smx, which also has a protective effect against bacterial infections and cerebral toxoplasmosis [ , ] . daily administration is possibly more effective than three doses a week [ ] . in cases of moderate cutaneous allergic reactions, desensitization is possible [ ] . monthly pentamidine inhalations are a welltolerated alternative [ , ] . a suitable inhalation system should be chosen and an inhalative ß-sympathomimetic should be administered beforehand. other options are dapsone [ , ] and atovaquone, both of which have proved to be similarly effective as tmp/smx, dapsone, and pentamidine in two multi-center trials [ ] [ ] [ ] . atovaquone, however, proved inferior to tmp/smx in another study [ ] . pcp prophylaxis can be discontinued after successful immune reconstitution on art to c cd t-cells/ll for at least months [ ] [ ] [ ] [ ] . only a few cases of reoccurring pcp have been reported for discontinuation at [ cd t-cells/ll [ , ] . if the hiv rna is well suppressed, [ cd t-cells/ll may be sufficient to discontinue prophylaxis [ ] . however, larger trials would be needed to submit a general recommendation regarding discontinuation for these patients. the recommendations concerning therapy and prophylaxis of pcp are summarized in table . the incidence of cerebral toxoplasmosis has decreased to less than a quarter of that during the earlier years of the hiv epidemic, [ ] . nevertheless, it remains the most important neurological oi in hiv-infected patients in europe [ ] . cerebral toxoplasmosis almost always results from a reactivation of a latent infection with toxoplasma gondii. extracerebral manifestations are rare. standard therapy is a combination of pyrimethamine and sulfadiazine, which is effective in - % of cases [ , ] . an equivalent alternative is pyrimethamine and clindamycin [ , ] . tmp/smx is also possible, with the same doses as used in pcp [ , ] . tmp/smx proved to be as effective as sulfadiazine/pyrimethamine in two rcts on ocular and cerebral toxoplasmosis [ , ] . a cochrane review showed no superiority of any one specific regimen [ ] . for pyrimethamine, a ''loading dose'' within the first few days has been used since the first studies [ ] . however, the efficacy of this approach has not been proven. due to the myelotoxicity of pyrimethamine, it is important to add folinic acid (not folic acid) from the start [ ] . other alternatives are atovaquone/pyrimethamine [ ] or azithromycin/pyrimethamine [ ] ; however, data are limited. acute therapy lasts for a period of at least (to ) weeks-longer for alternative therapies. in most cases, empiric treatment of toxoplasmosis is initiated upon identification by radiographic testing. any improvement or clinical deterioration should be evaluated clinically and by magnetic resonance imaging (mri) scanning during therapy (after days). in the case of progression, an alternative diagnosis (i.e., cerebral lymphoma, tuberculoma) and a brain biopsy should be considered. maintenance therapy with a reduced dosage should be initiated when lesions have resolved at least by %, the clinical course has improved, and contrast enhancement has been reduced or eliminated. art should be initiated as soon as possible. in cases of increased intracranial pressure or extensive edema, steroids can be given (dexamethasone, - - mg/day). the choice for steroid therapy must be considered carefully as steroids distort possible differential diagnoses. for example, primary cerebral lymphomas also respond to steroids, and in the case of therapeutic failure, the validity of a potential biopsy can be reduced with steroids. antiepileptic therapy is indicated if epileptic attacks occur. due to rare interactions with art, gabapentin, pregabalin, and levetiracetam are applied. levetiracetam is also available as infusion. a distinction must be made between exposure prophylaxis, primary prophylaxis, and secondary prophylaxis after cerebral toxoplasmosis. • exposure prophylaxis: immunoglobulin g (igg)-negative patients should avoid eating raw or undercooked meat. an increased risk due to proximity to cats has not been proven [ ] . stricter measures of hygiene should be followed. however, the importance of this recommendation under effective art is questionable. • primary prophylaxis: igg-positive patients with \ cd t-cells/ll require primary prophylaxis. the drug regimen of choice is tmp/smx. in cases of allergy, desensitization may be considered [ ] . see above for alternatives. primary prophylaxis can be discontinued if cd t-cell count is[ cells/ll for at least months. • secondary prophylaxis: in the absence of immune reconstitution, patients require lifelong secondary prophylaxis, usually consisting of half the dose needed for acute therapy [ ] . clindamycin is presumably less suitable as secondary prophylaxis as it cannot cross the intact blood-brain barrier [ ] . tmp/smx also seems less effective for secondary prophylaxis. however, it may be considered because it is simple. a higher dose than that for pcp is definitely required [ , ] . prophylaxis may be discontinued safely if initial therapy has led to radiological resolution and if there is an immune reconstitution of [ cd t-cells/ll for at least - months [ , [ ] [ ] [ ] . the recommendations on therapy and prophylaxis of cerebral toxoplasmosis are summarized in table . in germany, seroprevalence of cmv infection in the adult population is - %. the risk of a reactivation of cmv infection increases when the cd t-cell count is \ cells/ll. in addition to cmv retinitis, impairment of other end-organs may occur. due to the limited data on cmv manifestations, the same systemic therapy is recommended in these latter cases as for cmv retinitis [ ] . international guidelines are also available for this approach [ ] . all patients with manifest cmv infection should start art immediately. the cmv-specific immune response is restored [ ] , leading to a reduction of cmv viremia [ ] and delaying progression of an existing cmv retinitis or its recurrence [ , ] . in addition to art, a cmv-specific therapy should be initiated at the time of diagnosis. therapy of cmv retinitis can be performed locally or systemically. a local therapy alone does not provide protection against dissemination of infection in the contralateral eye or other organs, but it can be considered if systemic drug toxicity is high. for systemic therapy, four substances are available: gancyclovir, foscarnet, cidofovir, and valgancyclovir (valgcv). the reader is referred to the product information on these substances for the respective side effects. valgancyclovir is the only drug that can be administered orally. it is almost completely hydrolyzed to gancyclovir after resorption in the gastrointestinal tract [ , ] . gancyclovir and foscarnet are both recommended as first choices for treating cmv retinitis even though foscarnet proved to be superior in pre-art times [ , ] . the side effects of both drugs differ, but the response rates to therapy are similar with both substances [ ] [ ] [ ] . as foscarnet must be administered via a central catheter, the administration of gancyclovir is easier and often preferred. valgancyclovir has proven to be effective in a comparative study and has the advantage of being less complicated to administer than intravenous infusion. intravenous treatment, however, may be necessary if foveal infections occur with acute risk of impairing visual acuity. in these cases, gancyclovir and foscarnet are equally recommended for first-line therapy. treatment with both agents consists of an induction therapy followed by life-long maintenance therapy. induction therapy usually lasts for at least - weeks until lesions resolve. without sufficient art, selection of resistant cmv mutations is frequent and accumulates as the infection progresses [ , ] . several authors recommend valgcv for first-line therapy based on the results of a prospective randomized trial with valgcv and parenteral gancyclovir [ ] and on those of studies on the pharmacokinetics of ganciclovir, with both showing similar results after the administration of valgcv [ , , ] . other studies on the pharmacokinetics of gancyclovir following the administration of valgancyclovir either lack a comparison with parenteral gancyclovir [ ] , or the administered doses were too low to show bioequivalence of valgcv and gancyclovir [ ] . in summary, a clear recommendation in favor of valgcv cannot be given at the present time. in the presence of sight-threatening lesions, the panel strongly recommends against treatment with valgancyclovir due to the lack of clear evidence. some experts recommend a combination therapy of gancyclovir and foscarnet in full doses for acute sightthreatening lesions. maintenance therapy with valgcv can be initiated after lesions have completely resolved [ ] ; however, this recommendation also lacks data. without sufficient art, a relapse is likely to occur, even under maintenance therapy with valgancyclovir. if lesions (zone ii and iii) are more anterior, therapy with valgcv may be attempted with weekly monitoring of the fundus. cidofovir has not been tested in controlled trials against gancyclovir or foscarnet. compared to a delayed therapy, cidofovir significantly slows down the progression of the infection [ ] ; however, cidofovir is not recommended as first-line therapy due to its side effects. it does remain an important agent in the treatment of progredient cmv retinitis under gancyclovir or foscarnet therapy. sufficient art is crucial for a successful therapy of cmv retinitis. patients with progredient cmv retinitis on a gancyclovir regimen can be treated successfully with foscarnet or a combination of foscarnet and gancyclovir [ ] . a good response is obtained in many cases with treatment with cidofovir, and this drug can therefore be an alternative. if foscarnet should fail, gancyclovir or a combination of gancyclovir and foscarnet can be effective. here too, therapy with cidofovir can prevent further progression. gancyclovir implants can still be effective after therapy failure under systemic gancyclovir or foscarnet due to the significantly higher intraocular gancyclovir concentration produced by the implants [ ] . however, there is no protection against further spread of the infection to other organs or to the contralateral eye [ ] [ ] [ ] . extraocular manifestations are always treated in the same way as a cmv retinitis, although only a few studies support this recommendation. in the presence of a cmv encephalitis or ventriculitis, clinical experience and smaller case studies indicate that a combination therapy with gancyclovir and foscarnet is superior to monotherapy [ ] [ ] [ ] [ ] [ ] [ ] . due to the toxicity of this therapy, the diagnosis should be confirmed. • primary prophylaxis: gancyclovir prophylaxis for cmv retinitis with a cd t-cell count of \ cells/ll is effective, but this is usually too toxic. fundoscopy every months is recommended but not necessary in the opinion of most experts (especially at a cd t-cell count of [ cells/ll). • a dose-reduced secondary prophylaxis should be initiated, preferably with oral valgcv after about weeks of acute therapy and after lesions have formed scars [ ] . discontinuation of secondary prophylaxis to avoid side effects as soon as possible is recommended and feasible [ , , ]-however, not before at least months of maintenance therapy and immune reconstitution at a cd t-cell count of[ - cells/ ll. a small study showed that discontinuation after months of art/maintenance therapy is already safe at a cd t-cell count of [ /ll [ ] . in the first stage after discontinuation, patients undergo an ophthalmology control at least once a month. the required duration of a recurrence prophylaxis is not clear, nor is it as yet known for how long recurrences with other organ manifestations should be monitored. duration should therefore be handled as for cmv retinitis. the recommendations on therapy and prophylaxis of cmv manifestations are summarized in table . from the roughly candida species only about different species are encountered in clinical daily practice. the most frequent species by far is c. albicans. clinical response to fluconazole of infections caused by c. albicans and candida parapsilosis is mostly good, whereas that to infections caused by c. glabrata or c. krusei is poor or totally missing. primary in vitro resistance of c. albicans to azoles is rare [ ] . secondary resistance development under long-term azole therapy (fluconazole) was frequently observed in the pre-highly active art (haart) era. for the treatment of oral and vulvovaginal candidiasis, the reader is referred to the respective awmf guidelines [ , ] . esophageal candidiasis (thrush) does not require an endoscopy to confirm the diagnosis in the presence of a typical clinical course and a mouth sore. the imidazole antimycotics, such as clotrimazole and the hydroxypyridone ciclopirox olamine, are suitable for local therapy of cutaneous candidiasis. if the immune status of the patient is good and/or in the case of a first episode of an oral candidiasis (oc), topical antimycotics, such as suspensions or pastilles (nystatin, amphotericin b, miconazole), are more inexpensive therapy options, although inferior to a therapy with fluconazole [ ] [ ] [ ] . however, adherence is restricted with topically effective suspensions/pastilles. alternatives are mucoadhesive applications, although these are clearly more expensive. oral therapy with systemical azole derivatives (fluconazole, itraconazole, posaconazole, voriconazole) show a more rapid response, provide longer protection against recurrences, and are tolerated better by patients [ ] [ ] [ ] [ ] . fluconazole can be considered the drug of choice for oc and esophageal candidiasis. a once-daily oral therapy ( mg for - days) has been established as the standard for oc [ ] . single doses of up to mg fluconazole have been tested in a small patient group (mostly without art) and was considered to be equivalent to a -day therapy. this therapy, however, should be confined to patients with compliance problems, as data on late relapses are limited [ , ] . esophageal candidiasis is usually treated for - days with doses of - mg fluconazole qd. patients presenting with severe dysphagia can initially be treated intravenously and switched to oral application as symptoms improve. if fluconazole resistance has been detected, treatment with other azole derivatives is usually still effective and should be attempted before parenteral therapy is initiated (e.g., with echinocandin). traconazole, voriconazole, and posaconazole have demonstrated clinical efficacy for cases of fluconazole refractory oropharyngeal and esophageal candidiasis [ ] [ ] [ ] [ ] . all azole derivatives require a double dose on the first day of the regimen (loading dose). therapy with a higher dose of fluconazole (b mg/day & mg/kg/day) or an antimycotic combination therapy [ ] can be considered, but data are insufficient. therapy failure and/or fast relapses occur most frequently in patients with poor immune status (\ cd t-cells/ll). data from randomized studies have shown that echinocandins (caspofungin, micafungin or anidulafungin) are as effective and well tolerated as fluconazole for the treatment of candida esophagitis [ ] [ ] [ ] . however, application should be restricted to azole refractory infections with clear fluconazole resistance [ , , ] . art should be initiated immediately if chronic recurring oropharyngeal/esophageal candidiasis is present and at the latest if resistance problems occur. azole refractory candidiasis as well as azole-resistant strains can disappear with sufficient immune reconstitution as a consequence of art [ , ] . regular change of toothbrush and thorough cleaning of dentures are a basic recurrence prophylaxis for oc. oc in hiv-infected children and adults can be treated and relapses prevented by applying disinfecting mouth rinses containing chlorhexidine . % - daily for a -day period [ , ] . in the pre-haart era, secondary prophylaxis or life-long therapy with fluconazole led to significant reductions of chronic recurring oropharyngeal candidiasis-but it has also led to the development of secondary resistance [ , ] . in a randomized study comparing secondary prophylaxis after oc with intermittent therapy on oc recurrence, relapses and infections of systemic candidiasis were reduced by the long-term prophylaxis. however, no survival benefit has been demonstrated for any candidiasis prophylaxis [ ] . primary prophylaxis is not recommended, and indications for secondary prophylaxis should be restricted to individual case. the recommendations on therapy and prophylaxis of candidiasis are summarized in table . herpes simplex virus (hsv) infections are frequent in hiv-infected patients. chronic and atypical courses are possible especially in the setting of severe immune deficiency (\ cd t-cells/ll). organs such as the esophagus, central nervous system (cns), eyes, and respiratory tract may also be affected. in these cases and with persistence of lesions for a period of[ weeks, hsv infection is an aids-defining illness. topical treatment with acyclovir is adequate for patients with a good immune status and only discrete oral lesions. pencyclovir cream is probably as effective [ ] . genital herpes lesions do not respond as well to topical treatment. for systemic treatment against hsv- and hsv- , the drug of choice is still acyclovir. resistance is rare [ ] , and healing of lesions can be accelerated by the therapy [ ] . severe cases with organ involvement should be treated intravenously. as hsv levels are lower in the cns than in plasma, the dose to treat encephalitis should be increased. valacyclovir (valacv) and famcyclovir are equally effective alternatives to acyclovir [ , ] . however, they are not approved for patients with immune deficiency and should only be applied if response to acyclovir fails [ ] . for uncomplicated genital herpes lesions, shorter regimens of days of mg famcyclovir may be as effective, provided there is no immune deficiency [ ] . according to the opinion of some experts, brivudine is an alternative for hsv- and vzv, although contraindicated for immunosuppressed patients and only approved for the treatment of vzv. however, results from controlled studies with hiv-infected patients are not available. in cases of painful mucocutaneous lesions, a local anesthetic can also be applied. treatment with foscarnet for several weeks may be helpful in exceptional cases, especially if lesions remain refractory to standard treatment [ ] . primary prophylaxis is not recommended. an earlier meta-analysis in which acyclovir was found to reduce the risk of both hsv and vzv disease by more than % [ ] must be viewed in the context of art today. nevertheless, long-term treatment with low-dose acyclovir or valacv can still be effective treatments for recurrent hsv [ , ] . the risk of hiv transmission, which is increased threefold by genital hsv-infection [ ] , is not reduced by treatment with acyclovir [ ] [ ] [ ] . between and % of patients with symptomatic hsv- infection and at least - % of patients with symptomatic hsv- infection experience recurring episodes within the first year. possible causes are local trauma, uv exposure, fever, and immune suppression. a long-term prophylaxis for at least months is recommended for frequent recurrences. this prophylaxis can prevent further episodes in - % of cases. the recommendations on therapy and prophylaxis of genital hsv infections are summarized in table . patients infected with hiv are at increased risk for vzv infection. multisegmental zoster or zoster generalisatus are often observed with low cd t-cell counts. chronic courses with ulcerating forms and involvement of other organs are rare. pneumonia or cns involvement should be considered. a monosegmental zoster can be treated with oral acyclovir. famcyclovir and valacv are alternatives. each complicated, multisegmental or facial zoster should be treated intravenously for - days. after clinical improvement is evident, a switch to oral therapy is possible. zoster neuralgia occurs less frequently in hiv-negative patients treated with the alternative drugs valacv, famcyclovir, and brivudine than when treated with acyclovir table therapy and prophylaxis of genital herpes simplex virus infections a therapy/prophylaxis drug therapeutic regimen acute therapy (duration: - days), daily doses first choice acyclovir ( -) mg p.o. severe cases - mg/kg i.v. mg p.o. alternatives valacyclovir - , mg or - , mg (expert opinion) therapy for recurrent herpes simplex infection virus episodes acyclovir mg p.o. for - days valacyclovir , mg for - days famciclovir mg for - days long-term prophylaxis (duration: at least days) acyclovir - - mg valacyclovir mg famciclovir mg a daily doses [ ] . however, according to a cochrane analysis, the results of this study are not clear [ ] . brivudine is not licensed for the treatment of immunocompromised patients. acyclovir resistance is rare and most frequently observed under long-term therapy [ , ] ; in these cases, foscarnet ( mg/kg) or cidofovir ( mg/kg, maximum mg /week) can be given. early concomitant and monitored pain management with nsaids and/or other opiates in combination with amitriptyline and/or pregabalin is important. for further information on zoster pain, the reader is referred to the awmf guidelines. varicella vaccination seems to be fairly safe and effective for patients with a cd t-cell count of [ /ll [ ] . vaccination should be considered if vzv serology is negative. in individuals with negative serology and exposure to vzv, administration of hyperimmunoglobulin may be attempted. long-term primary prophylaxis is usually not effective; however, a long-term low-dose therapy can be considered in the presence of persistent recurring episodes. the recommendations on therapy and prophylaxis of vzv-infections are summarized in table . progressive multifocal leukoencephalopathy (pml) is a severe demyelinating disease of the cns caused by the john cunningham virus (jcv). prognosis for pml was poor in the pre-haart era, with the median interval between the onset of the first symptoms and death being - months. with effective art, there are significantly fewer cases of disease progression, and even complete remission seems possible [ ] . nevertheless, mortality of patients with pml remains high at %, albeit art [ ] . there is no specific pml treatment with proven efficacy; consequently, the mainstay of therapy is immune reconstitution. as such, priority remains on the initiation and optimization of an art. treating physicians are recommended to apply intracerebral penetrating agents. a successful immune reconstitution accounts for a significant reduction in mortality [ ] [ ] [ ] [ ] [ ] [ ] . after initiation of art, a paradoxical worsening of clinical symptoms in terms of an immune reconstitution inflammatory syndrome (iris) has been observed in approximately - % of pml cases. administration of corticosteroids for pml-iris has only been described in case studies [ ] , and evidence of a benefit was not provided. given the slight difference in the -year survival rate for pml patients and pml-iris patients [ ] , the use of corticosteroids or a temporary discontinuation of art must be weighed up against the risks of a possible decline of the jcv-specific immune response. several supportive immunomodulatory approaches have been tested, but to date there is no convincing evidence for the efficacy of treatments with immunoglobulin, interleukin- (il- ), or il-a [ ] . therapeutic regimens aimed at inhibiting jcv replication have also been attempted, but as yet relevant evidence supporting the clinical use of drugs such as cytosine arabinoside is not available [ , ] . antiviral treatment with acyclovir, cidofovir, ganciclovir, brivudin, ribavirin, foscarnet and the combination therapy foscarnet and zidovudine have also proven to be ineffective [ ] . recently, -ht a inhibitors and/or serotonin receptor antagonists have been discussed for pml treatment. in vitro data for the suppression of jcv replicates via ht( a)r inhibitors are contradictory [ ] [ ] [ ] [ ] [ ] [ ] . results from controlled clinical studies are missing. based on promising in vitro data [ ] a phase i/ii study of mefloquine was initiated-only be stopped due to a lack of efficacy. in summary, specific treatments for pml cannot be recommended outside clinical trials. there is no prophylaxis. exposure prophylaxis is also not possible. the recommendations for therapy and prophylaxis of pml are summarized in table . cryptosporidiosis is a parasitic intestinal disease with fecal-oral transmission, mainly caused cryptosporidium parvum (two other frequent types: c. hominis and c. [ ] . infection of the biliary tract leading to sclerosing cholangitis is frequent, particularly among patients with severe immunodeficiency, but may be reversible with immune reconstitution [ ] [ ] [ ] (level of evidence c). other rare manifestations are infections of the pancreatic duct and pulmonary infections [ , ] . successful immune reconstitution under art can lead to complete resolution of clinical crytosporidiosis [ , ] . symptomatic treatment with loperamide and/or tincture of opium should be given. octreotide (off label) can also be applied. sufficient hydration is important and infusions may even be required. no specific treatment has been validated [ ] . rifaximin is promising, as first studies with aids patients show [ ] ; however, results from randomized studies are still missing. nitazoxanide was found to be effective in a small randomized study in immunocompetent patients [ ] . however, this drug is not approved for aids patients and showed no effects in a double-blind randomized study in hiv-infected children with cryptosporidiosis [ ] . paromomycin has been found to have favorable effects on diarrhea [ ] . however, a double-blind randomized study showed no benefit compared to placebo [ ] . in a cochrane review for the prevention and treatment of cryptosporidiosis, paromomycin did not reduce diarrheal frequency permanently [ ] . there is no generally accepted prophylaxis, although a protective effect of rifabutin and clarithromycin has been reported from retrospective studies. azithromycin showed no effect [ ] . the usual hygienic measures (gloves) are usually adequate. patients do not need to be isolated. however, accommodation with other immunosuppressed patients should be avoided. the recommendations on therapy and prophylaxis of cryptosporidiosis are summarized in table . for further information, refer to guidelines by the cdc for cryptosporidiosis in hiv-infected patients (cdc ; http://www.cdc.gov/mmwr) [ ] . cryptococcosis occurs much more frequently in africa, the usa, and southeast asia than in europe. bird droppings (especially of pigeons) are presumably a key reservoir, but a direct transmission between humans has not been observed. although transmission occurs via inhalation, pulmonary symptoms or lung infiltration are only seen in - % of cases of hiv-infected patients. cryptococcosis infection is often followed by disseminated disease in hiv patients with severe immunodeficiency (\ cd t-cells/ ll) and often involves the cns ([ %, meningitis) [ ] . recommended treatment for a cryptococcal meningitis is the combination regimen of amphotericin b deoxycholate (amb-d; . - . mg/kg/day i.v.) and flucytosine ( mg/kg/day i.v. or p.o. if available), divided into four doses a day. acute therapy should be given for at least days. if clinical response is good, a switch to monotherapy with fluconazole ( mg/day) for another weeks is possible [ ] . liposomal amphotericin is slightly more effective than conventional amb-d and provides an alternative, if amb-d is not well tolerated [ ] . monotherapy with fluconazole as initial treatment in hiv-infected patients is not sufficient, even with higher daily doses of - , mg. thus, it is only considered as an option in countries with limited resources [ , ] . in the pre-haart era, a triple combination therapy with amb-d, flucytosine, and fluconazole was favored for the treatment of cryptococcal meningitis in germany [ ] . however, in one randomized study, the triple combination was not more effective than a combination with amb-d and flucytosine or amb-d and fluconazole or a monotherapy with amb-d [ ] . the combination with amb-d and fluconazole is an alternative in regions with limited resources where flucytosine is not available. in a small study in thailand, a higher dose of fluconazole ( mg/day) combined with amb-d ( . mg/kg/day) was more effective than monotherapy with amb-d alone or a regimen of amb-d ? fluconazole ( mg/day). other combination therapies (e.g. fluconazole ? flucytosine) are possible alternatives, but lack sufficient data [ ] . itraconazole plays no role in primary therapy and is less effective than fluconazole in maintenance therapy [ ] . monotherapy with posaconazole showed a response rate of up to % in a small case study on refractory diseases and therefore provides an alternative for this indication [ ] . efficacy of voriconazole in salvage therapy is still not clear [ ] . echinocandines show no in vitro effect against c. neoformans. in the case of an iris when art is initiated during antimycotic treatment, additional treatment with corticosteroids ( . - . mg/kg/day prednisolone equivalent) is required [ ] . in refractory treatment situations, additional administration of c-interferon might be useful in individual cases [ ] . treatment success is monitored based on the clinical course and repeated lumbal punctures. patients should have their intracranial pressure measured at time of diagnosis. if the intracranial pressure is very high, several punctures should be made in the first week until it is reduced to b cm. in individual cases, cerebrospinal fluid (csf) drainage can be considered to reduce the intracranial pressure if there are no contraindications [ ] . for mild, isolated cryptococcal pneumonia (negative csf diagnosis), monotherapy with fluconazole ( mg/day) is possible. treatment should continue for - months. severe cases of pneumonia with or without acute respiratory distress syndrome (ards) should be treated the same way as meningitis (see above). art-naïve patients at the time of diagnosis should start an art after a wo-week induction therapy with antimycotics. however, an optimal time for initiation of art is not yet clearly defined. primary prophylaxis can not be recommended to hivinfected patients in germany due to lack of a clear survival benefit [ ] . after acute therapy of cryptococcal meningitis, secondary prophylaxis should be introduced. fluconazole ( mg/day) is the regimen of choice and is also more effective than itraconazole [ ] . secondary prophylaxis can be discontinued after at least months maintenance therapy with sufficient immune reconstitution ([ cd t-cells/ll and hiv-rna below detection limit for over months). the risk of a relapse is high if maintenance therapy is discontinued too early [ ] . the recommendations on therapy and prophylaxis of cryptococcosis are summarized in table . human immunodeficiency virus-associated infections of nontuberculous mycobacteria (ntm) have declined in countries where art is available [ ] [ ] [ ] . in addition to disseminated ntm diseases, which develop almost exclusively in the setting of severe cd t-cell depletion (\ cd t-cells/ll) and which are mainly ([ %) caused by the mycobacterium avium complex or m. intracellulare (mycobacterium avium intracellure complex, mai), incidences of ntm-iris as well as pulmonary ntm diseases are also observed. pulmonary ntm is frequently caused by other species, such as m. kansasii, m. xenopi, m. malmoense, and m. abscessus. for further information on diagnosis, the reader is referred to the american thoracic society criteria [ ] . due to the ubiquitous occurrence of ntm, pre-exposure prophylaxis is not possible and an isolation of infected patients is not necessary. some specialists, however, recommend a screening of generalized mai infections in patients with cd t-cell counts of\ /ll prior to initiation of an art. given here are only recommendations for the mai therapy. with respect to ntm species other than mai, the reader is referred to the appropriate literature [ ] or advised to consult experts (ntm-net). a combination treatment of macrolide (clarithromycin or azithromycin) and ethambutol plus/minus rifabutin is recommended [ ] . rifabutin is preferred to rifampicin due to its in vitro efficacy against mai and its lower interaction potential. following the publication of data showing that rifabutin could be omitted from the treatment regimen [ ] , another randomized study demonstrated a survival benefit with the triple combination clarithromycin, rifabutin, and ethambutol compared to clarithromycin with either ethambutol or rifabutin-the mortality rate was halved in the treatment arm receiving this triple (clarithromycin-containing) combination [ ] . the doses for rifabutin must occasionally be adjusted to the art regimen [ ] . clarithromycin increases the rifabutin serum level, while rifabutin decreases the clarithromycin level. treatment duration with rifabutin has not yet been determined in studies; however, experts recommend discontinuing rifabutin after a few weeks and with clinical improvement. the daily doses for clarithromycin should not exceed mg, as a higher mortality risk has been described for patients receiving higher dosages [ , ] . azithromycin can be administered instead of clarithromycin, as these two drug are comparably effective in combination with ethambutol, with slightly more rapid sterilization of blood cultures with clarithromycin [ , , ] . as macrolides are the cornerstone of therapy, the development of resitance to macrolides must be avoided, and monotherapy with macrolides should not be administered. in the case of intolerance, alternative substances, such as fluoroquinolone, amikacin, cycloserine, dapsone, linezolid, or mefloquine, are available. however, clinical evidence for the treatment of mai infections with these alternative substances is still insufficient. in the case of ntm-iris, the extent and duration of an antimycobacterial therapy are not clear. it is possible that partial virus suppression is enough for a ntm-specific immune reconstitution [ ] . it is easier to evaluate the clinical response to localized ntm infections. in cases of localized lymphadenitis and skin manifestations, therapy duration of months is recommended after patients are culture-negative. if the clinical response is good and cd t-cells continue to increase under a still effective art, the regimen can be reduced after months to a recurrence prophylaxis with a macrolide for a further months. patients with abdominal localization have a poorer response and require a more aggressive and longer therapy [ , ] . additive corticoid therapy has symptomatic indications. the treatment of patients with pulmonal ntm diseases not deriving from an iris are based on the guidelines for non-hiv-infected patients [ ] . in the usa, placebo controlled trials for clarithromycin, azithromycin and rifabutin showed that primary prophylaxis significantly reduced mai-morbidity and -mortality in severely immunocompromised patients [ ] [ ] [ ] [ ] . all these studies, however, were undertaken in the pre-ha-art era. in addition, mai-infections are less frequent in europe, so that only a few patients receive primary prophylaxis [ ] . due to the declining incidences since the introduction of art, primary prophylaxis can only avoid a small number of diseases [ ] . ntm-associated iris can also not be prevented by prophylactic drugs [ ] . therefore primary prophylaxis is not recommended in germany. after treatment of a disseminated mai-infection, patients lacking other art options, should receive secondary prophylaxis with a macrolide, provided cd t-cell count is under cells/ll. weekly doses of azithromycin are convenient and efficacy is comparable to daily rifabutin [ ] . secondary prophylaxis or maintenance therapy can be discontinued under an art and if patients are without symptoms and cd t-cell count is [ /ll for months. the recommendations concerning therapy and prophylaxis of disseminated mai-diseases are summarized in table . globally, tb is the most prevalent hiv-associated opportunistic infection. in germany, tb is rare. hiv-infected patients are affected by tb independent of their cd t-cell count [ ] , although incidences increase with advanced immunodeficiency [ ] . uncomplicated cases of tb can successfully be treated with a standard therapy regimen over a period of months, regardless of hiv status. first-line drugs are rifampicin, inh, ethambutol, pyrazinamide, and streptomycin, with inh and rifampicin being the most effective. tb should always be treated with a combination of four drugs in the initial phase to prevent drug resistance. standard initial phase therapy is a -month course of rifampicin, inh, ethambutol, and pyrazinamide, followed by a continuation phase therapy of months rifampicin and inh. in individual cases, such as incompliance, it may be necessary to extend the standard treatment duration to c months, especially if sputum cultures are still positive after months. recurrences after successful therapy appear more frequently in hiv-infected patients [ ] . if standard therapy has not been initially applied, treatment should always last for at least months. alternatively, ethambutol, streptomycin, and reserve drugs such as ofloxacin or moxifloxazin, cycloserine, and linezolid may be administered. since this treatment is no different from that for multiresistant tb, these patients should be treated in specialized centers. adverse effects occur frequently with anti-tb therapy (refer to individual drug information for side effects, necessary testing, and drug interactions). severe side effects are observed more often in hiv-infected patients than in hiv-negative patients [ ] . antiretroviral therapy significantly reduces the morbidity and mortality rate in hiv-infected patients [ ] . a -month tb standard therapy achieves similar success in both hiv-infected and hiv-negative patients [ ] . although a large retrospective and a large open-label, randomized trial showed a survival benefit with simultaneous art and anti-tb treatment, this approach proves to be difficult in practice due to overlapping drug interactions and side effects [ ] . for tb meningitis, side effects are more frequent during the first months of therapy if art and anti-tb therapy are initiated simultaneously. in this case, a delay of art by months is possible without risking a higher mortality [ ] . with regard to other forms of tb, - % of patients develop an iris in the first months of art treatment [ ] . a consensus on a uniform case definition of tb-iris was reached in [ ] , which we refer to in the chapter on iris of this guideline. adherence to simultaneous hiv and mycobacterium tb treatment is difficult to achieve due to the high pill burden and overlapping toxicities. both rifampicin and protease inhibitors (pis) are metabolized by cytochrome p a. concomitant therapy is therefore not recommended [ , ] (table ). rifabutin can be combined with boosted unboosted protease inhibitors are no longer recommended due to insufficient plasma levels. consider tdm pis, however the dose must be adjusted (table ). it may be useful to determine serum levels [ ] ; however, this approach has not been tested in clinical research with clear endpoints. recommendations can be given for first-line art therapy with tenofovir (tdf), tdf ? emtricitabine (ftc), and ftc plus efavirenz in combination with rifampicinbased tb therapy. alternatives are other efavirenz-based regimens (without adjustment of dose) with rifabutin [ ] . to date, clinical data on combinations of rifamycin with new drugs, such as darunavir, raltegravir, or maraviroc, are limited. due to the strong inducing potential of cytochrome p a, pis should be avoided and maraviroc should only be given under close observation. rifampicin also induces the enzyme ugt a , leading to increased glucoronidation and reduced plasma levels of raltegravir [ ] . no interactions have been reported with tenofovir and t- [ ] . the recommendations on the adjustment for combination of art/rifampicin in tb therapy are summarized in table . treatment of active tb has clinical priority over art. in patients with \ cd t-cells/ll, simultaneous treatment of both infections is indicated [ , ] . however, even in this situation it is recommended to start tb therapy first for weeks before initiating art to prevent possible side effects. for patients with - cd t-cells/ll, art can be delayed for months until the anti-tb drugs can be reduced for the continuation phase. there is no evidence for an optimal timing of art when the cd t-cell count is [ cells/ll [ ] . the results of a large randomized trial indicate that mortality rate in patients with - cd t-cells/ll is reduced when art is initiated during tb therapy [ ] . for hiv patients with\ cd t-cells/ll, the results of a recent study show a benefit of a delayed art. the decision should be made carefully under consideration of the situation of each single patient [ , ] . hiv-infected patients already on a successful art should remain on art, although the regimen may need to be modified [ ] . the recommendations for co-administering art with rifabutin are summarized in the statement that adherence is the most important factor for therapeutic success and to avoid resistant tb strains. the world health organization (who) recommends a directly observed therapy for these patients. latent tuberculosis infection (ltbi) is defined by a positive mycobacterium tb-specific immune response in the tuberculin skin test (tst) or an interferon gamma release assay (igra) in the absence of active tb. clear values for a positive mycobacterium tb-specific immune response in hiv-infected patients do not exist. patients are not infectious as the tb is not active. however, hiv-infected patients with ltbi carry a higher risk of developing active tb. according to guidelines for the treatment of ltbi by the cdc [ ] , hivinfected patients with a tst of [ mm should be given treatment with inh for months. this probably also applies to patients with positive igra test results, but convincing data are still missing [ ] . alternatively, a -month course of rifampicin can be given. a -month course of rifampicin and pyrazinamide is no longer recommended, as it has been associated with significantly higher toxicities in hiv-negative patients [ , ] . in , . % of all tb patients showed multidrug resistance (at least resistance against inh and rifampicin). among these, % were hiv-infected [ ] . in addition to incidences of multidrug resistance (mdr), incidences of extensive drug resistance (xdr) were reported in at least countries in [ ] . xdr tb is defined by the who as tb which is additionally resistant to fluoroquinolones and at least one of the injectable drugs amikacin, capreomycin, or kanamycin. due to the complex therapy and an overall poor prognosis, patients with mdr/xdrtb should be treated in specialized centers. conflict of interests conflict of interest statements of all authors are published online: http://daignet.de/site-content/hiv-therapie/ open access this article is distributed under the terms of the creative commons attribution license which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. final consent to this version by the steering committee of the Ö ag given on november . hiv-associated opportunistic infections-going, going, but not gone: the continued need for prevention and treatment guidelines patients presenting with aids in the ha-art era: a collaborative cohort analysis guidelines for prevention and treatment of opportunistic infections in hiv-infected adults and adolescents: recommendations from cdc, the national institutes of health, and the hiv medicine association of the infectious diseases society of america cytomegalovirus retinitis after initiation of highly active antiretroviral therapy focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced hiv- disease immune reconstitution inflammatory syndrome: more answers, more questions aids: immune reconstitution inflammatory syndrome: a reappraisal immune reconstitution syndrome in hiv: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus case definitions in a south african cohort incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse hiv type -infected cohort incidence and risk factors for the immune reconstitution inflammatory syndrome in hiv patients in south africa: a prospective study immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for hiv infection: a systematic review and meta-analysis immunereconstitution inflammatory syndrome in a prospective german cohort. abstract . kit tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in south africa early antiretroviral therapy reduces aids progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial integration of antiretroviral therapy with tuberculosis treatment early versus delayed initiation of antiretroviral therapy for concurrent hiv infection and cryptococcal meningitis in sub-saharan africa cryptococcal immune reconstitution inflammatory syndrome after antiretroviral therapy in aids patients with cryptococcal meningitis: a prospective multicenter study randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome clinical practice guidelines for the management of cryptococcal disease: update by the infectious diseases society of america reducing tuberculosis incidence by tuberculin skin testing, preventive treatment, and antiretroviral therapy in an area of low tuberculosis transmission immune reconstitution inflammatory syndrome in the first year after haart: influence on long-term clinical outcome noninvasive ventilation for treating acute respiratory failure in aids patients with pneumocystis carinii pneumonia good outcome with trimethoprim mg/kg/day-sulfamethoxazole mg/kg/day for pneumocystis jirovecii pneumonia in hiv infected patients adjunctive corticosteroids for pneumocystis jiroveci pneumonia in patients with hiv-infection treatment of mild to moderately severe pneumocystis carinii pneumonia with cotrimoxazole versus pentamidine aerosol. preliminary results of a prospective randomized therapy study pentamidine aerosol versus trimethoprim-sulfamethoxazole for pneumocystis carinii in acquired immune deficiency syndrome intravenous or inhaled pentamidine for treating pneumocystis carinii pneumonia in aids. a randomized trial inhaled or intravenous pentamidine therapy for pneumocystis carinii pneumonia in aids. a randomized trial treating opportunistic infections among hiv-infected adults and adolescents: recommendations from cdc, the national institutes of health, and the hiv medicine association/infectious diseases society of america comparison of atovaquone ( c ) with trimethoprim-sulfamethoxazole to treat pneumocystis carinii pneumonia in patients with aids oral atovaquone compared with intravenous pentamidine for pneumocystis carinii pneumonia in patients with aids. atovaquone study group clindamycin with primaquine vs. trimethoprim-sulfamethoxazole therapy for mild and moderately severe pneumocystis carinii pneumonia in patients with aids: a multicenter, double-blind, randomized trial (ctn ). ctn-pcp study group second-line salvage treatment of aids-associated pneumocystis jirovecii pneumonia: a case series and systematic review clinical efficacy of first-and second-line treatments for hiv-associated pneumocystis jirovecii pneumonia: a tri-centre cohort study a metaanalysis of the relative efficacy and toxicity of pneumocystis carinii prophylactic regimens efficacy of trimethoprim-sulfamethoxazole for the prevention of bacterial infections in a randomized prophylaxis trial of patients with advanced hiv infection a randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of pcp in hivinfected persons trimethoprim-sulfamethoxazole (tmp-smz) dose escalation versus direct rechallenge for pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to tmp-smz meta-analysis of prophylactic treatments against pneumocystis carinii pneumonia and toxoplasma encephalitis in hiv-infected patients a randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. niaid aids clinical trials group atovaquone compared with dapsone for the prevention of pneumocystis carinii pneumonia in patients with hiv infection who cannot tolerate trimethoprim, sulfonamides, or both. community program for clinical research on aids and the aids clinical trials group atovaquone suspension compared with aerosolized pentamidine for prevention of pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides atovaquone suspension for treatment of pneumocystis carinii pneumonia in hiv-infected patients discontinuation of prophylaxis for pneumocystis carinii pneumonia in hiv- -infected patients treated with highly active antiretroviral therapy discontinuation of pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in hiv- infection. euros-ida study group a randomized trial of the discontinuation of primary and secondary prophylaxis against pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with hiv infection. grupo de estudio del sida / pneumocystis carinii pneumonia recurrence in hiv patients on highly active antiretroviral therapy: secondary prophylaxis pneumocystis carinii pneumonia after the discontinuation of secondary prophylaxis discontinuation of secondary prophylaxis for pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients: a randomized trial by the ciop study group pneumocystis jiroveci pneumonia prophylaxis is not required with a cd ? t-cell count\ cells/microl when viral replication is suppressed incidence and risk factors for toxoplasmic encephalitis in human immunodeficiency virusinfected patients before and during the highly active antiretroviral therapy era prevalence, associated factors, and prognostic determinants of aids-related toxoplasmic encephalitis in the era of advanced highly active antiretroviral therapy treatment of toxoplasmic encephalitis in patients with aids. a randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. the california collaborative treatment group treatment of central nervous system toxoplasmosis with pyrimethamine/sulfadiazine combination in patients with the acquired immunodeficiency syndrome. efficacy of long-term continuous therapy pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with aids cotrimoxazole therapy of toxoplasma gondii encephalitis in aids patients cotrimoxazole for treatment of cerebral toxoplasmosis: an observational cohort study during - randomized trial of trimethoprim-sulfamethoxazole versus pyrimethamine-sulfadiazine for therapy of toxoplasmic encephalitis in patients with aids. italian collaborative study group prospective randomized trial of trimethoprim/sulfamethoxazole versus pyrimethamine and sulfadiazine in the treatment of ocular toxoplasmosis management of toxoplasmic encephalitis in hiv-infected adults (with an emphasis on resource-poor settings) central nervous system toxoplasmosis in hiv pathogenesis, diagnosis, and therapy randomized phase ii trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome: actg /anrs study. aids clinical trials group /agence nationale de recherche sur le sida, essai a prospective, randomized trial of pyrimethamine and azithromycin vs pyrimethamine and sulfadiazine for the treatment of ocular toxoplasmosis cats and toxoplasmosis risk in hiv-infected adults thrice-weekly sulfadiazine-pyrimethamine for maintenance therapy of toxoplasmic encephalitis in hiv-infected patients. spanish toxoplasmosis study group comparison of high and low doses of trimethoprim-sulfamethoxazole for primary prevention of toxoplasmic encephalitis in human immunodeficiency virusinfected patients maintenance therapy with cotrimoxazole for toxoplasmic encephalitis in the era of highly active antiretroviral therapy discontinuation of primary and secondary toxoplasma gondii prophylaxis is safe in hiv-infected patients after immunological restoration with highly active antiretroviral therapy: results of an open, randomized, multicenter clinical trial immune recovery under highly active antiretroviral therapy is associated with restoration of lymphocyte proliferation and interferon-gamma production in the presence of toxoplasma gondii antigens restoration of toxoplasma gondii-specific immune responses in patients with aids starting haart guidelines for the treatment of cytomegalovirus diseases in patients with aids in the era of potent antiretroviral therapy: recommendations of an international panel restoration of cytomegalovirusspecific cd ? t-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with hiv- loss of cytomegalovirus (cmv) viraemia following highly active antiretroviral therapy in the absence of specific anti-cmv therapy cytomegalovirus retinitis in advanced hiv-infected patients treated with protease inhibitors: incidence and outcome over years long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virusinfected patients pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in hiv-and cmv-seropositive volunteers single-dose pharmacokinetics of valganciclovir in hiv-and cmv-seropositive subjects increased survival of a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis who received sodium phosphonoformate studies of ocular complications of aids research group in collaboration with the cytomegalovirus retinitis trial. . visual outcomes. studies of ocular complications of aids research group in collaboration with the foscarnet and ganciclovir in the treatment of cmv retinitis in aids patients: a randomised comparison cytomegalovirus retinitis and viral resistance: ganciclovir resistance. cmv retinitis and viral resistance study group incidence of foscarnet resistance and cidofovir resistance in patients treated for cytomegalovirus retinitis. the cytomegalovirus retinitis and viral resistance study group a controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis a safety study of oral valganciclovir maintenance treatment of cytomegalovirus retinitis intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with aids. a randomized, controlled trial combination foscarnet and ganciclovir therapy vs monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with aids. the cytomegalovirus retreatment trial. the studies of ocular complications of aids research group in collaboration with the treatment of relapsed cytomegalovirus retinitis with the sustained-release ganciclovir implant cytomegalovirus (cmv) retinitis in aids. gancilovir implantation in comparison with systemic therapy local therapy for cytomegalovirus retinitis treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant the development of cytomegalovirus encephalitis in aids patients receiving ganciclovir cytomegalovirus ventriculoencephalitis in aids. a syndrome with distinct clinical and pathologic features progressive cytomegalovirus encephalitis in successful ganciclovir therapy of cytomegalovirus retinitis in an aids patient cmv encephalitis during ganciclovir therapy of cmv retinitis cytomegalovirus encephalitis in two patients with aids receiving ganciclovir for cytomegalovirus retinitis ganciclovir therapy for cytomegalovirus (cmv) infection of the central nervous system in aids patients: monitoring by cmv dna detection in cerebrospinal fluid lack of reactivation of cytomegalovirus (cmv) retinitis after stopping cmv maintenance therapy in aids patients with sustained elevations in cd t cells in response to highly active antiretroviral therapy discontinuation of maintenance therapy for cytomegalovirus retinitis in hiv-infected patients receiving highly active antiretroviral therapy resistance of candida species to antifungal agents: molecular mechanisms and clinical consequences effendy i, et al. oral candidiasis guideline vulvovaginal candidosis: guideline of the german dermatological society, the german speaking mycological society and the working group for infections and infectimmunology of the german society for gynecology and obstetrics oropharyngeal candidiasis in immunocompromised children: a randomized, multicenter study of orally administered fluconazole suspension versus nystatin. the multicenter fluconazole study group the treatment of oropharyngeal candidiasis in hiv-infected patients with oral amphotericin b suspension oropharyngeal candidiasis in patients with aids: randomized comparison of fluconazole versus nystatin oral suspensions a multicenter randomized trial evaluating posaconazole versus fluconazole for the treatment of oropharyngeal candidiasis in subjects with hiv/aids fluconazole compared with itraconazole in the treatment of esophageal candidiasis in aids patients: a double-blind, randomized, controlled clinical study a randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients a double-blind comparison of itraconazole oral solution and fluconazole capsules for the treatment of oropharyngeal candidiasis in patients with aids mucosal and systemic fungal infections in patients with aids: prophylaxis and treatment single-dose fluconazole versus standard -week therapy for oropharyngeal candidiasis in hiv-infected patients: a randomized, double-blind, double-dummy trial single-dose therapy for oral candidiasis with fluconazole in hiv-infected adults: a pilot study itraconazole cyclodextrin solution-effective treatment for hiv-related candidosis unresponsive to other azole therapy treatment of fluconazole-resistant candidiasis with voriconazole in patients with aids posaconazole for the treatment of azole-refractory oropharyngeal and esophageal candidiasis in subjects with hiv infection safety and efficacy of posaconazole in the longterm treatment of azole-refractory oropharyngeal and esophageal candidiasis in patients with hiv infection high-dose therapy with fluconazole [or = mg/day a randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis a randomized, double blind, comparative trial of micafungin (fk ) vs. fluconazole for the treatment of oesophageal candidiasis a randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis a phase , open-label study of the safety and efficacy of intravenous anidulafungin as a treatment for azolerefractory mucosal candidiasis a randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis resolution of azole-resistant oropharyngeal candidiasis after initiation of potent combination antiretroviral therapy declining rates of oropharyngeal candidiasis and carriage of candida albicans associated with trends toward reduced rates of carriage of fluconazole-resistant c. albicans in human immunodeficiency virus-infected patients efficacy of chlorhexidine gluconate rinse for treatment and prevention of oral candidiasis in hiv-infected children: a pilot study. oral surg oral med oral pathol oral radiol endod a randomized clinical trial of chlorhexidine in the maintenance of oral candidiasis-free period in hiv infection detection and significance of fluconazole resistance in oropharyngeal candidiasis in human immunodeficiency virus-infected patients development of resistance in candida isolates from patients receiving prolonged antifungal therapy a randomized study of the use of fluconazole in continuous versus episodic therapy in patients with advanced hiv infection and a history of oropharyngeal candidiasis: aids clinical trials group study /mycoses study group study a comparison of topical application of penciclovir % cream with acyclovir % cream for treatment of genital herpes: a randomized, double-blind, multicentre trial resistance of herpes simplex virus infections to nucleoside analogues in hiv-infected patients impact of aciclovir on ulcer healing, lesional, genital and plasma hiv- rna among patients with genital ulcer disease in malawi valaciclovir: a review of its long term utility in the management of genital herpes simplex virus and cytomegalovirus infections valaciclovir versus aciclovir for herpes simplex virus infection in hiv-infected individuals: two randomized trials famciclovir for the treatment of recurrent genital herpes: a clinical and pharmacological perspective -day versus -day famciclovir as treatment of recurrences of genital herpes: results of the fast study treatment of acyclovir-resistant herpes simplex virus infections in patients with aids clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a metaanalysis of randomized individual patient data valacyclovir for the suppression of recurrent genital herpes in human immunodeficiency virusinfected subjects efficacy and safety of valacyclovir for the suppression and episodic treatment of herpes simplex virus in patients with hiv herpes simplex virus infection increases hiv acquisition in men and women: systematic review and metaanalysis of longitudinal studies effect of aciclovir on hiv- acquisition in herpes simplex virus seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial acyclovir and transmission of hiv- from persons infected with hiv- and hsv- effect of herpes simplex suppression on incidence of hiv among women in tanzania clinical practice. herpes zoster antiviral treatment for preventing postherpetic neuralgia. cochrane database syst rev prevention and treatment of vzv infections in patients with hiv clinical and virologic characterization of acyclovirresistant varicella-zoster viruses isolated from patients with acquired immunodeficiency syndrome highly active antiretroviral therapy significantly improves the prognosis of patients with hiv-associated progressive multifocal leukoencephalopathy treatment options for aids patients with progressive multifocal leukoencephalopathy haart improves prognosis in hivassociated progressive multifocal leukoencephalopathy progressive multifocal leukoencephalopathy: improved survival of human immunodeficiency virus-infected patients in the protease inhibitor era progressive multifocal leukoencephalopathy in patients with aids receiving highly active antiretroviral therapy clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy pml-iris in patients with hiv infection: clinical manifestations and treatment with steroids determinants of survival in progressive multifocal leukoencephalopathy progressive multifocal leukoencephalopathy: what's new? failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. aids clinical trials group team activities of various compounds against murine and primate polyomaviruses inhibitory effect of serotonin antagonists on jc virus propagation in a carrier culture of human neuroblastoma cells serotonin receptor a blocker (risperidone) has no effect on human polyomavirus jc infection of primary s human fetal glial cells mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera risperidone-induced reduction in jc viruria as a surrogate marker for efficacy against progressive multifocal leukoencephalopathy and hemorrhagic cystitis -ht a inhibitors for progressive multifocal leukoencephalopathy: old drugs for an old disease mirtazapine use in human immunodeficiency virus-infected patients with progressive multifocal leukoencephalopathy identification and characterization of mefloquine efficacy against jc virus in vitro cryptosporidiosis among patients infected with human immunodeficiency virus. factors related to symptomatic infection and survival the natural history of cryptosporidial diarrhoea in hiv-infected patients sclerosing cholangitis with papillary stenosis in an hiv-infected patients with cryptosporidium infection a report of cases aids and multiple system involvement with cryptosporidium respiratory cryptosporidiosis in a patient with malignant lymphoma treatment of hiv- -associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy eradication of cryptosporidia and microsporidia following successful antiretroviral therapy prevention and treatment of cryptosporidiosis in immunocompromised patients resolution of severe cryptosporidial diarrhea with rifaximin in patients with aids treatment of diarrhea caused by cryptosporidium parvum: a prospective randomized, double-blind, placebo-controlled study of nitazoxanide high dose prolonged treatment with nitazoxanide is not effective for cryptosporidiosis in hiv positive zambian children: a randomised controlled trial paromomycin in cryptosporidiosis paromomycin: no more effective than placebo for treatment of cryptosporidiosis in patients with advanced human immunodeficiency virus infection possible effectiveness of clarithromycin and rifabutin for cryptosporidiosis chemoprophylaxis in hiv disease. hiv outpatient study (hops) investigators liposomal amphotericin b (ambisome) compared with amphotericin b both followed by oral fluconazole in the treatment of aids-associated cryptococcal meningitis management of cryptoccocal meningitis in resource-limited settings: a systematic review therapy of candidiasis and cryptococcosis in aids combination antifungal therapies for hivassociated cryptococcal meningitis: a randomised trial treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. national institute of allergy and infectious diseases mycoses study group and aids clinical trials group activity of posaconazole in the treatment of central nervous system fungal infections voriconazole treatment for less-common, emerging, or refractory fungal infections recombinant interferon-gamma b as adjunctive therapy for aids-related acute cryptococcal meningitis a randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. niaid aids clinical trials group long-term outcome of aids-associated cryptococcosis in the era of combination antiretroviral therapy aids-defining opportunistic illnesses in us patients, - : a cohort study mycobacterium avium complex in patients with hiv infection in the era of highly active antiretroviral therapy disseminated mycobacterium avium-intracellulare complex (mac) infection in the era of effective antiretroviral therapy: is prophylaxis still indicated? an official ats/idsa statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases a randomized, double-blind trial comparing azithromycin and clarithromycin in the treatment of disseminated mycobacterium avium infection in patients with human immunodeficiency virus a prospective, randomized trial examining the efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated mycobacterium avium complex disease in persons with acquired immunodeficiency syndrome pharmacokinetic evaluation of rifabutin in combination with lopinavir-ritonavir in patients with hiv infection and active tuberculosis clarithromycin therapy for bacteremic mycobacterium avium complex disease. a randomized, double-blind, dose-ranging study in patients with aids. aids clinical trials group protocol study team a prospective randomized trial of four three-drug regimens in the treatment of disseminated mycobacterium avium complex disease in aids patients: excess mortality associated with highdose clarithromycin. terry beirn community programs for clinical research on aids randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. veterans affairs hiv research consortium effect of potent antiretroviral therapy on immune responses to mycobacterium avium in human immunodeficiency virus-infected subjects nontuberculous mycobacterial immune reconstitution syndrome in hiv-infected patients: spectrum of disease and long-term follow-up mycobacterium avium complex immune reconstitution inflammatory syndrome: long term outcomes prophylaxis against disseminated mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. california collaborative treatment group incidence of mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients once weekly azithromycin therapy for prevention of mycobacterium avium complex infection in patients with aids: a randomized, double-blind, placebo-controlled multicenter trial a randomized trial of clarithromycin as prophylaxis against disseminated mycobacterium avium complex infection in patients with advanced acquired immunodeficiency syndrome regional differences in use of antiretroviral agents and primary prophylaxis in european hiv-infected patients. eurosida study group response to treatment, mortality, and cd lymphocyte counts in hiv-infected persons with tuberculosis in abidjan risk factors for developing tuberculosis in hiv- -infected adults from communities with a low or very high incidence of tuberculosis hiv- and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in south african mineworkers adverse events and treatment interruption in tuberculosis patients with and without hiv co-infection outcome of hivassociated tuberculosis in the era of highly active antiretroviral therapy treatment of hiv-related tuberculosis in the era of effective antiretroviral therapy timing of initiation of antiretroviral drugs during tuberculosis therapy when to start antiretroviral therapy in hiv-associated tuberculosis clinical characteristics of iris syndrome in patients with hiv and tuberculosis office of aids research advisory council (oarac). guidelines for the use of antiretroviral agents in hiv- -infected adults and adolescents. department of health and effect of rifampin, a potent inducer of drugmetabolizing enzymes, on the pharmacokinetics of raltegravir lack of enzyme-inducing effect of rifampicin on the pharmacokinetics of enfuvirtide treatment of tuberculosis in hiv-infected persons in the era of highly active antiretroviral therapy timing of antiretroviral therapy for hiv- infection and tuberculosis detection and prediction of active tuberculosis disease by a whole-blood interferon-gamma release assay in hiv- -infected individuals managing drug interactions in the treatment of hiv-related tuberculosis. division of tuberculosis elimination national center for hiv/ aids, viral hepatitis, std, and tb prevention treatment of latent tuberculosis infection in hiv infected persons multidrug-and extensively drug-resistant tuberculosis multidrug and extensively drug-resistant tb (m/xdr-tb): global report on surveillance and response. who/htm/tb/ . . . who acknowledgments we are indepted to fiona diekhoff for translation and preparation of the manuscript. key: cord- - fs f b authors: youde, jeremy title: is universal access to antiretroviral drugs an emerging international norm? date: - - journal: j int relat dev (ljubl) doi: . /jird. . sha: doc_id: cord_uid: fs f b the international community appears to have embraced a new norm — that of universal access to antiretroviral drugs. the process by which this norm has found acceptance raises interesting questions about how norm entrepreneurs frame their arguments, the role of non-state actors in realizing a norm, and the importance of existent complementary norms. to understand the success of the norm of universal antiretroviral access, i examine the failure of an earlier health-related norm — that of universal primary health care. the campaign for universal antiretroviral access points to a need for a more nuanced understanding of norm evolution within the international community and a more holistic vision of which actors can facilitate the realization of a norm. most visible by the  (to provide million hiv-positive persons in the developing world with arv access by the end of ) and all by (to provide universal access by the end of ) campaigns, promotes providing access to these drugs regardless of ability to pay or country of residence. according to the precepts of this new norm, those infected with hiv in developing countries will have access to similar arvs as are available to people in developed countries. in , only , people in low-and middle-income countries had access to arvs. by , the number had jumped fivefold to . million. in addition, low-and middle-income countries offered arvs to at least half of their citizens in need (unaids : ) . all regions of the world have seen dramatic increases in arv availability. because they see it as the right thing to do, national governments, donor states, international organizations, nongovernmental organizations, private philanthropic organizations, and multinational corporations have come together in a coalition to further expand arv access to those individuals who do not have the ability to pay for these drugs. the emergence and apparent adoption of a new norm is, in and of itself, a remarkable event. even more remarkably, this new norm emerged less than years after an earlier attempt to promote universal health care for all failed to take hold within the international community. universal arv access is perhaps the most ambitious global public health campaign undertaken since the successful quest to eradicate smallpox. achieving this target will require international cooperation, vastly increased levels of financial assistance from developed countries, the active participation of international pharmaceutical companies, and rethinking and reapplying international intellectual property rights. perhaps more importantly, this new programme will require the international community to embrace a new norm that places the right to health and health care above concerns about the ability to pay and the sovereign right of states to manage their national health programmes. in their ambition, promoters set explicit deadlines for realizing this new norm's behavioural expectation. even though the  campaign failed to meet its target, the international community has remained energized around this idea of universal arv access and continues to move towards it -though its strategies for doing so are different from those generally recognized by the literature on norm evolution and acceptance. how has this new norm emerged and why has it emerged now? these two questions raise provocative and important concerns about the nature of norm entrepreneurs, the life cycle of norms in the international arena, and how norms evolve over time. in this case, universal arv access' norm entrepreneurs framed their campaign as an issue of individual human rights (an already existent and resonant norm) instead of as a collective public good (as the earlier promoters of universal health care for all did). reframing the norm allowed it to achieve greater success. most research on norm adoption and evolution focuses largely on the role of state actors and nongovernmental organizations, often presenting norms in relatively discrete terms. the case of universal arv access demonstrates the importance of actors who fall outside both traditional state structures and mass social movements. it also shows how norms adapt to changing international contexts to resonate with existing ideas. examining the case of universal arv access, we gain a nuanced view of norm adoption and internalization, a better appreciation for the range of actors important for promoting a norm, and an understanding of the importance of complementary international norms for successful norm adoption. to explain why the norm of universal arv access has emerged when earlier health-related norms failed, i begin by reviewing the literature on how norms evolve and take root within the international community. i then turn my attention to a case of a failed norm: universal primary health care, most prominently embodied in the alma-ata declaration and its attendant health for all by campaign. the third section focuses explicitly on universal arv access: where it came from, how entrepreneurs promoted it, and where we see evidence of its acceptance. i next look at the factors that allowed universal arv access to take root within the international community despite previous health-related norm failures. finally, i tie the specifics of universal arv access' history to our broader understanding of norm evolution, showing how it illustrates the need to reconsider the factors that promote the acceptance of international norms. finnemore defines norms as 'shared expectations about appropriate behaviour held by a community of actors ' ( : ) . a norm spells out how members of a group believe each other should act. it may or may not be explicitly codified, but members of a community understand the standards expected by the norm and hold each other accountable for conducting themselves in a manner consistent with it. it both constrains and enables action by defining the boundaries of acceptable behaviour (klotz : - ) . for example, the norm of sovereignty posits that one state does not have the right to interfere or intervene in the affairs of another state. states share an understanding that following the norm of sovereignty is appropriate behaviour for members of the international community, and those who violate the norm face possible sanctioning. such behavioural expectations are not always formalized by international law or treaties, though they may eventually be; rather, they operate most prominently as a shared social expectation. this social aspect is crucial, since norms can and will change as shared understandings change. to return to the sovereignty example, the behavioural expectations that go along with it today are radically different than those from previous eras (hall ) , and continue to evolve today (wheeler ; finnemore ) . norms go beyond simple behavioural modifications. states begin to reenvision their own identities as they embrace a norm. as states internalize new standards of behaviour, they come to new understandings of themselves. they answer the question 'who am i?' in a different manner. states are willing to forgo the costs associated with upholding normative precepts because these norms are constitutive of how the state sees itself. when a state fails to live up to these behavioural expectations, they justify their actions by referencing the norm itself. in an important sense, the state has violated its own understanding of who it is. instead of taking actions to abide by the rules, states take certain actions and engage in certain behaviours (and refrain from others) because 'good people do (or do not do) x in situations a, b, and c' (fearon : ) . they connect their preferences to policy choices and instruments in different ways as their self-understandings change (kowert and legro : ) . finnemore and sikkink ( ) offer a three-stage 'life cycle' for norms. in the first stage, a norm emerges and is championed by norm entrepreneurs. these entrepreneurs use their organizational platforms (such as a nongovernmental or intergovernmental organization) to promote the norm to members of the international community. they actively promote the norm as 'appropriate or desirable behavior in their community' (finnemore and sikkink : ) . they must persuade a critical mass of important actors to adopt and embrace the norm in order to reach the second stage -the norm cascade. during this second phase, an increasing number of states begin to adopt the norm, even in the absence of domestic pressures or economic self-interests to do so, because they increasingly see it as appropriate. if enough states do this, the norm becomes internalized in the third stage. it becomes 'common sense' and few would even question the behaviours expected by the norm. states abide by the norm and its behavioural expectations because that is just what members of the international community do. it becomes part of the state's sense of itself and its obligations to others. despite the efforts of norm entrepreneurs, not all norms find a home within the international community. scholars have identified three particular factors that appear to increase the likelihood of a norm's acceptance: if its precepts concern the protection of vulnerable populations (keck and sikkink : ) , if the norm contains clear, consistent rules with a previous history of observance (legro : - ) , and if the norm is both coherent and prominent (florini : - ) . if a norm is going to stick, states need to share an understanding of what a given norm means from both a behavioural and a constitutive perspective (van kersbergen and verbeek ) . norm entrepreneurs, according to most scholars, concentrate their attentions at the state level (finnemore and sikkink ; ingebritsen ) . they tailor their actions to encourage government policymakers to change their understanding of a particular issue, modify their behaviour, and incorporate the norm's idea into the state's overall identity. they try to get a critical mass of states to adopt, and eventually internalize, a norm in hopes of creating a norm cascade that leads to the norm becoming 'common sense'. while this focus on states is understandable, it ignores the plethora of actors whose actions can put a norm's ideas into practice. international organizations, nongovernmental organizations, private philanthropic organizations, and even multinational corporations play an ever-increasing role in providing services and taking on traditional governance roles. because of this, norm entrepreneurs have started to recognize the utility of targeting these groups as well. these nonstate actors may have financial resources beyond those available to states. they may also possess a greater level of legitimacy and lack much of the historical baggage of states. universal arv access is not the first health-related norm to be promoted to the international community. in the s and s, norm entrepreneurs sought to inculcate the norm of universal primary health care. despite strenuous efforts by some actors, the international community failed to embrace this norm. the reasons for universal primary health care's failure are highly instructive for understanding universal arv access' apparent success. , delegates from countries and international organizations met in alma-ata, ussr (now almaty, kazakhstan), from to september at the international conference on primary health care. the conference, organized by the world health organization and unicef, was the first international meeting devoted solely to primary health care. unanimously adopted, the alma-ata declaration listed eight crucial components of primary health care: education on health concerns and how to treat them, promoting proper nutrition, ensuring adequate supplies of clean drinking water and proper sanitation, providing maternal and child health care, including family planning, immunizing populations against major infectious diseases, preventing and controlling local endemic diseases, providing appropriate treatment for injuries and illnesses, and providing access to essential drugs (world health organization ) . in order to achieve these goals, the alma-ata declaration set specific targets for signatory states. these goals included: spending at least five per cent of gross national product on health, having per cent of children at the appropriate weight for their age, providing clean water within a -min walk of all homes and adequate sanitation either in the home or the immediate vicinity, making available trained personnel to attend to pregnancy and childbirth, and offering child care for children at least through one year of age (world health organization ) . these programmes sought to make essential health care accessible to all at an affordable cost and in line with a country's sovereign right to selfdetermination (world health organization ) . they afforded the majority of the country's population access to basic health care in line with locally determined needs. if states attained these goals and ensured the provision of primary health care, then it was hoped that the international community could meet its new goal -health for all by . the impetus for promoting this new norm grew out of changes in the international community. the s and s saw a great wave of decolonization and liberation throughout the third world, and new governments often came to power promising better health care for all their citizens. while initially many of these new governments took steps to improve health care, often with the support and aid of western states, services tended to be overly concentrated in urban areas and failed to reach rural areas. this meant that the majority of the population in many newly independent states still had limited access to health care facilities (hall and taylor ) . at the same time, an increasing number of studies criticized the idea that improved health in developing states was simply a matter of transferring western technologies and health care systems to new places. these studies called for a more holistic approach to health care that emphasized integrating health care into overall social development (cueto (cueto : . researchers and activists increasingly called for a 'bottom-up' approach to health care that focused on local needs and ensuring equitable access without an emphasis on large hospitals or expensive technologies (magnussen et al. : ) . china, tanzania, and venezuela successfully trained local personnel to provide essential basic health care programmes. these programmes offered basic yet comprehensive health care services to rural areas. for example, china's 'barefoot doctors' focused their energies on preventative care within the communities from which they were drawn and combined western and traditional cures for treatment (cueto (cueto : . inspired by their example, and drawing upon his own experiences with health care policies in developing countries, who director-general halfdan mahler of denmark called upon the international community to apply the lessons from these cases throughout the world. he urged who and unicef to ensure 'health for all' by changing both the provision of health care in developing countries and the role of developed states in ensuring this aim. the conference in alma-ata concentrated on spreading the message of health for all and devising strategies for putting this idea into practice. it is hard to underestimate how revolutionary the alma-ata declaration and its health for all by programme were. up to this point, health care had generally been considered the sovereign domain of states. previous cooperation on international public health issues, while it certainly existed, had been driven largely by specific disease outbreaks that threatened commercial interests. the international health regulations, adopted in , best reflect this concern. the ihr sought to 'ensure the maximum protection against the international spread of disease with minimum interference with world traffic' (world health organization ). states were required to report outbreaks of and take measures to prevent the spread of yellow fever, cholera, and plague -three diseases whose spread had long been associated with trade and travel (fidler and gostin : ) . the ihr thus made public health concerns subservient to economic relations among states, obligating national governments (and only national governments) to act only when disease threatened trade. the delegates to the alma-ata conference in functioned as norm entrepreneurs. they sought to create a change in how states viewed their responsibilities to their own citizens and those in other countries. much like the campaigns against slavery and apartheid (klotz ) , the alma-ata delegates engaged in normative debates that crossed ideological and economic lines. in the midst of the cold war, they sought to bring together democratic and communist states, encouraging them to look beyond their economic and political self-interest to embrace a greater good for the international community. by promoting the alma-ata declaration and health for all by , norm entrepreneurs sought to have states declare that public health was no longer simply a concern for national governments. they wanted national governments to set specific targets and adopt a normative framework that equated good governance with the provision of adequate health care standards. they encouraged states to move beyond reactive concerns with specific maladies and toward a more proactive holistic understanding of health and health care. universal primary health care's advocates framed their advocacy in relatively amorphous terms. as noted above, they spoke of decolonization, fairness, and development. they saw the provision of primary health care, especially in terms of having developed countries provide funding for such programmes, as an obligation owed to developing states by those who had already prospered. they also framed universal primary health care as a public good -one that required more generalized economic and social development. according to the norm entrepreneurs, the market could not adequately provide primary health care, so the state should do so (gostin : ) . the alma-ata declaration noted that health care inequalities were 'politically, socially, and economically unacceptable andytherefore, of common concern to all countries' (world health organization ) . interestingly, the norm entrepreneurs generally saw the push for universal primary health care as something that developed states should support largely on altruistic grounds. the declaration reads, 'all countries should cooperate in a spirit of partnership and service to ensure primary health care for all people' (world health organization ) . universal primary health care was a public good that developed states should provide in conjunction with developing states out of a sense of moral obligation and fairness and in the spirit of decolonization. this framing shared many affinities with calls for a new international economic order (nieo). indeed, the third clause of the alma-ata declaration specifically located universal primary health care within the broader calls for the nieo. working through the united nations conference on trade and development, developing countries put forward a number of proposals that sought to improve their terms of trade, increase economic assistance, reduce the north-south divide, and rewrite the international economic rules to favor developing states. these proposals all fell under the rubric of the nieo (murphy ) . representatives from developing states argued that the nieo would correct structural imbalances and allow developing states to receive the same benefits as developed states. critics countered that blaming developed states for the lack of development in poorer states was misplaced. they dismissed charges that western development was immoral or that developed states needed to sacrifice their wealth for the benefit of the less fortunate (johnson ). the acceptance of universal primary health care had the potential to be a major shift in the international community's normative framework, as it would fundamentally alter what it meant to be a 'good' state. it could alter the framework from one that emphasized individual responsibility for health care to one that gave governments primary responsibility for ensuring the public's health, both in their own countries and abroad (fidler : ) . despite the efforts of the alma-ata delegates, the goals of health for all by quickly ran into difficulties. it soon became obvious that the norm entrepreneurs were failing to attract a critical mass of supportive states who could further propel and promote the idea of universal primary health care within the international community. no norm cascade developed, and states did not alter their behavioural expectations of themselves or others. the very idea of primary health care itself came under attack as wildly unrealistic and inappropriate. government officials in many developed countries refused to believe that developing states could or should implement the wide-ranging programmes encompassed in health for all by (hall and taylor ) . instead, they proposed a new solution, selective primary health care (sphc), that would provide only those health care services that would have the greatest benefit to children under five (walsh and warren : - ) . primary health care's supporters, the norm entrepreneurs from alma-ata, saw sphc as a betrayal of the incipient norm's core beliefs. wisner ( ) alleged the sphc assumed that poor people were too ignorant to make proper health decisions, ignored existing local infrastructures and cultural practices, overlooked the role of grassroots efforts, and reinforced urban biases. hall and taylor remark, 'in effect, sphc took the decision-making power and control central to phc away from the communities and delivered it to foreign consultants with technical expertiseythese technical experts, often employed by the funding agencies, were subject to the policies of their agencies, not the communities ' ( : ) . sphc undercut the basic goals and ideals of health for all by and the alma-ata declaration. instead of encouraging broadbased participation and the equitable provision of health care to all groups within a society, the move towards sphc encouraged states to think in terms of economic self-interest. it removed the ability of developing states to determine their own needs and the best solutions to address those needs. sphc denied states policy autonomy. in the end, the norm of universal primary health care failed to gain much traction in the international community. its behavioural precepts failed to make an appreciable difference in state actions, and the shifts in identity associated with internalizing a norm never occurred. improvements in health care happened largely on an ad hoc basis with little international coordination or overriding guiding principles. what prevented the norm of universal primary health care from being adopted and internalized by the international community? a cursory examination highlights three key deficiencies. first, universal primary health care's supporters framed the norm as a collective public good. they called on developed states to provide a large outlay of funds to developing states en masse to right a perceived wrong. these pleas arose as the international community was dealing with a global recession, higher oil prices, and great economic uncertainty. few, if any, developed states were inclined to increase their foreign aid budgets. if anything, they were less inclined to provide assistance for health care in developing countries (people's health movement et al., : - ) . further, as part of providing this collective public good, developed states were being asked to allow developing states to independently determine their health care policies (hall and taylor ) . the frame for universal primary health care combined large financial outlays with little oversight, making it rather unpalatable to many developed states. second, the norm of universal primary health care failed to resonate with existing norms in the international community. norm entrepreneurs argued for universal primary health care as an element of a fundamental right to health at a time when the right to health was highly contested. their arguments that universal primary health care fit with a broader context of decolonization and fairness failed to find a perch. in the same way that the nieo largely failed to resonate and led to little but token actions, universal primary health care put forward an idealistic vision that did not resonate with broader trends in the international community at the time. additionally, conceptualizing health as a collective public good with a prominent role for national governments to provide services ran counter to the increasingly prominent rhetoric of neoliberalism and privatization that emerged in the late s and early s (thomas and weber ) . us state department officials also derided universal primary health care as 'too political' and feared how it could potentially alter the balance between themselves and the soviet union (werner ) . when director-general mahler called the soviet union 'a pioneer since the first days of its revolution more than years ago in placing health in the forefront of social goals and in linking its attainment with social justice and economic development' in his opening remarks at alma-ata (heyward ) , government officials in some states feared the relationship between universal primary health care and communism. murphy notes, 'american policy makers held that on fundamentals northern and southern views were incompatibleythey did not want to debate until both north and south had a single view of their common interests' (murphy : ) . interestingly, while american officials worried about how the ideological content of universal primary health care could promote communism and soviet ideals, the soviet union and people's republic of china vigorously disagreed with each other about the nature of universal primary health care (cueto ) . the disagreements between the two leading communist states further undermined universal primary health care's ability to find state supporters. finally, the norm entrepreneurs themselves were poorly placed to influence state governments or promote behavioural changes. universal primary health care's supporters targeted their appeals toward state governments, believing them to be the key to this norm being embraced by the international community. many were delegates to the alma-ata conference. most were bureaucrats either within their national health ministries or the world health organization. they may have had the technical expertise to understand the important of universal primary health care and perhaps the experience to implement it, but they lacked the political sway within governments to get them to reassess their behaviours and identities. in other words, they may have been norm entrepreneurs, but they were poorly placed norm entrepreneurs who lacked the ability to persuade enough others to adopt the norm. health ministries unfortunately have a tendency to be political backwaters with little influence beyond technical matters (vaughan et al. ) . the world health organization also lacked the stature to significantly affect international debates over universal primary health care. it lacked significant financial resources and, despite a near-universal membership, its political clout among member-states was negligible. the world health organization's low status was largely a reflection of the relatively low priority afforded to health within the international community. most states considered health to be a national responsibility and envisioned a limited role for the international community. the world health organization also sought, for much of its history, to consciously avoid political battles so as to avoid antagonizing its members (godlee ) . when it did try to take a more assertive role with universal primary health care, it faced the very real threat of having states like the united states withdraw its funding (walt ) . with the failure of health for all by , international health norms largely fell off the global agenda. the international community came together to combat various diseases, but no overarching normative ideas concerning the behavioural obligations of states to others within the international community received much attention. the  initiative changed things, bringing the idea of the norm of universal arv access to the forefront of the international community. on september , the who, unaids, and the global fund to fight aids, tuberculosis, and malaria announced a new initiative to combat the failure to deliver arvs to people with hiv in developing countries. that year, unaids estimated that six million hiv-positive people in the third world required arvs, but less than eight per cent actually received them. while per cent of those in need in central and south america had access to arvs, only two per cent of those in africa, the continent hardest hit by the aids epidemic, did (world health organization/unaids : - ) . this new programme sought to correct that. it pledged to provide a sustainable and reliable supply of arvs to three million people in the developing world, half the number who needed the drug, by the end of . although the leaders of this effort acknowledged that it was an incredibly ambitious goal, they based their calculations on an article published in in science. the article's authors cautioned that reaching this target would require optimal levels of both financing and technical capabilities. still, they considered it doable (schwartla¨nder et al. ) -as did, apparently, who and unaids. who and unaids declared the lack of arv access to be a global health emergency and an issue that urgently needed to be addressed. the  initiative did not create calls for universal arv access by any means (see, e.g. farmer and headley and , but it focused them and gave them far greater prominence within the international community. instead of being a relatively amorphous call to help people with aids, this new norm framed its calls for action in relatively concrete terms, of providing something tangible to individuals who could not otherwise acquire it, as a human right. by declaring a health emergency, though, the  initiative's promoters hoped to 'propel action and upend ''business as usual'' attitudes'. this new programme would 'demand new commitment and a new way or working across the global health community' (world health organization/unaids : ). to achieve this commitment, they situated the call within a framework of country ownership, human rights, and equity. not only would success require high-level political commitment but also the attendant financial outlays would also be quite high. when announcing the new programme, who estimated that it would cost at least us$ . billion to achieve the target (world health organization/unaids : ). however, the focus was not on the cost, it was on the realization of the norms of respect for universal human rights. who also saw the initiative as promoting the un's human rights agenda in two ways. first, the universal declaration of human rights declares that all people have the right to the highest possible standard of health -a promise reaffirmed to explicitly include hiv/aids during the united nations special session on hiv/aids in . second, the initiative pledged to pay special attention to vulnerable groups who may have limited access to treatment and prevention programmes. by emphasizing equity, the initiative sought to overcome economic barriers that had prevented most people in developing nations from being able to afford arvs. it utilized the ideas of access to essential medicines and non-discrimination in the provision of care evident in the alma-ata declaration. harris and siplon identified a growing recognition, by developed states, of a norm promoting international assistance to developing states as 'the right thing to do ' ( : ) . in their paper, schwa¨rtlander et al. referenced the movement for realizing the right to health in africa as emblematic of the international community's growing respect for this ideal ( : ). the  initiative's own materials were even more explicit. on its website, the initiative proclaimed that its efforts were 'a step towards the goal [sic] of making universal access of hiv/aids prevention and treatment accessible for all who need them as a human right' (world health organization n.d. a; emphasis added). from the earliest days, activists and organizations connected the drive for universal arv access back to the earlier efforts to promote health as a human right. tactically, norm entrepreneurs for universal arv broadened their reach. they did not solely focus on states as the entities responsible for realizing this norm. instead, they called on international organizations, nongovernmental organizations, multinational corporations, and private philanthropic groupsin addition to national governments -to work together. the norm entrepreneurs explicitly recognized this connection, noting, ''' by '' is a target that many organizations are working together to achieve, including national authorities, un agencies, multilateral agencies, foundations, nongovernmental, faith-based and community organizations, the private sector, labour unions and people living with hiv/aids. to succeed, full support and participation from all partners and governments are needed' (world health organization n.d. b). this shift moved the norm from being a collective public good whose realization depended solely on developed states to being targeted toward individuals with diffuse responsibility for protecting the human rights of those in need. such a frame resonated with the increasing international embrace, for better or worse, of public-private partnerships and more holistic interpretations of governance (see bovaird ; flinders , therien and pouliot for detailed discussions on the evolution of public-private partnerships and their associated costs and benefits). spearheading this drive, lee and piot played particularly important roles in mobilizing commitment, attracting international attention and support, and offering guidance. they served as norm entrepreneurs in every sense of the term. they made it their mission to try to convince donors, both governmental and nongovernmental, that the  initiative was in fact achievable. they had to convince a diverse array of actors to work together to find ways to lower the cost of arvs while still allowing the pharmaceutical manufacturers to earn a profit. they needed to get states to re-envision who they were and how they interacted with the rest of the world. they also had to convince states, private organizations, and multinational corporations that this was an issue of individual human rights as well as one in which they could play a significant role. at the end of the  initiative's timeframe, only . million people in developing countries were receiving arv treatment. this was less than half of the initiative's publicly stated goal. in many ways, this was still a remarkable success. in the span of two years, over one million new people gained access to life-prolonging drugs. over per cent of those who needed arvs in the developing world now had them -a significant improvement over the seven per cent who had them in . eighteen countries announced that they had met or exceeded their arv treatment targets (world health organization/ unaids : ). these are stunning accomplishments over an incredibly short period of time. these stunning accomplishments cannot diminish the fact that who and unaids failed to meet their goals. they pledged to provide arvs to half of the people in developing countries who needed them (a number that continued to grow over the two-year period from ), and they failed to do so. even with greater access to arvs, the worldwide rates of hiv infection continued to increase -meaning that even more people now required arv therapy and did not have access to it. critics lambasted the programme for being overly optimistic, relying on unrealistic modelling, and failing to properly coordinate programmes among the myriad of actors involved (economist ) . others noted that national aids control programmes often fell prey to petty turf battles and corruption, making them ineffective (itpc : - ) . despite this apparent failure, the basic norm of universal arv access continues to hold sway within the international community. state governments, international organizations, nongovernmental organizations, private philanthropic organizations, and multinational corporations have repeatedly reaffirmed their belief in the norm and pledged additional funds (though still short of what is necessary) toward its realization. given the apparent failure of the  initiative, it was realistic to assume that the norm of universal arv access was dead. its proponents had set an explicit target with a very explicit timeframe -and they failed to achieve this. remarkably, this was not the case. instead of walking away from failure, the international community has embarked on an even more ambitious goal -all by . all by is the latest attempt to put the emerging norm of universal access to arvs into practice. like the  initiative, all by combines the efforts of state and non-state actors to provide universal arv access as a constituent element of individual human rights. the central goal of all by is universal access to arv treatment. this means, according to most definitions, ' per cent of all people in urgent need of treatment are receiving it' (avert n.d.) . based on current projections, the best estimate is that the all by programme will need to get million people worldwide on arvs by the end of to meet its goals (as a shorthand, some also call this program  ). as with the  initiative, the leaders of all by explicitly state that this effort is designed to mobilize stakeholders, maintain momentum, and encourage states to contribute. the norm entrepreneurs are using their organizational platforms within who and unaids to encourage the adoption and internalization of a new norm. while expressing regret at its inability to achieve its initial target, the who and unaids' final report on the initiative discussed ways to rectify the problems it faced. the report argued the end of the initiative was just the beginning toward ensuring universal arv access for all. this provides evidence for the internalization of the norm through rhetoric and changes in constitutive identities. failure to achieve and the behaviours associated with it were explained within the context of the norm itself. 'the '' by '' target needs to be seen as an interim step toward the ultimate goal of universal access to antiretroviral therapy for those in need of care, as a human right, and within the context of a comprehensive response to hiv/aids' (world health organization /unaids : ) . the g nations, the very nations that provided the vast majority of funding for the programmes that came under the  initiative's umbrella, pledged in july to work toward universal access to arvs worldwide by . at the g summit in gleneagles in july , the leaders of the world's largest economies pledged at least an extra us$ billion in aid annually, part of which would be specifically pledged for universal arv access (office of the prime minister ). two months later, the united nations passed a resolution calling on member states to work toward this goal and to pledge the necessary resources (avert n.d.) . in , the un high-level meeting on aids produced a resolution that stated in part, '[we commit] to pursue all necessary efforts to scale up nationally driven, sustainable and comprehensive responses to achieve broad multisectoral coverage for prevention, treatment, care and support, with full and active participation of people living with hiv, vulnerable groups, most affected communities, civil society and the private sector, towards the goal of universal access to comprehensive prevention programmes, treatment, care and support by ' (united nations ) . african heads of state made a similar pledge in may at a summit in abuja, nigeria (agence france-presse ) . the clinton foundation and the gates foundation have both continued their arv access efforts and have expanded them beyond their initial plans. the international community has clearly embraced the normative rhetoric of universal arv access, tying it to the realization of individual human rights and a broadened conceptualization of governance. the united nations' declaration of commitment on hiv/aids resolved that 'access to medication in the context of pandemics such as hiv/aids is one of the fundamental elements to achieve progressively the full realization of the right of everyone to the enjoyment of the highest attainable standard of physical and mental health' (united nations ) . within months of the unveiling of the  initiative, all member states of the who publicly endorsed the program and the norm contained within it. they publicly pledged to aggressively work toward the realization of this goal and, in a broader sense, to ensure that all those who needed arvs could get them. the un economic and social commission for asia and the pacific passed a resolution that called on states in the region to scale up their public health programs specifically in response to the  initiative (unescap ) . in may , over delegates from around the world came together in geneva to coordinate efforts to rapidly scale up efforts to expand access to arvs across political, economic, and religious lines. the us president's emergency plan for aids relief (pepfar), its primary aids programming effort, strongly emphasizes antiretroviral therapy (and its attendant infrastructure), considering it an integral part of its aids programmes and part of the us' obligation as a leading member of international society (office of the global aids coordinator ). when announcing pepfar during his state of the union address, us president george w. bush noted, 'because the aids diagnosis is considered a death sentence, many do not seek treatment. almost all who do are turned away. a doctor in rural south africa describes his frustration. he says, ''we have no medicines. many hospitals tell people, you've got aids, we can't help you. go home and die.'' in an age of miraculous medicines, no person should have to hear those words' (bush ) . this statement received a tremendous amount of applause. making this proclamation during his most important speech of the year shows that the norm of universal arv access is at least fomenting rhetorical changes. four years later, when bush called on congress to reauthorize pepfar by providing us$ billion over the next five years, he highlighted the normative aspects of the programme. acknowledging the costs and the number of people affected by the programme, he emphasized, 'the statistics and dollar amounts i've cited in the fight against hiv/aids are significant. but the scale of this effort is not measured in numbers. this is really a story of the human spirit and the goodness of human heartsyour citizens are offering comfort to millions who suffer, and restoring hope to those who feel forsaken' (bush ) . evidence also shows that recipient states internalized this new norm. within months of the initiative's debut, countries approached who, asking for assistance through this new programme (world health organization : ). these states sought to make the changes in their policies and infrastructure that would allow them to expand the ability of their citizens to access these drugs. they publicly acknowledged that they did not have the resources to enact such a programme, yet by approaching who, they also publicly acknowledged their desire to work with the international community to implement the norm's programme. further, nearly every country has created a country coordinating mechanism (ccm) to receive funding from the global fund and coordinate aids activities. these ccms explicitly incorporate representatives from the public and private sectors to promote the incorporation of all relevant voices (global fund to fight aids, tuberculosis, and malaria n.d.). these efforts show a willingness to adapt state structures in order to facilitate the provision of arvs. non-state actors play an increasingly important role in realizing the behavioural expectations of this new norm. international organizations like the world health organization and the joint united nations program on aids (unaids) serve as conduits of information for the international community. they gather and disseminate data, provide technical resources to actors trying to implement arv access programmes, and sponsor international meetings to facilitate networking. while they also provide some direct funding, they largely focus their energies on supporting the technical and logistical resources needed to bring the norm's objectives to fruition. for funding, the global fund to fight aids, tuberculosis, and malaria emerged in . the global fund is an independent organization, with representatives from donor and recipient governments, nongovernmental organizations and the private sector, with responsibility for funding aids-related programmes. it explicitly does not implement programmes on its own. instead, it provides a centralized source for donors to contribute money and recipients to receive grants to implement programmes (van kerkhoff and szleza ) . unique among most international bodies, the global fund relies upon funds from national governments, nongovernmental organizations, private philanthropies, and the sale of specially branded consumer products (dyer ) . programmes funded by the global fund may be implemented by governments or nongovernmental organizations, broadening the realm of actors who can help realize the behavioural expectations of this new norm. private philanthropies and multinational corporations have also played a significant role in working toward universal arv access' behavioural precepts. the clinton foundation, former us president bill clinton's organization, has focused its energies on transforming the economic incentives for pharmaceutical companies. recognizing that these companies will not produce arvs without an ability to make a profit, the clinton foundation has helped to aggregate demand for arvs. it has sought to 'transform the antiretroviral marketplace from a low-volume, high-margin market to a high-volume, lowmargin market that serves millions of hiv/aids patients' (clinton foundation n.d.) . this strategy significantly reduces the price for arvs while still allowing generic and branded pharmaceutical manufacturers to recoup their investment in developing arvs. the foundation has forcefully argued that it has not asked for charity, but rather sought to ensure supply at an affordable price in the face of large demand (rauch ) . the bill and melinda gates foundation, the world's wealthiest philanthropic organization, collaborated with the government of botswana and the pharmaceutical company merck to create the african comprehensive hiv/aids partnership. this arrangement brings together the financial resources of the gates foundation, the manufacturing and distribution capabilities of merck, and the infrastructure of botswana to deliver arvs to those in need (gates foundation ; ramiah and reich ) . these two efforts demonstrate the significant role that non-state actors play in actualizing universal arv access. it is indeed true that, even with the diversity of actors involved, international funding for universal arv access has remained far below what experts and norm entrepreneurs claim is necessary. six months before the initiative formally ended, 'unaids estimates that at least an additional us$ billion above what is currently pledged is needed for global hiv/aids efforts over the next three years' (world health organization : ; emphasis added). african governments pledged to increase their own budgetary outlays for health programmes within their own borders. by , they promised to devote per cent of their national budgets to health (including hiv/aids programmes) -but none of them met this target by 's end (itpc : ) . funds from some donor states like the united states have come with conditionalities that have hampered their ability to be accessed in a timely and efficient manner. despite this reality, the commitment to realizing the norm of universal arv access appears to remain intact. stephen lewis, the un's special envoy for hiv/aids in africa, proclaimed, 'mind you, i can even now hear the curmudgeonly bleats of the detractors, whining that we will fall short of the target of three million in treatment by the end of this year. tell that to the million people who are now on treatment and who would otherwise be dead. the truth is that the by initiative -which, i predict, will be seen one day as one of the un's finest hours -has unleashed an irreversible momentum for treatment' (un news service ; emphasis added). it is highly significant that no state ever predicated its behaviour on a rejection of the norm. no state stated that universal arv access was undesirable or unworthy. questions did arise as to how best to provide these medications to people in challenging environments and ensuring compliance with the drug regimen's requirements. even these discussions, though, referenced back to the emerging norm of universal arv access. the issue was not one of the appropriateness of universal arv access; it was one of delivery. these actions do not mean that the debates over universal arv access are over. the battles over funding levels alone demonstrate the continued discussion. those debates, though, are not evidence of the lack of a norm. van kersbergen and verbeek ( ) remind us that the details over implementing a new norm's behavioural expectations can continue for a while and even be contentious. what we see with universal arv access is a debate over how to realize the norm, not over whether the norm is appropriate. whereas the attempts to promote a norm of universal primary health care got bogged down in debates over its very appropriateness, universal arv access' norm entrepreneurs appear to have successfully convinced a significant portion of the international community that the basic idea is sound. the norm for universal arv access obviously picks up on some of the same themes as the earlier push for universal primary health care, yet it appears to be having more success in establishing itself and being internalized by the international community. what explains the difference? i suggest two important differences: the norm entrepreneurs themselves and the international normative context. first, norm entrepreneurs themselves make a difference, and this appears particularly true for aids-related issues. in the s, many national governments specifically cited the personal lobbying of jonathan mann, then the head of the united nations' global program on aids, as the reason they increased their contributions to aids control efforts (gordenker et al. : ) . in the case of universal arv access, the effort was really spearheaded by lee, piot, and feachem (mann died in a plane crash in ) . these three had the connections and experience that allowed them access to the highest levels of governments. they also took a very intense personal interest in the promotion of this newly developing norm. all three men had impressive resumes working with hiv/aids and ensuring access to health care in developing nations. lee, who himself died suddenly in may , devoted one of his last speeches to building on the lessons from the  initiative to promote universal arv access (lee ) . in addition, these three key norm entrepreneurs had impressive organizational bases -the world health organization, unaids, and the global fund to fight aids, tuberculosis, and malaria, respectively -from which to promote their norm and encourage states to adopt it. successful norm entrepreneurs can benefit from such a platform. mahler, during the promotion of health for all by , held the same position as lee, so what explains the difference? for one thing, his was a more solitary voice. mahler was essentially the only leader on the international stage promoting universal primary health care. this made his task more daunting. second, international health organizations have greater prominence today than they did in the s and early s. the international community came together to form the global fund, unaids builds on the strengths of multiple un-affiliated agencies, and the who has received greater attention and respect thanks to its successful handling of crises like sars, avian flu, and the asian tsunami recovery efforts. in addition to the efforts of lee, piot, and feachem, a wide range of nongovernmental organizations took an active role in promoting the norm. these groups put pressure on their governments to live up to their promises, provided research to demonstrate the benefits of greater arv access, and worked to forge seemingly odd political coalitions (witness the alliance of irish rock star bono and conservative former us senator jess helms) to promote their cause. groups like the treatment action campaign, healthgap, and the international treatment preparedness campaign have forced governments around the world to respond to the burgeoning movement for universal arv access. the gravitas of figures like bill clinton, nelson mandela, and bill gates adds even more momentum to the calls for universal arv access. in addition, these groups regularly interacted with one another, sharing strategies and collaborating on international efforts. with norm entrepreneurs working from above (at the international organization level) and below (at the nongovernmental organization level), national governments found it harder to resist. second, the international normative environment has changed in a way more favourable to the embrace of universal arv access. cold war tensions, which partially bedeviled debates over universal primary health care, disappeared but it would be a mistake to attribute too much to this change. more importantly, universal arv access has also benefited from the internalization of related complementary norms within the international community. there is increasing recognition of health as a human right (mann et al. ) , which itself builds upon the embrace of universal human rights. farmer has written extensively and eloquently on the connections between health and human rights. he sees medical workers as the new vanguard for promoting human rights, as their actions can actually put the notion of health as a human right into practice. addressing health concerns in an unbiased manner necessarily involves the recognition of social and economic rights when healthcare workers provide these services for their fellow human beings without regard for ability to pay (farmer : ) . in this way, health promotes human rights in a less overtly political manner. within the framework of health as a human right, a number of groups specifically cite hiv/aids as a human rights issue -and a number of states have internalized this framework (youde forthcoming). if states agree with the idea that health is itself a universal human right and that aids, in particular, is a human rights issue, then it is a small stretch to embrace the notion that providing access to the drugs that combat aids is itself an important normative issue. by avoiding frames that emphasize providing collective goods for developing countries and instead focusing on realizing individual rights through broadbased participation, universal arv access' supporters positioned their ideas to resonate with existing international norms. this new norm then became seen as a natural extension of already-existing ideas. it fit in with prevalent norms about individual human rights and public-private partnerships. the growing discussions around health as a human right allows proponents of the norm of universal arv access to frame their issue in a manner that resonates with government officials and the public. advocates can use frames that match with ideas or images already present in a culture to gain support. this can be particularly important when high costs are involved. the proper frame encourages policymakers to look past their financial concerns to understand how that frame matches with an underlying constitutive identity. busby ( ) uses frames to understand how jesse helms, a conservative us senator, and bono, the irish rock star, came together to support debt relief for poor countries when the issue was framed as one of biblical justice. making this appeal in the context of an existing belief -a shared christian faith, in this case -allowed the issue of debt relief to move forward in spite of the financial cost. in the same way, universal arv access' advocates could draw upon the growing recognition that developed states have an obligation to help those less fortunate and that health is a fundamental aspect of dignified human existence (mann et al. ; harris and siplon ) . the international normative environment was thus primed to be more receptive to a call for widespread drug access in the early s that was not present at earlier junctures. in many ways, universal arv access' path to acceptance has so far followed a path similar to that previously trodden by the norm of human rights. like universal arv access, human rights norms not only prescribe certain behaviours but they also allow states who internalize these norms to define themselves as liberal (risse and sikkink : ) . human rights norms did not simply emerge on their own, and states did not adopt them thoughtlessly. instead, the diffusion of human rights norms depended upon a sustained network of domestic and international networks that could connect to policymakers and international regimes. these networks put pressure on states, helped redefine the international normative context in a manner amenable to the embrace of these norms, and empowered actors to appeal for recognition of the norms (risse and sikkink : ) . activists framed human rights norms in ways that would resonate with existing domestic political cultures in various countries (risse and ropp : ) . some states may have initially embraced human rights norms for instrumental reasons (risse and sikkink : ) , but this process itself encouraged states to redefine their identities. human rights norms went from being policy choices to constitutive elements of how states saw themselves and their respect for basic human morality (donnelly : ) . human rights norms depended upon a combination of norm entrepreneurs and a favorable international normative context to succeed -the same processes that have assisted with the internalization of the norm of universal arv access. the moves toward universal access to arv therapy as embodied by the  initiative and all by programme represent the emergence of a new international norm born out of the ashes of an earlier failed attempt to inculcate a norm of universal primary health care access. it demonstrates how norms can evolve within the international community and take on new life when international political situations and norm entrepreneurs change. states are working toward universal arv access despite the very high costs and the potentially negative consequences for western pharmaceutical companies. to uphold the norm, they engage in actions that may not be economically profitable and explain their failures to live up to the norm's obligations in terms of those obligations themselves. this is more than just a story about arvs, though. the emergence of universal arv access enriches our understanding of how and why the international community embraces certain norms. it has shown the importance of moving beyond a state-centric view of norm emergence and adoption. nonstate actors, such as nongovernmental organizations, philanthropic groups, and multinational corporations play an increasingly important role in international governance, and that role extends to their influence on international norms. universal arv access also makes clear the importance of complementary norms for successful adoption. universal primary health care failed, in part, because it did not resonate with dominant norms within the international community at the time. finally, universal arv access highlights just how important framing by norm entrepreneurs can be. universal arv access' supporters cast the issue as one of individual human rights being realized by a broad-based coalition of state and non-state actors. this worked far better than the broader collective public good supported by developed states frame employed in the discussions around universal primary health care. universal arv access is indeed an ambitious goal but it could have immense international benefits. by internalizing this norm, states are redefining their obligations to each other when it comes to providing health care. they are establishing new standards of behaviour, standards by which their actions will be judged by others. international ethical obligations are changing for the better of humanity. earlier efforts to inculcate progressive norms that ensure access to health care may have failed, but contemporary norm entrepreneurs demonstrate that it is indeed possible to foster international health-related norms. african leaders pledge more access to aids, malaria treatment aids treatment target and results: all by public-private partnerships: from contested concepts to prevalent practice bono made jesse helms cry: jubilee , debt relief, and moral action state of the union address president bush announces five-year, $ billion hiv/aids plan hiv/aids initiative: drug access the origins of primary health care and selective primary health care preface the social construction of international human rights new fund-raising scheme fuses profit with philanthropy spin doctors infections and inequalities: the modern plagues pathologies of power: health, human rights, and the new war on the poor what is identity (as we now use the word)?', unpublished manuscript disease and globalized anarchy: theoretical perspectives on the pursuit of global health the new international health regulations: an historic development for international law and public health national interests in international society the purpose of intervention international norm dynamics and political change the politics of public-private partnerships the evolution of international norms working with botswana to confront its devastating aids crisis global fund to fight aids, tuberculosis, and malaria (n.d.) 'country coordinating mechanisms who in retreat: is it losing its influence? health for all beyond : the demise of the alma-ata declaration and primary health care in developing countries' international relations and global ethics of hiv/ aids roadblocks on the road to treatment: lessons from barbados and brazil report of the alma-ata conference scandinavia's role in world politics missing the target: a report of hiv/ aids treatment access from the frontlines the new international economic order', university of chicago graduate school of business selected papers no norms in international relations: the struggle against apartheid transnational activism and global transformations: the anti-apartheid and abolitionist experiences norms, identity, and their limits: a theoretical reprise opening remarks at the consultation on aids and human resources for health which norms matter? revisiting the ''failure'' of internationalism comprehensive versus selective primary health care: lessons for global health policy the emergence of the nieo ideology gleneagles : chairman's summary people's health movement, medact and global equity gauge alliance ( ) global health watch building effective public-private partnerships: experiences and lessons from the african comprehensive hiv/aids partnerships (achap) this is not charity the socialization of international human rights norms into domestic practices: introduction international human rights norms and domestic change: conclusions resource needs for aids the global compact: shifting the politics of international development? the politics of global health governance: whatever happened to ''health for all by declaration of commitment on hiv/aids', general assembly resolution a/res/s- / draft political declaration - high-level meeting on aids regional call for action to enhance capacity-building in public health. resolution / un goal of treating million hiv/aids victims by unlikely to be met linking local knowledge with global action: examining the global fund to fight aids, tuberculosis, and malaria through a knowledge system lens the politics of international norms: subsidiarity and the imperfect competence regime of the european union can ministries of health support primary health care? some suggestions for structural reorganization and planning selective primary health care: an interim strategy for disease control in developing countries who under stress: implications for health policy elusive promise' saving strangers: humanitarian intervention and international society gobi versus phc? some dangers of selective primary health care the by initiative world health organization (n.d. b) 'partnerships: working together for declaration of alma-ata world health organization ( ) international health regulations progress on global access to hiv antiretroviral therapy: an update on '  treating million by : making it happen progress on global access to hiv antiretroviral therapy: a report on ''  '' and beyond hiv/aids as a human rights issue emily atkinson provided invaluable research assistance for this article. i also wish to thank brent steele, tracy slagter, and jird's anonymous reviewers and editors for their thoughtful comments. any errors, of course, are solely my responsibility. key: cord- -anadq j authors: lai, yi-horng title: network analysis of comorbidities: case study of hiv/aids in taiwan date: - - journal: multidisciplinary social networks research doi: . / - - - - _ sha: doc_id: cord_uid: anadq j comorbidities are the presence of one or more additional disorders or diseases co-occurring with a primary disease or disorder. the purpose of this study is to identify diseases that co-occur with hiv/aids and analyze the gender differences. data was collected from hiv/aids admission medical records out of , , admission medical records from to in taiwan. in this study, the comorbidity relationships are presented in the phenotypic disease network (pdn), and φ-correlation is used to measure the distance between two diseases on the network. the results show that there is a high correlation in the following pairs/triad of diseases: human immunodeficiency virus infection with specified conditions ( ) and pneumocystosis pneumonia ( ), human immunodeficiency virus infection with specified malignant neoplasms ( ) and kaposi’s sarcoma of other specified sites ( ), human immunodeficiency virus acquired immunodeficiency syndrome, and unspecified ( ) and progressive multifocal leukoencephalopathy ( ), and lastly, human immunodeficiency virus infection with specified infections ( ), meningoencephalitis due to toxoplasmosis ( ), and human immunodeficiency virus infection specified infections causing other specified infections ( ). the human immunodeficiency virus infection and acquired immune deficiency syndrome (hiv/aids) epidemic is one of the most important and crucial public health risks facing governments and civil societies in the world. adolescents were at the center of the pandemic in terms of transmission, impact, and potential for changing the attitudes and behaviors that underlie this disease. therefore, hiv/aids prevention has become a priority all over the world. the first hiv/aids case in taiwan was reported in . as of the end of , the total number of hiv/aids cases had been accumulated to , . faced with this serious situation, taiwan's centers for disease control worked with other departments and dedicated a tremendous amount of effort and resources to introduce harm reduction programs. total reported cases dropped in , which was the first trend reversal since . in and thereafter, the epidemic took a turn; infections mainly occurred through sexual encounter [ ] . there are no clear boundaries between many diseases, as diseases can have multiple causes and can be related in several dimensions. from a genetic perspective, a pair of diseases can be related because they have both been associated with the same gene, whereas from a proteomic perspective, diseases can be related because diseaseassociated proteins act on the same pathway [ ] . during the past half-decade, several resources have been constructed to help understand the entangled origins of many diseases. many of these resources have been presented as networks in which interactions between disease-associated genes, proteins, and expression patterns have been summarized. goh, cusick, valle, barton, vidal, and barabási created a network of mendelian gene-disease associations by connecting diseases that have been associated with the same genes [ ] . besides, more and more studies have applied the network approach in diseases, such as neurodegenerative diseases [ ] , infertility etiologies [ ] , sars, and hiv/aids [ ] . a comorbidity relationship exists between two diseases whenever they affect the same individual substantially more than chance alone. in the past, comorbidities have been used extensively to construct synthetic scales for mortality prediction [ , ] , yet their utility exceed their current use. studying the structure defined by entire sets of comorbidities might help the understanding of many biological and medical questions from a perspective that is complementary to other approaches. for example, a recent study built a comorbidity network in an attempt to elucidate neurological diseases' common genetic origins [ ] . heretofore, however, neither this data nor the data necessary to explore relationships between all diseases is currently available to the research community. this present study decided to provide this data in the form of a phenotypic disease network (pdn) that includes all diseases recorded in the medical claims. additionally, this study illustrates how a pdn can be used to study disease progression from a network perspective by interpreting the pdn as the landscape where disease progression occurs and shows how the network can be used to study phenotypic differences between patients of different demographic backgrounds. this study indicates the directionality of disease progression, as observed in our dataset, and finds out that more central disease in the pdn are more likely to occur after other diseases and that more peripheral diseases tend to precede other illnesses. in order to guide hiv/aids-related diseases prevention program, this study conducted the pdn of hiv/aids to explore the relationship between hiv/aids and other diseases. the objective of this study is to identify diseases that are highly correlated with hiv/aids, and discuss gender differences. the national health insurance (nhi) program was initiated in taiwan in and covers nearly all residents. in , the bureau of nhi began to release all claims data in electronic form to the public under the national health insurance research database (nhird) project. the structure of the claim files is described in detail on the nhird website and in other publications [ ]. nhird offers reliable, systematic, and complete data for disease detection. the datasets contained only the visit files, including dates, medical care facilities and specialties, patients' genders, dates of birth, and the four major diagnoses coded in the international classification of disease, th revision, clinical modification (icd- -cm) format [ , ] . in total, the icd- -cm classification consists of different categories at the digit level and , categories at digits. human immunodeficiency virus infection and acquired immune deficiency syndrome (hiv/aids) is coded as human immunodeficiency virus (hiv) infection disease, as human immunodeficiency virus infection with specified infections, as specified infections causing other specified infections, as human immunodeficiency virus infection with specified malignant neoplasms, and as acquired immunodeficiency syndrome, and unspecified. to protect privacy, the data on patient identities and institutions had been scrambled cryptographically. the visit files in this study represented , , admission activities within the nhi from to . demographically, the data set consists of , , admission medical records from , , patients. of all these patients, . % were females, . were males, . % were over years of age, and persons were diagnosed with hiv/aids (table ) . these hiv/aids admission medical records included females ( . %) and males ( . %). of all the hiv/aids records, ( . %) had major diagnoses coded , ( . %) had major diagnoses coded , (. %) had primary diagnoses coded , and ( . %) had major diagnoses coded (table ). there are several limitations to the current study. first, although data gathered from nhird is comprehensive and reliable, there are still some mistakes that the system couldn't find, such as code entry errors. these errors may be carried into data y.-h. lai pre-processing, and it is beyond the control of this study. second, the data was not upto-date. although future researchers are still recommended to apply the method of this study to analyze the characteristics of patients for the purpose of disease prevention, changes of medical treatments and other factors should be considered. third, this study does not have a global sample, so there might be limits to replicate the findings of this study in all the other countries. it might, however, be generalized to other ethnic chinese population due to the similarity in genes and physiology. to measure the comorbidity relationships, it is necessary to quantify the strength of comorbidities by introducing a notion of distance between two diseases. a difficulty of this approach is that different statistical distance measures have biases that over-or under-estimate the relationships between rare or prevalent diseases. these biases are important given that the number of times a particular disease is diagnosed, such as its prevalence, follows a heavy tailed distribution [ ] , meaning that while most diseases are rarely diagnosed, a few diseases have been diagnosed in a large fraction of the population. in this study, the φ-correlation is used to quantify the distance between two diseases. the φ-correlation, which is pearson's correlation for binary variables, can be expressed mathematically as [ , ] : where c ij is the number of patients affected by both diseases, n is the total number of patients in the population and p i and p j are the prevalence of diseases i and j. the distribution of φ values representing all disease pairs where c ij > is presented in fig , and . this research utilizes data from nhird to obtain the four major diagnoses codes of all patients. this study calculates φ-correlation with equation . pajek . program was used to compute the compute the degree of centrality and betweenness of each node and the path value (φ-correlation). this study is focused on the path between each disease as network and the correlation as the value of line (path weight), and they could be affected by different populations, which indicates differences in gender for each population. it can be summarized the set of all comorbidity associations between all diseases expressed in the study population by constructing a phenotypic disease network (pdn). in the pdn, nodes are disease phenotypes identified by unique icd codes, and links phenotypes that show significant comorbidity according to the measures introduced above. in principle, the number of disease-disease associations in the pdn is proportional to the square of the number of phenotypes, yet many of these associations are either not strong or are not statistically significant [ ] . the structure of the pdn can be explored by focusing on the strongest and the most significant of these associations. the pdn can be seen as a network of the phenotypic space. this network allows people to understand the relationship between illnesses. the distribution of φ-values representing all disease pairs is presented in figure . most of them are between . and . . a discussion on the confidence interval and statistical significance of these measures can be found in hidalgo, blumm, barabási, and christakis's study, and φ-correlation > . is statistically significant [ ] . in figure , nodes are diseases; links are correlations. node color identifies the icd category; node size is proportional to disease prevalence. link color indicates correlation strength. the pdn built using φ-correlation. all statistically significant links where φ-correlation>. are shown here. human immunodeficiency virus infection with specified conditions ( ) and pneumocystosis pneumonia ( ), cryptococcal meningitis ( ), candidiasis of mouth ( ), unspecified secondary syphilis ( ), kaposi's sarcoma of unspecified ( ), cryptococcosis ( ), kaposi's sarcoma of palate ( ), neurosyphilis, unspecified ( ), kaposi's sarcoma of lung ( ), kaposi's sarcoma of lymph nodes ( ), and late syphilis, latent ( ) are highly correlated. those φ-correlations are all above . . the relationship between human immunodeficiency virus infection with specified conditions ( ) and pneumocystosis pneumonia ( ) is the strongest. pneumocystis pneumonia is a form of pneumonia, caused by the yeast-like fungus pneumocystis jirovecii. pneumocystis pneumonia is not commonly found in the lungs of healthy people, but, being a source of opportunistic infection, it can cause a lung infection in people with a weak immune system [ ] . human immunodeficiency virus infection with specified infections ( ) and human immunodeficiency virus infection specified infections causing other specified infections ( ), kaschin-beck disease ( ), pneumocystosis ( ), meningoencephalitis due to toxoplasmosis ( ), falciparum malaria ( ), kaposi's sarcoma of other specified sites ( ), with specified malignant neoplasms ( ) are highly correlated. those φ-correlations are all above . . y.-h. lai the φ-correlation of human immunodeficiency virus infection with specified infections ( ) and meningoencephalitis due to toxoplasmosis ( ) is highest. toxoplasmosis is a parasitic disease caused by the protozoan toxoplasma gondii. the parasite infects most genera of warm-blooded animals, including humans, but the primary host is the felid family. infection occurs by eating infected meat, particularly swine products. by ingesting water, soil, or food that has come into contact with infected animals' fecal matter [ ] . besides, human immunodeficiency virus infection with specified infections ( ) and specified infections causing other specified infections ( ) is highly correlated, and the φ-correlation is . . human immunodeficiency and kaposi's sarcoma of sk specified infections ( ) highly correlated. those φ- the φ-correlation of hu lignant neoplasms ( ) a highest. human immunodeficien specified ( ) and prog correlated. those φ-correlat the distribution of w va most of them are between . in pdns for females (figure ), human immunodeficiency virus infection with specified conditions ( ) and cryptococcal meningitis ( ), kaposi's sarcoma of unspecified ( ), and pneumocystosis ( ) are highly correlated. human immunodeficiency virus acquired immunodeficiency syndrome, unspecified ( ) and other cerebellar ataxia ( ), and progressive multifocal leukoencephalopathy ( ) are highly correlated. those φ-correlations are all above . . the distribution of w values representing all disease pairs is presented as fig. . most of them are between . and . . in pdns for males ( figure ), human immunodeficiency virus infection with specified conditions ( ) and unspecified secondary syphilis ( ), cytomegaloviral disease ( ), kaposi's sarcoma of palate ( ), amebic liver abscess ( ), kaposi's sarcoma of lung ( ), kaposi's sarcoma of lymph nodes ( ), cryptococcosis ( ), late syphilis, latent ( ), candidiasis of mouth ( ), cryptococcal meningitis ( ), neurosyphilis, unspecified ( ), kaposi's sarcoma of unspecified ( ), and pneumocystosis ( ) are highly correlated. those φ-correlations are all above . . the φ-correlation of human immunodeficiency virus infection with specified conditions ( ) with pneumocystosis ( ) is highest. human immunodeficiency virus infection with specified infections ( ) and specified infections causing other specified infections ( ), meningoencephalitis due to toxoplasmosis ( ), pneumocystosis ( ), kaschin-beck disease ( ), kaposi's sarcoma of other specified sites ( ), with specified malignant neoplasms ( ), and falciparum malaria ( ) are highly correlation. those φ-correlations are all above . . the φ-correlation of specified infections causing other specified infections ( ) with human immunodeficiency virus infection with specified infections ( ) is highest. human immunodeficiency virus acquired immunodeficiency syndrome, unspecified ( ) and hiv infection, unspecified ( ) is highly correlation, and the φcorrelation is . . through the pdn, this paper has identified the diseases that are associated with hiv/aids. it could be showed that the pdn has a complex structure where some diseases are highly connected while others are barely connected at all. while not conclusive, these observations can explain the observation that more connected diseases are seen to be more lethal, as patients developing highly connected diseases are more likely those at an advanced stage of disease, which can be reached through multiple paths in the pdn. the findings suggest that human immunodeficiency virus infection with specified conditions ( ) and pneumocystosis pneumonia is highly correlated ( ). this result is consistent with aliouat-denis, chabé, demanche, aliouat el, viscogliosi, guillot, delhaes, and dei-cas's study [ ] . pneumocystis pneumonia is especially seen in people with cancer undergoing chemotherapy, hiv/aids, and the use of medications that suppress the immune system. human immunodeficiency virus infection with specified infections ( ) and meningoencephalitis due to toxoplasmosis ( ) is highly correlation. besides, it is also highly correlation with human immunodeficiency virus infection specified infections causing other specified infections ( ). the result is the same as dubey, hill, jones, hightower, kirkland, roberts, marcet, lehmann, vianna, miska, sreekumar, kwok, shen, and gamble''s study [ ] . human immunodeficiency virus infection with specified malignant neoplasms ( ) and kaposi's sarcoma of other specified sites ( ) is highly correlation. the result is the same as holmes, hawson, liu, friedman, khiabanian, and rabadan's study [ ] . since patients infected with hiv/aids have a high risk of developing kaposi sarcoma, the prevention of this malignant disease should be prioritized. human immunodeficiency virus acquired immunodeficiency syndrome, and unspecified ( ) and progressive multifocal leukoencephalopathy ( ) is highly correlation. the result is the same as casado, corral, garcía, martinez-san millán, navas, moreno, and moreno's study [ ] and sano, nakano, omoto, takao, ikeda, oga, nakamichi, saijo, maoka, sano, kawai, kanda [ ] . progressive multifocal leukoencephalopathy is a usually fatal viral disease characterized by progressive damage or inflammation of the white matter of the brain at multiple locations. it is caused by the jc virus, which is normally present and kept under control by the immune system. jc virus is harmless except in cases of weakened immune systems. progressive multifocal leukoencephalopathy occurs almost exclusively in patients with severe immune deficiency, most commonly among patients with acquired immune deficiency syndrome, but people on chronic immunosuppressive medications including chemotherapy are also at increased risk of progressive multifocal leukoencephalopathy [ , ] . for females, human immunodeficiency virus infection with specified conditions ( ) and cryptococcal meningitis ( ), kaposi's sarcoma of unspecified ( ), and pneumocystosis ( ) are highly correlation. human immunodeficiency virus acquired immunodeficiency syndrome, unspecified ( ) and other cerebellar ataxia ( ), and progressive multifocal leukoencephalopathy ( ) are highly correlation. for males, human immunodeficiency virus infection with specified conditions ( ) and pneumocystosis ( ) is highly correlation. human immunodeficiency virus infection with specified infections ( ) and meningoencephalitis due to toxoplasmosis ( ), and falciparum malaria ( ) are highly correlation. human immunodeficiency virus infection with specified malignant neoplasms ( ) and kaposi's sarcoma of other specified sites ( ) is highly correlation. human immunodeficiency virus acquired immunodeficiency syndrome, unspecified ( ) and hiv infection, unspecified ( ) is highly correlation. exploring comorbidities from a network perspective could help determine whether differences in the comorbidity patterns expressed in different populations indicate differences in races, country, or socioeconomic status for each population. here this study show as an initially stage that there are differences in the strength of comorbidities measured for patients of different gender. the pdn could be the starting point of studies exploring these and related questions. communicable diseases & prevention-hiv/aids, health topics a dynamic network approach for the study of human phenotypes the human disease network a network approach to clinical intervention in neurodegenerative diseases infertility etiologies are genetically and clinically linked with other diseases in single meta-diseases network-based analysis of comorbidities risk during an infection: sars and hiv case studies chronic conditions and risk of in-hospital death improved comorbidity adjustment for predicting mortality in medicare populations probing genetic overlap among complex human phenotypes international classification of diseases, ninth revision the phi-coefficient, the tetrachoric correlation coefficient, and the pearson-yule debate pneumocystis species, co-evolution and pathogenic power. infection prevalence of viable toxoplasma gondii in beef, chicken, and pork from retail meat stores in the united states: risk assessment to consumers discovering disease associations by integrating electronic clinical data and medical literature continued declining incidence and improved survival of progressive multifocal leukoencephalopathy in hiv/aids patients in the current era rituximab-associated progressive multifocal leukoencephalopathy derived from non-hodgkin lymphoma: neuropathological findings and results of mefloquine treatment acknowledgements. this study is based in part on data from the national health insurance research database provided by the bureau of national health insurance, department of health and managed by national health research institutes (nhri). the interpretation and conclusions contained herein do not represent those of bureau of national health insurance, department of health or national health research institutes. key: cord- - i bn m authors: nan title: bilateral and multilateral financing of hiv/aids programs: the world bank, the international monetary fund, the global fund, bilateral donors and the private sector date: journal: global lessons from the aids pandemic doi: . / - - - - _ sha: doc_id: cord_uid: i bn m this chapter examines the operations of the world bank (a multilateral development institution), the international monetary fund (a multilateral financial institution) and the global fund to fight aids, tuberculosis and malaria (a multilateral fundraising and financing institution) to fight hiv/aids. we also examine the role of bilateral donors and the private sector in financing the fight against hiv/aids. we examine the relationships among bilateral donors and international organizations, what distinguishes their roles in the global hiv/aids pandemic and the extent to which their activities overlap. in addition, we consider how funding strategies and parameters may affect the effectiveness of aids funding in preventing transmission and providing treatment. the following series of tables ( . - . ) show the funding requirements for hiv/aids and break down those requirements by area in which the funding is needed. table . contrasts the actual funding available and the funding gap. (in chap. , we considered the potential economic impact on recipient countries of while the increase in funding for hiv/aids is a positive development, the multiplicity of donors has created problems regarding overlapping actions and conflicting conditions attached to the aid. in , over one hundred ministers, heads of agencies and other senior officials endorsed the paris declaration on aid effectiveness, an international agreement to increase efforts in harmonization, alignment and managing aid for results with a set of monitorable actions and indicators (oecd ) . also in , the unaids global task team on improving aids coordination among multilateral institutions and international donors (gtt) published a set of recommendations on how countries and multilateral institutions can streamline their aids-related activities. many of these recommendations are aimed at improving the coordination of the aids-related activities of multilateral organizations and minimizing overlap. the recommendations build upon the principles of the "three ones" -the three principles for coordinated response at the country level: ( ) one agreed hiv/aids action framework that provides the basis for coordinating the work of all parties; ( ) one national aids coordinating authority, with a broad based multi-sector mandate; and ( ) one ing to a unaids report, more than % of national aids plans were not serving as the framework for contributions by donors (unaids ) . more than % of national aids plans were not evaluated for cost or provided sufficient clarity on inputs and outputs, with the result that donors preferred to engage more poor alignment of donor strategies with national efforts and poor harmonization among donor procedures for aid management are significant impediments to achieving universal access to treatment for hiv/aids, because of the number and diversity of organizations that have become involved in addressing the pandemic. duplication of work and high transaction costs by individual agencies, together directly with countries (sidibe et al., ) . with the absence of important learning exchanges, economies of scale and synergies, impedes the speed, quantity, and quality of the response to the pandemic (sidibe et al., ) . thus, while pursuing affordable access to medicine and expanding medical services infrastructure are both essential elements for expanding access to treatment, they form a two-legged stool. the harmonization of donor and governance processes represents a key third element in the efforts to expand access to information and treatment. donald kaberuka, president of the african development bank, has noted that in the late s, members of the development assistance committee of the oecd (oecd/dac) accounted for % of total aid to developing countries. twenty years later, aid to developing countries is delivered through more than multilateral agencies, bilateral members of the oecd/dac and at least non-dac governments. as a result, some developing countries have more than active projects and receive more than missions a year, each with its own spectives, more resources, greater innovation and competition, which could reduce costs and improve program delivery. however, this has not been the result thus far (kaberuka ) . figure . shows the sources of the estimated and projected funding for the aids response from to . government ministries, not just the health ministry) (patel ) . however, even where the host government has donor coordination mechanisms in place, coordination is made more difficult when individual donors come with pre-established priorities, without involving host countries in the setting of priorities (dekay ) . one clear example is pepfar. it has established abstinence-only as a priority, and denied funding for needle exchange programs, which are priorities for the us government that do not necessarily coincide with the priorities of host governments (see chap. for details). in addition to the multiplicity of players, donors and host governments with different interests, ideologies, demands and expectations make coordination more difficult for host countries. when donors are driven by their own national ideologies and interests, at the expense of scientifically proven approaches, they undermine coordination and local leadership. moreover, when donors focus on civil society, they may undermine adherence to a national hiv/aids framework (mwale ). there has also been a proliferation of recipients. figure . shows the distribution of entities that participated in the preparation of funding proposals for round four of the global fund. with respect to the lack of donor coordination, some argue that the source of the problem is the host government, which may fear losing control over the agenda to a well-coordinated group of donors, rather than the donors themselves. the center for global development has analyzed the policies and practices of pepfar, the global fund and the world bank's map in mozambique, uganda and zambia, and compared these systems against six key funding practices that can help donors support the national aids response in a manner consistent with the aid effectiveness principles of the paris declaration. these best practices are: donor commitments and disbursements can diverge. table . shows that, in the case of some bilateral donors, commitments have exceeded disbursements, while for (oecd ) . others the reverse is true. in most cases, the actual disbursements lag commitments since its foundation since the end of the world war ii, the world bank has grown in size and importance. in , it provides financial and technical assistance to developing countries through two development institutions owned by member countries -the international bank for reconstruction and development (ibrd) and the international development association (ida). the world bank's current mission is to reduce global poverty and to improve living standards. the ibrd working with the government; building local capacity; keeping funding flexible; ing data. this study made the following recommendations to all three donors to increase the effectiveness of aid: ( ) jointly coordinate and plan activities to support the national aids plan; ( ) assist the host government in tracking total national aids funds; ( ) focus on building and measuring capacity; ( ) develop strategies with host governments and other donors to ensure financial sustainability; and ( ) strengthen financial data collection and disclosure. the study also offered specific recommendations for how each donor can improve its own prorecommendations are addressed further below. focuses on middle income and creditworthy poor countries, while ida focuses on the poorest countries. together they provide low-interest loans, interest-free credit and grants to developing countries for education, health, infrastructure, communications and other development programs. the world bank's traditional loan package integrates loans with analytic and advisory services. the world bank's research program supports studies on a range of development issues (http://web. worldbank.org). the world bank provides loans to national governments to assist in the implementation of national hiv/aids programs. the bank also does research and provides assistance to make national aids programs more effective. the world bank's first hiv/aids-related project was in . between and , the bank the world bank organizes its aids-related activities globally, through its "global hiv/aids program of action" and six regional hiv/aids programs: ( ) sub-saharan africa, ( ) east asia and the pacific, ( ) europe and central asia, ( ) latin america and the caribbean, ( ) middle east and north africa, and ( ) south asia. the purpose of this organizational structure is to have a global focus gram to increase the effectiveness of aid (oomman et al., ) . these specific selecting appropriate recipients; making the money move; and collecting and shar- bilateral and multilateral financing of hiv/aids programs loaned over usd . billion to finance national hiv/aids programs. the world bank's programs seek to focus support where national programs need it the most. the world bank has adopted the "three ones principles", noted above. the world bank monitors and evaluates its programs to ensure hiv/aids programs are context-specific. the world bank also seeks to integrate hiv/aids issues into the broader development planning process. the world bank recognizes the need to make all of the key players part of each national strategy -governments, the private sector, community and civil society organizations, people living with hiv/aids, ngos and international organizations (world bank a). the bank's program of action focuses on five areas: ( ) sustained funding for hiv/aids programs and health systems; ( ) better national hiv/aids planning, focused on high-risk groups and locations; ( ) accelerating implementation of national hiv/aids plans by overcoming administrative constraints that delay the use of new funding; ( ) building country monitoring and evaluation systems and that takes regional differences into account and to define the world bank's role in relation to other multilateral and international actors. the overall goals of these programs are prevention and treatment, taking into account local transmission patterns and sources of infection, in order to avoid a mismatch between funding and sustained funding is crucial. once people with hiv begin taking medication, they be monitored on an ongoing basis. if the underlying funding is not sustained, and more infectious and develop drug-resistant viruses. thus, the suspension of treatment is not only inhumane, but also makes prevention and treatment more difficult. resources are limited and need to be used effectively. targeting tripartite preventiontreatment-human rights strategies at high-risk groups has proved effective in countries like brazil (see chap. ). targeting high-risk groups is a key component of an effective national hiv/aids strategy, particularly when those groups have been marginalized through discrimination. while funding for hiv/aids programs has increased, there remains an "implementation gap" between the available funding and its deployment. this is due to impediments to quick implementation: a lack of skilled personnel; unpredictable or conditional funding; burdensome disbursement and procurement processes; government reluctance to contract out implementation to civil society or the private sector; and multiple systems of management, monitoring and evaluation to meet different donor requirements. to address this problem, the world bank is simplifying its own processes and procedures, strengthening its implementation advisory service and coordinating un, global fund and world bank actions through the global joint problem-solving and implementation support team (gist) (world bank a). the global aids monitoring and evaluation support team (gamet) seeks to build a well-functioning monitoring and evaluation system in each country, to enhance the impact of national programs. gamet provides field support to build country systems and capacity, as well as training and guidelines (world bank a). the world bank's main focus has shifted from getting resources to countries to ensuring that more impact evaluations are done of bank-supported hiv/aids et al., ) . the scope of the world bank's operations is quite wide, covering a wide range of development issues in a large number of countries, in addition to its work related to hiv/aids. projects with an hiv/aids component of more than usd one million, in countries. these projects include health sector support and reform, prevention and control ( http://siteresources.worldbank.org / inthivaids / projects / / gramsupport. programs, human resources development and education and national aids prowas designed to help countries intensify and expand their multi-sector national financing - - .xls) some of these projects are conducted as part of the responses to the hiv epidemic, to dramatically increase access to hiv prevention, in rwanda the world bank used map community grants for hiv initiatives to fund over civil society organizations to provide preventive, medical and support services for people living with hiv. in , rwanda was among the ten countries most severely affected by hiv and had recently emerged from a genocide/war. the usd . million grant became effective on august, and was fully committed and almost fully disbursed by the end of . the world bank board of directors approved additional financing of usd million on sustainability. building, and monitoring and evaluation of programs. just over % paid for hiv/ one part of this project was to help female sex workers to find different sources of income. several factors contributed to the success of this project. first, the project engaged local champions to mobilize people (in this case, the deputy mayor in charge of social welfare on the district hiv/aids commission became personally engaged in designing the program design). second, to break the aids-poverty cycle, poverty mitigation accompanied preventive measures (in this case, new sources of income provided a basis for further, community-based economic development projects). third, the project sought to empower women to benefit the whole family (in this case, empowering them to provide better education and health care for their children). fourth, ongoing support was provided to sustain the success of the project (in this case, to prevent the women returning to prostitution when challenges arise) (world bank ) . however, as we will see in chap. , programs for sex workers that focus on alternative employment have been criticized for contributing to their stigmatization and failing to address the needs of those who continue to earn their income from sex work. another part of the rwanda map project provided orphans and vulnerable children with sewing machines and training as tailors so that they could start a clothes-manufacturing association. this program combined information about hiv and aids, reproductive health and life skills with income generating activities. the children then served as role models and sources of information on hiv and aids for other vulnerable children. the experience with this program suggests three key factors for success. first, establish solidarity among participants, in this case by bringing the children together to find solutions to their problems and design their own interventions. second, enable beneficiaries to be role models for behavioral change. third, address poverty and vulnerability in order to make aids prevention effective (world bank ). in yet another part of the map project, the rwanda national youth council (cnjr) created a voucher system for expanding access to hiv testing for youths aged - (almost % of the population). the rationale behind promoting testing is that enabling people to learn their hiv status is a first critical step in changing behavior. the cnjr trained peer educators in behavioral change communication and reached out to youth through anti-aids clubs and sports and cultural activities. the voucher system enabled youths to go to local health facilities on designated days, minimizing waiting times. the map funding was used to pay for these services. this approach was more cost-effective (usd per person) than using mobile units to reach these youths (usd per person). it also enhanced the returns on global fund investments in facility-based services. in the first months almost , youths were tested. about % tested hiv positive. the three main lessons from the cnjr campaign were ( ) hiv testing is critical to modifying sexual behavior and expanding condom use; ( ) better knowledge leads to greater empathy and solidarity with people living with hiv; and ( ) awareness campaigns foster a culture of responsibility, trust and faithfulness among young couples (world bank ) . the rwandan government developed a treatment plan with the support of the clinton foundation. a user fee policy with a sliding scale results in most rwandans receiving free care because they live below the poverty line. the rwandan government, the world bank, the clinton foundation, the global fund, us centers for disease control and prevention (cdc) and the us government/pepfar worked together to design, implement and monitor the treatment program. different sites were funded by different donors (the world bank, the global fund and the us government/pepfar). patients receiving treatment increased from patients at seven sites at the end of to roughly , patients at sites national procurement system, the world bank and the global fund finance generic drugs and the us government/pepfar pays for brand name drugs. the clinton foundation has helped to lower the prices paid for drugs and diagnostics. pepfar funded the "tracnet" system, which uses mobile phones to transmit information. it tracks the number of patients on treatment and the drugs dispensed nation-wide, to manage the treatment program and supplies efficiently and to avoid drug shortages that would lead to interruptions in treatment. interruptions in treatment could diminish the effectiveness of treatment by creating resistance to the drugs being used and raise costs by requiring the use of other drugs and medical treatments. performance-based contracting and bonuses for health care staff expanded key hiv services rapidly in a relatively short time (for example, the number of hiv tests performed by staff) (world bank ). the world bank has also addressed the hiv/aids epidemic in central america on a regional basis. four of the six countries in latin america with the highest hiv prevalence are in central america. two central american countries have prevalence rates above %, which is a key threshold for an hiv epidemic to run out of control unless prevention efforts are improved among high-risk groups, such as commercial sex workers, men who have sex with men and prisoners (see chap. ). the adult hiv prevalence rates are as follows (in alphabetical order): costa rica ( . %); el salvador ( . %); honduras ( . %); guatemala ( %); nicaragua ( . %) and panama ( . %). by , the adult hiv prevalence rate may reach % in the region. hiv transmission in central america is primarily associated with heterosexual sex (with the exception of costa rica), as in africa and the caribbean (world bank ) . the world bank has developed a model to help governments to allocate resources efficiently to prevent the maximum number of new infections (world bank ) . in central america, the world bank also studied the extent of discrimination and stigmatization and identified areas where changes in general legislation or hiv/aids laws are necessary (world bank ). economist jagdish bhagwati has taken the world bank to task for not having a sufficiently narrow focus. in particular, he has opined that the world does not need a global think tank staffed by , people and that the world bank should not be involved in intellectual programs for countries, like india, that have sufficient resources to handle their own affairs. thus, in his view, the world bank should be cut to staff to focus on a good intellectual program for countries that need it (bbc news a). easterly ( ) has accused the world bank of wasting resources on inefficient bureaucracies and for having a late response to the hiv/aids epidemic (it had only implemented one project by and only completed ten by ). in a comparative study of us and world bank funding for hiv/aids between and , smith ( ) found that, although there is a positive correlation between the incidence of hiv/aids and poverty and the likelihood of receiving aid from the world bank, the us government is more responsive to the incidence of hiv/aids and poverty with its foreign aid donations. moreover, the world bank allocates more money to countries with political systems that are less likely to use the funds for public goods like education, treatment and health care, and does not do as well as the united states in targeting aid to countries most in need of funding (smith ). it is difficult to assess the success of the world bank's hiv/aids programs, since they are ongoing, diverse and numerous. however, the world bank's current programs have incorporated several features that suggest that they will be effective: following "the three ones", ongoing support, monitoring and evaluation of programs for effectiveness, sharing information regarding the factors that contribute to the success of individual projects and working with other multilateral and bilateral donors to reduce overlap. the world bank has undertaken or commissioned three reviews of its hiv/aids work (world bank a). the "interim review of the multi-country hiv/aids program for africa", was done in early . this review listed the following key barriers and challenges: ( ) many national hiv/aids plans are not strategic, and are poorly prioritized; ( ) prevention, care and treatment efforts are too small, and coverage is too low; ( ) management and implementation constraints hamper action; ( ) health systems are weak and overwhelmed, particularly with efforts to expand access to treatment; ( ) the effort to expand antiretroviral (arv) treatment raises difficult issues of equity, sustainability and adherence; ( ) prevention remains inadequate, regardless of the stage of the epidemic in a given country; ( ) stigma and discrimination, denial and silence persist, to the point that some people would rather die than let others know they are hiv positive; and ( ) donors sometimes create additional problems for countries, for example in tanzania, where program managers spend more time meeting the needs of visiting donors than implementing the programs. the world bank's operations evaluation department (oed) has assessed the development effectiveness of the world bank's country-level hiv/aids assisimpact of the aids epidemic) (world bank b). the oed's assessment found more focused and cost-effective way. it has helped raise political commitment, create or strengthen aids institutions, enlist ngos, and prioritize activities. the oed's assessment also found that political commitment and capacity had been overestimated and needs continuous assessment. moreover, failure to reach people with the highest risk behaviors likely had reduced the efficiency and impact of assistance. the effectiveness of the national response had been hampered by weak monitoring and evaluation and the failure to ensure that country-based research as a result of its assessment, the oed made several recommendations for the future work of the world bank in the hiv/aids epidemic. first, it should help governments use human and financial resources more efficiently and effectively. second, the world bank should help governments to be more strategic and selective, and to prioritize activities that will have the greatest impact. third, it should work to strengthen national institutions for managing and implementing the long-run response, particularly in the health sector. fourth, it needs to improve the local evidence base for decision-making and create incentives to ensure that program bilateral and multilateral financing of hiv/aids programs tance (defined as policy dialogue, analytical work and lending to reduce the scope or that the world bank's assistance has induced governments to act earlier or in a is focused on priorities areas. decisions are guided by relevant local evidence and rigorous analytical work. wilson has concluded that the world bank's map programs must place far greater emphasis on improved surveillance, research and analysis in order to design more intelligent maps that take into account prevalence and transmission patterns, the distinction between generalized and concentrated epidemics, the effect of stigma and community values on treatment programs and the role of political leadership in national aids strategies. the money must follow the epidemic by focusing primarily on normative and behavioral change in the general population in generalized epidemics and on high coverage of vulnerable groups in concentrated epidemics. in generalized epidemics, emphasis must shift from knowledge and awareness to normative change. in more concentrated epidemics, the world bank needs greater focus on groups and areas where transmission is occurring (wilson ) . a survey revealed that more than a third of patients on hiv medication in sub-saharan africa die or discontinue their treatment within years of starting; only . % of all patients were still receiving medication. the study found that many were too late taking up arv drugs and died within a few months of commencing treatment. for some it was impractical to travel to distant clinics. the researchers also found evidence that, in cases where patients had to pay for arvs, some stopped treatment. some people also suffered from stigma: in some workplaces, people are not able to carry their arvs and take their arvs freely at workplaces. retention rates between individual arv programs varied widely across africa. one program in south africa retained as many as % of their patients after years while another in uganda retained only % of patients after the same period of time (bbc news b). the world bank was a member of the gtt. the agreements reached by the gtt, including the division of labor, are reflected in the world bank's program of action (world bank a). however, as noted above, more work is needed to resolve the problems created by the proliferation of donors. in its study of funding practices, the center for global development made the following recommendations to the world bank regarding map: ( ) focus resources on building government capacity; ( ) become a knowledge bank, with a focus on prevention; ( ) make the transition to the use of existing government systems; ( ) increase individual disbursement amounts; and ( ) publicly dis- dominique strauss-kahn, who became the director general of the imf on november , has noted the need for the imf to adapt to a new global economic order (to better reflect the rise of emerging market economies and the interests of less developed ones, plus the need to better regulate globalization) and to downsize or die. in strauss-kahn's view, the imf needs to reach out to other multilateral organizations, in particular the world bank. the imf also needs to mend fences in a meaningful way with regions of the world that felt hard done by during close data (oomman et al., ) . the imf is an international organization that was established to promote international monetary cooperation, exchange stability and orderly exchange arrangements; to foster economic growth and high levels of employment; and to provide temporary financial assistance to countries to help ease balance of payments adjustment. it has member countries. the imf is to be guided in all its policies and decisions by the purposes set forth in article i of the articles of agreement of the international monetary fund. article i sets out these purposes as follows: . to promote international monetary cooperation through a permanent institution which provides the machinery for consultation and collaboration on international monetary problems. . to facilitate the expansion and balanced growth of international trade, and to contribute thereby to the promotion and maintenance of high levels of employment and real income and to the development of the productive resources of all members as primary objectives of economic policy. . to promote exchange stability, to maintain orderly exchange arrangements among members, and to avoid competitive exchange depreciation. . to assist in the establishment of a multilateral system of payments in respect of current transactions between members and in the elimination of foreign exchange restrictions which hamper the growth of world trade. the fund temporarily available to them under adequate safeguards, thus providing them with opportunity to correct maladjustments in their balance of payments without resorting to measures destructive of national or international prosperity. . in accordance with the above, to shorten the duration and lessen the degree of disequilibrium in the international balances of payments of members. since inception the imf's purposes have remained the same, but its operations have developed over time, particularly with respect to surveillance of public expenditure management systems, financial assistance and technical assistance. the imf focuses on three kinds of operations. first, surveillance operations moni- the imf also provides emergency assistance to support recovery from natural dis- the imf can allocate additional spending to hiv/aids as part of national poverty-reduction strategies. the imf also provides advice to countries on the macroeconomic impact of hiv/aids and how to manage inflows of foreign aid. reduction strategy papers, which provide the operational basis for imf and world bank loans to low-income countries and fo r debt relief under the heavily indebted poor countries (hipc) initiative (imf ) . unlike development banks, the imf does not lend for specific projects. thus, unlike the world bank and the global fund, the imf does not have projects specifically aimed at hiv/aids. rather, hiv/aids issues are addressed as part of the imf's general operations. the research of the imf on hiv/aids has been focused primarily on its macroeconomic impact. with respect to hiv/aids, imf (and world bank) policies have been criticized for not considering the impact of structural adjustment requirements (austerity making debt repayment a higher priority than health care, thereby undermining the ability of national governments to finance health care. peter lurie et al. ( ) argued that export-oriented, structural-adjustment policies were undermining hiv/aids control by contributing to social changes that favor the spread of hiv in the developing world, through increased mobility, migration, urbanization and dislocation of family units. tor economic and financial developments and provide policy advice, aimed especially at crisis prevention. second, the imf also lends to countries with balance of payments difficulties, to provide temporary financing and to support policies aimed aimed at poverty reduction. third, the imf provides countries with technical assis-at correcting the underlying problems. loans to low-income countries are also tance and training. the imf also conducts economic research and gathers statistics shocks facility. non-concessional loans are subject to the imf' s market-related related to these three types of operations. an imf loan usually stipulates the specific policies and measures a country has to implement to resolve its balance interest rate, which is revised weekly to take account of changes in short-term in-of payments problem. low-income countries may borrow at a concessional interest rate through the poverty reduction and growth facility and the exogenous country-level hiv prevention and treatment programs form part of many poverty asters and conflicts, in some cases at concessional interest rates (http://www.imf.org). terest rates in major international money markets. large loans carry a surcharge. measures) on the spread of hiv/aids. the imf has also been criticized for hanlon ( ) noted that the imf required the mozambican government and other african governments to reduce spending in the s without decreasing repayments of its debts, thereby contributing to cuts in spending on health services that increased corruption in hospitals. the international community later recognized that much of africa's debt could not be paid and agreed to cancel some debts. this led to the hipc initiative in . however, hanlon reported that with the hipc mozambique would still be paying back usd million a year, because the world bank and imf agreed to cancel only the part of the debt that mozambique was not paying. the hipc only canceled the uncollectable debt. thus, mozambique was paying usd , per day in debt service, but only usd , per day for its entire health service. in , african ministers of finance, planning and economic development warned that the enhanced hipc initiative was not delivering long-term debt sustainability. they recommended that the imf impose fewer structural conditions and provide for outcomes-based conditions where appropriate. the ministers also urged the imf and world bank, bilateral partners and the african development bank to avoid "cross-conditionalities" that impede access to resources. they recommended that to provide greater fiscal flexibility, the imf should also analyze the linkages, trade-offs and policy choices required to attain the millennium development goals (which include addressing the hiv/aids pandemic). they also proposed that evaluating exogenous shocks should be a standard feature of imf discussions with member states, and that access to loans should be extended to countries suffering from exceptional exogenous shocks such as the onslaught of imf and world bank to consider revising the eligibility criteria for assistance to middle-income countries affected by the aids epidemic, and to find ways of ensuring that countries could expand expenditure on health and social welfare without violating conditions that impose limits on public spending (eca ) . the imf restricted aid to mozambique's budget in order to control inflation and required donors' aid to fund more projects outside the state budget, contrary to the policy of many donors (hanlon ) . the imf resident representative mozambique argued that it was difficult for the government to be certain about the level of donor payments in the medium term, and it might not be prudent to make medium term expenditure commitments (such as the hiring of health personnel) given the uncertainty about whether the money would still be available over the next budget cycle. the imf representative recognized the need to improve the design of the imf fiscal target taking into account that donor aid has increasingly moved away from lending to support capital investment projects, and toward direct budget support for hiring personnel and purchasing medicine (perone ) . this story highlights the ongoing importance of policy coordination on the ground between the imf, donors and national governments and the need for sustainable funding from donors. the global fund was created to raise and disburse additional private and public sector funds for the fight against aids, tuberculosis and malaria. as of october , the global fund had committed usd . billion in countries. it provides around two thirds of all international financing for tuberculosis and malaria and close to a quarter of the global resources for aids. as we saw in chap. , malaria prevention is a cost-effective means to prevent hiv/aids in areas with high malaria prevalence, because of the impact of life-expectancy on incentives to change sexual behavior to reduce the risk of hiv/aids. the prevalence of hiv/aids also has a direct impact on the spread of extensively drug-resistant tuberculosis (xdr-tb). people living with aids are especially susceptible to xdr-tb because of their depressed immune systems, increasing the risk that xdr-tb will spread rapidly in sub-saharan africa (picard ). in turn, an xdr-tb epidemic could reduce life expectancy, thereby hampering hiv/aids prevention. thus, it is important to attack all three diseases together. there are two key differences between the global fund and the world bank. first, the global fund is a hands-off operation that focuses on financing rather than implementation, whereas the world bank is very involved in the implementation of its programs. second, the global fund has a much narrower scope of operations with respect to the issues that it tackles, being restricted to aids, tuberculosis and malaria. the world bank has a much broader development agenda, albeit one that incorporates health care in general, and hiv/aids in particular, into its development programs. section ii of the framework document of the global fund sets out its purpose in the following terms: the purpose of the fund is to attract, manage and disburse additional sustainable and significant contribution to the reduction of infections, illness and death, thereby mitigating the impact caused by hiv/aids, section ii of the framework document clarifies that the fund's mandate is to finance prevention, treatment, care and support in an integrated and balanced way, not to implement such programs. the framework document provides further that the global fund "should make use of existing international mechanisms and health plans". in making its funding decisions, the global fund is to focus on best . the global fund: a fundraising and financing institution ). resources through a new public-private partnership that will make a reduction as part of the millennium development goals (global fund tuberculosis and malaria in countries in need, and contributing to poverty expansion of government/private/ngo partnerships. the global fund is required to support programs that reflect "national ownership", by focusing upon the technical quality of proposals, while leaving the design of programs and priorities to partners within recipient countries. "country coordinating mechanisms" (ccms) are country-level partnerships that develop and submit grant proposals to the global fund based on priority needs at the national level. after grant approval, they oversee progress during implementation. ccms include representatives from the public and private sectors, including governments, multilateral or bilateral agencies, non-governmental organizations, academic institutions, private businesses and people living with the diseases. the proposals that are supported by the global fund must be consistent with international law and agreements, respecting intellectual property rights laws, such as trips. at the same time, the programs should encourage efforts to make quality drugs and products available at the lowest possible prices and give priority to the most affected countries and communities, and to those countries most at risk. the framework document provides specifically for programs that aim to eliminate the stigmatization of and discrimination against those infected and affected by hiv/aids, especially for women, children and vulnerable groups. the framework document requires the global fund to use, wherever possible, existing monitoring and evaluation mechanisms. monitoring at the country level is country-driven, but also linked to the fund's monitoring and evaluation system at a global level. grantees need to be: ( ) accountable to donors for the use of funds and achievement of results; ( ) responsive to developing countries; and ( ) responsive to the needs of those infected and directly affected by the three diseases. the framework document contemplates the following options for who oversees the process of monitoring both global and local program progress on behalf of the global fund board: global fund secretariat; ad hoc monitoring and evaluation working group; the world bank's operations evaluation department; a un agency; existing mechanisms (unaids, stop tb, roll back malaria); an independent monitoring and evaluation oversight committee appointed by the global fund board; or a third party (for example, an accounting firm or university). the world bank serves as the trustee for the global fund. the trustee has primary responsibility for financial accountability, including: ( ) collection, investment, and management of funds; ( ) disbursement of funds to national-level entities, on the instruction of the global fund board; ( ) reporting to stakeholders on the financial management of the fund and the allocation of fund resources; and ( ) independent audits. local funding agents are organizations (mainly multinational audit firms) that the global fund contracts to provide the secretariat with the information used to practices and performance, linking resources to the achievement of clear, measurable and sustainable results. another focus is on the creation, development and report on the capacity of the agencies that implement funded programs and on program results and make recommendations regarding future funding. the outfor global fund offices in the relevant countries, thereby enabling the global fund to have a leaner administration and to set up more rapidly in a country (euro the framework document requires the highest priority to be given to proposals from countries and regions with the greatest need, based on the highest burden of disease and the least financial resources. these are identified as including sub-saharan africa, currently the region most affected, as well as some countries within the caribbean, asia-pacific, latin america and central and eastern europe. the criteria for identifying these proposals include: ( ) disease burden for hiv, tb and/or malaria; ( ) poverty indicators, such as per capita gnp and the un human such as recent disease trends, size of population at risk, prevalence of risk factors, extent of cross-border and internal migration, conflict, or natural disaster; ( ) political commitment, as indicated by contribution to the financing of the proposal, public spending on health, existence of supportive national policies or the presence of a national counterpart in the proposal; ( ) existence of a country coordination mechanism, which consists of an inclusive collaborative partnership, with all relevant partners engaged in planning, decision-making and implementation. the framework document requires the global fund to provide grants to public, private and non-governmental programs for the prevention, treatment, care and support of the infected and directly affected, which may include: increased access to health services; provision of critical health products (for example, bed nets; condoms; antiretroviral, anti-tb and anti-malarial drugs; treatment for sexually transmitted infections; laboratory supplies and materials; and diagnostic kits); training of personnel and community health workers; behavioral change and outreach; and community-based programs, including care for the sick and orphans. technical review panels, made up of independent, impartial teams of experts appointed by the global fund board, review grant proposals, based on criteria set by the board, and make recommendations to the board for final decision. the global fund's technical evaluation reference group (an independent advisory body) was charged with overseeing a five-year evaluation on the operations of the global fund, during - . the first area of evaluation is "organizational efficiency", which analyzes whether the global fund is efficient and effective in fulfilling its core principles, including acting as a financial instrument rather than implementation agency and furthering country ownership. the second area of evaluation is "partnership environment", which considers how effective a striking feature of the global fund's very user-friendly web site is the global fund evaluation library (http://www.theglobalfund.org/en/links_resources/ brary/). this web page makes both internal and external evaluations of the global fund readily available and has the stated aim of improving the global fund's delivery of key services for hiv/aids, tuberculosis and malaria by stimulating open debate and evaluation of the fund. this novel method of inviting and inciting critical evaluations, in order to improve performance, stands in contrast to the world bank and imf approaches to external criticism. the global fund has been criticized for funding drugs without strengthening the underlying health systems. in response, the global fund opened the possibility of funding health system improvements, but this was not used often and rarely covered staff remuneration. the world bank has proposed leaving the strengthening of health systems up to the world bank, in order to avoid overlap. however, the world bank itself has been criticized for poor performance in supporting and reinforcing public health services, particularly given its role, together with the international monetary fund, in maintaining limits on public health expenditures and wages. the global fund, with its narrow funding mandate, has also been criticized for not placing more conditions on the use of the resources provided and for giving into technical advisors from the world bank and bilateral donors who oppose the exceptional nature of aids (philips ) . and efficient the global fund partnership system is in supporting hiv, malaria and tb programs at the global and country level. the third area of evaluation is "health impact", which studies the global fund's contribution to reducing the burden of the three diseases. fig. . global fund, sector of recipients ( ) ( ) ( ) ( ) ( ) ( ) the global fund evaluates program performance after years. the center for global development analyzed data on of the first global fund grants evaluated in . due to the subjective nature of the evaluation process, this analysis should be seen as an analysis of evaluation scores rather than of the actual performance of the programs. moreover, the results were not intended to be used to influence the distribution of funding, but rather to allocate resources for oversight and risk management. the programs that scored lowest had government agencies as principal recipients, had a large amount of funding, were focused on malaria, had weak initial proposals or were evaluated by the accounting firm kpmg. countries with a high number of doctors per head, high measles immunization rates, few health-sector donors and high disease-prevalence rates had higher evaluation scores. poor countries, those with small government budget deficits and those that have or have had socialist governments also received higher scores. programs in which a government was the principal recipient received significantly lower scores than those with civil society, private sector or multilateral recipients. malaria programs were . % less likely than hiv/aids or tuberculosis programs to receive an a. in addition, evaluation scores were slightly higher in countries with higher prevalence rates for the target disease of the program (radelet countries with stronger health systems and larger numbers of trained health workers were more likely to have successful programs. this suggests that the global fund needs to ensure greater oversight in countries with weaker systems and capacity, and underscores the importance of building strong health systems rather than focusing narrowly on short-term targets. however, evaluation scores were lower in programs where there were many other donors. this may have been due to the greater administrative and management burden placed on recipients when there are multiple donors. alternatively, it may indicate that the incentives for strong performance are weaker when recipients have many funding alternatives the global fund's country coordination mechanism has been criticized for focusing on government actors and not including people with hiv/aids (gonzalves ; mckai ) . faith-based organizations in host countries have also not been included in country coordination mechanisms to the degree that they would like, often due to a lack of information from governments, a lack of access to guidelines for funding proposals and a need for assistance in preparing funding the center for global development convened a high-level independent working group to help the new executive director of the global fund define the major tasks that require attention, and provided specific recommendations for action. the working group consisted of members, including relevant experts in government, civil society organizations, foundations, academia, private sector companies and disease-based partnership initiatives. some of the working group's key recommendations were: ( ) convene a "heads of agencies group" with the director general of the who, the executive director of unaids, and the president of the proposals (lee et al., ) . ( radelet and siddiqi, ) . world bank to jointly tackle key problems in technical assistance, procurement, monitoring, evaluation and other key issues; ( ) work with other agencies to develop an information market for technical assistance, building on existing mechanisms with unaids, the stop tb partnership and roll back malaria; ( ) provide early warning information on country programs to recipients, ccm members, governments, international partners and key ngo groups so that actions can be taken quickly to get programs back on track; ( ) commission a management audit of the secretariat, consider hiring additional portfolio managers and consider shifting from one portfolio manager per country to teams of two or three working across countries; ( ) hire a full-time professional fund raising team, led by a senior professional and comprised of experts with diverse skills to work with traditional, non-traditional and private sector donors; ( ) make the executive director a nonvoting member of the board so that the experiences and insights of the executive director and the secretariat are more fully reflected in board discussions (radelet ) . in its study of funding practices, the center for global development made gaps; ( ) re-examine strategies to build local capacity; ( ) simplify procedures for a external evaluation of the global fund's local funding agent system evaluation found that the system needs: ( ) greater emphasis on health program skills (since few local funding agents have staff with health backgrounds); ( ) to implement a quality assurance system to verify the adequacy of local funding agent methods (for example, with respect to documentation of audits); ( ) to provide more complete capacity assessments of the organizations that implement programs; ( ) to increase the use of in-country partnerships; ( ) to implement a comprehensive performance evaluation system for local funding agents; and ( ) management process (euro health group ). an internal evaluation made similar findings: ( ) that there were gaps in local funding agent documentation that failed to meet professional auditing standards; ( ) adherence to specific auditing standards needed to be integrated as a requirement in the tendering process; ( ) a lack of a consistent management approach; ( ) that the global fund secretariat should introduce a systematic performance evaluation system for local funding agents and a handbook; ( ) that capacity assessment should extend to sub-recipients, not just principal recipients of funding; ( ) the health program skills and experience of local funding agents was inadequate; and ( ) that local funding agents needed to develop partnerships with other health-sector players through networking, to have greater access to health sector intelligence and improve coordination with other players (technical evaluation reference group ). the united states government accountability office (gao) also conducts reviews of the global fund, since the united states contributes funds. in , the gao review of grant disbursements and grant renewal decisions found that good performers; and ( ) publicly disclose data (oomman et al., ) . bilateral and multilateral financing of hiv/aids programs the following recommendations to the global fund: ( ) keep the focus on funding concluded that the system should be maintained, but needs to be improved. the to create an operational manual or handbook to govern the local funding agent bilateral governmental donations are an important source of financing for hiv/aids programs. in , the resources available from all sources totaled usd . billion, out of which g /ec and other donor government commitments for hiv/aids totaled roughly usd . billion. of these donor government commitments, usd . billion were bilateral commitments and usd million were contributions to the global fund. the g /ec commitments were % of the total donor govern-they were well documented and that documentation had improved since . the gao also noted that the global fund has begun developing a risk assessment framework to improve the identification of risks that may affect grant implementation, having found that an earlier risk assessment model was inadequate. however, the gao also found that the lack of a mandatory system of local funding agent performance assessment limits the global fund's ability to determine the quality of local funding agent monitoring and reporting (gao ). as we noted earlier, commitments and disbursements are not the same thing. for example, while the united states accounted for . % of bilateral commit- . and . ). many donors prefer to channel funding through bilateral programs ( % of g / ments). however, preferences vary from one donor country to the next. for example, at on end of the spectrum, the uk made % of its commitments through bilateral ec commitments), rather than the multilateral channel ( % of g /ec commit- channels and % through the global fund. at the other end of the spectrum, italy made % of its commitments through bilateral channels and % through the global fund. canada was in the middle, with % of its commitments through bi- ). engaging the private sector in hiv/aids prevention and treatment is increasingly becoming a major focus for governments, advocates and public health practitioners. the private sector, through domestic firms or the foreign direct investment of multinational firms, is a significant source of financing for the prevention and treatment of hiv/aids. private charitable foundations have also become an important source of funding in the fight against hiv/aids. two issues regarding private sector donors provoke controversy. one is the issue of donations of goods and services in kind by the private sector. critics argue that such donations impede the ability of recipient governments to build their own infrastructure. supporters argue that such donations give a boost to local efforts to build infrastructure, provided they take place in close cooperation with recipient governments. a second issue is donor reliability and sustainability, particularly with respect to donations from the private sector (although this issue is also raised regarding other sources of funding). here, the concern is that host governments will be unwilling to integrate funding for hiv/aids into general revenues that support the overall health infrastructure (for example, salaries for medical personnel) unless there is some assurance that the funding will be ongoing (mckinnell ) . while the participation of the private sector in addressing the hiv/aids pandemic is very important, its efforts need to be coordinated with the other players (governments, donors and ngos) and the roles of the various players need to be well defined. for example, oxfam has criticized developed countries and the world bank for undermining governments' ability to deliver public services by advocating inappropriate private sector projects in health. oxfam acknowledges that the private sector has a role to play, but argues the private sector cannot provide services on the necessary scale, geared to the needs of all citizens (oxfam ) . companies have an incentive to invest in hiv/aids programs due to the impact of the pandemic on enterprise performance. this impact depends on worker attrition due to sickness and death, the corresponding costs to the firm for providing health and sickness benefits, replacement costs to obtain new workers and the . the role of the private sector in funding prevention and treatment lateral channels and % through the global fund (see fig. . ) (kates and lief, same time, the health of a country's population may affect inflows of foreign hiv/aids pandemic thus creates a catch- situation. hiv/aids has clear effects on a company's workforce and its customer base. the literature suggests that skilled workers are most likely to contract the virus, waterhousecoopers survey found that only % of organizations in eastern vention among employees and their families and providing access to treatment. for example, in botswana an early and innovative program by debswana, a diamond mining company that is the country's largest non-government employer, made it the first company to provide free anti-retroviral treatment to employees and their spouses (center for global development ). however, as with multilateral organizations such as the world bank, the imf, the global fund and the un, it is important to have an overarching framework in order to ensure the adoption of best practices by individual firms and to minimize overlap between the private sector and the other players that are involved in addressing the pandemic. in this regard, there have been some important national and global initiatives. an example of a national initiative is the commercial market strategies (cms) project, which was a -year usaid-funded project ( ) ( ) ( ) ( ) ( ) ( ) . cms's aids treatment brochure articulated the business case for providing arvs to employees as part of their health care benefits. the key global initiative is the global business coalition on hiv/aids (gbc), which has members, headquartered in thirty countries, employing over eleven million people in more than countries and is supported almost entirely by its member companies. the gbc and booz allen hamilton conducted a baseline survey and interview program to establish a basis to look at the scope and depth of the response being made by the global business community. the study highlighted variations in business response by region, industry and enterprise scale. the study found that business increasingly sees hiv/aids as a strategic as well as a social responsibility issue, and manages programs and resources based on bottom line impact (gbc and booz, allen, hamilton ) . the data source was the expertise and experiences of gbc member companies across industries that were surveyed in april and companies who participated in a detailed interview program. the baseline showed business response in the form of an index, on a scale of - . the index was calculated from the number of companies active in each of global business hiv/aids categories of best practice aids standard (bpas), each with five levels of action. the impact of hiv/aids on worker productivity (ramachandran et al., ) . at the and that these are extremely difficult to replace. customers, suppliers and inves-direct investment to low-and middle-income countries (alsan et al., ) . the tors in a company are also likely to be affected by hiv/aids, and this effect is expected to increase as the virus spreads (bloom et al., ) . however, a price-on an individual basis, firms can have a tremendous impact in promoting pre-africa had hiv/aids policies in place (pricewaterhousecoopers ). surveyed companies had an average index score of . . this was equivalent to being active in more than of categories with two actions underway in each. the most active % scored . and the least active % scored . . this variation was primarily due to perceived business needs and the length of time the companies had been addressing the hiv/aids issue. of the bpas categories there are two in which the business response was particularly strong -prevention initiaoil) (gbc and booz, allen, hamilton ). were twice as likely to fully subsidize treatment for employees in high prevalence ments, suggesting that program design and follow up could be enhanced. with the survey found that developing and implementing a company hiv/aids pro- the gbc survey had several key findings regarding ways to improve the global business community's response to hiv/aids. first, there is a need to develop strategies to work closely with suppliers and business associates to expand the network of business engagement. second, there is a need to partner with ngos, community, and local government to develop and fund programs and initiatives with greater reach. third, companies should extend confidential testing and treatment programs, including monitoring of testing participation rates, access to viral load tests and, in high prevalence areas, treatment for dependents and post employment. fourth, companies should focus on balanced prevention and treatment programs that target behavior change in conjunction with treatment. fifth, there is a need to increase the role of business in advocacy and to extend programs into emerging markets. in particular, ceos and senior management should provide leadership to dispel myths and stigma, break down workplace barriers and influence community change. in this regard, the gbc study concluded that the private sector can enhance their response to hiv/aids by treating it like any other disease and integrating responses into broader packages supporting health and well-being. employment contracts and health benefits packages should include hiv as a normal component rather than an exception. rather than isolating hiv/aids, interventions should be part of a comprehensive health system for employees and the broader community (gbc and booz, allen, hamilton ) . the gbc study recommends that an hiv/aids response be a core component of an overall business strategy, whether the response takes the form of cause-related marketing, co-investments with governments on hiv programs or comprehensive overall market leader and will also help sustain markets and serve a need in countries like india and china, with rapidly growing young, sexually active middleclass populations (gbc and booz, allen, hamilton ). in addition to direct company participation in prevention and treatment programs, there have been efforts to create market-based incentives for the private sector to donate more funds to combating hiv/aids. the most notable example is product red, an economic initiative designed to deliver a sustainable flow of private sector money to the global fund to fight aids, tuberculosis and malaria. this initiative was announced at the world economic forum annual meeting in by bono and bobby shriver. with product red, the world's leading companies made a commitment to channel a portion of their profits from sales of speciallydesigned products to the global fund to support aids programs for women and children in africa. another market-based initiative for the private sector is "social marketing". population services international (psi), a nonprofit organization based in washingpanies seeking to fight hiv/aids in the workplace. psi, a large aid contractor, uses commercial marketing strategies to promote health products, services and healthy behavior in low-income and vulnerable populations in developing countries. products and services are sold at subsidized prices rather than being provided free of charge. the logic behind social marketing is that charging money will enhance the perceived value of products and services, increase the likelihood needs to be charged for hiv treatment in order for the recipients to see "value" in the drugs has been discredited. arata kochi, the director of the world health organization's malaria program, has concluded that the social marketing approach is not an effective means to expand the use of mosquito nets to prevent malaria. using the social marketing approach, mosquito nets were sold through local shops at subsidized prices, with donors underwriting the losses and paying consultants to come up with brand names and to advertise the nets. the social marketing approach was also used to distribute condoms and oral rehydration salts. however, it was revealed that the united states agency for international development (usaid) was spending % of its malaria budget on consultants and % on goods like nets, drugs and insecticide. experiences in kenya helped to persuade the who to change its policy. a -year study of health districts revealed that a psi social marketing scheme for malaria nets only increased coverage from % of the population to about % between and . in contrast, when the health ministry got a grant from the global fund that allowed it to hand out . million free nets in weeks, coverage rose to %, and distribution became more equitable. under social marketing, the richest of the poor had % coverage, while the poorest of the poor had only %. after the distribution of free nets, they were about equal and deaths of children dropped %. free distribution was also cheaper. with consultant fees, transportation, advertising and shipping, social marketing added about usd to the cost of each net beyond the usd to usd that manufacturers charged. even with payments to volunteers, the added cost of free distribution was only about usd . médecins sans frontières (msf) has criticized donors for proposing to continue having patients make a financial contribution to the cost of arv treatment in populations where incomes are barely adequate for people to feed themselves (médecins sans frontières ) . aids patients need to receive treatment their entire lives without interruption in order to avoid death or creating drug-resistant mutations of hiv. requiring patients (who do not have enough money for food) to pay for treatment reduces the effectiveness of arv treatment, reduces adherence and decreases survival rates. even where arv treatment is free of charge, where countries define aids care narrowly many direct treatment costs must be covered by patients. for example, the high cost of laboratory tests can deter patients from . the role of the private sector in funding prevention and treatment ton, dc., created a comprehensive corporate aids prevention program for comof use, and motivate commercial sector involvement. however, the notion that fee per net (kyama and mcneil, ) . monitoring the effectiveness and side effects of arv treatment. a related problem is the cost of treatment for opportunistic infections (such as pneumonia), which may bankrupt patients before they even start arv treatment. other costs, such as consultation or hospital fees, can also constitute a barrier to treatment for patients in developing countries. as a result, msf has recommended that major international donors such as the global fund, pepfar, and the world bank should require recipients to provide arv treatment and other essential elements of aids care without patient contributions, and to slightly increase funding to include these complementary costs (philips ) . the world bank president, former us trade representative robert zoellick, has called on the bank's member nations to give the private sector a bigger role in development (reuters ) . with respect to the world bank's aids programs, as well as other health-related issues, careful thought will have to be given to the appropriate role for the private sector, particularly the failure of social marketing to achieve adequate and equitable coverage in poor populations. the experience of the private sector thus far indicates that the business response to the aids pandemic needs to be standardized and coordinated with the activities of other players, notably national governments, ngos and multilateral institutions. while some companies limit their response to donations of money, goods and services, others have taken a more proactive approach by implementing prevention and treatment programs for their employees and, in some cases, the dependents of employees. this proactive approach is particularly useful in areas with high prevalence rates and poor public health care infrastructure. global multinational companies are in a position to use their influence with suppliers and other business associates to expand the use of best practices, particularly with respect to prevention and treatment programs. in this regard, the gbc plan to review the state of business and aids annually and to use the results of these assessments to adapt the best practice aids standard is to be commended. the gbc study notes that companies have addressed child labor, wage equity and occupational safety through their supply chains, including distributors, business associates and small and medium enterprises. however, this network of global suppliers has been a weak link in the aids response. if tapped, the reach of employee and community networks could make a tremendous impact in mobilizing communities around hiv prevention and treatment. similarly, enhanced supply chain practices promoting youth education and gender equity can help to address underlying social factors that contribute to the spread of hiv/aids (gbc and booz, allen, hamilton ). the further standardization of best practices would be a useful next step. the international standards organization (iso) certification process that is currently used to improve business processes could serve as a model. the iso has specific standards for the automotive industry and has specific standards for environmental processes. while these standards are voluntary, many multinational companies require their suppliers to be iso-certified. the creation of specific iso standards for hiv/aids policies, or for company health policies more generally, would be a private charitable foundations have become a significant source of funding, research and political leadership in fighting hiv/aids. in this section, we examine the hiv/aids activities of three us foundations: the bill & melinda gates foundation, the kaiser family foundation and the william j. clinton foundation. it is notable that these foundations have largely avoided overlap in the nature of their operations related to hiv/aids, by specializing in addressing different needs. the first two foundations have also collaborated closely. useful vehicle for standardizing best practices and expanding the adoption of best practices to suppliers. as with iso, the standards could be voluntary, but major multinationals could require their suppliers to get certified in order to qualify as suppliers. as of december , the bill & melinda gates foundation had net assets totaling usd billion, which it uses to fund global development and global health initiatives. the mission of the foundation's global health program is to encourage the development of lifesaving medical advances and to help ensure they reach the people who are disproportionately affected. the foundation is guided by the belief that all lives, no matter where they are lived, have equal value. with respect to global health, the foundation focuses its funding in two main areas: ( ) access to existing vaccines, drugs and other tools to fight diseases common in developing countries; and ( ) research to develop health solutions that are effective, affordable and practical. in developing countries, the foundation supports efforts to prevent and treat diseases and conditions that meet three criteria: ( ) they cause widespread illness and death in developing countries; ( ) they represent the greatest inequities in health between developed and developing countries; and ( ) they receive inadequate attention and funding. hiv/aids is one of the foundation's priority diseases. to slow the global spread of hiv, the foundation supports the development of vaccines and other tools and strategies with the potential to prevent tens of millions of infections and deaths. the foundation also funds comprehensive initiatives that include both prevention and treatment (http://www.gatesfoundation. org/globalhealth/). the bill & melinda gates foundation's primary focus with respect to hiv/aids is on prevention. illustrative examples of the programs funded by the foundation are: ( ) avahan (which means call to action in sanskrit), an aids prevention initiative established in india in , to which it has committed usd million; ( ) the global hiv prevention working group, an international panel of experts; and ( ) the global hiv vaccine enterprise. through the avahan program, the foundation is working to expand access to effective prevention in the six states with india's highest infection rates and along the nation's major trucking routes. the working group is an international panel of more than leading public health experts, clinicians, researchers and people affected by hiv/aids. it is coconvened by the henry j. kaiser family foundation and the bill & melinda gates foundation. the global hiv prevention working group has developed reports and other materials about critical hiv prevention issues, such as scaling up the combined use of proven prevention strategies (male circumcision, aids education, condoms, hiv testing and prevention of mother-to-child transmission) in order to cut the number of projected new infections to in half (global hiv prevention working group ). the global hiv vaccine enterprise is an international alliance of independent organizations dedicated to accelerating the development of an hiv/aids vaccine through collaborative research efforts. the bill & melinda gates foundation serves as interim chair and funds vaccine research. in july , the bill & melinda gates foundation funded grants totaling usd million to create an international network of collaborative research consortia focused on accelerating the pace of hiv vaccine development (http://www.gatesfoundation.org). the kaiser family foundation is a non-profit, private operating foundation focusing on the major health care issues facing the united states, but has a growing role in global health. the foundation has an endowment of over half a billion dollars and an operating budget of over usd million per year. unlike grant-making foundations, kaiser develops and runs its own research and communications programs, sometimes in partnership with other non-profit research organizations or major media companies. this foundation focuses on three areas of activity: ( ) producing policy analysis and research; ( ) operating a large-scale health news and information service on the web and a series of specialized websites; and ( ) developing and helping to run large-scale public health information campaigns in the united states and around the world, through direct partnerships with major media companies. the current focus of the latter is on hiv/aids, with an emphasis on reaching young people (http://www.kff.org/about/index .cfm). the william j. clinton foundation is president bill clinton's vehicle for strengthening the capacity of people in the united states and throughout the world to meet the challenges of global interdependence. one of the foundation's main initiatives is focused on hiv/aids. in , the foundation helped to negotiate major price reductions for developing countries for medicines critical to fighting hiv/ aids, in an agreement with pharmaceutical manufacturers (see chap. ). these countries together have % of aids cases in the developing world. the foundation's hiv/aids initiative (chai) has also involved political leadership from president clinton to reduce fear and ignorance of the disease and to discourage discrimination. donations are the primary source of revenue for the foundation, making up usd , , of the usd , , in revenue for (http:// www.clintonfoundation.org). the clinton foundation also funds access to treatment and information. it has committed usd million to fund a -year program to ensure all hiv-positive children in kenya receive treatment. the funds would pay for a public awareness campaign and purchase anti-retroviral drugs to rapidly scale up the number of infected children under treatment from to . half all hiv-positive children in kenya die before their second birthday; % of those die because they are not provided with treatment. anti-retroviral therapy would increase the life expectancy to years. of an estimated , hiv-positive children, , are in need of treatment and only , are on life-saving anti-retroviral therapy. a survey commissioned by the kenyan ministry of medical services showed that % of mothers and caregivers were unaware of the availability of hiv testing for children and that only % had taken their children for hiv testing (ndegwa ) . there is also collaboration among private firms, private foundations and host governments. for example, an innovative model for fighting hiv/aids in africa is being piloted in botswana through a public-private partnership involving the government of botswana, the bill & melinda gates foundation and merck & co., inc. the partnership is intended to help botswana achieve an "aids-free generation by " by expanding prevention, supporting treatment, increasing counseling and testing and empowering communities (center for global development and merck ). the main focus of this chapter has been on multilateral financial institutions. however, it is important to note the role of other financial donors, notably bilateral governmental arrangements. private actors and ngos also make significant contributions to addressing the global aids pandemic. as important as it is to marshal the resources of numerous governmental and non-governmental agencies, the multiplicity of donors involved in the aids epidemic, together with a multiplicity of donor requirements, is a significant issue in seeking to expand prevention and treatment programs. national political leadership is a crucial part of any hiv/aids strategy. in many countries, statements made by politicians who make decisions on resource allocation have been appalling. in south africa, tshabalala-msimang, the health minister, shares south african president mbeki's rejection of the international scientific consensus that aids is caused by the hiv. the health minister has also criticized the use of standard anti-retroviral drugs to treat aids, recommending instead that south africans with aids follow a diet of beetroot, garlic, olive oil and african potato. in a recent south african population survey, a quarter of the population said they didn't believe in a link between hiv and aids (wilson ) . figure . reveals the impact of misinformation on south africans perceptions regarding the sources of hiv transmission. of mozambique's population is hiv positive (bbc news a). these lapses in political leadership highlight the need to incorporate political leadership into aids programs that are funded by multilateral, bilateral and private sector donors. multilateral institutions, such as the world bank, the imf and the global fund, and bilateral donors, including ngos and national governments, need to coordinate and harmonize their policies and financing conditions further in order to reduce were also infected "in order to finish quickly the african people". the catholic assigned to the private sector in delivering aid, in order to avoid the unnecessary diversion of funds away from the core goal of health care. in this regard, the experience to date suggests that social marketing is less effective and less equitable than the free provision of goods and services. particularly in the case of fastmoving infectious diseases, equitable and effective distribution should be paramount, since such diseases are unlikely to respect socio-economic boundaries, as the experience with hiv/aids and malaria has demonstrated. in particular, donors should not impose requirements to use patented medicines in place of cheaper, generic alternatives. the global business community has an important role to play in addressing global diseases. there are several key lessons that arise from the gbc's experience with hiv/aids. first, it is important to integrate health issues into overall business strategy, particularly since it takes about years to fully implement such strategies. second, there is a need to standardize best practices on a more systematic the administrative burden on recipients and in order to avoid imposing conflicting conditions on recipients. donors also need to be careful with respect to the role basis and to create incentives for those best practices to be adopted by suppliers and business partners of global companies. in this regard, the creation of iso standards for company health policies would be extremely useful, particularly for fastmoving global infectious diseases that have the potential to cause widespread economic damage and human suffering, such as avian influenza and sars. the global response to the hiv/aids pandemic has highlighted the need to strengthen health care infrastructure in developing countries. there is a concern that the high profile given to the hiv/aids pandemic may have diverted funds away from other important health issues (england et al., ) . in chap. we concluded that the focus on hiv/aids is justified, but it is important to address the hiv/aids pandemic in a way that strengthens the ability of national governments and multilateral organizations to address health concerns more generally. the following chapter examines the role of global health organizations in the hiv/aids pandemic, with a particular focus on the world health organization, which is the multilateral institution that is charged with addressing global health issues. the effect of population health on foreign direct investment private sector responses to hiv/aids: the case of debswana, botswana's diamond company funding the response to aids: why are donors not working together? are we spending too much on hiv? global fund to fight aids, tuberculosis and malaria: pdf global fund to fight aids, tb and malaria has improved its documenta-d the framework document of the global fund to fight aids bringing hiv prevention to scale: an urgent global priority funding the response to aids: why are donors not working together? pound of flesh: joseph hanlon reports on how local people have wised up to a huge international hoax donor concern over imf cap on aid increases tion of funding decisions but needs standardized oversight expectations and assessments evaluation of the local fund agent system international assistance for hiv/aids in the developing world: taking stock of the g , other donor governments, and the european commission. kaiser family foundation, center for strategic and international studies/unaids, data distribution of nets splits malaria fighters. www. nytimes.com. accessed the new international aid architecture: new players, new challenges strengthening partnerships in hiv monitoring and evaluation: how joint missions build and strengthen partnerships to support the realization of national m&e systems global fund responsiveness to faith-based organizations imf must adapt and downsize or die socioeconomic obstacles to hiv prevention and treatment in developing countries: the roles of the international monetary fund and the world bank funding the response to aids: why are donors not working together? funding the response to aids: why are donors not working together? access to healthcare, mortality and violence in reports funding the response to aids: why are donors not working together? kenya: clinton foundation provides $ m for children living with hiv/aids the paris declaration following the funding for hiv/aids: a comparative analysis of the funding practices of pepfar, the global fund and the world bank map in mozambique, uganda and zambia the public interest: health, education, and water and sanitation for all funding the response to aids: why are donors not working together? a response to joseph hanlon's recent article, donor concern over imf cap on aid increases aids: free access to treatment, a public health necessity or an economic heresy? picard a ( ) quarantine sought for harsh tb strain: variant poses 'extreme risk hiv/aids: what is business doing? a survey of the business community's response to hiv/aids in kenya challenges and opportunities for the new executive director of the global fund: seven essential tasks global fund grant programmes: an analysis of evaluation scores hiv/aids and the private sector in africa: evidence from the investment climate survey data world bank chief calls for new direction for lender summary paper on the evaluation of the studies/specific_evaluations/terg_summary_paper the evolving hiv epidemic: what have we learned since the map began? powerpoint presentation hiv/aids in central america: the epidemic and priorities for its prevention an oed evaluation of the world bank's assistance for hiv our commitment: the world bank's africa region hiv/aids agenda resources/wb_hiv-aids-afa_ - _advance_copy external /default/ wdscontentserver/ wdsp/ib/ / / / _ / aids situation and response to the epidemic key: cord- -tcq lnwg authors: cunningham, anthony l.; grohman, gerhard s.; harkness, john; law, carmela; marriott, deborah; tindall, brett; cooper, david a. title: gastrointestinal viral infections in homosexual men who were symptomatic and seropositive for human immunodeficiency virus date: - - journal: j infect dis doi: . /infdis/ . . sha: doc_id: cord_uid: tcq lnwg gastrointestinal viruses, predominantly rotaviruses and adenoviruses, were detected by enzyme-linked immunosorbent assay, electron microscopy, or cell culture in > % of two groups of homosexual men with symptomatic human immunodeficiency virus (hiv) infection, who did ( %) or did not ( %) have diarrhea. lower detection rates were observed in hiv-seronegative ( %) and asymptomatic hiv-seropositive ( %) men. in the patients with diarrhea, % of the isolates of virus were found in the most immuno suppressed patients, those patients with aids-related complex or opportunistic infections associated with aids. high excretion rates of these viruses are probably associated with both anal-oral transmission and immunosuppression. these viruses apparently cause acute episodes or relapses of diarrhea in some patients but may be co-pathogens or noncontributory to chronic diarrhea in others. or parasitic etiology. chronic diarrhea in the absence of cryptosporidium or other pathogens has been described as a common presenting feature of aids in africa [ ] . hiv has been shown to infect colonic cell lines and has been suggested as the main cause of most idiopathic cases [ ] . viruses may be significant gastrointestinal pathogens in other groups of patients with severe t lymphocyte deficiencies, such as bone marrow transplant recipients, although this group has the additional problem of graft-versus-host disease and chemoradiation damage that may involve the gut. yolken et al. [ ] and we ( . m., j. h., g. s. g., k. atkinson, and j. c. biggs, unpublished observations) have observed that adenoviruses, coxsackieviruses, rotaviruses, and clostridium difficile toxin are detectable in the feces of marrow transplant recipients and hematology patients receiving chemotherapy. in yolken's study, patients infected with these organisms had significantly increased rates of diarrhea and abdominal cramps. the infections with rotaviruses and adenoviruses occurred at the same time that these viruses were prevalent in the normal pediatric population. the presence of these pathogens was associated with a marked increase in mortality [ ] . adenoviruses have also been associated with diarrhea or colitis in patients with aids [ ] . we have recently detected sporadic, as well as epi-demic, cases of norwalk-like viruses in adults [ ] . immunosuppressed patients (including the marrow transplant recipients) have not been previously examined for these pathogens because of a lack of available antibody specific for norwalk virus. we report here the detection of viruses from the stools of a large proportion of patients with symptomatic hiv infection (aids, arc, and pol) and acute or chronic diarrhea when no other microbial pathogen could be identified. hiv-seronegative and -seropositive homosexual men presenting for hiv antibody screening provided control groups to examine the effects of transmission via anal-oral contact and infection with hiv, with or without significant depression of concentration of circulating cd lymphocytes. we studied stool samples from two groups of patients for the presence of viral and other microbial pathogens. group . all patients with symptomatic hiv infection (aids, arc, or pol) who presented with acute or chronic diarrhea to the st. vincent's hospital aids service between january and january were entered in the study. diarrhea was defined as more than three fluid stools (i.e., assuming the shape of the container) per day and as chronic if it persisted for more than three weeks. exacerbations of chronic diarrhea were defined as a transient marked increase in stool frequency and volume. fecal specimens were collected early in the course of acute diarrhea, during exacerbations of chronic diarrhea, or on several occasions during persistent chronic diarrhea. the specimens were examined (microbiology laboratory, st. vincent's hospital) by microscopy and culture, using standard methods, for the full range of potentially pathogenic bacteria and parasites occurring in these patients (including salmonella spp., shigella spp., campylobacter jejuni, yersiniaenterocolitica, aeromonas hydrophila, plesiomonas shigelloides, vibrio parahaemolyticus, atypical mycobacteria, cryptosporidium spp., isosopora belli, giardia lamblia, amoebae, strongyloides stercoralis, and c. difficile; toxigenic and enteropathogenic escherichia coli were excluded). c. difficile toxin was detected by a standard cytotoxic assay. group (controls). homosexual men presenting to a sexually transmitted diseases (stds) center for routine examinations for stds and for hiv antibody screening during the same period provided a comparison group. they were all examined by one of us (c. l.). on examination, of these men had acute diarrhea, and % had proctitis. stool specimens were obtained on three separate days over a one-to two-week period from all men in the group. all three specimens were screened for protozoa and helminths at the school of public health and tropical medicine (sydney university). two specimens were cultured for the same range of bacterial pathogens, and the first specimen was examined for viruses. all specimens for virological examination were transferred immediately to the virology department (institute of clinical pathology and medical research, westmead hospital), where they were examined for viruses. fecal specimens were processed for viral diagnosis as follows: a % solution was prepared in pbs (ph . ), held overnight at c, and clarified by low-speedcentrifugation. aliquots of supernatant were inoculated into cell cultures (primary monkey kidney, hep- , and human diploid fibroblasts) and also tested for rotavirus antigen by elisa (enzygnost'"; calbiochem-behring, sydney). the elisa-positive samples were later examined by electron microscopy (em) and tested in a blocking elisa (kallestad, shaska, minn) for rotavirus by using goat antibody to rotavirus (kallestad). the remainder of the supernatant was treated with arklone ( , , -trichlorotrifluoroethane; sigma, st. louis), held for i h at c, and then ultracentrifuged. the pellet was resuspended, negatively stained with phosphotungstic acid, and examined by em. to detect norwalk virus by immune em, we incubated the resuspended pellet, before ultracentrifugation, with antiserum specific for norwalk virus. in the group of homosexual men presenting to the std clinic for hiv antibody screening, the proportions of hi v-seronegative ( of ) and asymptomatic seropositive men (seven of ) with virus in their stools was not significantly different ( % vs. lamblia) did not significantly alter these proportions ( . % vs. . %; 'y} = . ). in the hivseropositive group, rotaviruses and adenoviruses were the predominant viruses detected (table ) , and none of these viruses were associated with acute diarrhea. in the hlv-seronegative group, one of three rotaviruses identified and one of five enteroviruses was associated with acute diarrhea. in the group of hospital patients with diarrhea, stool specimens were examined for viral and other pathogens. twenty-eight patients had one episode of acute diarrhea, six had acute exacerbations of chronic diarrhea, and had persistent chronic diarrhea. as shown in table , pathogens were isolated from % ( of ) of the patients, most commonly from those with arc (cdc class iva) and aids-associated opportunistic infections (aids-oi; t two patients progressed from arc to aids-oi and are included in both classes. (table ) . almost all of these isolates were obtained from patients with arc or aids-o!. fifty percent of the adenoviruses detected were noncultivable and probably pathogenic. isolation of these strains in graham cells, and subsequent typing, is in progress. none of the cultivable adenoviruses were type [ ] . in the hospital group (patients with diarrhea), of the patients with gastrointestinal viruses isolated had dual infections (five with adenovirus and five with rotavirus), whereas these viruses were found much less commonly in the randomly screened group (one of ; ' . = . , p < . ). no seasonal clustering of rotavirus or adenovirus was observed. fifteen of the rotavirus and of the adenovirus ( noncultivable) isolates were associated with acute diarrheal episodes or exacerbations of chronic diarrhea. the remaining isolates of virus weredetected in patients with persistent chronic diarrhea, often in association with likely primary pathogens such as cryptosporidium or mycobacterium avium-mycobacterium intracellulare (table ). in seven patients from whom three or more serial stool specimens were examined, rotaviruses or adenoviruses were found in two consecutive specimens in three patients. rotavirus was detected in specimens that were obtained and d apart, and adenovirus was detected in specimens obtained nine days apart. all the rotavirus-positive stool specimens reported in this study were initially detected by elisa (enzygnost) and later examined by em. the elisa and em results correlated well, with all but three elisapositive stool specimens being confirmed by em. one specimen was em-positive for rotavirus but elisa negative. twenty-threeof the elisa-positive ( ) note. for an explanation of cdc classes see table . * data are reported as the mean ± sd cd + cell concentration/mm" (normal concentration~ /mmj); n = no. of patients. stool specimens were available for retesting in a blocking elisa assay for rotavirus (kallestad). all were confirmed positive. no reoviruses were isolated in cell culture. other common enteric viruses were, however, isolated, as shown in tables i and . as reported above, the prevalence of viruses in stools showed a marked increase from asymptomatic to symptomatic hiv-infected patients, and / of the diarrheal patients with virus in their stools were found in the two most immunosuppressed classes (aids-oi and arc). the mean cd + lymphocyte concentrations for patients who did or did not have virus in their stools were not significantly different in any of the groups of patients (table ). as expected there was a significant difference between the mean cd cell concentrations of asymptomatic and symptomatic hiv-seropositive men (t = . ; dj = , p < . ). persistent, profuse, watery diarrhea; malabsorption; or colitis are the most dramatic gastrointestinal manifestations of aids. most studies of gastrointestinal pathogens in patients with aids have focused on the microbial causes of these syndromes, including cryptosporidium spp., i. belli, m. avium-m. intraeellu/are, and cmv. in addition there are the usual pathogens that also cause diarrhea in hiv-seronegative homosexual men: campy/obaeter, salmonella, shigella, yersinia, giardia, and e. histo/ytiea. the common occurrence of acute diarrhea or exacerbations of chronic diarrhea in symptomatic hiv-seropositive patients and the possible association of this diarrhea with gastrointestinal viral pathogens other than cmv has often been overlooked in the literature, although a recent association between colitis and adenovirus has been reported [ ] . in this study we showed that patients with aids or arc may present with acute diarrhea or exacerbations of chronic diarrhea and that in patients with symptomatic hiv infection and diarrhea, > % excreted gastrointestinal viruses. the majority of these were rotaviruses and adenoviruses. these high detection rates for rotavirus and adenovirus in patients with arc or aids-oi are similar to those observed in marrow transplant recipients who also have a t cell immunodeficiency and often have gastrointestinal mucosal damage from graft-versus-host disease [ ] . prolonged diarrhea and fecal excretion of rotavirus for more than six weeks have also been observed in children with t cell immunodeficiency. comparisons of stool isolation rates in hiv-seronegative homosexual men and asymptomatic or symptomatic hiv-seropositive men strongly suggested there were two factors responsible for the high detection rate: ( ) life style factors involving transmission by direct or indirect anal-oral contact, a possibility supported by the lack of seasonal variation, and ( ) immunosuppression. the latter factor was further supported by the predominance of gastrointestinal viruses (particularly adenoviruses and rotaviruses) in patients with arc or aids-o!. the demonstration of a high detection rate of gastrointestinal viruses (especially rotavirus) in patients with symptomatic hiv infection but no diarrhea and the transient association of rotaviruses and cultivable adenoviruses with other more-certain microbial pathogens in patients with aids-oi or arc and diarrhea suggest that these viruses may often be "passengers." however, the presence of rotaviruses and the usually pathogenic, noncultivable adenoviruses as the only significant microbes in the stools of patients with acute diarrhea (a finding that could not be readily attributed to other causes such as drug toxicity) strongly suggests a pathogenic role. this observation needs to be confirmed in future studies by testing serial stool samples during the course of acute episodes of diarrhea and by excluding other pathogens, including hiv itself, by using intestinal biopsies. the serial studies should also assist in determining the role of dual viral infection (especiallywith rotaviruses and adenoviruses) in the etiology of diarrhea in these patients. malabsorption and mucosal abnormalities of the small intestine in the acquired immunodeficiency syndrome slim disease: a new disease in uganda and its association with htlv-iii infection productive persistent infection of human colorectal cell lines with human immunodeficiency virus infectious gastroenteritis in bonemarrow-transplant recipients cytomegalovirus" colitis: can it be caused by adenovirus [abstract no. th . j? in: program and abstracts of the iii international conferece on aids viral diarrhoea in children in australia molecular epidemiology of adenovirus type infections in immunocompromised hosts chronic rotavirus infection in immunodeficiency intestinal infections in patients with the acquired immunodeficiency syndrome (aids) note added in proof in a recent study of homosexual men with aids and diarrhea and homosexual men with aids but without diarrhea, smith et at. [ ] were unable to detect rotavirus antigen in any patients' stools by using elisa (abbott laboratories, north chicago, ill).in contrast, in the year after our study ended ( ), rotavirus continued to be the predominant virus detected in the stools of homosexual men with aids and diarrhea in sydney ( [ %] of patients). such disparate results suggest marked geographic variations in gastrointestinal viral infections in these patients. key: cord- -pg jmvw authors: johnson, richard t. title: the virology of demyelinating diseases date: - - journal: ann neurol doi: . /ana. sha: doc_id: cord_uid: pg jmvw infectious agents have been postulated as causes of multiple sclerosis for over a century. the possible role of a virus or viruses is supported by data that ( ) a childhood exposure is involved and “viral” infections may precipitate exacerbations of disease, ( ) experimental infections in animals and natural infections in humans can cause diseases with long incubation periods, remitting and relapsing courses, and demyelination, and ( ) patients with multiple sclerosis have abnormal immune responses to viruses. the pathogenesis of three human demyelinating diseases of known viral etiology is discussed. in progressive multifocal leukoencephalopathy, a papovavirus selectively infects oligodendrocytes and causes focal areas of demyelination. in postmeasles encephalomyelitis, the virus is lymphotrophic and disrupts immune regulation that can result in an autoimmune perivenular demyelinating illness without evidence of infection of the central nervous system. in human immunodeficiency virus‐encephalopathy and myelopathy virus is present in macrophages and microglia and the myelin abnormalities apparently are caused by soluble factors such as viral proteins, cytokines, or neurotoxins. these findings may have implications on how, when, and where to seek viruses in multiple sclerosis. in jean martin charcot described the clinical features of the first human demyelinating disease, multiple sclerosis, and postulated that the disease resulted from exposure to dampness or from injuries or emotional stress. over the next two decades koch and pasteur blazed the new era of microbiology; therefore, it was a natural sign of the times that in pierre marie, one of charcot's students and a successor to his chair in neurology at the university of paris, postulated an infectious etiology for multiple sclerosis. because a rabies vaccine had just been introduced by pasteur, marie believed a vaccine for multiple sclerosis would soon be produced . speculation of a viral etiology of multiple sclerosis has recurred during the past century. this speculation has been given credence by three areas of investigation. first, epidemiologic studies have indicated a childhood exposure factor (possibly an infectious agent) in the genesis of multiple sclerosis , and also have suggested that infections may precipitate acute exacerbation in established disease , . second, studies in a wide variety of animal models (table ) and human diseases have shown that viruses can cause diseases with prolonged incubation periods, with remitting and relapsing courses, and with myelin destruction mediated by a variety of mechanisms. thud, studies of patients with multiple sclerosis consistently have shown higher levels of antibody against measles virus in serum and cerebrospinal fluid (csf) than in controls and in some studies antibodies have been elevated to other viral agents as well (table ) . subsequent to the description of multiple sclerosis three human demyelinating diseases have been defined in which viral causes are known. in each, the causative virus is from a different family and in each the pathogenesis of demyelination appears to be different. progressive multifocal leukoencephalopathy (pml) was originally described by astrom and collaborators ) in as a rare complication of leukemia and lymphoma it was subsequently seen in a variety of immunodeficiency states caused by other diseases and medical therapy. over the last decade, the disease has increased greatly in frequency as a complication of the acquired immunodeficiency syndrome (aids). clinically, against the background of immune deficiency, multifocal neurological signs develop and follow an ingravescent course usually ending in death in less than months. very rare cases have stabilized or recovered , . the csf is usually normal. neuropathology shows demyelinated foci, particularly in the subconical white matter. within these foci the oligodendrocytes are gone and astrocytes are enlarged, misshapen, and often multinucleated. surrounding the foci many of the ohgodendroglia are enlarged and contain intranuclear inclusions. the neurons and many of their axons coursing through the demyelinated areas appear normal. despite the paucity of inflammation, richardson [ } postulated that this disease might be a viral infection of the brain in an immunocompromised host. in usually causes infection of the human populations during childhood, and is not associated with disease. the development of human fetal dial cultures was necessary to make its recovery possible. the bizarre forms and mitoses in astrocytes are described in the original study as being "ordinarily met with only in neoplastic processes" ). indeed, many of these astrocytes contain viral dna and express tumor antigen (t antigen), while relatively smaller numbers express viral antigen or contain virions . this nisms have not proved as straightforward. postinfectious encephalomyelitis (aka acute disseminated encephalomyelitis, postexanthematous encephalomyelitis, and perivenular leukoencephalitis) is a perivenular demyelinaung disease that occurs as an unusual complication of a variety of viral infections. it was most common following measles and vaccination with vaccinia v i m , . the clinical and pathological disease was defined in clinical-pathological reports in the s and was differentiated from typical acute encephalomyelitis with cortical inflammation and n e w nophagia. this syndrome characteristically follows a febrile illness and is characterized by perivenular demyelination. postmeasles encephalomyelitis, the commonest form that still occurs, will be discussed. postinfectious encephalomyelitis complicates clinical measles in approximately per , cases. it is less frequent in children under years of age. following uncomplicated measles in otherwise healthy children, the disease typically comes on to days after the rash. the rash coincides with the onset of the immune response and the clearance of virus. after the rash abates and the child is returning to activities outside the house, there is a sudden recurrence of fever, decrease in consciousness, often seizures, and multifocal neurological signs. the disease has an abrupt onset, often reaching its nadir within the first hours. mortality is approximately , and sequelae persist in the majority of survivors. the electroencephalogram is slow but nonspecific, and the csf usually shows a mild elevation of protein and some mononuclear cells, but in about one-third of the patients the csf is entirely normal. neuropathologic examination shows diffuse perivenular infiltration of mononuclear cells with demyelination. inflammation of the meninges is limited or absent. histologically the lesions resemble those that were subsequently induced experimentally by injection of animals with myelin proteins with adjuvant, that is, experimental autoimmune encephalomyelitis. indeed, the pattern of myelin loss in ,the lesions is the same as that seen in the experimental autoimmune disease . because the encephalomyelitis develops after the acute exanthem and because of the unusual pathological changes, it was postulated that this was not the direct virus invasion of the nervous system but some toxic reaction. subsequent to the discovery of experimental autoimmune encephalomyelitis in animals in the s it has been assumed that this disease represented an autoimmune response induced by viral infection. historically, approximately one-third of the cases of encephalitis were thought to be of this form, but with the elimination of vaccination to prevent smallpox and the widespread use of measles vaccine, few cases are seen in north america. cases continue in much of the world where measles continues partially or totally unabated. indeed, measles remains one of the three major killing infectious diseases worldwide, causing about . million childhood deaths per year [ . the majority of these deaths are not due to encephalomyelitis, however, but to opportunistic infections that complicate the decreased immune responses seen for several weeks following the measles rash. thus, in contrast to pml, measles virus appears to induce the immune deficiency, and opportunistic infections lead to death. this immunodeficiency was first observed in by von pirquet c who found that children converted their tuberculin reactions at the time of rash and over subsequent weeks. indeed, this was the first documented virus-induced acquired immunodeficiency syndrome. a paradox is evident. the majority of measles deaths are due to immunodeficiency and opportunistic infections, whereas in per , patients encephalomyelitis develops, which is thought to have an autoimmune mechanism. in studies of patients with uncomplicated measles, measles with pneumonia, and encephalomyelitis, the degree of nonresponsiveness of lymphocytes to mitogens is equal [ . in all three groups similar leukopenia develops with maintenance of the normal t /t ratios ). all lose their cutaneous tuberculin reactions; those with infectious complications remain negative for a longer period of time . it is clear, however, that these findings do not represent simple immunosuppression. there is activation of lymphoid cells and spontaneous proliferation of lymphocytes (t , t , and b cells) (table ). rather than immunosuppression, measles virus produces an activation of lymphocytes and macrophages stimulating immunoresponsive cells such as those responsive to myelin basic protein; proliferation of culture lymphocytes in the presence of myelin basic protein was found in % of the cases of measles without neurological findings and in % of those who developed encephalomyelitis . evidence suggests that measles virus may not directly invade the nervous system. virus has only rarely been isolated from the central nervous system and our isolation attempts have failed. in studies of csf we found no intrathecal synthesis of antibody in posuneasles encephalomyelitis to suggest antigenic stimulation subsequently, a variety of diseases of the central and peripheral nervous system and muscle have been described as complications of hiv infection [ , . these occur at varying times. an acute meningitis or an acute demyelinating polyneuritis may occur at the time of seroconversion; hiv encephalopathy and myelopathy usually evolve years later with full-blown aids. these different syndromes show very varied pathological changes, and in all probability have different mechanisms of pathogenesis. in several syndromes, demyelination is a prominent feature both early in disease, when a neuropathy resembling guillain-bard syndrome is usually seen, and accompanying aids, when unusual myelin changes are seen in the encephalopathy and myelopathy. aids dementia and myelopathy usually evolve insidiously afer the patient has developed an aidsdefining illness. dementia is the aids-defining disease in about % of the patients, is evident in to % of ambulatory aids patients [ }, and may develop in more than % by the time of death . aids dementia is a so-called subcortical dementia with apathy, memory loss, and withdrawal, and with few features of cortical dementia such as behavioral problems and disorders of language and perception. signs of a myelopathy are evident in approximately % of patients by the time of death. this often accompanies the encephalopathy but can occur independently. patients develop weakness, spasticity of the legs, and prominent loss of posterior column function three distinctive white matter lesions are found in patients with encephalopathy and myelopathy e . the pathological finding that correlates best with dementia is diffuse myelin pallor, which is characterized by hyperintensity of t -weighted images in the deep white matter with magnetic resonance imaging and by reduced intensity of staining with lux fast blue. immunocytochemical staining for myelin proteins does not show decrease staining intensities in areas of myelin pallor, and light and electron microscopic studies fail to show demyelinated axons or active demyelination . these imaging and staining changes appear to be due to alterations in the blood-brain barrier. the second type of white matter lesions consists of small perivenular areas of demyelination that are found randomly through white matter; they bear a remarkable resemblance to the lesions described above in postinfectious encephalomyelitis. whether these lesions evolve at the time of lymphocyte activation and autoimmune diseases early during hiv infections or whether they develop through some other mechanism is unknown, because there is no clinical correlate for these lesions. the third abnormality is vacuolar myelin damage found in hemispheric white matter, fiber tracts, and most strikingly in spinal cord primarily in the white matter tracts of the posterior and lateral columns. it is most prominent in the thoracic cord. the vacuoles may be very asymmetrical, few perivasculat inflammatory cells or microgllal nodules are found, and multinuclear cells are rare. ultrastructurally, vacuolitation represents inualaminar edema; the vacuoles are not intracytoplasmic. macrophages are seen within these intralaminar gaps. both demyelination and remyelination are found by electron microscopy . the pathogenesis of these myelin changes associated with hiv infection are unknown. virus is usually detectable by immunocytochemical staining for hiv antigens and consistently present by polymerase chain reactions in the brains of demented patients. localization of virus is limited largely, if not exclusively, to cells of macrophage origin, i.e., microgha, macrophages, and perivascular macrophages. limited defective infection of astrocytes may occur, but there is no convincing evidence of infection of neurons or oligodendrocytes despite the pathological changes in these cells or their membranes. the alterations in myelin membranes and neurons are thought to be mediated by secretory products of infected macrophages and microgha virus proteins, cytokines and neurotoxins have d been implicated either directly or via indirect effects on astrocytes or ohgodendrocytes , . in visna, another lentivirus infection, infected monocytes when they differentiate into tissue macrophages express surface viral proteins that, in turn, induce neighboring lymphocytes to release a lymphokine that induces class i antigen expression on endothelial and possibly ghal cells [ }. marked inflammation ensues. a similar cytokine-mediated disease has been postulated in hiv infection, and the correlation of tumor necrosis factor* levels to the dementia and myelopathy , would be consistent with such a speculation. more than a century has past since pierre marie postulated an infectious agent in multiple sclerosis, and a number of virus isolations have been reported, but none have been convincingly linked to the disease (table ). even those who hold to the idea of a viral etiology are undecided whether it may be many viruses or only one, whether a childhood viral infection is important for laying the ground work of the disease, the so-called common exposure factor, or whether one or many viruses may precipitate exacerbations. what have we learned from other demyelinating diseases? we have learned that viruses can produce disease with long incubation periods, remimng and relapsing courses, and the loss of myelin with relative sparing of axons. in the case of progressive multifocal leukoencephalopathy, the most straightforward mechanism of demyelination proved operative, i.e., selective infection destroys ohgodendrocytes. the identification of the infectious agent, however, required two steps. first, electron microscopic studies were necessary to know what kind of viruses to look for, and second, laboratory methods had to be developed to recover a new and previously unknown papovavirus. in posuneasles encephalomyelitis and in hiv infections, no infection of oligodendrocytes has been found to explain virus-induced demyelination. in postmeasles encephalomyelitis the etiologic agent has been identified only by the very characteristic manifestation of the systemic disease. at the time encephalitis develops, usually no intrathecal antibody synthesis is found and the virus is not recovered from the central nervous system. indeed, out studies suggest that virus may have never been in the central nervous system. in this disease an indirect mechanism may be operative, and if an anale gous mechanism occurred in multiple sclerosis virus would need to be sought in lymphoid tissues prior to the clinical manifestations of the demyelinating disease. demyelination of the central nervous system in aids shows unique morphological changes in a new disease, due to a new virus. the virus is present in the central nervous system, but it is present in the "wrong" cells; a correlation between the amount of virus and the amount of disease is lacking, making it hard to fulfill even the most liberal modifications of koch's postulates [ ] . the obvious mediators of demyelination appear to be virally infected macrophages or microglta and current work focuses on the possible role of their soluble products in disruption of myelin sheaths. in these studies the knowledge of what virus to look for, and when and where and how to search, is evident. that the virus has not been identified consistently in multiple sclerosis is certainly not evidence against the role of a virus. "absence of evidence is not the same thing as evidence of absence" . studies on the mnral history of multiple sclerosis. . epidemiologic analysis of the army experience in world war on the risk of multiple sclerosis according to age at immigration to south africa clinical viral infections and multiple sclerosis viral infections trigger multiple sclerosis relapses: a prospective seroepidemiological study simian virus (sv )-induced disease in rhesus monkeys with simian acquired immunodeficiency syndrome resmcted canine distemper virus infection of ohgodendrocytes molecular basis of neuropathogenicity of mouse hepatitis virus determinants of neurological disease induced by theiler's murine encephalomyelitis virus treatment of encephalomyocarditis virus-induced central nervous system demyelination with monoclonal anti-t-cell antibodies semliki forest virus-induced, immune-mediated demyelination: adoptive transfer studies and viral persistence in nude mice ross river virus-induced demyelination: . pathogenesis and histopathology virus-induced demyelination. production by a viral temperature sensitive mutant biology and pathogenesis of lentiviruses measles antibodies in multiple sclerosis epstein-barr virus infection and antibody synthesis in patients with multiple sclerosis viral antibodies in multiple sclerosis intrathecal antibody synthesis to virus antigens in multiple sclerosis sera from patients with multiple sclerosis react with human t cell lymphouopic virus-i gag proteins but not env proteins-westem blotting analysis antibodies against the paramyxovirus sv in the cerebrospinal fluids of some multiple sclerosis patients progressive multifocal leukoencephalopathy progressive multifocal leukoencephaloparhy: a burnt-out case prolonged survival and partial recovery in aids-associated progressive multifocal leukoencephalopathy progressive multifocal leukoencephalopathy particles resembling papovavirus in human cerebral demyelinating disease pova-like virus from human brain with progressive multifocal leukoencephalopathy papovavirus of jc type in progressive multifocal leukoencephalopathy etiology of progressive multifocal leukoencephalopathy-identification of papovavirus progressive multifocal leukoencephalopathy: jc virus detection by in situ hybridization compared with immunohistochemisuy slow virus infections of rhe central nervous system postinfectious encephalomyelitis postinfectious encephalomyelitis a quantitation of myelin-associated glycoprotein and myelin basic protein loss in different demyelinating diseases measles: summary of worldwide impact das verhalten der kutanen tuberkulin-reaktion wahrend der masern cellular immune responses during complicated and uncomplicated measles virus infections of man peripheral blood mononuclear cells during nacural measles virus infection: cell surface phenotypes and evidence for activation prospective study of the magnitude and duration of changes in tuberculin reactivity during complicated and uncomplicated measles development of antibody to measles virus polypeptides during complicated and uncomplicated measles virus infections immune activation during measles spontaneous proliferation of peripheral mononuclear cells in natural measles virus infection: identification of dividing cells and correlation with mitogen responsiveness changes in plasma ige levels during complicated and uncomplicated measles virus infections changes in serum c-reactive protein during complicated and uncomplicated measles virus infections immune activation during measles. p- microglobulin in plasma and cerebrospinal fluid in complicated disease cytokine production in vitro and the lymphoproliferative defect of natural measles virus infection measles encephalomyelitis: clinical and immunological studies dulac , et al. interferon-r in acute and subacute encephalitis johnson: virology of demyelinating diseases s immune activation during measles: p -microglobulin in plasma and cerebrospinal fluid in complicated and uncomplicated disease distribution of measles virus antigen and rna in acute measles with and without neurologic involvement infection of monocytes during measles pneumocystis pneumonia-hs angeles kaposi's sarcoma and pneumocystis pneumonia among homosexual men isolation of htlv- from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome isolation of aidsassociated retroviruses from cerebrospinal fluid and brain of patients with neurological symptoms htlv- infection in brains of children and adults with intrablood-brain-barrier synthesis of htlv- -specific igg in patients with neurologic symptoms associated with aids or aids-related complex sequence homology and morphologic similarity of htlv-i and visna virus, a pathogenic lentivirus neurologic manifestations of aids the neurobiology of human immunodeficiency virus infections the aids dementia complex: vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome morphological spectrum, distribution and clinical correlation of white matter lesions in aids brains cerebral white matter changes in acquired immunodeficiency syndrome dementia: alterations of the blood-brain barrier vacuolar myelopathy in human immunodeficiency virus (hiv) infection: central remyelination cytokines and arachidonic metabolites produced during human immunodeficiency virus (h v)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of hiv disease hiv-related neurotoxicity ghotbi , et al. persistent expression of ia antigen and viral genome in visna-maedi virus-induced inflammatory cells: possible role of lentivirus-induced interferon messenger rna expression in acquired immunodeficiency syndrome dementia cytokine expression of macrophages in hiv- -associated vacuolar myelopathy aetiology and pathogenesis of acute sporadic disseminated encephalomyelitis and multiple sclerosis viruses isolated from patients with encephalomyelitis and multiple sclerosis. i. pathogenic and antigenic properties virus isolated from the brain of a patient with multiple sclerosis transmission experiments with multiple sclerosis decreased percentage of polyrnorphonuclear neutrophils in mouse peripheral blood after inoculation with material from multiple sclerosis patients fusion of culcured multiple sclerosis brain cells with indicator cellspresence of nucleocapsids and virions and isolation of parainfluenza-type virus viruses in multiple sclerosis? isolation of an infectious agent from bone-marrows of patients with multiple sclerosis cytomegalovirus isolation from a chimpanzee with acute demyelinating disease after inoculation of multiple sclerosis brain cells two coronaviruses isolated from central nervous system tissue of two multiple sclerosis patients isolation of virus from the spinal fluid of three patients with multiple sclerosis and one with amyotrophic lateral sclerosis isolation of the ack-borne encephalitis virus from a patient with multiple sclerosis multiple sclerosis and human t-cell lymphotropic retroviruses leptomeningeal cell line from multiple sclerosis with reverse transcriptase activity and viral particles isolation of herpes simplex virus type during first attack of multiple sclerosis viral aspects of multiple sclerosis koch's postulates and slow infections of the nervous system alexander von humboldt foundation, bi-national colloquium for humboldt awardees in cooperation with the institute for advanced study key: cord- -u cxiej authors: podder, c. n.; sharomi, o.; gumel, a. b.; strawbridge, e. title: mathematical analysis of a model for assessing the impact of antiretroviral therapy, voluntary testing and condom use in curtailing the spread of hiv date: - - journal: differ equ dyn syst doi: . /s - - - sha: doc_id: cord_uid: u cxiej this paper presents a deterministic model for evaluating the impact of anti-retroviral drugs (arvs), voluntary testing (using standard antibody-based and a dna-based testing methods) and condom use on the transmission dynamics of hiv in a community. rigorous qualitative analysis of the model show that it has a globally-stable disease-free equilibrium whenever a certain epidemiological threshold, known as the effective reproduction number [formula: see text], is less than unity. the model has an endemic equilibrium whenever [formula: see text]. the endemic equilibrium is shown to be locally-asymptotically stable for a special case. numerical simulations of the model show that the use of the combined testing and treatment strategy is more effective than the use of the standard elisa testing method with arv treatment, even for the use of condoms as a singular strategy. furthermore, the universal strategy (which involves the use of condoms, the two testing methods and arv treatment) is always more effective than the combined use of the standard elisa testing method and arvs. from hiv-related illnesses during the last years. aids is now the leading cause of death in sub-saharan africa and the fourth-leading cause of death globally [ ] . in addition to being a serious public health menace, hiv/aids has far reaching consequences to all social and economic sectors of society. it exacerbates poverty, reduces educational opportunities, devastates the workforce, creates large numbers of orphans, and exerts tremendous pressure on already limited health and social services [ , , , , , , ] . another more troubling aspect of hiv disease is the fact that a sizable proportion (about % in north america) of those infected with the virus are not aware of their hiv status [ , ] . thus, these individuals continue to unknowingly transmit the virus to others (in addition to not being able to benefit from clinical care to reduce morbidity and mortality). control measures against the spread of hiv are wide and varied. they include preventive measures (such as the use of condoms, public health education and counselling about safer sex practices, sterilization of needles in health care delivery, voluntary hiv testing) and the use of therapeutic agents. the currently available anti-hiv therapeutic measure is based on using anti-retroviral therapy, especially the highly-active anti-retroviral therapy (haart), which is known to significantly reduce viral load in treated individuals [ , , , , ] . unfortunately, haart is still not widely accessible in many resource-poor nations, where hiv prevalence is the highest (an estimated . million people in low-and middle-income countries were receiving life-saving hiv treatment at the end of [ ] ). the purpose of this study is to use mathematical modelling to gain insight into the impact of voluntary testing, the use of condoms and the use of anti-retroviral drugs in curtailing the spread of hiv in a community. two different testing methods, namely a standard antibody test (such as the enzyme linked immuno absorbent assay (elisa)) and a dna-based test, known as the nucleic acid amplification testing (naat), will be considered. unlike the standard antibody test (which typically detect antibodies in the blood after a minimum of three to four weeks of infection), naat can detect early infection (within the first few days of occurrence) [ , , ] . the model to be developed in this study incorporates some of the well-known properties of hiv disease. these notably include the staged-progression aspect, where a typical hiv-infected individual passes through several infection stages, being highly infectious during the pre-antibody phase (characterized by high viremia with over million viral copies per ml), maintaining low infectivity during the asymptomatic phase and becoming highly infectious as s/he progresses toward aids (i.e., the aids stage of hiv infection) [ , , , , , , , ] . these stages are sometimes categorized into four groups namely, acute sero-conversion stage (less than days of infection), early infection stage (less than days of infection but prior to development of symptoms), established infection stage (after days of infection) and the aids stage (characterized by the presence of clinical symptoms of aids and very reduced level of cd count) [ ] . another important aspect of hiv disease is the fact that hiv rna levels are positively correlated with infectiousness [ , ] . in addition to developing a reasonably realistic model for hiv spread, this study also contributes by including numerous anti-hiv strategies and carrying out rigorous qualitative analysis of the resulting model. the paper is organized as follows. the model is formulated in "model formulation" section, and rigorously analysed in subsequent subsections. numerical simulations are reported in third section. a deterministic compartmental modelling approach is used to design the model as follows. the total population at time t, denoted by n (t), is sub-divided into mutually-exclusive compartments of susceptible individuals (s(t)), newly-infected individuals unaware of their status in the acute sero-conversion stage (i u (t); less than days of infection), infected individuals unaware of their hiv status in the asymptomatic stage (i u (t); - days of infection), infected individuals unaware of their hiv infection status in the established (pre-aids) stage (i u (t)), infected individuals unaware of their status in the aids stage of infection (a u (t)), treated individuals (t (t)), and (corresponding) infected individuals aware of their infection status (due to positive hiv diagnosis) at the aforementioned infection stages, denoted by i k , i k , i k and a k , respectively. thus, the susceptible population is increased by the recruitment of new sexually-active individuals (at a rate ). susceptible individuals acquire infection, following effective contact with untreated infected individuals, at a rate λ, where in ( ), β is the effective contact rate and the modification parameters η i (i = , , ) are estimated as follows. the average transmission rate per coital act during the primary infection stage (i.e, less than days of infection) is estimated to be . [ ] . assuming that an infected individual in this stage of infection has an average of six sexual acts per month, it follows that the transmission rate in the primary infection stage is β = . × × = . per year. for the second stage of infection (i.e., - days of infection), it is assumed that the average transmission rate per coital act is . . this gives a transmission rate of β = . per year (so that, η = . ). for the third stage of hiv infection (i.e., from days of infection to the onset of clinical symptoms of aids), the transmission rate per act is . [ ] , so that (by using an average of acts per month) β = . per year (hence, η = . ). finally, following [ ] , the per coital transmission probability in the aids stage is assumed to be . . using an estimate of acts per month, it follows that the transmission rate in this stage is β = . per year (thus, η = . ). it should be mentioned that, in the above, it is assumed that individuals in the pre-aids and aids stages have reduced number of sexual acts in comparison to those in the primary and early infection stages (the justification for this assumption is that individuals in the pre-aids and aids stages are too sick to engage in active sexual activity). in summary, these estimates (for show that the rate of hiv transmission is the highest during the primary infection stage (β = ). it decreases during the second infection stage to β = . , and further decreases to β = . in the pre-aids stage. the transmission rate then increases to β = . in the aids stage. these estimates are consistent with the conclusions drawn in numerous hiv modelling studies, such as those reported in [ , ] (it should, however, be mentioned that some studies, such as that reported in [ ] , show that hiv transmission rate is the highest during the aids stage of infection). once infected individuals are made aware of their infection status (by positive hiv diagnosis), it is assumed that these individuals (who are moved to the class of individuals who know their positive hiv infection status) will reduce their risky behaviour by a factor of r . marks et al. [ , ] estimated that knowledge of hiv status resulted in % reduction in unprotected sex (so that, r . ). condom use is modelled in terms of reduction in the infection rate, λ, by a factor of ( − c κ), where < c < is the condom efficacy and < κ < is the fraction of sexually-active individuals that use condoms consistently and correctly (condom compliance). it is assumed that newly-infected individuals are unaware of their infection status until they are detected either by naat or the standard antibody test. it is assumed that individuals unaware of their infection status progress from the acute sero-conversion stage (i u ) to the asymptomatic stage (i u ), at a rate σ . progression from the asymptomatic stage (i u ) to the pre-aids stage (i u ) occurs at a rate σ . finally, pre-aids individuals progress to the aids stage at a rate σ . individuals that are unaware of their infection status in the i u class are tested (using naat) at a rate τ n , with efficacy n ( < n < ). those that are positively diagnosed move to the corresponding i k class. standard (elisa) testing is used for individuals in the i u , i u and a u classes at a rate τ , with efficacy ( < < ); and those positively identified move to their corresponding i k class. individuals aware of their infection status progress through the various infection stages at the same rate (σ i ; i = , , ) as those who are not (in other words, it is assumed that knowledge of hiv infection status does not alter the progression rate among untreated infected individuals). individuals aware of their status in the infection stages i k , i k , i k and a k are treated at rates ψ , ψ , ψ and ψ k , respectively. it is assumed, for mathematical tractability, that these (treated) individuals do not transmit infection. further, natural mortality occurs in all epidemiological classes at a rate μ (i.e., /μ represents the average duration of acquisition of sexual partners), and individuals in the aids stage suffer an additional disease-induced death (at rates δ u and δ k , for individuals unaware or aware of their status, respectively). it is assumed that treated individuals eventually succumb to the disease (at a reduced disease-induced rate θ δ k , with < θ < ). putting the aforementioned formulations and assumptions together, it follows that the model for hiv transmission, in the presence of the two testing methods, condom use and arvs, is given by the following system of differential equations (a schematic description of the model is given in fig. , and the variables and parameters of the model are described in table ): infected individuals unaware of their status in acute sero-conversion stage i u (t) infected individuals unaware of their status in the asymptomatic stage infected individuals unaware of their status in the pre-aids stage infected individuals unaware of their status in the aids stage infected individuals aware of their status in acute sero-conversion stage infected individuals aware of their status in the asymptomatic stage infected individuals aware of their status in the pre-aids stage infected individuals aware of their status in the aids stage total population the model ( ) is a modification of the model presented in [ ] , in that it accounts for four hiv infection stages (as against the three infection stages considered in [ ] ). furthermore, this study provides a rigorous mathematical analysis of the model (this is not given in [ ] ). to be epidemiologically meaningful, it is important to prove that the solutions of the basic model ( ), with positive initial data, will remain positive for all time t > . thus, t > . it follows from the first equation of the differential equation system ( ) that which is equivalent to, thus, so that, similarly, it can be shown that i u thus, all solutions of the model, with non-negative initial data, remain non-negative for all t > . adding all the equations of the basic model ( ) gives, thus, local stability of disease-free equilibrium (dfe) since the model ( ) monitors human populations, it is assumed that the variables and associated parameters are non-negative for all t ≥ . the dfe of the model ( ) is given by consider the biologically-feasible region the following steps are taken to establish the positive invariance of d (i.e., solutions in d remain in d for all t > ). the rate of change of total population, obtained by adding all the equations of the model ( ), is given by since the right hand-side of ( ) is bounded by − μn , a standard comparison theorem can be used to show that thus, d is positively-invariant. hence, it is sufficient to consider the dynamics of the flow generated by ( ) in d. in this region, the model can be considered as been epidemiologically and mathematically well-posed [ ] . the linear stability of e is studied using the next generation operator technique in [ , ] . the associated non-negative matrix, h, for the new infection terms, and the non-singular m-matrix, v , for the remaining transfer terms, are, respectively, given by it follows that the effective reproduction number, denoted by r eff , is given by where ρ denotes the spectral radius, and the threshold quantity, r eff , measures the average number of new secondary cases generated by a single infected individual in a population where the aforementioned anti-hiv control measures are implemented. it is worth stating that, in ( ) , β is the infection rate and k i (i = , . . . , ) represent the respective mean duration in the infection classes an associated epidemiological threshold is the basic reproduction number (r ), obtained in a similar way by considering the model ( ) in the absence of any anti-hiv intervention (i.e., κ = c = τ n = n = τ = = ψ = ψ = ψ = ψ k = ), is given by where a is as defined earlier (but with the aforementioned intervention-related parameters set to zero). the threshold quantity r measures the average number of new infections generated by a single infected individual in a completely susceptible population. using theorem of [ ], the following result is established. the dfe, e , of the system ( ), given by ( ), is locally-asymptotically stable (las) if r eff < , and unstable if r eff > . the epidemiological implication of lemma is that hiv can be eliminated from the community when r eff < , provided the initial sizes of the sub-populations of the model ( ) are in the basin of attraction of e . in other words, an influx of small number of infected individuals into the community will not generate large outbreaks if r eff < . to ensure that disease elimination is independent of the initial population sizes of the state variables of the model, a global asymptotic stability result (of the dfe) is established below. the dfe of the model ( ), given by ( ), is globally-asymptotically stable (gas) in d whenever r eff ≤ . proof consider the lyapunov function with lyapunov derivative given by (where a dot represents differentiation with respect to t) it follows, from the lasalle's invariance principle [ ] , that i u in the first and last equations of the model ( ) shows that s → μ and t → as t → ∞. thus, an alternative proof for theorem , using a comparison theorem argument, is given in appendix a. the existence of possible endemic equilibria of the model (that is, equilibria where the disease is endemic) is explored as follows. let, represents an arbitrary endemic equilibrium of the model ( ) . further, let solving the equations in the model ( ) at steady-state, in terms of λ * * s * * , gives t * * = b λ * * s * * , with, using ( ) in ( ), and simplifying, gives where, the positive endemic equilibrium of the model ( ) can then be obtained by solving for λ * * in ( ) and substituting the result into ( ) . clearly, λ * * = is a solution of ( ), which corresponds to the dfe (e ). for λ * * = , the quadratic ( ) can be simplified to since all the model parameters are non-negative, it follows that b > and c > for r eff > . thus, the linear equation ( ) has a unique positive solution, given by λ * * = c b , whenever r eff > . the components of this solution are obtained by substituting the unique value of λ * * into ( ). since r eff < implies that c < , it follows that, for r eff < , λ * * < (which is epidemiologically meaningless). similarly, if r eff = , the coefficient c = , so that λ * * = (which corresponds to the dfe, e ). hence, the model has no positive solution whenever r eff ≤ . these results are summarized below. the model ( ) has a unique positive endemic equilibrium, given by e , whenever r eff > , and no positive equilibrium otherwise. the local stability of the unique eep, e , will now be explored for the special case where the disease-induced mortality is negligible (i.e., δ u = δ k = ). setting δ u = δ k = in the model ( ) gives hence, it follows from ( ) that n (t) → μ = n * as t → ∞. further, using the substitution ( ) gives the following reduced model: where k = k | δ u = , k = k | δ k = and k = k | δ k = . it can be shown, using the above approach, that the system ( ) has a unique endemic equilibrium, given by further, the following result holds (see appendix b for the proof): the unique endemic equilibrium, e , of the reduced model ( ) , is las whenever r c > . the epidemiological implication of theorem is that hiv will persist in the community if the reproduction threshold (r c ) exceeds unity. the model ( ) is simulated using the parameter values given in table (unless otherwise stated). some of the parameter values are obtained from the literature (such as in [ , , , , , , ] ). in particular, the stage progression parameters are estimated as follows. since the period for the acute sero-conversion stage (i ) is less than days of infection [ ] , the average duration in this stage is set at σ = (so that, σ = per year). similarly, the average duration in the second infection stage (i ) is approximately weeks ( - days [ ] ). thus, σ = (so that, σ = . per year). the duration in the third (i ) stage is assumed to be years [ ] (thus, σ = per year). it should be stated that although the model is parameterized using data largely from resource-rich countries, it is robust enough to allow for the evaluation of scenarios for resource-poor nations (by using appropriate parametrization). first of all, the model ( ) is simulated to evaluate the effect of condom use, as a single anti-hiv intervention. comparisons are made with the following three different effectiveness levels of the combined testing (standard elisa and naat) and treatment strategy: (i) low effectiveness level of the combined testing and treatment strategy: τ n = τ = ψ = ψ = ψ = ψ k = . ; (ii) medium effectiveness level of the combined testing and treatment strategy: τ n = τ = ψ = ψ = ψ = ψ k = . ; (iii) high effectiveness level of the combined testing and treatment strategy: the aforementioned effectiveness levels, chosen arbitrarily, are used to address the problem of the uncertainty in the estimate of the values of the parameters related to the testing and treatment rates. using the low effectiveness level of the combined testing and treatment strategy, it is shown that the combination of the two testing methods and treatment is more effective (saves more new cases) than the use of condoms as a singular anti-hiv strategy followed by the use of only the standard elisa testing method with arv treatment (fig. a ). using the medium effectiveness level of the combined testing and treatment strategy, it is also shown that the combination of the two testing methods and treatment is more effective than the use of the only the standard testing method with arvs followed by the condom use as a singular strategy (fig. b) . similar trends were observed for high effectiveness level of the combined testing and treatment strategy (fig. c) . it should, however, be mentioned that the use of condoms as a singular anti-hiv intervention is marginally more effective than the low effectiveness level of the standard testing and arv strategy (but this situation is reversed if the effectiveness of the standard testing and arv strategy is increased to medium or high levels). figure shows simulation results comparing the effect of the combined use of standard testing and arvs against a universal strategy (that entails the use of condoms, the two testing methods and arvs). here, too, the aforementioned three effectiveness levels of the combined cumulative number of cases averted using condoms only and various effectiveness levels of the combined testing and arvs intervention strategy. a low effectiveness level of the combined testing and treatment strategy (τ n = τ = ψ = ψ = ψ = ψ k = . ; so that, r eff = . and r = . ), b moderate effectiveness level of the combined testing and treatment strategy (τ n = τ = ψ = ψ = ψ = ψ k = . ; so that, r eff = . ), and c high effectiveness level of the combined testing and treatment strategy (τ n = τ = ψ = ψ = ψ = ψ k = ; so that, r eff = . ). all other parameters are as given in table testing and treatment strategy are used. the universal strategy saves more cases than any of the three effectiveness levels of the combined testing and treatment strategy (see fig. a-c) . a deterministic model is designed and used to monitor the impact of voluntary hiv testing (based on the use of a standard antibody-based and a dna-based testing methods), condom use and the use of arvs in curtailing the spread of hiv in a population. rigorous qualitative analysis of the model reveals that it has a globally-asymptotically stable disease-free equilibrium whenever a certain threshold quantity is less than unity. furthermore, the model has a unique endemic equilibrium when the threshold quantity exceeds unity. the endemic equilibrium is shown to be locally-asymptotically stable for a special case. numerical simulations of the model, using a reasonable set of parameter values, show the following: (i) the combined testing and treatment strategy is more effective than the use of the standard elisa testing method with arv treatment. the use of condoms as a sole anti-hiv strategy is marginally more effective than the low effectiveness level of the standard testing and arv strategy (this situation is reversed if the effectiveness of the standard testing and arv strategy is increased to medium or high levels). table (ii) the universal strategy is always more effective than the combined use of the two testing methods and arvs (regardless of the effectiveness level of the latter strategy). overall, this study shows that the prospects of effectively controlling the spread of hiv using the interventions considered in this study are bright (particularly if they are used in combination). it is worth stating, however, that the simulation results presented in this study are sensitive to the choices of parameter and initial values used in the simulations. the uncertainties associated with the parameters related to the testing and treatment rates are accounted for by considering three (arbitrarily chosen) effectiveness levels of the combined testing and treatment strategy (a more detailed uncertainty analysis, based on latin hypercube sampling [ , , , ] for example, can be applied if more data (related to the testing and treatment rates) becomes available). proof it should be noted, first of all, that the equations for the infected components in the model ( ) can be written in terms of and h and v are as defined in "local stability of disease-free equilibrium" section. using the fact that the eigenvalues of the matrix h − v all have negative real parts, it follows that the linearized differential inequality system (a. ) is stable whenever r eff < . consequently, (i u , i u , i u , a u , i k , i k , i k , a k , t ) → ( , , , , , , , , ) as t → ∞. it follows, by comparison theorem [ ] , that (i u , i u , i u , a u , i k , i k , i k , a k , t ) → ( , , , , , , , , ). substituting i u = i u = i u = a u = i k = i k = i k = a k = t = into the first equation of the model ( ) gives s(t) → μ as t → ∞. thus, → μ , , , , , , , , , as t → ∞ and r eff < . hence, e is gas in d if r eff < . proof let r c > , so that the unique eep of the reduced model ( ), given by e , exists. the proof of theorem is based on using the technique in [ ] (see also [ , ] ), which employs a krasnoselskii sub-linearity trick. assume, first of all, that the linearization of the system ( ), around the equilibrium e , has solution of the form: ) . substituting a solution of the form (b. ) into the linearized system of ( ), around the unique endemic equilibrium e , gives the following system of linear equations where, system (b. ) is simplified as follows. firstly, the negative terms in the last nine equations of system (b. ) are moved to their respective left-hand sides. we then solve for z from the second, z from the third and so on. the results are then substituted into the first equation of the system (b. ). finally, all the negative terms of the first one equation are moved to the left-hand side. these algebraic manipulations result in the following general system: where, the notation m(z ) i (with i = , . . . , ) denotes the ith coordinate of the vector m(z). it should further be noted that the matrix m has non-negative entries, and the equilibrium e satisfies e = me . furthermore, since the coordinates of e are all positive, it follows then that ifz is a solution of (b. ), then it is possible to find a minimal positive real number s such that where, ||z ||= (|| z ||, . . . , || z ||) with the lexicographic order, and || · || is a norm in c. the main goal is to show that re(τ ) < . assume the contrary (i.e., re(τ ) ≥ ). we then need to consider two cases: τ = and τ = . assume the first case, τ = . then, (b. ) is a homogeneous linear system in the variables z i (i = , . . . , ) . the determinant of the system (b. ) corresponds to that of the jacobian of the system ( ) evaluated at e , which is given by = eλs * * p n * + k k k k k k k k k − s * * n * r c , (b. ) where, e = m k σ {σ σ k [k k (q k + k )] + σ k k (k + k ) + k k k k k ( + k ) + k k k k (k a + σ k + a σ )} + m k k k {σ σ [σ (k + ) + k ( + k )] + k k [k + k (σ + k ) + σ ]} + k k k k k [σ σ (σ + k ) + k k (k + σ )]. by solving the equations of the model ( ), at the endemic steady-state e , and using the first equation of ( ) , it can be shown that thus, using (b. ) in (b. ) shows that > . consequently, the system ( ) can only have the trivial solutionz = (which corresponds to the dfe, e ). now we consider the case τ = . in this case, re(f i (τ )) ≥ (i = , . . . , ) since, by assumption, re(τ ) ≥ . it is easy to see that this implies | + f i (τ ) |> for all i. now, define f(τ ) = min | + f i (τ ) | (for i = , . . . , ) . then, f(τ ) > . hence, s f(τ ) < s. the minimality of s implies that ||z ||> s f(τ ) e . but, on the other hand, taking norms on both sides of the second equation of (b. ), and using the fact that m is non-negative, we obtain then, it follows from the above inequality that || z ||≤ s f(τ ) i u * * , which contradicts re(f i (τ )) ≥ . hence, re(τ ) < . thus, the equilibrium e is las if r c > . proceedings of the th pims industrial problem solving workshop antiretroviral therapy coverage rate in low-and middle-income countries randomized, controlled intervention trial of male circumcision for reduction of hiv infection risk: the anrs trial sensitivity and uncertainty analysis of complex models of disease transmission: an hiv model, as an example predicting the unpredictable: transmission of drug-resistant hiv the effectiveness of condoms in reducing heterosexual transmission of hiv on the definition and the computation of the basic reproduction ratio r in models for infectious diseases in heterogeneous populations the impact of hiv and aids on africa's economic development theoretical assessment of public health impact of imperfect prophylactic hiv- vaccines with therapeutic benefits influence of vertical and mechanical transmission on the dynamics of dengue disease qualitative study of transmission dynamics of drug-resistant malaria immunopathogenic mechanisms of hiv infection developing economies shrink as aids reduces workforce mathematical study of a staged-progression hiv model with imperfect vaccine the mathematics of infectious diseases stability of the endemic equilibrium in epidemic models with subpopulations the differential infectivity and staged progression models for the transmission of hiv role of the primary infection in epidemics of hiv infection in gay cohorts stability analysis of nonlinear systems the stability of dynamical systems. regional conference series in applied mathematics. siam statistical analysis of the stages of hiv infections using a markov model global burden of disease and risk factors. a co-publication of the world bank meta-analysis of high-risk sexual behaviour in persons aware and unaware they are infected with hiv in the united states: implications for hiv prevention programs estimating sexual transmission of hiv from persons aware and unaware that they are infected with the virus in the usa a model of hiv/aids with staged progression and amelioration sensitivity and uncertainty analysis for a sars model with time-varying inputs and outputs plasma viral load and cd + lymphocytes as prognostic markers of hiv- infection adherence to antiretroviral therapy in sub-saharan africa and north america: a meta analysis mathematical analysis of hiv- dynamics in vivo detection of acute infections during hiv testing in north carolina mathematical study of the impact of quarantine, isolation and vaccination in curtailing an epidemic designing hiv vaccination policies subtypes and cross-immunity for the rakai project study group: viral load and heterosexual transmission of human immunodeficiency virus hiv epidemics driven by late disease stage transmission report on the global aids epidemic: executive summary/unaids: a unaids th anniversary special edition cost effectiveness of screening for acute hiv-infection: the north carolina stat program unaids: more than five million people receiving hiv treatment united nations department of economic and social affairs/population division: the impact of aids global health policy: the global hiv/aids epidemic: fact sheet reproduction numbers and sub-threshold endemic equilibria for compartmental models of disease transmission rates of hiv- transmission per coital act, by stage of hiv- infection who: the world health report: changing history. world health organization confronting aids: public priorities in a global epidemic key: cord- - ra uda authors: snowden, frank m. title: emerging and reemerging diseases: a historical perspective date: - - journal: immunol rev doi: . /j. - x. . .x sha: doc_id: cord_uid: ra uda summary: between mid‐century and , there was a consensus that the battle against infectious diseases had been won, and the surgeon general announced that it was time to close the book. experience with human immunodeficiency virus/acquired immunodeficiency syndrome, the return of cholera to the americas in , the plague outbreak in india in , and the emergence of ebola in zaire in created awareness of a new vulnerability to epidemics due to population growth, unplanned urbanization, antimicrobial resistance, poverty, societal change, and rapid mass movement of people. the increasing virulence of dengue fever with dengue hemorrhagic fever and dengue shock syndrome disproved the theory of the evolution toward commensalism, and the discovery of the microbial origins of peptic ulcer demonstrated the reach of infectious diseases. the institute of medicine coined the term ‘emerging and reemerging diseases’ to explain that the world had entered an era in which the vulnerability to epidemics in the united states and globally was greater than ever. the united states and the world health organization took devised rapid response systems to monitor and contain disease outbreaks and to develop new weapons against microbes. these mechanisms were tested by severe acute respiratory syndrome in , and a series of practical and conceptual blind spots in preparedness were revealed. in the long contest between humans and microbes, the years from mid-century until marked a distinctive era. in those euphoric decades, there was a consensus that the decisive battle had been joined and that the moment was at hand to announce the final victory. almost as if introducing the new period, the us secretary of state george marshall declared in that the world now had the means to eradicate infectious diseases from the earth. marshall's view was by no means exceptional. for some, in the early postwar years, the triumphant vision applied primarily to a single disease. the heady goal arose first of all within the field of malariology, where the rockefeller foundation scientists fred soper and paul russell thought that they had discovered in ddt (dichlorodiphenyltrichloroethane) a weapon of such unparalleled power that it would enable the world to eliminate the ancient scourge forever. with premature confidence in , russell published man's mastery of malaria ( ), frank m. snowden in which he envisaged a global spraying campaign that would free mankind from malaria -cheaply, rapidly, and without great difficulty. rallying to russell's optimism, the world health organization (who) adopted a global campaign of malaria eradication with ddt as its weapon of choice. the director of the campaign, emilio pampana, elaborated a one-size-fits-all program of eradication through four textbook steps -'preparation, attack, consolidation, and maintenance' ( ). russell's followers alberto missiroli, the director of the postwar campaign in italy, and george macdonald, the founder of quantitative epidemiology, reasoned that so signal a victory over mosquitoes could be readily expanded to include the elimination of all other vector-borne tropical diseases, ushering in what missiroli called a contagion-free eden, where medicine would make man not only healthy but also happy ( ) ( ) ( ) . if malariologists, who dominated the international public health community, launched the idea of the final conquest of infectious diseases, it rapidly developed into the prevailing orthodoxy. e. harold hinman, chief malariologist to the tennessee valley authority and member of the who expert committee on malaria, extrapolated from the conquest of malaria to the conquest of all contagion in his influential work world eradication of infectious diseases ( ) . aidan cockburn, a distinguished epidemiologist at johns hopkins and advisor to the who, gave expression to this new creed in his revealingly titled work the evolution and eradication of infectious diseases ( ) . as cockburn noted, '''eradication'' of infectious disease as a concept in public health has been advanced only within the past two decades, yet it is replacing ''control'' as an objective' ( ) . although not a single disease had yet been destroyed by his time of writing in , cockburn believed that the objective of eradication was 'entirely practical,' not just for individual illnesses but for the whole category of communicable diseases. indeed, he argued, 'it seems reasonable to anticipate that within some measurable time, such as years, all the major infections will have disappeared' ( ) . by that time, he explained, 'the major infections of today should have disappeared, and only remaining should be their memories in textbooks, and some specimens in museums. . . . with science progressing so rapidly, such an end-point is almost inevitable, the main matter of interest at the moment is how and when the necessary actions should be taken' ( ) . cockburn's timetable of total eradication by was, in fact, too slow for some. just a decade later, in , the australian virologist and nobel laureate frank macfarlane burnet went so far as to proclaim, together with his colleague david white, that 'at least in the affluent west,' the grand objective had already been reached. 'one of the immemorial hazards of human existence has gone,' he reported, because there is a 'virtual absence of serious infectious disease today' ( ) . the who also saw the entire planet as ready to enter the new era by the end of the century. meeting at alma ata in , the world health assembly adopted the goal of 'health for all, ' ( ) . what could possibly have led to such overweening confidence in the power of science, technology, and civilization to vanquish communicable disease? one factor was historical. in the industrialized west, rates of mortality and morbidity from infectious diseases began to plummet in the second half of the th century, in large part as a result of 'social uplift' -dramatic improvements in wages, housing, diet, and education. at the same time, developed nations erected the solid fortifications of sanitation and public health: sewers, drains, sand filtration, and chlorination of water as defenses against cholera and typhoid; sanitary cordons, quarantine, and isolation against bubonic plague; vaccination against smallpox; and the first effective 'magic bullet' -quinine -against malaria. meanwhile, improvements in the handling of food, pasteurization, retort canning, and the sanitation of seafood beds, yielded major advances against bovine tuberculosis (tb), botulism, and a variety of food-borne maladies. already by the early th century, therefore, many of the most feared epidemic diseases of the past were in headlong retreat for reasons that were initially more empirical and spontaneous than the result of the application of science. science, however, soon added new and powerful weapons. the foundational work of louis pasteur and robert koch had established the biomedical model of disease that promoted unprecedented understanding and yielded a cascade of scientific discoveries and new sub-specialties (microbiology, immunology, parasitology, and tropical medicine). the dawn of the antibiotic era with penicillin and streptomycin provided means to treat syphilis, staph infections, and tb. the development of a series of vaccines dramatically lowered the incidence of smallpox, pertussis, diphtheria, tetanus, rubella, measles, mumps, and polio. ddt seemed to furnish a means to abolish malaria and other insect-borne pathogens. by the s, therefore, scientific discoveries had provided effective weapons against many of the most prevalent infectious diseases. extrapolating from such dramatic developments, many concluded that it was reasonable to expect that communicable diseases could be eliminated one at a time until the vanishing point was reached. indeed, the worldwide campaign against smallpox provided just such an example when the who announced in that the disease had become the first ever to be eradicated by intentional human action. those who asserted the doctrine of the conquest of infection viewed the microbial world as largely static or only very slowly evolving. for that reason, there was little concern that the victory over existing infections would be challenged by the appearance of new diseases for which humanity was unprepared and immunologically naive. falling victim to historical amnesia, they ignored the fact that the last years even in the west had been punctuated by the appearance of a series of catastrophic new diseases: bubonic plague in , syphilis in the s, cholera in , spanish influenza in - . macfarlane burnet in this regard was typical. burnet was a founding figure in evolutionary medicine who acknowledged, in theory, the possibility of the emergence of new diseases as a result of mutation. but, in practice, he believed that such appearances are infrequent and that they occur only at such distant intervals as to occasion little concern. 'there may,' he wrote, 'be some wholly unexpected emergence of a new and dangerous infectious disease, but nothing of the sort has marked the last fifty years' ( ) . the notion of microbial fixity, that the diseases that we have are the ones that we will face, even underpinned the international health regulations adopted in (ihr ) , which specified that the three great epidemic killers of the th century were the only diseases requiring notification: plague, yellow fever, and cholera. the regulations gave no thought to what action would be required if an unknown but deadly and transmissible new microbe should appear ( , ) . if belief in the stability of the microbial world was one of the major articles of faith underpinning the eradicationists' vision, a second misplaced evolutionary idea also played a crucial role. this was the doctrine that nature was fundamentally benign. over time, eradicationists believed, the pressure of natural selection would drive all communicable diseases toward a decline in virulence. the principle was that excessively lethal infectious diseases would prevent their own transmission by prematurely destroying their hosts. the long-term tendency, the proponents of victory asserted, is toward commensalism and equilibrium. new epidemic diseases are virulent almost by accident as a temporary maladaptation, and they therefore evolve toward mildness, ultimately becoming readily treatable diseases of childhood. examples were the evolution of smallpox from variola major to variola minor; the transformation of syphilis from the fulminant 'great pox' of the th century into the slow-acting disease of today; and the transformation of classic cholera into the far milder el tor biotype. similarly, the doctrine held a priori that, in the family of four diseases of human malaria, the most virulent, i.e. falciparum malaria, was an evolutionary newcomer relative to the less lethal vivax, ovale, and malariae malaria, which were believed to be older and to have evolved toward commensalism. against this background, the standard textbook of internal medicine in the eradicationist era, the th edn of harrison's principles of internal medicine of , claimed that a feature of infectious diseases is that they 'as a class are more easily prevented and more easily cured than any other major group of diseases' ( , ) . the most fully elaborated and most cited theory of the new era was the 'epidemiologic transition' or 'health transition' theory represented by abdel omran, professor of epidemiology at johns hopkins, in and refined by him in and . omran's theory of the transition was an account of the encounter of human societies with disease in the modern period. according to omran and his followers in such journals as the health transition review, humanity has passed through three eras of modernity in health and disease. although omran is ambiguous about the precise chronology of the first era, the 'age of pestilence and famine,' it is clear that it lasted until the th century in the west and was marked by malthusian positive checks on demography: epidemics, famines, and wars. there followed the 'age of receding pandemics' that extended from the mid- th century until the early th in the developed west and until later in non-western countries. during this period there was a declining mortality from infectious diseases in general and from tb in particular. finally, after world war i in the west and after world war ii in the rest of the globe, humanity entered the 'age of degenerative and man-made diseases.' whereas in the earlier stages of disease evolution, social and economic conditions played the dominant role in determining health and the risk of infection, in the final phase medical technology and science played a major part. in this period, mortality and morbidity from infectious diseases have been progressively replaced by the rise of degenerative diseases such as cardiovascular disease, cancer, diabetes, and metabolic disorders, by man-made diseases such as occupational and environmental illnesses, and by accidents ( ) ( ) ( ) . adopting the perspective of 'health transition' theory, us surgeon general julius b. richmond announced in that infectious diseases were simply the 'predecessors' of the degenerative diseases that succeed and replace them. the course of nature, in his view, was simple, unidirectional, and benign ( ) . if memory of the power of public health and science provided a major impetus to overconfidence, forgetfulness also played a vital role. us surgeon general william steward reported in that the time had come to 'close the book on infectious diseases.' this view was profoundly eurocentric. even as medical experts in europe and north america snowden Á emerging and reemerging diseases r the authors journal compilation r blackwell munksgaard immunological reviews / declared final victory, infectious diseases remained the leading cause of death worldwide, and nowhere more disastrously than in the poorest and most vulnerable countries of africa, asia, and latin america. while the tb sanatoria were closing their doors in the developed north, the disease continued its ravages in the south. indeed, the disease continued to ravage the marginalized underclasses of the north itself: the homeless, prisoners, intravenous drug users, immigrants, and racial minorities. as paul farmer has argued, tb was emphatically not disappearing; it was just that the bodies it affected were either distant or hidden from sight ( , ) . indeed, in the best estimates suggest that there are more people ill with tb today than at any time in human history and that nearly two million will die of it during the course of the year ( , ) . ultimately, by the early s, the eradicationist position became untenable. rather than witnessing the rapid fulfillment of the prediction that science and technology would eliminate all infectious diseases from the globe, the industrial west discovered that it remained painfully vulnerable and to a degree that had seemed unimaginable. the decisive event, of course, was the arrival and upsurge of human immunodeficiency virus (hiv)/acquired immunodeficiency syndrome (aids). aids was first recognized as a new disease entity in , and its etiologic pathogen was identified in . by the end of the decade, it was clear that hiv/aids embodied everything that the eradicationists had considered unthinkable. aids was a new infectious disease for which there was no cure, it reached the industrial world as well as developing countries, and it unleashed in its train a series of exotic additional opportunistic infections. furthermore, it had the potential to become the worst pandemic in history as measured not only by mortality and suffering but also by its profound social, economic, and security consequences. from the front lines of the battle against aids, a series of voices sounded the alarm in the s about the severity of the new threat. most famous of all was the case of the us surgeon general c. everett koop, who became the chief federal spokesman on the disease. in he produced the brochure understanding aids and took the pioneering step of having it mailed to all million households in the nation ( ) . working in greater obscurity in sub-saharan africa, peter piot, who later directed unaids, warned in that aids in africa was not a 'gay plague' but an epidemic of the general population. he warned that it was transmitted by heterosexual as well as homosexual intercourse and that in fact it affected women more readily than men. the warnings of the s, however, were confined to the issues of aids: they did not directly confront the larger issue of eradicationism or announce a new era in medicine and public health. that task fell first to the national academy of science's institute of medicine (iom) and its landmark publications on emerging diseases that began in with emerging infections: microbial threats to health in the united states ( ) . once raised by the iom, the cry of alarm was taken up widely and almost immediately: by the centers for disease control and prevention (cdc), which devised its own response to the crisis in and founded a new journal emerging infectious diseases devoted to the issue; by the national science and technology council (nstc) in ; and by of the world's leading medical journals that agreed to take the unprecedented step by which each devoted a theme issue to emerging diseases in january , which they proclaimed 'emergent diseases month' ( ) ( ) ( ) . in , in addition, president bill clinton ( ) issued a fact sheet entitled 'addressing the threat of emerging infectious diseases' in which he declared them 'one of the most significant health and security challenges facing the global community.' there were also highly visible hearings on emerging infections in the us congress ( ) . in opening those hearings before the senate committee on labor and human resources, senator nancy kassebaum, the committee chairperson, noted, new strategies for the future begin with increasing the awareness that we must re-arm the nation and the world to vanquish enemies that we thought we had already conquered. these battles, as we have learned from the year experience with aids, will not be easy, inexpensive, nor quickly resolved. ( ) finally, to attract attention at the international level, the who, which had designated april of each year world health day, declared that the theme for was 'emerging infectious diseases -global alert, global response' with the lesson that in a global village, no nation is immune ( ) . in addition to the voices of scientists, elected officials, and the public health community, the popular press gave extensive coverage to the new and unexpected danger, especially when the lesson was driven home by three events of the s that captured attention worldwide. the first was the onset of a large-scale epidemic of asiatic cholera in south and central america, beginning in peru in and rapidly spreading across the continent until cases and deaths were reported in countries ( ) . since the americas had been free of the disease for a century, the arrival of the unwelcome visitor reminded the world of the fragility of painfully won advances in public health. because cholera is transmitted by the contamination of food and water by fecal matter, it is a 'misery thermometer' -an infallible indicator of societal neglect and substandard living conditions ( ) . its outbreak in the west late in the th century, therefore, caused shock and a sudden awareness of unexpected danger. indeed, the press informed its readers of the 'dickensian slums of latin america,' where the residents of lima and other cities drew their drinking water directly from the 'sewage-choked river rimac' and similarly polluted sources ( , ) . who director-general hiroshi nakajima proclaimed the south american epidemic an 'emergency situation. ' the second news-catching event in the matter of epidemic diseases was the outbreak of plague in the indian states of gujarat and maharashtra in september and october . the final toll for the epidemic was limited - cases and deaths were reported ( ) . nevertheless, the news that plague had broken out in both bubonic and pneumonic forms unleashed an almost biblical exodus of hundreds of thousands of people from the industrial city of surat. it cost india an estimated $ . billion in lost trade and tourism, and it sent waves of panic around the world. the disproportionate fear, as the new york times explained, was due to the fact that the very word plague was explosively charged. it evoked cultural memories of the black death that killed a quarter of the population of europe in the th century. india's plague, the paper continued, 'is a vivid reminder that old disease, once thought to have been conquered, can strike unexpectedly anytime, anywhere' ( ) . the third major epidemic shock of the s was an outbreak of the frightening disease of ebola hemorrhagic fever at the city of kikwit, zaire (now democratic republic of the congo), in . cholera claimed international attention because of the numbers of those it afflicted, even though it had a low case fatality rate if treated early. plague demanded attention because of its all too familiar potential. ebola, by contrast, did not inspire terror by giving rise to a major epidemic: it infected only people between january and july . nor did it create fear because of historical memories of disaster since it was a new disease first recognized in . nevertheless, ebola set off a tidal wave of fear -a 'modern nightmare' in the words of le monde -across the globe. the reasons were that it dramatically revealed the lack of preparedness of both industrial and developing nations to deal with a public health emergency. it ignited primordial western fears of the jungle and of untamed nature, and it fed on racial anxieties about 'darkest' africa. as a result, a prominent aspect of the kikwit outbreak was its capacity to generate what the journal of infectious diseases termed 'extraordinary' and 'unprecedented' press coverage that amounted at times to the commercial 'exploitation' of human misery and a 'national obsession' ( ) . descending onto the banks of the kwilu river, the world's tabloids stressed in vivid hyperbole that ebola was a zoonotic disease that had sprung directly from the jungles of africa as a result of the encounter between native charcoal burners and monkeys and now threatened the west. in the revealing headline of the daily telegraph of sydney, 'out of the jungle a monster comes' ( ) . even the most legitimate investigators, however, were disturbed to discover that ebola had eluded public health attention for weeks between the death of the index case on january and the notification of the international community on april , despite the fact that the disease had left clusters of severely ill and dying patients in its train. with such a porous surveillance network in place, ebola aroused the fear that it might spread unnoticed km from kikwit to kinshasa, and then throughout the world by means of the zairian capital's intercontinental airport. there the virus could be loaded on board as 'a ticking, airborne time bomb' ( ) . most of all, however, the kikwit outbreak commanded attention because ebola is almost invariably fatal and because its course in the human body is excruciating, dehumanizing, and dramatic. commenting on the scenes that he had observed in zaire, the author richard preston explained on television at the height of the outbreak that the mortality rate among sufferers was % and that there was no known remedy or prophylactic. he continued: the victims suffer what amounts to a full-blown biological meltdown. . . . when you die of ebola, there's this enormous production of blood, and that can often be accompanied by thrashing or epileptic seizures. and at the end you go into catastrophic shock and then you die with blood pouring out of any or all of the orifices of the body. and in africa where this outbreak is going on now, medical facilities are not all that great. i've had reliable reports that doctors . . . were literally struggling up to their elbows in blood -in blood and black vomit and in bloody diarrhea that looks like tomato soup, and they know they're going to die. ( ) in combination with the announcement by scientists that the world was highly susceptible to new pandemics of just such infections, these events on three continents generated hordes, and of nature exacting its revenge for human presumption. as forrest sawyer reported on abc news, 'once the western world thought it was safe from these invisible killers. not anymore. we are now biologically connected in a web or a net.' in addition, there was an outpouring of films devoted to the possibility of pandemic disaster such as wolfgang petersen's thriller outbreak and of widely read books on the same theme, including richard preston's best-seller, the hot zone; laurie garrett, the coming plague: newly emerging diseases in a world out of balance; and william close, ebola. in the words of david satcher, director of the cdc, the result was the 'cnn effect' -the perception by the public that it was at immediate risk even at times when the actual danger was small ( ) . in this climate of anxiety, the term 'emerging and reemerging diseases' was coined for the iom by joshua lederberg, winner of the nobel prize for medicine, to mark a new era. lederberg defined these disease entities as follows: 'emerging infectious diseases are diseases of infectious origin whose incidence in humans has increased within the past two decades or threatens to increase in the near future' ( ) . emerging diseases were those that, like aids and ebola, were previously unknown to have afflicted humans; reemerging diseases, such as cholera and plague, were familiar scourges whose incidence was rising, or whose geographical range was expanding. lederberg's purpose in devising a new category of diseases was to give notice that the age of euphoria was over. instead of receding to a vanishing point, he declared, communicable diseases 'remain the major cause of death worldwide and will not be conquered during our lifetimes . . . we can also be confident that new diseases will emerge, although it is impossible to predict their individual emergence in time and place' ( ) . indeed, the contest between humans and microbes was a darwinian contest with the advantage tilted toward the microbes. the stark message of the iom was that, far from being secure from danger, the united states and the west were at greater risk from contagious and epidemic diseases than at any time in history. an important reason for this new vulnerability was the legacy of eradicationism itself. the belief that the time had come to close the books on infectious diseases had produced a pervasive climate that critics labeled variously as 'complacency,' 'optimism,' 'overconfidence,' and 'arrogance.' the conviction that victory was imminent had led the industrial world to premature and unilateral disarmament. assured by a consensus of the leading medical authorities for years that the danger was past, federal and state governments in the united states dismantled their public health programs dealing with communicable diseases and slashed their spending. at the same time, investment by private industry on the development of new vaccines and classes of antibiotics dried up, the training of health care workers failed to keep abreast of new knowledge, vaccine development and manufacture were concentrated in fewer laboratories, and the discipline of infectious diseases struggled to attract its aliquot share of research funds and of the best minds. at the nadir in , the united states spent only $ million for infectious disease surveillance as public health officials prioritized other concerns -chronic diseases, substance abuse, tobacco use, geriatrics, and environmental issues. for these reasons, the assessment of american preparedness to face the challenges of the new era was disheartening. in the words of the cdc in : the public health infrastructure of this country is poorly prepared for the emerging disease problems of a rapidly changing world. current systems that monitor infectious diseases domestically and internationally are inadequate to confront the present and future challenges of emerging infections. many foodborne and waterborne disease outbreaks go unrecognized or are detected late; the magnitude of the problem of antimicrobial drug resistance is unknown; and global surveillance is fragmentary. ( ) more bluntly, michael osterholm, the minnesota state epidemiologist, informed congress in that, 'i am here to bring you the sobering and unfortunate news that our ability to detect and monitor infectious disease threats to health in this country is in serious jeopardy. . . . for twelve of the states or territories, there is no one who is responsible for food or water-borne disease surveillance. you could sink the titanic in their back yard and they would not know they had water' ( ) . a striking example of the effects of complacency on infectious disease is the case of tb in new york city. tb had once been the leading cause of death in the city, but improvements in hygiene and education, followed by the discovery of streptomycin, led to the conviction by the middle of the th century that the disease was on the verge of being entirely conquered. as a result, funding was diverted, and demonstrably effective tb programs were dismantled although the social determinants of the disease worsened dramaticallyimmigration, crowding, homelessness, and rates of incarceration. meanwhile, hiv/aids continued to provide large numbers of patients with compromised immunity. as a result, the risk of infection increased, while access to health care became increasingly difficult, and the city experienced a remarkable and entirely preventable resurgence of the 'white plague,' primarily among african american and hispanic residents. between and , the numbers of cases tripled, while drug resistance developed as a significant additional problem. new york city led the way in a national resurgence of tb as cases increased by % between and . overweening confidence led directly and rapidly to a local epidemic and a partial reversal nationally of decades of tireless campaigning ( ) . if the experience of the united states with tb suggests how fragile advances in health remained even in the industrial world, the situation in developing countries was still more disquieting. there, progress toward the germ-free eden during the eradicationist era was nil. in david satcher's uncompromising observation, 'persons living in tropical climates are still as vulnerable to infectious disease as their early ancestors were' ( ) . the critique of years of hubris went deeper than just a protest against a decline in vigilance. in addition, the theorists of emerging diseases argued that, unnoticed by the eradicationists, society since world war ii had changed in ways that actively promoted the emergence and reemergence of epidemic diseases. one of the leading features most commonly cited was the impact of globalization in the form of the rapid mass movement of goods and populations. as william mcneill noted in plagues and peoples ( ) , the migration of people throughout history has been one of the most dynamic factors affecting the balance between microbes and man. humans are permanently engaged in a kind of war in which the social and ecological conditions that they create exert powerful evolutionary pressure on micro-parasites. by mixing gene pools and by providing access for microbes to populations of non-immunes living in conditions in which the microbes thrive, globalization gave microorganisms a powerful advantage. in the closing decades of the th century and the early years of the st, the speed and scale of this phenomenon amounted to a quantum leap, as . billion passengers boarded airplanes in ( , ) . in the words of the popular press, the daily movement of people around the globe by airplane means that a disease breaking out today in kikwit can arrive in new york, mumbai, and mexico city tomorrow. the numbers of voluntary travelers, moreover, are massively supplemented by millions of involuntary refugees and displaced persons in flight from warfare, famine, and religious, ethnic, or political persecution. for lederberg and the iom, these rapid mass movements have tilted the advantage in favor of microbes, 'defining us as a very different species from what we were years ago. we are enabled by a different set of technologies. but despite many potential defenses -vaccines, antibiotics, diagnostic tools -we are intrinsically more vulnerable than before, at least in terms of pandemic and communicable diseases' ( ) . after globalization, the second factor most frequently underlined was demographic growth, especially because this growth occurred in circumstances that were the delight of microorganisms and of the insects that often transmit them. in the postwar era, population has soared above all in the poorest and most vulnerable regions of the world, with the global urban population growing at four times the rate of the rural. its hallmark has been wholesale, chaotic, and unplanned urbanization, led by the resource-poor nations of sub-saharan africa, which is the most rapidly urbanizing region on the planet ( ) . the results have been escalating poverty, widening social inequality, the birth of 'megacities' exceeding million inhabitants, and the spawning of teeming peri-urban slums without sanitary, educational, or other infrastructures. such places were ready-made for ancient diseases to expand, as cholera demonstrated in the shantytowns and barrios of cities like lima, mexico city, and rio de janeiro, where millions lived without sewers, drains, secure supplies of drinking water, or appropriate waste management. already in the th century, cholera had flourished in the conditions created in european cities by rapid and unplanned urbanization. in the final decades of the th century and the start of the st, a much larger process on a global scale reproduced in the cities of africa, asia, and latin america the anomalous sanitary conditions propitious for cholera ( ) . another clear indication of socio-economic conditions in these new urban ecosystems is the appearance of trench fever (bartonella quintana) among the inhabitants of homeless shelters in north american cities. trench fever first emerged in the filth and crowding of soldiers in the trenches of the western front in the first world war, when millions of combatants were infected by the lice that covered their bodies. bartonella quintana, however, had never been documented apart from the vermin and the grime of wartime. the reemergence of the disease in urban america is therefore a clear measure of the insalubrious conditions of marginalized populations among the urban poor ( , ) . here too in urban poverty were the social determinants that made possible the global pandemic of dengue fever that began in and has continued unabated until today, when . billion people are at risk every year and - million people are infected. dengue is the ideal type of an emerging disease. an arborovirus transmitted primarily by the highly urban, daybiting, and domestic aedes aegypti mosquito, dengue thrives in crowded tropical and semi-tropical slums whenever there is standing and unregulated water. it breeds abundantly in gutters, uncovered cisterns, unmounted tires, stagnant puddles, and plastic containers, and it takes full advantage of societal neglect and the absence or cessation of vector control programs. particularly important for the theorists of 'emerging diseases' was the manner in which dengue demonstrated the hollowness of the reassuring dogma that infectious diseases evolve inexorably toward commensalism and reduced virulence. the dengue virus is a complex of four closely related serotypes (den- , den- , den- , and den- ) that have been known to infect humans since the th century. until , however, dengue infections in any geographical area were caused by a single virus that gave rise to a painful illness marked by fever, rash, headache behind the eyes, vomiting, diarrhea, prostration, and joint pains so severe that the infection earned its nickname 'break-bone fever.' but 'classical' dengue was a self-limiting disease that was followed by lifelong immunity. the movement and mobility of populations, however, have allowed all four serotypes to spread indiscriminately around the globe, so that for the first time individuals who have already experienced infection with one dengue virus can subsequently be infected with one or more of the others, as there is no crossover immunity from one serotype to another. through mechanisms that are still imperfectly understood, the disease is much more severe in patients suffering re-infections with different serotypes. instead of becoming milder, therefore, dengue has become a growing threat, giving rise to far more frequent outbursts and to sudden, devastating epidemics in which large numbers of patients suffer the severe and often lethal complications of dengue hemorrhagic fever (dhf) and dengue shock syndrome (dss) that were once unknown. in the americas, the first modern epidemic of dengue fever broke out in in cuba, producing cases, of whom suffered dhf and dss ( ) . moreover, since the dengue vectors a. aegypti and aedes albopictus are present in the united states, scientists at the national institute of allergy and infectious diseases (niaid), such as its director anthony fauci, have noted that dengue fever has broken out in both hawaii and puerto rico, and that they see no inherent reason it could not include the continental united states in its ongoing global expansion ( ) . dengue therefore demonstrates the following important evolutionary lessons: (i) infectious diseases that do not depend on the mobility of their host for transmission (because they are vector-borne, waterborne, or foodborne) are not under selective pressure to become less virulent; (ii) overpopulated and unplanned urban or peri-urban slums provide ideal habitats for microbes and their arthropod vectors; and (iii) modern transportation and the movements of tourists, migrants, refugees, and pilgrims facilitate the process by which microbes and vectors gain access to these ecological niches. paradoxically, the very successes of modern medical science also prepared the way for the emergence of new infections. by prolonging life, medicine gives rise to ever larger numbers of elderly people with compromised immune systems. as part of this process, significant numbers of immunocompromised populations have appeared at earlier ages as well-diabetics, cancer and transplant patients undergoing chemotherapy, and aids patients whose lives have been radically extended by antiretroviral treatment. furthermore, such people are frequently concentrated in settings where the transmission of microbes from body to body is amplified, such as hospitals, facilities for the elderly, and prisons. the proliferation of invasive procedures has also increased the opportunities for such diseases. modern nosocomial infections emerged in these conditions, and have become a major problem of public health as well as an ever growing economic burden. of these infections, the so-called 'superbug' staphylococcus aureus -the leading cause of nosocomial pneumonia, of surgical site infections, and of nosocomial bloodstream infections -is the most important and widespread. a recent study notes that in the united states by : each year approximately two million hospitalizations result in nosocomial infections. in a study of critically ill patients in a large teaching hospital, illness attributable to nosocomial bacteria increased intensive care unit stay by days, hospital stay by days, and the death rate by %. an earlier study found that postoperative wound infections increased hospital stay an average of . days. ( ) a further threatening byproduct of the advance of medical science is the development of ever increasing antimicrobial resistance. already in his nobel prize acceptance speech, alexander fleming, who discovered penicillin, the first antibiotic, issued a prophetic warning. penicillin, he advised, needed to be administered with care, because the bacteria susceptible to it were likely to develop resistance. the selective pressure of so powerful a medicine would make it inevitable. echoing fleming's warning, the emerging diseases theorists argue that antibiotics are a 'non-renewable resource' whose duration of benefit is biologically limited. by the late th century, this prediction was reaching fulfillment. on the one hand, the discovery of new classes of antimicrobials had slowed to a trickle, especially in a market in which profit margins are compressed by competition, by regulations requiring large and expensive clinical trials before approval, and by the low tolerance for risk on the part of regulatory agencies charged with the safety of the public. on the other hand, while antiinfective development stagnates, many microorganisms have evolved extensive resistance. as a result, in one telling metaphor, physicians are rapidly emptying their quiver, and the world stands poised to enter the postantibiotic era ( ) . some of the most troubling examples of the emergence of resistant microbial strains are the emergence of plasmodia that are resistant to all synthetic antimalarials, of s. aureus that is resistant both to penicillin and to methycillin (mrsa), and of strains of mycobacterium tuberculosis that are resistant not only to first-line medications (mdr-tb) but to second-line medications as well (xdr-tb) ( ) . antimicrobial resistance has become a global crisis, and many anticipate the early appearance of strains of hiv, tb, staph a, and malaria that are not susceptible to any available therapy. in part the problem of antimicrobial resistance is a simple result of darwinian evolution. as a rand corporation study ( ) notes, there are tens of thousands of viruses and species of bacteria that are capable of infecting human beings, and many of them replicate and evolve billions of times in the course of a single human generation. evolutionary pressures, in this context, work to the long-term disadvantage of human beings. but unwise human actions have dramatically hastened the process. farmers spray crops with pesticides and fruit trees with antibiotics, and they add subtherapeutic doses of antibiotics such as virginiamycin and avoparcin wholesale to animal feed to prevent disease, promote growth, and increase the productivity of chickens, pigs, and feedlot cattle. indeed, half the world output of antimicrobials by tonnage is used in agriculture ( ) . at the same time, the popular confidence that microorganisms will succumb to a chemical barrage has led to a profusion of antimicrobials in domestic settings where they serve no purpose ( ) . physicians, pressured to give priority in clinical settings to the immediate risk of individual patients over the long-term interest of the species and to meet patients' expectations, have succumbed to profligate prescribing fashions, administering antibiotics even for non-bacterial conditions for which they are unnecessary or entirely useless. the classic case in this regard is the pediatric treatment of otitis media (or middle ear infection), for which the overwhelming majority of practitioners in the s prescribed antibiotics, even though two-thirds of the children derived no benefit from the medication. widespread possibilities of self-medication in countries with few regulations or through opportunities created by the internet amplify the difficulties. in the case of diseases such as malaria and tb that require a long and complicated therapeutic regimen, there is also the issue of patients who interrupt their treatment after the alleviation of their symptoms instead of persevering until their condition is cured. here the problem is not the overuse but the underuse of antibiotics. sometimes described as simple non-compliance by patients, the issue in fact raises complex questions of education, poverty, and lack of access to health care. here the who strategies of dots (directly observed treatment short course) and dots-plus are helpful but cannot solve the underlying problems. a further issue raised by the new era was the overly rigid conceptualization of disease by the eradicationists, who drew too sharp a distinction between chronic and contagious diseases. infectious diseases, it became clear during the s, are a more expansive category than scientists previously realized because many diseases long considered noninfectious in fact have infectious origins. in demonstrating these causal connections, the decisive work was that of the australian nobel laureates barry j. marshall and robin warren with regard to peptic ulcers in the s. peptic ulcers are a significant cause of suffering, cost, and even death, as one american in develops one during the course of a life time, over one million people are hospitalized by them every year, and die. marshall noted in his acceptance speech for the nobel prize in , however, that the chronic etiology of peptic ulcer in the s was universally accepted as scientific truth. in his words, 'i realized that the medical understanding of ulcer disease was akin to a religion. no amount of logical reasoning could budge what people knew in their hearts to be true. ulcers were caused by stress, bad diet, smoking, alcohol and susceptible genes. a bacterial cause was preposterous.' what marshall and warren were able to demonstrate, therefore, was a medical watershed. they proved, in part by means of an auto-experiment, that the bacterium helicobacter pylori was the infectious cause of the disease and that antibiotics rather than diet, lifestyle change, and surgery were the appropriate therapy ( ) . this insight led to the realization that many other non-acute diseases, such as certain forms of cancer, chronic liver disease, and neurological disorders, are due to infections. human papillomavirus, for instance, is thought to give rise to cervical cancer, hepatitis b and c viruses to chronic liver disease, campylobacter jejuni to guillain-barré syndrome, and certain strains of escherichia coli to renal disease ( , ) . there are indications as well that infections serve as an important trigger to atherosclerosis and arthritis, and there is a growing recognition that epidemics and the fear that accompanies them leave psychological sequelae in their wake, including posttraumatic stress ( , ) . this understanding of these processes is what some have termed finally, and most emphatically, the concept of emerging and reemerging diseases was intended to raise the most important threat of all -that the spectrum of diseases that humans confront is broadening with unprecedented and unpredictable rapidity. the number of previously unknown conditions that have emerged to afflict humanity since exceeds , with a new disease discovered on average more than once a year. the list includes such frightening names as hiv, hantavirus, lassa fever, marburg fever, legionnaires' disease, hepatitis c, lyme disease, rift valley fever, ebola hemorrhagic fever, nipah virus, west nile virus, sars (severe acute respiratory syndrome), bovine spongiform encephalopathy, avian flu h n , chikungunya virus, and group a streptococcus -the so-called 'flesh-eating bacterium.' skeptics argue that simply to list the diseases that have emerged since s gives the misleading impression that diseases are emerging at an accelerating rate. this impression, they suggest, is largely an artifact of heightened surveillance and improved diagnostic techniques rather than a new development. the who has countered that not only have diseases emerged at record rapidity as one would expect from the transformed social and economic conditions of the postwar world, but also that they gave rise between the years and to a record worldwide epidemic events ( ) . the most recent and comprehensive examination of the question ( ), published in february in nature, involved the study of emerging infectious disease (eid) 'events' between and , controlling for reporting effort through more efficient diagnostic methods and more thorough surveillance. the conclusion was that, 'the incidence of eid events has increased since , reaching a maximum in the s. . . . controlling for reporting effort, the number of eid events still shows a highly significant relationship with time. this provides the first analytical support for previous suggestions that the threat of eids to global health is increasing' ( ) . there are no rational grounds, the public health community concluded, to fail to expect that as diseases emerge in the future, some of them will be as virulent and as transmissible as hiv or the spanish influenza of / . discussion has therefore shifted dramatically from the question of whether new diseases will emerge and old ones resurge to the issue of how the international community can best prepare to face them. in the stark words of the us department of defense, 'historians in the next millennium may find that the twentieth century's greatest fallacy was the belief that infectious diseases were nearing elimination. the resultant complacency has actually increased the threat' ( ) . a major aspect of the official response to the challenge of emerging and reemerging diseases is that microbes now are regarded as threats to the security of states and to the stability of the international order. for the first time, therefore, not only public health authorities but also intelligence agencies and conservative think tanks have classified infectious diseases as a 'non-traditional threat' to national and global security. they assumed therefore the task of envisaging the future and the challenge that communicable diseases would play. here a turning point was the central intelligence agency (cia)'s national intelligence estimate (nie) for ( ) , which was devoted to the danger posed by disease and presented defense against epidemic diseases as a major security goal for the united states. as a document, nie - d ( ) was divided into four major sections: alternative scenarios, impact, implications, and discussion. in the first section, the cia attempted to outline three possible scenarios for the course of infectious diseases over the next years: (i) the optimistic contemplation of steady progress in combating communicable disease; to (ii) the forecast of a stalemate with no decisive gains either by microbes or by humans in their long war of attrition; and (iii) the consideration of the most pessimistic prospect of deterioration in the position of humans, especially if the world population continues, as seems probable, to expand and if megacities continue to spring up with their attendant problems of crowding, sanitation, and unprotected drinking water. unfortunately, the cia regarded the optimistic first case as extremely unlikely. the probable course of events, in its view, is that americans will die from infectious diseases every year or considerably more if a pandemic of influenza or of a still unknown disease occurs, if there is a dramatic decline in the effectiveness of antiretroviral treatments for hiv/aids. only toward the end of the years did the report foresee possible advances due to enhanced public health initiatives, the development of new drugs and vaccines, and economic development ( ) . against this background, the succeeding sections on 'impact' and 'implications' outlined a series of likely economic, social, and political results that would occur in the new age of increasing disease burdens. in the most afflicted regions of the world, such as sub-saharan africa, the report anticipated 'economic decay, social fragmentation, and political destabilization.' the international consequences of these developments would be growing struggles to control increasingly scarce resources, accompanied by crime, displacement, and the degradation of familial ties. disease, therefore, would heighten international tensions while it weakened forces, such as international peacekeepers, who might otherwise have played a larger role in controlling regional tensions. us or european military forces deployed abroad in support of humanitarian or other operations would be at high risk. because the economic and social consequences of increasing burdens of communicable diseases in the developing world are certain to impede economic development, the nie also predicted that democracy would be imperiled, that civil conflicts and emergencies would multiply, and that the tensions between north and south would deepen. three years later, motivated by the cia's report, an influential national security think tank, the rand corporation, turned to the intersection of disease and security when it attempted to provide 'a more comprehensive analysis than has been done to date, encompassing both disease and security' ( ) . in so doing, it envisaged even more somber probabilities than the cia in the new global environment. the rand corporation intelligence report the global threat of new and reemerging infectious diseases: reconciling u.s. national security and public health policy ( ) had two leading themes. the first was that in the postwar era there was a sharp decline in the importance of direct military threats to security. the second was that there is a corresponding rise in the impact of 'non-traditional challenges,' of which diseases are the major but inadequately recognized component. it has always been accepted, the report stressed, that diseases kill and undermine the quality of individual lives. in addition, it was essential to recognize that the transition to the era of emerging and reemerging diseases marked the opening of a period in which infectious diseases would profoundly affect the ability of states to function and to preserve social order. the most striking portion of the global threat of new and reemerging infectious diseases ( ) was its imagining of a probable scenario in which south africa could become the first modern state to fail specifically because of infectious diseases in general and the hiv/aids pandemic in particular. as the report explained, 'the contemporary hiv/aids crisis in south africa represents an acute example of how infectious diseases can undermine national resilience and regional stability.' in absolute numbers, south africa has the highest number of hiv-positive inhabitants in africa - . million people in , or % of the country's adult population. already, such extreme prevalence of the disease has pervasive impacts, affecting all aspects of south african security. but south africa is just emerging from the first phase of the aids pandemic and is therefore far from experiencing the full effects of the crisis, which even in the absence of resistance to antiretroviral therapy, is expected to produce patients with hiv and with full-blown aids by . in these circumstances, over a quarter of the economically active population will have the disease, causing severe skill shortages, creating poverty, destroying economic development, undermining participation in political life, and giving rise to more than two million orphans who will be impoverished, uneducated, and easily drawn into crime and prostitution. the effects will also be deeply felt in the military, the police, and the legal system, which will be severely deprived of manpower and unable to function just as social tensions deepened. 'the net effect,' it concluded, 'will be entirely negative for south africa's civil stability, possibly reducing the country to widespread social anarchy within the next five to twenty years.' this disturbing outcome, moreover, could be hastened by the public health policies of president thabo mbeki, who espoused the theories of the aids denier peter duesberg and rejected the link between the hiv virus and the disease. the point the rand corporation stressed most about south africa, however, was that it was simply a dramatic illustrative example. what was occurring there as a result of hiv/aids could happen without warning elsewhere. 'a crisis of similar proportions,' it explained, 'could therefore break out in any country at any time.' indeed, in the context of a growing danger of bioterrorist attack, such an outbreak could be launched intentionally. it was precisely this point -the growing vulnerability of all in the age of globalization -that led the world community, the european union, and individual nations to rearm in preparation for the inevitable threats to come. in the new climate of preparedness, the united states took a prominent role, beginning almost immediately in the aftermath of the iom report. in the cdc -the chief monitoring agency -drafted a strategic plan that it then updated in , while niaid -the principal basic research center -established a research agenda. both agencies' plans were endorsed by the white house, where the nstc under the chairmanship of vice president al gore issued a 'fact sheet: addressing the threat of emerging infectious diseases,' which in turn was backed by a presidential decision directive of june , . the result, as gore explained, was the first national policy by the united states to confront the international problem of infectious diseases ( ) . the essential starting point of the plan envisaged by the cdc, niaid, and the white house was the iom's description of the darwinian struggle under way between humans and microbes. in the iom's analysis of that struggle, microbes possess formidable advantages. they outnumber human beings a billionfold, they enjoy enormous mutability, and they replicate, in lederberg's estimate, a billion times more quickly than man, with generations measured in minutes rather decades. in terms of natural evolutionary adaptation, therefore, microbes are genetically favored to win the contest. in lederberg's observation, 'pitted against microbial genes, we have mainly our wits' ( ) . taking this iom analysis as its starting point, the american response to the new challenge is best seen as the attempt to organize and deploy human wit, backed by newly found financial resources, to counter the microbial genetic challenge ( ) . the white house 'fact sheet' declared in clear alarm that, 'the national and international system of infectious disease surveillance, prevention, and response is inadequate to protect the health of u.s. citizens.' to remedy the situation, the white house established six policy goals, as follows: . strengthen the domestic infectious disease surveillance and response system, both at the federal, state, and local levels and at ports of entry into the united states, in cooperation with the private sector and with public health and medical communities. . establish a global infectious disease surveillance and response system, based on regional hubs and linked by modern communications. . strengthen research activities to improve diagnostics, treatment, and prevention, and to improve the understanding of the biology of infectious disease agents. . ensure the availability of the drugs, vaccines, and diagnostic tests needed to combat infectious diseases and infectious disease emergencies through public and private sector cooperation. . expand missions and establish the authority of relevant us government agencies to contribute to a worldwide infectious disease surveillance, prevention, and response network. . promote public awareness of eids through cooperation with non-governmental organizations and the private sector ( ) . in pursuit of goals , , and , nih funding was doubled between and . niaid established a research agenda to develop new weapons to combat epidemic diseases, giving rise to an explosion in knowledge while publications on infectious diseases burgeoned. indeed, the agency director, anthony s. fauci, claimed in that hiv/aids in particular has become the most extensively studied disease in human history. niaid's priority is the development of safe and effective vaccines and medications to combat hiv/aids, malaria, tb, and influenza. to that end, it has evaluated over hiv vaccine candidates, funded clinical trials, and developed antiretroviral medications. in the field of malariology, it has completed the genomic sequencing of plasmodium falciparum and of the feared malaria vector anopheles gambiae with the expectation that this genetic knowledge is the first step toward the capacity to design anti-malarial drugs, vaccines, and pesticides. the work of the federal agency, moreover, has been complemented by the work of private organizations such as the bill and melinda gates foundation, and university laboratories ( ) . at the same time that niaid stressed basic research, the cdc developed a defensive strategy against emerging pathogens in compliance with goal of the president's directive. the cdc articulated its plan in two seminal works published in and . there it articulated its objectives in four principal areas: surveillance; applied research; prevention and control; and the enhancement of the infrastructure and trained personnel needed for diagnostic laboratories at the federal, state, local, and international levels. in addition, the atlanta-based agency strengthened its links with the international public health community and with other surveillance agencies such as the fda and the department of defense. it enhanced its capacity to respond to outbreaks, and it launched the journal emerging infectious diseases as a forum to pool information on communicable diseases. it sponsored a series of major international conferences on the topic of emerging and reemerging diseases, beginning in with the participation of representatives from all states and countries. the cdc initiatives were widely regarded as a model for the establishment of surveillance and response capabilities in other countries as well ( , ) . at the global level, the un and its agency who also took major steps to strengthen international preparedness for the ongoing siege by microbial pathogens. a first step was the creation in of the disease-specific organization unaids with the function of raising awareness, mobilizing resources, and monitoring the pandemic. funding levels in the fight against the disease increased from $ million in to nearly $ billion a decade later ( ). a further step was that like the united states, the united nations announced that it regarded infectious diseases as threats to international security. in acknowledgement of this new development, the security council took the unprecedented step in june of devoting a special session to the hiv/aids crisis. the session adopted a 'declaration of commitment on hiv/aids: global crisis -global action.' the declaration declared the global epidemic a 'global emergency and one of the most formidable challenges to human life and dignity' ( ) . five years later, in june , the general assembly reaffirmed its commitment to the campaign, and adopted the ' political declaration on hiv/aids,' whose chief goal was the establishment of national campaigns to improve access to care and treatment ( ). a third step was the establishment of a new set of international sanitary regulations -ihr ( ) -to replace the outdated ihr ( ). whereas the old framework was disease-specific and required notification only in the event of plague, yellow fever, and cholera, the new rules required notification for any 'public health emergency of international concern,' thereby including unknown pathogens and emerging infections. the regulations specified the nature of the 'events' that should trigger international concern. they also committed all of the who member states to improve their capacity for surveillance and response and to designate 'national ihr focal points' as the units responsible for providing notification while requiring, in exchange, that the who provide assistance to member states in fulfilling their obligations ( , ) . in addition, recognizing that microbes do not acknowledge political frontiers, ihr ( ) called for effective responses wherever necessary to contain an outbreak on the basis of realtime epidemiological evidence instead of concentrating on taking defensive measures at international borders. finally, the who organized a rapid response capacity with the necessary supporting infrastructure. this was the global outbreak alert and response network (goarn), which was established in with the goal of ensuring that even most resource-poor countries would have access to the experts and resources needed to respond to an epidemic emergency. to that end, goarn pooled the resources of countries and organized experts in the field. in addition, it stockpiles vaccines and drugs, and supervises their distribution during epidemic events. between its founding and , goarn responded to outbreaks and attempted to learn from experience by establishing protocols to standardize such matters as field logistics, security, communication, and the deployment of field teams ( ). in addition to goarn, the who set up surveillance systems specifically designed to deal with pandemic influenza, which the un agency determined as its most feared security threat. these disease-specific networks are (i) the global influenza surveillance network, which provides recommendations twice a year on the appropriate vaccine for the subsequent influenza season by collecting samples from patients in countries and forwarding them to who collaborating laboratories for analysis, and (ii) flunet, which compiles the surveillance data thus collected to establish a global real-time early-alert system for the disease ( , ) . in practice, the first test of the effectiveness of the new structures was the sars pandemic of / -the first major emerging disease threat of the st century. after first appearing in the chinese province of guangdong in november , it erupted as an international health threat in march , when the who received notification and declared a global travel alert. between march and the declaration on july that the disease had been contained, sars affected people, caused deaths, brought international travel to a halt in entire regions, and cost $ billion in gross expenditure and business losses to asian countries alone. as retrospective studies have demonstrated, sars presented many of the features that most severely expose the vulnerabilities of the global system: sars is a respiratory disease capable of spreading from person to person without a vector; it has an asymptomatic incubation period of more than a week; it generates symptoms that closely resemble those of other diseases; it takes a heavy toll on caregivers and hospital staff; it readily spreads unobserved aboard aircraft; and it has a case fatality rate of %. at the time this new disease appeared, moreover, its causative pathogen (sars-associated coronavirus) was unknown, and there was neither a diagnostic test nor a specific treatment. for all of these reasons, it dramatically confirmed the iom's prediction that all countries were more vulnerable than ever to eids. sars demonstrated no predilection for any region of the globe and was no respecter of prosperity, education, technology, or access to health care. indeed, after its outbreak in china, sars spread by airplane primarily to affluent cities such as singapore, hong kong, and toronto, where it struck relatively prosperous travelers and their contacts, hospital workers, patients, and hospital visitors, rather than targeting the poor and the marginalized. more than half of the recognized cases occurred in well-equipped and technologically advanced hospital settings such as the prince of wales hospital in hong kong, the scarborough hospital in toronto, and the tan tock seng hospital in singapore ( , , ) . in terms of response to the crisis, the sars outbreak demonstrated and vindicated the reforms taken on both the national and international levels. after the debacle of chinese obfuscation at the start of the epidemic, national governments cooperated fully with ihr ( ). the world's most equipped laboratories and foremost epidemiologists, working in realtime collaboration via the internet, succeeded, with unprecedented speed, in identifying sars-cov in just weeks. at the same time the newly created goarn, together with such national partners as the canadian public health intelligence network, the cdc, and the who global influenza network, took rapid action to issue global alerts, monitor the progress of the disease, and supervise containment strategies before the disease could establish itself endemically. ironically, given the high-tech quality of the diagnostic and monitoring effort, the containment policies were based on traditional methods dating from the public health strategies against bubonic plague by the th century and the foundation of epidemiology as a discipline in the th. these measures were case tracking, isolation, quarantine, the cancellation of mass gatherings, the surveillance of travelers, recommendations to increase personal hygiene, and barrier protection by means of masks, gowns, gloves, and eye protection ( ) . although sars affected countries and every continent, the containment operation coordinated by goarn successfully limited the outbreak overwhelmingly to hospital settings with only sporadic community involvement, so that by july the who could announce that the pandemic was over. although sars tested the newly established global defenses against emerging diseases and the protective ramparts withstood the challenge, doubts relentlessly surfaced. the chinese policy of concealment between november and march had placed international health in jeopardy and revealed that even a single weak link in the response network could undermine the ihr ( ) system. indeed, resourcepoor countries that were compliant with the new framework of obligations nonetheless found it difficult or impossible to maintain the surveillance effort for the full -month duration of the emergency. still more tellingly, it was also clear that a major factor in the containment of sars was simple good fortune. the world was lucky that sars is spread by droplets and therefore requires extended contact for transmission, unlike classic airborne diseases such as influenza and smallpox. it was, relatively, much easier to contain, because except in the infrequent and still poorly understood case of so-called 'super shedders,' it is not readily communicable from person to person. as poorly transmissible as it was, however, sars exposed the absence of 'surge capacity' in the hospitals and health care systems of the prosperous and well-resourced countries it affected. the events of thereby raised the specter of what might have happened had sars been pandemic influenza, and if it had traveled to resource-poor nations at the outset instead of mercifully visiting cities with well-equipped and well-staffed modern hospitals and public health care systems. furthermore, sars arrived in peacetime rather than in the midst of the devastation and the dislocations of war. in that respect, too, it did not repeat the challenge of the spanish lady of - . the physician paul caulford, who fought the sars epidemic in the front lines at scarborough hospital in toronto, raised these matters. in december , after the passing of the emergency, he reflected: sars must change us, the way we treat our planet, and how we deliver health care, forever. will we be ready when it returns? sars brought one of the finest publiclyfunded health systems in the world to its knees in a matter of weeks. it has unnerved me to contemplate what the disease might do to a community without our resources and technologies. without substantive changes to the way we manage the delivery of health care, both locally and on a worldwide scale, we risk the otherwise preventable annihilation of millions of people, either by this virus, or the next. ( ) at the end of the victory over sars, the nagging question therefore remains: even after the impressive efforts at rearmament since , how prepared is the international community for upcoming emerging diseases? have we been forever changed? the reforms introduced since the iom report in have been profound and important. indeed, the manner in which the international community responded to sars was innovative and, in the circumstances, highly successful. there is, however, a disconcerting sense of a systematic blindness in the responses -at all levels -to the crisis described by the iom, the cia, the rand corporation, the who, and the white house. what has been done has been necessary but probably far from sufficient. some of the issues raised by those who sounded the alarm have been forcefully addressed, but others have been largely ignored. the responses to date have fit into two chief categories, both of which are essential and both of which were evident during the sars pandemic. the first is reactive: the ability to respond rapidly and effectively to the outbreak of new epidemic threats. through a series of initiatives, the years since have witnessed the establishment of organized networks for gathering public health intelligence, of an international legal framework to structure emergency interventions, and of well equipped response teams of experts to contain and monitor outbreaks. if one were to compare outbreaks of infectious diseases to forest fires, the world has provided itself with surveillance satellites, advanced communications infrastructures, and a well-equipped fire department. one could question details of the response to sars, such as implementation lapses that risked the spread of the disease from the hospital environment into the community, but overall the world's 'dress rehearsal' demonstrated far-sighted planning and coordination beyond anything ever attempted before on an international scale. the second category of initiatives is proactive and scientific: the attempt to discover new weapons to attack microbial threats. after half a century of dwindling resources for the fight against infectious diseases, the scientific and public health communities have successfully aroused worldwide awareness of the threat to health and security. they have, at least initially, attracted new levels of funding for basic research from both public and private sources, and they have set research agendas. the result has been an explosion of knowledge, grants, and publications with priority given to genomic approaches to microbes and vectors, to the development of vaccines, and to the search for new medications and diagnostic tools. naturally there are grounds for criticism of various aspects of these initiatives. there is, for example, general agreement that overall levels of funding remain inadequate to the extent of the crisis and that after initial enthusiasm, governments have not continued to increase their support. there are also reasonable grounds for disagreement as to the relative distribution of research efforts, with discussion, for example, about the balance struck between research against hiv/aids and that against such other major diseases as malaria, tb, and pandemic influenza. some have also questioned whether developing vaccines is the right paradigm on all fronts. for example, should priority be given to those diseases for which the human immune response gives grounds for optimism thaton the basis of historical experience -a safe and effective vaccine can be developed (e.g. influenza and dengue)? or should other strategies be followed with respect to diseases for which the human immune response makes the development of a vaccine a far more arduous and unpredictable endeavor (e.g. cholera and malaria)? nevertheless, although there is no basis for false confidence, global research efforts have been galvanized, and major advances have been made in the field of infectious diseases in comparison with the early decades after world war ii. there is also a consensus that the effort to find vaccines and medicines is vital and that it must be enhanced in order to replenish the quivers of clinicians and public health officials. what is more troubling in principle is that there are also systematic blind spots -areas of danger raised by those who first sounded the tocsin regarding emerging diseases that have not been addressed at all or only marginally and sporadically. broadly speaking, the global community has chosen to address those issues for which scientific and technological responses are appropriate, while giving little sustained priority to what might be termed the social, economic, and environmental determinants of infectious disease. here there is a considerable irony. the founding figures of the modern concept of emerging and reemerging diseases such as joshua lederberg and robert shope stressed that epidemics do not strike societies randomly or in accord with the caprices of angry gods. diseases instead reflect the relationships that human beings establish with one another and with the natural and built environments. they then spread by taking advantages of the fault lines created by demography, poverty, environmental degradation, warfare, mass transportation, and societal neglect. the very beginning of the iom's discussion of the new dangers was the recognition that our new vulnerability is not accidental but is the logical result of the type of society that we have become. in defining this vulnerability in a keynote speech in , for instance, lederberg stated: to our disadvantage, we have crowding; we have social, political, economic, and hygienic stratification. we have crowded together a hotbed of opportunity for infectious agents to spread over a significant part of the population. this condensation, stratification, and mobility is unique, defining us as a very different species from what we were years ago. ( ) if our problem results from 'condensation, stratification, and mobility,' there is a disturbing silence in the government response. ironically, the various agencies -niaid, the cia, the department of defense -tasked by the presidential directive with augmenting american preparedness in the fight against infectious diseases neither mention socioeconomic factors nor elaborate a long-term strategy to address them. the call to action aroused the will to find new means to attack microbes and their vectors, and to contain disease outbreaks in human populations, but not to ameliorate the underlying conditions that have made modern societies vulnerable in the first place. three crucial examples illustrate the problem. the first is condensation or the press of overpopulation. clearly unrestrained demographic growth as the world population approaches seven billion strains all resources, degrades the environment, gives rise to the megacities and peri-urban slums where dengue, tb, and cholera thrive, drives populations to intrude into forests where they are exposed to new zoonotic infections, and overwhelms educational, housing, and hygienic infrastructures. here, the medical and public health communities agree, is a driving factor in the new human vulnerability to emerging diseases. the remedies, moreover, are already known, involving voluntary universal access for women to family planning education and technologies. one of the few forums even to raise the issue was the 'first international conference on women and infectious diseases' held in atlanta, february - , , where it was noted that, 'women's health, in and of itself, rarely has been at the forefront of international development programs or national health planning and policies' ( ) . in the field of infectious diseases, this lacuna is especially glaring because women are, as the conference stressed, more susceptible to infections than men, both for biological reasons and due to their caregiving roles and their relative burden of unemployment and poverty. women, moreover, suffer more serious complications from infectious diseases, above all during pregnancy. a second illustration is stratification, the burden of poverty and inequality. nearly all of the leading studies on emerging diseases regard poverty and its sequelae of poor diet, substandard housing, lack of education, and inadequate access to health care as one of the chief determinants of epidemic disease. poverty prevents people from taking measures to protect their own health, it undermines the immune system, it complicates access to safe water supplies, it leads to overcrowding in unhygienic housing, and it creates patterns of labor mobility and migration that compromise health. health care workers and clinicians recognize the link between inadequate resources and disease, with the result that many of the leading epidemic infections are widely termed 'diseases of poverty' ( ) . the issue therefore surfaces in who campaigns to combat the three most important contemporary epidemics: hiv/aids, malaria, and tb. as the report addressing poverty in tb control stated: poverty is the greatest impediment to human and socioeconomic development. the united nations and its specialized agencies are focusing on poverty reduction as a leading priority. in the health sector, poverty represents a principal barrier to health and health care and, consequently, the world health organization has committed to integrate the promotion of pro-poor policies throughout its work. ( ) the reduction of extreme poverty and hunger also form part of the un 'millennium development goals' to be achieved by . except for exhortation and moral suasion, however, it is not clear that the who has developed specific plans to tackle the problem of poverty as a primary determinant of public health, and the promotion of greater equality is entirely ignored. more strikingly, neither issue forms part of the strategic public health thinking of the united states. american analyses recognize poverty as a factor creating an environment favorable for infectious diseases, but they avoid both poverty and inequality as matters of practical health policy. here is the antithesis of the strategic recommendation of the south african pediatrician nulda beyers, who commented: the western cape is in some ways a model of tb epidemiology . . .. tb is almost non-existent in the white population, but in the black and coloured populations, where unemployment is running at %, and malnutrition and crowded slum housing are the norm, tb deaths can reach per . if i had to put my money on only one option -science or social upliftthere is no doubt that social uplift would have the bigger impact. ( ) poverty, moreover, reinforces both condensation and mobility. poverty creates a vicious downward spiral by interacting with population pressure because impoverished women are unable to practice effective family planning. the population explosion of the st century is based in the poorest regions of the planet. given a free and informed choice, privileged families in the industrial world limit their fertility. at the same time, however, poverty also augments vulnerability to infectious disease by setting in motion great streams of mobile people -the poor who become migrants, refugees, and displaced persons, and who then crowd into slums, mining compounds, refugee camps, and homeless shelters. these are people who are at disproportionately high risk of falling ill and of transporting their microbial burden with them. finally, there is the question of access to care. here the position of the leading figures in the campaign to recognize the importance of emerging and reemerging diseases is strangely contradictory. the iom examined the managed care revolution in the united states and the implications of for-profit medicine for the preparedness of the nation to face infectious diseases ( ) . by , managed care already enrolled million americans and therefore dominated health care delivery. the performance of the managed care revolution, however, did not inspire the iom. on the contrary, it produced a list of the major problems that, in its view, managed care created for public health. this list was lengthy and devastating. according to the iom, managed care creates severe public health difficulties because it does the following: (i) it places such strict controls on reimbursements that it becomes an impediment to effective collaboration with the public health community; (ii) it lowers costs by fostering management of infectious diseases by nonspecialists; (iii) it promotes the shift from inpatient to outpatient treatment, where there are neither the specialists nor the infrastructure to diagnose or contain infectious diseases; (iv) it proliferates bureaucratic complexities that complicate prompt response to disease outbreaks; (v) it reduces the commitment to training and research; and (vi) it encourages excessive antibiotic use ( ) . by leaving tens of million of people in the united states without insurance coverage and therefore without effective access to care, for-profit medicine effectively removes them from the disease surveillance network. to the extent that uninsured people avoid care entirely or seek it only at a late stage of their illness, the prompt information on which effective public health depends is undermined. in addition, excluding people from coverage drives them further into poverty and creates an underclass of the marginalized. finally, managed care relentlessly cuts costs by squeezing out of the system the surge capacity on which populations depend in the event of a disease outbreak. nevertheless, despite these observations, the iom reached perfectly anodyne conclusions. it did not conclude that only a system that guaranteed universal access is compatible with defense against infectious disease threats. instead, it lamely urged a deeper partnership between the managed care industry and public health officials. for these reasons, one can only conclude that we are not, in fact, forever changed. on the contrary, on both the national and international levels the response to the challenge of emerging disease threats remains partial with major gaps that are potentially costly in terms of human life and suffering. the united states and the world health community have established a sophisticated and necessary rapid response system. they have also proclaimed -and partially funded -a new commitment to basic research aimed at finding new antimicrobial weapons. they have not, however, systematically addressed the underlying causes for the new vulnerability. man's mastery of malaria textbook of malaria eradication dynamics of tropical disease: a selection of papers with biographical introduction and bibliography by the late george macdonald: chapters - the malaria program -from euphoria to anarchy the conquest of malaria: italy, - world eradication of infectious diseases the evolution and eradication of infectious diseases infectious diseases: their evolution and eradication natural history of infectious disease world health assembly resolution . of , ''health for all international health regulations international health regulations harrison's principles of internal medicine, th edn plagues and peoples epidemiologic transition: changes of fertility and mortality with modernization a century of epidemiologic transition in the united states the epidemiologic transition theory. a preliminary update healthy people: the surgeon general's report on health promotion and disease prevention health, human rights, and the new war on the poor infections and inequalities: the modern plagues could a tuberculosis epidemic occur in london as it did in new york? the continued threat of tuberculosis emerging infections: microbial threats to health in the united states addressing emerging infectious disease threats: a prevention strategy for the united states. atlanta: us department of health and human services infectious disease -a global threat: report of the national science and technology council infectious diseases: a global approach to a global problem fact sheet: addressing the threat of emerging infectious diseases emerging infections: a significant threat to the nation's health how the cholera scare is waking latin america feeding on th century conditions, cholera spreads in latin america a -year respite ends: cases of plague reported in india's largest cities an introduction to ebola: the virus and the disease out of the jungle a monster comes. the daily telegraph quarantine at , feet: ebola virus as a ticking, airborne time bomb arthur richard preston discusses the deadly outbreak of the ebola virus in zaire public health systems and emerging infections: assessing the capabilities of the public and private sectors emerging infections: getting ahead of the curve transmission of infectious diseases during commercial air travel infectious diseases as an evolutionary paradigm malaria on the move: human population movement and malaria transmission naples in the time of cholera emergence of bartonella quintana infection among homeless persons trench fever identified in seattle's homeless. npr transcripts: ''all things considered dengue cases on the rise niaid experts see dengue as potential threat to u.s. public health. news release of the economic impact of staphylococcus aureus infection in new york city hospitals an emptying quiver: antimicrobial drugs and resistance world wide emergence of extensively drug-resistant tuberculosis the global threat of new and reemerging infectious diseases: reconciling u.s. national security and public health policy who. the medical impact of antimicrobial use in food animals antibacterial household products: cause for concern helicobacter connections chronic sequelae of foodborne disease emerging infectious determinants of chronic diseases potential infectious etiologies of atherosclerosis: a multifactorial perspective the global threat of new and reemerging infectious diseases: reconciling u.s. national security and public health policy the global infectious disease threat and its implications for the united states. nie - d global trends in emerging infectious diseases addressing emerging infectious disease threats: a strategic plan for the department of defense the global infectious disease threat and its implications for the united states. nie - d presidential decision directive ntsc- addressing the threat of emerging infectious diseases infectious disease -a threat to global health and security emerging infectious diseases: a -year perspective from the national institute of allergy and infectious diseases preventing emerging infectious diseases: a strategy for the st century. atlanta: us department of health and human services declaration of commitment on hiv/aids global public health security who. international health regulations flunet as a tool for global monitoring of influenza on the web global surveillance, national surveillance, and sars bell dmworld health organization working group on international and community transmission of sars. public health interventions and sars spread sars: aftermath of an outbreak infectious disease as an evolutionary paradigm steps for preventing infectious diseases in women targets now set by g countries to reduce ''diseases of poverty addressing poverty in tb control: options for national tb control programmes tuberculosis experts back social reform managed care systems and emerging infections: challenges and opportunities for strengthening surveillance, research and prevention key: cord- -vk gm j authors: selgelid, michael j.; kelly, paul m.; sleigh, adrian title: tb matters more date: journal: international public health policy and ethics doi: . / - - - - _ sha: doc_id: cord_uid: vk gm j tuberculosis (tb) is the second leading infectious cause of mortality worldwide and arguably the most important neglected topic in bioethics. this chapter: ( ) explains the ethical importance of tb, ( ) documents its neglect in bioethics discourse, ( ) maps the terrain of ethical issues associated with tb, and ( ) advocates a moderate pluralistic approach to ethical issues associated with tb. resistance (which may imply return to a situation analogous to the pre-antibiotic era); and the specter of bioterrorism. second, because they can be contagious and cause acute illness and death, infectious diseases raise difficult ethical questions of their own (smith et al. ; selgelid ) . public health measures for controlling epidemics may include surveillance, mandatory treatment or vaccination, and coercive social distancing measures such as isolation and quarantine. because measures such as these may conflict with human rights to privacy, consent to medical treatment, and freedom of movement, an ethical dilemma arises. how should the social aim to promote public health be balanced against the aim to protect human rights and liberties in the context of diseases that are to varying degrees contagious, dangerous or deadly? third, because infectious diseases primarily affect the poor and disempowered, the topic of infectious disease is closely connected to the topic of justice, a central concern of ethics. bioethics has not entirely ignored the topic of infectious disease. aids, in particular, has received a great deal of discussion in the bioethics literature. in a related development, public health ethics has become a rapidly growing subdiscipline of bioethics as is evidenced by a number of recent books (coughlin et al. ; beauchamp and steinbock ; gostin ; boylan ; anand et al. ; selgelid et al. ; balint et al. ; dawson and verweij ) and (as of ) a new journal-public health ethics (oxford university press). at least some of this literature has emphasized infectious disease in particular. with the exception of aids, however, bioethics discussion of infectious disease remains in its infancy, and coverage of topics has been patchy at best (tausig et al. ) . much of the emerging literature has focused on sars, pandemic influenza, and bioterrorism in particular. there has also been an increase in relevant debate about intellectual property rights in pharmaceuticals-and the barriers patents pose to medication access in poor countries (schüklenk and ashcroft ; cohen and illingworth ; sterckx ; pogge ; cohen et al. ). tuberculosis (tb) is a bacterial infectious disease that is usually spread by coughing. tb illness is debilitating in the short term; and it is associated with high mortality if untreated, and with significant disability even if successfully cured. whilst pulmonary tb (disease affecting the lungs) is the most common and most infectious form of the disease, tb can affect any part of the body. tb is strongly associated with poverty and is common in less-developed countries, particularly in asia, africa, and south america. there has been a resurgence of tb in relation to the hiv/aids pandemic, particularly in sub-saharan africa (dye et al. ). the public health implications of tb are enormous. until recently tb was the world's leading infectious cause of mortality, and it is now second only to aids. it is surprising and unfortunate that there has not been much focused discussion of ethical issues associated with tb, which is arguably the most important neglected topic in bioethics. because tb kills nearly as many people as aids each year, one would expect tb to receive a proportionate amount of discussion in health ethics literature. there are, furthermore, good reasons for thinking that the problem of tb is even more ethically important than aids. in the vast majority of cases tb drugs can provide cure, and they are much less expensive than aids medications. while . million people die from tb each year (who a) and . million die from aids (unaids ) , the former deaths are, economically speaking, much easier to prevent. a standard course of tb medication can cost as little as us$ or us$ , and tb therapy is considered to be one of the most costeffective health care interventions. in best case scenarios, aids medication costs as little as $ for a year of treatment in developing countries, but it often costs much more. in the case of aids, furthermore, lifelong treatment is required because no cure exists. given cost considerations, the case for increasing access to tb medication appears stronger than the case for increasing access to aids medication (which is not to say that the case for increasing access to aids medication is not itself enormously powerful). in , only % of those in need had access to tb therapy recommended by world health organization (who), and the rate was only % just a few years earlier in (lienhardt et al. ) . there have been impressive gains in access to tb services in many countries in recent years, and approximately % of those in need were receiving treatment in (floyd ). significant gaps remain, however, in many of the countries where tb is most prevalent (dye et al. ) . a final reason for thinking that tb is ethically more important than aids is that the former, being airborne, is both contractible via casual contact and much more contagious. while behavior modification (with respect to iv drug use and sexual practice) can essentially eliminate the risk of infection with aids, tb can be passed from one individual to another via coughing, sneezing, and even talking. in many ways, then, the threat to "innocent individuals"-and public health in general-is greater in the case of tb. though the ethical importance of tb at least rivals, if it does not surpass, the ethical importance of aids; the former has received comparatively little attention from bioethicists. the lack of attention to ethical issues associated with tb is revealed via searches on the internet. a pubmed search of titles and abstracts (conducted in october ) for the terms "ethics" and "aids" yielded , entries; while a similar search for the terms "ethics" and "tuberculosis" yielded only . rather than reflecting difference in ethical importance, the disproportionate amount of bioethics attention to aids in comparison with tb reflects the fact that the former disease has affected an economically powerful and articulate community and has been much more highly politicized. the global tb status quo, meanwhile, is alarming. the world health organization (who) declared tb a global health emergency in . one third of the world population is currently infected with latent tb. approximately nine million people develop active illness each year, and "there are between million and million persons with active tuberculosis at any one time" (gandy and zumla , ) . though a cure for tb has existed for over years, and though in the s tb was believed to be eradicable, tb "is now more prevalent than in any previous period of human history" (gandy and zumla , ) . the tb burden is highest in asia, which accounts for two thirds of the global burden of tb (who b). the southeast asia region has the largest number of new incident cases, accounting for % of incident cases globally. the incidence rate in sub-saharan africa, however, is nearly twice as high-"at nearly cases per , population" (who b) . like most other infectious diseases, the burden of tb is most heavily shouldered by the poor: % of tb cases and % of tb deaths occur in developing countries (gandy and zumla ) . this is because the poor lack good nutrition, and this weakens their immune systems. it is also because crowded living and working conditions, and lack of sanitation and hygiene, increase chances of exposure and infection. because the poor so often lack access to (even inexpensive) medical care, they are more likely to suffer adverse outcomes when infection occurs. direct and indirect costs of illness can have a catastrophic effect on tb sufferers and their families (bates et al. ; jackson et al. ) . matters have been made worse by the growing hiv/aids epidemic. those living with hiv/aids are much more likely to contract tb, and more likely to develop severe illness when they do (harries and dye ) . though the impact of tb is most heavily felt in developing countries, the emergence and spread of multidrug-resistant tb (mdrtb) poses serious threats to developed nations as well. a primary cause of drug resistance is the failure of patients to always complete a full course of tb medication. this often occurs in developing countries when patients cannot afford to continue therapy, cannot afford time off work to visit health providers, or cannot afford travel to clinics. another cause of drug resistance is the weakness of health care infrastructures in poor countries. patients often fail to complete therapy because hospitals and clinics in poor countries fail to maintain a steady supply of standard tb medications (farmer ; farmer ) . drug resistance is also driven by the market presence of drugs that are low quality, old, or often counterfeit. like ordinary tb, drug-resistant tb is contagious. with increased global trade and travel, drug-resistant tb spreads frequently from country to country. though it is usually curable, mdrtb requires longer and more expensive treatment. ordinary tb can be treated with a six month course of medication costing us$ - . mdrtb takes two years to treat, and treatment can be up to times more expensive. the "second-line" medications used to treat mdrtb are, furthermore, both more toxic and less effective than the "first-line" drugs used to treat ordinary tb. the problem of untreatable tb is suddenly on the rise. in , the us centers for disease control and prevention (cdc) and who announced the emergence and spread of "extreme" or "extensively" drug-resistant tb (xdr-tb). mdrtb is defined as tb resistant to at least two (namely isoniazid and rifampicin) of the four first-line tb medications. xdr-tb is defined as tb resistant to at least two of the four first-line tb medications and at least two of the six second-line medications (a fluoroquinolone and an injectable agent; cdc ; who a). a recent study showed that % of tb isolates from around the world were mdrtb and that % of these were xdr-tb. xdr-tb was found in every region, and the study showed that isolates of mdrtb obtained from the usa, latvia, and south korea were, respectively, %, %, and % xdr-tb (cdc ) . the most dramatic epidemic of xdr-tb is currently underway in south africa. a study in march showed that % of suspected patients in tugela ferry were infected with mdrtb and that % of these had xdr-tb. of the patients with the latter, died within days (msf ) . many are worried that xdr-tb may "swiftly put an end to all hope of containing the [aids] pandemic [in africa] through treatment". according to one expert: "there is no point investing hugely in arv [anti-retro viral] programmes if patients are going to die a few weeks later from extreme drug-resistant tuberculosis" (boseley ) . implications of xdr-tb for the international community are starkly revealed by the cdc's conclusion that xdr-tb "has emerged worldwide as a threat to public health and tb control, raising concerns of a future epidemic of virtually untreatable tb" (cdc ) . bioethics research in the context of tb should address the following issues. a common topic in bioethics discussion of infectious disease has been the question of health workers' duty to treat patients infected with diseases that pose risks to health workers themselves. a related question concerns the duty of society, or the health care system, to provide safe conditions for health workers through provision of masks, room ventilation, and other infection control measures in hospitals and clinics. most of the debate has thus far focused on aids, sars, and avian influenza. the existing literature reveals that there are no simple answers to these kinds of questions and that different issues arise in the context of different diseases (reid ) . though these questions are pertinent to tb, given that it is highly contagiousand increasingly dangerous in the context of mdrtb and xdr-tb, and/or when health workers are living with hiv (cobelens )-they have in the specific context of tb received little if any dedicated discussion in mainstream bioethics literature. bioethics should examine the extent of risk involved with treating tb patients; the nature and extent of health care workers' "duties" to face such risks; possible means (and ethical justification) for reducing such risks through improvement of infection control in health care settings; and the propriety of rewarding health workers willing to face greater risks (savulescu, in discussion) and/or the propriety of compensating those who actually become infected on the job (university of toronto joint centre for bioethics ). a major topic of debate in the context of hiv/aids research has been the question of what should count as an ethically acceptable control arm in studies involving human subjects. most of the attention has focused on placebo controlled studies of mother-tochild transmission of hiv in africa. critics argued that these studies conflicted with the declaration of helsinki requirement that patients in the control arm of a study should receive the "best proven" or "best current" therapy for the condition in question (lurie and wolfe ) . others argued that it would have been too expensive to provide such treatment in developing world contexts-and that no harm was done because patients were denied no treatment they would have received if they had not participated in the studies (because the standard of care in poor countries was no treatment to prevent vertical transmission of hiv). given that the who has recently declared that the standard of care for mdrtb requires provision of second-line drugs, it will not be surprising, given what commonly occurred in the context of hiv, if there are proposals for studies where control arm subjects would not receive this expensive, high level of care (apparently) still required by the declaration of helsinki. would it be wrong to deprive control arm subjects of second-line drugs if they would not receive them if they did not participate in the study in question-given the poverty situation in the local context? how are the ethical issues in the context of tb similar to, or different from, those that arose in the context of hiv/aids? another issue arising in clinical research involves the management of third-party risks. a study of a new drug for resistant strains of tb, for example, may pose risks to third parties. if the investigational drug is not effective, then a patient-subject who receives it may remain infectious and thus endanger family members and other close contacts. isolation of the patient-subject or informed consent of third parties might thus be called for. this general issue has been neglected by research ethics guidelines (francis et al. ). there have been reports of prescription practices in poor countries where health workers decide to exclude tb patients from treatment in cases where it is believed that the patient is unlikely to complete therapy (singh et al. ) . while withholding treatment from unreliable patients may serve the aim to avoid promotion of drug resistance, a practice like this may be inappropriately discriminatory. such a practice may also have counterproductive results if infectious patients remain at large in the community. because the ability of health workers to make sound judgments about such matters is suspect, the extent and quality of institutional policy calling for patient exclusion warrants further analysis. in addition to concerns about unjust discrimination, a major question is whether or not, or why, it is reasonable to think that the harm to excluded individuals would be outweighed by greater goods to society in the way of public health. these are partly, though not entirely, empirical questions-i.e., about what the actual harms and benefits are (to individuals and society, respectively). the more ethico-philosophical question is how benefits to society should be weighed against harms to individuals. if there is a duty to do no harm, then infected-or potentially infected-persons have duties to avoid infecting others (harris and holm ; verweij ) . this interesting and important topic has received surprisingly little attention in general, and discussion to date has primarily focused on aids and influenza. bioethics should examine the extent to which a duty like this applies in the context of tb in particular. because it would be unreasonable to expect potentially infected persons to take all possible measures to avoid infecting others, appropriate limitations to the duty must be considered. because tb is transmissible via casual contact, anyone who has been breathed or coughed on by someone who might (for all one knows) be infected with tb should, epistemologically speaking, consider herself to be "potentially-infected". but that means almost all of us! (this is just one of the ways in which the case of tb is different from aids.) even those who actually have been in (limited) contact with someone sick with active tb, however, will usually not themselves become infected as a result. though potentially deadly and considered highly contagious, tb is not nearly so contagious as the flu. (this is just one of the ways in which the case of tb is different from flu.) to what extent should someone who knows she has been exposed to tb limit her interactions with others afterwards? the answer will partly depend on whether we are talking about ordinary tb, mdrtb or xdr-tb-if these details are known. in cases where a contagious patient fails to take adequate precautions to avoid infecting others-and fails to warn close contacts about his infectious status-then the question of whether or not the health worker should inform identifiable third parties at risk arises. on the one hand, notification of third parties about a patient's health status would breach the widely acknowledged patient right to confidentiality. on the other hand, failure to warn could (especially in the context of xdr-tb) conflict with the innocent third party's right to life-which many would say is more important than the incautious patient's right to confidentiality. this matter is complicated because a routine practice of breaching confidentiality may decrease trust in the health care system, reduce health-seeking behavior, and thus drive the epidemic underground. what the actual public health implications of third-party notification would be is an empirical question that warrants further study. mandatory tb testing in schools, the workplace, or elsewhere in the community may potentially conflict with the right to privacy. if information concerning the health status of individuals is not well protected, then stigma and discrimination will result. surveillance measures, on the other hand, are sometimes important to the protection of public health. bioethics should consider the extent to which current surveillance measures are-or the extent to which more wide-reaching surveillance measures would be-justified in the context of tb, especially now that mdrtb and xdr-tb are growing threats to global public health. it is common for countries to screen migrants for tb before granting entry visas. some have questioned the public health efficacy and/or cost-effectiveness of a practice like this in comparison with other means of tb control (coker ) . whilst identification of active disease offshore is a commonly used method for tb control in countries with a low prevalence of tb (and sometimes countries with high prevalence), it is not always possible to perform due to the lack of resources or a lack of time prior to arrival (coker ) . additionally, one-off screening for tb with x-ray does not completely eliminate the risk of tb transmission to the public in the receiving nation due to the lifetime latency of the disease (macintyre et al. ) . the offshore tb screening policy relies on a "user pays" philosophy, where visa applicants are responsible for the costs incurred. aside from questions of equity, where the poor who are most likely to have tb are also least likely to be able to pay for the screening tests, this model works well when a private sector health system is in operation. the international organization for migration (iom) has called for a "paradigm shift from exclusion to inclusion" to address this, amongst other unintended effects of premigration screening for the benefit of the migrant and the host nation (maloney ) . in many countries from which refugees are resettled, there are no private for-profit radiological or microbiological facilities and government clinics are stretched to capacity. is it appropriate for developed countries to shift costs for their public health onto the overburdened health systems of other, less well-resourced, countries? additional ethical issues arise in the context of asylum seekers. this form of migration has posed enormous problems in the northern hemisphere. in situations like this, host countries' duties of beneficence potentially conflict with duties to protect public health. ethical issues associated with migrant screening in the context of infectious disease are a generally neglected area of discussion that is becoming increasingly important in the contemporary era of "globalisation" and "emerging infectious diseases". these issues are especially pertinent in the context of tb. in the past, patients with infectious tb were isolated in sanatoria for prolonged periods-and sometimes even for life. this was done to protect others from infection. even today, in many countries, it is common to isolate patients with pulmonary symptoms (i.e., "active tb") until they are deemed uninfectious-usually about two weeks after therapy is started. such detention is usually brief and voluntary. it is common, however, to coercively confine patients with active tb, and sometimes patients with inactive tb, when they refuse to take their medicine or when it is believed they are unlikely to adhere to treatment regimens (coker ) . bioethics should consider the extent to which (coercive) restriction of movement is ethically justified in the name of public health protection against tb. of particular importance is the question of what should be done with xdr-tb patients, who pose threats of infection with an especially dangerous form of tb whether they take their medicines or not. defenders of confinement in the context of treatable tb sometimes suggest that confinement is justified when patients are at least given a choice between confinement and treatment-the idea being that this respects their autonomy (bayer and dupuis ) . if xdr-tb patients are confined because they are untreatable, then no autonomous choice would remain. though this does not go to show that mandatory confinement is therefore inappropriate, the point is that the question of what to do with xdr-tb patients is not automatically settled by conclusions about what to do with noncompliant patients with treatable tb. additional new questions are whether or not, the extent to which, or the conditions under which, it would be ethical to quarantine the large number of people exposed to, though not known to be infected with, xdr-tb-or those suspected, though not known, to be infected with xdr-tb (singh et al. )-while diagnostic confirmation is awaited. coercive long-term confinement may again become common in the case of patients actually diagnosed with (untreatable) xdr-tb. in a widely reported case in arizona, for example, an xdr-tb patient has been detained in a prison hospital for over a year (democracy now ) . and there are already calls in africa for a return to compulsory sanatoria for such patients (sakoane ) . if the spread of untreatable xdr-tb becomes sufficiently alarming, we may be faced with quarantine and confinement at a scale not seen for decades. in a patient suspected of infection with xdr-tb was subjected to the first us federal isolation order since . among other questions, the following should be further considered: ( ) the extent to which coercive social distancing measures are justified in light of the available evidence (or lack thereof) regarding their efficacy and ( ) arguments calling for compensation provision to those whose liberties are coercively restricted. it is true that untreatable tb was the norm prior to development of cures in the middle of the th century, and we should examine historical debates regarding the social acceptability of confinement and so on that took place in public health circles in the pre-antibiotic era. no developed discipline of bioethics existed at that time, however, and so it remains to be seen how policy decisions made then will be viewed under the lens of rigorous ethical analysis. more importantly, given population growth and globalization, the contemporary world is different from that when untreatable tb previously existed. because population dynamics have changed, there is no reason to assume that public health solutions to untreatable tb in the past (even if it is determined that such policies were ethically and epidemiologically sound at the time) will be appropriate to the contemporary world. as indicated above, it is commonly the case that (treatable) patients are required to either undergo therapy or be held in confinement. insofar as the threat or actual use of force is involved, tb treatment involves coercion and thus conflicts with individual autonomy (despite the fact that patients are usually given at least some choice in the matter). the worldwide standard of care for tb treatment is known as directly observed therapy, short course (dots). among other things, dots involves health or social workers' observation of patients' medication-taking; and patient cooperation is (often) part of what is required to avoid detention. though dots has (arguably rightly) been hailed as a great success in global tb control (partly because it promotes patient "compliance" and thus helps prevent drug resistance) ethical issues are raised by the coercion involved. it is generally thought that informed consent to medical treatment is important-and that it must be voluntary. autonomy, however, may be outweighed by societal benefits if the stakes are sufficiently high. additional issues involve threats to privacy and dangers of stigmatization in contexts where dots practices are visible to the community; and the costs/ inconvenience of dots in comparison with unmonitored treatment (especially when we are talking about reliable patients). though issues associated with mandatory treatment and dots have perhaps received more bioethics attention than others considered in this chapter, much of the debate to date has focused on the limited context of new york city in the s and s (see bayer and dupuis and reference therein) . coercion is also involved in attempts to remove mycobacterium bovis ("bovine tb") from the food supply in rich countries by culling infected herds and pasteurizing milk. in part this is done to increase the safety and value of bovine (or ovine and other herbivore) products, especially milk and cheese. in poor areas of the world with ongoing high rates of tb among cattle or buffalo and use of raw milk products, bovine tb still causes much disease among humans, usually as an extrapulmonary infection of the throat (scrofula), stomach, abdomen or bones. although control of animal tb may seem to be of obvious benefit to a community, the affected farmers may object to testing and culling of their infected animals, even when paid compensation, if herds cannot easily be replaced with disease-free equivalents. also, farmers may be emotionally attached to the animals, especially dairy cattle, the main target for control of bovine tb. another issue arises with compulsory pasteurization of milk. some people even break the law to exercise their "right to consume natural products". how important are these liberties-and are they outweighed by public health benefits requiring coercion? again these are, but only partly, empirical issues. as a disease of poverty, tb raises issues of international distributive justice. though sufficient resources for health improvement are lacking in poor countries, there are numerous powerful moral (egalitarian, utilitarian, and libertarian) and self-interested reasons for wealthy nations to do more to help improve health care in poor countries (selgelid onlineearly ) . these issues are complex and intertwined with the above questions regarding liberty violating public health measures. if health care provision and thus global health were better to begin with, for example, then the occasions upon which liberty infringing public health measures are called for would arise less often. in addition to improving access to existing medications, increased r&d for drugs and diagnostics is sorely needed in the fight against tb. at present, "[w]orldwide only $ million is spent annually for clinical trials for tb drug[s] compared to around $ million for hiv drugs in the us alone" . bioethicists should debate recent proposals (pogge ; kremer and glennerster ) and current activities (moran et al. ) aimed at stimulating r&d on neglected diseases-and the extent to which they are apt for tb in particular. they should also examine the extent to which targeted funding for tb control is warranted in comparison with other infectious diseases. because it has been argued that donor aid should aim to improve developing countries' general health care infrastructures-and improvement of general health indicators-rather than targeting particular diseases such as aids and tb (garrett ) , the propriety of targeted tb funding should be evaluated. because infectious diseases, including drug-resistant infectious diseases such as xdr-tb, fail to respect international borders, bad health in poor countries threatens global public health in general. the strength of associated self-interested reasons for wealthy nations to help reduce tb in poor countries (through targeted or untargeted funding) should therefore, finally, be a major focus of analysis. our recommended approach to ethics and infectious disease may be characterized as "moderate pluralism". this approach aims to identify the plurality of (intrinsic) values at stake in the context under study and strike a balance between potentially conflicting values without giving absolute priority to any one value in particular. in the context of xdr-tb, for example, the utilitarian aim to promote public health might best be promoted through coercive confinement of infected patients. such a policy, however, would conflict with apparent rights and liberties of infected individuals; and it is not generally believed that individual rights and liberties should be sacrificed whenever this would promote the greater good of society. resolving a conflict like this requires assessment of the overall threat to society, assessment of the centrality/importance of the rights under threat, and consideration of features that might make one value (i.e., utility) or the other (i.e., liberty) especially important in the context in question. most ethicists, policymakers, and ordinary citizens would, upon reflection anyway, deny that either of these two social values should always be given absolute priority over the other. the ideal solution to conflict between values is to bypass the conflict to begin with. we should thus, whenever possible, aim for a policy that promotes both utility and liberty-and also equality, another legitimate social value-at the same time. tb reduction via increased health care provision would reduce the frequency of occasions where we are faced with the conflict between utility and liberty under consideration; and it would likely also promote equality (given that tb reduction would generally involve improving the situation of those who are worst off). this is not to say that the initially considered conflict would never eventuate if tb reduction occurs. difficult decisions will need to be made in cases where conflict is unavoidable; and a principled rationale for favoring one value over another is needed in cases of conflict. one idea is that the aim to promote utility should be weighted more heavily as a function of the extent to which utility is threatened. another idea is that the weight of a right/liberty should be weighted as a function of its centrality. more basic rights/liberties deserve more protection than others. when catastrophe would result from protection of the most basic rights, however, then even these must be compromised. we sometimes think it is appropriate to violate the most basic right of all-i.e., the right to life in time of war. when rights violations are found to be necessary in the context of tb, amends can be made by compensating individuals whose rights are compromised (ly et al. ). the living conditions of those confined should be made as comfortable as possible-and those who succumb to liberty restrictions should perhaps receive additional (e.g., financial) rewards. it would be unfair to expect coerced individuals to shoulder the entire cost of societal benefit. if a net social dividend results from liberty infringement, then part of this should be returned to the victims of coercive social policy. this is a matter for reciprocity (university of toronto joint centre for bioethics ). public health, ethics, and equity vulnerability to malaria, tuberculosis, and hiv/aids infection and disease. part : determinants operating at individual and household level tuberculosis, public health, and civil liberties new ethics for the public's health global alert over deadly new tb strains public health policy and ethics. dordrecht: kluwer. cdc . emergence of mycobacterium tuberculosis with extensive resistance to second-line drugs-worldwide tuberculosis risks for health care workers in africa the dilemma of intellectual property rights for pharmaceuticals: the tension between ensuring access of the poor to medicines and committing to international agreements the power of pills: social, ethical, and legal issues in drug development, marketing and pricing tuberculosis, non-compliance and detention for the public health asylum and migration working paper : migration, public health and compulsory screening for tb and hiv case studies in public health ethics ethics, prevention, and public health is sickness a crime? arizona man with tb locked up indefinitely in solitary confinement did we reach the targets for tuberculosis control infections and inequalities: the modern plagues pathologies of power: health, human rights, and the new war on the poor global progress towards the tb control targets (with a special attention to tb/ hiv and mdr-tb) how infectious disease got left out-and what this omission might have meant for bioethics infectious disease and the ethics of research: the moral significance of communicability the resurgence of disease: social and historical perspectives on the 'new' tuberculosis the challenge of global health public health law and ethics is there a duty not to infect others? poverty and the economic effects of tb in rural china strong medicine rethinking the social context of illness: interdisciplinary approaches to tuberculosis control unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries pandemic and public health controls: toward an equitable compensation system missed opportunities for prevention of tuberculosis in victoria national migration health policies: shifting the paradigm from exclusion to inclusion. iom's international dialogue on migration, seminar on health and migration the new landscape of neglected disease drug development extensive drug resistant tuberculosis (xdr-tb) no time to wait human rights and global health: a research program the health of nations: infectious disease, environmental change, and their effects on national security and development diminishing returns? risk and the duty to care in the sars epidemic the distribution of biomedical research resources and international justice xdr-tb in south africa: back to tb sanatoria perhaps? affordable access to essential medication in developing countries: conflicts between ethical and economic imperatives ethics and infectious disease improving global health: counting reasons why . ethics and infectious disease xdr-tb in south africa: no time for denial or complacency tb control, poverty, and vulnerability in delhi are there characteristics of infectious disease that raise special ethical issues? patents and access to drugs in developing countries: an ethical analysis taking sociology seriously: a new approach to the bioethical problems of infectious disease aids epidemic update stand on guard for thee: ethical considerations in preparedness planning for pandemic influenza obligatory precautions against infection the stop tb strategy. geneva, world health organization. who global tuberculosis control: surveillance, planning, financing. who report. geneva, world health organization we thank the brocher foundation in hermance, and the institute for biomedical ethics at the university of geneva, in switzerland, for hosting the lead author as a visiting researcher during the period this chapter was written. key: cord- -in r ww authors: nan title: the way forward: prevention, treatment and human rights date: journal: global lessons from the aids pandemic doi: . / - - - - _ sha: doc_id: cord_uid: in r ww there now is a considerable body of evidence to support the view that an effective hiv/aids strategy integrates prevention, treatment and human rights. in this chapter, we emphasize the importance of each of these aspects and draw upon the conclusions reached in previous chapters to map out the future of hiv/aids. while medicine and science have a crucial role to play in addressing pandemics, whether slow-moving (like hiv/aids) or fast-moving (like influenza), the social, legal, political, financial and economic ramifications of pandemics can not be ignored. well-considered social, legal, political and financial strategies are essential in order to address any pandemic effectively. united kingdom kingdom - source: global hiv prevention working group ( ) in chap. , we discussed how integrated prevention-treatment-human rights strategies aimed at high-risk groups have proved effective in countries like brazil. in chap. , we explained that limited resources need to focus on high-risk groups and locations to achieve the best possible results. however, as we showed in the sex workers, who are the source of almost % of hiv infections, a negligible amount of funding for hiv/aids is targeted at this group. the mismatch between the most affected group and the allocation of funding in ghana highlights the importance of matching funding to prevailing prevalence and transmission patterns in a given country or region. as we saw in chap. , an hiv prevalence rate above % is a key threshold for an hiv epidemic to run out of control unless funding for prevention efforts is targeted at high-risk groups, such as commercial sex workers, men who have sex with men, injection drug users and prisoners. however, in chap. we saw that pepfar -the largest bilateral donor of funding for hiv/aids programs in developing countries -prohibits the use of funding for programs for commercial sex workers and needle exchange programs. in chap. , we saw that african-americans make up % of hiv/aids patients, even though african-americans account for less than % of the us population. moreover, black men who have sex with men (msm) have the highest rates of unrecognized hiv infection, hiv prevalence and incidence rates and aids mortality rates among msm in the united states. in five us cities, % of african-american msm are infected with hiv. hiv and aids prevalence rates have affected black msm disproportionately since the beginning of the epidemic. black msm are the only group in the united states with hiv prevalence and incidence rates that are comparable to those in the most affected developing countries. however, the vast majority of hiv prevention intervention for african-americans does not target homosexual men and for homosexual men does not target black msm (millett and peterson ) . thus, the need to focus prevention efforts on the most vulnerable groups remains an issue not just in developing countries. while prevention strategies need to be tailored to the sources of hiv infections in specific contexts, there are several proven prevention strategies that need to be scaled up. the resources for prevention need to be focused according to the specific nature of the epidemic in different settings, as we showed in chap. . figure . shows the source of new hiv infections by region. table . summarizes the coverage levels of several essential prevention strategies and fig. . shows their deployment by region. it is important to emphasize that prevention and treatment are mutually supportive and need to be addressed simultaneously. access to treatment supports prevention by reducing risky behaviors, increasing disclosure of hiv status, reducing stigma and reducing infectiousness (global hiv prevention working group ) . prevention supports access to treatment by reducing the number of people that require treatment, thus making universal access to treat- group ( ) order to enhance the effectiveness of both. ment more affordable. hiv treatment and prevention should be integrated, in hiv prevention strategies fall into four general categories: ( ) prevention of sexual transmission; ( ) prevention of blood-borne transmission: ( ) prevention of mother-to-child transmission; and ( ) social strategies. the strategies for preventing sexual transmission are: ( ) behavioral change programs (to increase condom use, to delay the initiation of sexual behavior in young people and to reduce the number of sexual partners); ( ) condom promotion; ( ) hiv testing (knowledge of hiv status decreases risky behavior); ( ) diagnosis and treatment of sexually transmitted infections (which significantly increase the risk of hiv acquisition and transmission, particularly in the case of genital herpes); and ( ) adult male circumcision (which reduces the risk of female-to-male transmission by about %) (global hiv prevention working group ) . the effectiveness of these strategies varies. the promotion of condoms has been largely successful with respect to commercial sex and casual sex, but condom use remains low within marriage. as we noted in chap. , increasing life expectancy, in areas where it is low due to diseases like malaria, is a cost effective strategy for enhancing behavioral change to lower the risk of hiv infection. a survey by the who, on behalf of the global fund, reviewed anti-malaria operations in ethiopia, ghana, rwanda and zambia. in ethiopia, childhood malaria declined by % and the death rate was cut in half within years of the beginning of the mass distribution of mosquito nets. within a single year, both cases and deaths dropped by twodeaths by a third. in many cases, the distribution of free nets was accompanied by free drugs based on artemisinin, a substance to which the malarial parasite has yet to develop widespread resistance, and spraying ddt inside people's houses. free nets and malaria drugs would bring malaria under control in most of africa at a cost of usd billion (economist ) . these promising results also bode some studies suggest that treating sexually transmitted infections may not rediseases. moreover, as we noted in chap. , oster ( ) argues that the explanation for the substantial difference in the transmission rates between the united tions, which leave open sores from chlamydia, syphilis and gonorrhea that facili-there is significant evidence that male circumcision significantly reduces hiv a similar picture is seen in south and south-east asia, where overall hiv prevalence is much lower, but the countries with highest hiv prevalence have little thirds, in rwanda, and one-third in zambia. in ghana cases fell by an eighth and based on these results, the who believes that a -year campaign that distributes well for hiv prevention. association between the risk of infection with hiv and other sexually transmitted prevent as many as % of new infections over a decade duce hiv transmission significantly (halperin ) . however, there is a strong transmission. box . discusses the relationship between circumcision and hiv/ tate hiv transmission. thus, treating bacterial sexually transmitted infections could states and sub-saharan africa is due to other untreated sexually transmitted infec-male circumcision (papua new guinea, cambodia and thailand) . conversely, hiv prevalence is extremely low in those countries where most men are circumcised (pakistan, bangladesh, indonesia and philippines). there is ecological evidence that prevalence of circumcision is negatively correlated with prevalence of hiv/aids. specifically, there is a strong inverse correlation between the prevalence of circumcision in countries and the prevalence of hiv in those countries. all the highest hiv prevalence countries are those where circumcision is little practiced. in fact, no country with nearly universal circumcision coverage has ever had an adult hiv prevalence higher than %, including higher risk than that in countries with prevalence of around %. this fact is illus- fig. . ecological relationship between circumcision and hiv prevalence. source: bailey ( ) a large, randomized controlled trial in , men between the ages of and years showed that circumcision resulted in a significant % reduction in hiv vulnerability to hiv varies considerably from one epidemic to the next, as do the issues facing vulnerable groups. for example, in a concentrated epidemic, such as in asia and latin america, hiv transmission occurs primarily among vulnerable groups and prevention programs targeted at vulnerable groups would reduce infection (auvert et al., ) . these results were confirmed by two other trials. the way forward prevention, treatment and human rights trated in fig. . . countries such as cameroon, where a survey found sexual behavior to be overall infection. however, in a generalized epidemic, such as in several countries groups, halperin ( ) argues that transmission would continue unabated despite prevention programs targeted at vulnerable groups. however, as we noted in chap. , research regarding the relationship between trade routes, truckers, sex workers and hiv propagation contradicts this idea. in a generalized epidemic, where hiv is spread along trade routes, prevention programs targeted at truckers and sex workers would be effective in bringing down the growth rate of the spread of the disease. having multiple sex partners increases the risk of hiv infection in both concentrated and generalized epidemics, but the impact of this factor on hiv prevalence rates can vary considerably. for example, even though the united states and uganda have similar rates of multiple sex partners, and the number of sexual partners that men and women had over a -year period were much higher in the united states than in uganda, uganda's hiv/aids prevalence rate was about times higher than that of the united states (halperin ). however, as we noted in chap. , a recent study indicates that abstinence-only programs are as effective as providing no information at all when it comes to preventing pregnancies, unprotected sex and sexually transmitted diseases. abstinence-plus interventions, which promote sexual abstinence as the best means of preventing hiv, but also encourage condom use and other safer-sex practices, are more effective than the proven strategies for preventing blood-borne transmission are: ( ) to supply injection drug users with clean injection equipment; ( ) methadone or other substitution therapy to reduce drug dependence; ( ) blood safety programs, including screening of donated blood; and ( ) infection control in health care settings, including injection safety and antiretroviral treatment following exposure to hiv. as we noted in chap. , the risk of aids infection through the use of blood products was recognized as early as , but countries were slow to adopt measures to ensure the safety of the blood supply and the world health organization (who) passed a resolution on blood products that made no mention of aids as late as january . in the s, chinese health authorities promoted bloodselling by poor farmers to commercial blood collection centers, despite warnings from the who, spreading hiv/aids through the blood fractionation and reinjection process. in , new hiv infections through hospital blood transfusions continued to be reported in china, and illegal underground blood collection centers have continued to operate. box . recounts the story of the libyan scandal over blood-borne transmission to children. in southern africa, where hiv transmission occurs primarily outside vulnerable abstinence-only programs (underhill et al., ) . on december , , sixth sense productions, inc., an independent holly-snezhana dimitrova, valentina siropulo) and a palestinian medical intern (ashraf ahmad djum'a al-hadjudj) who were jailed in libya and faced the death penalty for allegedly infecting children with hiv. this news item is a postscript to a long international drama that began to unfold in when the medics were arrested on charges of injecting libyan children with hiv-tainted blood while at a benghazi hospital. of them, over had died by the end of . one important report was submitted by luc montagnier and vittorio colizzitwo leading experts on hiv/aids. their report concluded that the infection at the infections began before the arrival of the nurses and doctor in . through hospital records, and the dna sequences of the virus, they traced it to patient n. who was admitted times between and in ward b, iso and ward a. the first cross-contamination occurred during that patient's admission. montagnier and colizzi both testified in person at the trial of record for the defense. on that the strain of virus was already present before the arrival of the six accused. the accused were tried and retried. the libyans had signed confessions from them -which the accused said were extracted under torture. the final verdict in sentenced them to death by firing squad. the libyan president likened the scotland for the bombing of pan am flight over lockerbie, scotland, on and political favors in exchange for the release of the six. in the end, bulgaria, qatar and a group of european countries funneled usd million into the international fund benghazi to finance the treatment of the hiv-infected children and the improvement of the libyan health care system. france played a pivotal role in the final release of the accused. in exchange for the release, france agreed to sell antitank missiles and nuclear technology to libya. it was a win-win deal for france: they did multi-million dollar business with libya and got publicity for helping the release of the accused. when the nurses returned to bulgaria, the government endorsed a , leva reimbursement for each of the nurses. a bulgarian mobile telephony provider donated an apartment for each nurse. the way forward prevention, treatment and human rights december , nature ( , - ) published a report that also concluded wood producer, announced plans to make a usd million movie about five event to the case of abdel basset ali al-megrahi, who is serving a life sentence in hospital resulted from poor hygiene and reuse of syringes. they concluded that the bulgarian nurses (kristiyana vulcheva, nasya nenova, valya chervenyashka, december . thus, it became clear that libya was trying to extract economic the proven strategies for preventing mother-to-child transmission are: ( ) general hiv prevention for women of child-bearing age; ( ) a brief course of antiretroviral treatment in advance of delivery (which can reduce transmission by %, but is only received by an estimated % of women in need); ( ) prevention of undesired pregnancy in hiv-positive women; ( ) breast-feeding alternatives; and ( ) cesarean delivery where the mother has a high viral load (global hiv prevention working group ) . in developing countries, a small but growing number of children are dying of hiv/aids. as fig. . shows, some % of children died of hiv/aids in . hiv infected mothers carry additional risks for the baby. in table . , we indicate some of the major risks. some risks like stillbirth or high infant mortality have been found only in developing countries but not in developed countries. for these additional risks, it has been suggested that one way of eliminating vents mother-to-child transmission by %. thus, family planning could also help to reduce mother-to-child transmission: o t h e r ( % ) mother-to-child transmission is not to have the baby in the first place. this pre-another often neglected aspect of hiv prevention -one prohibited from funding by the bush administration's international aids programinvolves expanding family planning services, including for hiv-positive women who do not want to conceive. reducing unintended pregnancies could greatly decrease the number of infected infants as well as the number of children who eventually become orphans (halperin ). if an hiv-positive woman gives birth to a child, there is a risk of transmission of hiv itself, in addition to the other risks listed in table . . however, the transmission risk of hiv from mother to child is not %. it can be minimized through drug treatment of the mother and careful birthing. figure . clearly demonstrates this fact, using the data from the united states. the introduction of zidovudine (for the mothers before childbirth) has dramatically reduced the risk of hiv infection of the baby. since , most countries have applied a regimen of zidovudine from weeks, with nvp administered during labor and to the baby, and the addition of a day zidovudine/lamivudine postpartum regime. the result has been a dramatic reduction of infected newborns (see fig. . ). note that the reduction has been evident in europe and the united states since , when this regime was introduced. in thailand, the regime was introduced in and in most parts of africa years later. once a child is born, the question is whether the infected mother should breastfeed the child. on the one hand, unaids estimated that globally there are , babies infected through breastfeeding. on the other hand, the unicef estimates that , , children die every year from lack of breastfeeding by the breastfeed the baby. key factors that increase vulnerability to hiv include: ( ) gender inequality (which reduces women's access to information and services, reduces power to negotiate safe sex with partners, increases the risk of sexual violence and may create the need to depend on sex for economic survival); ( ) institutionalized discrimination against vulnerable groups (such as criminalizing drug use and needle possession, commercial sex work and sex between men); ( ) poverty (which reduces access to information and services and access to prevention tools, such as condoms); ( ) hiv stigma (which discourages individuals from seeking testing, disclosing their status, seeking hiv-related services or using alternatives to breast-feeding); and formation and social support by displacing populations and increase the risk of sexual violence) (global hiv prevention working group ). as we noted in chap. , there is no clear evidence that reducing poverty and income inequality will necessarily reduce hiv/aids prevalence. moreover, povcondoms and circumcision. significant percentage of men who have sex with men are hiv-infected in many africa; % in guyana; % in st. petersburg, russia; and % in urban ethiobetween vulnerable groups and the general population in bangladesh. the linkages between vulnerable groups, and between vulnerable groups and the general social strategies that address the factors that increase vulnerability to hiv innities and hiv-positive individuals in hiv/aids programs; ( ) visible political leadership; ( ) engaging a broad range of sectors in hiv awareness and prevention the way forward prevention, treatment and human rights hiv/aids prevention strategy. thus, if poverty reduces access to information and parts of the world ( % in bangkok; % in phnom penh; . % in urban sene-vulnerable groups are not compartmentalized. people infected through injection drug use can infect their sexual partners. a significant percentage of men who their clients, who in turn may infect their spouses or other sexual partners. in would be to find innovative ways to improve access to information, provide funding measures; ( ) gender equity initiatives to empower women; ( ) involving commution working group ). human rights are the core of most social strategies to gal; and % of african-american men in five us cities). sex workers can infect many areas, sex workers have very high rates of hiv infection ( % in south have sex with men also have sex with women (for example, % in asia) and a ( ) conflict and humanitarian emergencies (which reduce access to services, inerty reduction is too broad a goal to constitute what might be considered a concrete programs; and ( ) legal reforms to support hiv prevention strategies, such as laws clude: ( ) hiv awareness campaigns, including in the mass media; ( ) anti-stigma services and access to prevention tools, such as condoms, a concrete policy response to enhance access to services and provide free access to prevention tools, such as pia) (global hiv prevention working group ). figure . shows the linkages decriminalizing needle possession and anti-discrimination laws (global hiv preven-population, make effective prevention strategies for vulnerable groups essential. awareness of hiv status has a significant impact on rates of hiv transmission. when unaware of hiv seropositivity, the transmission rate is estimated at . - . the transmission rate to an estimated . - . % (holtgrave ). however, inorder to balance the need for more testing with the need to respect human rights, it has been recommended that health care providers offer and recommend hiv testing, in conjunction with counseling (the opt-in approach), rather than rely on the client to initiate this process. however, mandatory hiv tests and routine hiv testand confidentiality (jürgens ). the major barriers to increasing hiv prevention are: ( ) failure to target limited funding where it will have the greatest impact, due to ing unless the client opts out risk violating individuals' rights to informed consent lack of information on the nature of the epidemic or ideological, non-scientific creasing access to hiv testing and counseling also raises human rights issues. in increases in funding; ( ) failure to integrate hiv prevention in schools, workplaces and other health care programs, such as tb and reproductive health; and ( ) stigma and discrimination against hiv-positive people and vulnerable groups, which deter people from seeking testing and prevention services and discourage political leadership (global hiv prevention working group ) . we analyze the problems and solutions regarding stigma and discrimination against hivpositive people and vulnerable groups later in this chapter. we analyzed the issues of inadequate financing, targeted financing and donor coordination in chap. . as we noted in chap. , a lack of donor coordination is an obstacle to expanding treatment and prevention programs, due to the administrative burden that it imposes on recipients. as we noted in chap. , the us government's foreign aids program, pepfar, devotes only % of funding to prevention and requires that two-thirds of that amount be spent on abstinence-only programs that do not promote condom use, despite evidence that this approach to prevention is not effective and undermines best practices. pepfar guidelines also undermine hiv/aids prevention by further stigmatizing sex workers and prohibiting funding of needle exchange programs, despite evidence that such harm reduction programs are effective. the pepfar approach assumes that vulnerable groups do not interact with the rest of society. pepfar is perhaps the best example of ideological, non-scientific restrictions on the use of donor funding, although it also serves as an example of two of the other significant barriers to hiv prevention, due to its promotion of stigma and discrimination against vulnerable groups and the percentage of funding that it allocates to prevention. however, it is important to emphasize that pepfar has done more than any other bilateral funding program to address the need for adequate financing. the key point is that the money that has been made available through pepfar could be better spent. on december , us president bush signed legislation that lifted a ban that had made washington, dc the only us city barred by federal law from using municipal money for needle exchange programs. officials of the district of columbia health department planned to allocate usd million for such programs in (urbina ) . extending this change in policy to pepfar would enhance the effectiveness of prevention programs in the countries that receive pepfar funding. in chap. , we provided an overview of the history of drug developments to treat hiv/aids and saw the dramatic impact on survival of triple combination therapy. without this treatment, the chance of surviving years was about %. with this treatment, patients have a % chance of living another years. in the early s in the united states, the leading causes of death among - old year men come the leading cause of death in this group. following the introduction of universal access to triple combination therapy, deaths from aids fell to fourth place, behind accidents, cancer and homicide. as a result, whereas % of americans considered hiv/aids to be the most urgent health problem facing the united ents became so important, as we saw in chaps. and . this is also why access to there are five classes of anti-hiv drugs, which are known as antiretroviral verse transcriptase inhibitors (nnrtis), which began to be approved for use in , stop hiv from replicating within cells by inhibiting the reverse transcriptase protein. ( ) fusion or entry inhibitors prevent hiv from entering human immune sert its genetic material into human cells (http://www.avert.org/introtrt.htm). hiv-positive people are prescribed antiretroviral therapy once the number of cd cells falls below a certain threshold or when they develop clinical aids , an international panel of experts continued to recommend these guidelines in low-and middle-income countries, which represents % of those in need (who/unaids progress report on universal access to treatment). the " by lion people on arv therapy by the end of . during this period, the number of people in low-and middle-income countries receiving arv treatment increased from , to . million (who ) . and human resources, management capacity and the ability to identify new patients through testing and counseling (chai ) . in chap. , we examined multilateral funding programs that address these capacity constraints in developing ing treatment are just that -estimates. as we have noted, unaids hiv/aids estients that have been identified as requiring treatment. the reluctance of the united states to allow pepfar funding to be spent on who-approved drugs has also been criticized as an obstacle to expanding treatturer, cipla, created a triple-combination drug in a single pill (triomune) that could be taken twice daily, which it offered to sell for about usd per patient per year in . cipla's triomune offer made the by initiative a realizable goal and cipla has the production capacity to produce four million doses of triomune per day. the who approved triomune in december as a first-line treatment for hiv/aids (hamied ) . the pepfar restriction on the use of who-approved drugs had the effect of preventing the use of pepfar funding to buy triomune. moreover, the majority of pepfar funds have been used to purchase patented versions of hiv/aids drugs, rather than generic versions (see chap. ). figure . shows how generic competition has lowered the cost of triple combination antiretroviral therapy. between and , the price of the generic drugs has brought down the price of the originator substantially -from over usd , to under usd . at the same time, the generic prices have stayed in the - % range of the originator price. pepfar funds can be used to purchase other low-cost generic equivalents of several patented hiv/aids drugs, including some produced by cipla. pepfar requires that generic drugs be approved by the us fda, canada, japan or western europe to be eligible for funding (see chap. ). if us fda approval is sought for fixed dose combinations of previously approved antiretrovirals for the treatment of hiv, if one or more of the approved drug components are covered by a patent, the fda cannot approve an application until the patent expires. however, the application can receive tentative approval (which recognizes that at the time the tentative approval action is taken, the application meets the technical and scientific requirements for approval, but final approval is blocked by patent or exclusivity). products that receive tentative approval are eligible for procurement under the table . . lists the generic versions of hiv/aids drugs that have been approved by the fda for purchase with pepfar funds, along with the generic companies that own the patents for the specific generic formulations and the country of manufacture. the fact that the patents for hiv/aids drugs are owned by different companies has delayed combining different hiv/aids drugs in a single pill in markets protected by patents. one such pill, atripla, was created through a joint venture between merck and bristol-myers squibb with gilead sciences and combines efavirenz (bristol-myers squibb, merck) with emtricitabine and tenofovir (gilead sciences) (ib times ). atripla was approved for sale in the united states in , several years after the indian generic manufacturer, cipla, had started manufacturing a triple-combination pill and years after cipla's pill was approved by the who. approval to market atripla in the european union was sought in december . gilead sciences and merck have formed a joint venture to market atripla in developing countries (ib times ). table . shows the us patents, patent owners and patent expiry dates for selected hiv/aids drugs. zidovudine was the first drug to be approved for treatment of hiv infection. as table . shows, the patent for zidovudine expired in and the patent for lamivudine expires in . however, glaxo extended the life of these patents to by combining the two drugs into one pill (called combivir). while the new combination reduces the number of pills that a patient needs to take, it did not involve the invention of any new chemical entities. the patent history of zidovudine has been cited as a classic case of "evergreening" -the use of the patent system to extend drug monopolies far beyond the term of the original patent (hamied ). box . discussed evergreening. zidovudine was originally synthesized in , as a potential cancer treatment. research in showed that it was effective against hiv/aids, which formed the basis for glaxo's patent application. following clinical trials, the us fda approved zidovudine in march for advanced hiv disease in adults and the patent for zidovudine as a treatment for hiv/aids was granted in february (cochrane ) . while zidovudine alone only extended life by a matter of months, once it was combined with two other classes of hiv/aids drugs, it extended life for years. the fda expanded zidovudine approval in to include evergreening is a mechanism by which pharmaceutical and other companies can keep extending patents on drugs after the initial patents expire. over a fixed period of time. the intention of providing a monopoly is to provide an incentive to innovate. granting a patent requires three elements: ( ) novelty of the product. product; ( ) non-obviousness of the new product; and ( ) demonstrated utility of the the role of patents is to give exclusive rights to manufacture the patented product less-advanced stages of hiv disease (coffey and peiperl, ) . to understand evergreening in the united states, we need to examine the drug price competition and patent term restoration act, informally known as the "hatch-waxman act" . it is a united states federal law which established the modern system for generic drug approval. hatch-waxman generic. section ( j)( )(b)(iv), the so-called paragraph iv, allows -day exvolume). for pharmaceutical companies, the hatch-waxman act has created a perverse drugs by making marginal changes than to try the risky strategy of inventing completely new chemicals. thus, the two decades following its passage, the hatch-waxman act has resulted in more me-too drugs than drugs with new chemical case of prilosec -the so-called "purple pill" of astrazeneca (usd billion/year global blockbuster drug), the patent for which expired in only to be reincarnated as a new patented drug nexium. however, on april the supreme court of the united states issued a ruling in ksr international co v. teleflex et al., which raises the bar for patent holders to prove that their invention is not obvious, and therefore patentable. this ruling will make many existing patents more vulnerable, make it harder to gain approval for new patents and make evergreening more difficult in the future. if the patent claim extends to what is obvious, it is invalid. for example, a patent's subject matter can be proved obvious if there existed at the time of invention a known problem for which there was an obvious solution encompassed by the patent's claims. the supreme court noted that, "granting patent protection to advances that would occur in the ordinary course without real innovation retards progress and may, in the case of patents combining previously known elements, deprive prior inventions of their value or utility." it is worth quoting in full the court's description of the reason that patents are only granted for non-obvious innovations: "we build and create by bringing to the tangible and palpable reality around us new works based on instinct, simple logic, ordinary inferences, extraordinary ideas, and sometimes even genius. these advances, once part of our shared knowledge, define a new threshold from which innovation starts once more. and as progress beginning from higher levels of achievement is expected in the normal course, the results of ordinary innovation are not the subject of exclusive rights under the patent laws. were it otherwise patents might stifle, rather than promote, the progress of useful arts." the way forward prevention, treatment and human rights ents for branded counterparts. the hatch-waxman act encouraged the growth of generic industry, whose market share rose from % in to % in (by amended the federal food, drug, and cosmetic act. section ( j) sets forth clusivity to companies that are the "first-to-file" an anda against holders of pat-the process by which would-be marketers of generic drugs can file abbreviated incentive. it has given them more incentive to try to extend the life of existing abbreviated new drug applications (andas) to seek fda approval of the compounds. the most famous documented case of evergreening occurred in the who guidelines for arv treatment regimens provide a basis for a range of treatment protocols in individual countries. in individual countries, factors such as prices, drug efficacy and side effects are also taken into account. stavudine (d t) recommended that d t no longer be used, due to toxicity. instead, countries should switch to tenofovir (tdf) or zidovudine (azt). of these two, tdf is preferable, because of its efficacy and safety and because it can be taken only once a day. emtricitabine (ftc), in one, triple-combination pill that can be taken once a day. patients are more likely to adhere to this once-a-day regimen, thereby reducing azt and tdf, compared to d t, has delayed the shift to the new regimen in many below), the clinton foundation hiv/aids initiative (chai) has negotiated price reductions for several hiv/aids drugs for use in low-and middle-income countries (see table . ). the clinton foundation is discussed in chap. . as of may , , people were benefiting from medicines purchased under chai agreements in countries (chai ). table . . first, the prices are generally higher for middle-income countries than for low-income countries. thus, the pharmaceutical companies are pursuing a price discrimination strategy across different markets, selling drugs at a price that the markets can bear. therefore, there is clear room for generic products in these markets, especially for the low-income countries. compulsory licensing is a distinct possibility (see, however, our discussion in chap. about the difficulties many developing countries faced importing drugs under compulsory license from canada). some companies have used the world bank's country income index or the human development index as their criteria for setting prices. in chap. , we developed a much more comprehensive index that takes into account not just the level of development of the country but also level of prevalence of hiv/aids explicitly. second, the price of hiv/aids drugs in many cases in many developing countries is not necessarily lower than in developed countries. for example, in guatemala, between and , prices of most hiv/aids drugs were consistently higher than in the united states (hellerstein ). according to chai, in , , ( %) of those receiving arv treatment in low-and middle-income countries were taking second-line treatment. the reason that relatively few are on second-line treatment is that most only began treatment within the last years. as a result, relatively few have experienced treatment failure, which is defined as ( ) virologic failure (a viral load of more than copies per milliliter), ( ) immunologic failure (a declining cd cell count in spite of treatment) or ( ) clinical failure (progression to aids evidenced by weight loss or the appearance of opportunistic infections). another reason is that poor diagnostic and laboratory capacity in many countries has made treatment failure difficult to diagnose. by , chai estimates that close to , people will require second-line treatment in low-and middle-income countries (chai ) . the higher cost of second-line treatment means that access requires further funding. however, patents are not expected to be an obstacle to acquiring affordable second-line treatments in the most affected low-income countries, due to the delay of trips patent rules on pharmaceuticals to , although patent rules may affect affordability in middle-income countries (chai ) . in chap. we analyzed trips rules on patents for pharmaceuticals in developing countries. however, as we noted in chap. , the problem of regulatory capture in free trade agreements can undermine trips rules so that patents create obstacles to affordable treatment in some lowincome countries and political pressure on low-and middle-income countries can discourage the use of trips flexibilities to increase access to treatment. unitaid is a global health initiative for hiv/aids, tuberculosis and malaria that is funded by several national governments. with respect to hiv/aids, unitaid funding is focused on pediatric and second-line treatment and the prevention of mother-to-child transmission. unitaid will finance a free supply of second-line hiv/aids treatment in countries for months, after which the reduced prices achieved by chai will enable other funding sources, such as the global fund (discussed in chap. ) and pepfar (discussed in chap. ), to fund the purchase of second-line treatments at lower prices (chai ) . while high-income countries and middle-income countries with low prevalence rates are in a position to pay for hiv/aids treatment, middle-income countries with high prevalence rates and most low-income countries are not. low-income countries with high prevalence rates in particular will have to depend on external funding sources, such as pepfar and the global fund, to expand access to treatment and then to maintain treatment. medical care for people with hiv/aids in developing countries costs about usd , a year, in drugs and support facilities. the economist estimated that it would cost usd - billion a year to provide treatment for the - million people with hiv/aids in low-income countries that were in need of treatment in . however, expanding treatment means that fewer people will die. moreover, millions more will become infected, and even more so if prevention efforts are not improved. thus, universal treatment in lowincome countries could cost usd billion by the end of the next decade. this highlights the need to ensure that external funding is both increased and sustained and the importance of prevention in making universal access to treatment affordable (economist ). scientists have been trying to develop an hiv vaccine for more than years, although some have suggested that an effective aids vaccine may be a biological impossibility (epstein ) . in , about experimental hiv vaccines were being tested in clinical trials. most viral vaccines work by generating antibodies that neutralize or inactivate the invading virus. however, unlike other viruses, hiv- evades the antibody response, which, together with the large genetic variety found in hiv- strains, has made the development of an hiv- vaccine difficult. to date, antibody-based hiv- vaccines have only succeeded in neutralizing a minority of the copies of the virus that are found in a given patient. hiv- antibodies target the mechanism that hiv- uses to bind itself to the host immune cells in order to prevent hiv- from entering the cell. however, hiv- uses shielding mechanisms to prevent the antibodies from recognizing the virus, including a dense coating. current hiv- vaccine research therefore seeks to find vulnerabilities in these shielding mechanisms, but this requires research for multiple genetic subtypes of hiv- (montefiori et al., ) . for example, one recent study identified a place on the outside of the human immunodeficiency virus that could be vulnerable to antibodies that could block it from infecting human cells, which might be targeted with a vaccine aimed at preventing initial infection (dunham ) . a new class of hiv vaccines was designed to trigger cell-mediated immunity to create an extended immune defense. however, in , merck reported that its hiv vaccine, v , had failed. v was being tested by merck and the us national institutes of health in a clinical trial involving , people in highrisk groups in australia, brazil, canada, the dominican republic, haiti, jamaica, peru, puerto rico and the united states (associated press ). v used the common cold virus (the adenovirus) to transport three synthetic hiv genes into the body's cells (park ) . merck halted the trials after of volunteers who got the v vaccine later became infected with hiv, while only of participants that received a placebo also became infected (associated press ). the v vaccine was one of only two aids vaccine candidates in advanced human trials, the other being tested by sanofi-aventis sa (dunham ) . other approaches are also being explored. david ho (the inventor of triple combination therapy) and his team at the aaron diamond aids research center are researching the use of different vectors, or not using vectors at all, to produce stronger immune responses. scientists at the international aids vaccine initiative are studying the use of crippled, live strains of hiv and ways to stimulate a special class of antibodies that appear to be able to defuse hiv. the global hiv vaccine enterprise, which is funded by the gates foundation (discussed in chap. ), wellcome trust, the us national institutes of health and the european union, is seeking to accelerate research on hiv vaccines by linking together independent organizations so that researchers can learn from each other, rather than work in isolation (park ). as we noted in chap. , there are many subtypes of hiv- (the most commonly occurring hiv infection in humans). the major hiv- subtypes accounting for most infections in africa are subtype c in southern africa, subtypes a and d in eastern africa, and circulating recombinant form _ag (crf _ag) in westcentral africa (peeters and sharp ) . the most commonly occurring form of hiv- in north america and in europe is subtype b. the first hiv/aids vaccine ever to reach phase iii trial was for subtype b. the gp vaccine was not effective. however, what vaccine trials have indicated thus far is that, in the case of hiv/aids, there is pattern of development of potential vaccines not in the subtypes where the needs are the greatest but in the area where the biggest monetary rewards are expected. the economics of hiv/aids vaccines suggest that funding for vaccines for the worst-effected countries are unlikely to come from the private sector (see box . ). hiv/aids affects hundreds of millions and kills several million people every year. the disease was identified several decades ago. two nobel prizes have been awarded in the past two decades for identifying the cause and the transmission mechanism of hiv/aids. yet we still do not have a vaccine for hiv/aids. kremer and snyder ( ) have developed an argument as to why the private sector is very unlikely to develop a vaccine for aids. here, we illustrate the argument with one example. imagine there are people in the world. there are people (type l) who have a small chance of % of contracting hiv/aids. there are another ten people (type h) who would develop hiv/aids with a % chance. let us suppose that the harm from hiv/aids is usd for each person. let us also assume that for each usd decrease in harm, a consumer is willing to pay usd (technically, each consumer is risk neutral). suppose the drug is perfectly effective, has no side effects and is costless to produce. how much revenue will a pharmaceutical company generate in each of the following scenarios? ( ) it develops a drug d that cures hiv/aids (forever). ( ) it develops a vaccine v that prevents hiv/aids from developing. we show that under the assumption that the pharmaceutical company cannot distinguish between type h and type l, it is more profitable for the drug companies to produce the drug rather than the vaccine. if the pharmaceutical company develops the drug d, it will be able to sell it to all the people who get hiv/aids. by assumption, all the type h people will develop hiv/aids. thus, there will be ten people from type h who will get hiv/aids. in addition, nine people of type l will also develop hiv/aids. in total, there will be people with hiv/aids, including both types. by assumption, each person contracting hiv/aids will be willing to pay usd to reduce the effects of hiv/aids by %. therefore, the pharmaceutical company will be able to earn usd , in revenue from the entire population. given our assumption of zero cost of production, usd , will also be the profits of the pharmaceutical company. the vaccine has to be sold before hiv/aids strikes. for type l, there is a % chance of hiv/aids. thus, they will be willing to pay the average loss of ( / ) = usd for the vaccine. if the pharmaceutical company cannot distinguish between type l and type h, it can only charge usd to all. in that case, it will generate usd = usd , profits by selling the vaccine to all people. the other possibility is the following. the company sets a price of usd for the vaccine. in that case, no person of type l will buy the vaccine ex-ante (as their expected benefit before hiv/aids strikes is usd but the cost is usd ). the only people who will buy the vaccine will be of type h. since there are ten of type h, the profits will be usd = usd , . thus, in either price strategy, the profits of the company will be usd , . therefore, the profits of the company are bigger in the case of the development of drug d instead of the vaccine v. this argument is extremely general as long as the probability of the type l does not get close to the probability of type h getting the disease and the company cannot distinguish between the types. at the beginning of this book, we highlighted the need to integrate three interrelated issues into any comprehensive aids strategy -prevention, treatment and human rights protection. as we showed in chap. , each of these issues must be considered in the context of specific countries or regions, in order to take into account variations in cultural values, affected groups, infection rates, legal systems, economic resources and human resources. in this chapter, we have analyzed prevention and treatment issues in greater detail. the preceding discussion shows that great progress has been made on these two fronts and that greater progress is possible. our analysis of prevention issues in particular has shown the need to integrate prevention, treatment and human rights strategies. the primary reason that human rights need to be addressed is because discrimination keeps people away from both prevention and treatment programs (gruskin et al., ) . changing social attitudes in order to overcome stigma and discrimination is not an easy task, particularly given deep-seated fears and prejudices surrounding sex, blood, disease and death and the wide-spread perception that hiv/aids is closely supportive and enabling environment for women, children and other vulnerable to change attitudes of discrimination and stigmatization associated with hiv/aids variations in cultural values and legal systems make hiv/aids-related human rights particularly difficult to tackle on a global basis. however, hiv/aidsrelated human rights are the area where the least progress has been made and need to become a central focus in the global fight against hiv/aids (jürgens and cohen ) . in this section, we focus on three categories of laws: ( ) laws that discriminate against vulnerable groups; ( ) laws that discriminate against hiv-positive people, such as those that criminalize hiv transmission; and ( ) laws that prohibit discrimination against vulnerable groups, including hiv-positive people. we review the united nations international guidelines on hiv/aids and human rights and provide examples in each category. the way forward prevention, treatment and human rights to understanding and acceptance (united nations ). groups. the guidelines also recommend that states promote the wide and ongoing distribution of creative education, training and media programs explicitly designed united nations international guidelines on hiv/aids and human rights redialogue, specially designed social and health services and support to community commend that states, in collaboration with and through the community, promote a groups by addressing underlying prejudices and inequalities through community tied to deviant or immoral behavior (jürgens and cohen, ) . in this regard, the the law plays different roles with respect to infectious diseases. some health risks, such as poor access to sterile injection equipment, can be directly attributed to law, and laws have been used to change unhealthy behaviors, such as smoking and drunk driving. both international and national laws are used in disease control. in addition to the law's role as a source of disease control authority for government, the law has a countervailing role as a source of protection against excessive and unnecessary regulations (burris ) . the united nations international guidelines on hiv/aids and human rights acknowledge the inherent limitations in using law reform to enhance human rights. the effectiveness human rights laws depend on the strength of the legal system in a given society and on the access of its citizens to the system, both of which vary considerably from one country to the next. moreover, the law cannot serve as the only means of educating, changing attitudes, achieving behavioral change or protecting people's rights. nevertheless, since laws regulate conduct between the state and the individual and between individuals, they can either support or undermine the observance of human rights, including hiv-related human rights (united nations ) . for these reasons, we first consider laws that support human rights. while social attitudes may take time to change, an important first step is to reform laws, policies and practices that institutionalize discrimination against the groups of people who are most vulnerable to hiv/aids: women and girls; men who have sex with men; commercial sex workers; and injection drug users. the united nations international guidelines on hiv/aids and human rights recommend consistent with international human rights obligations and are not targeted against vulnerable groups (united nations ). laws in this category include those that prohibit sexual acts between consenting adults in private, laws prohibiting sex work that involves no victimization and laws prohibiting measures such as needle exchange that can reduce the harm associated with illicit drug use (elliot ). the united nations international guidelines on hiv/aids and human rights recommend the enactment of anti-discrimination and protective laws to reduce human rights violations against women and children in the context of hiv, to reduce the vulnerability of women and children to hiv infection and to the impact of hiv/aids. with respect to women, the guidelines recommend law reforms to ensure the equality of women regarding property and marital relations and access that states reform criminal laws and correctional systems to ensure that they are have a negative impact on hiv-related human rights and then consider laws that to employment and economic opportunity, such as equal rights to own and inherit property, to enter into contracts and marriage, to obtain credit and finance, to initiate separation or divorce, to equitably share assets upon divorce or separation and to retain custody of children. in addition, laws should ensure women's reproductive and sexual rights, including the right of independent access to reproductive and sexual health information and services and contraception, the right to demand safer sex practices and the right to legal protection from sexual violence. with children against sexual abuse and provide for their rehabilitation if abused and ensexual abuse by their husbands. when the husband is hiv-positive or engages in unsafe sex or drug use, this increases the risk of infection for women. child cusdren make it difficult for women to leave abusive relationships. while statutes allow property ownership regardless of sex, in practice women only have user rights under customary laws, not ownership. under inheritance laws, property remains in the man's family after he dies. thus, if a woman wants to leave an abusive husband or her husband dies, she cannot take any property with her, leaving women economically dependant upon their husbands or, as widows, their families. new laws have created inheritance rights for dependants, but are ignored by the man's family and not enforced. as a result, women and children widowed and women must either rely on their in-laws for support or become commercial sex workers (kelly ) . laws and cultural traditions thus increase women's vulnerability to hiv/aids, either within marriage or by forcing them to support themselves and their children as sex workers. recommend the enactment of anti-discrimination and protective laws to reduce discriminatory property, divorce and inheritance laws for same-sex relationships. the way forward prevention, treatment and human rights tody laws, customary practice and traditions that favor paternal custody of chil-sure that they are not subject to penalties themselves. protection under disability human rights violations against men having sex with men, including in the context orphaned by aids are left without adequate resources for medical treatment, and the united nations international guidelines on hiv/aids and human rights of hiv, including penalties for vilification of people who engage in same-sex respect to children, laws should provide for children's access to hiv-related inlaws, inheritance laws, and child custody laws. in many african countries marital rape does not exist as a legal concept, leaving women with no recourse against formation, education and means of prevention, govern children's access to volcontext of orphans, including inheritance and/or support. laws should also protect untary testing with consent, should protect children against mandatory testing, particularly if orphaned by aids, and provide for other forms of protection in the in sub-saharan africa, laws of particular concern include marital rape, property laws should also be ensured for children (united nations ). one key purpose of such anti-discrimination laws is to reduce the vulnerability of men who have sex with men to infection by hiv and to the impact of hiv/aids. the guidelines also recommend that the age of consent to sex and marriage be consistent for heterosexual and homosexual relationships and that laws and police practices relating to assaults against men who have sex with men ensure adequate legal protection (united nations ). in a internet-based survey of sexually active msm in new york city, % reported being hiv-positive and % reported being hiv-negative. the majority were white, college-educated and in their s. the race of the respondents was white ( %), latino ( %), black ( %) and other ( %). in the previous months, % had more than ten male sex partners, % had engaged in unprotected anal sex and % had used non-injection drugs. fifty percent of the hiv-positive men had unprotected anal sex in the previous months and % of the hiv-negative men had unprotected anal sex in the previous months (nyc health ). in a survey of black msm in new york city, % were hivhigh school education, % were unemployed and % had an annual income of less than usd , . fifty-six percent identified themselves as homosexual, % as bisexual, % as heterosexual and % as other. sixty-five percent had previously been diagnosed with a sexually transmitted infection and % had been raped ( % before they were years old). eighty-four percent knew that they were hiv-positive. of the % that were unaware that they were hiv-positive, % reported having been tested for hiv previously. of those who had never been tested for hiv, the reasons they gave were: ( ) being afraid to learn that they had the perception of not being at risk because they practiced safe sex ( %); and ( ) being afraid that results will be reported to the government ( %). fifty percent reported unprotected anal sex with a man in the previous months and % had exchanged sex for drugs, money or a place to stay in the same period. among those who had unprotected anal sex with a man in their last sexual encounter, % of the hiv-positive men had an hiv-positive sex partner and % of the hivnegative men had an hiv-negative sex partner (nyc health ). according to the unaids guidance note on hiv and sex work, despite high hiv prevalence among sex workers, only one in three receive adequate hiv prevention services and even fewer receive adequate treatment and health care (unaids ) . the unaids guidance note focuses on the reduction of hiv vulnerability among sex workers, who are defined as adults over the age of years in order to take into account that sexual exploitation of children under years of age is prohibited under international law. the key factors that lead people into sex work include poverty, gender inequality, indebtedness, migration, criminal hiv ( %); ( ) being worried that others might treat them differently ( %); ( ) positive. the median age of the respondents was years, % had less than a coercion, humanitarian emergencies, drug use and dysfunctional families. laws, policies and practices that drive sex work underground make hiv/aids prevention and treatment for sex workers and their clients more difficult. discrimination against sex workers among the police, health care services and other social services impede access to prevention and treatment. the unaids guidance note organizes its recommendations into three categories: ( ) reducing vulnerabilities and addressing structural issues; ( ) reducing risk of hiv infection; and ( ) building supportive environments and expanding choices. the strategies in the first category are to: ( ) address poverty and gender inequality by providing alternatives to sex work through micro-finance programs and reforms to property rights; ( ) address the demand for paid sex by seeking to changes men's behavior; ( ) expand access to education for girls and women; ( ) provide alternative job opportunities through employment growth and vocational training; and ( ) provide employment and education opportunities and access to social services for refugees, internally displaced persons and economic migrants. the strategies in the second category are to: ( ) involve sex workers in hiv prevention and treatment programs; ( ) make male and female condoms available for free or at low cost; ( ) increase access to antiretroviral treatment; ( ) address the specific needs of sex workers in sexual and reproductive health programs, taking into account the different needs of female, male and transgender sex workers; ( ) make hiv prevention information and condoms readily available to clients; ( ) seek to eliminate violence against sex workers by clients, managers, police and other government officials; ( ) seek to change attitudes towards sex workers to reduce stigma and discrimination; ( ) promote initiatives to enable sex workers to negotiate safe sex practices; and ( ) promote access to drug addiction treatment programs and harm reduction programs, such as needle exchange. the strategies in the third category are to: ( ) address sex work stigma and discrimination to reduce economic, cultural and social marginalization in families and communities; ( ) improve access to health care, education and training, microfinance and credit, social services, housing support and legal services; and ( ) promote community organizations that work with sex workers. the unaids guidance note on hiv and sex work has been criticized for emphasizing alternative livelihoods without offering concrete examples, rather than emphasizing the right to engage in sex work and workplace safety and national laws that undermine sex workers' rights, particularly criminal prohibition of sex work and related activities. the guidance note's strategy of reducing demand for sex work has been criticized as implicitly supporting the criminalization or repression of sex work, which can increase the risk of hiv infection by driving sex work underground, limit sex workers' choices regarding working conditions and clients and increase stigmatization. the guidance note was further criticized for not advocating enhanced human rights protection for those engaged in sex work -as women, men, transgender persons and workers. the process used for preparing the document was criticized for not meaningfully engaging sex workers. unaids' response to criticism of this document -to withdraw it as a public document and restrict it to internal use -was also criticized (canadian hiv/aids legal network b) the united nations international guidelines on hiv/aids and human rights recommend that criminal law prohibiting sexual acts (including adultery, sodomy, fornication and commercial sexual encounters) between consenting adults in private should not be allowed to impede provision of hiv prevention and care services and should be repealed. with regard to adult sex work that involves no victimization, the international guidelines on hiv/aids and human rights recommend de-criminalizing and legally regulating occupational health and safety conditions to protect sex workers and their clients, including support for safe sex during sex work. more generally, criminal law should not impede provision of hiv prevention and care services to sex workers and their clients and should ensure that children and adult sex workers who have been coerced into sex work are not prosecuted for such participation but rather are removed from sex work and provided with medical and psycho-social support services, including those related to hiv (united nations ). in eastern europe and central asia, unaids ( ) estimates that the use of contaminated injection equipment accounts for more than % of hiv/aid cases and accounts for about % of new infections outside sub-saharan africa. the united nations international guidelines on hiv/aids and human rights recommend that criminal law not be an impediment to measures taken by states to reduce the risk of hiv transmission among injecting drug users and to provide them with hiv-related care and treatment. they further recommend that criminal law be reviewed to consider: ( ) the authorization or legalization and promotion of needle and syringe exchange programs; and ( ) the repeal of laws criminalizing the possession, distribution and dispensing of needles and syringes (united nations ) . in saint petersburg, russia, a study found that % of injection drug users had shared needles in the days prior to their first use of a needle exchange program. in early , there were four syringe exchange facilities in saint petersburg -one mobile service (a bus) and three fixed facilities. however, the most important source of sterile syringes for injection drug users was drug stores. human rights watch found that state-supported impediments to access to both needle exchange points and drug stores were important barriers to hiv prevention, including: ( ) police patrols of drug stores, which deterred injection drug users from purchasing syringes; ( ) police patrols of needle exchange bus stops; and ( ) arrests, fines or bribes for possession of syringes, even though carrying syringes is not illegal in the russian federation. however, while police interference with the syringe exchange bus was a problem in the late s, it lessened in the early s. humanitarian action, an ngo that delivers syringe exchange services in saint petersburg, visited with police chiefs to talk about the importance of syringe exchange for hiv prevention and organized a training session in for police officers that included the participation of former drug users and people living with hiv/aids. however, due to past incidents, the fear of apprehension by the police kept some drug users from using fixed as well as mobile syringe exchange facilities (human rights watch ) . table . shows the dramatic increase in hiv prevalence among injection drug users in saint petersburg from to . a survey of injection drug users (idus) in new york city found that % had obtained a syringe from an exchange program in the previous year, % at a pharmacy, % from a medical provider, % from a friend or sexual partner and % from a drug dealer. the self-reported hiv prevalence rate in the group was %. idus who obtained syringes from sterile sources (exchange, pharmacy or provider) were less likely to share syringes than those who obtained them from non-sterile sources (friends, relatives or the street). those who obtained syringes from exchange programs were significantly less likely to share syringes. nevertheless, % of idus had shared a syringe at least once in the previous months and % had engaged in unprotected sex. idus that had shared a syringe were . times more likely to engage in unprotected sex (nyc health ). another category of laws discriminates directly against people with hiv/aids, such as laws that criminalize hiv transmission and travel restrictions based on hiv status. there is a concern that the criminalization of hiv transmission will discourage people from seeking testing (tarantola and gruskin ) . there is evidence that knowledge of hiv status results in behavioral changes that reduce transmission. in addition, where knowledge of hiv status leads to antiretroviral treatment, treatment also reduces transmission by reducing the amount of virus in the body. thus, the criminalization of hiv transmission may have the effect of increasing, rather than reducing, hiv transmission. one possible response is mandatory hiv testing in health care settings (that is, testing without the informed consent of the patient). however, this policy, too, may be self-defeating if it discourages people from nations international guidelines on hiv/aids and human rights recommendation that public health legislation ensure that hiv testing of individuals should several studies have concluded that the criminalization of hiv transmission is unlikely to serve the goals of public health policy or the goals of criminal law, and ommended that governments and the judiciary take into account the following principles in determining policy regarding the use of criminal sanctions under modes and risk of hiv transmission to rationally determine when and if conduct should attract criminal liability; ( ) the primary objective should be to prevent public health and conform to international human rights norms, particularly nondiscrimination and due process; and ( ) policy makers should assess the impact of law or policy on human rights and prefer the least-intrusive measures possible to achieve a demonstrably justified objective of preventing disease transmission. with respect to the four functions of criminal law (harm prevention through response to the epidemic: ( ) imprisoning an hiv-positive individual does not prevent transmission through conjugal visits or high-risk behavior with other prisoners; ( ) criminal penalties are unlikely to change sexual activity and drug use, due to the complexity of these human behaviors; ( ) punishment/retribution do not achieve the goal of hiv prevention and risk reinforcing prejudice and discrimination against already stigmatized hiv-positive people; and ( ) criminal sanctions are unlikely to act as a deterrent, given that drug use and sexual activity persist even with the risk of criminal prosecution and are more likely to be driven underground when prosecuted, hindering hiv prevention. moreover, overly broad use of criminal laws risks spreading misinformation regarding how hiv is transmitted. in an empirical study conducted in the united states, burris et al. ( ) found that laws prohibiting unsafe sex or requiring disclosure of infection do not influence people's normative beliefs about risky sex and did not significantly influence sexual behavior. the study concluded that criminal law is not a clearly useful in-moreover, given concerns about possible negative effects of criminal law, such as stigmatization or reluctance to cooperate with health authorities, criminal law should be used with caution as a behavioral change mechanism for hiv-positive people. seeking health care. moreover, mandatory hiv testing runs counter to the united thus may do more harm than good. in a unaids policy paper, elliot ( ) bution; and deterrence), elliot ( ) concluded that criminal law is an ineffective imprisonment; prevention of future harm through rehabilitation; punishment/retri-hiv transmission in common law countries. in some cases, courts have applied existing criminal laws to cases involving hiv, where the laws themselves do not refer specifically to hiv. in this context, law reforms could come from the legislature, through amendments that clarify the application of relevant criminal laws to cases involving hiv, or through the evolution of precedents in the courts. the united nations international guidelines on hiv/aids and human rights recommend the reform of criminal laws and correctional systems to ensure that they are consistent with international human rights obligations and are not misused in tization of the judiciary, in ways consistent with judicial independence, on the legal, ethical and human rights issues relative to hiv, including through judicial education and the development of judicial materials (united nations ). criminal laws should not include specific offences against the intentional transmission of hiv but rather should apply general criminal offences to these exceptional cases. such application should ensure that the elements of foreseeability, intent, causality and consent are clearly and legally established to support a guilty verdict and/or harsher penalties (united nations ) . in the united states, a series of cases involving spitting have gone in different directions. in ohio v. bird ( ) , an hiv-positive man was convicted of felonious assault, which requires the knowing attempt to harm by use of a weapon capable of inflicting death, after spitting in a police officer's face, even though all medical and scientific evidence demonstrated that saliva does not transmit hiv. in state v. jones ( ) , another case of an hiv-positive individual accused of spitting on an officer, the new mexico court of appeals ruled that criminal liability for battery could not be based upon the victims' subjective and unsubstantiated fears that they could develop a disease, and reversed the lower court on this issue. in weeks v. state ( ) , the texas court of appeal sustained the attempted murder conviction of an hiv-positive inmate who spat in a guard's face. the spitting cases show how the application of criminal laws to hiv-positive individualswhen based on hiv status, stigma and discrimination rather than on medical or scientific evidence -can undermine genuine efforts to reduce hiv transmission by spreading misinformation and increasing stigma and discrimination. in cases involving behavior that does carry a risk of hiv transmission, such as unprotected sexual intercourse or sharing drug injection equipment, the central issue is consent. in r v. cuerrier ( ) the supreme court of canada established that there is a duty to disclose one's hiv status before engaging in any activity that poses a "significant risk" of hiv transmission. failure to do so legally invalidates a sexual partner's consent to sexual intercourse. the lack of consent to have intercourse with a partner that is hiv-positive converts the sexual intercourse into a criminal assault. in that case, the complainants did not become infected with hiv as a result of the unprotected sex. however, if the complainants believe that their partner is hiv-free and the accused puts the complainants at significant risk to their health, failure to disclose hiv status vitiates consent to sexual intercourse. the way forward prevention, treatment and human rights there have been numerous cases in which criminal laws have been applied to the context of hiv/aids (united nations ). they also recommend the sensi-this decision suggests that there might not be a duty to disclose hiv status prior to engaging in activities that do not pose a significant risk of transmission, such as kissing and oral sex, or where an hiv-positive individual uses a condom. in r v. edwards, a lower court judge ruled that there is no duty to disclose hiv status prior to engaging in unprotected oral sex because it is a low risk activity (canadian aids society ) . on november , the defendant learned that he was hiv-positive, but did not reveal his status to the complainant and continued to have unprotected sex with her. the supreme court of canada ruled that the defendant was not guilty of the act itself, but rather the consequences of the act. because it was likely that the defendant had infected the complainant before he learned of his hiv status, it could not be proved beyond a reasonable doubt that he had endangered the life of the complainant. however, the defendant was guilty of attempted aggravated assault for continuing to have unprotected sex with the complainant after having learned of his hiv status. the court ruled that there is sufficient criminal intent for a conviction on a sexual assault charge if a person acts "recklessly". in canadian law, a person acts "recklessly" if they know that their conduct risks committing a crime but they commit the act nevertheless. in this case, the supreme court ruled that criminal recklessness is established once an individual becomes aware of a risk that he or she has contracted hiv, but continues to have unprotected sex without disclosure of hiv status, thereby creating a risk of further hiv transmission. in this case there was no evidence before the court regarding the defendant's awareness of the risk that he might be hiv-positive, prior to november , other than the fact that he had been asked to take an hiv test. this aspect of the ruling raised the issue of whether there is a duty to disclose the mere awareness of a risk that one might be hiv-positive before having unprotected sex. the court also suggested that an hiv-positive person might be held criminally liable for failure to disclose hiv status before having unprotected sex with another hivpositive individual, where this results in the transmission of a different strain of hiv or a drug-resistant strain of hiv. the supreme court of canada cases have been criticized, on the one hand, for discouraging people from seeking testing in order to avoid the possibility of a criminal conviction based on knowledge of hiv status and, on the other hand, for risking undesirable invasions of privacy if courts are required to determine whether an individual was aware that their past activities put them at risk of hiv infection (canadian hiv/aids legal network ) . however, in r v. williams, the fact that the defendant had been asked to take an hiv test, because he was on a list of former partners provided by an individual who had tested hiv-positive, was not sufficient to establish that he was aware that his past activities had put him at risk in r v. williams ( ) , the defendant began a sexual relationship with the comthe complainant". what distinguishes aggravated assault from mere assault is not plainant in june , in which they had unprotected sex on numerous occasions. requires that the assault "wounds, maims, disfigures or endangers the life of aggravated assault under section ( ) of the canadian criminal code, which of hiv infection. nevertheless, the decision has been criticized for extending the without defining the nature of the awareness that might be required. more generally, the use of criminal law to prevent hiv transmission has been criticized for stigmatizing all hiv-positive people because of the conduct of a few individuals, for discouraging those most at risk from seeking testing and for being unlikely to stop people from having risky sex or sharing needles and syringes. moreover, all of the hiv-related criminal prosecutions in canada have occurred in the context of heterosexual intercourse, rather than homosexual intercourse or injection drug use, creating a perception of discriminatory application (or non-application) of the laws (betteridge ). sion of hiv/aids between and , in which eight accused pleaded guilty, two were convicted and one was acquitted (klein ) . a new zealand court has ruled that people living with hiv/aids are not required to disclose their hiv status if they use condoms during vaginal sex (klein ) . in particular, the use of criminal laws to prevent hiv transmission also has been criticized for not taking into account that hiv-positive individuals living in abusive relationships may fear the consequences of disclosing their status to partners and may not be able to use a condom or insist that their partner use a condom (canadian aids society ) . in a literature review of hiv/aids and genderbased violence, the harvard school of public health program on international health and human rights ( ) found that gender-based violence (which is not limited to violence against women) can interfere with safe sex practices and access to treatment. not only is gender-based violence a risk factor for acquiring hiv/ in summary, the use of criminal laws to prevent hiv transmission may undermine overall public health initiatives by: ( ) reinforcing hiv/aids-related stigma; ( ) spreading misinformation about hiv/aids; ( ) creating a disincentive for hiv testing; ( ) hindering access to counseling and support services; ( ) creating a false expectation that criminal laws eliminate the danger of unprotected sex for people who believe that they are hiv-negative; ( ) creating the risk of selective prosecution of marginalized groups; ( ) criminalizing behavior that results from gender inequality, in the case of hiv-positive people living in abusive or economically dependent circumstances; and ( ) invading privacy through the disclosure of medical records and hiv status in public court proceedings (elliot ) . however, the use of criminal laws may be warranted in some circumstances, where hiv status is an aggravating or otherwise relevant factor in cases involving physical assault that would constitute criminal behavior even in the absence of hiv, such as rape or the use of needles as weapons (elliot ) . finally, a distinction should be made between criminal laws and public health laws that are quasi-criminal in nature, particularly those regarding quarantine. while quarantine laws, such as isolation, detention or quarantine, may be suitable the way forward prevention, treatment and human rights criminal law beyond cases where individuals know that they are hiv-positive, in the united kingdom, there were eleven prosecutions for reckless transmis-aids, but hiv/aids is also a risk factor for gender-based violence. for casually communicable and curable diseases, such laws run the same risk of misuse as do criminal laws (elliot ) . in this regard, the united nations international guidelines on hiv/aids and human rights recommend that public health law provisions applicable to casually transmitted diseases not be applied inappropriately to hiv/aids and that they be consistent with international human rights obligations (united nations ). some countries have restricted the entry of people living with hiv/aids, for shortterm or long-term stays, through mandatory testing or a requirement to declare one's hiv status. as we saw in chap. , the who international health regulations also contain provisions regarding health measures applied to travelers. these provisions encourage states to base their determinations upon scientific principles, available scientific evidence of a risk to human health and any available specific guidance their dignity, human rights and fundamental freedoms and minimize any discomfort or distress associated with such measures. governments cite two main reasons for imposing travel restrictions on people living with hiv/aids -public health protection and reducing demand on health care and social services (unaids/iom ) . in the united kingdom, another source of demands for hiv screening of migrants has been a concern over "health tourism" -hiv infected migrants from developing countries that go to europe to receive health care. however, research shows that access to treatment is rarely the after having arrived in the host country, and there is no uniform policy in european union countries regarding screening of migrants for hiv (carballo ) . hiv/aids is not considered to be a condition that poses a threat to public health in relation to travel because hiv/aids is already present in virtually every country in the world and hiv is not transmitted through casual contact. unlike highly contagious diseases with short incubation periods, such as sars, cholera and plague, hiv transmission can be prevented through safe sex and safe drug injection, which can be used by both the infected and the non-infected to prevent transmission. there is no evidence to support the assumption that both the infected and the non-infected will engage in unsafe practices. as a result, the presence of hiv-positive individuals, by itself, does not pose a risk to public health. in addition, travel restrictions are not effective in preventing the entry of hiv-positive individuals, since hiv tests do not detect the virus in newly infected people and nationals that are returning from travel abroad (who may have been infected while outside the country) are not subject to hiv/aids-related travel restrictions and are not prevented from entering their own country. moreover, travel restrictions can undermine hiv/aids-related public health initiatives by increasing stigma and discrimination and mislead the public into thinking that hiv/aids can be or advice from the who. they also require states to treat travelers with respect for reason for migration to europe, since most migrants only learn of their hiv status prevented through border measures, rather than through proven prevention strategies (unaids/iom ) . unaids and the international organization for migration (iom) recommend that exclusion on the basis of possible costs to health care and social services only occur on an individual basis, where the following considerations are shown: ( ) the person requires the health care and social services and is likely to use them in the near future; ( ) the person has no other means of meeting those costs (for example, through private or employment-based insurance or personal resources); and ( ) these costs will not be exceeded by the benefits of the person's skills, talents, contribution to the labor force, payment of taxes, contribution to cultural diversity and capacity for revenue or job creation (unaids/iom ) . they also recommend that countries treat similar conditions alike, rather than singling out hiv/ aids. one study showed that the -year economic impact of admitting immigrants with asymptomatic hiv infection would be similar to admitting immigrants with asymptomatic coronary heart disease (zowall et al., ) . the canadian immigration and refugee protection act provides that foreign nationals can be deemed "medically inadmissible" based on a medical condition, danger to public health or public safety; or ( ) they might reasonably be expected to cause excessive demand on health or social services. since , canadian danger to public health or public safety by virtue of their hiv status. the issue of excessive demand on health or social services is mainly a consideration in cases of immigration or stays that exceed months, is determined on a case-by-case basis permanent residents (spouses and children). demand on health or social services of health or social services for the average canadian resident; or ( ) the demand the united states has had a travel and immigration restriction in place for people living with hiv/aids since (human rights watch ) . under the united states are inadmissible if they have "a communicable disease of public high level meeting on aids a "designated event" for which an hiv waiver would be available. visitors entering the united states on the visa waiver program (which waives the requirement to apply for a visa prior to traveling to the united the way forward prevention, treatment and human rights government policy has been that people living with hiv/aids do not represent a and therefore denied a visa or entry at the border, if: ( ) they are likely to be a would add to existing waiting lists for those services and would increase the rate us immigration and nationality act, applicants for a visa or for admission to the health significance", which includes hiv infection, although waivers are available ces by canadian citizens or permanent residents. the social or economic contribu-and does not apply to refugees or close family members of canadian citizens or tions the individual is expected to make to canada are not taken into account. or mortality and morbidity in canada by denying or delaying access to those servi- hiv status or to be tested for hiv (canadian hiv/aids legal network a) . on a case-by-case basis. for example, the us attorney general named the people entering canada for less than months are not required to disclose their is considered excessive if: ( ) the anticipated costs would likely exceed the costs states, for certain countries) must fill out an i- w form, which asks, "have you ever been afflicted with a communicable disease of public health significance." if the visitor answers yes to the question or the us border authorities suspect a visitor to be hiv-positive the person may be: ( ) placed into secondary inspection; ( ) questioned by an official of the us department of homeland security; ( ) placed into deferred inspection; ( ) asked to withdraw the application for admission into the united states; ( ) placed into the expedited removal process; or ( ) placed into an us department of homeland security detention center and detained until the case is heard by an immigration judge (gmhc ) . hiv-positive non-immigrants seeking to enter the us on a temporary basis for business, pleasure, or education are eligible for a waiver under which they can be allowed to enter the united states. in practice, a waiver is granted in most cases if: ( ) they are not symptomatic; ( ) it is a short visit; ( ) they have insurance or other assets sufficient to pay medical expenses; and ( ) they don't appear to be a public health risk. permanent residency and immigration applicants can also apply for a waiver, but they are usually rejected. to receive a waiver as an immigrant, the person must be the spouse, unmarried son or adopted child of a united states citident as their son or daughter. in addition, an hiv-positive immigration applicant must prove that: ( ) he will not be a danger to public health; ( ) the possibility of spreading the disease is minimal; and ( ) there will be no cost incurred by any level of government without its prior consent (tarwater ) . june the us public health service added aids to the list of excludable conditions, noting that the exclusion was not based on any new scientific knowledge and that aids is not spread by casual contact, which is the usual public concept of contagious. in july , republican senator jesse helms also added hiv infection to the exclusion list, through the us congress, together with a prohibition on funding from the us centers for disease control for aids programs that "promote, encourage or condone homosexual activities" (koch ; aids treatment news ) . senator helms accompanied the introduction of his amendments with the following statement: "we have got to call a spade a spade, and a perverted human being a perverted human being" (koch ) . in july , senator jesse helms advocated spending less money on hiv/aids, because it resulted from "deliberate, disgusting, revolting conduct" and was "a disease transmitted by people deliberately engaging in unnatural acts" (associated press ). ten years later, he had this to say: "it had been my feeling that aids was a disease largely spread by reckless and voluntary sexual and drug-abusing behavior, and that it would probably be confined to those in high-risk populations. i was wrong" . in , the us centers for disease control (cdc) recommended that all diseases except active tuberculosis be removed from the list of excludable conditions. hiv was left on the list because it had been put on the list by congress. in november the political history of the us hiv travel restrictions is an interesting story. in zen or permanent resident or have a united states citizen or lawful permanent resi- , the immigration reform act of directed the cdc to establish a new list of excludable conditions, based solely on current epidemiological principles and medical standards. in january , the cdc again proposed that only active tuberculosis remain on the list of excludable conditions. religious leaders campaigned to maintain the ban and the us house of representatives opposed removing the hiv ban (aids treatment news ) . in august , democratic representatives barbara lee and hilda solis introduced the "hiv nondiscrimination in travel and immigration act". the proposed legislation would restore the authority of the secretary of health and human services to determine whether hiv status is a communicable disease of public health significance. the decision to maintain or remove the ban would then be based on public health analysis instead of a formal ban made by congress (latino commission on aids ). in november , the us department of homeland security proposed a new rule that would allow short-term visas to be granted to hiv-positive people by us consulates in their home countries. however, applicants would have to agree to conditions, including ceding the right to apply for longer stays or permanent residency in the united states. democratic members of the us house of representatives objected that the changes would only shift decision-making authority to local consular officers, who may lack the appropriate medical expertise. moreover, there would be no appeal process (werner ) . the united states and canada are similar societies, both culturally and economically, but have adopted very different approaches to hiv/aids travel restrictions. the hiv prevalence rate in the united states is higher than in canada. this suggests that the us travel restriction has not been effective in preventing hiv transmission in the united states, and that the lack of such a restriction in canada has not had the effect of increasing hiv prevalence. health care costs, measured as a percentage of gdp, are also higher in the united states than in canada. while this difference is attributable to many factors, making it difficult to determine the impact of the different travel restriction policies on health care costs without further study, it is an indication that the canadian approach has not led to a significant increase in health care costs compared to the american approach. in , americans spent usd , per capita on health care, compared with usd , in canada. americans spent . % of gdp on health care compared with . % of gdp in canada. interestingly, this gap was not always there. in , both countries spent exactly . % of their respective gdp on health care (oecd ) . another factor that suggests that us travel restrictions are unlikely to prove successful is illegal immigration. there are several million illegal entries into the united states each year. they are obviously not screened. thus, from a practical point of view, travel and immigration restrictions for hiv-positive individuals are unlikely to be effective in preventing the entry of many hiv-positive individuals and may provide additional incentives for some individuals to migrate illegally. the united nations international guidelines on hiv/aids and human rights recommend that states enact or strengthen anti-discrimination laws that protect vulnerable groups, people living with hiv/aids and people with disabilities from discrimination in both the public and private sectors, and provide for speedy and effective administrative and civil remedies (united nations ). human rights laws in many jurisdictions prohibit discrimination against vulnerable groups or against people with hiv/aids, as well as providing other rights that are relevant to hiv/aids, such as the right to life and the right to health. human rights laws fall into two categories. the first category applies to governments, prohibiting governments from passing discriminatory laws or requiring governments to uphold certain human rights. the second category of human rights law prohibits discrimination on the part of private actors, for example with respect to employment practices or rental of housing. while it is not possible to eliminate individual or societal prejudices with legislation, human rights laws provide victims of discrimination with legal recourse against acts of discrimination and create economic disincentives through fines or other legal remedies, thereby contributing to social change. canada provides one example of the sources and functioning of human rights laws. section of the canadian charter of rights and freedoms, which is part of the constitution of canada, guarantees equality rights in the following terms: the equal protection and equal benefit of the law without discrimination and, in particular, without discrimination based on race, national or ethnic origin, colour, religion, sex, age or mental or physical disability. canadian courts have interpreted the term "disability" to include hiv/aids, which means that people living with hiv/aids have constitutional protection listed, but also covers analogous grounds, such as sexual orientation. any law that is inconsistent with constitutional provisions may be struck down or interpreted by courts to make it consistent with the constitution. the charter applies to all levels and branches of government, all government acts, government corporations and ment government policies or programs. however, the charter does not otherwise apply to acts by private citizens. instead, discrimination by an employer, a landlord or a private business is addressed under other federal and provincial human rights laws, such as the canadian human rights act, which apply to both the public and private sectors. by virtue of a policy of the canadian human rights commission and decisions of canadian courts and tribunals, the prohibition against disability-based discrimination in the every individual is equal before and under the law and has the right to against discrimination by the state. section is not limited to the grounds that are private persons or bodies that exercise authority granted by a statute or that imple-canadian human rights act and its provincial counterparts cover discrimination based on hiv/aids status (elliott and gold ) . the remainder of this section provides an overview of court cases in a variety of countries that have applied constitutional law, international law and other legislation to uphold the rights of people living with hiv/aids with respect to employment and access to hiv-related medical care and treatment. in march , mexico's national supreme court of justice ruled that a provision in article of the social security institute law for the armed forces (issfam) that required hiv-positive individuals to be discharged from the military was unconstitutional, because it was not based on an individual assessment of the pering people living with hiv/aids. the court ordered that three soldiers be reinduty, which would include an obligation to reinstate their social security benefits with respect to hiv/aids, laws in south africa and latin america that provide a action campaign used this provision to challenge the government's program that limited the use of nevirapine to prevent mother-to-child hiv transmission to test sites. the court ruled that the government's restriction on the use of nevirapine was unreasonable and that the policy should be reformed to meet the government's constitutional obligation (singh et al., ; elliot et al., ) . in argentina, five court cases between and repeatedly ordered the argentine ministry of health to supply antiretroviral treatment to people living with hiv/aids, in accordance with the right to health set out in international treaties, which had been incorporated into domestic law. the failure of the ministry of health to act in a timely fashion, which led to interruptions in the supply of antiretroviral drugs, ultimately led to a court order that would fine the ministry of health usd , per day (funds which would then be used to implement the national aids plan) until it complied with the courts' previous orders, and the threat right to health care have been used to induce governments to provide access to and equality and was inconsistent with mexico's international obligations regardvides a right to health care that is binding on the government. the treatment mexico's national supreme court of justice ruled for a fifth time that this provision was unconstitutional, thereby creating jurisprudence that is binding on all federal son's ability to work, violated constitutional protections of non-discrimination judges in mexico (avilés allende ). table . summarizes several other antiretroviral treatment (gruskin et al., ) . the south african constitution pro-cases involving hiv-related discrimination in employment from various juris- (pearshouse ; medina and reyes ; scjn a, b) . in september , dictions around the world. stated until medical certificates were issued to determine whether they were fit for (elliot et al., ) . an argentine court also relied on the right to health set out in international treaties to order the government to produce and administer a vaccine within a set period of time, in order to protect people living in a region affected by argentine haemorrhagic fever (singh et al., ) . the constitutional court of ecuador relied on the right to health set out in international treaties to rule that the ministry of health had failed to meet its obligations when it suspended its hiv treatment program (singh et al., ; elliot et al., ) . in costa rica, the supreme court ruled in that the costa rican social security fund could not argue that financial constraints justified failure to comply with its very reason for its existence, which is to provide coverage for necessary medical care. shortly after this ruling, the supreme court ordered the social security fund to develop a plan to provide coverage to all persons living with hiv/aids that were in need of antiretroviral treatment. a few weeks later, costa rica became the first central american country to include cov- ) . in india, the courts have interpreted the right to life in the indian constitution to sources to uphold the right to health in a variety of cases (singh et al., ) . table . summarizes several other cases from various jurisdictions around the world where litigation has increased access to hiv-related medical treatment. these cases suggest that human rights laws can be instrumental in promoting health care reforms through litigation, provided that judicial authorities are independent and competent and governments respect the rule of law (singh et al., ) . in addition to laws that institutionalize or prohibit discrimination, institutional policies and practices can represent an important force with respect to stigma, discrimination and access to health care. the united nations international guidelines on hiv/aids and human rights recommend that states ensure that government and the private sector develop codes of conduct regarding hiv/aids issues that translate human rights principles into codes of professional responsibility and practice, with accompanying mechanisms to implement and enforce those codes. in many jurisdictions, the courts have the power to order changes in policies and practices of both governmental and non-governmental institutions. however, litigation is an expensive and time-consuming process that creates additional stress for the people living with hiv/aids who choose to litigate. thus, it is important to promote the voluntary adoption of appropriate policies and practices. one example in this category is the policies and practices of health care institutions. for example, in the mid s, in british columbia, canada, all hospitals refused to treat aids patients, with the exception of st. paul's hospital, which adopted appropriate policies based on the commitment of the founding sisters of include a right to health, and have obliged the indian government to dedicate re-erage for antiretroviral drugs in its national health insurance plan (elliot et al., another example in this category is the policies and practices of employers. as we showed in chap. , hiv/aids affects the productivity of workers substantially, making it cost effective for companies to have prevention programs and to provide treatment for employees, from a purely financial point of view. business leaders have an economic incentive to invest resources in fighting the epidemic. moreover, as we saw in chap. , firms can have a tremendous impact in promotment. however, it is important to have an overarching framework that ensures the adoption of best practices by individual firms and to minimize overlap between the private sector and the other players that are involved in addressing the pandemic. in this regard, the global business coalition on hiv/aids has provided leadership, particularly in its efforts to identify ways to improve the global business community's response to hiv/aids, including through leadership to dispel myths and stigma, break down workplace barriers and influence community change. given the economic and legal incentives, an effective hiv/aids response the way forward prevention, treatment and human rights providence to care for all who were in need, regardless of financial or social standing (gratham ) . in , the city of philadelphia agreed to resolve a complaint regarding the refusal of emergency medical services personnel to touch or lift a patient because of his hiv status, by paying monetary compensation and agreeing to implement a mandatory paramedic/emt training program on hiv and infectious diseases (john gill smith and united states v. city of philadelphia ) . ironically, "philadelphia" was the name and setting of the first high-profile hollywood film to take aids seriously, in . we can think of hiv/aids as a disaster from the point of view of a country as a whole. unlike other disasters (such as an outbreak of an influenza pandemic), this kind of risk, we need to measure the severity and the frequency of occurrence of that risk. once we measure the risk, we need to find ways of managing the risk in a dynamic way. that means putting a risk management plan in place, monitoring the plan and modifying the plan as events unfold. most often, at the national level, hiv/aids is seen as a public health problem and is managed as such. thus, various measures are taken to reduce the incidence of hiv/aids by taking steps against the main channels through which the disease strikes: ( ) actions to reduce the contamination of the blood supply; ( ) special steps to promote health care for key groups, such as sex workers; ( ) needle exchange programs; ( ) promoting safe sex through the use of condoms; and ( ) minimizing hiv transmission from infected mothers to newborns. disaster unfolds over many years. however, the standard operating procedure for ing prevention among employees and their families and providing access to treatdisaster management also applies to managing hiv/aids risk. for managing any must be a core component of an overall business strategy. another approach to risk management is risk avoidance. at the country level, risk avoidance could imply two extreme actions: quarantining people who are already infected and preventing infected people from coming into the country. neither of these policies is feasible for most countries, as they directly go against human rights. thus, extreme forms of risk management and the respect for human rights pose a tradeoff for a country. cuba provides a striking example of how containment of hiv/aids can be conducted at a national level. cuba started promoting public health messages against hiv/aids in , years before the first hiv case was reported in the country. between and , cuba undertook a massive testing exercise, which tested more than % of the adult population. those who were seropositive were quarantined indefinitely in sanitariums. over the years, cuba has relaxed the rule. today, anybody found seropositive is required to attend an week course. after that, they are free to leave. nearly half the people choose to stay in the sanitariums, where they get free food and a place to stay, along with retraining if they choose to help with the logistics of the sanitariums. such a curtailment of freedom of movement without committing a crime is unprecedented anywhere in the world. it has been criticized by many. it did produce a result that is also unprecedented. cuba has an hiv incidence rate of . %. in the neighboring island of haiti, the rate is times as high, at . %. it should be noted that quarantine of individuals who have committed no crime is not unheard of. there was the case of mary mallon in the united states in better known as the "typhoid mary" -who carried typhoid without every showing any symptoms. she was quarantined against her will for a number of years. similarly, during the outbreak of influenza in the united states in , many families were quarantined on public health grounds. individuals with sars were also quarantined in toronto. the future of hiv/aids presents a mixed picture. while hiv/aids incidence has begun to level off in some high-prevalence countries, new infections have increased in many developed countries. while several science-based prevention strategies need to be scaled up significantly, the increase in mother-to-child prevention has dramatically reduced infections among newborns and male circumcision is a promising new prevention strategy. while millions still lack access to treatment, there has been a large increase in funding, drug prices have dropped dramatically, several key drug patents will expire in the near future and efforts to develop new treatments continue. while stigma and discrimination remain obstacles to effective prevention and treatment, human rights laws have proved to be an effective vehicle for addressing discrimination and increasing access to treatment around the world. thus, while hiv/aids continues to pose a significant threat to public health, there are many signs that progress in fighting this pandemic can and will continue, as knowledge gradually replaces ignorance. travel/immigration ban: background senator jesse helms: cut aids funding experimental aids vaccine falls short randomized, controlled intervention trial of male circumcision for reduction of hiv infection risk: the anrs trial amplía corte protección a militares con vih male circumcision: the road from evidence to practice. division of epidemiology, school of public health, university of illinois at chicago betteridge g ( ) criminal law and hiv transmission or exposure: new cases and developments law as a structural factor in the spread of communicable disease the way forward prevention, treatment and human rights do criminal laws influence hiv risk behavior? an empirical trial hiv disclosure & the criminal law in canada supreme court of canada decision in r v canada's immigration policy as it affects people living with hiv/aids a human rights-based commentary on unaids guidance note: hiv and sex work communicable diseases: challenges for health in the age of migration c fe c/ /chpt eu.pdf. accessed a% human% rights-based% commentary% on % unaids % guidance % zidovudine's patent history look to the future: the war against aids. the economist net benefits: giving bed nets and drugs away free may be the way to deal with malaria criminal law, public health and hiv transmission: a policy options paper protection against discrimination based on hiv/aids status in canada: the legal framework the effect of pregnancy on survival in women infected with hiv: a systematic review of the literature and meta-analysis global hiv prevention working group ( ) bringing hiv prevention to scale: an urgent global priority history, principles and practice of health and halperin d ( ) evidence-based behavior change hiv prevention approaches for sub-saharan africa harvard school of public health program on international health and human rights hamied yk ( ) trading in death lessons not learned: human rights abuses and hiv/aids in the russian federation family, unvalued: discrimination, denial, and the fate of binational same-sex couples under memoir, jesse helms says he was no racist a salute to the sisters. promise fall/winter literature review increasing access to hiv testing and counseling while respecting human rights reasons why human rights should occupy the center of the global aids struggle. open society institute the way forward prevention, treatment and human rights conspiring to kill: gender-biased legislation, culture, and aids in sub-saharan africa new hiv cases drop but rise in young gay men. www.nytimes senator helms's callousness toward aids victims the latino commission on aids supports the hiv nondiscrimination in travel and immigration act discriminación por vivir con vih: fuerzas armadas, a punto del revés, letra s the known hidden hiv/aids epidemic among black men who have sex with men in the united states plos medicine : nyc health ( ) hiv epidemiology and field services research unit report accessed november human rights watch ( ) family, unvalued: discrimination, denial, and the fate park a ( ) assessing a failed aids vaccine mexico: supreme court rules discharge of hiv-positive troops unconstitutional genetic diversity of hiv- : the moving target seeds of change in rwanda sesión pública núm the tuberculosis & hiv debate in immigration law: critical flaws cuerrier ( ) scr , supreme court of canada new mexico court of appeals, nm ohio state court appellate amicus brief us food and drug administration ( ) guidance for industry fixed dose combina antiretrovirals for the treatment of hiv /nr/rdonlyres/ ef e-cf - abb-ab f- adf / / demarzode do human rights matter to health? lancet marde state ( ) texas court of appeal united states academic anti-exclusion arguments. georgetown immigration law journal hivlawandpolicy.org /resources /partial % case % &resource % list-lambda packaged drug products, and single-entity versions of previously approved tarantola d, gruskin s ( ) new guidance on recommended hiv testing and hiv_data/ globalreport/default.asp. accessed the way forward prevention, treatment and human rights consolidated version new law allows needle exchanges in washington modeling health care costs attributable to hiv infection and hiv prevention programs in high-income countries systematic review of abstinence-plus aids epidemic -planning, policy and predictions limited setting: treatment guidelines for a public health approach scaling up antiretroviral therapy in resouurce lawmakers, gay-rights groups protesting new hiv/aids travel unaids/iom ( ) statement on hiv/aids-related travel restrictions international guidelines on hiv/aids and human rights key: cord- -qgqzr n authors: albrecht, harro title: global health. die gesundheit der welt in der internationalen politik date: - - journal: nan doi: . /s - - - sha: doc_id: cord_uid: qgqzr n with the adoption of the millenium development goals in , global health attracted notice to a worldwide public. this article analyzes the origins, the concept and the universal relevance of global health, discusses several international development programs (supported by the usa, the un, as well as and by private organizations) and examines their effects and their sustainability. während dieser sechs tage knüpfte george w. bush an seine am wenigsten gewürdigten außenpolitischen erfolge an. unbemerkt v.a. von der europäischen Öffentlichkeit hatte der us-präsident eines der umfangreichsten gesundheitsprogramme für entwicklungsländer angeschoben. schon hatte er den president's emergency plan for aids relief (pepfar) aus der taufe gehoben und zwei jahre später die president's malaria initiative (pmi). diese entscheidungen waren zwei erkenntnissen zu verdanken: erstens stellte die weltbank fest, dass gesundheitsprobleme in entwicklungsländern keineswegs nur lästige geldvernichter seien, sondern eine fundamentale ursache der armut. zweitens hatte die clinton-administration um die jahrtausendwende die weltweite aids-epidemie als mögliche gefährdung der inneren sicherheit der usa eingestuft. es ging um eine milliarde menschen weltweit, die bis heute keinen zugang zu einem gesundheitswesen haben, um , millionen kinder unter fünf jahren, die jedes jahr durch vermeidbare ursachen sterben, um zusammen fünf millionen menschen, die jedes jahr einer von nur drei krankheiten zum opfer fallen: aids, tuberkulose und malaria. mehr entwicklungshilfe im kampf gegen krankheiten und insbesondere aids, so die hoffnung der us-regierung, würde nicht nur den betroffenen helfen, sondern auch einen spürbaren wirtschaftlichen aufschwung in den ärmsten ländern nach sich ziehen und dadurch weltweit die sicherheitslage verbessern. diese außenpolitischen interessen decken sich mit den humanitären anstrengungen der weltgemeinschaft. unter diesem vorzeichen eröffnet sich die chance auf eine neue, nachhaltige verbesserung der gesundheitssituation der Ärmsten. zum ersten mal besteht die möglichkeit, dass die visionäre erklärung der weltgesundheitsorganisation (world heath organization, who) "gesundheit für alle" von alma ata aus dem jahr gestalt annimmt. doch wirken die außen-und sicherheitspolitischen motive maßgeblicher staaten darin nicht als störfaktoren? am anfang der neuen entwicklungshilfepläne stand ein diplomatisches problem, für das dringend eine lösung gefunden werden musste. john ruggie, zu diesem zeitpunkt persönlicher berater des un-generalsekretärs kofi annan, war mit einer heiklen mission betraut. die vereinten nationen steckten in den vorbereitungen für das gipfeltreffen zum millennium im september in new york. "die regierungen waren tief beunruhigt darüber, dass das treffen ähnlich inhaltsleer verlaufen würde wie das fünfzigste jubiläum der un-gründung", erinnert sich ruggie , der inzwischen politikwissenschaft an der harvard kennedy school of government lehrt. ohne ein vorzeigbares gemeinsames arbeitsziel hätten viele staaten ihre teilnahme abgesagt. also suchte annans berater mit seinen kollegen nach themen, die von möglichst allen staatsoberhäuptern akzeptiert werden würden. gesundheit und entwicklung erschienen unverdächtiger als sicherheitsfragen. die idee kam an, und so zielten schließlich drei von acht beschlossenen millennium-entwicklungszielen ( alle diese anstrengungen führen das wort global im namen. doch was genau ist global health? nach der definition des institute of medicine in washington, d.c. beschäftigt sich global health mit gesundheitsproblemen, welche die nationalen grenzen überschreiten, die lebensumstände und erfahrungen anderer staaten beeinflussen und die am besten durch kooperation gelöst werden können. in global health trifft also definitionsgemäß gesundheit auf außenpolitik. erdacht werden die global health-konzepte vor allem an us-universitäten wie harvard und columbia und dort vor allem an den schools of public health. für diese art von "schulen" existierte bislang im deutschen sprachraum keine entsprechung. das ist insbesondere deshalb erstaunlich, weil die public health-idee sich aus Überlegungen des deutschen arztes und politikers rudolf virchow aus dem . jahrhundert ableitet (goschler (marmot/ wilkinson ) . weil public health dabei nicht nur die pathologie spezifischer erkrankungen, sondern auch die lebensbedingungen des menschen einbezieht, berührt das fachgebiet unter anderem auch fragen der wirtschaft, psychologie, politik und kultur -oder wie rudolf virchow es ausdrückte: "die medicin ist eine sociale wissenschaft, und die politik ist nichts weiter als medicin im großen." global health als ausdehnung von public health im weltweiten maßstab ist eines der umfassendsten wissenschaftsgebiete. es beschäftigt sich mit problemen der lebensumwelt, des handels, des wirtschaftswachstums, der sozialen entwicklung, der nationalen sicherheit und der menschenrechte. weil in entwicklungsländern das geld für staatlich finanzierte individuelle therapien fehlt, ist public health hier die vorherrschende medizinische ausrichtung. dies bedeutet, dass krankheitsprävention priorität vor der behandlung von krankheiten genießt, und wenn therapiert werden muss, dann möglichst nur solche erkrankungen, bei denen mit minimalem einsatz die größte wirkung für die meisten menschen erzielt werden können. viele schwere erkrankungen, etwa fortgeschrittene krebserkrankungen, werden also nicht mit hilfe öffentlicher mittel therapiert. wer eine individuelle gesundheitsleistung dringend benötigt, muss sie in entwicklungsländern selbst bezahlen, und so verwundert es nicht, dass in diesen ländern über achtzig prozent der gesundheitskosten von den kranken übernommen werden. weil global health vor allem public health-methoden anwendet, sind die zielgebiete dieser disziplin die entwicklungsländer. die einseitige ausrichtung des blickes der wohlhabenden staaten auf die ärmeren länder aber erscheint in zeiten der globalisierung wenig sinnvoll. heute liegt es näher, das wort global wörtlich zu nehmen und keine unterschiede zwischen nord und süd, reich und arm zu machen. durch das rapide bevölkerungswachstum, den abbau der handelsschranken und den internationalen massenverkehr ist zum ersten mal in der geschichte der menschheit die gesundheit jedes einzelnen relevant für die gesundheit aller anderen. die klimaerwärmung, v.a. von den industrieländern verursacht, verändert die lebensbedingungen weltweit. die radioaktiven substanzen des explodierten kernreaktors in tschernobyl hatten noch tausende kilometer entfernt auswirkungen auf die gesundheit der menschen. wenn in einem deutschen krankenhaus eine krankenschwester aus malawi oder den philippinen arbeitet, dann fehlt sie in ihrem heimatland. infektionskrankheiten wie influenza oder sars sind unter umständen nur einige flugstunden von einer der megastädte der welt entfernt. umgekehrt übernehmen jene menschen in den entwicklungsländern, die über ein wenig wohlstand verfügen, den westlichen lebensstil mit Überernährung und bewegungsmangel. inzwischen hat die zahl der herzinfarkte und diabetesfälle auch in tropischen breitengraden extrem zugenommen (kawachi/wamala ) . die idee von global health wörtlich zu nehmen hieße aber auch, dass jedes land verantwortung für die gesundheitsprobleme in einem anderem übernehmen muss. genauso wie im zusammenhang mit der Öffnung der weltmärkte und der globalisierung über notwendige neue soziale standards diskutiert wird, braucht auch die weltgesundheit ethische rahmenbedingungen. es darf nicht sein, dass entwicklungen in einem staat auf kosten der bevölkerung eines anderen gehen. ansätze dieses verantwortungsprinzips sind in den internationalen gesundheitsvorschriften der weltgesundheitsorganisation verankert. sie geben der who das recht, im fall von epidemien untersuchungen in einem land durchzuführen und reisewarnungen auszusprechen. viele fragen bleiben bisher jedoch unberücksichtigt -etwa jene, ob etwas unternommen werden soll, wenn medizinisches personal aus einem entwicklungsland durch bessere bezahlung in reiche länder gelockt wird. gleichzeitig eröffnet die globalisierung aber auch chancen, die gesundheit im globalen maßstab zu verbessern. inzwischen haben schwellenländer wie brasilien und indien mit der produktion günstiger medikamente begonnen und beispielsweise die therapie von tuberkulose auch in den ärmsten ländern ermöglicht. die Überwachung von epidemien und die frühwarnung vor naturkatastrophen und hungersnöten über die moderne telekommunikation und internet sind heute besser denn je entwickelt. erfahrungen aus vielen tausend gesundheitsprojekten liegen vor, die wege aufzeigen, wie menschen mit wenig geld geholfen werden kann. allein die orale rehydrationstherapie (ort) mit einer einfachen zucker-salz-lösung rettete millionen durchfallerkrankter kinder das leben (banerjee ; levine ) . daneben sind aufgrund der zunahme chronischer erkrankungen public health-konzepte auch in entwickelten ländern mehr denn je gefragt. global health aber kennt im augenblick vor allem eine blickrichtung: die aus dem reichen norden in den armen süden. der begriff ist zum synonym geworden für gesundheitsbezogene entwicklungshilfe vor allem durch die usa (kickbusch ) . zwar geben die usa mit , prozent des bruttoinlandsprodukts vergleichsweise wenig für die entwicklungshilfe aus. in absoluten zahlen aber überragt diese summe zusammen mit dem gewaltigen privaten spendenaufkommen z.b. von microsoft-gründer bill gates und dem investor warren buffet die entwicklungshilfeausgaben aller anderen länder. die amerikanische agenda folgt einem geist, den der brite alex de waal, direktor des social science research council in new york city, als das ergebnis einer "erlösungs-agenda" beschrieb, "der Überzeugung, dass eine kombination aus geld, technologie und gutem willen jedes problem lösen kann. religiöse gruppen fügen noch den ‚glauben' hinzu" (de waal : ) . so ist die bill & melinda gates-stiftung für ihre suche nach technischen lösungen, etwa neuen impfstoffen, und für ihre zielorientiertheit bekannt. genauso strebt die us-regierung schnell erreichbare ergebnisse an, die der wählerschaft präsentiert werden können. eine umfassende strategie zur langfristigen verbesserung der lebensverhältnisse, wie sie rudolf virchow vorschwebte und wie sie auch an vielen amerikanischen schools of public health gelehrt wird, passt allerdings nicht zu den vorstellungen amerikanischer politik. in den usa ist alles, was im entferntesten nach sozialismus aussieht, verpönt. public health aber ist vom grundgedanken her sozialistisch, weil sie die fürsorgepflicht des staates für die gesundheit der bürger fordert. so glänzen sozialistische staaten wie kuba, der indische bundesstaat kerala oder früher russland bei geringem mitteleinsatz oft mit bemerkenswerten gesundheitsdaten. die durchschnittliche lebenserwartung in kerala beträgt jahre bei einem pro-kopf-jahreseinkommen von rund us-dollar. auf welche weise ideologie und außen-und innenpolitische agenden die neuen großprogramme prägen, zeigt eindrücklich das beispiel von uganda, das im zentrum der neuen global health-bewegung steht. schon kurz nach der machtübernahme klärte ugandas neuer präsident yoweri museveni als einer der wenigen afrikanischen staatsoberhäupter die bevölkerung schonungslos über die neue immunschwächekrankheit aids auf ( de waal ; green ) . museveni war dabei nicht in erster linie von der sorge um die gesundheit der massen getrieben, sondern von jener um die potentielle schwächung seiner streitkräfte. nach der rebellion hatte der sozialist sechzig offiziere zum training nach kuba fliegen lassen. dort waren zu dieser zeit hiv-tests obligatorisch. als der noch ahnungslose ugandische präsident wenig später auf einer konferenz in simbabwe erschien, nahm ihn fidel castro zur seite und warnte seinen bundesgenossen: "du weißt, dass du ein großes problem in deinem land hast?" es hatte sich in kuba herausgestellt, dass achtzehn der getesteten soldaten das tödliche virus in sich trugen. die antiretrovirale therapie war noch nicht weit entwickelt und ohne geld in der staatskasse blieb museveni nichts anderes übrig, als seine landsleute in radiospots, mit plakaten, kundgebungen und theatershows zur enthaltsamkeit und ehelicher treue anzuhalten. das konzept ging offenbar auf, denn in den folgenden jahren sank die aids-rate deutlich. diese erfolgsgeschichte war der anfang des wandels der erkrankung aids zum politikum aids. deshalb ist uganda heute der größte nutznießer des neuen engagements der internationalen gemeinschaft in sachen aids. allein im jahr flossen vom global fund, von weltbank und pepfar millionen us-dollar in die staatskasse ugandas. dies ist mehr als das gesamte gesundheitsbudget für alle anderen krankheiten zusammen genommen. der ununterbrochene strom an aids-gebundenen zuwendungen versetzt den präsidenten in die lage, seinen landsleuten immer neue programme offerieren zu können. mitsprache und demokratische prozesse entwickeln sich unter diesen bedingungen nur zögerlich, und nun steht yoweri museveni im zweiundzwanzigsten jahr seiner alleinherrschaft. man könnte sagen, die aids-hilfsgelder haben diese un-demokratische regierung erst stabilisiert. dass es auch anders geht, zeigt das konzept des global fund. dieser gibt seine gelder zwar direkt an die regierungen und überlässt ihnen die verteilung. in uganda zog er jedoch nach gravierenden fällen von korruption weitere geldzusagen zurück -eine aufsehen erregende maßnahme, die noch heute von ugandas zeitungen intensiv diskutiert wird und die zeigt, wie eine schärfere kontrolle bei der vergabe von hilfsgeldern auch demokratische debatten begünstigen kann. die pepfar-uganda-liason begann mit einem treffen zweier sehr ungleicher männer in einem flugzeug: edward green, medizin-anthropologe aus harvard, und richard holbrooke, ehemaliger us-botschafter bei den vereinten nationen. holbrooke hatte sich schon lange für den kampf gegen aids eingesetzt, weil er die infektionskrankheit für eine größere bedrohung der nationalen sicherheit hielt als etwa die verbreitung von nuklearwaffen und die explosive lage im nahen und mittleren osten. anfang des jahres übernahmen die usa den vorsitz des sicherheitsrates der vereinten nationen, und holbrooke nutzte die chance, um aids auf die agenda zu bringen. zum ersten mal in der geschichte des un-sicherheitsrates war gesundheit der gegenstand der debatte. im folgenden jahr schied holbrooke aus den vereinten nationen aus und setzte sich vehement bei kofi annan und george w. bush für einen aids-fond im umfang von zehn milliarden us-dollar ein. es sollte noch zwei jahre dauern, bis holbrookes vorstellungen sogar übertroffen wurden. gab george w. bush den president's emergency plan for aids relief aus: milliarden us-dollar, auf fünfzehn länder verteilt für einen zeitraum von fünf jahren. ende des jahres flogen green und holbrooke zusammen mit einer -köpfigen delegation auf eine aids-informationstour in vier afrikanische länder. green war begeistert und inspiriert von den anfänglichen erfolgen der treue-kampagne musevenis. im gepäck trug der harvard-professor deshalb ein exemplar seines damals frisch veröffentlichten buches "rethinking aids prevention" (green ) . darin legt green dar, dass er die reduktion der anzahl der sexualpartner für die schärfste waffe im kampf gegen aids halte -wobei er den einsatz von kondomen nicht ausschließe. holbrooke "hat in den ersten tagen mein buch gelesen und war davon sehr angetan. er hat gesagt: das ist wirklich gut", erinnert sich green. aber auch der us-gesundheitsminister tommy thompson hatte im flugzeug gesessen und den medizin-anthropologen nach der reise zum gespräch einbestellt. auf diese weise wurde green zum berater der konservativen us-regierung und uganda einer der hauptempfänger des geldsegens. das daraus resultierende programm war jedoch höchst umstritten. ein drittel des pepfar-geldes sollte zur verfügung stehen für kampagnen zur enthaltsamkeit und treue unter dem motto "abstinence, be faithful and condoms" (abc) -wobei kondome nur unter risikogruppen wie prostituierten und drogensüchtigen propagiert werden durften. die liberale aids-szene in den usa hielt die an christlichen werten orientierte abc-kampagne für eine katastrophale abkehr von der in den usa bewährten strategie des "safer sex und kondome für alle". außerdem bemängelten kritiker, dass pepfar-projekte vollständig parallel zum restlichen gesundheitssystem implementiert würden. sie verfügten über die besseren laborausstattungen, über autos und einen konstanten strom an medikamenten, und sie zahlten dem personal höhere gehälter. dadurch sei das programm zwar effektiv, aber belaste die ressourcen des restlichen gesundheitssystems und sei somit nicht nachhaltig. eine bessere alternative sei das finanzierungsmodell des global fund gewesen, statt das gros der mittel in die us-anstrengung pepfar zu investieren. sicherheitspolitische bedenken des größten entwicklungshilfefinanziers hatten aids auf die internationale agenda gebracht, und die vorstellungen der usa hatten die ausführung der programme geprägt. die konzepte funktionieren im kern noch immer nach dem prinzip der helfenden hand in zeiten des krieges, bei Überflutungen, dürrekatastrophen oder epidemien. dieses herkömmliche, karitative motiv aber verfolgt nicht die langfristige konsolidierung maroder gesundheitssysteme. "wir leben angetrieben durch den gates-buffet-effekt in glücklichen zeiten der globalen public health", schrieb susan erikson ( ) , "doch es gibt ein paar gesundheitsziele, die man nicht mit geld wird kaufen können, weil einflussreiche staaten aktiv eine außenpolitik verfolgen, die diesen zielen diametral entgegengesetzt ist." dazu zählen handelsabkommen, die die ernährungssicherheit bedrohen, lockangebote für medizinisches personal armer länder und multinationale unternehmen, die erfolgreich ihre patente für essenzielle medikamente verteidigen. "wenn andere interessen wie die nationale sicherheit als bedroht angesehen werden, ist gesundheit von zweitrangiger bedeutung", schreibt erikson. (masanja et al. ) . das moratorium zeitigte schon bald einen erfolg: gerade haben wissenschaftliche studien belegt, dass das ostafrikanische land auf gutem wege ist, das millenniumsziel der verminderung der kindersterblichkeit zu erreichen. csis commission on smart power. a smarter, more secure america health is global. proposals for a uk government-wide strategy getting political. fighting for global health rudolf virchow. mediziner -anthropologe -politiker. köln rethinking aids prevention. learning from successes in developing countries globalization and health influence and opportunity. reflections on the u.s. role in global public health case studies in global health. millions saved social determinants of health oslo ministerial declaration -global health. a pressing foreign policy issue of our time aids and power. why there is no political crisis -yet key: cord- -dipjubn authors: serlin, michael h.; dieterich, douglas title: gastrointestinal disorders in hiv date: - - journal: global hiv/aids medicine doi: . /b - - - - . - sha: doc_id: cord_uid: dipjubn nan gastrointestinal disease in human immunodeficiency virus (hiv) spans the entire gi tract from the mouth to the rectum. the spectrum of gastrointestinal symptoms in hiv ranges from odynophagia and dysphagia, to nausea and vomiting, to abdominal pain and fi nally diarrhea and tenesmus. as with normal hosts, gastrointestinal disorders are very common in hiv patients, whether it be from opportunistic infections secondary to the patient's immunosuppressed status, medication induced, or through other etiologies. almost all hiv and aids patients have some gastrointestinal complaints throughout the course of their illness. with the dramatic changes in hiv care because of highly active antiretroviral therapy (art) in the mid- s, the incidence of opportunistic infections are decreasing, and as a result, the clinical picture of gastrointestinal illnesses in hiv is changing. the evaluation of the hiv patient with gastrointestinal complaints requires a thorough history and physical exam, in addition to selected studies, in order to diagnose the correct disease and treat accordingly. patients with hiv and aids typically can have upper gastrointestinal symptoms, which can range from dysphagia, or diffi culty swallowing, to odynophagia, or the feeling of pain upon swallowing. at least one-third of patients with hiv before the art era had esophageal complaints, and the incidence increased with the progression of the disease. most of the symptoms in these patients are secondary to opportunistic infections caused by the patient's immunosuppressed state, and related to the degree of immunosuppression. the most common etiologies of esophageal pathology and esophagitis in aids patients (table . ) are candida species, herpes simplex virus (hsv), and cytomegalovirus (cmv). in addition, there is also an entity of idiopathic esophageal ulcers (ieu) that is also seen in hiv patients, which may be immunologically mediated, or caused by hiv itself. other etiologies of esophageal complaints include malignancy (especially lymphoma and kaposi's sarcoma) and other noninfectious causes. however, with the introduction of protease inhibitors (pis) in and art, and the decreased incidence of aids, more esophageal complaints in hiv these days are related to common etiologies like gastroesophageal refl ux disease (gerd) than opportunistic infections. in addition to the most common symptoms of dysphagia and odynophagia, other symptoms can also suggest esophageal disease in hiv patients, like chest pain, nausea, vomiting, anorexia and weight loss. the symptoms can be acute or have a more chronic, progressive course. in addition, dysphagia is often associated with candidal esophagitis, whereas odynophagia is generally symptomatic of esophageal ulcerative disease. patients can have both dysphagia and odynophagia, and because they also may have more than one illness concurrently, it is imperative to pursue a thorough investigation as to the etiology of esophageal complaints in hiv patients. the evaluation of hiv patients with esophageal symptoms does not defi nitively need to include endoscopy with biopsy, but this is the gold standard, as it allows the physician to visualize the esophageal lumen, and to biopsy affected sites ( fig. . ) . the history and physical exam is obviously important, as it may lead to a discovery of gerd, or pill-induced esophagitis. in addition, patients with disseminated cmv (e.g. cmv retinitis) with esophageal symptoms (especially odynophagia) may respond to cmv antiviral therapy in the absence of diagnostic endoscopy and biopsy. the most common sign on physical exam that relates to esophageal complaints is oral thrush, which can be suggestive of esophageal candidiasis in patients with esophageal complaints. in these patients, especially those with only dysphagia (or dysphagia and odynophagia, but not those with solely odynophagia) it may be benefi cial to document the response from an empiric trial of oral fl uconazole, as opposed to endoscopy. if there is a symptomatic response to the fl uconazole, then it can be presumed the patient had candidal esophagitis and proceed accordingly. in addition to history and physical exam, there are other ways to evaluate esophageal complaints. barium esophagography is relatively insensitive and non-specifi c and should not be used for diagnostic purposes, but the most characteristic fi nding in candidal esophagitis is diffuse mucosal irregularity resulting in a 'shaggy' appearance mimicking diffuse ulceration. cmv and ieu may appear as well circumscribed ulcers that may be shallow or deep, and are indistinguishable on barium swallow. of course, radiography can determine a neoplastic origin to dysphagia in patients with malignancies. another form of evaluation is brush cytology, where a cytology brush is passed through a nasogastric tube and obtains tissue for viral cultures and immunohistochemistry. unfortunately, this leads to large sampling error, because it is done blindly without visualization of the lumen, and misses diagnoses (as patients may have two infectious processes, and ieu cannot be diagnosed). viral culture and cytologic brushings add little in the evaluation of aids patients with esophagitis over endoscopy with biopsy. endoscopy with biopsy generally yields a viral or fungal diagnosis based on culture and hematoxylin and eosin staining (which will exclude a viral etiology); only after several biopsy samples do not show any etiology of the ulcerations can a tentative, exclusionary diagnosis of ieu be made. candidal esophagitis is the most common cause of esophagitis in hiv patients, especially in patients with complaints of dysphagia, or odynophagia and dysphagia. the fungal isolate is generally candida albicans, though other species of candida can also affect the esophagus. it should be suspected in patients with a cd + lymphocyte count of < cells/mm (though can occur at any cd + count), and esophageal symptoms with or without thrush, which can be absent in % of patients. in patients with hiv and new onset symptoms, an empiric trial of standard dosed fl uconazole is an effective strategy, as % of patients in a prospective study responded. if there is no response, endoscopy can be pursued. in patients that fail empiric antifungal therapy, the most common etiology (in % of the patients) is ulcerative esophagitis as opposed to persistent candidiasis. fluconazole is the drug of choice for candidiasis, with a loading dose of mg orally followed by mg daily from - days. clotrimazole troches are also successful, as topical treatment of esophageal candidiasis, but nystatin is not. itraconazole and ketoconazole are effi cacious systemic therapies, but not as effective as fl uconazole. , amphotericin b is also a helpful therapy, but is generally used only in azole-resistant patients because of the toxicity of the medication. low-dose amphotericin ( . - . mg/kg per day for - days) is usually adequate. caspofungin can also be used in candidal esophagitis, and is felt to be as effi cacious as fl uconazole and well tolerated. however, it is only available in intravenous form and is more expensive, but may be the drug of choice for azoleresistant mucosal candidiasis because of the relative lack of toxicity compared with amphotericin b. primary prophylaxis of candidal disease is not recommended because of the non-life-threatening nature of the disease, the effectiveness of acute therapy, and the risk of antifungal resistance. while candida is the most common esophageal pathogen, it can also occur in addition to ulcerative esophagitis in hiv patients. cmv esophagitis is the most common etiology of odynophagia in hiv patients and therefore esophageal ulcerations, up to % of patients in one prospective study. fever and substernal chest pain can be reported in addition to odynophagia, and thrush can be concomitant, but dysphagia is very uncommon. the diagnosis of cmv is best made by endoscopy and biopsy, with the pathology showing viral cytopathic effect in the gastrointestinal mucosa via intranuclear inclusions. immunohistochemistry is also helpful for confi rmation, as viral cultures are less sensitive and specifi c. cmv is the most common viral pathogen in the esophagus in hiv patients, and esophagitis is the most common extraocular manifestation of cmv. it can appear as a diffuse esophagitis, single or multiple ulcers, or giant ulcers involving the whole esophagus, and generally occurs when the cd + lymphocyte count is < . it may be discovered only after treatment for candida, as they may exist concurrently in % of patients. the incidence of cmv esophagitis has declined dramatically in the art era. treatment for cmv esophagitis involves a wide array of antiviral medications, namely ganciclovir, valganciclovir, foscarnet, and cidofovir. ganciclovir was the fi rst agent used to combat cmv and has the most data behind it; the response rate is about - %. it is given intravenously in a - week induction period, - mg/kg per day, but has dose limiting side-effects, mainly bone marrow suppression (and resultant neutropenia and thrombocytopenia). oral ganciclovir can also be used as maintenance therapy, but the data is limited. intravenous foscarnet ( mg/kg b.i.d., - weeks) is seen as equally effective to intravenous ganciclovir in the treatment of cmv esophagitis, but comes with a nephrotoxic side-effect profi le; however, randomized studies have shown equal effi cacy and safety. foscarnet is generally used in cases of clinical failure after ganciclovir induction. oral valganciclovir ( mg/ day) has not been tested in cmv esophagitis, but does have % of the bioavailability of intravenous ganciclovir. cidofovir also can treat cmv, but is not typically used because of nephrotoxicity. hsv esophagitis is a relatively uncommon cause of esophageal ulceration in hiv patients compared with cmv and ieu. the endoscopic appearance is described as being well circumscribed and having a 'volcano' like appearance, distinguishing them from the ulcers seen in cmv infection, which tend to be linear or longitudinal and are deeper. treatment is with oral acyclovir ( - mg/kg per day), though if patients have diffi culty with swallowing, intravenous acyclovir can be used. valacyclovir and famci-clovir can also be used because of their effi cacy and convenient dosing schedules. foscarnet intravenously ( mg/kg b.i.d.) is used in cases of acyclovir resistance. secondary prophylaxis with valacyclovir ( - mg/day) is recommended in patients with frequent relapses. idiopathic esophageal ulcers (ieu) are a diagnosis of exclusion if none of the pathologic, fungal, or viral studies return a diagnosis. the treatment of idiopathic esophageal ulcers is done with oral corticosteroids, generally starting at mg of oral prednisone daily. if the patient cannot take medications orally, then the corticosteroids can be given intravenously. in addition, thalidomide can also be used for ieu if corticosteroids are not effi cacious. in addition to the infections and ulcerations discussed above, there are other esophageal issues in hiv, namely motility and neuropathic issues. there is a form of hiv neuropathy that could lead to gastrointestinal complaints, like gastroparesis. these would be treated symptomatically, with prokinetic agents like metoclopramide. additionally, in patients with both symptomatic esophageal complaints, as well as those that are asymptomatic, there are fi ndings of esophageal motility abnormalities. this is probably because of the neurotropic nature of hiv leading to autonomic dysfunction in the gastrointestinal neurologic plexus. the problems associated with the stomach in hiv patients are similar to the stomach problems of non-hiv infected individuals. opportunistic infections that affect hiv patients typically do not affect the stomach. symptoms and presentation are often related to abdominal pain, nausea or vomiting. the most common manifestations of gastric illness in hiv patients is like the general population, namely gerd, peptic ulcer disease (pud) and gastritis. care needs to be used when prescribing histamine- (h ) blockers or proton-pump inhibitors (ppis), however, as these medications can interact with art, especially ppis. work-up is the same as with the general population, and endoscopy with biopsy is the gold standard for diagnosis. helicobacter pylori, a common cause of peptic ulcer disease in non-hiv positive patients, seems to have a decreased incidence in hiv patients compared with the general population; cmv may actually be the leading cause of pud in hiv patients. as far as actual hiv-related gastric pathology, gastric lymphoma, kaposi's sarcoma, and some of the opportunistic organisms (e.g. cmv, tuberculosis, toxoplasmosis, and cryptococcosis) can be seen. in addition, dyspepsia, nausea and vomiting can all be related to the side-effects of various antiretroviral medications. one of the most common complaints of hiv patients is diarrhea. the reasons for diarrhea are multifold, but most commonly relate to opportunistic infection and antiretroviral medications. a more in depth coverage of diarrheal illness in hiv patients is discussed later in ch. : etiology and management of diarrhea in hiv-infected patients and impact on antiretroviral therapy, but an overview will follow here. as with esophageal disease, the incidence of opportunistic infections has decreased in the art era, though the incidence of chronic diarrhea has remained steady even in the art era. the evaluation of diarrhea includes a thorough history and physical, as much can be determined from just eliciting the patient's history of symptoms. if the diarrhea occurs with upper abdominal cramps, or bloating, this suggests an upper intestinal source, or enteritis. bloody diarrhea, tenesmus, and lower abdominal cramping imply colonic involvement. in addition, patients with a history of receptive anal intercourse have a higher involvement of colitis and sexually transmitted pathogens (e.g. gonorrhea, hsv, etc.) in the anorectal area. homosexual or bisexual men have a -fold higher incidence of diarrhea than patients in other risk groups. obviously, travel and diet history can also be important in the histories of hiv patients with diarrhea. as with other aspects of hiv, opportunistic infections tend to be more common in the setting of lower cd + lymphocyte counts (and therefore greater immunosuppression). the diagnostic studies involved in the work-up of diarrhea in the hiv patient are similar to those in the general population. in addition to history and physical exam (exam specifi cally adds little to diagnosis, other than evidence of malnutrition), the fi rst route of investigation is often the stool examination. the tests to order include bacterial culture, clostridium diffi cile toxin assay, as well as looking for ova and parasites, especially isospora, cryptosporidium, and microsporidia. these generally need to be specifi ed as potential pathogens when the sample is sent to microbiology when looking at ova and parasites. in addition, a gram stain or methylene blue stain for fecal leukocytes can also be helpful, as evidence of fecal leukocytes may point towards a picture of colitis. another form of non-invasive testing is blood cultures and serologies, which can be helpful for the diagnosis of systemic opportunistic infections like mycobacterium avium intracellulare (mai) or viral etiologies like cmv. especially in the patients who have diarrhea and fever, mai may be a possibility. however, with all of these etiologies, a diagnosis may be treated, and symptoms may still persist as secondary infections may also be present. for colitis, a barium enema or abdominal radiography may detail the presence of a toxic megacolon, a complication of clostridium diffi cile colitis. in addition to the non-invasive studies listed above, in the absence of a diagnosis, the workup for diarrhea should include some invasive studies as well. the fi rst step is generally a fl exible sigmoidoscopy, which can give visualization of the colon (to diagnose or rule out pseudomembranous colitis, among other etiologies) and provide tissue for biopsy. abnormal tissue should be biopsied, but if the mucosa is normal then random tissue can be sent. the fl exible sigmoidoscopy is better than the alternatives as it does not require sedation. if small intestinal etiology is suspected, an egd (going past the second portion of the duodenum) can help determine the cause of the diarrhea through biopsies of the small bowel, sent not only for pathology, but also electron microscopy and culture analysis. if the fl exible sigmoidoscopy is nondiagnostic, and there is still no diagnosis from other studies, a colonoscopy can be performed so more biopsies can be done to rule out opportunistic infections, especially in the ileum. this is rarely done, however, and in general, the absence of defi nitive diagnosis leads to treatment and evaluation (as will be discussed later). the symptoms associated with enteritis are typically associated with diarrhea and prolonged malabsorption leading to malnutrition. this is generally because of opportunistic infections, and, similar to other pathologies in hiv patients, the incidence of enteritis has decreased in the highly active antiretroviral therapy (art) era. the main symptoms of enteritis are copious voluminous diarrhea (> l/day) with dehydration and malabsorption, as opposed to colitis, which is a bloody, painful diarrhea. the work-up of enteritis is detailed above, but specifi cally should include stool studies, and, if non-diagnostic, esophagogastroduodenoscopy (egd) with biopsy. the etiologies of enteritis in hiv patients are multifold, and include bacterial, viral, infections of the small intestine (enteritis) fungal, and parasitic pathogens. these can be diagnosed by the stool studies detailed earlier. parasites may be the most common etiology for enteritis, especially in those patients not on art and greatly immunosuppressed. parasites are typically diagnosed through stool analysis for ova and parasites, including direct fl uorescent antibody (dfa), enzyme-linked immunosorbent assay (elisa) or polymerase chain reaction (pcr). light microscopy can be used, though pcr can be diagnostic at much lower levels of parasitic infection. cryptosporidium parvum is the most commonly identifi able pathogen in aids related persistent diarrhea, especially in patients with cd + lymphocyte counts < . it is typically treated with paromomycin - mg every - h orally, or azithromycin - mg four times a day, though albendazole mg twice a day has also shown to be effective. nitazoxanide ( g twice daily for at least weeks) can also be used in the treatment of cryptosporidiosis, but a cure is generally not possible if the cd + lymphocyte count is < . however, a study with children showed no benefi t to nitazoxanide at all in hiv+ children (just hiv seronegative ones). hyperimmune bovine colostrums can also be used, but typically not to cure the parasitic infection. microsporidiosis is the next most commonly identifi able refractory diarrhea in hiv patients. this can be treated with albendazole as well ( - mg every h orally) but most cases are poorly responsive to treatment and require indefi nite therapy. isospora belli is rare in the usa, but is more common in developing countries. trimethoprim-sulfamethoxazole, one double strength tablet every h for days is the treatment of choice, but pyrimethamine - mg four times daily (with folinic acid mg orally four times daily) is acceptable for patients with allergies to sulfa medications. lastly, giardia lamblia and amoebic dysentery can also occur in hiv patients, at the same incidence as the general population, and can be treated with metronidazole mg thrice daily for - days, or tinidazole g orally once for giardiasis, days for amebic dysentery. for strongyloidosis, thiabendazole mg/kg twice daily orally is the drug of choice. albendazole seems to be active against all of the parasitic organisms associated with diarrhea in hiv patients, and could be the fi rst line of therapy when parasitic infection is suspected, pending microbiological study. with all of the aforementioned parasites, treatment cannot only be targeted at the pathogen, but also at the diarrheal symptoms, with the use of somatostatin analogs like octreotide to try to reduce the amount of diarrhea. in addition, since the para-sites are both more common and more chronic at lower cd + lymphocyte counts, art, which reduces the degree of immunosuppression, can also be curative. opioids such as tincture of opium or codeine can provide symptomatic relief in cases of severe diarrhea through its constipating actions, as well as pain relief. bulking agents, lactose-free diets, and antidiarrheal medications like diphenoxylate with atropine or loperamide are also benefi cial in treating diarrheal symptoms. viral infection in hiv patients can cause diarrhea, typically through colitis, but also rarely through an enteritis. cmv, in addition to causing esophagitis, can also affect the gi tract through diarrheal illness, and runs the spectrum from asymptomatic carriage to severe diarrheal illness including appendicitis, bleeding and perforation. it typically occurs in the setting of severe immunosuppression with a cd + lymphocyte count < . the diagnosis of cmv enterocolitis is best made through demonstrating a viral cytopathic effect in tissue specimens, but viral stool cultures can also signify disease (though are less sensitive). the treatment for cmv enterocolitis is mainly ganciclovir and foscarnet, as described earlier in the esophagitis section. valganciclovir may not achieve adequate bioavailability because of the enterocolitis. other viruses can affect the hiv patient gastrointestinal tract, including rotavirus, adenovirus, norwalk virus, or unusually, picornaviruses, and coronaviruses. these tend to be less common than the other pathologies previously described, and are diffi cult to diagnose as well. adenovirus can cause a hemorrhagic colitis; acute diarrhea is seen in patients with only adenovirus in stools, but patients with adenovirus on biopsy specimen generally have a chronic diarrhea. hsv can cause diarrhea via systemic infection in end-stage hiv patients, or can cause a colitis and proctitis through hiv mucosal lesions. hsv can be treated with acyclovir, valacyclovir, famciclovir, or, if acyclovir resistant, foscarnet (as previously described in the esophagitis section). in addition, hiv itself may be a cause of hiv enteropathy and a diarrheal pathogen, and may be identifi ed in gut tissue in up to % of patients, but this is controversial. idiopathic aids enteropathy, on the other hand, is the term used for a chronic diarrhea in an aids patient that is without identifi able pathogen or diagnosis (despite intensive investigation). mucosal hyperproliferation is noted on biopsy. for these etiologies, in addition to art to increase cd + lymphocyte count and reduce immunosuppression, should be treated symptomatically with bulking agents, antidiarrheals, and opioids. the combination of antidiarrheal therapy with art has been shown to be more benefi cial than antidiarrheal therapy alone in hiv patients with chronic diarrhea. other agents that can cause enteritis include mycobacterium avium intracellulare (mai) and pneumocystis jiroveci (pcp). small intestinal disease is the most common site of gastrointestinal luminal involvement by mai. it is often seen with diffuse small bowel infi ltration (mimicking whipple's disease) and causes severe malabsorption in patients with cd + lymphocyte counts of < . if a malabsorptive diarrhea occurs with fever and night sweats, in addition to weight loss, mai must be considered, and blood cultures or a bone marrow biopsy may be diagnostic for disseminated mai infection. diagnosing mai enteritis is more diffi cult, however, as a positive stool is not diagnostic for gastrointestinal disease (though can suggest subsequent disseminated disease). an endoscopic biopsy and acidfast staining can show acid-fast bacilli and give an ideal diagnosis. treatment is with a multitude of options, using combinations of clarithromycin mg twice daily, ethambutol - mg orally daily, azithromycin mg daily, rifampin mg daily, rifabutin mg daily, amikacin mg/kg three times weekly, and ciprofl oxacin mg twice daily. these can reduce, but not eradicate, mai. luminal tuberculosis can also occur as an example of extrapulmonary involvement, but is rare; in contrast to mai, it can generally be treated to cure with antituberculous therapy. pneumocystis jiroveci (pcp) can also be seen as the cause of diarrhea in hiv patients, but is very uncommon, especially in the setting of pcp prophylaxis for aids patients; treatment is with antipneumocystis therapy, generally with trimethoprim-sulfamethoxazole. bacterial infections in hiv patients typically cause a picture of colitis instead of enteritis, with bloody diarrhea and tenesmus. the most common bacterial pathogens seen in hiv patients include salmonellae, shigella, e. coli, campylobacter jejuni, and clostridium diffi cile. salmonellosis is times more common in hiv patients than in immunocompetent hosts, and recurrent salmonella bacteremia establishes the diagnosis of aids in an hiv patient. the diagnosis is straightforward, as salmonella can normally be cultured in stool specimens in addition to blood culture results. salmonella gastroenteritis can present with either watery diarrhea or dysentery (mucopurulent diarrhea) with or without fever, abdominal pain, or nausea and vomiting. though the diarrhea may be self-limited, the treatment is generally ciprofl oxacin mg orally twice a day, for - weeks, for eradication. shigella has a similar presentation to salmonellosis, with a similar wide spectrum of presentation of illness. it does come with a high rate of severe complications, including anemia, hypoglycemia, sepsis, hemolytic uremic syndrome, disseminated intravascular coagulopathy and renal failure, with which mortality obviously increases. it also can be treated with ciprofl oxacin - mg twice a day orally for - days, and is diagnosed by stool culture as well. campylobacter jejuni generally presents as a watery diarrhea, and its incidence is probably decreased due to widespread pcp prophylaxis with trimethoprimsulfamethoxazole. it is typically harder to culture from stool, and may be diagnosed by endoscopic biopsy. antimicrobial therapy is not essential, though erythromycin - mg orally four times daily, or ciprofl oxacin mg orally twice a day for - days may reduce the duration of the illness. e. coli may be seen (in any of several strains), and, like the other enteric bacterial diarrheal illnesses, can be treated with a fl uoroquinolone like ciprofl oxacin. as illustrated, in cases of suspected bacterial diarrhea, ciprofl oxacin would cover most enteric pathogens and would be the empiric drug of choice. clostridium diffi cile is seen in hiv patients not only in the presence of antibiotic therapy, but also in the absence of recent antibiotic therapy. the most common antibiotics that cause c. diffi cile are clindamycin, ampicillin, cephalosporins and aminoglycosides. the clinical presentations and response to therapy are not different in hiv patients than in patients without hiv. diagnosis is made by detecting c. diffi cile toxin in stool assay, and treatment is with metronidazole - mg orally every - h for - days, or tinidazole, in addition to stopping the offending initial antibiotic therapy. in resistant cases, oral vancomycin mg every h can be used, as can rifaximin mg three times daily, though it is not as effective as vancomycin. in cases of suspected c. diffi cile without diagnosis via stool toxin assay, a fl exible sigmoidoscopy can look for pseudomembranous colitis, which can be diagnostic for c. diffi cile. fungal etiologies of diarrhea in hiv patients are relatively rare, but can occur in patients with immunocompromised states and low cd + lymphocyte counts. gastrointestinal histoplasmosis appears to be the most commonly described fungal etiology of diarrhea in hiv patients, and typically occurs in the colitis setting of a systemic infection. diagnosis is made by fungal culture and smear of tissue or blood, and treatment is with amphotericin b . - mg/kg per day intravenously initially, with maintenance therapy with itraconazole mg orally daily. coccidiomycosis and cryptococcosis are also rare, and occur in the presence of systemic infections as well. in addition, as candidal infections are the most common opportunistic infections of hiv patients, a dehydrating diarrhea can also occur as a manifestation of the infection. obviously, not all causes of diarrhea in hiv patients are secondary to opportunistic infections. several noninfectious etiologies of diarrhea in hiv patients can occur as well, including the most common, drug-induced diarrhea. the most common drugs that cause diarrhea in hiv patients are nucleoside reverse transcriptase inhibitors (nrtis) and protease inhibitors (pis). with protease inhibitors, diarrhea is the most common side-effect reported with nelfi navir and saquinavir, most commonly occurs at the initiation of treatment, and is a cause of cessation of therapy and lack of adherence to treatment. newer agents like lopinavir-ritonavir seem to cause less diarrhea than older pis like nelfi navir. treatment is generally guided towards treatment of symptoms, namely with bulking agents or antidiarrheals like loperamide. other causes of diarrhea in hiv patients include infl ammatory bowel disease, including crohn's disease and ulcerative colitis, neither of which have increased incidence in hiv patients. treatment is tailored according to the disease process itself, though an active disease process may decrease cd + lymphocyte count; this may be reversed by colectomy. in addition, aids related illnesses that are noninfectious but can also cause diarrhea and gastrointestinal issues include lymphoma and kaposi's sarcoma, both of which are diagnosed by biopsy. infi ltration of the mucosal tract by the neoplasm can lead to diarrhea and weight loss. anorectal disease is a big component of hiv gastrointestinal care, especially among homosexual males. interestingly, the incidence of anorectal pathology in hiv patients has not been affected by art. many anorectal pathologies are seen in hiv patients, including anal fi stulas and fi ssures, perirectal abscesses, ulcerations and proctitis (box . ). in addition, anal neoplasms as a result of human papillomavirus (hpv) and other etiologies can also occur. anorectal carcinoma has an increased incidence in both hiv patients and among homosexual males, and is the fourth most common malignancy seen in hiv; hiv+ homosexual men have twice the incidence than hiv negative homosexual men. anal squamous cell carcinoma is frequently associated with squamous intraepithelial neoplasia and hpv, much like cervical carcinoma, and can be detected by anorectal cytology, similar to papanicolaou smears. the gold standard for diagnosis of anorectal neoplastic disease is still anoscopy with biopsy, though anorectal cytology can be useful as a screening test. in addition to anal carcinoma, other anorectal symptoms are common in the hiv population, especially among homosexual males. anal condyloma is the most common hiv related anal pathology, and is associated with hpv infection; treatment options include a variety of surgical options, including cryotherapy. the four most common infectious causes of proctitis in men who have sex with men are gonorrhea, herpes simplex, chlamydia and syphilis. gonorrhea and chlamydia are typically treated together with ceftriaxone mg i.m. once and azithromycin g orally once; fl uoroquinolones, oral cephalospo- rins and doxycycline ( mg orally twice a day for days) can also be used. primary syphilis is treated with benzathine penicillin g . million units i.m. once (or doxycycline mg twice daily for weeks if penicillin allergic). hsv infections, as described earlier with esophagitis and colitis, can also cause perianal and rectal ulcerations, with associated symptoms of tenesmus, pain, and bleeding. treatment is with antiherpetic medications like acyclovir, valacyclovir, or famciclovir, as explained earlier, with foscarnet in acyclovir-resistant cases. other etiologies of proctitis include lymphogranuloma venereum, as well as other causes of colitis detailed above; clinical overlap can also happen in hiv patients. in addition to a thorough physical examination, all patients with anorectal symptoms should have anoscopy and sigmoidoscopy with mucosal biopsy to look for fi ssures, perirectal abscesses, and fi stulas in addition to searching for opportunistic infections, with microbiological studies sent for viral, fungal and bacterial cultures. oesophageal symptoms, their causes, treatment and prognosis in patients with aids esophageal motility disorders in hiv patients odynophagia from aphthous ulcers of the pharynx and esophagus in aids chronic idiopathic esophageal ulceration in aids: characterization and treatment with corticosteroids declining prevalence of opportunistic gastrointestinal disease in the era of combination antiretroviral therapy fluconazole compared with endoscopy for human immunodefi ciency virus-infected patients with esophageal symptoms aids therapy prospective endoscopic characterization of cytomegalovirus esophagitis in patients with aids prospective comparison of brush cytology, viral culture, and histology for the diagnosis of ulcerative esophagitis in aids natural history of hivassociated esophageal disease in the era of protease inhibitor therapy prospective evaluation of oropharyngeal fi ndings in human immunodefi ciency virusinfected patients with esophageal ulcer etiology of esophageal disease in human immunodefi ciency virusinfected patients who fail antifungal therapy comparison of oral fl uconazole and clotrimazole troches as treatment of oral candidiasis in patients infected with human immunodefi ciency virus oropharyngeal candidiasis in patients with aids: randomized comparison of fl uconazole versus nystatin oral suspensions fluconazole versus itraconazole for candida esophagitis in aids fluconazole compared with ketoconazole for the treatment of candida esophagitis in aids: a randomized trial a randomized double-blind study of caspofungin versus fl uconazole for the treatment of esophageal candidiasis esophageal ulceration in human immunodefi ciency virus infection: causes, response to therapy, and long-term outcome frequency of positive tests for cytomegalovirus in aids patients: endoscopic lesions compared with normal mucosa cytomegalovirus infection in patients with hiv infection cytomegalovirus and candida esophagitis in patients with aids treatment of cytomegalovirus esophagitis in patients with acquired immune defi ciency syndrome: a randomized controlled study of foscarnet versus ganciclovir foscarnet treatment of cytomegalovirus gastrointestinal infections in acquired immunodefi ciency syndrome patients who have failed ganciclovir induction herpes esophagitis: clinical syndrome, endoscopic appearance, and diagnosis in patients successful foscarnet therapy for acyclovir-resistant mucocutaneous infection with herpes simplex virus in a recipient of allogeneic bmt a pilot study of oral corticosteroid therapy for idiopathic esophageal ulcerations associated with human immunodefi ciency virus infection thalidomide for the treatment of esophageal aphthous ulcers in patients with human immunodefi ciency virus infection. national institute of allergy and infectious disease aids clinical trials group low prevalence of helicobacter pylori but high prevalence of cytomegalovirusassociated peptic ulcer disease in aids patients: comparative study of symptomatic subjects evaluated by endoscopy and cd counts the changing etiology of chronic diarrhea in hiv-infected patients with cd cell counts less than cells/mm effect of nitazoxanide on morbidity and mortality in zambian children with cryptosporidiosis: a randomised controlled trial management of protozoal diarrhoea in hiv disease management of diarrhea in hiv-infected patients palliative care and aids: -gastrointestinal symptoms enteric viral infections as a cause of diarrhoea in the acquired immunodefi ciency syndrome impact of protease inhibitors on the outcome of human immunodefi ciency virus-infected patients with chronic diarrhea atypical mycobacterial infection of the gastrointestinal tract in aids patients mycobacterium avium complex in the respiratory or gastrointestinal tract and the risk of m. avium complex bacteremia in patients with human immunodefi ciency virus infection pneumocystis colitis in a patient with the acquired immunodefi ciency syndrome risk factors for primary bacteremia and endovascular infection in patients without acquired immunodefi ciency syndrome who have nontyphoid salmonellosis disseminated histoplasmosis in the acquired immune defi ciency syndrome: clinical fi ndings, diagnosis, and treatment, and review of the literature management of protease inhibitorassociated diarrhea differences in rates of diarrhea in patients with human immunodefi ciency virus receiving lopinavir-ritonavir or nelfi navir infl ammatory bowel disease in individuals seropositive for the human immunodefi ciency virus anorectal pathology in hiv/aids-infected patients has not been impacted by highly active antiretroviral therapy cancer incidence in a population with a high prevalence of infection with human immunodefi ciency virus type anorectal cytology as a screening tool for anal squamous lesions: cytologic, anoscopic, and histologic correlation etiology of clinical proctitis among men who have sex with other men key: cord- -s omm authors: kaufman, joan title: civil society involvement in national hiv/aids programs date: - - journal: hiv/aids in china doi: . / - - - - _ sha: doc_id: cord_uid: s omm globally, the aids response relies on active participation of nongovernmental organizations (ngos) and civil society. in china, the government is the main provider of health and social services, and the role of ngos is more limited than in other countries. despite this, china has opened the door for ngo participation in its aids response, initially because of donor pressure but increasingly due to official acknowledgment of the important role these groups play in controlling the epidemic. since the first aids ngos were established in china in the s, chinese aids ngos have made unique contributions to china’s aids response in critical areas like access to drugs, support for treatment compliance, outreach to marginalized at-risk groups, and efforts to reduce stigma among marginalized populations. however, there has been a substantial drop-off in donor funding in recent years, and although the chinese government has filled the funding gap, demonstrating its commitment to the sector, recent policy moves toward greater control over the work and funding of ngos threatens their survival. thus far, china’s aids response has been noteworthy, but these new ngo funding and regulatory developments pose significant challenges to the next phase of outreach, prevention, treatment, and care. in the last years, china's aids response has gone from denial to global example. the combination of a strong national authority with resources and political will and a determination to apply evidence-based approaches has demonstrated the importance of both. in the years following the sars epidemic in , china's public health leaders have aggressively analyzed and addressed their hiv/aids epidemic, putting in place pragmatic new policies and programs like harm reduction for people who inject drugs (pwid) and test-and-treat programs for large numbers of previously unidentified people living with hiv (plwh). in china, where government is the main actor for policy formulation and service provision, the role of nongovernmental organizations (ngos) has historically been weak. nevertheless, china's hiv/aids response has provided an opportunity for its fledgling ngo community to demonstrate its importance as an essential partner in achieving national goals, in this case the control of china's hiv epidemic. globally the hiv/aids response relies on active participation of ngos and civil society, and important progress has been made in the response due to their advocacy in critical areas like access to medicines, treatment compliance support, and outreach to marginalized at-risk groups. china has opened the door for ngo participation in the response, partly due to donor pressure, but also because of official acknowledgment of the important role these groups must play in controlling the epidemic. there is now strong policy support for the role of ngos in china's hiv/aids response, but this role is under threat as the political space for ngos shrinks. this may threaten future efforts to control china's hiv epidemic. in this chapter, the unique contributions of china's hiv/aids ngos and the expansion of the political space for their role over the last years are reviewed. additionally, recent government moves to more closely control ngos, and their work and funding through more restrictive legislation is discussed as this may undermine china's success in controlling the epidemic in the coming years. since the beginning of the global aids epidemic, ngos have played a decisive role in the response, both for advocacy and for services. groups representing plwh have a mandated role in most international and national aids policy, program, and funding bodies. advocacy groups representing gay men and aids patients in the "global south" have put pressure on governments and industry to increase funding and access for treatment and prevention programs. this led to new norms about ensuring access to essential medicines and lifesaving drugs in poor countries. services provided by aids ngos, for outreach to gay men and other men who have sex with men (msm), condom distribution and promotion for sex workers, syringe exchange for pwid, youth sex education programs, sex worker legal protection services, treatment and support to aids patients, aids orphans support programs, and many other critical parts of global and national aids programs, have been a key feature of successful aids responses in many countries. these groups have been able to reach and represent hidden and underrepresented groups with essential risk-reduction education, recruitment for hiv testing and treatment, and assistance in accessing care and support. these ngos have also played an important role in representing the needs and perspectives of marginalized groups in policy and program formulation. once effective aids treatment became available in the s, community groups and local ngos became the backbone of aids treatment support in rural communities where trained medical personnel are scarce (farmer et al. ). many of the important advances in the aids response have come through ngo organizing and advocacy. for example, act up in the united states (us) pushed for fast tracking approvals for aids medications. the treatment access campaign in south africa spearheaded a global movement for affordable aids drugs (heywood ). and finally, sonagachi in india demonstrated that protecting sex workers' rights increased their condom use and found that in project cities, hiv prevalence among sex workers was % compared to other indian cities where it exceeded % (jana et al. ) . these examples and many others attest to the effectiveness of both peer group approaches and prevention services provided by ngos and their value for supporting treatment programs in their communities. the participation of ngos in the aids response is mandated in numerous international agreements from global agencies. the joint united nations programme on hiv/aids (unaids) and the united nations (un) general assembly (ga) both support the essential role of civil society in responding to the epidemic, and unaids includes ngo representatives on its board. the global fund to fight aids, tuberculosis, and malaria (hereafter the global fund) requires civil society participation in its governance board, the ccm (country coordinating mechanism), for proposal submission and execution. furthermore, the "gipa" principle ("greater involvement of people living with hiv/aids") is promoted by unaids and calls for the greater participation in the response of people infected and affected by hiv. this has become an important mechanism for patient groups to form and participate in policy and program decision-making as well as service delivery. these global norms have secured a novel and secure political space for ngos in the global aids response (sidibé et al. ). while ngos are fully part of the architecture for service provision, governance, and advocacy in many countries, they have a more restricted and different role in china. there has been rapid growth of the civil society sector in china in the last years. as of , there were approximately foreign ngos in china and many times more domestic ngos-roughly , that were registered and perhaps as many as three million unregistered (hsu et al. ) . in other countries ngos often deliver direct services, but in china, the government system is the main provider of health and other social services to its vast population. as the number of chinese ngos has expanded, some have assumed roles in service delivery in partnership with government, but most operate as research organizations and as advocacy groups on issues like the environment, energy policy, hiv/aids, consumer rights, legal reform, and other issues of social and political concern. many of these organizations are linked to global and transnational networks, which have provided important support both financially and on strategy development, often in collaboration with global agencies and bilateral and multilateral donors. unique to china is the gongo sector-government-sponsored ngos. these parastatal agencies operate under the leadership of respective technical ministries or party-led organizations, and they are often led by former government officials. many receive government funding to carry out community-based or donor-funded initiatives through their networks at province and local levels. the ngo sector in china is highly restricted and governed by laws and regulations aimed at preventing anti-government political actions. the registration process for independent chinese ngos has involved registration with the ministry of civil affairs, which has included identification of a sponsoring government agency and a minimum amount of operating capital. requirements for social organizations include having an office, professional employees, and funds of , rmb, while requirements for "people-run non-enterprise" organizations include having an office, professional employees, and funds of , - , rmb. many ngos do not bother to officially register with the ministry of civil affairs and operate either without any registration or register as a company, a much easier path to legal status. some service-providing ngos work closely with government agencies or with gongos either through direct contract work or as members of advisory and governance boards, like the global fund's ccm. but other ngos, especially those doing advocacy or research, can be viewed with suspicion by government leaders, especially at the local level, who see them as outside government supervision and authority structures. there are restrictions on establishing nationwide networks (except for gongos). a new law, which went into effect at the start of , has shifted oversight of foreign ngos from the ministry of civil affairs to the public security bureau, a move that will likely increase local mistrust. under the new law, foreign ngos are subjected to close scrutiny by the government and by police who have been given the right to question workers, inspect and close offices, review documents, and seize assets. only a fraction of foreign ngos in china has yet re-registered under the new law, and it is expected that some will instead pull out of the country (gan ). in china as elsewhere, the highest-risk groups for hiv infection are often among the most highly stigmatized groups in society (e.g., gay men, drug users, sex workers). the necessity of reaching these groups with hiv prevention services has contributed to limited societal acceptance and to a more sympathetic attitude to the ngos representing them. the hiv/aids response has often been cited as an example of how the policy environment has expanded for ngos in china. the combination of internal recognition of the essential roles that such ngos have played in the global response and external pressures and advocacy through funding mandates and global norms promoted by international partners has pushed forward a more embracing policy environment (kaufman ). the first time a government program involving ngos became involved in china's aids response was in and happened somewhat accidentally. this represented a milestone event in the history of ngo participation in china's response to hiv/ aids. australia's foreign aid agency, ausaid, provided million australian dollars as a supplemental grant to a million us dollar world bank project in china on disease prevention, known as health . health worked with the ministry of health and the chinese academy of preventive medicine, which was the predecessor of the chinese center for disease control and prevention (china cdc). the initiative targeted provinces and cities. the ausaid funds were exclusively to support ngo participation in hiv/aids programs. at that time, china had limited funding in the health sector and government institutes had little funding for hiv/aids programs. even while government partners were surprised and a bit shocked by the ausaid mandate, china's government felt obliged to follow the donor's requirement. but china aids ngos at that time had limited capacity and were unable to write project proposals or draft work plans. thus, the government worked with the ngos, wrote work plans for them, and gradually helped them increase their capacity. following the example of health , the united kingdom's department for international development (dfid) provided support for ngos for the world bank's basic health services project (health ), which began in . in china, real action often only happens in response to political will demonstrated via public endorsement by political leaders. the importance of such endorsements cannot be overstated. beginning in , chinese government leaders have increasingly endorsed the role of ngos in the hiv/aids response. at the end of , wu yi, who served as the vice-premier of the state council from to and as the minister of health from to , clearly announced her support for a greater role for ngos in china's aids response and endorsed efforts to build a framework for government and ngo cooperation to effectively control and prevent the spread of hiv (cctv international, ) . her statements were echoed by many other high-ranking government officials including the then-party secretary to the ministry of health, gao qiang. officials in china's ministry of health stated that they hoped to further promote cooperation between government and ngos in hiv/aids control and prevention by way of public bidding and purchase of services. a new policy entitled "regulation on the prevention and treatment of hiv/ aids," drafted by the ministry of health and issued by the state council in , provided an official endorsement and framework for promoting ngo participation in hiv/aids prevention and control. this was further elaborated in the state council's "decree no. " in (state council ), which contained language endorsing the purchase and contracting of services from ngos, as follows: reflecting this change in attitude, top leaders now regularly express their support for hiv/aids ngos and include ngos in important relevant meetings. former premier wen jiabao invited ngo leaders to participate in a panel discussion and premier li keqiang has done so as well. in november , ahead of december , international aids day, china's then newly designated prime minister li keqiang promised to offer greater support to ngos tackling hiv/aids in china and has kept this promise with a special fund to support their work. these changes indicate the large government change in attitude toward aids ngos and their important role in supporting the formal health system. as noted above, the initial inclusion of ngos in china's hiv/aids response was driven by external forces (bilateral donors), even with little confidence among chinese officials that they had any real role to play. now, government officials and health sectors, even at local levels, recognize the important roles that ngo and community organizations play in the hiv/aids response in china and that without their active participation and critical contributions, it would be impossible to achieve national goals. support for aids ngos was enshrined in china's th five-year plan ( - ) and again in its th five-year plan ( - ). the hiv/aids action plan portions of these policies and related monitoring and evaluation frameworks contain clear language about the roles of ngos and include specific indicators for measuring it. at the local government level, support for ngos can vastly differ. some local governments have had long-term cooperation with ngos through work in poverty alleviation and social welfare and have had good experiences. for those, cooperation with hiv/aids ngos has been easier. in many instances they have been able to establish effective models for shared service provision and have provided funding for ngo partners. for example, in sichuan province in , the provincial government declared its intention "to promote social forces to participate in aids prevention and treatment" and passed china's first local legislation to this effect. item of the legislation states that "non-profit organizations held by social forces (including enterprise, public unit, village/community committee, civil organization and other related organization and individuals) and aiming at hiv/aids prevention and control, after being examined and approved by their local health administration, civil affair departments should approve their registration in accordance with related regulations." this provided professional authority for ngo participation in local hiv/aids programs. but in most places, local officials prefer to work with gongos, such as the labor union, communist youth league, and women's federation, rather than independent ngos. they are concerned about the political risk of engaging with independent ngos, a concern that has grown in recent years. although hiv/aids prevention and control efforts by gongos may be valuable, they rarely represent local communities. china has two main gongos working on hiv/aids, the chinese association for hiv/aids and std prevention and control (caspac) and the china preventive medicine association (cmpa), both with provincial and local branches, as well as many independent ngos operating at the national and local levels. both gongos are led by former government officials from the china cdc or ministry of health. both have been active and valuable players in china's aids response, serving as implementing agencies for government-supported and donor programs, especially the global fund and the bill and melinda gates foundation. in both instances they have served as pass-through organizations for many independent ngos and provided capacity building training and assistance in operations and management of funds. the independent ngos, however, are more legitimate representatives of their communities and to some degree have suffered in their own growth and funding by the concentration of funding to gongos instead of to them directly. the number of independent chinese aids ngos has grown rapidly in the last years and peaked during the years in which the global fund provided funding from to . the earliest groups operated online newsletters, networking activities, and education and outreach efforts. as funding increased for hiv prevention and care, many of the volunteer groups working with marginalized populations and plwh evolved and professionalized. china only openly acknowledged the extent of its aids epidemic in following the sars crisis. prior to that, the epidemic was played down, the government's response was weak, and policy was poorly organized (kaufman and jing ) . the epidemic was represented as mainly limited to china's southwest border areas and mostly among pwid. there were few independent chinese ngos working on hiv/aids. the china-uk hiv/aids prevention and care project funded by the united kingdom's department for international development (dfid) was the first bilateral project to tackle china's growing aids epidemic, even before official acknowledgment of the seriousness of the epidemic in . launched in and working in yunnan and sichuan provinces in china's southwest, the china-uk hiv/aids prevention and care project provided important early funding to ngo outreach activities among msm, commercial sex workers, and pwid and helped foster good working relations with local government. groups like the chengdu community cares group (working with gay men) and daytop in yunnan (working with drug users) received funding and technical assistance to work with marginalized groups at risk for hiv. the program replicated best practices from neighboring countries like thailand for hiv prevention among sex workers and aimed to promote % condom use (yip ) . from the early s, the ford foundation's china office also provided support for independent aids ngos in yunnan, beijing, and elsewhere. this funding built a backbone of technically strong, independent ngos working on hiv prevention for msm, sex workers, and youth and representing plwh. groups like yiteng, based in hong kong, worked to educate and protect the legal rights of chinese sex workers in hong kong and on the guangdong-hong kong border. aizhi action, an online platform started by chinese aids activist yanhai wan, documented the emerging and unacknowledged epidemic among paid plasma donors in henan province and profiled the work of dr. yaojie gao, an outspoken doctor on the frontlines of the epidemic calling for government accountability and action. it was one of the earliest accurate sources of information on the aids epidemic among paid plasma donors in central china and has remained an important advocacy group for the villagers in henan province who were inadvertently infected. positive art, a beijing-based art collective, and mangrove group at ditan hospital were two of the earliest support groups for plwh. finally, the chinese alliance of people living with hiv/aids (cap+), launched in the early s, formed a larger coalition for grassroots groups, bringing together diverse groups such as rural women and young men living with hiv and linking them to the global network of people living with aids (gnp+) and other global and regional networks of plwh (kaufman et al. ) . one important group, friends exchange (with modest support by ford foundation, then barry and martin trust, and later unaids), played a critical role in mobilizing hiv prevention among msm in china. hiv infection among msm continues to grow in china. while now an acknowledged problem, at that time it was still a hidden issue. as of the end of , . % of all newly diagnosed hiv cases in china were acquired via male-male sexual contact. it was up more than tenfold since from . % (pisani and wu ) . in the words of china's top aids prevention official, dr. zunyou wu, "the expanding epidemic among msm is undoubtedly the gravest of these new challenges regarding transmission of hiv." in the late s, it was nearly impossible to find an entry point for work with msm in china. homosexuality and homosexual behavior were a hidden reality, highly stigmatized, and not acknowledged by the government, and there were no obvious groups with which to engage. friend exchange, an underground magazine that was providing information on safe sexual practices for homosexual men in china, was the exception, with each issue passed hand to hand so that it reached a wide audience. the magazine played a unique role in providing aids education to msm and also gave voice to a stigmatized and isolated community. the magazine eventually became official and began formal publication. the magazine's editor, beichuan zhang, a professor at qingdao medical university, also gave voice to the community's perspectives. the increasing tolerance and understanding of homosexuality in china is in no small way due to the influence of friend exchange and beichuan zhang's tireless efforts to humanize individual stories of stigma, the power of family expectations and roles in chinese society, and the journey and progress of sexual rights in china. at the same time, the publication opened political space for engagement and work on sexual rights and aids prevention, in part by challenging social conventions and forcing the chinese psychiatry association to remove homosexuality from its list of mental diseases (zhang and kaufman ) . published for years, friend exchange reached countless homosexual, bisexual, and transgender men and women in china with lifesaving information about aids prevention as well as psychological support and understanding for lifestyles and sexual orientations that are still highly stigmatized in china. it became the most respected and authoritative source of information on homosexuality and lgbt (lesbian, gay, bisexual, transgender) issues in china, conducting countless surveys among its extensive readership and thereby generating information from the community itself on critical issues (e.g., condom use, numbers of sexual partners, attitudes toward safe sexual practices) for the understanding of the hiv epidemic among this key, vulnerable population. after , donor funding for hiv/aids programs in china increased substantially and more funds were directed to the ngo sector. the global fund contributed over million us dollars, the bill and melinda gates foundation provided million us dollars, and usaid supported work in china's southwest provinces, all three with funding going directly to ngos. in china, the global fund entered the scene in the early s and between and , with six rounds of funding for aids programs, worked closely with the chinese government on numerous projects aimed at supporting government and ngo efforts to prevent and treat hiv, with specific funding earmarked to support organizations within civil society (huang and ping ; kaufman ) . as part of the global fund mandate, a country coordinating mechanism (ccm) was established with ngo representatives. this normalization of ngo participation in governance opened the door for the chinese aids ngo community to really demonstrate their value and build effective partnerships with national and local government agencies. empowered by donor engagement and funding, many groups professionalized and moved from volunteer organizations to organizations with greater capacity both technically and managerially. government and donor funding supported this process with trainings and capacity building workshops. when the global fund was established in , its own mandated governance mechanism required establishment of a "country coordinating mechanism" (ccm) with civil society representatives to review, approve, and submit applications. china established a ccm, but initially it worked more as a "rubber stamp" for applications developed and executed by china's ministry of health and the china cdc. domestic aids ngos had a limited voice in the process. in , the first ngo election was held to elect an ngo representative to the ccm. however, it was disputed, which precipitated a thorough review by the global fund and unaids. the result was a new election that was uniquely transparent, participatory, and accountable. the election, facilitated by the international republican institute (iri), a us ngo that has worked around the world to promote democratic elections, provided an opportunity for internet discussions and networked disparate groups around the country. several widely attended local meetings brought groups together often for the first time, with iri, unaids, and donor representatives to teach them how to conduct the elections. the election resulted in two elected representatives and two ngo committees, each constituted with elected representatives from groups representing people with hemophilia, msm, former blood plasma donors (fbpd), and migrant workers (zhang and kaufman ) . the global fund election controversy and resolution served as a door opener for ngo participation in the aids response in china and established a mechanism, albeit still limited, for input by ngos into china's aids response. the global fund's round was seen by many as a further mechanism to institutionalize the role of aids ngos in china's aids response because all of the fund's contributions were to be dispersed by ngos rather than by the government. however, its intended implementing agency (principal recipient) was switched at the last moment from a gongo, the china association for std and aids prevention and control, to the government's aids agency, the national center for aids/std control and prevention (ncaids) of the china cdc. after a negative review of the china program, china's global fund program was suspended in . conditions tied to lifting the suspension of global fund moneys included the creation of a new sub-recipient that truly represented ngos and a commitment to channel % of funding to ngo groups (wong ) . however, before that happened, the global fund's round grant to china was cancelled amid pressure from some donor countries to deploy global fund resources to africa instead of middle-income countries like china. the chinese government then announced that it would use domestic resources to substitute for cancelled global fund moneys and accelerated a process to contract directly with local ngos for program implementation, indicating the government's recognition of the essential role that ngos play. the acknowledgment of the need for ngo implementation resulted partly from the initial pressure and requirement from the global fund and partly from networking and advocacy by the groups themselves aided by external partners like iri, the hiv/aids alliance, icaso, pact, and other international ngos. china global fund watch, established around , was an ngo that monitored compliance with global fund rules and published a regular online newsletter, modelled on a similar global watchdog organization (aidspan, which publishes the "global fund observer" online newsletter). china global fund watch played a leading role in publicizing the suspension of aids funding to china by the global fund and in representing the position of china's grassroots ngos in calls for reform of the governance mechanism of the china global fund grants (wong ) . china global fund watch played a watchdog role in raising and publicizing many issues and developments with china's own substantial global fund grants. the organization formed close alliances with similar groups in the region and the world and served as a forum for raising other important issues related to access to essential aids medicines, laws compensating plwh who were accidentally infected through medical procedures, and other sensitive issues. an important group working on the frontlines of stigma against plwh has been aids care china. this group, started by a guangzhou man who became infected with hiv and was evicted from his apartment when his hiv status became known, has gone on to become one of china's most well-established aids ngos, receiving funding from both the chinese government and international donors. originally focused on addressing stigma and providing shelter for plwh who were evicted from their homes, the group received substantial funding from donors and developed and expanded into a professional organization working in four provinces with counseling and treatment education centers known as red ribbon centers. these centers focused on improving treatment outcomes and adherence to medication by working with healthcare providers and hospital officials. aids care china and its founder and leader, thomas cai, received the red ribbon award from the un for work supporting care and treatment of plwh. funding for civil society from the global fund was critically important for the growth and development of china's aids ngo sector. many volunteer msm and plwh groups in many cities developed during this period and played a major role in china, reaching out to their communities with information and support often through contracted work to local cdcs. ngos working with aids orphans in central china (e.g., chi heng, aids orphan salvation association, and china orchid) emerged and began working closely with government agencies. all had designated representatives of their communities on the global fund's civil society board, the ccm. the bill and melinda gates foundation also provided substantial funding for hiv prevention during this period, mainly focused on testing for msm and prevention and treatment for plwh (yip ) . while most funding was channeled through the ministry of health and china's two main aids gongos (china preventive medicine association and china association for std and aids prevention and control), money passed through to local branches of these organizations, which engaged with local msm ngos to reach their communities with hiv testing. the testing program was controversial because those who chose to test were paid. however, the effort was important for helping to demonstrate the effectiveness of new, internationally recognized "test-and-treat" strategies, which are now a major thrust of china's national hiv/aids program. the last several years have seen a substantial drop-off in international funding for hiv/aids programs in china as china's economy has grown. today, its own resources and technical capabilities are the primary driver of its hiv/aids response, and global donors have called for a re-direction of funding to countries in greater financial need (chow ) . the global fund cancelled round and ended its new funding to china. the bill and melinda gates foundation, usaid, and other donors have shifted their focus from supporting china's own response to hiv/aids to a "china in the world" orientation, focused on how to work with china as a development partner or source for lower-cost drugs in africa and elsewhere. an unfortunate consequence of the drop-off in funding has been the drying up of support for china's ngo sector working on hiv/aids. after the global fund's round program to china was cancelled, the chinese government announced that it would use domestic resources to substitute for cancelled global fund moneys and accelerated a process to contract directly with local ngos for program implementation. but while some organizations have continued to operate with chinese government support contracted locally by local cdcs who depend on them for outreach, many others, especially those working on advocacy rather than service delivery, have struggled to continue their missions. as an indication of how valued the ngo service contribution to the aids response now is in china, the chinese government set up a special fund in , exclusively for the support of ngos to ensure their continued input. the ministry of finance allocated million rmb, but premier li keqiang felt this was insufficient, so he used his premier funds to add another million rmb, for a total of million rmb in . the fund supports ngos to do outreach work with the msm, sex worker, drug user, and plwh communities. while the space afforded civil society organizations and ngos has expanded greatly over the past two decades, it appears to again be contracting. the foreign ngo law, which was passed in april and took effect in january , shifted responsibility for foreign ngo oversight to the ministry of public security from the ministry of civil affairs and significantly increased the bureaucratic and regulatory requirements for all not-for-profit foreign organizations that work in china or provide funding to china-based organizations. restricting foreign funding to chinese ngos has adversely affected the operations of the domestic advocacy ngos even further. and, in light of the reductions in foreign donor funding in recent years, this could have serious negative consequences for china's hiv/aids response. many of the organizations highlighted in this chapter that have played a critical role in advocacy and research had already felt the impact of the draft law, which was issued in . in many cases, their foreign funders retreated for fear of being out of legal compliance. yirenping, an ngo that has worked on employment discrimination against hiv and hepatitis b virus patients, had already been targeted by those tasked with enforcing this new law, most likely because of the foreign donor that supported its efforts. this law is one of a suite of new state security-oriented legislation recently passed. the ngo law, while primarily aimed at preventing foreign-funded civil society groups from organizing political movements that might challenge the authority of the current regime, has spilled over into work in the social sectors, even in areas like hiv/aids which is fully supported by the government. the type of donor-supported efforts that led to the development of ngos and the expansion of their roles in china's aids response for stigmatized groups like msm and criminalized populations like commercial sex workers and pwid is threatened at a time when access to these marginalized populations is essential for achieving national goals. global experience demonstrates, that it is nearly impossible to achieve success in aids prevention without actively involving the communities themselves in efforts to reach their members. in china, government is the almost exclusive provider of public services, and since , the china cdc has done an admirable job of tackling many sensitive aids prevention challenges and achieved many successes in controlling and responding to the epidemic. the government frequently contracts with ngos for service provision for marginalized groups, especially msm and plwh, and has helped to begin normalizing the sector and formalizing the partnerships. however, although government effort is necessary, it is not sufficient to achieve success in hiv prevention among msm and other marginalized and stigmatized groups. ngos representing these groups are becoming less able to play the roles required of them because of the tightening political situation for chinese ngos accompanying the new foreign ngo law and reductions in overseas funding. these organizations, which are critical for reaching communities throughout china, are plagued by the lack of core financing (as opposed to project funding) especially in recent years and often depend too much on volunteers rather than staff. many groups have struggled to grow beyond their original vision and leadership and often compete for the more limited donor and government funds that trickle down to groups on the frontline of the epidemic. this situation is likely to worsen and may lead to the demise of some important groups that are unable to secure funding. to some degree, financial competition contributes to a lack of cohesion in the sector, further constrained by a regulatory environment that prohibits establishment of branches in different places (except for the gongo sector) or transnational networking. however, competition and poor capacity among china's ngos should not be used as an excuse to dismiss their value and necessity. without genuine capacity, core funding, networking, and better governance, these organizations are unable to play their much-needed role. true partnership of these ngos with government, the main service provider, architect, and enabler of policies and programs in china, is essential. without active engagement of china's aids ngos in china's hiv/aids response, the chinese government's effort to control the aids epidemic will be only partially successful. china's hiv/aids epidemic response has been noteworthy, but these significant challenges to the next phase of prevention must be taken seriously. non-governmental organizations will play a greater role in the field of aids prevention and control. cctv international china's billion-dollar aid appetite communitybased approaches to hiv treatment in resource-poor settings why foreign ngos are struggling with new chinese law-thousands could be operating in a risky legal limbo south africa's treatment action campaign: combining law and social mobilization to realize the right to health the state of ngos in china today ny: council on foreign relations creating an enabling environment: lessons learned from the sonagachi project china's evolving aids policy: the influence of global norms and transnational nongovernmental organizations china and aids-the time to act is now gender and reproductive health in china: partnership with foundations and united nations singapore: people's medical publishing house people, passion and politics: looking back and moving forward in the governance of the aids response notice of the state council on further strengthening hiv/aids response. regulation on the prevention and treatment of hiv/aids global fund lifts china grant freeze international philanthropic engagement in three stages of china's response to hiv/ aids the rights of people with same sex sexual behavior: recent progress and continuing challenges in china new paradigm of aids governance. beijing: peking union medical college press key: cord- - gsq l authors: li, hongjun title: hiv/aids related respiratory diseases date: - - journal: radiology of hiv/aids doi: . / - - - - _ sha: doc_id: cord_uid: gsq l lungs are the most commonly involved organ by hiv/aids related diseases, and pulmonary infections are the main reasons for the increasing death rate from aids. pathogens of hiv related pulmonary infections include parasites, fungi, mycobacteria, viruses, bacteria and toxoplasma gondii. according to international reports, pathogens have different geographical distribution, which is also closely related to the socioeconomic status of the region to produce varied aids related diseases spectra. for instance, in the united states, pneumocystis carnii pneumonia (pcp), tuberculosis and recurrent bacterial pneumonia (at least twice within year) occur frequently in hiv infected patients. an international report published years ago indicated that pcp is the most common and serious pulmonary opportunistic infections in hiv infected patients. now its incidence has dropped with the application of antiretroviral treatment and preventive measures. pcp will continue to occur initially in patients who are aware of their hiv infection. in addition, hiv related viral and parasitic infections have been reported both domestically and internationally. in this section, the clinical manifestations and imaging findings of hiv related pulmonary infections are analyzed and discussed, which provide effective diagnosis basis, so as to reduce the incidence of hiv-related pulmonary infections. lungs are the most commonly involved organ by hiv/aids related diseases, and pulmonary infections are the main reasons for the increasing death rate from aids. pathogens of hiv related pulmonary infections include parasites, fungi, mycobacteria, viruses, bacteria and toxoplasma gondii. according to international reports, pathogens have different geographical distribution, which is also closely related to the socioeconomic status of the region to produce varied aids related diseases spectra. for instance, in the united states, pneumocystis carnii pneumonia (pcp), tuberculosis and recurrent bacterial pneumonia (at least twice within year) occur frequently in hiv infected patients. an international report published years ago indicated that pcp is the most common and serious pulmonary opportunistic infections in hiv infected patients. now its incidence has dropped with the application of antiretroviral treatment and preventive measures. pcp will continue to occur initially in patients who are aware of their hiv infection. in addition, hiv related viral and parasitic infections have been reported both domestically and internationally. in this section, the clinical manifestations and imaging fi ndings of hiv related pulmonary infections are analyzed and discussed, which provide effective diagnosis basis, so as to reduce the incidence of hiv-related pulmonary infections. pneumocystis has been believed to be a kind of protozoon. recently, based on its ultrastructure and ribosomal rna phylogenetic analysis, pneumocystis is now believed to be a kind of fungus, with high affi nity to the lung tissues. due to the compromised immunity, % aids patients sustain different types of pulmonary infections, of which pcp is the most common life-threatening opportunistic infection with an incidence rate of about - %. about - % patients suffering from aids complicated by pcp are adolescents and adults with their cd t cell counts being less than / μl. clinical manifestations of typical pcp are fever, cough (dry cough without phlegm), dyspnea, chest distress and shortness of breath. dyspnea is shown as progressive difficulty in breathing, which initially occurs after physical activities and develops into diffi culty breathing even in resting state. pcp is commonly accompanied by weight loss, fatigue, anemia, general upset and lymphadenectasis. all these symptoms are non-specifi c, but patients often report subjective feelings of severe symptoms while physical signs are mild. by auscultation, the lungs are normal or with slightly dry, moist rales. these are the clinical fi ndings characteristic to aids complicated by pcp. in most patients with pcp, the serum ldh level increases but it is non-specifi c. in cases of aids complicated by pcp, the blood po reduces, commonly being lower than mmhg in patients in the middle and advanced stages. the diagnostic imaging for pcp includes chest x-ray and ct scanning. due to the low resolution of chest x-ray, its demonstrations are negative for pcp patients in the early stage or only include thickened pulmonary markings and decreased pulmonary transparency. however, ct scanning demonstrates tiny lesions or more detailed changes in lungs. especially with the application of hrct, the detection rate of pcp lesions has been greatly improved. it has been internationally reported that nearly % of pcp patients show negative fi ndings by the chest x-ray but with abnormal fi ndings by hrct. due to the rapid progression of pcp as well as its complex pathological changes, ct scanning demonstrations are diverse with specifi city. according to different pulmonary ct scanning demonstrations in different stages of the illness, pcp is divided into early stage (exudative and infi ltrative stage), middle stage (fusion and parenchymal stage) and advanced stage (absorption or fi brosis stage). the early typical manifestations include intrapulmonary multiple miliary nodules, mainly distributed in both middle and lower lung fi elds. it may be accompanied by enlarged hilar shadow, which should be differentiated from acute miliary tuberculosis. the middle stage is a period of infi ltration. as the disease progresses, miliary and patchy shadows fuse and expand into a dense infi ltrative shadow with even density, showing a diffuse ground glass liked change. the typical manifestations include bilaterally symmetric foci with the hilus as the center. the foci infi ltrates from the hilus to bilateral pulmonary interstitium, progressing from the both middle lungs to both lower lungs. hrct can more clearly demonstrate the foci, showing a map liked or gravel road liked appearance, with clearly demonstration of gas containing bronchus penetrating the foci. the pulmonary apex is involved later. the exterior stripe of the lung fi eld has increased transparency, showing typical willow leaf sign or moon bow sign which is the manifestation of compensatory pulmonary emphysema. during the late compensatory repair period, the intrapulmonary lesions are mainly parenchymal changes and fi brosis, with large fl aky high density shadows as well as cords liked and reticular changes. pneumothorax, mediastinal emphysema, pneumatocele, pleural effusion and other complications may occur, with an incidence of pneumatocele in about - % patients. the autopsy grossly demonstrates swelling of the lung tissue, and the alveoli are fi lled with large quantity foamy liquid. the pathological changes mainly manifested as interstitial pneumonia, with early manifestations of increased permeability of the capillary wall basement membrane in the alveolar walls, which leads to fl uid exudation. the pneumocystis carinii proliferate in large quantity and adhere to cause degeneration of the type i alveolar epithelial cells and shedding of the basement membrane. vascular congestion, edema as well as infi ltration of lymphocytes, plasma cells and mononuclear cells can be found in the pulmonary interstitium. due to the extensive existence of aspergillus in natural world, sputum smear positive often fails to defi ne its invasive infection. in the cases with aspergillus infection, hyphae can be found in the sputum. fungal infections often occur in patients with cd t cell count below /μl, of which the most common pulmonary infection is aspergillus infection, followed by penicillium marneffei infection. pulmonary infections caused by candida albicans and histoplasma are rarely found. the incidence of cryptococcal pulmonary infection is still in a disagreement, which is increasing recently. there are also some common endemic fungal infections, such as the most commonly found fungal infections of aids complicated by penicillium infections in guangxi zhuang autonomous region and hong kong, china. aspergillus has an extensive existence in the natural world. aids complicated by aspergillus infection is related to the application of corticosteroid hormone or broad-spectrum antibiotics, which occurs commonly in the advanced/critical stage of aids. the cases of pulmonary fungal infections, with fi ndings of hyphae (aspergillus or candida) or yeast in cytoplasm (histoplasma capsulatum) in tissue sections and simultaneous fi ndings of histiocytic reactions including the infi ltration of neutrophilic granulocyte and the necrosis of histocytes, can be diagnosed as having invasive fungal infection. candida albicans is yeast liked fungus, which is widespread in the natural world. it can parasitize in the mocous of skin, oral cavity, intestinal tract and vagina of the human being. candida albicans cannot cause disease in immunocompetent people but is pathogenic in immunocompromised population. after its invasion into the tissues, it turns into mycelia and multiplies in large quantity with great toxicity. it also has the ability to fi ght against phagocytosis. clinically, its infection is characterized by a chronic onset and clinical symptoms of low and moderate grade fever but rarely high fever, cough, shortness of breath, cyanosis, irritation or dysphoria. the pulmonary signs include weakened breathing sounds by auscultation and obvious moist rales of lungs. the serious cases may have symptoms of systemic poisoning. the illness is prolonged and repeated during its whole progression. by diagnostic imaging demonstrations, it can be divided into the following types: ( ) bronchitis type, with chest x-ray demonstrations of increased pulmonary markings in lower fi elds of both lungs; ( ) pneumonia type, commonly with accompanying extrapulmonary lesions. the lesions are mainly located in the middle and lower lung fi elds and lesions in the lower lung fi eld are more common. the apex is generally not involved. the lesions are recurring one after another. a small number of patients may sustain complications of exudative pleurisy. ( ) disseminated type, with miliary shadows, diffuse nodular shadows or multiple small abscesses. the lesions often involve the middle and lower lungs. chest x-ray demonstrates thickened pulmonary markings and accompanying spots, small fl akes and large fl akes of parenchyma shadows, in manifestations of bronchial pneumonia. in some serious cases, the foci may fuse together and enlarge to involve the entire lobe. ct scanning demonstrates pulmonary nodules and few have ground glass liked changes of the lungs. pathological changes include acute infl ammatory lesions in the lungs, alveolar exudation and infi ltration of monocytes, lymphocytes and neutrophils. acute disseminated lesions often cause multiple small abscesses, central caseous necrosis, spores and hyphae in and around the lesions. histoplasma capsulatum belongs to moniliales family, deuteromycetes class and fungal kingdom, whose growth requires organic nitrogen. it is often isolated from the soil with abundant contents of birds or bats faeces and spreads along with chickens, birds, dogs, cats, and mice. when the conidia and mycelial fragments of histoplasmosis are inhaled, most can be expelled by the defense mechanism of the human body. granulomas may form, but in immunocompromised patients, it may cause disseminated histoplasmosis. when the cd t cell count in aids patients is less than /μl, histoplasma capsulatum infection of lungs may occur. histoplasma capsulatum pneumonia has a higher incidence in south america, africa and india. in the slight cases, the clinical manifestations are similar to symptoms of the cold, with low-grade fever, cough, and general upset. in the serious cases, there are symptoms of infl uenza, including chills, high fever, cough, chest pain, dyspnea, fatigue and poor appetite. in the cases of acute cavity, thin-walled cavity may form within a month. complications may be pericarditis, arthritis, skin nodules, rash fi brous mediastinitis and mediastinal granuloma. diagnostic imaging demonstrations are non-specifi c, with scattering pulmonary acinus exudation, multiple nodules in a diameter of about mm with accompanying thickened septa, and formation of granulomas with accompanying calcifi cation. it should be differentiated from bacterial pneumonia, tuberculosis and other pulmonary fungal infections by laboratory tests to defi ne the diagnosis. the specifi city of the glycogen antigen detection of histoplasma capsulatum is up to %. mucor spreads through the respiratory tract. it commonly invades the blood vessels, especially arteries. it reproduces locally or causes thrombosis and embolism. clinical manifestations are high fever, cough, sputum, shortness of breath, chest distress, chest pain and hemoptysis (pulmonary artery involvement). the diagnostic imaging demonstrates fl akes infl ammatory foci, with manifestations of pulmonary cavity and pulmonary infarction. the pathological changes are hemorrhagic infarction of local tissue, pneumonia and exudation of neutrophils. hemorrhagic infarction of local tissue may be related to hyphae induced minor arteries lesions. it is estimated that one third of the world population was/is infected with tubercle bacillus and % of them are aids patients. the who reported that there are , newly infected patients of tb each year and . % of them are caused by aids. it is estimated that each year in , hiv infected patients, - sustain active tb, and there is a great risk of active tb progressed from the latent tuberculosis infection. hiv infected patients with tuberculosis are commonly young and middle aged adults, with more male patients than female patients. tuberculosis can occur at any stage of aids and at any level of cd t cell counts. it has been internationally reported that hiv infection complicated by tb has no specifi c imaging demonstrations. it has an acute onset, with an incidence of acute onset . times as high as that in non-hiv infected patients. the lesions are morphologically diverse, which are different from non-hiv infected patients with tb. hiv infection complicated by tb has commonly an acute onset, while tb in non-hiv infected patients is commonly secondary to other lesions, with cavities, fi brosis, pleural thickening and calcifi cation. a study conducted in china has demonstrated that for aids complicated by tb, the acute cases mainly have military and exudative lesions, with an incidence of and % respectively; while the incidence of chronic cases including cavity, fi brosis and calcifi cation is declining, being , and respectively. a later occurrence of tuberculosis in hiv infected patients indicates a more seriously immunocompromised immunity, with less typical clinical manifestations and imaging demonstrations. when the cd t cell count level is above - /μl, the systemic symptoms are fever, chills, night sweating, fatigue, poor appetite and weight loss. respiratory symptoms are cough, expectoration, hemoptysis, chest pain and dyspnea. it manifests as primary tuberculosis, with its foci distributing in the middle and lower lungs, involving multiple lobes and segments. when the cd t cell count decrease, the impact of tb increase including the occurrence of extrapulmonary tuberculosis and disseminated disease. when the cd t cell count drops below /μl, pulmonary tuberculosis manifests as acute onset (such as miliary tuberculosis) or extrapulmonary tuberculosis (such as ileocecal tuberculosis) and peripheral lymph nodes tuberculosis. its difference from the clinical manifestations of non-hiv infected patients is as the following: ( ) more common pulmonary infi ltration with multiple involvements and rare cavities; ( ) higher incidence of dissemination ( - %) commonly along with blood fl ow and higher incidence of extrapulmonary tuberculosis ( - %); ( ) more common lymph node tuberculosis, such as hilar, mediastinal and extrapleural lymphadenectasis; ( ) lower positive rate of tuberculin test (ppd); ( ) more patients with no expectoration, with sputum smear for acid-fast bacilli staining is negative; ( ) higher incidence of resistant strains, high recurrence rate, and higher mortality (table . ). foci in the cases with aids complicated by pulmonary tuberculosis are change quickly. after anti-tb treatment, the lesions are absorbed quickly. those receiving no anti-tb therapy, the foci tend to fuse together to form a mass or diffusely distribute. bacterial septicemia often occurs in aids patients. many opportunistic pathogens can cause respiratory infections, including bacterial bronchitis, pneumonia and pleuritis. the incidence rate of bacterial pneumonia (bp) is - %. bp has a larger range of impact on hiv infected patients than on non-hiv infected groups. repeated episode of bp is considered to be the fi rst manifestations of latent hiv infection. therefore, for those individuals who have recurrent pneumonia without other risk factors, they should be alert to hiv infection. the common pathogenic bacteria include streptococcus pneumoniae, staphylococcus aureus, rhodococcus equi, haemophilus and pseudomonas aeruginosa. as non-hiv infected patients, the most common pathogens of pneumonia are streptococcus pneumoniae and haemophilus infl uenzae. legionella and klebsiella are also common. many factors, such as the reduced t lymphocytes in hiv infected patients, manufacturing disorders of neutrophils, mononuclear cells and cytokines, and dysfunctional b lymphocytes, provide chances for opportunistic bacterial infections. in addition, the application of broad-spectrum antibiotics also increases the chance of opportunistic infections. bp can occur in any stage of hiv and at any level of cd t cell count. when the cd t cell count decreases, the incidence of bp also increases. the clinical manifestations of hiv infected patients are the same as non-hiv infected patients, with acute onset ( - days) , high fever ( - °c) , chills, chest pain, dyspnea, cough, purulent sputum (bloody or rusty). being different from non-hiv infection, pulmonary infection in hiv-infected patients is often recurrent. the imaging demonstrations of hiv/aids related bacterial pneumonia are similar to those in non-hiv infected patients. most cases of streptococcal pneumonia and haemophilus pneumonia have unilateral, confi ned and partially fused foci with accompanying pleural effusion. the imaging demonstrations include thickened and deranged pulmonary markings, alveolar fi lling of infl ammatory exudates with the progression of the illness, large fl aks infl ammatory infi ltration shadows or parenchymal shadows, bronchial gas fi lling phase in the parenchymal shadows. the lesions distribute along the pulmonary segments or lobes, rarely with accompanying pleural effusion. during the absorption period, the density of the parenchymal shadows gradually reduces and the scope narrows down. there may be cavities in some individual cases. but in most cases it is completely absent after poor effi cacy and more side effects favorable effi cacy and less side effects - weeks. lesions absorption are slow in elderly patients and recurrent patients, which is diffi cult to be completely absorbed and often develop into organic pneumonia. rhodococcus equi was initially discovered in and nominated as corynebacterium equi. after structure analysis of the cell wall, it was found to be different from corynebacterium, and therefore it is classifi ed into rhodococcus. rhodococcus equi is generally considered as the pathogens of horses, pigs and cattle. human rhodococcus equi infection is rare. but in recent years, due to an increase in patients with immunodefi ciency syndrome, reports of rhodococcus equi induced human respiratory infection and sepsis are increasing. rhodococcus equi is an intracellular facultative parasitic bacterium. its optimum temperature for growth is °c, and suitable temperature for its growth is - °c. the acid-fast staining for rhodococcus equi shows uncertain results. due to its various morphology, it is commonly mistaken as diphtheroids bacilli, bacillus or micrococcus. on sheep blood agar plate, the bacterium can have synergistic hemolysis with staphylococcus aureus, mononuclear listeria and corynebacterium pseudotuberculosis. toxicity mechanisms of rhodococcus equi has been recently discovered the existence of toxic plasmid, which provides a new idea for the full understanding of its pathogenesis. clinical symptoms are usually cough, orange red sputum, high fever and other symptoms. e marchiori et al. in studied fi ve cases of aids complicated by rhodococcus equi pulmonary infection. all the patients had a case history of cough and fever history for - months with accompanying shortness of breath and chest pain. li et al. in [ ] studied a group of cases. all patients had fever, with a body temperature being - °c, cough, orange red sputum. the typical clinical manifestations of the disease are fever, dyspnea and chest pain. other symptoms such as weight loss, diarrhea and joint pain are not representative. based on the course of the disease, the diagnostic imaging demonstrations of rhodococcus equi pulmonary infection can be divided into early stage, showing round liked fl aky blurry shadows surrounding unilateral hilum that has blurry boundary; middle stage (parenchymal change), showing central sphere liked high density shadow surrounding unilateral hilum, in parenchymal changes and with clear boundary; advanced stage (necrosis) showing secondary cavity of the pulmonary mass, possibly with hydropneumothorax and pleurisy. the imaging demonstrations are characteristic, but lack of specifi city. and it should be differentiated from pulmonary tumors. the pathological changes include the most commonly chronic suppurative bronchopneumonia and extensive pulmonary abscesses. the histopathology demonstrates massive bleeding in alveolar space, large quantity erythrocytes, intact cellular wall and large quantity epithelial cells. the predominant pathological changes may also be fi broblasts, with parenchymal changes of lung tissue and thickened alveolar septa. accumulating piles of strip liked purple rhodococcus equi can be found by pas staining. common pathogenic viruses of the opportunistic pulmonary infections in hiv infected patients are cytomegalovirus (cmv) and infl uenza virus. cmv is the most common pathogen of hiv/aids related pulmonary infection. by autopsy, - % patients with hiv/aids have cmv infection, only second to pneumocystis carinii pneumonia. moskowitz et al. [ ] reported that among the direct causes of death in aids patients, % is due to pulmonary cytomegalovirus infection. because of the lack of typical clinical manifestations and sensitive examinations for its early diagnosis, the defi nitive diagnosis rate of cytomegalovirus pneumonia is only - % before autopsy. the clinical manifestations of cmv infection are non-specifi c. the systemic symptoms are fever, soreness of joints and muscles. respiratory symptoms are paroxysmal dry cough, progressive shortness of breath, diffi culty in breathing during activities. pulmonary cmv infection may develop secondary fungal infection or be complicated by bacterial, fungal, and pneumocystis carinii infections. the cytomegalovirus can widely spread in the organs and tissues of the infected patients, and the infections can directly lead to the damage of infected host cells. in addition, the virus can also cause pathogenic effects via immune pathological mechanism. some scholars classifi ed cmv pneumonia into diffuse, miliary necrosis and cytomegalic. diffuse and cytomegalic cmv pneumonia are often accompanied by diffuse alveolar damage (dad), which is more common in the diffuse type of cmv pneumonia but less common in cytomegalic type of cmv pneumonia. the pathological basis of diffuse small nodules in lungs is hemorrhagic necrosis. sometimes cmv infection is concurrent with other infections in the lungs, and even co-infects one cell. pulmonary parenchymal changes indicate bacterial and fungal infections, such as fi ndings of inclusion bodies in the cells, commonly known as eagle's eye sign. the imaging demonstrations of cytomegalovirus pneumonia are diverse. some studies summarize that the lungs commonly have manifestations of diffuse interstitial infi ltration or alveolar infi ltration, with ground glass liked changes, pulmonary parenchymal changes, grid liked changes, thickend bronchial wall, bronchiectasis, pulmonary nodules or masses. the principal changes include the early lesions of ground glass liked changes and advanced lesions of pulmonary masses. lymphoid interstitial pneumonia is the abnormal hyperplasia of the pulmonary lymphoid tissue. its occurrence is related to autoimmune diseases, and is believed to be a direct response of the lungs to hiv. the clinical manifestations are recurrent infections, poor appetite, hepatomegaly and splenomegaly, and arrested development. the diagnostic imaging demonstrates no characteristic changes by ct scanning, with thickened bronchial wall, diffuse central lobular nodules or bronchiectasis, grid liked and cords liked shadows in uneven thickness. the pathological changes include accumulating lymphocytes and plasma cells that are mixed to infi ltrate the pulmonary interstitium and expand to surrounding areas of the bronchi. toxoplasma pneumonia is caused by the infection of the intracellular parasite, toxoplasma gondii. ludlam et al. in fi rstly proposed the concept of pulmonary toxoplasmosis, which was believed to cause atypical pneumonia [ ] . the clinical manifestations are cough and expectoration. in the serious cases, dyspnea and cyanosis can occur. in the chronic cases, there are long term low grade fever, cough, weight loss and enlarged lymph nodes. the diagnostic imaging demonstrates bronchopneumonia, interstitial pneumonia and pleurisy. ( ) bronchial pneumonia is also known as lobular pneumonia, with scattered patchy and blurry density shadows. ( ) interstitial pneumonia has typical manifestations of reticular and nodular shadows. ( ) pleurisy is rare, showing pleural effusion, limited diaphragmatic activity. the imaging demonstrations are non-specifi c, which can be defi ned in combination with the etiologic examinations. the pathological changes are congestion and edema of the surrounding connective tissue of the alveolar wall and bronchial walls, widened pulmonary interstitium, small quantity serous fi brin exudation from alveoli and pulmonary interstitium, and infi ltration of macrophages and lymphocytes. toxoplasma cysts and tachyzoites may be found in pulmonary interstitium and macrophages as well as alveolar epithelium. kaposi's sarcoma, a vascular tumor, was discovered in , and is also known as multiple hemorrhagic sarcomas, multiple vascular sarcomas, or multiple pigmented sarcomas. kaposi's sarcoma is believed to be the defi ning tumor of aids. outbreak of ks occurred in male homosexuals in europe and the united states. data show that in about % caucasian homosexuals, kaposi's sarcoma is a major complication of in hiv/aids patients. it has been confi rmed that, though kaposi's sarcoma has strong invasion, the disease itself has little impact on the mortality of aids. the cause of death in majority of the patients is still opportunistic infections. the clinical manifestations include face and neck lesions in dark red to purple red plaques. the plaques do not fade away when pressed, with surrounding brown ecchymosis. it commonly involves multiple organs including lungs, spleen, oral cavity, lymph nodes, gastrointestinal tract and liver. the lungs are the major target of invasion. the diagnostic imaging demonstrates hilar lymphadenectasis and its surrounding nodular infi ltration, bilateral interstitial changes, and pleural effusion that are its typical x-ray demonstration. early pathological changes are similar to those of common angioma; with gathering of capillaries into groups containing histocytes engulfed hemosiderin and orderly arranged vascular endothelial cells. it further progression see active proliferation of endothelial cells and fi broblasts, increased nuclear mitosis with anaplasia, and scattered lymphocytes and histocytes between blood vessels. in the advanced stage, occlusion and necrosis of the vascular lumen can be found. irregular lumen and fi ssures of the new capillaries can be commonly found in the tumor, fi lled with blood and common hemorrhage. in china, ks is relatively rare. its defi nitive diagnosis can be made by pathological examination. other hiv/aids related malignancies include burkitt's lymphoma, non-hodgkin's lymphoma, hodgkin's lymphoma and lung cancer. in summary, hiv/aids related pulmonary infections are important diseases in the disease spectrum of hiv/aids imaging. the diagnostic imaging is irreplaceable examinations for pulmonary infections. early prevention and correct diagnosis are the keys to improve the quality of life and prolong the lives of patients. the complexity and multiplicity of hiv/aids related pulmonary diseases present challenges for the clinicians. firstly, hiv/aids related diseases should be optimally classifi ed. each type should has a disease spectrum, which can be used for exclusion in combination with immunological indices to make the diagnosis and differential diagnosis. the diagnosis of hiv/ aids related pulmonary infections should be made in combination with case history and laboratory tests for targeting individualized diagnosis to serve clinical practice. carnii pneumonia (pcp) the pathogen is the trophozoites and cysts produced by pneumocystis carinii, principally living in the lungs. pneumocystis carinii was used to being categorized as as protozoon, but recently, it is believed to be belonged to fungus according to its ultrastructure and pneumocystis ribosomal rna phylogenetic analysis. the main infection route of pcp is airborne transmission and reactivation of in vivo latent pneumocystis carinii. infl ammatory and immune responses of the host include phagocytosis of pneumocystis carinii by the alveolar macrophages, infi ltration of lymphocytes in peribronchial and vascular area, proliferation of type ii alveolar cells, local and systemic increase of antibody. by naked eyes observation, there are extensive and diffuse invasion of lungs, which is soft like waterlogged sponge and in milky white with black spots. the fi lled foamy substance in the alveoli and bronchioles is a mixture of necrotic fungus and immunoglobulin. the alveolar septum has infi ltration of plasma cells and lymphocytes, resulting in thickened alveolar septa up to - times as the normal thickness that occupy / of the entire lung volume. the cysts are fi rstly located in the macrophage cytoplasm of the alveolar septa. subsequently, the alveolar cells containing cysts sheds off into the alveolar space. after the rupture of the cystic wall, sporozoite is discharged to turn into free trophozoites, which gains its access into the alveolar space. the alveolar exudates include plasma cells, lymphocytes and histocytes ( fig. . a-c ). the clinical symptoms include dry cough, shortness of breath and an indoor hypoxia. about % aids patients have multi-pathogens induced pulmonary infections. the most signifi cant laboratory abnormality in most pcp patients is hypoxemia. based on correlation between pcp and arterial oxygen partial difference, hypoxemia is divided into three degrees. the slight cases at indoor conditions have their pao being above mmhg, or alveolar-arterial oxygen pressure difference being less than mmhg, or both. the moderate and severe cases have their pao being usually less than mmhg, or alveolar-arterial oxygen pressure difference being above mmhg, or both. the most common manifestations of aids complicated by pcp are progressive subacute onset of dyspnea, fever, dry cough and chest distress, the symptoms aggravating in a few days or weeks. pulmonary examination is usually negative in slight cases. as the disease aggravates, the cases show shortness of breath, cyanosis, tachycardia, and diffuse dry rales. pneumocystis carinii infection accounts for - % of aids patients, which is one of the major causes of death in aids patients. the diagnostic imaging examinations include chest x-ray, ct scanning and nuclear medicine examination. ( ) chest x-ray is the conventional examination for screening. early lesions tend to be missed for the diagnosis due to the limited resolution or atypical lung lesions. ( ) ct scanning with high resolution is superior to chest x-ray. ( ) nuclear medicine examination demonstrates increased uptake of the isotope-labeled monoclonal antibodies in the lung tissues of the pcp patients. ( ) by tracheal suction or lung tissue biopsy, the detection rate of pneumocystis carinii is up to %. by tissue section staining, abundant protozoa can be found in intra-alveolar foamy eosinophil substance mass (by methenamine silver nitrate staining, the dark brown round or oval shaped cysts can be found in a diameter of - μm out of the cells). ( ) by elisa, pneumocystis igg antibody can be detected and by latex particle agglutination test, the protozoa antigen can be detected. ( ) molecular biology techniques, such as pcr can be applied for early diagnosis. the following examinations are non-specifi c, but can be used to assess the severity of pcp and its progression. ( ) by arterial blood gas analysis, the patients may show reduced blood oxygen saturation and respiratory alkalosis. ( ) by serum enzyme spectrum analysis, the patients may show increased ldh. ( ) it can be detected to have increased alveolar-arterial oxygen partial pressure difference. in the early stage (exudation period), alveolar fl uids exudate, with diffuse granular shadows in the bilateral lung fi elds extend from the hilum to the surrounding. in the middle stage (infi ltration and fusion period), the intrapulmonary lesions fuse, with ground glass liked or cloudy shadows that are bilaterally symmetric like butterfl y wings. in the middle and advanced stages (parenchymal changes period), the lung tissues show parenchymal changes, with high density shadows and accompanying air bronchogram. the lung periphery shows stripes of transparent shadows. in the advanced stage (pulmonary fi brosis period), the pulmonary interstitium is thickened in dense cords liked appearance, with interval irregular patchy shadows. the pulmonary ventilation improves and the lung periphery shows dense parenchymal shadows with emphysema, pneumomediastinum and pneumothorax. in the early stage (exudation period), the lesions radiatus develop from the hilum to lung fi eld. in the early stage, the diffuse exudative lesions distribute as pulmonary acinus, with changes similar to pulmonary interstitial changes. it was believed to be interstitial pneumonia. however, acute pcp is actually exudation of alveoli and spaces containing a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of dyspnea, cyanosis and wheezing for weeks, with obviously decreased oxygen saturation. his cd t cell count was /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of dyspnea, cyanosis and wheezing for weeks, with obviously decreased oxygen saturation. her cd t cell count was / μl. patients with acquired immunodefi ciency. the early symptoms include fever, dry cough and shortness of breath. the advanced symptoms are serious dyspnea, cyanosis, progressive hypoxemia and respiratory failure. by pulmonary examinations, scattered dry and moist rales can be heard. trophozoites of pneumocystis cysts can be found by liquid giemsa staining. slight and moderate interstitial infl ammation responses mainly involve lymphocytes and alveolar macrophages. the detection of cysts containing sporozoites is the basis to defi ne the diagnosis. chest x-ray chest x-ray demonstrations of pcp can be classifi ed into four types. ( ) early pulmonary interstitial infi ltration and diffuse miliary alveolar exudation; ( ) in the middle stage, there are alveolar exudates, with fusion and parenchymal changes; ( ) in the middle-advanced stage, diffuse parenchymal changes; ( ) pulmonary interstitial fi brosis and lung cavity or lung bulla, as well as pneumothorax and emphysema. for the cases with negative or atypical fi ndings by chest x-ray, ct scanning with high resolution should be performed. ct scanning demonstrates early lesions of multiple symmetric diffuse miliary nodal shadows, which have clear boundaries. in the middle stage, there are thin cloudy shadows or ground glass liked density shadows. in the middleadvanced stage, the lung tissues show parenchymal shadows, with trachea-bronchial sign. in the outer strip of the lung, a transparent area in shape of willow leaf can be demonstrated. in the advanced stage, fi brous cords liked shadows are demonstrated some lung tissues with compensatory emphysema and even pulmonary pseudocysts. the intake of the isotope-labeled monoclonal antibody by lung tissues of pcp patients increases. hiv/aids related pcp should be differentiated from bacterial pneumonia, pulmonary tuberculosis, viral pneumonia, fungal pneumonia, ards, and lymphocytic interstitial pneumonia (lip). bacterial pneumonia has more focal lesions but less diffuse lesions. pulmonary mycobacterium tuberculosis infection has manifestations of military pulmonary tuberculosis by chest x-ray, which is diffi cult to be differentiated from early pcp. hiv/ aids related pcp shows miliary nodules, which further fuse into cloudy or ground glass liked shadows or parenchymal changes. the lesions are commonly symmetrical, with the hilus as the center. the clinical manifestations include fever, dry cough or accompanying diffi culty breathing, and even cyanosis. but in the cases of pulmonary mycobacterium tuberculosis infections, most show miliary nodules, which further fuse into large nodules or mass. after about weeks treatment in the early stage, the military nodules in both lungs can be absent, with common clinical symptom of high fever. correlation studies of miliary tuberculosis and peripheral blood cd t cell count have demonstrated that the general incidence of miliary tuberculosis is low, only - %, but it is the main manifestation of hiv/aids related pulmonary miliary tuberculosis. generally, when cd t cell count is below /μl, the incidence of cavity lesions is %, noncavity lesions %, complicated by pleural effusion % and lymphadenectasis %. when cd t cell count is between and /μl, the incidence of cavity lesions and non-cavity lesions each accounts for %, complicated pleural effusion % and lymphadenectasis %. when cd t cell count above /μl, the manifestation is commonly pneumonia type, in fl aky shadows or parenchymal shadows in just one pulmonary segment. the incidence of cavity lesions is %, non-cavity lesions %, complicated by pleural effusion % and no lymphadenectasis. chest x-ray demonstrates cytomegalovirus pneumonia negative in / patients. the foci are commonly bilateral, with reticular particles in % patients, alveolar foci in % patients, nodular foci in % patients, complicated by cavity in % patients, cysts in % patients, pleural effusion in % patients and lymphadenectasis in % patients. the incidence of diffuse foci in the cases of cryptococcus neoformans pneumonia is %, interstitial foci or mixed foci %, alveolar foci %, nodular foci %, lymphadenectasis % and pleural effusion %. hiv/aids related pcp is more likely to occur in children with aids, which presents diffi culty for its differentiation form lymphoid interstitial pneumonia. however, lymphoid interstitial pneumonia commonly has a chronic onset, with commonly manifestations of cough and dry rales. systemic lymphadenectasis and enlargement of salivary glands can also be found. by lung tissues biopsy, ebv-dna can be detected, which provides basis for their differentiation. pneumocystis, a unicellular organism, is the pathogen of pneumocystis carinii pneumonia. pneumocystis carinii pneumonia is one of common opportunistic infections in aids patients, which is also the leading cause of death in aids patients. in the initial episode of pcp, most patients have a cd t cell count of less than /μl. diagnostic imaging demonstrates bilaterally symmetrical ground glass liked shadows, which can be diffusely distributed and tend to mainly involve the periphery of the hilus or the middle and lower lung fi elds. hrct scanning is commonly applied to assess early pcp that is demonstrated negative by chest x-ray. hrct scanning demonstrates bilaterally symmetric patchy or fused ground glass liked shadows. the pathological basis of ground glass liked shadows and parenchymal areas refl ect that the acinus is fi lled by the foamy exudates, which are composed of surface active substances, cellulose and cell debris. all of the ground glass liked shadows, overlapping septa and the intralobular linear shadows are in gravel road liked manifestation. the septa and intralobular linear shadows demonstrate pulmonary interstitial edema or cellular infi ltration. in the middle-advanced stage of pcp, there are manifestations of small pulmonary nodules, pulmonary parenchymal changes, thickened interlobular septa, intralobular linear shadows, mass like lesions, pleural effusion, and lymphadenectasis. the cysts tend to mainly involve the upper lobes, which can be unilateral or bilateral pulmonary cysts, pneumothorax, mild or severe interstitial fi brosis and traction bronchiectasis. hrct scanning demonstrations of pcp are non-specifi c. its diagnosis should be in combination with hivph and etiological examinations. bacterial infections mycobacterium tuberculosis is still an important pathogen for pulmonary infection in hiv positive patients. since the mid- s, the main cause of the increasing incidence of tuberculosis is the prevalence of hiv infection. the incidence of tuberculosis in aids patients is - times higher than the general population. hiv infection is the most dangerous factor for progression of latent tuberculosis into active tuberculosis. tubercle bacillus belongs to mycobacterium family of mycobacterium genus, which is divided into types of human, bovine and murine. the main cause of human tuberculosis is human mycobacterium tuberculosis, which is known as acid-fast bacilli. tubercle bacillus wall is the complex containing high molecular weight fatty acids, lipids, proteins and polysaccharides, which are related to its pathogenicity and immune responses. lipid can cause the infi ltration of human monocytes, epithelial cells and lymphocytes to form tuberculous nodules. its protein contents can cause allergic reactions, and infi ltration of neutrophils and mononuclear cells. polysaccharides participate in certain immune responses (such as agglutination). these pathogenic factors lay the foundation for the occurrence of tuberculosis in aids patients. human immunity, allergic responses as well as the number and pathogenicity of tubercle bacilli are closely related to the quality, range, spreading rate and the progression of tuberculosis. its pathological changes are characterized by exudation, infi ltration, proliferation and hyperplasia, degenerative necrosis (caseous necrosis) and cavity formation. the manifestations include congestion, edema and infi ltration of leukocytes. the exudative lesions occur in early stage of tuberculosis infl ammation or when the lesions deteriorate. it can also be found in the serosa tuberculosis. there is neutrophilic granulocytes in the exudative lesions, which are gradually substituted by monocytes (phagocytes). the engulfed tubercle bacilli can be found in the large mononuclear cells. the exudative lesions are absorbed and dissipated through the phagocytosis of the mononuclear-phagocyte system, even with no scar. when large mononuclear cells engulf and digest tubercle bacilli, the phospholipid of the bacteria render the large mononuclear cells to enlarge and be fl at, similar to epithelial cells, which is known as epithelioid cells. these epithelioid cells gather into groups, with central langhans giant cells that pass the messages of the bacteria antigens to lymphocytes. surrounding the langhans giant cells, there are often many lymphocytes to form typical tuberculous nodules, which are characteristic lesions of tuberculosis. this is why it is called tuberculosis. in the tuberculous nodules, tubercule bacilli are usually undetectable. proliferation based lesions often occur in the cases with less bacteria invasion and when human cells mediated immunity is predominant. degeneration often occurs on the basis of the exudative or proliferative lesions. tubercle bacilli overcome macrophages and then continually proliferate in large quantity. after the cells become cloudy and swelling, the foci show fatty degeneration, dissolved into fragments, until the occurrence of necrosis. after the death of infl ammatory cells, proteolytic enzymes are released to dissolve the tissues that results in necrosis, which is coagulative necrosis. by naked eyes observation, they are yellowish gray, with loose and brittle quality like caseous. therefore it is known as caseous necrosis. microscopic examination demonstrates an area of solid and eosin staining red necrotic tissues with no tuberculosis. tubercle bacilli in the foci of caseous necrosis proliferate in large quantity to cause liquefaction, which is related to infi ltration of neutrophile granulocytes and large monocytes. part of liquefi ed caseous necrotic substances can be absorbed and part can be discharged by the bronchus to form cavities. otherwise, it may cause intrapulmonary spreading along with bronchi. the small caseous necrosis or proliferative lesions can be shrunk and absorbed after treatment, with only residues of slight fi brous scars. due to the compromised immunity in aids patients, the lesions rarely show fi ber tissues proliferation, but form cords liked scar. calcifi cation rarely occurs. if the necrotic lesions erode the blood vessels, tubercle bacilli can cause systemic miliary tuberculosis along with blood fl ow, including brain, bones and kidneys. large quantity sputum containing tubercle bacilli gains its access into the gastrointestinal tract. it can also cause intestinal tuberculosis and peritoneal tuberculosis. pulmonary tuberculosis can cause tuberculosis pleurisy via direct spreading to the pleura ( fig. . a-c ). clinically, it is a chronic progression, with rare acute onset. the clinical symptoms are commonly systemic, with fever and fatigue. the respiratory symptoms include cough and hemoptysis. pulmonary tb can be divided into primary and secondary, with the initial episode commonly being primary (type i). the residual bacteria after primary infection can cause secondary infection (type ii-iv) when the immunity is compromised via spreading along blood fl ow or direct spreading. it is common in hiv positive children. most cases are asymptomatic, sometimes with symptoms of low grade fever, mild cough, sweating, rapid heartbeat, and poor appetite. hiv/aids related miliary tuberculosis is one of the major manifestations of pulmonary tuberculosis, which is more common. the onset of acute miliary tuberculosis is rapid, with symptoms of chills and high fever with a body temperature up to °c, mostly remittent fever or continuous fever. there may be decreased leukocytes count and accelerated sedimentation rate. the progression of subacute and chronic hematogenous disseminated pulmonary tuberculosis is relatively slow. infi ltrative pulmonary tuberculosis in aids patients commonly occurs in both middle and lower lung fi elds, with fl aky and fl occulent foci or parenchymal changes in lobes or segments. caseous lesions are rare. the early stage of infi ltrative pulmonary tuberculosis is commonly asymptomatic, with later occurrence of fever, cough, night sweating, chest pain, weight loss, expectoration and hemoptysis. this type of pulmonary tb rarely occurs in aids patients. in non-aids patients, chest x-ray demonstrates three major changes, namely cavity, fi brosis, and bronchial dissemination. in the aids patients, the pulmonary manifestations include single or multiple nodular shadows with clear boundaries. tuberculous pleuritis is an exudative infl ammation caused by the direct invasion of tubercle bacillus from the primary lesion near the pleura into the pleura, or hematogenous dissemination via the lymphatic vessels to the pleura. the routes for occurrence of tuberculous pleurisy include: ( ) the bacteria in the hilar lymph tuberculosis counterfl ow to the pleura along lymph vessels. ( ) tb lesions adjacent to pleura rupture to cause direct access of the tubercle bacilli or products of tuberculosis infection into the pleural cavity. ( ) acute or subacute hematogenous disseminated tuberculosis causes pleuritis. ( ) due to the increased allergic responses, the pleura highly respond to tuberculosis toxins to cause exudation. ( ) thoracic tuberculosis and rib tuberculosis rupture into the pleural cavity. clinically, pleuritis can be divided into three types, dry pleuritis, exudative pleuritis and tuberculous empyema (rare). the common clinical manifestations are fever, cough with accompanying chest pain of the affected side and shortness of breath. ( ) sputum smear examination is simple to manipulate, with high accuracy rate. the fi ndings of the tubercle bacilli can defi ne the diagnosis. it still is the golden criteria for the diagnosis of pulmonary tuberculosis. ( ) sputum tubercle bacilli culture has high reliability. tubercle bacilli drug sensitivity test can be performed but requires - weeks to obtain the results. therefore, its application is limited. ( ) tuberculin purifi ed protein derivative (ppd) test is commonly used. its positive result is one of the evidence confi rming a past history of tb infection. ( ) bactec test can be performed to detect the metabolites of mycobacterium tuberculosis. generally, mycobacterium can be detected in weeks. the quantity of mycobacteria can affect the period required for test results. ( ) pcr has poor specifi city but high sensitivity of up to - %. both can be applied to observe the enlarged lymph nodes in the chest and mediastinum. in addition, they can be applied to obtain specimens for biopsy, which facilitates the diagnosis and differential diagnosis. diagnostic imaging examinations include chest x-ray and ct scanning. chest x-ray can demonstrate the location, quality and range of the lesions. it can also help to assess the therapeutic effi cacy. ct scanning can demonstrate small or hidden lesions, with a high resolution. primary pulmonary tuberculosis, also known as primary syndrome, is rare in adult aids patients. chest x-ray demonstrates intrapulmonary patchy or large fl aky parenchymal changes, hilar and mediastinal lymphadenectasis in connection to irregular cords liked shadows (located between intrapulmonary lesion and the hilum). lymph node tuberculosis is demonstrated to have mediastinal lymphadenectasis that sometimes fuse into mass. in aids patients, simple mediastinal lymph node tuberculosis is more common than primary syndrome. tuberculosis ( ) the acute cases are demonstrated to have diffused miliary nodules in both lungs with even distribution, even size and even density. ( ) the subacute and chronic cases are demonstrated to have nodules in both lungs, with uneven distribution, uneven size and uneven density. sometimes calcifi cation occurs in the nodules, with fi brous cords and thickened pleura. infi ltrative pulmonary tuberculosis are demonstrated to have patchy parenchymal changes in the middle and lower lung fi elds as well as parenchymal changes, cavities and fi brous cords liked foci in the segments and lobes. it can also occur in the upper lung fi elds, commonly with accompanying mediastinal and hilar lymph node tuberculosis. it commonly occurs in the advanced stage of aids,, with manifestations of pulmonary interstitial fi brosis and formation of cavities. this type of pulmonary tuberculosis is less common. it rarely occurs, mostly in the early stage of aids. it is rare in the middle and advanced stages of aids. dry pleuritis has manifestations of blunt costophrenic angle and limited diaphragm mobility. exudative pleuritis is manifested as small quantity pleural effusion and thickened pleura, commonly with encapsulated effusion of the lateral pleura. calcifi cation is rare. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of dull chest pain, dyspnea, fever, night sweating, fatigue and anorexia. his cd t cell count was /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of dull chest pain, dyspnea, fever, night sweating and fatigue. her cd t cell count was /μl. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he was infected hiv via blood transfusion, with complaints of cervical lymph node tuberculosis, ascites and abdominal infection, fungal stomatitis, biliary stones with infection and severe anemia. his cd t cell count was /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of fever and night sweating. her cd t cell count was /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she was hospitalized due to complaints of chest distress, cough and expectoration for months, with after noon low grade fever and weight loss. on admission, she was confi rmed hiv positive and a cd t cell count of /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of fever and chest pain for months, with acid-fast bacilli positive in the pleural fl uid culture. her cd t cell count was /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of fever and chest pain for months, with acid-fast bacilli positive in the pleural fl uid culture. her cd t cell count was /μl. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of fever and chest pain for months, with acid-fast bacilli positive in the pleural fl uid culture. her cd t cell count was /μl. cough expectoration, chest pain, dyspnea, fever, night sweating, fatigue, anorexia, lymphadenectasis and rapid progression of the conditions. ppd skin test with a resulted diameter of more than mm should be considered as tuberculosis infection. but its positive rate remains low. the culture of sputum and bronchoalveolar lavage fl uid can detect the pathogens. nucleic acid analysis or dna probe technique, pcr and chromatography can be applied to detect tubercle bacilli. the commonly used diagnostic imaging examinations include chest x-ray and ct scanning. the main demonstrations include ( ) intrapulmonary and extrapulmonary lymphadenectasis; ( ) miliary tuberculosis manifestations; ( ) infi ltrative (pneumonia type) pulmonary tuberculosis; ( ) pulmonary interstitial fi brosis, cavity, pulmonary emphysema, nodules, emphysema, and bronchiectasis with accompanying infections. in the cases with their cd t cell count being above /μl, the imaging demonstrations are similar to those of non-hiv/aids patients with pulmonary tuberculosis. in the cases with their cd t cell count being above /μl, the manifestations are intrapulmonary large fl aky parenchymal changes, surrounding satellite lesions as well as mediastinal and hilar lymphadenectasis. sometimes the manifestations may be only mediastinal lymphadenectasis and their fusion into mass. in the cases with cd t cell count being above /μl, there may be accompanying extrapulmonary tuberculosis, such as tuberculous peritonitis, bone tuberculosis, brain tuberculosis and splenic tuberculosis. in the cases with their cd t cell count being lower than /μl, the manifestations are mostly miliary tuberculosis. hiv/aids related tuberculosis should be principally differentiated from pneumocystis carinii pneumonia, fungal infections, other pneumonia and lung cancer. hiv/aids related tuberculosis should be differentiated from pcp. pcp is mainly manifested as multiple lesions with hilum as the center to extending symmetrically to outside of the lungs. in the advanced stage, pcp has main lesions of pulmonary interstitial fi brosis, with less accompanying mediastinal and hilar lymphadenectasis. the laboratory tests can facilitate to defi ne the diagnose. hiv/aids related tuberculosis should be differentiated from fungal infections. fungal infections are relatively less common than tuberculosis. the imaging fi ndings of hiv/aids related pulmonary fungal infections are diverse, with manifestations of miliary, fl aky fl occulent liked, parenchymal, mass, and interstitial changes. in general, the diffuse lesions are mainly interstitial changes, while confi rmed lesions, compared to tb lesions, are more likely to have thick walled cavities. satellite lesions of fungal infections are less than those of tuberculosis, with less accompanying mediastinal and hilar lymphadenectasis. sometimes laboratory tests are necessary to defi ne the diagnosis. hiv/aids related tuberculosis should be differentiated from non-tuberculosis mycobacteria pneumonia. their imaging fi ndings are similar to each other, which presents challenges for their differential diagnosis. molecular biology examinations play an important role in the differentiation. hiv/aids related tuberculosis should be differentiated from other pneumonia. non-bacterial pneumonia (mycoplasma, viral and allergic) often shows patchy shadows, which are similar to the manifestations of early infi ltrative pulmonary tuberculosis. when bacterial pneumonia shows lobar lesions, it may be confused with tuberculous caseous pneumonia, which should also be differentiated for the diagnosis. symptoms of mycoplasma pneumonia are mild, with imaging fi ndings being always inconsistency with the clinical symptoms, which usually subside within - weeks. in the cases of allergic pneumonia, eosinophils in the blood increase, with intrapulmonary mobile shadows, which are the basis for their differentiation. bacterial pneumonia can have acute onset, with chills, high fever, rust colored sputum, and streptococcus pneumoniae positive. recovery is rapid after antibiotic treatment and all these symptoms can subside within month. hiv/aids related tuberculosis should be differentiated from pulmonary abscesses. in the cases of infi ltrative pulmonary tuberculosis with cavities, it should be differentiated from pulmonary abscess. especially, tuberculosis with cavities in the apical segment of inferior lobe should be differentiated from acute pulmonary abscess. chronic fi brous cavity tuberculosis should be differentiated from chronic pulmonary abscess. the key points for the differentiation are tubercle bacilli positive by sputum culture in the cases of tb, while tubercle bacilli negative by sputum culture in the cases of abscesses. pulmonary abscess has an acute onset, with increased leukocytes and neutrophils as well as favorable therapeutic effi cacy of antibiotics. but sometimes tuberculosis with cavity may develop into bacterial infection, with undetectable tubercle bacillus by sputum culture. hiv/aids related tuberculosis should be differentiated from lung cancer. the central type of lung cancer has nodular shadow in the hilum or hilar and mediastinal lymph node metastasis, which should be differentiated from lymphatic tuberculosis. the peripheral type of lung cancer has small fl aky infi ltration and nodules in the periphery of the lungs, which should be differentiated from tuberculoma or tuberculosis infi ltrative lesions. lung cancers occur commonly in people aged above years. the central type mainly is squamous carcinoma and the cases often have a history of long term smoking, with symptoms of no fever but diffi culty breathing or chest distress as well as gradually increasing chest pain. there are also symptoms of irritated cough with blood phlegm and progressive weight loss. the cases with supraclavicular metastasis have palpable harden lymph nodes. the intrapulmonary nodules can lobulated with fi ne spikes, no satellite lesions, generally no calcifi cation and possible vacuole sign. the peripheral type of lung cancer shows pleura invagination sign. tuberculin test often shows negative in the cases of lung, positive or weakly positive in the cases with tb, and negative or weak positive in aids patients. hiv infection is known to be the main factor for the development of latent tuberculosis into active tuberculosis. immunosuppression are similar to those in the cases with primary tuberculosis, with characteristic abnormal manifestations of hilar and/or mediastinal lymphadenectasis and parenchymal changes of the air chambers. ct scanning demonstrates enlarged nodules with low density. enhanced scanning demonstrates marginal enhancement of the lymph nodes. the incidence of military tuberculosis in aids patients is increasing due to reduced thymic t lymphocytes in aids patients and the defects of delayed allergic responses, which result in the formation of granulomas and impaired functions to kill bacilli and confi ne the lesions. nontuberculous mycobacteria (ntm) refer to the mycobacteria except for mycobacterium tuberculosis complex (human, cattle, african and vole) and mycobacterium leprae. the most commonly known nomination is nontuberculous mycobacteria (ntm). more than kinds of ntm have been found so far. according to berger manual of systematic bacteriology, ntm is divided into two categories, rapid growth type and slow growth type. ntm are widely spread in nature, such as soil, dust, fl owing water and raw milk. under a microscope, ntm is morphologically similar to tubercle bacilli, with red stained fi ndings by acid-fast staining. according to the growth of ntm in solid medium, the runyon classifi cation divides ntm into the following four groups, light chromogenic bacteria; dark chromogenic bacteria that can cause cervical lymphnoditis in children, intrapulmonary or extrapulmonary infections and abrasive abscess; non-chromogenic bacteria including mycobacterium avium complex, intracellular mycobacteria that can cause pulmonary infections, lymphnoditis, arthritis and meningitis; rapid growth bacteria including mycobacterium fortuitum, mycobacterium, mycobacterium abscessus that can cause pulmonary diseases and skin infections. immunocompromised populations, such as hiv infected patients, patients with neoplasms, patients with long-term use adrenocortical hormone or immunosuppressive agents, are more susceptible to disseminated ntm infection. immunocompetent people may have mycobacterium kansasii and mycobacterium avium infections. it was reported in the united states that the occurrence of mycobacterium avium complex infection in hiv positive patients is up to more than %. the pathological changes of ntm infections are similar to those of tuberculosis. ntm lymphnoditis is pathologically characterized by granulomatous infl ammation. tuberculous nodules formed by epithelioid cells and langhans giant cells are rare, with no accompanying central caseous necrosis. due to the weak pathogenicity of ntm, the pathological changes are slight, but there is difference in the pathological changes of ntm infections in terms of location, type and host. cavities are common in the cases with pulmonary ntm infection, commonly being multiple or multilocular thin wall cavities. the pleuron is rarely involved, with non-specifi c pathological changes of infl ammation but with large quantity pathogens of ntm. patients often have a history of chronic obstructive pulmonary disease, tuberculosis, silicosis, pulmonary abscess, bronchiectasis, cystic fi brosis, diabetes, ulcer as well as use of hormone or immunosuppressive agents. its occurrence is more common in males than in females. the symptoms include cough, expectoration, hemoptysis, chest pain, diffi culty breathing, low grade fever, weight loss and fatigue. the symptoms are nonspecifi c and the conditions progress slowly. for patients with suspected diagnosis of pulmonary ntm infection, sputum smear for acid-fast staining, sputum culture and bronchial lavage specimen culture can be performed. the positive fi ndings should be identifi ed with two to three times repeated culture. the same fi nding of ntm can defi ne the diagnosis. pathological biopsy can be performed for the diagnosis of ntm lymphnoditis. using s- srdna gene spacer sequence (igs) of ntm for pcr-restriction fragment length polymorphism analysis (pcr-rflp), ntm species can be identifi ed, which is more accurate, faster and simpler than the conventional morphological and biochemical examinations. mycobacterium tuberculosis and ntm have common antigen. ppd skin test produces cross-reaction, but there are still differences between mycobacterium tuberculosis and ntm. ppd-t of the mycobacterium tuberculosis and ppd-ntm of ntm are simultaneously obtained for mantoux skin tests. the induration diameter of ppd-t in ntm patients is generally within mm. for the cases with the induration diameter of ppd-ntm skin test being mm larger or over % larger than that of ppd-t skin test, ntm infection can be confi rmed. both are the most commonly used imaging examinations. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of cough and chest distress for half a month, fever for days, day after cesarean section and fi nding of hiv positive for day. her cd t cell count was /μl, with treponema pallidum antibody negative and ppd test negative. imaging demonstrations include various lesions such as infi ltration, cavity, nodules, fi brous caseation and extensive fi ber contraction in unilateral or bilateral lungs. the incidence of cavity is up to %, being singular or multiple. cavities caused by intracellular mycobacterium are mostly found in the pleura, with thin wall and less surrounding exudates. the incidence of non-tuberculous mycobacterial infections in aids patients is high. mac infection is usually caused by the initial exposure rather than the reactivation of latent pathogens. in patients with complications of mac related lung diseases, most of the imaging fi ndings are normal. the most common manifestation is mediastinal or hilar lymphadenectasis. and the pulmonary symptoms are similar to those of tuberculosis. in the cases with multiple patchy parenchymal changes, cavities can be found, as well as nodules with blurry boundaries, pleural effusion and rarely found miliary nodules. sputum or bronchoalveolar lavage fl uid culture positive, clinical symptoms, imaging fi ndings, and response to treatment can defi ne the diagnosis. staphylococcus aureus is a gram positive coccus and is coagulase positive staphylococcus. the pathogenic substances of staphylococcus aureus mainly are toxins and enzymes, such as hemolytic toxins, leukocidin and enterotoxin, which play a role in hemolysis, necrosis, killing leukocytes and vascular spasm. the staphylococcus aureus coagulase is the main reason for suppurative infection. pneumonia caused by inhaled staphylococcus aureus through the respiratory tract often shows lesions in the large lobes or extensive fusion of bronchopneumonia lesions. bronchial and alveolar rupture allows gas to enter the pulmonary interstitium, which is communicated with the bronchi. in the cases of bronchiolar blockage by necrotic tissues or pus, the one-way valve effect is formed to cause tension pulmonary emphysema. in the cases with superfi cial pulmonary emphysema with excessively high tension, it ruptures to form pneumothorax or pyopneumothorax, as well as bronchooleural fi stula ( fig. . a, b ) . the symptoms include chills, persistent high fever, cough, expectoration, chest pain and other symptoms. there is no sign in the early period. symptoms are scattered moist rales in both lungs, being in consistency to severe toxic symptoms and respiratory symptoms. yellow purulent sputum is the typical characteristics of staphylococcus aureus pneumonia. in the cases with larger lesions or fusion of lesions, signs of parenchymal changes, pneumothorax or pyopneumothorax can be found. in the sputum or pleural fl uid smears examinations, the bacteria with a concentration being no less than cfa/ml is the pathogen, the bacteria with a concentration being - cfa/ml is the suspected pathogen, and the bacteria with a concentration being less than cfa/ml is the contaminated bacteria. there are increased wbc count and neutrophils, leftward migration of the nucleus and possibly no increase of wbc count in aids patients. immunofl uorescence, enzyme-linked immunosorbent assay and counter immunoelectrophoresis can be performed to detect serum antigen or antibody of the pathogenic bacteria, which can defi ne the diagnosis. polymerase chain reaction has certain signifi cance in pathogen detection. the protected bronchoscopic specimen (pbs) and bronchoalveolar lavage (bal) can be applied to collect the specimen, which has reduced chances of specimens contamination by oral bacteria. biphasic tv monitors guided pulmonary puncture and suction for pulmonary tissues examinations can be performed to detect the real pathogenic bacteria. both are the most commonly used imaging examinations. the diagnostic imaging demonstrates staphylococcus aureus pneumonia as lesions in the inner zone of both middle lower lungs. there are singular or multiple parenchymal changes in patchy or lobar distribution that may fuse into large fl akes. it may be complicated by cavity and pulmonary emphysema, with surrounding compensatory emphysema. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of high fever with a body temperature of about °c and chest pain for months. his cd t cell count was /μl. chills, fever, cough, expectoration, chest pain and other symptoms commonly; hemoptysis and dyspnea rarely the patients may be found with fever appearance, rarely shortness of breath and cyanosis. in the serious cases, the body temperature can be as high as - °c and blood pressure decreases, with signs of shock. by chest examinations, decreased ipsilateral respiratory motion; increased or decreased fremitus, dull sound in percussion; bronchial breathing sounds or moist rales by auscultation; rarely pleural friction and weakened breathing sounds. increased wbc count and neutrophils, possible the nucleus left shift; no increase or even decrease of wbc count in aids patients; staphylococcus aureus positive by blood culture. sputum or pleural fl uid smears examinations for pathogenic bacteria culture is positive, and antibiotic sensitivity test is positive. by chest x-ray and ct scanning, the most common demonstrations are lesions of bronchial pneumonia. the fi ndings of pulmonary emphysema and cavities can facilitate the diagnose. the lesions should be differentiated from infi ltrative parenchymal bronchioloalveolar carcinoma. the smaller lesions should be differentiated from pulmonary infarction. the large lesions should be differentiated from obstructive pneumonia. it is diffi cult to identify the types of common bacterial pneumonia simply by chest x-ray and ct scanning. in combination to the laboratory tests, the diagnosis can be defi ned. the incidence of pyogenic bacterial infection is increasing in aids patients, which is caused by their weakened cellular and humoral immunity. the manifestations of these most common bacterial infections are similar to those of non-hiv infected patients by chest x-ray. bacterial pneumonia and purulent bronchitis are the most common causes of pulmonary infections in aids patients. particularly, they are frequently found in patients with a history of intravenous drug abuse and smokers. they are histologically characterized by infl ammations of the bronchi and bronchioles as well as infl ammatory exudates and mucus in the airway lumens. ct scans facilitates the diagnosis of bronchiolitis and early bronchial pneumonia. the demonstrations are characterized by ( ) small centrilobular nodular shadows, which is the cross sectional demonstration of bronchioles fi lled with infl ammatory substances and its surrounding infl ammations; rhodococcus equi infection is one of the zoonotic diseases, which commonly occurs in the grazing areas. patients with t lymphocyte immunodefi ciency caused by aids and other factors are especially susceptible to the infection. rhodococcus equi was fi rstly discovered in and was nominated as corynebacterium equi. after structure analysis of the cell wall, it was found that the bacterium is quite different from corynebacterium, and therefore classifi ed as rhodococcus. rhodococcus equi infection in human is rare. but in recent years, due to an increase of patients with immunodefi ciency syndrome, reports on rhodococcus equi caused human respiratory infections and sepsis are increasing. in the past, the toxicity mechanism of rhodococcus equi was mostly speculated. until recently, the damage process of toxic plasmid to human tissue is discovered, which presents a new way for the study of the pathogenesis of rhodococcus equi infections. rhodococcus equi is one of the facultative parasites in the cells and its optimum growth temperature is °c, with a suitable growth temperature of - °c. acid-fast staining of rhodococcus equi shows uncertain results. due to its morphological diversity, it is often mistaken as diphtheroid bacillus, bacillus or micrococcus. in sheep blood agar, rhodococcus equi can have synergistic hemolysis with staphylococcus aureus, listeria monocytogenes and corynebacterium pseudotuberculosis, which is a characteristic manifestation of rhodococcus equi. the most common pathological changes in rhodococcus equi infection are chronic purulent bronchitis and extensive lung abscess. imaging often demonstrates subacute pneumonia, commonly with cavities. the clinical manifestations are poor appetite, drowsiness, fever and shortness of breath. studies by e marchiori et al. [ ] in revealed that all the cases of aids complicated by rhodococcus equi pulmonary infection have cough and fever lasting for - months, with accompanying shortness of breath and chest pain. all the cases, studied by li et al. in [ ] , have fever with a body temperature up to - °c and cough. in addition, there are also expectoration with orange red sputum in cases, hemoptysis in cases, dyspnea in cases, moist rales of lungs in cases, emaciation in cases, poor appetite in cases, diarrhea in cases, joint pain in case, oral candidiasis infections in cases, oral herpes in cases, chest pain in cases, no obvious symptoms in case and hepatitis b in cases. typical clinical manifestations of this disease are fever, cough, dyspnea and chest pain, while others such as emaciation, diarrhea and joint pain are not representative symptoms. identifi cation of the bacteria various specimens were inoculated on blood plates at a temperature of °c for - culture, with bacteria growth of strains. they are biologically characterized by a diameter of about . mm, non-transparent and slight yellowish colonies. after - h, the colonies expand to - mm, which can be emulsifi ed in mucous fl uid liked state. most of the colonies produce orange and orange red pigments, which can be cultured in ordinary agar. histopathological fi ndings are typical for rhodococcus equi infection. h&e staining demonstrates mainly bleeding in the alveolar space, large quantity epithelial cells, possibly predominant fi broblasts, parenchymal changes of lung tissue and thickened alveolar septa. pas staining demonstrates scattered or clustered rhodococcus equi in pink or purplish red. both are the most commonly used imaging examinations. biphasic tv monitor guided lung puncture can be performed to suck lung tissues for biopsy, based on which the real pathogenic bacteria can be detected. the typical demonstrations include central hilar sphere liked shadow with increased density in unilateral lung, accounted for %. there are also manifestations of exudative infi ltration and large fl aky or spherical mass shadows in the right or left hilar area. the lesions are in patchy or fl aky appearance, radiating from the hilum to the lung fi eld with blurry boundaries. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of recurrent fever, cough and chest pain for days; and was found hiv positive for days. he was also a carrier of hepatitis c virus, with symptoms of fever with no known causes, cough, chest distress and weak limbs. by examinations, he was found to have complexion of chronic conditions; many moist and dry rales by cardiopulmonary auscultation. he had a past history of hiv positive for years, with drug abuse and extramarital affairs. the history of present illness includes fever, paroxysmal cough with a little whitish yellow thick sputum since may , . he also had subjective paroxysmal dull pain in the left chest, and hemoptysis once which was bright red with blood clot in a volume of about ml. his cd t cell count was /μl. by sputum culture, rhodococcus equi was found positive. after receiving antibiotic treatment, his conditions improved and he was discharged from the hospital. catalase test of the strain is positive, which is confi rmed as rhodococcus equi by api coryne system. examinations h&e staining demonstrates mainly bleeding in the alveolar space, large quantity epithelial cells or mainly fi broblasts, parenchymal changes of lung tissue and thickened alveolar septa. pas staining and masson staining demonstrate scattered or clustered distribution of rod rhodococcus equi in pink or purplish red. aids complicated by pulmonary rhodococcus equi infection shows subacute infl ammation. firstly, there are exudates in the surrounding area of unilateral hilum as well as sphere shaped mass shadows which is centrally dense and peripherally blurry, with its apex pointing to the hilum. the lesions can be complicated by cavities and fl uid level, with thick wall of the cavities. as the disease progresses, the abscess cavities have increased tension, with gradually thinner abscesss cavity walls and uneven wall thickness, even showing pleural effusion. these are its characteristic imaging fi ndings. it often needs to be differentiated from pneumocystis carinii pneumonia, tuberculosis, staphylococcus aureus pneumonia, central type lung cancer and other diseases. imaging fi ndings of pneumocystis carinii pneumonia usually are ground glass liked changes in the lung fi eld, with parenchymal changes and centrilobular nodules. tuberculosis often shows miliary tuberculosis, with lymphadenectasis, large tubercles and parenchymal changes. these characteristic pathological and imaging fi ndings of staphylococcus aureus pneumonia are similar to those of bronchial pneumonia (lobular pneumonia). the lesions are nodules with blurry boundaries in a diameter of - mm. the disease progresses rapidly, while pulmonary rhodococcus equi infection has a chronic progression. hrct scanning demonstrates staphylococcus aureus pneumonia as centrilobular nodules and branch linear shadows (tree buds sign), which can be found in % patients, with - % will develop into commonly singular pulmonary abscess. chest ct scanning demonstrates round liked abscess cavity with thick wall and liquid level in it. the inner wall of the abscess cavity is often irregular, with various changes within short period. the central type of lung cancer is commonly demonstrated as round liked shadow of unilateral hilum with rough boundary. lobulation or bronchial stenosis sometimes occurs. however, aids complicated by rhodococcus equi pneumonia is demonstrated as sphere liked mass in the hilum; mostly sphere liked increased density shadow with hilum as the center. the shadow is centrally dense and peripherally blurry, with no bronchial stenosis. rhodococcus equi was fi rstly discovered in and was nominated as corynebacterium equi. after structure analysis of the cell wall, it was found that the bacterium is quite different from corynebacterium, and therefore classifi ed as rhodococcus. rhodococcus equi is generally believed to be the pathogen for horses, pigs and cattle. [ ] showed a ct t cell count of lower than /μl. all the results are in consistency. in conclusion, aids complicated by pulmonary rhodococcus equi infection is mainly subacute infl ammation. there are exudation around the unilateral hilum as well as centrally dense and peripherally blurry sphere shaped mass shadows, with secondary cavities and parenchyma changes and even pleural effusion. all of these are characteristic imaging demonstrations. most cases of hiv positive complicated by respiratory or pulmonary diseases are caused by aspergillus fumigatus. aspergillus fumigatus belongs to filamentous fungi, which is a common opportunistic fungus and has a wide distribution in the nature. as conditional pathogenic bacteria, it can parasitize in the human skin and upper respiratory tract. human has certain resistance to aspergillus so it commonly fails to cause diseases. in immunocompromised aids patients, the pathogenic bacteria can pass through the defects in the skin and mucous membrane into the blood flow to infect the tissues and organs. aspergillus commonly violates bronchus and lung, with involvements of rhinal sinuses, external auditory canal, eye and skin. otherwise, it disseminates to organs of the body along with blood fl ow. the early lesions are diffuse infi ltrative and exudative changes. and advanced lesions are necrosis, pyogenesis or granuloma. large quantity hyphae can be found in the lesions. the hyphae penetrate the blood vessels to cause vasculitis, perivascular infl ammation and thrombosis. and thrombosis can cause ischemia and necrosis of the tissue. according to the pathological changes and imaging fi ndings, it can be divided into three major types: vascular invasion type, bronchopneumonia type and allergic bronchopulmonary aspergillosis type. ( ) the vascular invasion type is the result caused by toxins released in the process of aspergillus spreading extensively from the primary focus to the lungs. vascular infi ltration of the pulmonary parenchyma and coagulative necrosis are believed to be the cause of vascular occlusion and pulmonary infarction. ( ) bronchopneumonia type is acute bronchitis caused by inhalation of aspergillus spores. in the cases of hyphae invasion into the lung tissues, extensive infi ltrative pneumonia or focal granuloma are resulted in. it can also cause necrosis, pyogenesis and multiple small abscesses. spherical pulmonary aspergillosis is often secondary to bronchiectasis, tuberculosis, carcinous cavity and other lung diseases. mycelia multiply and gather in the cavities of the lungs to form a spherical mass with fi brin and mucosal cells, which are called aspergillar glomera, which do not invade the lung tissue. ( ) allergic bronchopulmonary aspergillosis type is the proliferation and germination of inhaled aspergillus spore in the airway, often showing obvious related mucosal lesions and eventually resulting in bronchiectasis ( fig. . a-c ) . the cases with acute onset have symptoms of high fever or irregular fever, cough, shortness of breath and green purulent sputum. the cases with a chronic onset have symptoms of repeated cough and hemoptysis, which are similar to those of tuberculosis. the pulmonary signs are not obvious, with occasional fi ndings of moist rales. most cases are asymptomatic and sometimes there are fever, cough, shortness of breath, and mucous purulent sputum. the main symptoms are persistent fever, cough and chest pain. in the serious cases, there is dyspnea. by microscopic examination of sputum, aspergillus hyphae can be found. the culture for aspergillus fumigatus is positive. serum ige is commonly above , μg/l. skin test for aspergillus antigen is positive. serum anti-aspergillus antigen igg antibody precipitin is positive. puncture of lungs and pleura for biopsy facilitates the diagnosis of pulmonary fungal infections. both are the most commonly used imaging examinations. hiv/aids related aspergillus bronchopneumonia is commonly demonstrated to have increased pulmonary markings, diffuse patchy blurry shadows and mass shadows in both lungs. spherical pulmonary aspergillosis is commonly demonstrated to have sphere liked aspergillar glomera suspending in the cavities to form a crescent shaped transparent area, in characteristic meniscus sign, rolling ball sign and fi ngertip sign. meniscus sign is nominated due to a meniscus liked space between the aspergillar glomera growing in the cavity and the cavity wall. rolling ball sign means that the aspergillar glomera moves along with the changes of posture. fingertip sign indicates that the substance formed by aspergillar glomera in dilated bronchi is in a fi nger shape, sometimes in v shape sign and y shape sign. invasive lesions refer to lesions invading or destroying lung structures, such as pneumonia, parenchymal changes and necrosis. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of cough and chest distress, with increased eosinophilic granulocytes. her cd t cell count was /μl. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of high fever or irregular fever, cough and shortness of breath. his cd t cell count was /μl. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of high fever or irregular fever, cough and shortness of breath. his cd t cell count was /μl. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he was hospitalized due to complaints of fever for week, chest distress and shortness of breath for day. on admission, he was confi rmed as hiv positive, with a cd t cell count of /μl. by physical examinations, he was in poor physical conditions, respiratory rate /min, lips cyanotic, coarse breathing sounds of both lungs with small quantity dry rales. his conditions progressed rapidly and death occurred due to respiratory failure after days. lung and pleura puncture for biopsy can detect the growth of aspergillus hyphae. sputum culture can detect aspergillus hyphae, with fi ndings of aspergillus fumigatus positive. in the cases with allergic bronchopulmonary aspergillosis, the serum ige is above , μg/l. skin test of aspergillus antigen is positive. the serum anti-aspergillus antigen igg antibody precipitin is positive. characteristic ct scanning demonstrations of hiv/aids related parasitic aspergillar glomera include pulmonary cavities or cavity lesions with spherical contents, smooth boundaries of the spherical contents with even density, lunate shaped or ring shaped transparent shadows between cavity or cavity walls and the contents, migration of the contents with the body postures. according to the pathological and imaging demonstrations, it can be divided into three major types: in the early stage, ct scanning demonstrates soft tissue density nodules or light ground glass liked halo sign around the mass, which is the evidence for the diagnosis of the invasion type pulmonary aspergillosis. air cresent sign refers to round pulmonary infi ltration with accompanying central necrosis and surrounding lunate or ring shaped cavity. other noncharacteristic ct scanning demonstrations include multiple lobular parenchyma lesion shadows or lobular fusion shadows, parenchyma lesion shadows in the lobes, segments and subsegments, nodular or mass shadows and thin/thick wall cavities or low density areas in the mass shadows. it is demonstrated to have parenchymal lesions around the airway or/and central small nodules in the lower lobes. the parenchymal lesions prove the occurrence of mycotic bronchopneumonia. the most common imaging fi nding is the thickened bronchial wall. central bronchiectasis is its characteristic demonstration. in the cases of dilated bronchi containing sputum bolt or mucus, it shows fi ngertip shaped or toothpaste shaped shadow, which should be considered as its characteristic demonstration. hiv/aids related pulmonary aspergillosis should be differentiated from congenital bronchial atresia. most cases of the congenital bronchial atresia are atresia at the proximal pulmonary segment of the bronchi, often with a clearly defi ned mass. in the typical cases, there are bronchial branches and more branches in fi ngertip shape, pointing to the pulmonary hilum. confi ned pulmonary air retention in the pulmonary lobe and segment of the atresic bronchi is the important evidence for the diagnosis of congenital bronchial atresia. hiv/aids related pulmonary aspergillosis should be differentiated from allergic bronchial-pulmonary aspergillosis. in the cases of allergic bronchial-pulmonary aspergillosis have no clearly defi ned mass, with demonstrations of v shaped, y shaped, grapes shaped or fi ngertip shaped shadows with clearly defi ned boundaries, which are characteristic in those patients with bronchial asthma or a case history of exposure to dusts containing fungi. there is also increased proportion of eosinophilic granulocytes in the peripheral blood. detection of aspergillus in phlegm can defi ne the diagnosis. hiv/aids related pulmonary aspergillosis should be differentiated from central lung cancer. central lung cancer also can cause mucus impaction of the distal bronchi, with manifestations of bronchial arctia and/or truncation, and the surrounding soft tissue mass shadows. hiv/aids related pulmonary aspergillosis should be differentiated from pulmonary cavities and abscesses induced by dissolved tuberculoma, secondary pulmonary tb, chronic lung abscess and peripheral lung cancer as well as cystic bronchiectasis. except aspergilloma, spheric morphology caused by other causes is commonly irregular. the cavity contents cannot migrate with body postures, which is the key point for the differential diagnosis. hiv/aids related pulmonary aspergillosis can be caused by many pathogenic bacteria and aspergillus fumigatus is the most common one. the infection is often caused by inhaled aspergillus fumigatus in the environment. vascular invasion type of pulmonary aspergillosis usually has multiple lesions and nodular changes. generally in pathology, the center of nodule presents typical pale color; commonly with fi brous ring surrounding the nodules resulted from hemorrhage and/or lung parenchymal changes. histologically, they are characterized by coagulative necrosis of the lung tissues, infi ltration of large quantity hyphae in the necrotic tissue, pulmonary vascular infi ltration, but usually without responses of vasculitis and thrombosis. the enzymes released by neutrophile granulocytes can cause the separation of necrotic tissue from its adjacent lung tissues to form necrotic mass in the cavities. airway invasion type of pulmonary aspergillosis, also called aspergillus bronchopneumonia, accounts for - % of invasive aspergillosis. the most common imaging fi ndings are unilateral/bilateral fl aky parenchymal changes, centrilobular small nodules and branches liked linear shadows (tree buds sign). histologically, it is characterized by necrosis and infi ltration of neutrophil granulocytes. the lesions surround the bronchiole and the bronchiole. the invasion of the pulmonary artery can cause bleeding of the adjacent pulmonary parenchyma. allergic bronchopulmonary aspergillosis rarely has lesions, with no unknown pathogenesis, which is generally believed to be related to type i and type ii allergic reactions. it usually shows obvious asthma related mucosal lesions. hyphae generated by aspergillus fumigatus can induce the production of mucus and additional mucosal lesions, eventually leading to bronchiectasis. dilatate bronchial lumen is fi lled with mucus or with absence of epithelium, which is replaced by a granulomatous infl ammatory infi ltration. the most common imaging manifestations are migratory fl occulent, branched y shaped and v shaped (fi ngertip sign) shadows in the pulmonary parenchyma, which are related to the infi ltration of eosinophils. pathologically, bronchial cystic dilatation in the pulmonary segment and sub-segment occurs, with large quantity eosinophils in the bronchial mucus and scattered broken aspergillus hyphae. in combination with the case history, the diagnosis can be defi ned. compromised immunity is an important cause of cryptococcosis, especially in patients with aids or abnormal lymphoproliferative diseases. cryptococcus neoformans, a single phase mould, exists widely in the natural world. the cryptococcus has a diameter of less than μm, which can be inhaled into the human body via respiratory tract. under the impact of a high concentration carbon dioxide, it forms a clearly defi ned protective layer composed of polysaccharide capsule to antagonize the defense mechanisms of the host. thus, lung infection occurs after its inhalation in immunocompetent people, which is commonly asymptomatic. of cryptococcus, inhalation of cryptococcus by aids patients can lead to hilar lymphadenopathy, as well as singular or multiple subpleural small nodules, being similar to those in the cases of mycobacterium tuberculosis infection. in the early stage of cryptococcal infection, only a mild infl ammatory reaction or diffuse infi ltrative exudative changes occur. but in the advanced stage, necrosis, suppuration or granuloma is formed. large quantity hyphae can be found in the focus. in the cases with hyphae penetrating the blood vessels, vasculitis, perivascular infl ammation and thrombosis occur. and thrombosis leads to ischemia and necrosis of the tissue (fig. . ). pulmonary cryptococcus infection in aids patients often is extensively disseminating, with symptoms of fever, cough, diffi culty breathing, expectoration, chest pain caused by pleuritis, and even acute respiratory distress syndrome (ards). hiv/aids related pulmonary cryptococcus infection has no characteristic imaging demonstrations. chest x-ray and ct scanning show multiple morphology of the lesions. in the slight cases, there are thickened pulmonary markings in both lower lungs or isolated nodular shadows, and occasionally cavities. in the cases of acute interstitial infl ammation, there are diffuse infi ltrative or miliary foci, with infi ltration, nodules or exudation in any lobe which is more common in bilateral middle and lower lungs, in unilateral lung or confi ned to one lobe. the foci may be isolated huge spherical or multiple nodular, without obvious surrounding infl ammatory responses, similar to those of tubercles or tumors. otherwise, they are diffuse miliary shadows or fl aky infi ltrative shadows. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he was hospitalized on - - due to headache and vomiting for more than days. in the csf, cryptococcus was found. by blood and sputum culture, cryptoccocus was detected. the diagnosis was cryptococcal meningitis, cryptococcal pneumonia and cryptococcal sepsis. after receiving amphotericin b antifungal treatment and dehydration, headache and vomitting were relieved. but chest ct scanning reexamination demonstrated increased pulmonary lesions, which was considered as tuberculosis. on - - , he was given herv anti-tuberculosis treatment. twenty days ago he sustained weakened lower limbs, which gradually aggravated and completely paralyzed in the recent week, his cd t cell count was /μl. hiv/aids related pulmonary cryptococcus infections should be differentiated from tuberculosis, primary or metastatic lung cancer. tuberculosis mostly is secondary tuberculosis, which is caused by repeated infections of tubercule bacillus. lesions show fl aky or fl occulent shadows in the two upper lungs, with blurry boundaries. the wrapped necrotic foci by fi bers develop into nodules. it can also show miliary shadows, mostly with mediastinal lymphadenectasis. it should also be differentiated from primary or metastatic lung cancer. cryptococcus is a relatively common pathogen of pulmonary fungal infection, and mostly develops in aids patients. usually, it is a disseminated disease, with common involvement of the central nervous system and the lungs. in immunocompetent patients, the nodular granuloma caused by the pathogen is similar to those of other pulmonary fungal infections. in patients with serious immunosuppression, wide tissue infi ltration of the pathogens may occur in the lungs. liked shadows, parenchymal changes of air cavity and miliary nodules. the pathogenic fungi can be found mainly in the pulmonary interstitium. imaging fi ndings include singular or multiple nodules or masses, parenchymal changes of lung lobes and lung segments with clear or unclear boundaries in size of - cm. there may be also miliary lesions, lymphadenectasis and cavity shadows. candida is an opportunistic pathogen, which widely exists in nature. candida albicans parasitize in the oral cavity, laryngopharynx, upper respiratory tracts, vaginal and intestinal mucosa of human being. pulmonary and bronchial moniliasis is commonly caused by candida albicans which has the strongest pathogenicity. after its invasion into the tissues, candida transforms into hyphae and multiplies in a large quantity, with strong toxicity and ability to fi ght against phagocytosis. aids patients may have disseminated pathological changes. only when the immunity is compromised, the pathogen invades into the bronchus or lungs to cause diseases. therefore, pulmonary candida infection is commonly secondary. candidosis can cause acute infl ammation in bronchus and lungs, mainly exudation of neutrophils, which can be divided into two types: bronchitis type and pneumonia type. the pathological changes in the early stage are acute suppurative infl ammation, accompanied with the formation of abscesses. by the naked eyes observation, they are large fl aky parenchymal changes, with central grayish white coagulative necrosis. under a microscope, the lesions are large fl aky caseous necrosis, accompanied with the formation of abscesses, and surrounding infi ltration of hyphae and phagocytes. in the advanced, there are caseous necrosis, formation of cavities, fi brosis and granuloma. symptoms in aids patients are mild, with frequent cough, with a small amount of white mucous phlegm or thick phlegm, no fever or low grade fever; scattered spots of white membranes in the mucosa of oral cavity, throat and bronchus. dry rales can be heard occasionally in both lungs. in aids patients, the manifestations are mostly acute pneumonia or sepsis, with chills, fever, cough, expectoration of white mucous jelly liked phlegm or thick phlegm often with blood or necrotic tissue. the thick sputum, candidal hyphae and shedding cell debris can be condensed into small colloid clumps, with yeast smell. other symptoms include even haemoptysis and diffi culty breathing. dry and moist rales can be heard in lungs. symptoms may be diffi culty breathing, rhinocnesmus, runny nose and sneezing. wheezing rales can be heard in both lungs. chest x-ray chest x-ray demonstrates nodular shadows and fl aky parenchyma changes in unilateral or bilateral lungs. sometimes there is miliary infection. ct scanning demonstrates most lesions in the middle and lower lung fi elds, with rare involvement of the apex. there are thickened lung markings or diffuse small fl aky/patchy shadows, some of which can fuse into large fl aky dense shadows, with blurry boundaries. nodules, due to bleeding around it, may be surrounded by ground glass liked shadows, which is necrotic bronchopneumonia, usually accompanied with a large quantity neutrophils. cough expectoration with white mucous phlegm or thick phlegm, hemoptysis and shortness of breath. examinations of the oral cavity and the throat demonstrate spots liked white membrane covering the surface, and dry and moist rales in the lungs. successive cultures of phlegm, lung tissue, pleural fl uid or cerebrospinal fl uid repeatedly demonstrate the same strain of candida, or direct microscopic fi ndings of large quantity pseudohyphae or hyphae and groups of spores can defi ne the diagnosis. it is demonstrated to have thickened and deranged lung markings in double lung, diffuse small fl aky/patchy shadows, fusion of some small shadows into large fl aky dense shadows, with blurry boundaries, enlarged hilum and blurry structures. the conditions progress rapidly, with repeated lesions occurrence. hiv/aids related pulmonary candida infection should be differentiated from bacterial pneumonia. bacterial pneumonia often has symptoms such as high fever, cough, expectoration, chest pain and shortness of breath. ct scanning demonstrates fl occulent infi ltrative shadows or parenchyma changes and cavities. the pathogen can be detected in the sputum or chest liquid. hiv/aids related pulmonary candida infection should be differentiated from virus pneumonia. viral pneumonia fi rstly causes upper respiratory tract infection, which spread downward to cause pulmonary infl ammation. the demonstrations a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of high fever, cough, expectoration, chest pain and shortness of breath, with pulmonary parenchymal changes sign and moist rales. his cd t cell count was /μl. include ground glass liked changes in the lung fi elds or mass shadows. the defi nitive diagnosis should be based on throat swabs, virus isolation from the sputum and serum specifi c antibodies test. hiv/aids related pulmonary candida infection should be differentiated from pulmonary tuberculosis. in the early stage, the symptoms and signs include irritative dry cough, expectoration, hemoptysis and cavities in lungs. (detailed manifestations of tuberculosis see the section about tuberculosis in this chapter) its diagnosis mainly should be based on chest x-ray and fi ndings of tubercule bacillus in sputum or other specimens, or tuberculosis specifi c pathological changes. hiv/aids related pulmonary candida albicans is a widespread dimorphism bacteria. the oval shaped budding yeasts and hyphae both can be found in the tissues. candidiasis is a common disease in aids patients. chest x-ray demonstrates unilateral or bilateral patchy parenchymal changes of the air cavity and nodules with unclear boundaries. miliary lesions are common. hrct demonstrates multiple nodular shadows in both lungs, often accompanied with parenchymal changes. its defi nitive diagnosis should be based on the fi ndings of candida albicans in the tissues. penicillium marneffei (pm) is a newly found penicillium in , which is a special strain with a distribution in south east asia and southern china. rhizomys is its natural host. in , disalvo et al. [ ] reported the fi rst case of natural human pm infection. in , the fi rst case of human pm infection in china was reported in guangxi zhuang autonomous zone. pm is an opportunistic pathogen and immunocompromised people are susceptible to its infection. its spreading is along with soil contaminated by rhizomys feces to invade human body via the respiratory tract, the digestive tract and skin defects. pm infection is believed to be one of the most common opportunistic infections in aids patients in southeast asia, which has an increasing incidence. pm is the only dimorphic fungus in hyphomycetes penicillium, which is a special strain of penicillium. at different culture temperatures, it shows conversion of biphasic forms: fungal phase at °c and yeast phase at °c. the fungal phase is the hyphae of many cells, with certain biological morphology, such as penicillus, conidiophore, chain liked conidiospore and chains between spores. the yeast phase shows unicellular or bicellular form. in the growth process of pm, large quantity bright rosy or dark rosy pigments are produced, which is characteristically pm. the pigment of yeast phase is secondary metabolites of cells with strong hydrophobicity, which can promote the adhesion of conidiums in fungal phase and cells in yeast phase to the alveolar macrophages and other cells surface in the human body. the pigment monoclonal antibody (mab) can interrupt the pathological process of adhesion. in addition, this pigment can determine the expression of cluster-encoding genes mbr through diffusion and penetration of drugs to the cell membrane, thus preventing the penetration of hydrophilic antifungal drugs, such as fl uconazole. that is to say, it improves the natural antifungal resistance level of pm. the soluble components of the pigment in fungal phase can trigger the generation of anti-conidium antibody (only igg) in animals to prevent its spreading in the body. the phenomenon proves that, in terms of tissue invasion, fungal phase is less powerful than yeast phase. conidium in fungal phase is the carrier of pathogen while the cells in yeast phase are the real pathogenic factors. when pm spreads to the target organ along with the blood fl ow, it is engulfed by mononuclear phagocytes. in the cases of replication itself and further spreading, reactive proliferation of phagocytes is caused. mononuclear phagocyte system has strong defense ability. in the cytoplasm of proliferated mononuclear phagocytes, various amounts of pm can be found. pm mainly invades into the body via the respiratory tract, digestive tract and skin defects. in immunocompetent people, local abscesses form in the invasion site, which is characterized by the thick mucus fl uid, with mainly necrosis and liquefaction. vascular reactions and exudation of neutrophil leukocytes and body fl uids is less than abscesses induced by common purulent bacteria. the clinical manifestation is confi ned suppurative infl ammation. when the immunity is compromised, due to the insuffi ciency of immunologic factors, it is diffi cult for the immune cells to restrict and digest the engulfed pathogens, which leads to confi ned suppurative reaction. therefore, it often presents with diffuse lesions. the pulmonary lesions are principally interstitial exudative infl ammation. the typical penicillium marneffei disease has acute or subacute onset, along with fever, chills and shivers, cough and expectoration, hemoptysis, shortness of breath, abdominal pain, diarrhea, bloody stool, fatigue, central necrotic papula mainly in the head and face and scattering in the trunk and extremities as well as hepatosplenomegaly. bone marrow smear and pas staining can be performed to detect the pathogen. blood, bone marrow, pleuroperitoneal fl uid, phlegm and skin defect tissue are collected for the culture at double temperatures with sabouraud'broth medium. at the temperature of °c, the colony is in dark red with villous surface, with surrounding red wine liked pigments to gradually spreading into the medium. biopsy of lymph nodes and skin defects with pas staining and wright & gimsa staining can be performed. wbc count, hemochrome, platelets, ast and cd t cell count. ct scanning and routine chest x-ray are the diagnostic imaging examinations of choice, which can facilitate to understand the size, morphology, location, quantity and density of the lesions. it demonstrates multiple small nodular shadows in the lungs, multiple honeycomb liked cavities in both lungs and mediastinal lymphadenectasis. abdominal scanning demonstrates different degrees of hepatic, splenic and retroperitoneal lymphadenectasis, which can fuse into a huge mass. routine chest x-ray it demonstrates thickened, deranged and blurry pulmonary markings, small cavities, military nodular shadows, mass liked shadows, spots and patchy shadows, ground glass liked changes, pleuritis and pleural effusion. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. her husband had a history of drug abuse and she complained of abdominal pain and fever for more than months, with accompanying face rash and diarrhea. her cd t cell count was /μl. by examinations, she sustained skin palpula, abdominal tenderness, central concave skin rashes on the face, neck, and upper limbs. there was a palpable mass in the upper left abdomen, hard and tenderness, in a size of × cm. more than months before her admission, she had persistent dull abdominal pain that is commonly in the upper left abdomen, with accompanying fever and face skin rashes that is gradually increasing and spreads to the neck and upper limbs. she also had hepatosplenomegaly, abdominal aortic lymphadenectasis and ascites. a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she had an unhealthy sexual life, with complaints of fever and cough for more than month. her cd t cell count was /μl. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he had been found to be hiv positive for years, with complaints of irregular fever, cough, fatigue and dizziness for days to be hospitalized. by examinations, his cd t cell count was /μl, hiv positive, subcultivation of strains demonstrated typical biphasic penicillium. by fungus culture, typical penicillus was found. by bone marrow smear, the round corpuscles mainly located in the macrophages. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he had a history of extramarital affair, with complaints of fever, cough, chest distress, shortness of breath, fatigue, poor appetite, poor sleep, weight loss and shortness of breath after activities for more than months. his cd t cell count was /μl. chest x-ray and ct scanning both demonstrate multiple nodules in different sizes and cavity shadows. the cavities cluster into honeycomb liked changes with uneven thickness of the walls, clear boundaries and surrounding infl ammatory exudates. some of the nodules infuse into mass dense shadows. lesions in both lungs have a symmetrical or asymmetric distribution, with no characteristic leions. mediastinal lymph nodes are obviously enlarged. sputum smear for direct microscopy demonstrates candida. pms are found by fi brobronchoscopy lavage smear and biopsy. ( ) candida skin test shows positive. ( ) fluorescent antibody test for pms is performed in procedures of direct smear, fungal colony culture and histopathological examination of the tissue sections. metabolites test of pm and pcr can be performed to determine the gene sequences of pm for the early diagnosis. hiv/aids related penicillium marneffei pneumonia should be differentiated from bronchiectasis and blood borne staphylococcus aureus pulmonary abscess. although the cases of bronchiectasis are demonstrated to have clustering round shadows on the cross sections, the wall is thinner and even, accompanying to the spots liked vascular shadows. some lesions have typical railway liked bronchial dilation signs. it is demonstrated to have multiple small cavity lesions in both lungs in line with the evenly distributing blood borne lesions. the lesions are rarely clustering. the wall of the cavities is thick and even with surrounding marginal exudates and blurry boundaries. with the steady increasing of hiv infections, reports on the complication of pm disease have also been increasing recently. the disease can be localized but mostly disseminated, with the involvement of lungs, liver, skin, lymph nodes and other tissues and organs. therefore, it is known as penicilliosis marneffei or disseminated penicillium marneffei infection in literature reports. due to the insuffi cient knowledge about the disease, diagnosis is delayed or missed. in thailand, penicilliosis marneffei has been the indicator disease of aids. about % aids patients are infected by pm and % have necrotic papula, which is characteristically disseminated penicillium marneffei infection. ct scanning demonstrates hiv/aids complicated by disseminated penicillium marneffei infection as fl aky parenchyma shadows in the lungs, clustering of cavities and nodular shadows, mediastinal lymphadenectasis and pleural infl ammation responses, which can facilitate its clinical diagnosis. mucormycosis is a rare kind of conditional fungal disease, with its pathogen, mucor, distributing widely in the natural world. it generally fails to cause diseases, but can cause systematic infections in immunocompromised people. mucor often invades into the human body via the nose to cause paranasal sinuses and orbital infections, which can further invade into the brain to cause meningitis and frontal abscesses. pulmonary mucormycosis is only second to the nasal-cerebral infection. it can spread via the respiratory tract to cause pulmonary infections. in addition, there are also skin and gastrointestinal mucormycosis as well as disseminated mucormycosis. the pathological changes of hiv/aids related pulmonary mucormycosis are mainly hemorrhagic necrotic infl ammation. the defense mechanism of immunocompetent people is to kill the fungal spores with the phagocytosis of macrophages and oxidation killing mechanism. in immunocompromised or immunodefi cient patients, the macrophages are often too weak to restrain the engulfed spores from germinating. therefore, the disease occurs. vascular vessels are susceptible to the invasion of mucor, especially the arteries. mucor can locally multiply to cause the formation of blood clots and embolization, and disseminate to other organs along with the blood fl ow. the main lesions are hemorrhage and necrosis of local tissues and exudation of neutrophils. the lesions of hemorrhage and necrosis are possibly related to the arteriole lesions caused by hyphae. the clinical manifestation of hiv/aids related pulmonary mucormycosis is a nonspecifi c pneumonia. the most common symptoms reported in literatures are persistent high fever, cough, hemoptysis, chest pain and diffi culty breathing. it has a rapid progression, with a high mortality rate of - %. lung lesions are hemorrhagic infarction or pneumonia, which can cause high fever, cough, expectoration, shortness of breath, chest distress, chest pain, hemoptysis (pulmonary artery involved) and other symptoms. moist rales can be heard in both lungs and pleural rubs can be heard in the cases of pleura involvement. . assisted by bronchofi broscopy, lung biopsy can be performed. . histological examinations include bronchial lavage fl uid examination, exploratory thoracotomy and puncture of lung tissues for biopsy. . chest x-ray and ct scanning are conventional effective examinations. the lesions are frequently found in the dorsal and medial segments of both lungs. early exudation shows miliary shadows, cavity shadows with no wall or with thin wall and small bronchiectasis shadows. their further progression may cause fusion infi ltration, parenchymal changes, nodules, masses, thick-walled cavities and pleural effusion, with accompanying mediastinal lymphadenectasis. . the fi ndings of mucor or their hyphae by sputum and bronchofi broscopic biopsy. . the diagnostic imaging demonstrates lesions commonly in the dorsal and medial segments of both lungs. there are diffuse scattering miliary shadows, cavity shadows with no wall or with thin walls and small bronchiectasis shadows. they further progress into fusion infi ltration, parenchymal changes, nodules, masses, thick-walled cavities and pleural effusion. . often with accompanying mediastinal lymphadenectasis. chest x-ray of pulmonary mucormycosis demonstrates progressive infi ltrated parenchymal changes, or masses, nodules, cavities and pleural effusion. it needs to be differentiated from miliary tuberculosis. hiv/aids related miliary tuberculosis are commonly demonstrated as chronic blood borne disseminated tuberculosis, with lesions distributing symmetrically in both lungs. its long term progression causes fusion into masses. otherwise, it can be cured by anti-tb therapies. the early lesions are no-wall cavities or thin wall cavities and small bronchioectasis shadows, based on which the differential diagnosis can be made. almost all cases of hiv/aids related pulmonary mucormycosis are found in immunocompromised patients. chest x-ray demonstrates parenchyma changes and isolated or multiple nodules or masses. the parenchyma changes are patchy or fuse, with unilateral or bilateral distribution. about % patients have pleural effusion and less than % patients have hilar or mediastinal lymphadenosis. ct scanning demonstrates singular or multiple nodules or masses, commonly with clustering or honeycomb liked cavities. cytomegalovirus pneumonia has extensive pathological changes in the lungs. pathologically, it shows interstitial pneumonia, with the lesions randomly blood borne distributing in the lungs. the distribution can be diffuse, panlobular or focal. the target cells of pathological changes include alveolar cells and macrophages. diffused pulmonary interstitial edema and fi brosis as well as alveolar swelling, focal necrosis, bleeding and hyperplasia occur after cmv infections to cause hypoxemia. gross observation of fresh specimens demonstrates pulmonary surface edema and fl aky blooding spots. fixed specimens demonstrate brown hard lung tissues. under a microscope, pulmonary interstitial congestion as well as infi ltration of lymphocytes and mononuclear cells can be found, with the involved epithelial cells enlarged. in the pulmonary interstitium and alveoli, there are intranuclear inclusions, cytoplasmic inclusions and fl uid containing abundant proteins. the classical intranuclear inclusions can be found in the cells, purplish red or purplish blue, round or oval, with surrounding halos in eagle eyes sign. atypical cytomegalic inclusions in cells are slender, long and round liked with abundant cytoplasm and accentric nucleolus, which are blurry, unclear and atypical ( fig. . a-e ). immunohistochemitry demonstrates hiv p antigen positive. the systemic symptoms of cmv infection include fever, joint and muscle soreness and pain, abdominal distension and orthostatic hypotension. the respiratory symptoms include paroxysmal dry cough, diffi culty breathing, cyanosis and three depressions sign. according to the imaging fi ndings of cmvp, cmv pneumonia can be classifi ed as diffuse, miliary and mass types, among which the diffuse type is the most common. cytomegalovirus can be separated from respiratory secretions culture and urine culture by using human embryonic fi broblasts. by urine sediment smear, giant cell with inclusions can be found. by using immunofl uorescence, indirect hemagglutination inhibition and complement fi xing test, the antibody titer can be found increased. indirect immunofl uorescence test and immunoenzymic staining test can be applied to detect the anti-cmv-igg and igm antibody. in addition, enzyme-linked immuno sorbent assay (elisa) can also be performed to detect the anti-cmv-igg and igm antibody. cmv-igm antibody positive indicates a recent infection, which has diagnostic value. a single serum cmv-igg antibody positive indicates a previous infection. and during the acute and recovery phases, double serum cmv-igg antibody titer being no less than four times increase has diagnostic value, indicating a recent infection. pcr can be applied to quantitatively determine the viral load in the whole blood, blood plasma, leukocytes, urine, bronchoalveolar lavage fl uid (balf), cerebrospinal fl uid and the tissue specimens, which is believed to be the best way for the diagnosis of invasive cmv infection. chest x-ray is the most commonly used examination. chest ct scanning is superior to chest x-ray in terms of resolution and detection rate of the lesions. pulmonary demonstrations by cmvp include diffuse interstitial infi ltration and alveolar infi ltration to form reticular shadows, nodules and parenchymal changes. a baby boy aged months was confi rmatively diagnosed as having aids by the cdc. he was infected via vertical transmission from mother to child, with recurrent cough after being born and the most recent cough for days as well as wheezing cough in throat for day before he was hospitalized. he had a past history of premature birth, with primary apnea and bronchial pneumonia and was hospitalized for treatment. later, he was admitted for three times due to cough, which was diagnosed as interstitial pneumonia. by examinations, wbc . × /l, lym lymphocyte count . × /l, cmv-ab weak positive, blood sedimentation mm/h, and tuberculosis antibody negative. after treated by broad-spectrum antibiotic therapy, the therapeutic effi cacy is unfavorable. cytomegalovirus (cmv) infection is an important cause of pneumonia in patients with compromised immunity. imaging fi ndings include nodular shadows with blurry boundaries and bilateral fl aky parenchymal changes of the lungs. the nodules tend to be bilaterally symmetric or asymmetric, with centrilobular distribution. histopathological manifestations are nodular alveolar hemorrhage, necrosis and infl ammatory lesions, and diffused alveolar lesions. the nodules tend to have a centrilobular distribution, indicating occurrence of bronchiolitis. in aids patients, if the diameter of nodules is under cm, it is most likely to be viral infection. the size of the nodules can facilitate the differential diagnosis of pulmonary infections. herpes simplex viral pneumonia (hsvp) often occurs in the upper respiratory tract, and rarely in the lower respiratory tract. human herpes simplex virus can be divided into two types, namely herpes simplex virus type i (hsv-i) and herpes simplex virus type ii (hsv-ii). herpes simplex viral pneumonia mostly occurs in patients with immunodefi ciency. herpes simplex viral pneumonia can be caused by hsv-i and hsv-ii, both of which have a nucleocapsid with surfaces. the thickness of the nucleocapsid is about nm, which is composed of capsomeres. the nucleocapsid contains the core of the virus dna. the virion gains the phospholipid rich viral envelope when it passes through the nuclear envelope. the nucleocapsid gemmates after it passes through the nuclear membrane and is released to the cell surface. the nucleocapsid can also be released outside the cells or gains its access into the neighbour cells for further reproduction. herpes simplex virus replicates itself in the cell nucleus to produce histopathologic changes of herpes virus replication, with visible cowdry a type intranuclear inclusions. the pathogenesis process of herpes simplex virus infection in the body can be divided into fi ve stages: initial skin mucosa infection, acute ganglia infection, latent infections, re-activation, and recurrent infections in susceptible hosts. patients infected by herpes simplex virus can produce igm, igg and iga antibodies to fi ght directly against virus protein, which may play a role in changing the severity of the infection. interferon also participates in the control of herpes simplex infection by inhibiting the virus or regulating the defense mechanism. genetic factors may be also related to the herpes virus infection. cellular immunity can confi ne the infection. herpes virus cannot reproduce in the alveolar macrophages of human body, which is also the reason why herpes virus is less than cytomegalovirus in lungs. currently, it is believed that herpes simplex virus is an important pathogen of respiratory infections, especially in immunocompromised patients. localized herpes simplex viral pneumonia occurs due to the direct spreading of virus in the upper and lower respiratory tract. diffuse herpes simplex viral pneumonia is caused by the virus spread from the reproductive organs lesions or oral lesions (most possibly blood borne). viremia caused by hsv-i or hsv-ii has been reported, and both are related to diffused infections. but in patients without herpes simplex viral infection in skin mucosa, herpes simplex viral pneumonia can also occur. herpes simplex viral pneumonia is caused by the direct spreading of the virus from the upper and lower respiratory tract. diffuse herpes simplex viral pneumonia is cause by the spreading of the virus from the reproductive organs lesions or oral lesions (most possibly blood borne). viremia cause by either hsv-i and hsv-ii have been reported, both of which are related to diffuse infections. in such cases, the lung tissues may have infl ammatory infi ltration, lung parenchyma necrosis, bleeding, cellular swelling and round, diffuse interstitial pneumonia. and in most cases, there are accompanying cellular changes of herpes virus infection such as the intranuclear eosinophilic inclusions, necrotic herpes simplex viral trachitis. herpes simplex viral bronchitis has demonstrations of mucosa erythema, edema, exudation and ulcer, with coverage of the surface by fi brous purulent membranous secretions. the common initial clinical symptoms of herpes simplex viral pneumonia are shortness of breath, cough, and fever with a body temperature being higher than . °c, decreased wbc count, hypoxemia, respiratory dysfunctioning and azotemia. hsv pneumonia may be accompanied by mucocutaneous lesions by hsv, which show earlier than those of pneumonia. there may be concurrent fungus, cytomegalovirus or bacteria infection. herpes simplex viral tracheobronchitis may show tracheal or bronchial spasm or stenosis. etiological examinations hsv can be detected in tracheobronchial secretions, bronchoalveolar lavage fl uid and lung tissues. early sampling should be performed under the guidance of a bronchofi broscope. tissue culture is the most sensitive and specifi c method for the diagnosis, which can also be used for the classifi cation of the virus. papanicolaou (pap) or tzank test is a fast and cheap method for cellular diagnosis. elisa can be used to detect herpes simplex virus, with a sensitivity of up to % and a high specifi city. chest x-ray demonstrations are less valuable for the differential diagnosis. pulmonary ct scanning can be applied for the differential diagnosis. herpes simplex viral pneumonia includes three types, namely local, multiple or diffuse interstitial infi ltration. in the early stage, typical hilar or diffuse interstitial shadows with increased density can be found, with thickened bronchial wall. as the disease progresses, cloudy or patchy alveolar tamponade and fusion can be found. chest x-ray may demonstrate negative for herpes simplex viral trachitis and bronchitis. herpes simplex viral pneumonia should be differentiated from bacterial pneumonia, cmv pneumonia, and infl uenza pneumonia. hiv/aids related herpes simplex viral pneumonia is mostly demonstrated by multiple signs, including small nodules, ground glass liked shadows and patchy parenchymal changes. the nodules are in centrilobular distribution, mostly with accompanying branches liked shadows (tree buds sign). chest x-ray demonstrates diffuse lung parenchymal changes. imaging fi nding are parenchymal change areas with bilaterally blurry boundaries. generally, the nodules have a diameter of - mm. ct scanning with high resolution demonstrates nodules with surrouding ground glass liked density lesions. lymphoid/lymphocytic interstitial pneumonia (lip) is more common in children with aids. the cdc in the united states has defi ned lip in children under the age of years as the diagnostic indicator of aids. the predictive diagnostic criteria include chest x-ray demonstration reticular nodular changes in pulmonary interstitium of both lungs for no less than months, undetectable pathogens and no responses to the antibiotic therapy. currently, hiv/aids related lymphocytic interstitial pneumonia is considered to be related to hiv and epstein-barr virus, human t cell leukemia-lymphoma type i virus (htlv-i) and hiv-i. the infection of the above viruses causes pulmonary lymphatic hyperplasia and other systemic diseases. about - % children with hiv infection sustain lip, and % in adults. most cases of non-hiv infected patients with lymphoid interstitial pneumonia are women, at average age of years old, more commonly in the age group of - years old and above years old. the pathological manifestations are infi ltration of small and mature lymphocytes as well as plasma cells in alveolar septum and the alveolus, extensive interstitial fi brosis and non-caseous granuloma. it is characterized by diffuse infi ltration of lymphocytes, plasmocytes and histocytes in the pulmonary interstitium. the lymph follicle with germinal center is more common. hyperplasia occurs in type ii alveolar epithelium, and the macrophage increases in the alveolar cavity. there are rare or mild intraalveoli organization and macrophage aggregation. staining of the immune globulin light chain demonstrates poly-clone b cells. the clinical symptoms are in progressive development, with cough and suffocation, rare hemoptysis and sjogren syndrome commonly in mouth and eyes. by examinations, the signs have slight difference between adults and children. in children, there are lymphadenectasis, hepatosplenomegaly, enlargement of parotid gland, clubbing fi ngers and wheezing sound. in adults, there are lymphadenectasis, slight fi ne bubbling rales, as well as hepatosplenomegaly and enlargement of parotid gland in / patients. . peripheral hemogram demonstrates increased lymphocytes and eosinophilic granulocytes. . myelogram demonstrates increased lymphocytes, plasmocytes and eosinophils. . blood biochemical examination demonstrates increased immune globulin, predominantly lgm. . blood gas analysis demonstrates hyoxemia. . pathogenic examinations by bronchofi broscopy, bronchial alveolar lavage and biopsy can defi ne the diagnosis. . pulmonary function examinations demonstrate restrictive ventilatory disorder, lower lung compliance and impaired diffusion function. impaired diffusion function is a more sensitive indicator in monitoring the progress of the disease. . chest x-ray is the most commonly used imaging examination, while chest ct scanning is commonly applied for the differential diagnosis. chest x-ray demonstrates hiv/aids related lymphoid interstitial pneumonia as reticular or reticular nodular shadows of lung markings in both lungs. hrct demonstrates bilateral diffuse ground glass liked density shadows. perivascular thin-walled pneumatocele is common. pneumatocele induced by lip is commonly found in the middle lung fi eld, which probably is due to the valve effects caused by infi ltration of cells around bronchioles. manifestations of pneumatocele, together with ground glass liked density shadows, highly indicate lip. centrilobular and subpleural small nodules and thickened intralobular septa can be occasionally found. dysfunctional diffusion is a more sensitive indicator in monitoring the progress of the disease. hiv/aids related lymphoid interstitial pneumonia should be differentiated from allergic pneumonia, carcinomatous lymphangitis and pneumocystis carinii cysts. ct scanning with high resolution demonstrates characteristic lesions of hiv/aids related lymphoid interstitial pneumonia, including intralobular linear shadows and honeycomb liked changes, with common involvement of the subpleural area and the basal lung. its characteristic manifestations are clustering gas containing thin-walled cyst in a diameter of - mm, with clear cyst wall. shared wall between cysts is its characteristic demonstration. the surrounding ground glass liked density indicates infl ammation. intralobular linear shadows indicate interstitial fi brosis. pulmonary toxoplasmosis (pt) is caused by the toxoplasma parasitizing in cells. ludlam et al. fi rstly proposed the concept of pulmonary toxoplasmosis in [ ] , arguing that toxoplasma can cause atypical pneumonia. later, there are some pathological reports about pulmonary toxoplasmosis or disseminated toxoplasmosis with lung involvement. in recent years, due to the global prevalence of aids, the incidence of pulmonary toxoplasmosis is increasing, with most cases being disseminated toxoplasmosis with lung involvement. pt has been one of the important opportunistic infections in patients with immunosuppression, especially aids patients. hiv/aids related pulmonary toxoplasmosis is a zoonotic disease, with cats as its main transmission source, followed by pigs and sheep. people are infected by intake the water or food contaminated by cats' feces or without cooked meat. immunocompromised aids patients are susceptible to this disease, and its occurrence is rare in immunocompetent people. after its invasion into the human body, the sporozoite in the cystozygote and intracystic cystozoite overfl ows to penetrate the intestinal wall mucosa and spread to the whole body tissues along with blood or lymph fl ow. the brain, heart, lymph nodes, and lung are the most vulnerable tissues and organs for the infection. any abnormality in the process of defense mechanism can cause impaired immune functions to eliminate the toxoplasma, which ultimately causes systemic and pulmonary infections. pulmonary toxoplasma infection may also be caused by the blood borne spreading of reactivated toxoplasma infection in other body parts, with no exclusion of reactivated pulmonary infection or primary pulmonary infection. ludlam et al. generally nominated toxoplasmosis as atypical pneumonia [ ] . catterall et al. divided toxoplasmosis into three types: necrosis, infl ammatory infi ltration and toxoplasma invasion [ ] . it can also be classifi ed as type a: subclinical or occult infection; type b: interstitial and atypical pneumonia; type c: necrotic pneumonia; type d: lobar pneumonia; and type e: granulomas pneumonia (toxoplasmoma). by naked eyes observation, the involved lungs are solid, with congestion and red brown section. the pleura have bleeding spots, with moderate peribronchial lymphadenectasis. under a light microscope, there is exudation of serous fl uids in alveolar cavities, occasional formation of transparent membrane or fi brin purulent exudation, infi ltration of small quantity neutrophils, proliferation and shedding of alveolar wall cells, and trophozoite and/or cysts of toxoplasma in epithelial cells and macrophages. the pulmonary interstitium may have infi ltration of lymphocytes and plasmocytes as well as visible fi broblasts and macrophages. the granuloma changes are also found in the lung tissues, with central stripes or localized necrosis and surrounding lymphocytes and small quantity multinucleated giant cells. it is diffi cult to fi nd toxoplasma in granuloma, but it can be found in the normal tissues around or near the granuloma. almost all cases of aids complicated by pulmonary toxoplasmosis are caused by disseminated toxoplasmosis with pulmonary involvement. it is commonly diffuse pulmonary infl ammation with serious symptoms, including high fever, cough, cyanosis, breathing diffi culty, possible occurrence of skin rashes, lymphadenectasis and meningitis. the chronic cases may have long-term low grade fever, cough, and weight loss. direct light microscopy of the specimen smear and enprint such as blood, cerebrospinal fl uid, bone marrow, anterior aqueous humor, phlegm, urine, saliva, and other osmotic solutions, as well as lymph nodes, muscle tissue or other living tissues can be performed for pathogen examinations. sabin proposed that the staining test have high sensitivity and specifi city according to the fi ndings that mixture of fresh toxoplasma with normal serum can be stained deep by alkaline methylene blue staining, while its mixture with immune serum can be stained light or blank by the same staining. other assays including indirect fl uorescent antibody, indirect blood coagulation, and complement fi xation test can provide valuable reference for the diagnosis. toxoplasm is tested in pathological eaminations that can provide valuable reference for the diagnosis. chest x-ray is the most commonly used diagnostic imaging examination. and chest ct scanning can be applied for the differential diagnosis. imaging fi ndings of hiv/aids related pulmonary toxoplasmosis can be divided into four types: bronchial pneumonia, interstitial pneumonia, pleuritis and complication of cardiovascular disease. the type of bronchial pneumonia is also known as lobular pneumonia, with thickened pulmonary markings that distribute along with the bronchi in the middle and lower lung fi elds, scattered patchy shadows with uneven density and blurry boundaries, fusion of some shadows into large fl aky shadow and widened hilar shadow. the type of interstitial pneumonia is demonstrated as reticular and nodular shadows. the interstitial lesions widen the space between the bronchiole and the alveolar wall, with stripes and fl occulent shadows. the type of pleuritis is rare, with signs of pleural effusion. the type of complication of cardiovascular disease is demonstrated as heart failure (acute pulmonary edema), with signs of pericardial effusion. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of cough and fever. his cd t cell count was /μl. by direct light microscopy, toxoplasma tachyzoites can be found in the specimens such as blood, cerebrospinal fl uid, bone marrow, anterior aqueous humor, phlegm, urine, saliva, and other osmotic solutions, as well as lymph nodes, muscle tissues or other living tissues. the fl uorescent antibody and complement fi xation test are positive. the biopsy tissue culture and inoculation test are positive. in the lesions and their surrounding tissues of interstitial e c d fig. . (continued) pneumonia, necrotic bronchitis or granuloma, toxoplasma can be found. the diagnostic imaging demonstrates any one type of pulmonary toxoplasmosis, including bronchial pneumonia, interstitial pneumonia, pleuritis and cardiovascular disease, can be used as the evidence for the diagnosis of pulmonary toxoplasmosis. the type of bronchial pneumonia is also known as lobular pneumonia, with thickened pulmonary markings with a distribution in both middle and lower lung fi elds along with the bronchi, scattered patchy shadows with uneven density and blurry boundaries, fusion of some patchy shadows into large fl aky shadow and widened hilum. the type of interstitial pneumonia has typical demonstrations of reticular and nodular shadows. the interstitial lesions widen the space between the bronchiole and the alveolar wall, with strip and fl occulent shadows. the type of pleuritis is rare, with signs of pleural effusion. the type of cardiovascular disease may have signs of heart failure (acute pulmonary edema), and signs of pericardial effusion. hiv/aids related pulmonary toxoplasmosis should be clinically differentiated from infectious mononucleosis and mycoplasma pneumonia. with primary pulmonary lesions. pulmonary low malignant b cell lymphoma is the most common primary pulmonary lymphoma which is derived from mucosa related lymphoid tissue. the manifestations include slowly decreased alveolar transparency. pulmonary high malignant b cell lymphoma is extremely rare, which often occurs with singular lesion and primary disease such as immunodefi ciency. hiv/aids related malignant lymphoma is mostly caused by compromised immunity. hiv/aids related hodgkin's lymphoma is relatively rare. there are also reports about hiv/aids related t cell lymphoma with pulmonary involvement. hiv/aids related malignant lymphomas are mostly highly malignant large cells lymphoma. cerebral lymphoma is one of the defi ning diseases of aids. it has been reported that the clinical incidence of pulmonary infi ltration by malignant lymphoma is - %, but - % by autopsy. in the early stage, it is commonly asymptomatic. with its progression, symptoms of dry cough, suffocation, and small quantity clear phlegm occur. mediastinal lymphadenosis includes lymphadenectasis to compress the trachea by, blood vessels and nerves and lead to breathing diffi culty, superior vena caval obstruction syndrome, and hoarse voice. the pulmonary parenchyma lesions include reticular structure in the lungs. the clinical symptoms are cough, expectoration, suffocation and breathing diffi culty. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of chest distress and cough for more than month. his cd t cell count was /μl. in patients with hiv/aids related kaposi's sarcoma, its serologic positive rate is %. kaposi's sarcoma cells can produce il- , during which il- plays a role as an autocrine factor to maintain the cell growth, paracrine cytokines, stim-ulate proliferation of other interstitial cells and induct the vascular growth. therefore, kaposi's sarcoma is a kind of tumor with abundant blood vessels. before the application of harrt, the incidence of kaposi's sarcoma in male homosexuals is %. after the clinical application of harrt treatment, the incidence is decreasing. in addition to hhv- , some studies indicated that most patients with kaposi's sarcoma have hia-dr alleles, suggesting a possible relationship between kaposi's sarcoma and the heredity. there is no obvious difference between hiv/aids related kaposi's sarcoma and classic kaposi's sarcoma in pathological changes. early pathological manifestations are chronic infl ammation or granulomatous infl ammation, with formation of new vascular and lymphatic vessels and accompanying edema and bleeding. the fi ndings of large and protruding endothelial cells in granuloma tissue with accompanying erythrocytic exudation and hemosiderin particles have great signifi cance for the early diagnosis. the pathological changes in the advanced stage are signifi cant proliferation of the endothelial cells, and proliferation of fi broblasts around capillaries. in the advanced stage, the lesions are often accompanied by extensive connective tissue hyperplasia, which presents diffi culty for its differentiation from common sarcoma. when it is diffi cult to defi ne the diagnosis by light microscopy, immunohistochemical examinations can be used to defi ne the diagnosis. the pathological changes are characterized by lesions confi ned to the epithelial lamina propria, gathering of spindle cells with mild heteromorphism around many lacuna vasorum with irregular lumen, erythrocytic exudation and hemosiderin sedimentation. the atypical lacuna vasorum can be compressed by proliferative spindle cells to be absent. vascular endothelial cells and peripheral spindle cells may have mitotic phase in the advanced stage, with increased heteromorphism cells. the infl ammatory cells are mainly plasma cells, with acidophilic corpuscles and pas staining positive, which can assist the pathological diagnosis. pulmonary kaposi's sarcoma in aids patients rarely has symptoms. it is commonly concurrent with pulmonary opportunistic infections, with symptoms of cough, diffi culty breathing and fever. other symptoms are related with the location of the tumors. the involvement of trachea or bronchi can cause luminal stenosis. the mediastinal tumor can compress and obstruct lymph vessels to cause pulmonary edema or a large quantity pleural fl uids, which result in respiratory diffi culty, and even respiratory failure. ( ) sampling by bronchoscopy or endoscopy to prepare pathological section. ( ) chest x-ray demonstrates its typical manifestation of pleural effusion. dr demonstrates enlarged and deranged hilum in both lungs in bird nest liked appearance. there is light density fl aky shadows in the both lower lungs. ct scanning demonstrates multiple rounds liked nodular shadows in the middle and lower lung fi elds of both lungs with clear boundaries. there are also mediastinal and hilar lymphadenectasis, with common involvement of the pleura and bilateral pleural effusion in a small quantity. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he had been detected as hiv positive for months, with complaints of recurrent cough and nausea for days and was hospitalized on jan. , . the transmission route was unknown because he denied histories of intraveneous drug abuse, paid blood donation, blood transfusion and unhealthy sexual behaviors. five months ago, he was diagnosed as aids in the stage of aids in our hospital, and hospitalized to treat pcp, with a cd t cell count of /μl. his symptoms were quickly relieved after pcp treatment and he continued the antiviral therapy for almost months after being discharged. by physical examinations, he was in poor spiritual condition, a light blue nodule in size of . × . cm in the left upper chest wall with medium hardness, palpable lymph nodes in size of . × . in the opisthotic area and inguen, no tenderness and being movable. by the digital rectal examination, a palpable prominent nodule with wide base at cm points away from the anus, with fl exible texture and smooth surface. by the auxiliary examinations, wbc . × /l, neμt . %, lym . %, mon . %, eos . %, rbc . × /l, hgb g/l, plt × /l, routine urine test normal, blood sedimentation mm/h. by hepatitis b examinations, hbsag, anti-hbe and anti-hbe positive. his cd t cell count was /μl. by abdominal b ultrasound, multiple low echo nodules in the abdominal cavity, the largest in size of . × . cm, which are suspected to be enlarged lymph nodes. on jan. , he received inguinal lymph node biopsy, with pathological report of kaposi's sarcoma. during the treatment and following up, the involvement of lungs, digestive tract, lymph nodes and skin is suspected, with the diagnosis of phase ii kaposi's sarcoma and chemotherapy was recommended. reexamination by chest x-ray demonstrated normal cardiopulmonary phrenic. abdominal b ultrasound failed to fi nd enlarged lymph nodes. ct scanning demonstrated shrinkage of lesions in both lungs and mediastinal lymph nodes, with only palpable soybean sized submandibular lymph node. by examinations after chemotherapy, cd t cell count /μl, viral load , copies/ml. the patients had multimorphological erythema drug eruptions, which was suspected as drug allergies of chemotherapy, which were absent after symptomatic treatment. the following ups so far show no recurrence of kaposi's sarcoma, with his cd t cell count fl uctuating around /μl. he can work as usual. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he had a history of homosexual behaviors, with complaints of fever and cough for months as well as chest distress for more than days. since, july , fever with a body temperature of about . - . °c occurs, with cough, yellowish bloody sputum, and dark purplish patchy skin rashes. by examinations, his anti-treponema pallidum antibody positive, multiple dark purplish patchy skin rashes on the face, eyelid, lower jaw, hairline, chest and abdomen with skin surface desquamation, palpable bilateral cervical lymphadenectasis and the largest in size of × mm. by laboratory tests, wbc . × /l, n . %, rbc . × /l, hgb g/l, plt × /l, cd /μl. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of cough for more than months, chest distress for more than month, and bloody sputum for half a month and was hospitalized. he had a history of homosexual behaviors. by examinations on admission, multiple round purplish blue skin rashes nodules on the limbs. his cd t cell count was /μl. demonstrations can also be fl aky fl occulent areas with blurry density or parenchymal density areas along with bronchi. . lung puncture for histopathological biopsy demonstrates irregular vascular lumen in the dermis, proliferation of endothelial cell with accompanying heteromorphism. in some cases, there are tumor masses composed of spindle cells and epithelial cells. other sarcoma and vascular tumor hiv/aids related kaposi's sarcoma should be differentiated from other sarcoma and vascular tumor. ks invasion of the digestive mucosa can cause bleeding and upper gastrointestinal symptoms. the pathological lesions can be diagnosed by upper gastrointestinal endoscopy or biopsy. in the cases of no fever and exclusion of infections, the typical imaging demonstrations and bronchoscopy fi ndings can defi ne the diagnosis of pulmonary ks. hiv/aids related kaposi's sarcoma should be differentiated from pneumocystis carinii pneumonia. the lesions of pcp are mostly symmetric ground glass liked density shadows extending outwards from the hilum in both lungs. in the middle and advanced stages, nodules, fi brosis and cavities occur, rarely with pleural effusion. lung cancer commonly refers to the cancer in lung parenchyma, usually does not include those mesodermal tumors originating from other pleura, or other malignancies like carcinoid, malignant lymphoma, or metastatic malignancies for other body parts. therefore, the following lung cancer we are discussing about refers to the malignancies originating from bronchial, or bronchiolar epithelial cells, accounting for - % of the lung parenchyma malignancies. the cause of lung cancer is still not completely known. data have indicated that the risk factors of lung cancer include smoking (including second-hand smoke), asbestos, radon, arsenic, ionizing radiation, halogen alkenes, polycyclic aromatic compounds and nickel. long-term smoking can cause proliferation of the bronchial mucosal epithelial cells and proliferation of squamous epithelium to induce squamous epithelium carcinoma or undifferentiated small cell carcinoma. non-smokers can also develop lung cancer, but adenocarcinoma is more common among them. long-term exposure to radioactive substances, like uranium and radium, and its derivatives; carcinogenic hydrocarbons, like arsenic, chromium, nickel, copper, tin, ferri, coal tar, bitumen oil, petroleum, asbestos and mustard gas, all can induce lung cancer, which is commonly squamous carcinoma and undifferentiated small cell carcinoma. some chronic pulmonary diseases, such as tuberculosis, silicosis and pneumoconiosis, can concurrent with lung cancer. in the cases with these chronic pulmonary diseases, the incidence of cancer is higher than the general population. in addition,bronchopulmonary chronic infl ammation and pulmonary fi brous scar lesions may cause metaplasia or hyperplasia of squamous epithelium during their healing processes, based on which some cases can develop into cancer. the internal factors of the human body include family heredity, compromised immunity, metabolism and endocrine dysfunction. the lung cancers distribute more in the right lung than in the left lung, more in the upper lobe than in the lower lobe. its locations range from the major bronchus to the bronchioles. the central type of lung cancer has its origination from the major bronchial lobes and locates adjacent to the pulmonary hilum. the peripheral type of lung cancer has its origination from the lower parts of pulmonary segment bronchi and locates in the peripheral areas in the lungs. in the growth process of the lung cancer, it causes the extension and dilation of the bronchial walls, and penetrates the bronchial walls to invade the adjacent lung tissues and form masses. meanwhile it intrudes into the bronchi to cause luminal stenosis or obstruction. with its further progression and dissemination, it spreads from the lungs and directly extends into the chest walls, mediastinum, heart, major vessels and other adjacent organs and tissues. lung cancer can also transfer to other parts of the body along with blood and lymph fl ows or disseminates to other pulmonary lobes via the respiratory tract. the growth rate and transferring paths of lung cancer depend on its histological types, differentiation degree and other biological characteristics. lung cancer has no special symptoms in the early period, only has the common symptoms with common respiratory diseases, including cough, bloody sputum, low grade fever, chest pain and chest distress. therefore, it is often misdiagnosed. ( ) face and neck edema; ( ) hoarse voice is the most common symptom; ( ) shortness of breath. lung cancer tends to occur distant metastases in the early stage. in the cases with metastatic lesions to the brain, the patients sustain persistent headache and blurry vision. in the cases with metastatic lesions to the bone, bone destruction may occur to cause fracture. ( ) restrictive wheezing sound, mostly occurring in the inspiratory phase and recurring after cough; ( ) hoarse voice, caused by lymph nodes transferring to compress and invade the recurrent laryngeal nerve; ( ) superior vena cava syndrome, caused by the compresses or invasion to the superior vena cava by the mass and venous obstruction, with edema in the head, face, neck, and upper limbs, varicose veins and edema in the upper chest, and accompanying dizziness, chest distress, shortness of breath and other symptoms; ( ) horner's syndrome, with enophthalmos of the affected side, blepharoptosis, shrinkage of the pupils, eye fi ssure stenosis, increased skin temperature in the upper chest of the affected side and no sweating due to compression or invasion of the apical cancer to the cervical sympathetic ganglia; ( ) should and arm pain, which is radial burning pain in the shoulder and upper limbs of the affected side due to compression or invasion of apical cancer to the brachial plexus nerve; ( ) phrenic nerve paralysis, with symptoms of shortness of breath and chest distress due to invasion to the phrenic nerve; ( ) dysphagia, caused by compressed esophagus by mediastinal lymphadenectasis; and diffi culty breathing caused by compressed trachea by mediastinal lymphadenectasis; ( ) pericardial effusion, shortness of breath, arrhythmia and heart dysfunctions due to pericardial invasion; ( ) pleural metastasis, with chest pain and cancerous pleural effusion; ( ) lung cancer metastasis, spreading of lung cancer along with blood fl ow to the bone, liver, brain, kidney, adrenal gland and subcutaneous tissues. intrapulmonary metastasis is also common. metastasis to different locations shows different symptoms and signs. ( ) extrapulmonary signs, commonly including joint pain or joint hypertrophy, clubbing fi ngers and mental disorders. the diagnostic imaging is the most commonly used and an important examination for the diagnosis of lung cancer. it can facilitate to fi nd some specifi c manifestations in the lesions, which provide clues for the diagnosis of lung cancer. it is also the main basis for the staging of lung cancer, but fails to defi ne the qualitative diagnosis. chest x-ray is the main examination for the diagnosis of lung cancer. anteroposterior and lateral chest x-ray are used for preliminary screening. chest ct is the diagnostic imaging examination of the choice for the diagnosis of lung cancer. for the central type of lung cancer in the early stage, there are direct signs to defi ne the diagnosis. in the early stage, thin layer scanning with a layer thickness of . - mm can be performed to observe the bronchial changes. mr imaging can demonstrate intraluminal nodules, luminal thickness and luminal stenosis of the bronchi from the transverse, coronal, and sagittal perspectives. mr imaging demonstrates favorably cancer in the lesions of obstructive pneumonia, and masses covered by the hilum. pet/ct scanning can be used for the screening of lung cancer metastasis and assessing the therapeutic effi cacy after treatment. dsa is used for infusion chemotherapy of bronchial artery in the cases of primary lung cancer. bronchoscopy is an important examination for the diagnosis of lung cancer. the pathological changes of the endothelium and the lumen of bronchi can be directly observed by using bronchoscopy. for the cases with caner or cancerous infi ltration by bronchoscopy, sampling of the tissues under the guidance of bronchoscopy for biopsy can be performed. otherwise, bronchial secretions can be suctioned under the guidance of bronchoscopy for cytological examinations to defi ne the diagnosis and the histological classifi cation. in most cases of primary lung cancer, the shed cancer cells can be found in the sputum, which can also facilitate to defi ne its histological classifi cation. after several examinations and short-term exploratory therapies, the qualitative diagnosis cannot be defi ned and the possibility of lung cancer cannot be excluded. therefore, exploratory thoracotomy can be performed if the patient's physical conditions permit. chest x-ray early lesions are confi ned within the bronchi, causing valve ventilatory disorder and changes of obstructive emphysema. the manifestations include restrictive pulmonary gas increase and sparse lung markings. in the cases with certain degree of bronchostenosis due to unfavorable discharge of the secretions, obstructive pneumonia occurs, showing patchy blurry shadows. in the cases with complete blockage of the bronchi, obstructive atelectasis occurs, showing decreased pulmonary volume, increased density and migration of the mediastinum to the affected side. obstructive pulmonary bronchiectasis has demonstrations of intrapulmonary cords liked shadows. lung a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of repeated cough for more than month and reported to have a history of unhealthy sexual behaviors. his cd t cell count was / μl. cancer in the middle and advanced stages are mainly manifested as hilar mass and atelectasis. the mass has a high density with clear boundary. however, the cancer cannot be observed due to its common immersion in the large fl aky obstructive pneumonia lesion or large quantity pleural effusion. atelectasis is commonly manifested as shrinkage of pulmonary segments or shrinkage of unilateral lung, with high density. the shadow of atelectasis widens at the hilum to show prominent mass. in the cases of central type lung cancer in the right upper lobe, a transverse s shape is at the hilum (commonly known as pancoast cancer). early diagnosis of central type lung cancer by plain chest x-ray only shows some indirect pulmonary manifestations caused by bronchial obstruction. and these indirect signs are not characteristically lung cancer. in the cases of local obstructive emphysema, these indirect signs can be caused by foreign substances in the bronchi or early infl ammation. obstructive pneumonia is diffi cult to be differentiated from common pneumonia. obstructive atelectasis needs to be differentiated from many other conditions. ( ) pathological changes in the bronchial lumen including polypoid, nodular or fl at papula masses. benign tumor has smooth boundary and malignant tumor has unsmooth boundary, commonly with wider base and thickened lumen wall. even the slight bronchial changes caused by the central type of lung cancer can be demonstrated by thin layer ct scanning, including slightly thickened bronchial wall, intraluminal small nodules and lumen stenosis or obstruction. in the middle and advanced stages, the direct signs of the central type lung cancer include thickened bronchial wall, irregular or unsmooth lining of the bronchial lumen. bronchial obstruction is suddenly truncation or gradual thinning of the lumen to obstruction. ( ) hilar mass locates adjacent or around the bronchi, with smooth or arch shaped boundary. the indirect signs of the central type lung cancer in the middle and advanced stages include secondary changes to bronchial stenosis. obstructive pneumonia is manifested as patchy blurry shadows or parenchymal changes of the pulmonary segments/lobes, and decreased lung volume. mr imaging demonstrates the tumor as long t and long t signals. in the cases of central type lung cancer with secondary obstructive atelectasis and obstructive pneumonia, enhanced t demonstrates the tumor in the lesion of pulmonary atelectasis and obstructive pneumonia. the signal of atelectasis is higher than that of the tumor. pet/ct scanning can demonstrates increased and thick stained metabolites of metastatic lesions or residual lesions, which has a diagnostic sensitivity of above %, and a reported specifi city of - %. in addition, it can be applied for the clinical consideration of it hilar, mediastinal lymph node metastasis and extrathoracic distant metastasis, which is an important method to decide clinical stages before lung cancer therapy. but pet has false negative diagnosis in the diagnosis of lung cancer with decreased metabolites, especially the alveolar cell carcinoma. for the diagnosis of pneumonia and pulmonary tuberculosis, it also has false positive results. dsa can demonstrate the blood supply of the tumors. miliary tuberculosis is more common in young adults, with obvious symptoms of systemic toxicity. anti-tuberculosis drug therapy can relieve the symptoms, with gradually absorbed lesions. ( ) chest x-ray demonstrates hilar lymph node tuberculosis as mass shadows in the hilum of lung, which may be misdiagnosed as the central type lung cancer. hilar lymph node tuberculosis is more common in teenagers, commonly with symptoms of tuberculosis infection but rarely hemoptysis. lung cancer can be concurrent with pulmonary tuberculosis. ( ) bronchial pneumonia; obstructive pneumonia induced by early lung cancer can be misdiagnosed as bronchial pneumonia. bronchial pneumonia has an acute onset with more obvious symptoms of infection. chest x-ray demonstrates patchy or spots shadows, with blurry boundaries and uneven density. the lesions are not confi ned within one segment or one lobe. ( ) pulmonary abscesses; central necrosis and liquefaction of the lung cancer results in cancerous cavities. by chest x-ray, the central type lung cancer can be misdiagnosed as pulmonary abscesses. in the acute period, a pulmonary abscess has obvious symptoms of infection, with large quantity purulent sputum. chest x-ray demonstrates thin cavity wall, smooth inner wall, liquid level and infl ammatory changes in the surrounding lung tissues or pleura. pulmonary benign tumors including hamartomas, fi broma and chondroma have slow growth. chest x-ray demonstrates round liked mass shadow, with homogeneous density without lobation. joint united nations programme on hiv/aids (unaids) surveillance for aidsdefi ning opportunistic illnesses, - imaging and pathology of hiv related cytomegalovirus pneumonia roentgenographic patterns of pneumocystis carinii pneumonia in patients with radiology distinction of pyogenic pulmonary infection from pneumocystis carinii pneumonia in aids patients atlas of differential diagnosis in hiv/aids. beijing: pmph the national institutes of health (nih) the centers for disease control and prevention (cdc), and the hiv medicine association of the infectious diseases society of america (hivma/idsa) guidelines for prevention and treatment of opportunistic infections in hiv-infected adults and adolescents acute respiratory failure associated with cryptococcosis in patients with aids: analysis of predictive factors pulmonary cryptococcosis: localized and disseminated infections in patients with aids penicillium marneffei agent d'une mycose du system reticuloendothelial infection caused by penicillium marneffei description of fi rst natural infection in man cd + t cell-mediated fatal hyperinfl ammatory reactions in mice infected with penicillium marneffei infections caused by penicillium marneffei in china and southeast asia: review of eighteen published case and report of our mo re chinese cases disseminated histoplasmosis in the acquired immune defi ciency syndrome: clinical fi ndings, diagnosis and treatment, and review of the literature imaging of thoracic pathology in patients with aids clinical and radiographic features of hiv-related pulmonary tuberculosis according to the level of immunosuppression global tuberculosis incidence and mortality during - . bull world health organ tuberculosis in patients with human immunodefi ciency virus infection pulmonary tuberculosis in kigali, rwanda. impact of human immunodefi ciency virus infection on clinical and radiographic presentation relationship of the manifestations of tuberculosis to cd cell counts in patients with human immunodefi ciency virus infection radiology of pulmonary tuberculosis and human immunodefi ciency virus infection gulu, uganda bacterial pneumonia in persons infected with the human immunodefi ciency virus. pulmonary complications of hiv infection study group microbiology of community-acquired bacterial pneumonia in persons with and at risk for human immunodefi ciency virus type infection. implications for rational empiric antibiotic therapy the intracellular bacterium rhodococcus equi requires mac to mammalian cells virulence of rhodococcus equi isolates from patients with and without aids association between large plasmid and to kilo dalton antigens in virulent rhodococcus equi rhodococcus equi plasmids:isolation and partial characterization rhodococcus equi pneumonia in aids: high-resolution ct fi ndings in fi ve patients cytomegalovirus pneumonitis in patients with aids: fi ndings in an autopsy series immediate causes of death in acquired immunodefi ciency syndrome the causes of death in patients with humanimmunodefi ciency virus infection: aclinical and pathologic study with emphasis on the role of pμlmonary diseases cytomegalovirus pneumonitis: spectrum of parenchymal ct fi ndings with pathologic correlation in aids patients rhodococcus equi -an increasingly recognized opportunistic pathogen a highly representative two hybrid genomic library for the yeast yarrowia lipolvtica rhodococcus equi infection in hiv infected patients rhodococcus equi infection in patients with and without human immunodefi ciency virus infection radiological fi ndings in nine aids patients with rhodococcus equi pneumonia comparison of nucleic acid amplifi cation, serology, and microbiologic culture for diagnosis of rhodococcus equi pneumonia in foals cytokine modulation alters pulmonary clearance of rhodococcus equi and development of granulomatous pneumonia diseases of the lung: radiologic and pathologic correlations pneumonia: high-resolution ct fi ndings in patients radiologic distinction of pyogenic pulmonary infection from pneumocystis carinii pneumonia in aids patients high-resolution ct in the evaluation of clinically suspected pneumocystis carinii pneumonia in aids patients with normal, equivocal, or nonspecifi c radiographic fi ndings pneumocystis carinii pneumonia: spectrum of parenchymal ct fi ndings pulmonia in patient with aids discontinuation of prophylaxis for pneumo-cystis carinii pneumonia in hiv-infected patients treated with highly active antiretroviral therapy carcinoma of the lung in hiv-positive patients: fi ndings on chest radiographs and ct scans pulmonary complications of hiv-associated malignancies pneumocystis carinii infection and aids comparison of histologic stains in the diagnosis of pnemocystis carinii tuberculosis in patients with human immunodefi ciency virus infection comparative histopathological study of pulmonary tuberculosis in human immunodeficiency virus-infected and non-infected patients pulmonary tuberculosis in aids patients: transient chest radiographic worsening after initiation of antiretroviral therapy active pulmonary tuberculosis in patients with aids: spectrum of radiographic fi ndings (including a normal appearance) effect of hiv status on chest radiographic and ct fi ndings in patients with tuberculosis pulmonary mycobacterium avium complex disease without dissemination in hiv-infected patients mycobacterium avium complex infection in the acquired immunodefi ciency syndrome pulmonary disease due to infection by mycobacterium avium complex in patients with aids cd t lymphocyte count and the radiographic presentation of pulmonary tuberculosis. a study of the relationship between these factors in patients with human immunodefi ciency virus infection tuberculosis in the aids era mycobacterial pseudotumors of lymph node mycobacterial spindle cell pseudotumor of lymph node managenent of the hiv-infected patient tuberculosis in the aids era cytomegalovirus pneumonia in aids patients atypical cytomegalic cells are diagnostic for cytomegaloviral infection in aids cytomegalovirus as a primary pulmonary pathogen in aids infections with cryptococcus neoformans in the acquired immunodefi ciency syndrome endemic fungal pneumonia in immunocompromised patients disseminated histoplasmosis in adis: fi ndings on chest radiographs opportunistic fungal pneumonia pulmonary aspergillosis in the acquired immunodeficiency syndrome coccidioidomycosis during human immunodefi ciency virus infection. a review of patients cryptococcal pulmonary infection in patients with aids: radiographic appearance pulmonary aspergillosis in patients with aids. clinical and radiographic correlations cryptococcal pneumonia in aids: is cryptococcal meningitis preceded by clinically recognizable pneumonia pulmonary manifestations of disseminated cryptococcosis in patients with clinical and bacteriological aspects of nocardiasis lung abscess in patients with aids focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced hiv- disease rhodococcus equi endobronchial mass with lung abscess in a patient with primary pulmonary aids-related lymphoma: radiographic and ct fi ndings the expanding challenge of hiv-associated malignancies the pulmonary manifestations of aids-related non-hodgkin's lymphoma varied appearance of aids-related lymphoma in the chest lymphoma versus aids intrathoracic kaposi's sarcoma in women with intrathoracic kaposi's sarcoma. ct fi ndings distribution of human herpesvirus dna in tumorous and nontumorous tissue of patients with acquired immunodefi ciency syndrome with and without kaposi's sarcoma kaposi's sarcoma in lymphnodes concurrent with hodgkin's disease the natural history of kaposi's sarcoma in the acquired immunodefi ciency syndrome pulmonary toxoplasmosis in patients in-fected with human immunodefi ciency virus: a french national survey diagnostic imaging, preautopsy imaging and autopsy fi ndings of aids cases analysis on the imaging features of aids with pulmonary fungal infection liver injury in hiv- -infected patients receiving non-nucleosides reverse transcriptase inhibitors-based antiretroviral therapy mri demonstrations of aids complicated by toxoplasma gondii infection in cervical spinal cord: with cases reports diagnostic imaging in aids in china: current status and clinical application imaging and pathological fi ndings of aids complicated by pulmonary rhodococcus equi infection magnetic resonance spectroscopy in the diagnosis of cognitive impairment in aids patients ct image demonstrations of hiv-seropositive tuberculosis and their relationship with cd + t-lymphocyte count positron emission tomography of fdg uptake in localized pulmonary infl ammation penicilliosisde rhizomys sinensis accumulation of nuclear mitochondrial dna in the frontal cortex cells of patients with hivassociated neurocognitive disorders imaging fi ndings of aids complicated with pulmonary rhodococcus equi infection and correlated with pathology pulmonary toxoplasmosis? pathogenesis and prevention of rhodococcus equi infection pulmonary toxoplasmosis a female patient aged years was confi rmatively diagnosed as having aids by the cdc. she complained of cough, fever and no sputum. her cd t cell count was / μl. filariform larvae of strongyloides stercoralis invade into skin or mucosa and reach the lungs through lymphatic vessels or venous system and the right heart. they develop into schistosomula in - days. a few schistosomula develop mature in the lungs or bronchi. most schistosomula penetrate the pulmonary capillaries into alveoli to cause a series of respiratory symptoms. in the cases of serious infection and in patients with compromised immunity, disseminated lesions occur in lungs and other organs. hiv/aids related pulmonary strongyloidiasis can have manifestations of local small bleeding spots, pimples, migratory linear or strips urticaria on skin, as well as manifestations of allergic bronchitis, lobular pneumonia or asthma. aids patient may have severe diffuse infection and systemic infection, with symptoms of fever, severe cough, expectoration, hemoptysis, shortness of breath, breathing diffi culty, and asthma. . laboratory tests . the pathological examinations include biopsy tissue culture and inoculation test. . chest x-ray is the most commonly used examination. there are demonstrations of small spots and fl aky shadows, thickened hilar shadow and thickened pulmonary markings. mitchell reported in that interstitial or alveolar infi ltration in both lungs accounts for %, nodular shadows in both lungs %, hilar or mediastinal lymphadenectasis %, pleural fl uids %, septal line %, mediastinal lymphadenectasis and ascites are the important clues for the diagnosis. . the clinical manifestations of hiv/aids related pulmonary strongyloidiasis are non-specifi c. its diagnosis depends on the etiological examinations. the fi ndings of strongyloides sterocralis in the patient's sputum and feces can defi ne the diagnosis. increases to × ⁄l; eosinophils granulocytes - %, or even as high as - %; the serum total lge level increases by %; % cases with blood serum lgg and lge of fi lariform larvae antigen positive. in the cases with femal strongyloides stercoralis parasitizing in the bronchial epithelium, rhabditiform larva, fi lariform larva, schistosomula, adult strongyloides stercoralis and the eggs can be found in fresh phlegm, which can defi ne the diagnosis. . pathological examinations including biopsy tissue culture and inoculation test are positive. . by chest x-ray, the lungs have small spots and fl akes of shadows, thickened hilar shadow and thickened pulmonary markings. hiv/aids related pulmonary strongyloidiasis should be differentiated from hiv/aids related pulmonary toxoplasmosis, infectious mononucleosis and mycoplasma pneumonia. pulmonary infi ltration of hiv/aids related malignant lymphoma commonly has three types: primary pulmonary lymphoma, which is rare and accounts for . . the diagnostic imaging examinations are the most commonly used examinations for the diagnosis. the imaging demonstrations of hiv/aids related malignant lymphomas include: . mediastinal lymphadenectasis is the most commonly found pulmonary manifestations of malignant lymphoma. the lesions are mainly located in anterior and middle mediastinum, in asymmetric wave liked or lobulated mass. it occurs unilaterally or bilaterally, isolated or fusion. . the incidence of pulmonary parenchymal lesions is - %. chest x-ray demonstrates mediastinal lymph nodes extending directly into the lungs, which is susceptible to confusion with pneumonia. they are demonstrated as round shadows in the lung fi elds or distribute in the whole lung fi elds. chest x-ray demonstrates the lymphatic spread of lesions as military nodules in different sizes or isolated intrapulmonary nodules or cavities, commonly accompanying with mediastinal hilar lymphadenectasis. in the cases with its occurrence secondary to endobronchial membrance, obstructive pneumonia or atelectasis can be caused. some patients may have diffuse pulmonary interstitial changes. pulmonary infi ltration by non-hodgkin's lymphoma can also be divided into four types: ( ) nodular type; ( ) pneumoniaalveolar type; ( ) bronchial-vascular-lymphatic type, which can be further divided into the central bronchialvascular type, and diffuse lymphatic type; ( ) diffuse lymphatic type can have lesions of reticular or reticular nodular infi ltration and its progression into patchy changes. . miliary-blood borne spreading type is rare. . the pleural lesions is mainly pleural effusion, with bloody or serous pleural fl uid. a male patient aged years was confi rmatively diagnosed as having aids by the cdc. he complained of chest distress and chest pain for more than months. his cd t cell count was /μl. ( ) tuberculoma is diffi cult to be differentiated from the peripheral type of lung cancer. tuberculoma is more common in young adults, with a long term course of illness. the lesions are commonly found in the apical posterior segment of the upper lobe or dorsal segment of the lower lobe. chest x-ray demonstrates the lesions with uneven density and satellite lesions. ( ) miliary tuberculosis is diffi cult to be differentiated from diffuse bronchioloalveolar carcinoma. key: cord- -r jtoso authors: miller, tracie l.; cushman, laura l. title: gastrointestinal complications of secondary immunodeficiency syndromes date: - - journal: pediatric gastrointestinal and liver disease doi: . /b - - - - . - sha: doc_id: cord_uid: r jtoso nan secondary immunodeficiency syndromes constitute a spectrum of disorders. infections of the gastrointestinal tract pose the greatest risk for children with secondary immunodeficiencies. cellular changes in the gastrointestinal tract (the largest immune organ in the body) that lead to diarrhea and malabsorption, peptic disease, dysmotility, and liver disease are among some of the other disorders of the gastrointestinal tract faced by these children. worldwide, human immunodeficiency virus (hiv- ) infection and malnutrition are by far the most common secondary immunodeficiency states. however, in the united states and other developed countries, severe malnutrition and new cases of perinatal hiv- disease are rare because of relatively high standards of living and effective highly active antiretroviral therapies (haart) given to pregnant hiv-infected women that prevent transmission of hiv to the infants. between and , there were reported cases of perinatally acquired hiv and new diagnoses of unspecified origin in adolescents to years of age. hiv-infected children and adolescents are now surviving because of effective antiretroviral strategies, yet there is increased horizontal acquisition of hiv in adolescents owing to risky social behaviors. furthermore, children with chronic illness are among the highest population at risk for malnutrition and its sequelae. thus these two disorders serve as models for complications of other secondary immunodeficiency states. the first cases of the acquired immunodeficiency syndrome (aids) were described in the early s. later, in , hiv- was determined to be the causative agent, and hiv- infection was recognized as a spectrum of disease, ranging from asymptomatic infection to full-blown aids. the aids epidemic claimed an estimated million lives in , and an estimated . million people acquired hiv- in . an estimated million people globally are living with the virus. with the successful preventive strategies of elective cesarean section delivery and chemoprophylaxis of pregnant hiv- -infected women, the transmission rates plummeted from to % to less than to % of all hiv- -infected women delivering infants. the advent of haart in changed the natural history of hiv- in children in many countries. however, the successes of prevention and prophylaxis have not been realized as much in developing countries, where hiv infection continues to increase. for this reason, there are disparate accounts of opportunistic infections and other diseases in regions with high haart accessibility and those with limited haart accessibility. hiv- is an rna virus that belongs to the lentivirus family. it has a particular tropism for the cd surface antigen of cells, and the binding of hiv- to the cd receptor initiates the viral cycle. the virus may subsequently replicate within the host cell or, alternatively, the proviral dna within the host cells may remain latent until cellular activation occurs. human t lymphocytes and monocytes-macrophages are the primary cells that are infected with hiv- , although other cell lines may be infected as well. the net effect is suppression of the immune system and a progressive decline in cd + t lymphocytes, which leaves patients susceptible to opportunistic and recurrent bacterial infections. the gastrointestinal tract is the main source of hiv- infection when parenteral transmission is excluded. in vertical transmission, hiv- is found in the gastrointestinal tract after the fetus swallows infected amniotic fluid, blood, cervical secretions, or breast milk. the virus, inoculated in the gastrointestinal tract, infects the fetus as it enters into the gut-associated lymphoid tissue (galt) through the tonsil or upper intestinal tract. examination of both acute simian immunodeficiency virus (siv) and hiv infection have documented reduced cd cell levels in galt prior to a detectable reduction in t cells of the peripheral blood, highlighting the gastrointestinal tract's role and susceptibility. [ ] [ ] [ ] [ ] the rates of acquisition of hiv- through the gastrointestinal tract are likely related to the quantity of virus in the person transmitting it [ ] [ ] [ ] and the immunologic function and maturity of the patient being infected. mucosal infections with opportunistic infections may increase hiv- transmission. mycobacterial infections up-regulate cc chemokine receptor (ccr ) expression in monocytes, which facilitates the entry of ccr -tropic hiv- . other factors, such as tumor necrosis factor-α (tnf-α), which is induced by nuclear factor (nf)-кb (which itself is pathogen induced), are potent inducers of hiv- . , cellular routes that potentially can transmit hiv- across the gastrointestinal tract include m cells, dendritic cells, and epithelial cells. m cells are specialized epithelial cells that overlie the peyer's patches and transport large macromolecules tracie l. miller • laura l. cushman and microorganisms from the apical surface to the basolateral surface. human transport of hiv- by m cells in vivo has not been reported. dendritic cells bind hiv- through a dendritic cell-specific adhesion molecule. in vitro studies support the role of dendritic cells in transmitting hiv- [ ] [ ] [ ] [ ] ; however, the role of the dendritic cell in in vivo transmission of hiv- has yet to be determined. epithelial cells express ccr and can selectively transfer ccr -tropic hiv- . the epithelial cell can transport hiv- in vitro from the apical to the basolateral surface. , the r -tropic viruses are transferred in vitro through epithelial cell lines. once transmitted, the lamina propria lymphocytes express ccr and cxc chemokine receptor (cxcr ), which support hiv- replication. , early after infection, there is a greater proportion of infected lymphocytes in the lamina propria than in peripheral blood. , for the patients actively receiving haart, poles et al. described "cryptic replication" occurring in galt reservoirs in which viral replication is actively taking place at slower rates but hiv- rna levels remain undetected in peripheral blood. further, galt contained more than twice as many lymphoid cells ( , ) than peripheral blood mononuclear cells ( , ) possessing hiv- dna with viral replication capacity. there was no significant reduction in these values when the analysis was repeated after months. lymphocytes are able to disseminate the virus to distant sites, with depletion of cd cells in the lamina propria , and then in the blood. even with aggressive suppression of hiv- during the primary stages by highly active antiretroviral agents, cd cell depletion is observed in the effector subcompartment gut mucosa when cd levels in the peripheral blood have stabilized. as mucosal and peripheral t cells are depleted, monocytes and macrophages become important reservoirs for the virus. the intestinal macrophages do not promote inflammation and do not carry the receptor for ccr or cxcr ; however, the blood monocytes are different in their profile and are infected by hiv- . they are found infected in the blood and thereafter take up residence in the gut. they are stimulated by opportunistic agents and proinflammatory cytokines. recent in vitro studies have implicated the integrin receptor α β on which the hiv- envelope binds and transmits signals mediated by an epitope in the v loop of gp . this in turn activates lfa- and is pivotal in virological synapse formation, allowing rapid cellular dissemination of hiv- . villous atrophy and gastrointestinal tract dysfunction are coincident with high levels of hiv- viral load in the gut. altered epithelial permeability may permit microbial translocation and generalized immune activation leading to localized cytokine production and further replication of hiv. a dysfunctional gastrointestinal tract can produce clinical symptoms that contribute to both morbidity and mortality in children with hiv- infection. these symptoms include weight loss, vomiting, diarrhea, and malabsorption (table - ). the advent of antiretroviral treatment induces debilitating effects on mechanisms within the gut that promote chronic hiv infection. mainly, high levels of lipopolysaccharides (lps) are associated with marked systemic immune activation sustaining this infection; antiretroviral therapy decreases levels of lps, promotes cd + t cell reconstitution, and may subsequently decrease the systemic immune activation. additional studies examining this relationship stand to offer greater insight into hiv pathogenesis. as mentioned, there are distinct changes in the cellular milieu of the gastrointestinal tract in hiv- -infected patients. previous studies have shown that activated mucosal t cells play a role in the pathogenesis of enteropathy in the human small intestine and can affect the morphology of the villi and crypts in a manner similar to that seen in patients with hiv- infection. the magnitude of viral burden in the gastrointestinal tract is associated with villous blunting and other abnormal morphology. a number of studies in the s associated a distinct enteropathy with hiv- . diarrhea, weight loss, an abnormally low d-xylose absorption, and steatorrhea, without evidence of intestinal infection, were common findings. jejunal biopsies showed partial villous atrophy with crypt hyperplasia and increased numbers of intraepithelial lymphocytes. this was the first histologic description of a specific pathologic process that occurred in the lamina propria of the small intestine in some patients with hiv- . others found low-grade small bowel atrophy and maturational defects of enterocytes, supporting an hiv- enteropathy characterized by mucosal atrophy with hyporegeneration. however, some investigators have challenged this concept, suggesting that the findings could be attributed to an undiagnosed enteric infection. recently, genotype profiling for genes responsible for endothelial barrier maintenance and metabolic functioning has shown a decreased expression in the presence of increased viral replication in the galt and reduced cd + t cell levels. these findings are significant, because they offer an additional modality for evaluating microenvironmental alterations within the gastrointestinal tract of the patient. additional studies will help to determine the efficacy of gene expression profiling in hiv-infected individuals. miller et al. published histologic findings in children with hiv- infection. the majority of patients had normal villous architecture, and many of the children with villous blunting had an associated intercurrent enteric infection. distinct features of hyperplasia of the lamina propria and increased intraepithelial lymphocytes were not apparent. bjarnason et al. studied intestinal inflammation and ileal structure and function in patients with a wide spectrum of hiv- disease states. hiv- -infected patients who were minimally symptomatic had normal intestinal absorption and permeability, yet had greater gastrointestinal dysfunction as they progressed to aids. malabsorption of bile acids and vitamin b did not correlate with morphometric analysis of ileal biopsies and was unremarkable in these patients. thus, there was significant mucosal dysfunction with only minor ileal morphologic changes. malabsorption of bile acids may play a pathologic role in patients with aids diarrhea. the absorptive defect of aids enteropathy using a d-xylose kinetic model of proximal absorption was studied and correlated with the results of a schilling test for cobalamin absorption, which measures distal intestinal function. there were minimal histologic abnormalities in both the proximal and distal biopsy sites in patients with diarrhea and no enteric infection. d-xylose absorption was low, and the absorptive defect was more severe and greater than would be expected from the histologic abnormalities found. thus, these findings support the theory that there is little association between histologic characteristics of the small bowel and its absorptive function in patients with hiv- infection. most studies do not support a direct role for gastrointestinal malabsorption on growth failure or weight loss. ullrich et al. described gastrointestinal malabsorption in hiv- -infected patients who had low levels of lactase enzyme in the brush border, crypt death, decreased villous surface area, and decreased mitotic figures per crypt when compared with control patients. in addition, keating et al. described absorptive capacity and intestinal permeability in hiv- -infected patients. malabsorption was prevalent in all groups of patients with aids, but was not as common in the asymptomatic hiv- -infected patients. malabsorption correlated with the degree of immune suppression and with body mass index. there were mild decreases in the ratio of jejunal villous height to crypt depth, yet not as severe as the subtotal villous atrophy found in celiac disease. lim et al. found disaccharidase activity decreased proportionately with greater hiv- disease severity, although there was no association between disaccharidase levels and weight loss. in addition, mosavi et al. found no correlation between diarrhea and weight loss in hiv- -positive patients. taylor et al. found mild histologic changes accompanied by severe disaccharidase abnormalities; however, symptoms were severe enough to withdraw lactose in only % of the patients. collectively these studies suggest that gastrointestinal malabsorption may be present, but is not always associated with weight loss and diarrhea. formal studies of intestinal absorption in children with hiv- are more limited. malabsorption occurs frequently in hiv- -infected children and may progress with the disease. in one study, % of children had nonphysiologic lactose malabsorption and % had generalized carbohydrate malabsorption that was not associated with gastrointestinal symptoms or nutritional status. these findings have been confirmed by others. another study in children revealed an association between diarrhea and nutrition. abnormal d-xylose absorption has also been associated with enteric infections in children. fat and protein loss or malabsorption have also been described. sentongo et al. evaluated fat malabsorption and pancreatic exocrine insufficiency using fecal elastase- enzyme assay in hiv- -infected children. hormone-stimulated pancreatic function testing and -hour stool and dietary fat sample collection were performed in children with abnormal fecal elastase levels. the prevalence of steatorrhea was % and that of pancreatic insufficiency was % ( % confidence interval to %). there were no associations between steatorrhea and pancreatic insufficiency, growth, hiv- rna viral load, cd status, or type of antiretroviral therapy. other studies support the absence of association. thus, the clinical significance of steatorrhea in pediatric hiv- , similar to absorption of other nutrients, is unclear. the etiology of malabsorption in hiv- infection is probably multifactorial. the cellular milieu of the lamina propria is altered significantly with hiv- infection. , the depletion of the cd t lymphocytes in the intestinal tract may cause change in the cytokine environment and alter intestinal function. viral load in the intestinal tract may be considerably higher than that measured peripherally, and this can also affect mucosal gastrointestinal structure and function. recently, the hiv- tat protein was found to decrease glucose absorption through decreasing the activity of the sodium d-glucose symporter. studies suggesting these hypotheses include that of kotler et al., which looked at intestinal mucosal inflammation in hiv- -infected individuals. these authors found abnormal histopathology in % of the patients, and this finding was associated with altered bowel habits. high tissue p antigen levels were observed, and these correlated with more advanced hiv- disease. tissue p detection was associated with both abnormal bowel habits and mucosal histology. the tissue content of cytokines, including tnf, α-interferon, and interleukin- β, was higher in hiv- -infected individuals than in controls, and these increases were independent of intestinal infection. thus, hiv- reactivation in the intestinal mucosa could be associated with an inflammatory bowel-like syndrome in the absence of other enteric pathogens. small bowel bacterial overgrowth can be another source of gastrointestinal dysfunction leading to malabsorption. bacterial overgrowth may be due to aids gastropathy, , in which the stomach produces only small amounts of hydrogen chloride, allowing bacterial pathogens to escape the acid barrier of the stomach and colonize the duodenum. additionally, iatrogenic hypochlorhydria may be due to the use of acid-blocking agents as treatment for peptic disease. interestingly, some authors have found no relationship between gastric ph and small bowel bacterial colonization and diarrhea in hiv- -infected patients. enteric pathogens have been associated with enteric dysfunction, as discussed later. with the advent of haart, gastrointestinal symptoms, especially those associated with opportunistic infections, are less common. as viral burden decreases, immunosuppression has less effect on gastrointestinal function. compared to untreated patients, haart-treated patients had greater integrity of intestinal mucosal barrier and decreased villous atrophy. ritonavir, a protease inhibitor, in combination therapy resulted in restoration of gastrointestinal function in children with carbohydrate malabsorption, steatorrhea, protein loss, and iron deficiency. however, one study in adults found similar rates of fat malabsorption in patients taking haart and in those not taking haart. the gastrointestinal tract is a major target for opportunistic infections in hiv- -infected children. the spectrum of these infections is dependent on hiv- disease progression. in developed countries, with improved hiv- viral suppression associated with haart, opportunistic infections of the gut and elsewhere are less common. however, immunocompromised children are still at risk for infections with cytomegalovirus (cmv), herpes simplex virus (hsv), cryptosporidium, and microsporidia. previous dogma that much of the diarrhea found in children with hiv- infection is not associated with enteric pathogens has been challenged. unusual viral and parasitic infections can be diagnosed as a result of better diagnostic techniques. however, the cause of diarrhea in a significant number of patients with hiv- remains undiagnosed. occurrence of opportunistic disease and infection of the gastrointestinal tract in immunocompromised patients relies heavily on the accessibility of haart. as a result, there is great disparity of documented incidence of gastrointestinal infections dependent on access to haart in particular regions. for this reason, we have divided this section into two subsections: gastrointestinal infections in regions with low haart accessibility or in patients with cd t-lymphocyte counts less than cells/mm , and gastrointestinal infections in regions with high haart accessibility and successful viral suppression. this does not imply that any of the infections discussed here occur in isolation contingent on haart accessibility, because all hiv- patients regardless of haart may encounter these complications. in the post-haart era, it is helpful for a physician to know which backdrop lends itself to specific vulnerabilities. the detection of viral gastrointestinal infections in hiv- infected children can sometimes be difficult owing to the limitations of diagnostic techniques. the most common gastrointestinal viral pathogen in hiv- -infected children is cmv. other pathogens, such as hsv, adenovirus, epstein-barr virus, and a variety of other unusual viruses, can also contribute to intestinal dysfunction and diarrhea. hsv infection in an immunocompromised child usually represents reactivation of a latent virus that had been acquired earlier in life. gastrointestinal infection with hsv most commonly involves the esophagus and causes multiple small, discrete ulcers. hsv can also involve other areas of the intestinal tract, including the colon and small bowel. the diagnosis of hsv relies on recognizing the multinucleated intranuclear inclusion bodies (cowdry type a) with a ground-glass appearance and molding of the nuclei. the squamous epithelium is usually infected, although there may also be involvement of intestinal glandular epithelium in the mesenchymal cells. hsv monoclonal antibody staining is confirmatory for the diagnosis. in extensive involvement, there may be transmural necrosis and development of tracheoesophageal fistulas. treatment of hsv and other common gastrointestinal pathogens and their primary sites of involvement are outlined in table - . other herpes viruses have also been detected in the gut of hiv- -infected individuals. a case report of one -year-old hiv- -infected man with intestinal pseudo-obstruction and disseminated cutaneous herpes zoster revealed positive immunohistochemistry against herpes zoster in a resected portion of the terminal ileum. this area had focal ulceration. the virus was localized to the muscularis propria and myenteric plexi throughout the entire length of the specimen. the authors postulated that the location of the virus in the gut may have been the etiologic factor for the pseudo-obstruction. cytomegalovirus cmv in the immunocompromised child, like hsv, represents reactivation of a latent virus that was acquired in earlier life. cmv is one of the more common viral pathogens of hiv- infected children. the reported incidence of gastrointestinal involvement in the pre-haart era varied from . % to % of patients studied. the incidence rates may have varied based on the techniques of diagnosis. cmv infection is rare in patients with cd t-lymphocyte counts greater than cells/mm . cmv may involve any part of the gastrointestinal tract, with an increased incidence in the esophagus or colon. cmv infection usually results in one or two discrete single and large ulcers of the esophagus and colon. lesions may lead to severe gastrointestinal bleeding and hemodynamic instability. cmv inclusion bodies can be discovered incidentally in an asymptomatic patient, and this does not necessarily reflect disease. in patients with upper intestinal cmv disease, there can be dysphagia and upper abdominal symptoms, whereas diarrhea is more common with colitis. the diarrhea can be watery or bloody. children may be systemically ill. the colitis from cmv infection is patchy and can be associated with severe necrotizing colitis and hemorrhage. cmv usually affects the cecum and the right colon. diagnosis is confirmed by endoscopy and biopsy. the histologic appearance of cmv-infected cells is unique (figure - ). these cells are enlarged and contain intranuclear and cytoplasmic inclusion bodies. the nuclear inclusion bodies are acidophilic and are often surrounded by a halo. cytoplasm inclusion bodies are multiple, granular, and often basophilic. cells that are dying may appear smaller and smudged, with poorly defined inclusion bodies. staining for cmv antigen shows that many of the infected cells are endothelial cells with others being perivascular mesenchymal cells. cmv can cause vasculitis because of its target cell population. thus, the spread of cmv occurs with circulating infected endothelial cells. treatment options are outlined in table - . once haart is established, with decreased viral burden (both hiv- and cmv) and improved cd counts, cmv treatment may be discontinued without concern for reactivation. infections with other unusual viral pathogens have been described. these include the human papilloma virus and epstein-barr virus, which have been identified in esophageal ulcers of patients with hiv- . adenovirus of the stomach and colon have also been reported and are often difficult to identify. in the pre-haart era, patients who excreted adenovirus from their gastrointestinal tract had a shorter survival. there are unusual enteric viruses that have been associated with diarrhea in hiv- -infected children. these viruses, among others, include astrovirus and picobirnavirus. cegielski et al. studied children with hiv- infection in tanzania. they looked for enteric viruses identified by electron microscopy of fecal specimens. small round structured viruses (srsvs) were found more frequently in hiv- -infected children than in uninfected children with chronic diarrhea. rotavirus and coronaviruslike particles were not associated with hiv- infection. these authors considered that these srsvs may be associated with hiv- infection and could lead to chronic diarrhea in tanzanian children. bacterial infections that involve the gastrointestinal tract of children with hiv- infection may be divided into three groups: bacterial overgrowth of normal gut flora; pathogens that can affect immunocompromised children as well as immunocompetent children (salmonella, shigella, campylobacter, clostridium difficile, and aeromonas); and bacterial infections that are more common in immunocompromised children (mycobacterium avium-intracellulare complex; mac). few studies have evaluated bacterial overgrowth in hiv- -infected children, although gastric hypoacidity has been associated with opportunistic enteric infections and bacterial overgrowth in adult patients with hiv- . other studies have not found this association. small bowel bacterial overgrowth was not a common finding in a group of hiv- -infected patients, regardless of the presence of diarrhea, and it was not associated with hypochlorhydria. lactose hydrogen breath testing has shown high baseline readings in children that may indirectly suggest bacterial overgrowth of the small intestinal tract. detection of bacterial overgrowth in the small bowel is usually performed by quantitative duodenal aspirate for bacterial culture, with therapy directed at treating the organisms, which are often anaerobic. common bacterial pathogens include salmonella, shigella, campylobacter, clostridium difficile, and aeromonas. infection with these organisms occurs more frequently in immunocompromised patients. combined morbidity and mortality rates associated with hiv- and these bacterial pathogens in developing countries approach % in some studies. hiv- -infected patients with campylobacter infection have higher rates of bacteremia than the general population. deaths from sepsis due to this organism have been reported in severely immunodeficient patients with aids, despite haart. other entities, such as bacterial enteritis, have been described in adults with hiv- . a study by orenstein and kotler evaluated ileal and colonic biopsies in patients with aids and diarrhea and found bacteria similar to adherent e. coli along the intestinal epithelial border. similar findings were documented by kotler et al., who showed adherent bacteria in % of all adult patients with aids. the infection was localized primarily to the cecum and right colon, and three distinct histopathologic patterns of adherence were observed: attachment on effacing lesions, bacteria intercalated between microvilli, and aggregates of bacteria more loosely attached to the damaged epithelium. the bacterial cultures of frozen rectal biopsies yielded e. coli in of the patients. these findings suggest that chronic infection with adherent bacteria can also produce the syndrome of aids-associated diarrhea. in a "look back" evaluation, orenstein and dieterich found that enteropathogenic bacterial infections were overlooked on initial examination and concluded that, for accurate diagnoses, specimens should be evaluated by laboratories with expertise in hiv. intestinal infections with mycobacteria, including mycobacterium tuberculosis, mac, and other atypical mycobacteria, were the most frequently encountered bacterial infections in hiv- -infected patients in the pre-haart era and became more prevalent in the pre-haart era as patients were living longer with cd counts below cells/mm . , in the haart era, disseminated mac in colonized patients can be successfully prevented; however, the effects of haart on restoration of cd counts do not prevent mac colonization. infection with mac usually occurs in the very late stages of aids in children, when cd counts are lower than cells/mm . the most common clinical manifestations of gastrointestinal infections with mac include fever, weight loss, malabsorption, and diarrhea. intestinal obstruction, resulting from lymph node involvement and intussusception; terminal ileitis, which resembles crohn's disease; and refractory gastric ulcers are often found. severe gastrointestinal hemorrhage has also been described. endoscopically, fine white nodules may be seen in the duodenum, or the duodenal mucosa may look velvety and grayish in appearance. segments of the gastrointestinal tract can become infected with mac. histologically, there is a diffuse histiocytic infiltrate in the lamina propria with blunting of the small intestinal villi. these histiocytic infiltrates can be recognized on hematoxylin and eosin staining and on acid-fast stains and are pathognomonic for infection ( figure - ) . with the advent of haart, immune reconstitution disease has been described. , this is likely an immune reaction in which previously quiescent organisms become active because of the improved immune function associated with haart. this can occur in as many as % of patients who respond to haart. lymphadenitis is the most common condition, although abscesses can appear anywhere. severe abdominal complaints may result. appropriate therapies are outlined in table - , yet this organism is often frustrating to treat. azithromycin mg, when given in combination with ethambutol, is an effective agent for the treatment of disseminated m. avium disease in patients infected with hiv- . caution must be exercised in administering these multidrug regimens for mac in patients receiving concurrent haart. rifamycins induce cytochrome p enzymes and accelerate the metabolism of clarithromycin and hiv- protease inhibitors. conversely, clarithromycin inhibits these enzymes, resulting in increased rifabutin toxicity. the net result is treatment regimens that can be extremely difficult to tolerate and manage, especially for sicker patients. clarithromycin and azithromycin must be administered in combination with other agents, such as ethambutol, to prevent the emergence of macrolide resistance. in the early s, cryptosporidiosis was regarded as an aidsdefining disease and an opportunistic intestinal pathogen. it became an important cause of chronic diarrhea, leading to high morbidity and mortality rates in immunocompromised patients. to date, no effective chemotherapy is available. with the introduction of protease inhibitors in haart regimens, the incidence of cryptosporidiosis in patients with aids has declined substantially in developed countries. however, in developing nations, gastrointestinal infection with c. parvum is prevalent and carries high morbidity and mortality rates. , although cryptosporidium was initially described in animals, it was first noted to cause an enterocolitis in both immunocompromised and immunocompetent humans in . , an intact t-cell response is the primary mechanism that confers protection against this organism; thus, patients with abnormal t-cell function or number are at risk. the spectrum and severity of disease in immunocompromised individuals with cryptosporidiosis correlates with most severe disease found in individuals with defects in the t-cell response. the overall frequency of infection seems to be related to the severity of immunodeficiency and not the specific disorder. cryptosporidium usually affects the gastrointestinal tract, although it has been found in other organs including the biliary tract, pancreas, and respiratory tract. in immunocompetent individuals, the diarrhea is self-limiting, whereas in immunocompromised patients, it may be protracted and associated with significant malabsorption and nutritional compromise. the small intestine is the primary target, although it can occur in any part of the intestinal tract. esophageal cryptosporidiosis has also been described in one child and in adults. clayton et al. described two patterns of enteric cryptosporidiosis. one was accompanied by severe clinical disease with significant malabsorption, with the majority of the organisms found in the proximal small bowel, whereas less severe clinical disease was seen in patients with colonic disease or with infection noted only in the stool. patients with proximal small bowel infection with cryptosporidium showed crypt hyperplasia, villous atrophy, lamina propria inflammatory infiltrates, abnormal d-xylose absorption, greater weight loss, and shorter survival, with greater need for intravenous hydration and hyperalimentation than patients with colonic disease. in other studies, absorption of nutrients showed an inverse correlation with active infection, as shown by altered vitamin b and d-xylose absorption and lactulose and mannitol urinary excretion ratios. intestinal function improved in patients whose oocyte counts were reduced by treatment with paromomycin. symptomatic cryptosporidiosis has been documented in as many as . % of immunocompetent children and % of immunodeficient children, whereas in an asymptomatic population, cryptosporidium was found in . % of immunocompetent and . % of immunodeficient children. spiramycin at mg per kg daily for days caused a significant reduction in the shedding of infectious oocysts, and no gastrointestinal symptoms developed in children treated for asymptomatic infection, whereas children who were not treated developed gastrointestinal symptoms. the diagnosis of cryptosporidiosis is made by identifying the organisms in a duodenal aspirate, stool, or tissue sample (biopsies). on hematoxylin and eosin-stained sections, these organisms can be found as rows or clusters of basophilic spherical structures to μm in diameter, attached to the microvillous border of the epithelial cells (figure - ) . the tips in the lateral aspect of the villi show the greatest number of organisms in the small intestine. in the colonic epithelium, the crypt and surface epithelial involvement appears equal. cryptosporidium also stain positively with giemsa and negatively with mucous stains. the acid-fast stain on a stool sample is one of the most widely used methods of determining whether a patient has cryptosporidiosis. more recent sensitive and specific methods for diagnosing cryptosporidiosis include fluorescein-labeled igg monoclonal antibodies. , treatment of cryptosporidiosis in children with hiv- infection is often difficult. the disease can be chronic and protracted with diffuse watery diarrhea and dehydration. several different agents are used to eradicate the organism, with varying success rates. the most effective treatment is to improve immunologic function and nutritional status. with the advent of haart, many children's immune function has been restored with a lower incidence and prevalence of cryptosporidium infection. the introduction of haart in a patient with severe debilitating cryptosporidium infection not only resulted in an increased cd count in the peripheral blood and clearance of the organism, but also produced a marked increase in cd count in the rectal mucosa on biopsy, suggesting this may have been the main mechanism of clearing the parasite. octreotide therapy of acute and chronic diarrhea, with coincident improvement in nutritional status, eradicated cryptosporidium in one patient. , other investigators have used bovine hyperimmune colostrum with benefit. , the macrolides, such as azithromycin, have shown some promise in the treatment of cryptosporidium infection. , the effect of protease inhibitors as therapy against cryptosporidium has been tested in a cell culture system. nelfinavir moderately inhibited the host cell invasion over a period of hours. indinavir, nelfinavir, and ritonavir inhibited parasite development significantly. the inhibitory effect was increased when the aminoglycoside paromomycin was combined with the protease inhibitors indinavir, ritonavir and, to a lesser extent, saquinavir, compared with the protease inhibitor alone. thus, protease inhibitor therapy may directly (rather than indirectly, through its effects on the immune system) inhibit growth of cryptosporidium. amadi et al. found that a -day course of nitazoxanide improved diarrhea, helped eradicate the parasite, and improved mortality in hiv- -seronegative, but not hiv- seropositive, children in zambia. treatment with nitazoxanide on immunocompetent patients demonstrated parasitic load reduction, but its effects on immunocompromised patients are not yet palpable. microsporidia are obligate intracellular protozoal parasites that infect a variety of cell types in many different species of animals. these organisms were first described in , when recognized as a cause of disease in nonhuman hosts. the first description of microsporidia (enterocytozoon bieneusi) as a human pathogen was in , and microsporidia have since been described as more common human pathogens. infection with microsporidia typically occurs in patients with severely depressed cd t-lymphocyte counts. one of the largest case studies of intestinal microsporidiosis in patients with hiv- infection was described by orenstein et al. in adult patients with aids and aids-related complex and chronic nonpathogenic diarrhea. e. bieneusi was diagnosed by electron microscopy in of the patients. jejunal biopsies were more positive than duodenal biopsies. the parasites and spores were clearly visible by light microscopy in of the biopsies. infection was confined to enterocytes located at the tip of the intestinal villus, and the histologic findings included villous atrophy, cell degeneration, necrosis, and sloughing. other investigators [ ] [ ] [ ] found microsporidia in as many as % of hiv- -infected patients with chronic and unexplained diarrhea evaluated in the pre-haart era. e. bieneusi has been documented in to % of children with or without diarrhea in developing countries, making it fairly ubiquitous in these regions of the world. other species of microsporidia, including encephalitozoon (septata) intestinalis, can cause significant enteric disease with diarrhea, wasting and malabsorption. encephalitozoon intestinalis differs from enterocytozoon bieneusi in its tendency to disseminate, and it can infect enterocytes as well as macrophages, fibroblasts, and endothelial cells. microsporidia are found with increasing frequency in hiv- negative patients. infection has been documented in almost every tissue and organ in the body, and in epithelial, mesenchymal, and neural cells. microsporidia can cause inflammation and cell death and a variety of symptoms including shortness of breath, sinusitis, and diarrhea with wasting. if left untreated, microsporidiosis can be a significant cause of mortality. treatments for microsporidia include albendazole, which can relieve clinical symptoms and eliminate microsporidial spores in the feces, especially of the less common pathogen, e. intestinalis. e. bieneusi is more challenging to treat, although therapy with fumagillin or its analogue, tnp- (antiangiogenesis agents), has shown promising results. [ ] [ ] [ ] other studies show atovaquone as an effective treatment as well. indirect treatment by improving the immune system with haart has also effectively cleared these organisms. , , isospora belli is recognized as an opportunistic small bowel pathogen in patients with hiv- infection. this organism is most common in tropical and subtropical climates. isosporiasis can be diagnosed by identification of the oocyte in the stool or by biopsy. the diagnosis is critical because, in contrast to cryptosporidiosis or microsporidiosis, the therapy is very effective. i. belli is found within the enterocyte and within the cytoplasm. the organism stains poorly, although the central nucleus, large nucleolus, and perinuclear halo give it a characteristic appearance. the infection produces mucosal atrophy and tissue eosinophilia. a -day course of trimethoprim-sulfamethoxazole is effective therapy, and recurrent disease can be prevented by ongoing prophylaxis with this combination drug. ciprofloxacin, although not as effective, is an acceptable alternative for those with sulfa allergies. other therapies for isospora include pyrimethamine, also indicated for patients with sulfa allergies. blastocystis hominis is usually considered a nonpathologic parasite, but it has been described in patients with chronic diarrhea and hiv- infection. this organism is more pathogenic in immunocompromised patients and can cause mild, prolonged, or recurrent diarrhea. effective therapy includes diiodohydroxyquinoline mg orally three times daily for days. other protozoan infections that can be found in hiv- -infected patients are entamoeba histolytica, entamoeba coli, entamoeba hartmanni, endolimax nana, and giardia lamblia in % of cases. candidiasis of the gastrointestinal tract is the most common fungal infection in hiv- -infected children. the esophagus is the primary target of candida, and this infection occurred in the majority of patients during the course of their illness in the pre-haart era. it was also the second most frequent aidsdefining disease, second in prevalence only to pneumocystis jirovecii. patients with candida esophagitis complain of odynophagia or dysphagia and may often have vomiting and recurrent abdominal pain. children often have oral thrush, coincident with more disseminated and invasive candida esophagitis, although the absence of oral thrush does not preclude the diagnosis of candida esophagitis. in one study, oral candidiasis preceded the diagnosis of candida esophagitis in % of children. other risk factors include low cd count and prior antibiotic use. histopathologically, yeast forms within an intact mucosa confirm invasive disease. this is in contrast to colonization, where the yeast is found overlying intact mucosal surfaces or necrotic tissue. these organisms are best seen with grocott's methenamine silver method or periodic acid-schiff stain. upper gastrointestinal studies are suggestive of candida esophagitis with diffuse mucosal irregularities (figure - ) . upper gastrointestinal endoscopy with biopsy and appropriate staining is the most sensitive test for determining invasive candidiasis of the esophagus. candidiasis can also occur in the stomach, as well as the small bowel if the acid barrier has been suppressed either through an intrinsic decrease in gastric acid production or iatrogenically with the use of potent acid blockers. numerous effective therapies have been described to treat candida of the upper gastrointestinal tract, including fluconazole, ketoconazole, and itraconazole. , ketoconazole has more hepatic side effects than fluconazole. itraconazole is usually well tolerated and is effective. in severe and invasive disease, either topical or intravenous amphotericin can be used. agents such as oral miconazole and nystatin are not indicated for invasive candida. disseminated histoplasmosis develops in % of adult patients with aids in the midwestern region of the united states, and elsewhere. the clinical signs and symptoms related to this infection may be indolent, but left untreated can carry significant morbidity and mortality. the likelihood of disease is higher in patients with cd counts under cells/mm . there is enterocolitis associated with infection, and at colonoscopy, plaques, ulcers, pseudopolyps, and skip areas are frequently seen. cryptococcal gastrointestinal disease has been identified in patients with disseminated cryptococcus infection. the esophagus and colon are involved most frequently. p. jirovecii infection of the gastrointestinal tract has also been described. gastrointestinal pneumocystosis develops after hematogenous or lymphatic dissemination from the lungs, or reactivation of latent gastrointestinal infection. the administration of aerosolized pentamidine has increased the risk of developing extrapulmonary spread of p. jirovecii pneumonia. p. jirovecii pneumonia infection can occur throughout the gastrointestinal tract. in the lamina propria there are foamy exudates with p. jirovecii organisms found within them. although more rare, infection of the colon can also cause diarrhea. the effect of haart on rates of infection of the gastrointestinal tract are twofold. first, on a macro level, the advent of haart has led to a dramatic decrease in perinatal transmission of hiv, and therefore the rates of newly infected children have plummeted, with reports of vertical transmission falling between and %. second, haart has been successful in immune reconstitution, and therefore in regions with high haart accessibility, there has been a marked decrease in the number of hiv patients presenting with opportunistic infections. these infections have not been eradicated, but the majority of patients adhering to haart are able to achieve cd + cell reconstitution and therefore stave these off. patients who sustain chronically low cd + t lymphocyte levels in spite of haart accessibility and usage continue to be at risk for the opportunistic infections described in the previous section. when comparing incidence rates of opportunistic infection in the pre-(before january , ) and post-haart era, there was an overall decrease. , specifically: incidence rates of cmv decreased from . to . ; esophageal candidiasis from . to . ; herpes simplex virus from . to ; and chronic intestinal and cryptosporidiosis from . to per persons per year. additionally, nachman et al. reported successful withdrawal of opportunistic infection prophylaxis for a period of weeks in pediatric hiv-positive patients more than years old who had achieved cd reconstitution without significant incidence when compared to demographically matched hiv-negative patients. in light of this progress, we have integrated additional immunocompromised patient populations into our discussion of gastrointestinal vulnerabilities. colitis from c. difficile is also more common in the immunosuppressed population owing to chronic antibiotic use and impaired immune system. pulvirenti et al. studied hiv- -infected patients with c. difficile and found that they had longer hospital stays and more admissions than patients without c. difficile infection, as well as other opportunistic infections such as herpes virus. they found c. difficile-associated diarrhea in % of all study patients with diarrhea. however, infection with c. difficile appeared to have little impact on morbidity or mortality. in a , new york state screening study of hospitalized hiv- -infected patients in the haart era, . % were admitted with a diarrheal diagnosis, with . % of these having a c. difficile infection. thus, even with haart, diarrhea is prevalent and is often associated with identifiable pathogens. c. difficile infection has been reported to be one of the most common bacterial diarrheal pathogens among hiv-infected patients although its rates have decreased with haart. because of the serious complications that are associated with active bacterial enteric infections in immunodeficient children, treatment options are outlined in table - . h. pylori prevalence is not significantly different between hiv- -infected patients and hiv- -negative patients. , some investigators have found the seroprevalence of h. pylori to be lower in hiv- -infected patients, especially as cd counts decline with advancing disease. the protection from h. pylori may be a result of frequent antibiotic use or correlated with a more advanced, dysfunctional immune state that results in a decreased inflammatory response to the organism. remission of a high-grade gastric mucosa-associated lymphoid tissue (malt) lymphoma followed h. pylori eradication and haart in a patient with aids. however, a recent study of hivinfected adults showed that % of patients with peptic symptoms had h. pylori on biopsy, with those having cd counts above cells/mm at a higher risk. treatment of h. pylori in hiv- -infected children is similar to that in noninfected children, with special attention to drug interactions. in up to to % of hiv- -infected children, the etiology of the diarrhea is unclear. autonomic dysfunction is another potential mechanism of noninfectious diarrhea not previously described. clinically, children with autonomic neuropathy have sweating, urinary retention, and abnormal cardiovascular hemodynamics. it is possible that this autonomic denervation contributes to diarrhea in patients with hiv- infection, as suggested by griffin et al. when neuron-specific polyclonal antibodies were applied to jejunal biopsies, there was a significant reduction in axonal density in both villi and pericryptal lamina propria in patients with hiv- infection compared with controls, with the greatest reduction in patients with diarrhea. octreotide therapy has shown promising results in some patients. finally, drug side effects should be considered, with many of the antiretroviral therapies causing chronic diarrhea and other gastrointestinal toxicities (table - ) . motility problems of the esophagus and stomach have been reported [ ] [ ] [ ] and can be a source of upper gastrointestinal complaints including vomiting, dysphagia, nausea, and dyspepsia. the motility abnormalities may be primary, or they may be secondary to infectious or inflammatory disease of the respective organ. hypertension of the lower esophageal sphincter with incomplete relaxation, esophageal hypocontraction, and nonspecific motility disorders have been described in patients with normal intact esophageal mucosa. gastric emptying, especially in patients with infections or advanced disease, may be delayed, as documented by gastric scintigraphy. however, delayed gastric emptying does not always correlate with upper gastrointestinal symptoms or small bowel motility studies. in adults with hiv- infection and minimally advanced disease, gastric emptying of solids was delayed and emptying of liquids accelerated compared with that in controls. no abnormal esophageal motility patterns were found. all patients had a normal endoscopy prior to the motility studies. thus, in the absence of infectious and inflammatory disease in patients with appropriate symptoms, motility studies or empiric trials of prokinetic agents should be considered, with careful consideration of drug interactions. esophageal ulceration can be a result of an intercurrent opportunistic infection. idiopathic oral and esophageal ulcers have been described in both children and adults with hiv- . these ulcers are characteristically large and may be single or multiple (figure - ) . the ulcers are located in the mid to distal esophagus. controversy exists regarding the pathogenesis of these ulcers; some investigators have identified hiv- at the ulcer base, whereas others have not. treatment options for these ulcers are limited, but include steroid therapy, with encouraging results, and thalidomide. , however, chronic low-dose thalidomide does not prevent recurrence of the oral or esophageal aphthous ulcers. in addition to the potentially teratogenic effects, a significant portion of children receiving thalidomide develop a rash, which precludes use of the drug. significant caution should be exercised when using thalidomide. overall, haart has had a positive impact on esophageal disease occurrence and relapse. the diagnostic approach to the child with hiv- or other immunodeficiencies and gastrointestinal symptoms is outlined in table table - ). every effort should be made to correlate timing of the initiation of a drug with onset of symptoms. the clinician should keep in mind that children with active enteric infections may also have secondary problems with malabsorption. if the clinical history and physical examination are suspicious for malabsorption without enteric infection, the next step should include an evaluation of specific nutrient absorption. carbohydrate malabsorption can be detected through lactose breath hydrogen testing, which measures hydrogen production as a response to an oral lactose load. a raised baseline breath hydrogen or early peak of hydrogen production suggests bacterial overgrowth, and appropriate treatment can be initiated. lactose malabsorption results in a level of hydrogen production more than to parts per million over baseline, minutes after ingestion. dietary changes can then be made. d-xylose absorption testing also helps to determine the absorptive capacity of the gastrointestinal tract. d-xylose is an absorbable sugar that does not require active transport for uptake by enterocytes. thus, the d-xylose serum level, after administration of a test dose, reflects the absorptive ability of the gastrointestinal tract and the integrity of the mucosal surface. in younger children, the administered dose is . g per kg bodyweight, given orally after an overnight fast. in older children and adolescents, the maximum dose is g. a serum level is obtained hour after ingestion. urine samples may be obtained for hours after ingestion as well. plasma citrulline levels correlate with enterocyte mass and function and may be used to indicate gastrointestinal function. fat malabsorption is determined by a -hour fecal fat collection. a high-fat diet is administered several days before the collection is initiated and throughout the collection period. an alternative method is to keep a dietary fat intake record during the period of fecal fat collection. the stool is analyzed for total fat content, and the fecal fat is compared with the amount ingested; a coefficient of fat absorption is then calculated. ten percent or more of ingested fat in the stool is considered abnormal. alternatively, a sudan stain may be performed on a random stool sample. this may be helpful as a quick test for fat malabsorption, although it is not so reliable. quantification of fecal elastase may help to determine whether the fat malabsorption is pancreatic in origin. lastly, raised fecal α -antitrypsin levels suggest protein loss from the gut. if noninvasive studies, such as those described above, are not helpful in documenting and determining the etiology of the malabsorption, diarrhea, or vomiting, endoscopy (either upper or lower) with biopsy and appropriate culture of fluid may be useful. miller et al. confirmed histologic abnormalities in % of children undergoing upper endoscopy. in % of patients in this series, the clinical management of the child was changed because of the endoscopic evaluation. a high diagnostic yield has been supported by other investigators. specific gastrointestinal symptoms are not predictive of abnormal findings at endoscopy; advanced hiv- disease stage and an increased number of symptoms seem to be more predictive. histologic studies of the small bowel may aid in determining the degree of the villous blunting, and electron microscopy and special staining for opportunistic pathogens can be performed. quantitative bacterial cultures and parasite evaluation of the duodenal fluid should be obtained when an endoscopy is performed. characteristically, the detection of more than organisms per milliliter of duodenal fluid confirms bacterial overgrowth. it is important to obtain both anaerobic and quantitative cultures. however, other studies have shown that endoscopy does not improve the diagnostic yield compared with stool examination in patients with intestinal infection. the only exception is the diagnosis of cmv. an additional study found that flexible sigmoidoscopy was as useful as a full colonoscopy for diagnosing infection. special histologic stains for fungal, mycobacterial, or viral infections did not increase the diagnostic yield over routine hematoxylin and eosin staining. treatment for intestinal infections has been outlined in table - and previous sections. therapy for gastrointestinal malabsorption should be directed toward the underlying diagnosis. if clinically symptomatic lactose malabsorption is found, a lactose-free diet should be initiated. compliance may be difficult, because many foods contain lactose. children can limit the effects of dietary lactose by taking exogenous lactase or using lactase-treated milk. there should be careful consideration of calcium and vitamin d intake, because children with hiv- infection are susceptible to low bone mineral density. [ ] [ ] [ ] if there is malabsorption of protein and fat, a protein hydrolysate diet should be tried. many of these supplements are poorly tolerated because they are unpalatable. in some circumstances, specialized supplements may need to be administered through a supplemental feeding tube. , peptic and motility disorders can be treated as in other, non-hiv- -infected children, paying careful attention to potential drug interactions with antiretroviral regimens. a variety of other disorders (table - ) can cause secondary immunodeficiencies with effects on the gastrointestinal tract. overall, these disorders are more prevalent than either primary or hiv- -associated immunodeficiencies. premature infants, children with cancer and associated exposure to immunosuppressant and cytotoxic medications (including children with graft-versus-host disease), and children with protein-losing enteropathy with associated loss of immunoglobulins from the gastrointestinal tract can all be immunodeficient because of the underlying disorder. in general, children with these immunodeficiencies are at risk for many of the same complications that are experienced by children with hiv- infection. gastrointestinal tract infections are among the most common problems facing children with other secondary immunodeficiencies. malnutrition is the most common cause of immunodeficiency worldwide. nutritional status and immunity have long been linked in many disease states. before hiv- was described, p. carinii (now jirovecii) pneumonia and kaposi's sarcoma, known opportunistic diseases, were first described in otherwise healthy, but malnourished, children and adults in developing nations. , this association led investigators to conclude that nutrition alone can affect the immunologic response of an individual. in malnourished children there is a profound involution of lymphoid tissues, including thymic atrophy and diminished paracortical regions of lymph nodes. in young infants and children, protein-calorie malnutrition increases the risk of death by severalfold by increasing the susceptibility to infection. in many countries, the mortality rate increases from . % in children whose weight-for-height percentage of standard is greater than %, to % in children whose weight-for-height percentage of standard is less than %. in other diseases such as cystic fibrosis and cancer, nutritional status has been linked closely to survival and morbidity. malnourished children with leukemia and lymphoma have a higher risk of p. jirovecii pneumonia than children who have normal nutrition. biochemically, protein-calorie malnutrition leads to changes in several aspects of the immune system. cell-mediated immunity, microbial function of phagocytes, complement systems, secretory antibodies, and antibody affinity are consistently impaired in patients with significant malnutrition. additionally, deficiencies of micronutrients, especially zinc and iron, as well as many others, may also have deleterious effects on the immune system. other aspects of immunity that are altered by proteincalorie malnutrition include impaired chemotaxis of neutrophils, decreased lysozyme levels in serum and secretions, and interferon production in antibody response to t-cell-dependent antigens. a child with protein-calorie malnutrition may also have impaired mucosal immunity with lowered concentrations of secretory iga in saliva, nasopharynx, tears, and the gastrointestinal tract compared with well-nourished control children. similar to children and adults with hiv- infection, patients with malnutrition have depressed t-cell function not only in the peripheral circulation but also in the intestinal tract. subsequently, plasma cell function and macrophage activity may be impaired, leading to more frequent intestinal infections in children with severe protein-calorie malnutrition. not only does nutrition improve the immunologic functioning of the intestinal tract, but nutrients themselves are trophic and essential for the maintenance of the absorptive capacity of the intestines. in some studies, weight loss greater than %, due to other disorders, is associated with a reduction in pancreatic enzyme secretion of over %, villous atrophy, and impaired carbohydrate and fat absorption. these disorders are promptly reversed with appropriate nutritional rehabilitation. with villous blunting, antigen uptake can increase, leaving the child at higher risk of enteric infection. the pathogenesis of villous blunting is unclear but may be due to crypt hyperplasia as the primary event with premature sloughing at the villus tip versus loss of enterocytes at the villus tip with resultant proliferation at the crypts. malnutrition and its associated immunodeficiency are of global concern, and researchers have experimented with both dietary regimens and micronutrient supplementation to improve, and perhaps ultimately restore, adequate immunological function. , because of the low cost of many micronutrients when compared to pharmacological agents, success in such experimentation could have profound implications for those suffering from malnutrition, as well as other immunocompromised patients. zinc is accepted as a promoter of immune function and consequently has been evaluated in hiv- immunocompromised patients. in a south african study that treated patients with mg of zinc (elemental) daily for months and compared them to a control group receiving a placebo, there was a significant difference in patient presentation of diarrhea favoring zinc supplementation. further demonstrating its potential alleviatory effects, canani et al. observed that the transactivating peptide's (tat) secretory mechanism was inhibited by zinc and subsequently prevented diarrhea in pediatric hiv- patients. both of these positive outcomes, although documented in hiv- patients, present zinc as an additional treatment option for symptoms of malnutrition-related immunodeficiency. some studies have administered multivitamins to hiv- patients including adults and children and evaluated effects of specific micronutrients. adequate levels of vitamin a, when bolstered by supplementation in hiv- positive and hiv- negative children older than months, correlated with reduced mortality and morbidity. although not yet well-documented in children, multivitamin intake of hiv- positive adults demonstrated retarded progression of the virus. improved hematologic status, mainly decreased rates of anemia, was observed in women and their children in tanzania who were treated with iron supplements during and after pregnancy. this was marked by an average hemoglobin count that was . g/dl greater than that of the patient group who did not receive multivitamin treatment. these findings underscore the need for additional randomized control trials in pediatric populations to further understand the role of micronutrient supplementation as a complimentary treatment component. immunosuppressant medications are the mainstay of therapy for many diseases in children with autoimmune disorders, inflammatory bowel disease, chronic pulmonary disease, cancer, and organ transplantation. the best known immunosuppressants include corticosteroids, azathioprine, cyclosporin, tacrolimus, and anti-thymocyte globulin. unfortunately, the effects of these medications are not targeted toward specific organs, but rather indiscriminately suppress immune function throughout the child. thus, several immunologic functions including a decrease in monocyte adherence, neutrophil chemotaxis, and overall suppression of the inflammatory response are present. children are at risk of enteric infections, similar to those described in children with hiv- infection. pediatric patients undergoing transplant procedures, specifically solid organ transplant, are at increased risk of acquiring gastrointestinal infections when compared to their healthy counterparts. acutely, these complications present with vomiting, diarrhea, and cramping. the most frequently diagnosed posttransplant infection is cmv, [ ] [ ] [ ] but its onset has been reduced significantly with the administration of prophylactic drugs such as ganciclovir. [ ] [ ] [ ] [ ] another aspect of the gastrointestinal tract that renders importance in secondary immunodeficiency is the liver. although data regarding liver complications in pediatric hiv- patients are lacking, there are considerable reports on hiv- infected adults. hepatitis coinfection, biliary tract disease, and drugderived illness are some of the major complications we discuss in this section. liver complications in secondary immunodeficiency, in their own right, deserve extensive coverage beyond the scope of this chapter, and so this section offers only a snapshot of this complex topic. both hepatitis and hiv infections share similar transmission pathways, and for this reason, it is not surprising that rates of viral coinfections are considerable. hepatitis a is often thought of as the less serious of the hepatitis viruses when treated promptly, and coinfection with hiv does not seem to predispose an individual to adverse outcomes. in , coinfection rates of hepatitis b were reported to be between and % in the global hiv population. prolonged hepatitis b infection is one of the greatest concerns of for coinfected patients. hepatitis b virus e antigen (hbeag) is the protein associated with active hepatitis b in patients and is used by clinicians to determine efficacy of medications. for monoinfected hepatitis b patients, proper treatment can result in significant reduction of hbeag in to % of patients; however, this success is not mirrored in hiv-coinfected populations. there is also evidence for greater reactivation and replication in hepatitis b-hiv coinfected patients. , [ ] [ ] [ ] explanation for this focuses on hiv patients' increased proinflammatory cytokine production and their inability to eliminate hepatocytes infected with hepatitis b. , balancing dual treatment for both hepatitis b and hiv viruses presents a unique challenge for clinicians. acquired mutations of hepatitis b render additional treatment considerations, deepening the challenge. resistant hepatitis b strains have been identified, many of them falling under the tyrosine-methionine-aspartate-aspartate category, ymdd. iacomi et al. determined that of hepatitis b-hiv coinfected patients exhibited this specified resistance. lamivudine, once commonly prescribed, has become less effective because of developed resistance. of the various treatment options, only tenofovir is used in hiv treatment and is effective in both the wild-type hepatitis b virus and the resistant ymdd strain, and it is often concomitantly administered with emtricitabine. , mothers coinfected with hepatitis c and hiv are more likely to transmit hiv to their children, indicating greater risk of perinatal transmission in coinfected patients. , liver disease in coinfected patients may be accelerated when compared to their monoinfected counterparts. pathways that have been proposed to accelerate fibrosis in coinfected patients include direct viral effects, dysregulation of the immune system toward a profibrotic state, and other metabolic pathways that lead to liver toxicity and processes such as steatosis and insulin resistance. giovaninni et al. studied hiv-infected children, of whom were coinfected with hepatitis c. six of the coinfected patients had abnormal alanine aminotransferase (alt) levels. three of the six children had aids, and three had aids-related complex. five children with normal aminotransferase had no detectable viral progression. following acute hepatitis c infection, hepatitis c-hiv coinfected patients are over % more likely than monoinfected patients to develop chronic hepatitis c infection. [ ] [ ] [ ] interferon with ribavirin therapy is widespread in chronic hepatitis-c monoinfected patients, and its efficacy in hepatitis c-hiv coinfected patients is yet to be fully realized. , when compared to conventional interferon therapy (ifnα- a), μg/week pegylated interferon (pegifnα- a) plus mg/day ribavirin demonstrated enhanced histological effects that were also associated with improved virological response in hepatitis c-hiv coinfected patients. end-stage liver failure, cirrhosis, and hepatocellular carcinoma have been observed with greater frequency in hepatitis c-hiv coinfected patients. these findings reflect adult populations and may or may not be indicative of outcomes in pediatric patients. children with acute biliary tract disease may present with rightsided abdominal pain, vomiting, and jaundice. also, elevated serum bile levels may induce pruritus. despite a disproportionate increase in alkaline phosphatase levels, alt levels may or may not be elevated. an ultrasound of the biliary system may be needed when serum sampling is equivocal. biliary tract disease is often obstructive; thus, use of endoscopic retrograde cholangiopancreatography (ercp) will help to identify the obstruction, perhaps provide bile sampling, and even mitigate the obstruction via sphincterotomy. bile sampling may indicate the presence of cmv, cryptosporidium, mycobacterium, or microsporidia, which were all discussed in previous sections. in one study employing sonography, of hiv-infected children displayed hepatobiliary abnormalities, yet there was no evidence of infection. aids cholangiopathy is defined by intraand extrahepatic sclerosing cholangitis and is commonly linked to cmv and cryptosporidium infections. incidence in pediatric hiv populations remains to be thoroughly evaluated. the advent of haart, as discussed previously, has had profound effects on reducing many infections within the gastrointestinal tract. in the liver, however, there has been a negative association between receipt of antiretroviral therapy and development of liver complications, defined as immune restoration hepatitis. serum alt elevation is associated with liver tissue damage and therefore is used to detect liver disease. hepatitis-hiv patients on haart present with elevated alt levels in the blood principally derived from haart-induced hepatotoxicity, resistance to antiretrovirals, and haart noncompliancy. specifically, mitochondrial damage has been implicated as a contributor to liver death, which stems from coinfection and drug treatments. , current research aims to determine effective methodology for detecting hepatic mitochondrial toxicity as a means to identify patients at risk of developing liver complications due to treatment. gastrointestinal disorders in children with secondary immunodeficiencies cause considerable comorbidity. infection of the gastrointestinal tract is one the most common complications associated with secondary immunodeficiencies. however, malabsorption, peptic disease, and liver and biliary tract disease are also prevalent. these gastrointestinal complications contribute negatively to the overall clinical outcomes of children who have other chronic medical conditions, and they can often become life-threatening. thus, clinicians should be vigilant and aggressive in the evaluation and treatment of gastrointestinal tract dysfunction in children with secondary immunodeficiencies. incidence of opportunistic and other infections in hiv-infected children in the haart era microbial translocation is a cause of systemic immune activation in chronic hiv infection ritonavir combination therapy restores intestinal function in children with advanced hiv disease plasma citrulline is a biomarker of enterocyte mass and an indicator of parenteral nutrition in hiv-infected patients interactions of nutrition and infection coinfection with hiv- and hcv -a one-two punch see expertconsult.com for a complete list of references and the review questions for this chapter reduction of maternal-infant transmission of human immunodeficiency virus type with zidovudine treatment. pediatric aids clinical trials group protocol study group nutrition, child growth, and chronic disease prevention frequent detection and isolation of cytopathic retroviruses (htlv-iii) from patients with aids and at risk for aids aids epidemic update prevention of perinatal hiv transmission: a review of novel strategies efficacy of highly active antiretroviral therapy in hiv- infected children incidence of opportunistic and other infections in hiv-infected children in the haart era cd + t cell depletion during all stages of hiv disease occurs predominantly in the gastrointestinal tract primary hiv- infection is associated with preferential depletion of cd + t lymphocytes from effector sites in the gastrointestinal tract viral suppression and immune restoration in the gastrointestinal mucosa of human immunodeficiency virus type -infected patients initiating therapy during primary or chronic infection gastrointestinal tract as a major site of cd + t cell depletion and viral replication in siv infection transient high levels of viremia in patients with primary human immunodeficiency virus type infection a controlled trial of zidovudine in primary human immunodeficiency virus infection prognosis in hiv- infection predicted by the quantity of virus in plasma mycobacterium avium complex augments macrophage hiv- production and increases ccr expression cytomegalovirus induction of tumor necrosis factor-alpha by human monocytes and mucosal macrophages recruitment of hiv and its receptors to dendritic cell-t cell junctions replication of hiv- in dendritic cell-derived syncytia at the mucosal surface of the adenoid dc-sign, a dendritic cellspecific hiv- -binding protein that enhances trans-infection of t cells dendritic cells exposed to human immunodeficiency virus type- transmit a vigorous cytopathic infection to cd + t cells infection of colonic epithelial cell lines by type human immunodeficiency virus is associated with cell surface expression of galactosylceramide, a potential alternative gp receptor transcytosis of infectious human immunodeficiency virus across a tight human epithelial cell line barrier primary intestinal epithelial cells selectively transfer r hiv- to ccr + cells lamina propria lymphocytes, not macrophages, express ccr and cxcr and are likely target cell for hiv- in the intestinal mucosa biological parameters of hiv- infection in primary intestinal lymphocytes and macrophages gastrointestinal tract as a major site of cd + t cell depletion and viral replication in siv infection peripheral monocyte and naive t-cell recruitment and activation in crohn' s disease lack of decay of hiv- in gutassociated lymphoid tissue reservoirs in maximally suppressed individuals rapid mucosal cd + t-cell depletion and enteropathy in simian immunodeficiency virus-infected rhesus macaques human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity macrophage functions in hiv- infection hiv- envelope protein binds to and signals through integrin α β , the gut mucosal homing receptor for peripheral t cells macrophage hiv- infection and the gastrointestinal tract reservoir microbial translocation is a cause of systemic immune activation in chronic hiv infection disease progression: immune activation, microbes, and a leaky gut evidence that activated mucosal t cells play a role in the pathogenesis of enteropathy in human small intestine enteropathy associated with the acquired immunodeficiency syndrome small intestinal structure and function in patients infected with human immunodeficiency virus (hiv): evidence for hiv-induced enteropathy rapid onset of intestinal epithelial barrier dysfunction in primary human immunodeficiency virus infection is driven by an imbalance between immune response and mucosal repair and regeneration endoscopy of the upper gastrointestinal tract as a diagnostic tool for children with human immunodeficiency infection intestinal inflammation, ileal structure and function in hiv small intestinal human immunodeficiency virus-associated enteropathy: evidence for panintestinal enterocyte dysfunction intestinal absorptive capacity, intestinal permeability and jejunal histology in human immunodeficiency virus and their relation to diarrhea intestinal disaccharidase activity in human immunodeficiency disease lack of correlation between diarrhea and weight loss in hiv-positive outpatients in houston, tx the prevalence and severity of intestinal disaccharidase deficiency in human immunodeficiency virusinfected subjects malnutrition and carbohydrate malabsorption in children with vertically-transmitted human immunodeficiency virus- infection italian paediatric intestinal/hiv study group. intestinal malabsorption of hiv-infected children: relationship to diarrhoea, failure to thrive, enteric microorganisms and immune impairment gastrointestinal-dysfunction and disaccharide intolerance in children infected with human immunodeficiency virus association between steatorrhea, growth, and immunologic status in children with perinatally acquired hiv infection pancreatic dysfunction and its association with fat malabsorption in hiv infected children loss of cd t lymphocytes in patients infected with human immunodeficiency virus type is more pronounced in the duodenal mucosa than in the peripheral blood inhibitory effect of hiv- tat protein on the sodium-d-glucose symporter of human intestinal epithelial cells intestinal mucosal inflammation associated with human immunodeficiency virus infection gastropathy and ketoconazole malabsorption in the acquired immunodeficiency syndrome (aids) intestinal infections in patients with the acquired immunodeficiency syndrome (aids): etiology and response to therapy no relationship between gastric ph, small bowel bacterial colonisation, and diarrhoea in hiv- infected patients enteric pathogens associated with gastrointestinal dysfunction in children with hiv infection declining prevalence of opportunistic gastrointestinal disease in the era of combination antiretroviral therapy impairment of the intestinal barrier is evident in untreated but absent in suppressively treated hivinfected patients ritonavir combination therapy restores intestinal function in children with advanced hiv disease hiv-related diarrhea is multifactorial and fat malabsorption is commonly present, independent of haart declining prevalence of opportunistic gastrointestinal disease in the era of combination antiretroviral therapy cd counts and enteric infections in a community-based cohort of hiv-infected adults in uganda demonstration of varicella-zoster virus infection in the muscularis propria and myenteric plexi of the colon in an hiv-positive patient with herpes zoster and small bowel pseudoobstruction (ogilvie' s syndrome) laboratory diagnosis of cytomegalovirus (cmv) infections in immunodepressed patients, mainly in patients with aids cytomegalovirusassociated manifestations involving the digestive tract in children with human immunodeficiency virus infection massive lower gastrointestinal hemorrhage caused by cmv disease as a presentation of hiv in an infant viruses causing diarrhoea in aids the histopathology of consecutive colonoscopy biopsies from symptomatic patients with acquired immunodeficiency syndrome: original and look-back diagnoses shorter survival in hiv-positive patients with diarrhoea who excrete adenovirus from the gi tract enteric viruses and diarrhea in hiv-infected patients detection of picobirnavirus in hiv-infected patients with diarrhea in argentina enteric viruses associated with hiv infection in tanzanian children with chronic diarrhea association of gastric hypoacidity with opportunistic enteric infections in patients with aids non-typhoidal salmonella bacteraemia among hiv-infected malawian adults: high mortality and frequent recrudescence enteric and disseminated campylobacter species infection during hiv disease: a persisting but significantly modified association in the haart era diarrheogenic bacterial enteritis in acquired immunodeficiency syndrome: a light and electron microscopy study of cases chronic bacterial enteropathy in patients with aids incidence of mycobacterim avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients impact of opportunistic disease on survival in patients with hiv infection opportunistic diseases incidence and survival in aids patients who experienced very low cd + cell counts in the protease inhibitors era (tupe ) low incidence of colonization and no cases of disseminated mycobacterium avium complex infection (dmac) in brazilian aids patients in the haart era severe gastrointestinal hemorrhage due to mycobacterium avium complex in a patient receiving immunosuppressive therapy focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced hiv- disease treatment of mycobacterium avium complex immune reconstitution disease in hiv- -infected individuals immune restoration disease after the treatment of immunodeficient hiv-infected patients with highly active antiretroviral therapy a randomized, double-blind trial comparing azithromycin and clarithromycin in the treatment of disseminated mycobacterium avium infection in patients with human immunodeficiency virus risk-benefit assessment of therapies for mycobacterium avium complex infections epidemiology and clinical features of cryptosporidium infection in immunocompromised patients intestinal and systemic infection, hiv, and mortality in zambian children with persistent diarrhea and malnutrition enterocytozoon, and cyclospora infections in pediatric and adult patients with diarrhea in tanzania acute enterocolitis in a human being infected with the protozoon cryptosporidium overwhelming watery diarrhea associated with a cryptosporidium in an immunosuppressed patient a preliminary study of the prevalence of intestinal parasites in immunocompromised patients with and without gastrointestinal manifestations diarrhea and gallbladder hydrops in an immunocompetent child with cryptosporidium infection pancreatitis caused by cryptosporidium parvum in patients with severe immunodeficiency related to hiv infection a massive outbreak in milwaukee of cryptosporidium infection transmitted through the public water supply esophageal cryptosporidiosis in a child with acquired immune deficiency syndrome variation in the enteric distribution of cryptosporidia in acquired immunodeficiency syndrome intestinal function and injury in acquired immunodeficiency-related cryptosporidiosis asymptomatic carriage of intestinal cryptosporidium in immunocompetent and immunodeficient children: a prospective study cryptosporidium and isospora belli infection successful management of intractable cryptosporidial disease with intravenous octreotide, a somatostatin analogue eradication of cryptosporidia and microsporidia following successful antiretroviral therapy rapid increase of mucosal cd t cells followed by clearance of intestinal cryptosporidiosis in an aids patient receiving highly active antiretroviral therapy resolution of cryptosporidium infection in an aids patient after improvement of nutritional and immune status with octreotide treatment with hyperimmune colostrum of cryptosporidial diarrhea in aids patients cessation of cryptosporidiumassociated diarrhea in an acquired immunodeficiency patient after treatment with hyperimmune bovine colostrum azithromycin therapy for cryptosporidium parvum infection in children infected with hiv azithromycin as treatment for cryptosporidiosis in human immunodeficiency virus disease effect of antiretroviral protease inhibitors alone, and in combination with paromomycin, on the excystation, invasion and in vitro development of cryptosporidium parvum prevention and treatment of cryptosporidiosis in immunocompromised patients microsporidia: opportunistic pathogens in patients with aids occurrence of a new microsporidian: enterocytozoon bieneusi n.g., n. sp., in the enterocytes of a human patient with aids intestinal microsporidiosis as a cause of diarrhea in human immunodeficiency virus infected patients: a report of cases intestinal microsporidiosis in human immunodeficiency virus-infected patients with chronic unexplained diarrhea: prevalence and clinical and biologic features prevalence of microsporidiosis due to enterocytozoon bieneusi and enterocytozoon (septata) intestinalis among patients with aids-related diarrhea: determination of polymerase chain reaction to the microsporidian small-subunit rrna gene prevalence of intestinal microsporidia in hivinfected individual referred for gastroenterological evaluation intestinal microsporidiosis in hiv-infected children with diarrhea enterocytozoon bieneusi among children with diarrhea attending mulago hospital in uganda diagnostic pathology of microsporidiosis potential efficiency of funagillin in intestinal microsporidiosis due to enterocytozoon bieneusi in patients with hiv infection: results of a drug screening study np is an effective antimicrosporidial agent effects of albendazole, fumagillin and tnp- on microsporidial replication in vitro atovaquone is effective treatment for the symptoms of gastrointestinal microsporidiosis in human immunodeficiency virus- infected patients therapy for human gastrointestinal microsporidiosis effect of antiretroviral therapy on cryptosporidiosis and microsporidiosis in patients infected with human immunodeficiency virus type trimethoprimsulfamethoxazole compared with ciprofloxacin for treatment and prophylaxis of isospora belli and cyclospora cayetanensis infection in hiv-infected patients. a randomized, controlled trial isospora belli infection: treatment with pyrimethamine etiologies of acute, persistent, and dysenteric diarrheas in adults in bangui, central african republic, in relation to human immunodeficiency virus serostatus esophageal candidiasis in pediatric acquired immunodeficiency syndrome: clinical manifestations and risk factors treatment of fluconazole-refractory oropharyngeal candidiasis with itraconazole oral solution in hivpositive patients safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis gastrointestinal histoplasmosis in patients with aids: case report and review disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature systematic review of the efficacy of antiretroviral therapies for reducing the risk of mother-to-child transmission of hiv infection antiretrovirals for reducing the risk of mother-to-child transmission of hiv infection pediatric aids clinical trials group protocol c team. risk factors for opportunistic illnesses in children with human immunodeficiency virus in the era of highly active antiretroviral therapy trends in opportunistic infections in the pre-and post-highly active antiretroviral therapy eras among hiv-infected children in the perinatal aids collaborative transmission study the rate of serious bacterial infections among hiv-infected children with immune reconstitution who have discontinued opportunistic infection prophylaxis medical diagnoses and procedures associated with clostridium difficile colitis epidemiology and outcome of clostridium difficile infection and diarrhea in hiv infected inpatients hiv and diarrhea in the era of haart: new york state hospitalizations adult/adolescent spectrum of hiv disease study group. bacterial diarrhea in persons with hiv infection prevalence of helicobacter pylori and endoscopic findings in hiv seropositive patients with upper gastrointestinal tract symptoms at kenyatta national hospital helicobacter pylori in indian hiv infected patients helicobacter pylori infection in an urban african population decreased prevalence of helicobacter pylori infection in hiv patients with aids defining diseases remission of a highgrade gastric mucosa associated lymphoid tissue (malt) lymphoma following helicobacter pylori eradication and highly active antiretroviral therapy in a patient with aids dyspepsia in hiv-infected patients under highly active antiretroviral therapy damage to jejunal intrinsic autonomic nerves in hiv infection effect of octreotide on small intestinal motility in hiv-infected patients with chronic refractory diarrhea delayed gastric emptying in hu man immunodeficiency virus infection: correlation with symptoms, autonomic function, and intestinal motility esophageal motility disorders in hiv patients disturbed gastric motor activity in patients with human immunodeficiency virus infection idiopathic giant esophageal ulcer in an hiv-positive child chronic idiopathic esophageal ulceration in the acquired immunodeficiency syndrome, characterization and treatment with corticosteroids esophageal ulceration in human immunodeficency virus infection use of thalidomide in treatment and maintenance of idiopathic esophageal ulcers in hiv+ individuals thalidomide for the treatment of esophageal aphthous ulcers in patients with human immunodeficiency virus infection. national institute of allergy and infectious disease aids clinical trials group thalidomide in low intermittent doses does not prevent recurrence of human immunodeficiency virus-associated aphthous ulcers natural history of hiv-associated esophageal disease in the era of protease inhibitor therapy plasma citrulline is a biomarker of enterocyte mass and an indicator of parenteral nutrition in hiv-infected patients symptom-specific use of upper gastrointestinal endoscopy in human immunodeficiency virus-infected patients yields high dividends enteric infections and diarrhea in human immunodeficiency virus-infected persons: prospective community-based cohort study. swiss hiv cohort study a prospective study of endoscopy in hiv-associated diarrhea special histologic stains are rarely beneficial for the evaluation of hiv-related gastrointestinal infections predictors of bone mineral density in human immunodeficiency virus- infected children decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus alterations in circulating osteoimmune factors may be responsible for high bone resorption rate in hivinfected children and adolescents gastrostomy tube supplementation for hiv-infected children effect of enteral tube feeding on growth of children with symptomatic human immunodeficiency virus infection immunocompetence of nutritional disorders epidemiologic aspects of the current outbreak of kaposi' s sarcoma and opportunistic infection nutrition, immunity and infection: mechanisms of interactions interactions of nutrition and infection protein-calorie malnutrition: a host determinant for pneumocystis carinii infection nutrition and gastrointestinal disease the gut in malnutrition the enterocyte in celiac disease nutrition and hiv/aids in infants and children in south africa: implications for food-based dietary guidelines micronutrient supplementation in children and adults with hiv infection safety and efficacy of zinc supplementation for children with hiv- infection in south africa: a randomised double-blind placebo-controlled trial zinc fights diarrhoea in hiv- -infected children: in-vitro evidence to link clinical data and pathophysiological mechanism studies of vitamins and minerals and hiv transmission and disease progression multivitamin supplementation improves hematologic status in hiv-infected women and their children in tanzania immunocompromised hosts: perspectives in the treatment and prophylaxis of cytomegalovirus disease in solidorgan transplant recipients current management strategies for the prevention and treatment of cytomegalovirus infection in pediatric transplant recipients ganciclovir: an update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients safety and efficacy of prolonged cytomegalovirus prophylaxis with intravenous ganciclovir in pediatric and young adult lung transplant recipients hepatitis b in the hiv-coinfected patient hepatitis b or hepatitis c and human immunodeficiency virus infection influence of hiv infection on the response to interferon therapy and the long-term outcome of chronic hepatitis b effect of duration of hepatitis b virus infection on the association between human immunodeficiency virus type- and hepatitis b viral replication hepatitis b virus infection in the acquired immunodeficiency syndrome adolescent human immunodeficiency virus infection and gastrointestinal disease effect of hiv co-infection on mutation patterns of hbv in patients with lamivudine-resistant chronic hepatitis hepatitis b in hiv patients: what is the current treatment and what are the challenges? diagnosis and management of hepatitis b virus and hiv coinfection hepatitis c in patients with human immunodeficiency virus infection: diagnosis, natural history, meta-analysis of sexual and vertical transmission, and therapeutic issues maternal-infant transmission of hepatitis c virus and hiv infections: a possible interaction coinfection with hiv- and hcv -a one-two punch hiv and hepatitis c coinfection protection against persistence of hepatitis c the natural history of hepatitis c virus infection: host, viral, and environmental factors ribavirin in the treatment of chronic hepatitis c peginterferon-α- a ( kd) plus ribavirin: a review of its use in hepatitis c virus and hiv co-infection histological response to pegifnα- a ( kd) plus ribavirin in hiv-hepatitis c virus co-infection hepatobiliary abnormalities on sonography in children with hiv infection hiv and chronic hepatitis: co-infection with hiv and hepatitis b virus infection disease-and treatment-related predictors of hepatic mitochondrial dysfunction in chronic hiv infection assessed by non-invasive c-methionine breath test diagnostic alteration of cytochrome oxidase subunit i labeling is associated with severe mitochondropathy in nrti-related hepatotoxicity in hiv patients key: cord- -fp khzd authors: bonatz, k.; weiss, a.; hehlmann, r.; aßmus, h. -p.; heine, m. title: gram-negative bacterial pneumonia with secondary aspergillosis in an aids patient date: journal: klin wochenschr doi: . /bf sha: doc_id: cord_uid: fp khzd a -year-old, hiv-infected female patient received antibiotic treatment for a urinary tract infection. after the initial success of therapy and a symptom-free period, she developed pneumonia with septic shock and adult respiratory distress syndrome (ards). in spite of intensive care and respirator therapy with positive end-expiratory pressure (peep), she died of infectious toxic shock. autopsy findings showed relapsing, gramnegative, bacterial pneumonia (morphologically compatible with klebsiella pneumonia) and secondary, invasive aspergillosis. the pathogenesis and epidemiology of these unusual complications of aids are discussed. (cd ) lymphocytes (ll /gl, cd -cd ratio . ). the white blood count was ad with normal absolute lymphocyte count, the hemoglobin was . g/dl, and the platelet count, /gl. the patient refused zidovudine therapy because she feared the side effects of the drug; she was followed as an outpatient over the next year. in april , she observed transient fever associated with nocturnal sweats, weight loss, productive cough, and low back pain. physical examination on admission revealed diffuse crackles in both lungs. the heart sounds were normal. bilateral cervical and inguinal lymphadenopathy was present, with lymph nodes up to cm in diameter. pain in the left kidney was provocable. gynecological examination including cervical smear revealed signs of florid endometritis. abdominal ultrasound showed normal kidneys, hepatic steatosis, and slight splenomegaly. the chest radiograph was normal. the urine sediment contained leukocytes, bacteria, and epithelial cells. urine cultures grew enterococcus. hemoglobin measured l l. g/dl; white cell count, /gl; platelet count, / gl; helper lymphocytes, /pl; and cd -cd ratio, . . virus serology and cultures of spinal fluid and sputum were negative. serological tests for candida albicans (i : , iha) and aspergillus fumigatus ( : , iha) were not significant. the genitourinary tract infection responded clinically to treatment with oral cerfuroxime. on day a fever of ~ c reappeared, and cerfuroxime was replaced by intravenous teicoplanin because the urine isolate was multiresistant. we did not find a new focus, either by abdominal ultrasound, echocardiography, and chest radiograph, or by blood and spinal fluid cultures. in light of a rapidly downhill course with septic temperatures, teicoplanin was discontinued and intravenous ciprofloxacin was started on day , without effect. on day , imipenem was added to the treatment. at this juncture the patient developed the radiological signs of bilateral atypical pneumonia. she received an additional high-dose treatment with intravenous trimethoprim-sulfamethoxazole at mg per day in divided doses to include pneumocystis carinii in our spectrum. the further course was towards septic shock with manifestations of ards. on day the patient was intubated and treated by intensive care and controlled mechanical ventilation with peep. as we could not yet exclude p. carinii pneumonia, we administered methylprednisolone i.v., initially g per day, in rapidly reduced doses over days. disseminated intravascular coagulation and beginning acute renal failure due to the septicemia were reversed by appropriate therapy. for the respiratory infection we added ganciclovir to cover cytomegalovirus. serologically we did not see any change in virus antibody tests. p. carinii could not be isolated from tracheal specimens, and blood cultures were repeatedly sterile. bronchoalveolar lavage was not performed because of the unstable cardiopulmonary status (arterial po of mm hg during ventilation with % , severe arterial hypotension despite catecholamines). after weeks the infiltrates cleared and the respiratory status improved temporarily. the patient's last days were again marked by increasing temperatures and uncharacteristic cerebral symptoms (pupils unequal in size). neurologic examination gave evidence of a grade ii etiologically unclear bulbar lesion. tracheal cultures yielded enterococcus and staphylococcus. we observed candida growth in the urinary and gastrointestinal tracts and administered amphotericin b by the vesical and gastric catheters. on day of the respirator therapy, stomach secretions grew aspergillus fumigatus one time. we did not find a serum antibody response to aspergillus at this time or days later. cultures of stomach secretions and days later confirmed candida, but not aspergillus growth. candida igm tests turned positive, and finally candida was also isolated from tracheal specimens. subsequent chest radiographs showed new infiltrations in both mid-lung fields. we added intravenous miconazole to the treatment. the patient died after days of respirator therapy. a survey of the treatment and the course of the patient's body temperature is given in figure . the leukocyte counts are shown in table . autopsy examinations revealed generalized atrophic lymph nodes. the lungs presented the aspect of superinfected shock lung with multiple pneumonic infiltrations in all lobes; in addition, pulmonary infarctions with microabscess formation were found. brain sections showed frontal and occipital abscess formations up to cm in diameter. microscopic examination ;confirms advanced hiv-associated lymphadenopathy. the macrophagocytic alveolar exudate reveals a few cells and fibrin as well as gram-negative bacteria, corresponding to the morphological picture of klebsiella pneumonia. the pulmonary infarctions demonstrate invasion of organisms characteristic of aspergillus species. furthermore, the lungs show evidence of protracted shock lung, with hyaline membranes and reparative proliferation of pneumocytes (figs. , ) . some of the cerebral abscesses are due to aspergillosis through vascular invasion (fig. ) . the cause of death was septic and infectious shock with polyorganic failure. differential diagnosis of fever in hiv patients primarily involves the consequences of the impaired cell-mediated immunity which characterizes aids. humoral immunity is also altered in aids due to lack of b cell differentiation, resulting in reduced responses to new antigenic stimuli. moreover, macrophage function is impaired and neutrophils from patients with advanced hiv infection show decreased chemotaxis, phagocytosis, and bacterial killing -factors that contribute to an increased rate of bacterial infections. a significant factor in the death of these patients, at % is bacterial pneumonia [ , ] , most commonly caused by encapsulated organisms like s. pneumoniae (gram-positive) and h. influenzae (gram-negative) [ , ] . the source of our patient's initial gram-negative bacteremia appears to be the genitourinary tract. the presence of acute urinary tract infection on admission, the finding of enterogenic bacteria in urine cultures, and a history of recurrent urinary tract infection strongly support this opinion, even if bacteriological proof is lacking. the morphology of the alveolar exudate is uncharacteristic for nosocomial pathogens (pseudomonas aeruginosa, e. coli). klebsiella pneumoniae, the organism which histologically caused the pneumonia of our patient, is isolated in approximately % of all acute bacterial pneumonias, and it is the second most common urinary tract pathogen [ ] . its invasive properties are characterized by the antiphagocytic effect of a capsule and production of large, mucoid colonies with destructive action on the pulmonary tissue. in our case we were confronted with an unidentified pathogen and had to start an empirical antibiotic treatment with a broad spectrum. multicenter studies have proved the efficacy of ciprofloxacine and imipenem against multiresistant klebsiella [ ] , but in retrospect it is clear the duration of treatment was not long enough to eliminate the bacterium. in the course of the septic shock purulent cerebral microabscess formation appeared. invasive fungal infections have been recognized as a complication in hiv-infected patients with a frequency up to %, mostly caused by candida [ , ] . disseminated aspergillosis is diagnosed at only % to % in patients dying of aids, although exposure to aspergillus is universal [ , , , ] . the largest study of invasive aspergillosis so far, with hiv-infected patients, documents the diagnostic difficulties, as positive diagnosis mostly required bronchoalveolar lavage or transthoracic aspiration of pulmonary lesions. despite antifungal therapy, more than % of the patients died [ ] . manifestations of disseminated aspergillosis usually requires the setting of profound neutropenia [ , ] . the cases of aids patients with invasive aspergillosis described in the literature therefore had neutropenia related to zidovudine or to ganciclovir therapy, increased exposure to aspergillus by marijuana smoking, underlying pulmonary disease, or corticosteroid use as predisposing factors. in our patient, we did not find neutropenia (table ) , but lung sections reveal important pulmonary damage (fig. ) . at this point we have to review critically the recommendation of steroid therapy in addition to the antibiotic treatment in p. carinii pneumonia with severe respiratory failure, as it may cause neutrophil dysfunction [ ] . since no laboratory or imaging procedures yielded specific information that was helpful for etiologic diagnosis, an efficient antifungal therapy could not be initiated in our patient. at autopsy, dissemination to the brain with secondary infiltration of the cerebral abscesses was found. cerebral aspergillosis is rare, has a high mortality rate [ ] , and indicates an extremely bad prognosis [ ] . the case history of this -year-old patient stresses the importance and pathogenicity of common bacteria outside the range of opportunistic infections. it also indicates the possibility of increasing confrontation with disseminated fungal infections like invasive aspergillosis as secondary neutropenia due to drugs such as zidovudine and ganciclovir becomes more common. the poor results of therapy observed in pulmonary aspergillosis in aids justify invasive diagnostic procedures, including bronchoalveolar lavage and transthoracic aspiration of pulmonary lesions, in order to achieve earlier recognition and better therapy. multiresistenz gramnegativer erreger auf intensivstationen. ergebnisse einer multicenterstudie. arzneimitteltherapie invasive aspergillosis: an unusual manifestation of aids bacterial pneumonia in patients with human immunodeficiency virus infection aspergillus endocarditis and myocarditis in a patient with the acquired immunodeficiency syndrome (aids) pulmonary aspergillosis in the acquired immunodeficiency syndrome enteric bacilli, klebsiella aids and fungal infections oral corticosteroids prevent acute respiratory failure in aids-related pneumocystis carinii pneumonia (abstract) bacterial infections in the acquired immune deficiency syndrome opportunistic infections and malignancies in danish aids patients bacterial infections in aids patients aspergillus findings in aids patients suffering from cryptococcosis value of necropsy in acquired immunodeficiency syndrome aspergillus infection of the central nervous system in patients with acquired immunodeficiency syndrome key: cord- -dtveihrj authors: fong, i. w. title: litigations for hiv related complications date: - - journal: medico-legal issues in infectious diseases doi: . / - - - - _ sha: doc_id: cord_uid: dtveihrj in , a -year-old male with same sex exposure requested human immuno-deficiency virus (hiv) testing anonymously at a walk-in clinic. he was advised that the test (hiv serology) was positive and he requested a repeat test (anonymously) month later, which was also reported as being positive. about years later, he was assessed by a general practitioner for symptoms of depression and continued medical care. at that time, investigations revealed a cd t-cell count of about cells/ul. sometime in a repeat blood test revealed a cd cell count just < cells/ul. no consultation to an infectious diseases specialist or hiv clinic was made. the gp(general practitioner) then initiated a regimen consisting of didanosine, lamivudine, and saquinavir for hiv infection. at that time, testing for hiv viral load was not generally available to the medical community, but became procurable in . initially, the patient tolerated the regimen well and over the next years his cd cell count was maintained above – cells/ul and the hiv viral load remained undetectable (< copies). however, the patient started to show morphologic changes of moderate facial and peripheral lipoatrophy, developed mild sensory peripheral neuropathy, and increased liver enzymes attributable to fatty liver, and elevations of the fasting serum glucose. in the summer of , although the cd cell count remained stable, the hiv viral load was reported as being over , copies/ul. at this time, the patient was referred to a university hospital hiv clinic. load of > , copies/ul came to the conclusion that there was either a mix-up in the blood specimen samples or error in the labeling or reporting. efforts to verify or clarify the initial hiv serology were unsuccessful as no permanent records were kept for anonymous hiv serology results. the patient (plaintiff ) initiated litigation against the gp (defendant) for medical malpractice. specific charges were: ( ) the gp should have repeated the hiv serology to confirm that the plaintiff was hiv infected, ( ) the defendant was negligent in starting treatment for hiv infection without proof of disease, ( ) the physician lacked knowledge of hiv infection and should have referred the patient to a specialist or hiv clinic, ( ) treatment of toxic medications were given for several years without any clear indication, and ( ) the gp did not adequately inform the patient on the pros and cons of therapy, nor explain the potential toxicities and side-effects. financial compensation by the plaintiff was sought for psychological suffering over the years with the false impression that he was hiv infected, and physical suffering from the side effects of the medications and the need to take unnecessary large amounts of pills for several years. the side effects had affected his social life and left a permanent physical stigma, and also adversely affected his performance at work (due to absenteeism from adverse events). the latter had resulted in his inability to perform at a high level and thus retarded his progress in his career path. all these effects have indirectly affected his earning ability over - years, and also future earning capacity. the present aids pandemic is caused by the hiv- strain and hiv- is predominantly found in west and central africa but is rare in developed nations. seroconversion after exposure usually occurs within weeks to months, but occasionally may take months or longer. delayed or protracted time for seroconversion may be seen especially in immunosuppressed subjects. usually by months after exposure, seroconversion should occur in % or more of cases. a period of viremia and antigenemia without detectable antibodies occurs within - weeks of initial hiv infection. at this phase, high levels of plasma p antigen or viral rna can be detected, and the viremia and antigenemia decline to very low levels coinciding with seroconversion. detection of antibodies to hiv remains the most cost-effective and commonly used method to prove hiv infection. enzyme-linked immunoassay (elisa) is the most commonly used assay to test for hiv- and hiv- because of its low cost, standardized procedure, reliability, and rapid turnaround. for experienced laboratories under optimal conditions (commonly licensed kits) the sensitivity and specificity of the elisa are both %. false negative reactions can occur in infected persons early in the course before seroconversion and in immunosuppressed patients. false positive elisa results can occur for various reasons, including human error, variability in the test kits, hemodialysis, auto-immune disease, multiple myeloma, hemophilia, alcohol hepatitis, positive rapid plasma regain (rpr) test, and for unknown reasons (idiopathic). the elisa uses hiv antigen to bind igg hiv antibodies in the test sample. the western blot test (wb) is the most commonly used confirmatory test for the presence of hiv specific antibodies. compared to elisa, the wb is more expensive, time-consuming and requires more technical expertise to interpret. false negative wb can also occur in the very early phase of hiv infection before development of antibodies. false positive reactions can occur in auto-immune disorders, polyclonal gammopathies, hyperbilirubinemia, subjects with human leukocyte antigen (hla) antibodies, and healthy individuals. in low risk populations, the chance of false-positive reaction of elisa and wb combined is extremely low - in , . the probability of another test being false positive in the same person tested at another time for both tests would be : , Â , or in billion chance. although the polymerase chain reaction (pcr) can be used to detect the hiv genome before antibody production, the pcr is highly prone to contamination with nucleic acids, which causes many false-positive reactions and therefore has not been recommended for diagnostic purposes. these pcr tests are thus mainly used for serial measurements of plasma hiv- rna for quantitation over the range of - , rna copies/ml to monitor progress and response to therapy. in high risk populations, detection of hiv-dna by pcr has been found to have falsepositive rates of - . %. , data from bayer on the versant hiv- rna . assay (bdna) found that all of false-positive samples quantitated were , copies/ml or less (personal communication with dr. r. ziermann from bayer). the main issue in this case is related to acceptance of a patient's history of a serious disease (from a test performed elsewhere) without verifying the results. although physicians commonly accept the history of a patient's underlying illness as valid, treatment for a disorder with potentially toxic agents should always require verification of the diagnosis. it could therefore be argued that the gp was remiss in instituting a cocktail of medications without having a confirmed copy of the test result for hiv infection. this is particularly damaging for an asymptomatic subject with no history of opportunistic infection or clinical evidence of aids complication. moreover, a cd count cannot be used as a surrogate marker for the diagnosis of hiv infection. although the cd + t lymphocyte quantitative count is a very useful and standard test to monitor patients for progression of hiv disease or response to therapy, it can be low in many conditions. the normal cd + t lymphocyte count usually averages . - . Â cells/l ( - , /mm ), but the range of normality ( standard deviations of the mean) is quite wide ( - , cells/mm ). about % of the normal blood lymphocytes are t lymphocytes and nearly twothirds of blood t lymphocytes are cd + (helper) lymphocytes and most patients with lymphocytopenia have reduction in absolute number of cd + t lymphocytes. there are many conditions that can be associated with lymphocytopenia and lower than normal cd + lymphocyte count. although hiv infection is the most common viral infection associated with cd + lymphocytopenia, other viral infections can transiently decrease cd + cell counts (including measles, corona viruses and others). the list of conditions associated with cd + lymphocytopenia (besides viral infections) include bacterial and fungal sepsis (including tuberculosis), major surgery, recent trauma or hemorrhage, malignancy, glucocorticoid use, cytotoxic chemotherapy, radiotherapy, auto-immune diseases, nutritional deficiencies, organ transplantation, acquired common variable immunodeficiency, and idiopathic cd + lymphocytopenia. furthermore, it is common to observe biologic variations in the absolute cd + cell count even in hiv infected subjects without any other factors. a healthy adult may have, at some time, transient decrease in cd + cell count below . whether the plaintiff's cd + cell count decline was due to viral upper respiratory tract infection or other causes was not clear. in hiv-infected patients, the t lymphocytes decline by % per year for every log hiv rna copies/ml in the plasma. currently, the optimal time to start antiretroviral therapy (art) for asymptomatic hiv patients is not clear. there is consensus that patients with aids complications or symptomatic disease should be started on art. there is still controversy as to the optimal time to initiate art in asymptomatic patients. some guidelines recommend considering starting art below cells/mm and others recently < cells/mm , but there are no randomized controlled trials to provide a clear answer. how can we resolve the issue of two hiv serology tests taken at separate times in the same subject being false positive? there are several possibilities, none of which can be proven in or out of court. it is possible, that since blood samples taken in the clinic were labeled with a code number to provide anonymity, that the samples were mislabeled and originated from a truly hiv infected subject. however, the chance of that occurring twice in a row would be extremely low or unlucky. it is also possible that the plaintiff suffered from a mental disorder or delusion (such as munchausen's syndrome) and imagined that he had a positive hiv serology. there was no indication of a psychiatric disorder from the gps office records. rare false claims of a medical disease (including hiv infection) may be encountered under unusual conditions where the person can expect some form of material gain, i.e., financial, improved living conditions, sympathetic reduction in sentences for criminal offenses, etc. none of these appeared evident from review of the records. feigned hiv infection has been reported in malingering patients [ ] [ ] [ ] and in young women with psychosocial disorders with history of prolonged sexual, physical and emotional abuse. a retrospective study from an hiv clinic in a municipal hospital identified seven patients with fictitious hiv infections, six of whom had a history of illicit narcotic abuse. a survey of ten other local hospitals found that known cases of alleged (fictitious) hiv infection occurred at eight of the hospitals but only one of the ten hospitals routinely documented hiv infections before initiating care. in a specialist hiv unit in central london over a -year period, patients ( . % of admissions) with feigned hiv/aids were identified. a young man, aged years, presented to a new family physician (fp) in with symptoms of lb weight loss, chronic diarrhea for weeks and night sweats. he was found to be unwell, with evidence of significant weight loss from wasting, oral thrush, and oral hairy leukoplakia. an hiv serology performed was positive (screen and confirmatory), and his cd + lymphocyte count was cells/mm . he was started on antiretrovirals and prophylaxis for pneumocystic pneumonia. the patient was a practicing homosexual with multiple partners (none of whom were known hiv infected) and he used condoms sometimes, but inconsistently for sexual encounters. he had no known past medical illness and claimed to have previously tested negative for hiv infection in . he claimed to have requested an hiv test in but there was no record of this in his previous fp records. an hiv serology was performed in the summer of (which was positive), but the patient was never informed of the results and apparently was lost to follow-up. the records subsequently in indicated that the young man was attending an hiv clinic regularly with no opportunistic infection and was clinically stable on a combination of art with a stable cd + lymphocyte count of cells/mm and undetectable hiv (< copies). the patient in initiated lawsuit against his original fp for medical malpractice. the charges against the physician were that he failed to perform an hiv test in despite the plaintiff's request and he was negligent in failing to notify the plaintiff of the result of the hiv serology in . these acts of negligence by the defendant resulted in delay in the diagnosis and treatment, thus allowing his hiv infection to progress to aids. furthermore, failure on the part of the defendant had resulted in missed opportunities to start earlier treatment, and the delay in initiation of art resulted in a decrease in his expected life span and affected the quality of his life. the defendant countered that there was no record of the plaintiff ever requesting an hiv test in . furthermore, the plaintiff never kept the appointment after the positive hiv serology in to be notified of the result. moreover, since the plaintiff was subsequently lost to follow-up, he never had a chance to counsel him on hiv disease or institute treatment. following acute hiv infection, about - % of subjects develop clinical symptoms of variable severity, from mild flu-like illness to aseptic meningitis. there is also evidence that severity and duration of clinical acute illness of a primary infection is of prognostic importance. the risk of developing aids within years of seroconversion in subjects who were asymptomatic or had mild illness was only % versus % (eight times greater) in those with seroconversion illness of at least days. peak viral replication soon after infection occurs in - weeks and levels of virus can exceed > copies/ml in plasma. this is associated with a dramatic drop in circulating cd + lymphocytes, then a slowing of t-cell loss, and rebound by - weeks. this rebound of cd + cells corresponds to a decline in viral load, which reaches a steady state (set point), which is variable by - weeks. clinical progression of hiv disease has been tied to a set point level with lower levels associated with better prognosis. at year after seroconversion, patients demonstrate a fall of about cd + cells/mm (mean baseline cells/mm ), followed by a more gradual decline in cd + cells in the later period of infection. there is usually a variable period of - years span before patients develop aids (about %). the typical hiv-infected person shows a progressive decline of cd + lymphocytes ( - cells/year) over time. long-term non-progression or elite controllers represent < % of hiv-infected subjects who maintain relatively normal cd + cell count and very low or immeasurable viral load for years to decades without therapy. this is a heterogenous group of elite controllers whose benign course may result from robust immune responses against hiv, or defective poorly replicative virus secondary to deletion of the nef gene. , there is evidence that host factors that influence the course of hiv disease are correlated to polymorphisms dominating the hla region, with class i polymorphism dominating the hla associations. there is also evidence from studies in the united states and europe that hla-b and hla b- are strongly associated with long term survival or non-progression. not all long-term non-progressors are "elite or viremic controllers" (patients with undetectable hiv or plasma hiv rna levels of - , copies/ml). these patients with cd + cell counts of > cells/mm for at least years most often had hiv rna levels of > , copies/ml, but had significantly lower hiv rna than subjects with typical progression. thus plasma set point hiv rna levels explain < % of the variability in rates of clinical progression. the chemokine receptor (ccr ) protein serves as a co-receptor on cd + lymphocytes for certain strains of hiv- . homozygosity for a -base pair deletion allele (ccr d ) protects against hiv infection ( % of caucasians) and heterozygosity (individuals with one allele) show a decreased progression to aids. there is also evidence that co-infection with gb virus (gbv-c), a flavivirus not known to cause disease (in subjects with gbv-c viremia), have slower progression and slower decrease in cd + cell counts than those without gbv-c infection. although the reasons for this protective effect are unclear, there is evidence that gbv-c inhibits hiv replication in peripheral blood mononuclear cells in vitro, and since gbv-c infects cd + cells, this may compete with the hiv for target cells for infection. a minority of patients with hiv infection can rapidly progress to aids within - years of their infection. this may be related to host genetic factors and age at the time of infection and other extrinsic conditions. older age at the time of infection (> years) has been associated with faster progression of the disease in hemophiliacs and older homosexuals. concomitant co-infection with cytomegalovirus (cmv) has been associated with rapid progression to aids in hemophiliacs and others. , co-infection with htlv-i may increase the risk for development of aids while htlv- can delay the progression of disease. , , active tuberculosis can also enhance hiv replication and cause rapid progression to aids. however, although treatment of active tuberculosis for months is associated with increased cd + cell count, it does not markedly affect the hiv viral loads. the role of hepatitis c-virus (hcv) co-infection on the progression of hiv disease has been conflicting, with some studies showing more rapid progression, but others have found no effect on the development of aids. the clade or strain of hiv- may play a role in the course of the disease. clade d of hiv- is associated with faster progression to death in africa than clade-a and b. women in senegal infected with c, d or g hiv clade were eight times more likely to develop aids than those infected with clade a subtype (the predominant sub-type). infection with multiple strains of hiv- (more common in women) have also been associated with faster disease progression. socio-economic factors such as poverty, homelessness, drug and alcohol abuse, and black race play indirect roles in the prognosis and disease progression of hiv infection, primarily through lower access to medical management, delay in instituting antiretrovirals and poorer compliance with medications. although a previous study found that alcohol and psychoactive drugs did not accelerate hiv disease, there is in vitro evidence that alcohol, cocaine and narcotics can impair the immune response to hiv- and allow enhanced replication in peripheral blood mononuclear cells. a case report of rapid progression to aids within a year of infection has also been attributed to alcoholism. it would appear that the plaintiff became infected with hiv sometime between (reported hiv-negative) and (first noted hiv-positive). however, by he had progressed to symptomatic aids. thus, his course was more rapid than usual hiv infected individuals were, and especially as no other conditions or factors were recognized that could accelerate his course of disease. however, the failure of the fp to notify the patient of his hiv-positive status before recognition of his condition was only year. would an earlier diagnosis by year and assuming institution of art then, affected the outcome as to lifespan and quality of life? appropriate treatment a year earlier with art would likely have aborted or ameliorated his symptomatic disease, of weight loss, diarrhea, and malaise. however, it is less clear whether his expected lifespan would be any greater. if we assume that over the preceding year his cd + cell count probably declined by - cells/mm , then even at that time he would have already progressed to aids (cd + cell count < cells/mm ). there is reasonable good cumulated evidence that starting therapy when the cd + cell count is very low (< cells/ mm ) is associated with less chance of immune reconstitution and greater risk of opportunistic complications than those started on art when the cd + cell count was > cells/mm . the optimum cd + cell count for initiating art has not been well established although recent large observational cohort studies (retrospective and prospective ) and suggests better outcomes for hiv infected patients receiving earlier art with cd + cell count ! cells/mm or > cells/mm ; the data however is flawed and controversial. , lack of randomization in these studies could result in significant biases as motivated, health-conscious individuals would likely do better that those less motivated. it is not clear in these studies as to the cause of excess mortality in those not accepting treatment. for instance, it would be expected and predictable to find excess mortality (from any disease) in marginalized people (homeless, alcoholics, drug abusers), who are less likely to start art, which may be unrelated to hiv complications, such as suicides, homicide, accidents, drug overdose, liver failure or other diseases more prevalent in these groups (diabetes mellitus, cardiovascular disease, chronic lung disease and cancer). the defendant denied the plaintiffs claim that earlier hiv test (in ) was requested. it could be argued, however, that the fp should have been doing regular hiv serology in an individual that belongs to a high-risk group (with the patient's consent). the center for disease control and prevention (cdc) estimate that nearly % of men who have sex with men (msm) with hiv infection are unaware of their status. the cdc national behavior surveillance system of high-risk venue-based recruitment found % of msm tested to be infected with hiv, and nearly % of the hiv infected individuals were unaware of their infection. in new york city, the hiv incidence rate among msm was . %, with % of those infected being unaware of their hiv seropositivity. it is estimated that % of hiv-infected people in the us who are unaware of their infection may account for up to % of new infections. cdc hiv testing guidelines recommend annual testing for high-risk populations (including msm), and since have recommended universal opt-out hiv screening in all health care settings. thus, the plaintiff could argue that the defendant fell below the standard of care by not recommending and performing annual hiv tests. furthermore, if he were found to be hiv seropositive earlier, (by or before) with careful monitoring and institution of art before his cd + cell count fell < cells/mm , his quality of life and life expectancy would be greater. what is the effect of life expectancy with late treatment initiation for hiv disease? in a recent study using a state-transition model of hiv disease, the projected life expectancy of hiv uninfected and hiv infected persons with similar risk profiles were compared. those with hiv infection lost . years of life if they received care concordant with guidelines and late treatment initiation resulted in . additional years of life lost (greatest for hispanics [ . years]). an infectious disease (id) specialist/internist was consulted to assess a -year-old male with mild pancytopenia and a past history of bilateral pneumonia the year before. the patient had a history of multiple sexual contacts with prostitutes years prior and had refused hiv testing the year before when he developed pneumonia (which was suspected to be pneumocystic pneumonia [pcp]). at this office visit, he agreed to an hiv test and a cd + cell count. the patient was called for a return appointment to discuss the results of the test a month later, but this appointment was cancelled by the patient for personal reasons. the blood test revealed the patient was hiv seropositive with a very low cd + cell count of cells/mm , but the results were not given over the phone or by mail. thus, the subject remained unaware of his hiv status and severe immune deficiency. about months later, the patient attended an optician for blurred vision and he was referred to a hospital er for an ophthalmologist consultation. he was briefly assessed by the attending er physician, but due to the long waiting period pending full eye assessment, he left prematurely. the patient arranged an appointment with the id specialist in the er of the suburban community hospital. the subject was told of his hiv status and a brief retinal examination (without pupillary dilatation) by the id physician revealed no abnormality. an appointment was arranged for another office visit to the id specialist to discuss hiv therapy in weeks. one week later the subject returned to the er with respiratory symptoms and poor vision. he was admitted as possible pcp under the care of the id physician, but no eye examination was performed. a week after his admission to hospital, a neurologist who was consulted found very poor vision with light perception only in the right eye and finger counting on the left eye. fundoscopy revealed bilateral chorioretinitis and ophthalmology consultation was requested, but treatment of cmv retinitis was only instituted days later. his course was complicated by retinal detachment secondary to cmv retinitis with almost complete blindness in the right eye and severe visual impairment of the left eye -legally blind. malpractice litigation was brought by the patient against the id physician and the admitting er physician of the hospital. the charges against the id consultant were: ( ) failure to notify the plaintiff of his hiv status and seriousness of his condition, ( ) failure to do a proper eye examination or refer him to an ophthalmologist when he was first seen in the er a week before his admission, ( ) failure to do a fundoscopy or arrange urgent ophthalmology consultation on admission to the hospital, ( ) delay in starting appropriate treatment for cmv retinitis even after the neurologist findings were consistent with the diagnosis. the claim filed against the er physician was for neglect in performing an eye examination, despite the patient's symptoms of poor vision and failure to require an urgent ophthalmology consultation. that prompt recognition of cmv retinitis and immediate institution of antiviral therapy could have resulted in better visual result. failure of the id physician to inform the plaintiff of the seriousness of his condition, even by phone, could have resulted in prevention of visual loss and admission to hospital if treatment with art and pcp prophylaxis were started months before his hospital admission. the defendant (id specialist) countered that it was the plaintiff who canceled the follow-up appointment for counseling on his condition, and it was neither his policy nor the recommended standard to discuss these issues on the phone. therefore, failure to initiate earlier art before the aids complications was due to the fault of the plaintiff. furthermore, his eye examination performed at the first er visit revealed no abnormalities. visual complaints in hiv infected persons can be unrelated (as in normal people) or related directly to complications of aids or indirectly due to medications. ocular manifestations are common in people with aids, and before the advent of highly active art (haart), the majority of patients with aids developed some ocular involvement at some time. the most frequent ocular abnormality was usually silent or asymptomatic and occurred in nearly % of aids patients before the era of haart -hiv microangiopathy, consisting of cotton wool exudates, and less frequently hemorrhages. occasionally hiv retinopathy could present with visual impairment from larger branch vein or central retinal vein occlusion. the most dreaded ocular complications of aids were from opportunistic ocular infections (cmv retinitis, herpes zoster (vzv) retinitis, or herpes zoster ophthalmicus, toxoplasma retinitis and ocular syphilis), or neoplasm (kaposi sarcoma of the lids and conjunctivae, and orbital or intraorbital lymphoma). cmv retinitis is the most frequent sight threatening ocular complication of aids, occurring in the late stages when the cd + lymphocyte counts < cells/ml. in the pre-haart era cmv retinitis occurred in % of patients with aids, and the number of new cases has dramatically fallen since widespread use of haart by - % (average %). the incidence of cmv retinitis among patients with cd + cell count < cells/ml was % per year and for many patients with cd + cell count < cells/ml, it was % per year. symptoms of cmv retinitis include floaters, flashing lights, loss of visual field, or visual loss. in the early stages with small peripheral retinal lesions patients can be asymptomatic and - % of persons with cd + cell count cells/ml have asymptomatic cmv retinitis. lesions adjacent to the optic nerve or fovea (posterior pole of the retina or macula) are immediately vision threatening. the retina has been divided into three zones for clinical assessment of risk to vision. zone lies within , mm from the edge of the optic nerve, zone extends from the edge of zone to the equator of the eye, and zone extends from the equator to the pars plana (pigmented posterior zone of the ciliary body). see fig. . for the schematic diagram of the zones of the retina. lesions of zone are immediately sight-threatening and require urgent treatment, whereas lesions of zones - may be observed for short periods of time without risk of loss of visual acuity. the mean time for progression of peripheral lesions without treatment was found to be days (enlargement to uninvolved retina by ! mm in width). the complications of untreated or delayed treatment of cmv retinitis include impaired vision to blindness, secondary to progressive retinitis with hemorrhages, scarring and retinal detachment. in the pre-haart era, retinal detachment in cmv retinitis occurred in % at months and in - % at year. the diagnosis of cmv retinitis can be made reliably by an experienced ophthalmologist by dilated direct or indirect ophthalmoscopy. examination of the fundus through an undilated pupil is inadequate to diagnose or exclude cmv retinitis as only % of the retina can be evaluated. the aim of treatment with anti-cmv drugs (ganciclovir intravenously or oral valganciclovir) is to arrest progression of the disease, prevent further spread, and preserve vision. treatment with anti-cmv agents does not eradicate the virus but delays progression and relapse, until immunity can be restored by haart. anti-cmv therapy, half the dose after induction for weeks, can be discontinued once the cd + cell count is > - cells/ml for months. some experts advocate intravitreal injection or ganciclovir implant in addition to systemic therapy for zone cmv retinitis to avoid loss of vision. for persons recently discovered to be hiv-seropositive, it is ideal to give the results in person confidentially, and at the same time counsel the patient on the disease. however, there are several options available if the individual were reluctant to return for follow-up appointment (or cancels the appointment). the results could be forwarded to the fp and notify him or her of the patient's cancelation plus need for counseling, close monitoring, and for initiating art or pcp prophylaxis depending on the cd + cell count. if the subject has no fp, then the person can be notified of the results by letter or phone, or through the public health department. although some physicians are reluctant to discuss confidential issues on the phone, there is no edict against this practice. however, confidentiality needs to be maintained and the identification of the person on the phone should be verified. this has become a common practice with financial institutions and even lawyers who discuss medicolegal cases with medical experts on the phone. since the defendant knew the plaintiff had advanced hiv disease (aids) as indicated by the very low cd + cell count, it was mandatory that the patient be made aware of the seriousness of his condition as soon as possible by one of the above mechanisms. his failure to impart this information to the plaintiff directly or indirectly could be considered negligence by the court. failure of the defendant to perform a dilated ophthalmoscopy or arrange for urgent ophthalmology consultation when the plaintiff initially presented with impaired vision also falls below the standard of practice in an hiv infected individual with a cd + cell count of < cells/ ml. the physician ought to have known that cmv retinitis was a main concern, and could be sight threatening and that examination by un-dilated fundoscopy would be insensitive and inaccurate. based on the evidence presented, it could be argued by the plaintiff's lawyer that had the patient been notified earlier of the seriousness of his condition and accepted treatment with haart months before his hospital admission, it is likely that he would have had a better quality of life and preservation of his vision. although counsel for the defendant may counter that the plaintiff should be responsible for his own health (as he canceled the follow-up appointment), there were several avenues available to the defendant to ensure that the patient became aware of his serious illness, and he failed to utilize any of them. whether or not a court may consider these failures as human errors from oversight in a busy medical practice and not medical malpractice would be difficult to predict. review of testing for human immunodeficiency virus low sensitivity of elisa testing in early hiv infection duration of human immunodeficiency virus infection before detection of antibody measurement of the false positive rate in a screening program for human immunodeficiency virus infection detection of human immunodeficiency virus dna using polymerase chain reaction in a well-characterized group of homosexual and bisexual men concordance of polymerase chain reaction with human immunodeficiency virus antibody detection immunology of hiv infection william's hematology, th edition fraudulent aids factitious aids the baron has aids: a case of fictitious human immunodeficiency virus infection and review factitious hiv syndrome in young women factitious hiv infection: the importance of documenting infection feigned hiv infection/aids: malingering and munchausen's syndrome primary human immunodeficiency virus type i infection: review of pathogenesis and early treatment intervention in humans and animal retrovirus infection clinical course of primary hiv infection prognosis in hiv infection predicted by the quantity of virus in plasma cd + lymphocyte cell enumeration for prediction of clinical course of human immunodeficiency virus disease immunopathogenic mechanisms of hiv infection immunologic and virologic status after to years of infection with an attenuated strain of hiv- brief report: absence of intact nef sequence in a long-term survivor with non-progressive hiv- infection consistent associations of class i and ii and transporter gene products with progression of human immunodeficiency virus type i infection in homosexual men overall features of hiv pathogenesis prognosis for long term survival natural control of hiv- replication and long-term non-progression: overlapping but distinct phenotypes genetic restriction of hiv- infection and progression to aids by a deletion allele of the ckr structural gene cytomegalovirus infection and progression towards aids in hemophiliacs with human immunodeficiency virus infection cytomegalovirus seroconversion as a cofactor for progression to aids progression to aids in homosexual men coinfected with hiv- and htlv- in trinidad htlv-i/ii seropositivity and death from aids among hiv-i seropositive intravenous drug users influence of tuberculosis on human immunodeficiency virus (hiv-i): enhanced cytokine expression and elevated b -microglobulin in hiv-i associated tuberculosis human immunodeficiency virus-i rna levels and cd lymphocyte counts during treatment for active tuberculosis in south african patients different rates of disease progression of hiv type i infection in tanzania based on infecting subtype human immunodeficiency virus type i subtypes differ in disease progression infection with multiple human immunodeficiency virus type i variant is associated with faster disease progression no evidence for a role of alcohol or other psychoactive drugs in accelerating immunodeficiency in hiv-i positive individuals alcoholism and rapid progression to aids after seroconversion effect of early versus deferred antiretroviral therapy for hiv on survival timing of initiation of antiretroviral therapy in aids-free hiv-i infected patients: a collaborative analysis of hiv cohort studies hiv prevalence, unrecognized infection and hiv testing among men who have sex with men -five us cities sexually transmitted diseases treatment guidelines early versus standard antiretroviral therapy for hiv-infected adults in haiti cytomegalovirus retinitis and low cd + t-lymphocyte counts intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with aids what lessons can we learn from these cases? l all patients with self-reported hiv-seropositive status should be verified by repeating the test. l physicians should pay more careful attention to patients' symptoms and complaints and act with reasonable promptness. l deal with patients' complaints as you would want to be done to yourself or relatives. key: cord- -zc lsls authors: fulginiti, vincent a. title: what's in store for ? date: - - journal: infect dis newsl (n y) doi: . /s - ( ) -x sha: doc_id: cord_uid: zc lsls nan as indicated in john lawrence's letter, the infectious diseases newsletter will undergo a marked change in both the editorial direction and in format. i wish dr. paul hoeprich well in his endeavors and will do whatever i can to assist him in giving some energy to this new direction. for this first issue of idn in . i thought i would focus on areas that i believe will be of high activity in the coming year, some of which will culminate in definitive information which will change our concept, diagnostic practices, and therapeutic activities. : t a number of causes have been suggested as the basis for the occurrence of acquired-immune-deficiency syndrome (aids). initially, it was believed that intensive exposure to cytomagolovirus somehow influenced lymphocyte function and produced the aberrant immunologic findings in aids. i this premise has not held up and the search has continued for other possible etiologic agents. suggestions have been made that the immunologic aberrations may be secondary to drug use. this thesis has also not been sustained. the search for a viral cause did not end with the cytomegalovirus hypothesis. several observers have noted unusual morphologic changes such-as vesicular rosettes in lymph node lymphoid cells and a tubular reticular structure within cisterns of smooth endoplasmic reticulae of lymphocytes from patients with aids. , one hypothesis to explain their occurrence is viral infection of the lymphocytes. studies in hemophiliacs who received factor viii therapy butnot other forms of replacement suggest that a transmissible agent, possibly in the factor viii concentrate, results in immunologic aberrations that are not unlike those seen in aids. investigators have suggested a possible link between aids and human t-cell leukemia virus (htlv). , , , this agent has been associated previously with a rare type of human cancer. a number of lines of evidence suggest htlv'as a possible etiologic agent. first, htlv is prevalent in the caribbean area and in africa, the areas of occurrence of aids in some populations. htlv is an agent which affects t-cells on a very selective basis. since the primary aids defect appears to be in the t-lymphocytes, it is hypothesized that an agent which primarily infects these cells might be a logical candidate. htlv also appears to spread by intimate contact, a prerequisite in the theory of aids transmissior. one other analogy is that htlv causes both a cancer and an immunosuppression as is true for a number of leukemia viruses in animals. htlv is a retrovirus with rna in its core. transcribed viral dna has been found in the cells of a few patients with aids but not in healthy homosexual male controls. infectious htlv p~rticles were isolated from one patient's t-cells and from two patients who did not have evidence of viral dna. the virus has been identified as htlv-i, apparently the most common type among or more iso-.lares of the virus. antibodies against htlv have been found in a proportion of aids patients and very rarely among control individuals. there are some features of htlv which do not parallel the features of aids giving rise to scepticism as to whether this agent is, in fact, a cause of aids or simply one of the many agents with which aids patients can become infected. more recently a suggestion has been made that cyclosporin produced by infection with a saprophytic fungus,thermoacus crustaceus, may be the cause of aids. i the problem with all of the postulated infectious agents is that the immunodeficiency that is part of aids may predispose to infection with a wide variety of opportunistic agents. as a result, one cannot be certain that isolation of an agent or identification of host response to it in anyway reflects etiology. my guess is that will result in the discovery of the precise cause of aids and its mode of transmission. then, as with the legionella story that preceded it, we will be able to better understand the epidemiology of this disorder and the presumed lesser forms of the disease that may occur. lyme disease, an acute infiammatory disorder characterized by a very specific skin rash, erythema chronicum migrans, was a puzzle for some time until steere, benach and others discovered a spriochete both in patients and in the ixodes sp ticks which are the vectors.tttt --t~e spriochete is unique and evokes an antibody response which can be measured as both specific igm and igg. in we can expect further definition of infection with this agent, including, perhaps, milder forms of the disease and even asymptomatic infections. one of the most exciting findings reported in is the identification of plemorphic, gram negative bacteria in the vast majority of lymph node specimens from patients with cat scratch disease . the cause of this disease has been extremely elusive and therefore difficult to diagnose with certainty. if the bacteria can either be isolated or otherwise identified by host response during , i am certai that this will propel cat scratch disease from a medical oddity to a well characterized infection. will we discover new infectious diseases or the causes of some which have eluded us thus far? it is likely that the progression of infectious diseases in the past decade which are either newly identified or seem to arise de novo will continue. obviously, i cannot ~redict when and where or what the'nature will be, but i think physicians should be alerted to the pf~ssibility that the odd patient that they are seeing who does not conform to any textbook description may be the herald case of some new disorder. further, a cause for disorders such as kawaski disease may be discovered this year. one of the most intriguing findings in the past several decades has been the discovery of a genetic basis for immune responsiveness and, by inference, to susceptibility to infectious diseases. , , , work with carefully bred animals led to the segregation of specific factors that determine genetic responsiveness and genetic susceptibility. this information has been partially translated into human experience by the association of certain white cell types, which are the reflection of these genetic characteristics, with specific inflammatory disorders. further, ability to respond immunologically to certain antigens appears to be related at least in part to the genetic make-up of individuals in relation to certain gene loci. in i look forward to further definition of this relationship which may help to answer the several puzzling questions that confront clinicians, such as why does this child develop encephalitis with epstein-barr virus and this one not, or why does this child die with an overwhelming bacteremia whereas the majority of individuals do not, or why does poliovirus produce paralysis in certain individuals whereas the vast majority of exposed and infected individuals either have asymptomatic infection or nonparalytic illness? questions such as these have plagued us and we have vaguely related them to the patient's "constitution" or to his "germ plasm". i believe we are at the threshold of discovering what that characteristic is at a molecular level. the pathogenesis of cancer appears to be an exteremly complex matter but the discovery of oncogenes and their interrelationship with environmentai influences offers the hope that we may understand the complex interactions between infection with specific agents, immunologic response to these agents, immunosupt pression, and malignant transformation. ] among the many challenges confronting a clinician who deals with infectious diseases is the segregation of individuals infected with atypical mycobacteria from all other causes of skin, lymph node and pulmonary infection. some years ago we' had available skin test material which we thought was specific enough to help us sort out individuals infected with atypical mycobacteria from those who had infection or past experience with mycobacterium tuberculosis. these mate----~s were removed from our use because of questions of specificity and have not yet returned to general use. it is my belief that in we will have better diagnostic methods in this area, possibly with release of skin test antigens ~,hich may have greaater specificity than those we used in the past. one other "breakthrough" that can be anticipated with reasonable expectation is the development of rapid serologic diagnostic tests for sorting out the many viruses which produce gastrointestinal infections. rotaviruses have proved the pathfinder in this regard, first being detected solely by their morphologic appearance in electronmicroscopy of stool specimens. this test rapidly yielded to ria and elisa identification which is now readily available in many diagnostic laboratories. i suspect ~e will not only continue to refine the diagnostic tests for rotavirus infection but can anticipate that other agents such as the parvoviruses, coronavirus and ethers masy yield to similar techniqus the development of enzyme-linked immunosorbent assays (eliea) promises to greatly alter our diagnostic methods. capable of being adapted to measure either antigen or antibod~ response, this technique offers the routine ~icrobiologic laboratory the opportu[ity of a fairly specific, highly sensitive test for routine detection of a wide variety of antigens. in many ways this has obviated the necessity for some routine microbiologic procedures and has replaced more cumber-.~ some ones in the detection of very small amounts of antigen or antibody. the adaptation of this test to an increasing number of infectious igents offers the promise that may find routine laboratories equipped to make diagnoses more rapidly and with greater precision and sensitivity than ever before. we can anticipate wider use of the latex fixation test for the identification of bacterial antigens . this test has proved extremely useful in the detection of haemophilu { influenzae antigen and is so simple to perform that it does 'not require elaborate set-ups (such as is ~ecessary with counter-immunoelectrophoresis) nor does it require elaborate skills on the part of the technical staff. it is likely that the test may be adapted to other antigens that we commonly seek. therapeutic anticipation ,~ we will continue to see third generation cephalosporins entering the united states market. our task will be not so much to learn how to use them, but to learn which ones should not be used. it is clear from our early experience with moxalactam that these drugs seldom substitute for more standard forms of therapy but do have a place in resistant infections and in certan clinical circumstances. in we will see the advent of up to new rd generation cephalosporins, with heavy promotion and a plethora of clinical studies. we can look forward to the completion and publication of the third cooperative neonatal meningitis therapeutic study _headed by george mccracken. i can anticipate that it will demonstrate that the combination of ampicillin and moxalactam is as good as, but no better than, the combination of ampicillin and amikacin. one can only hope that dr. mccracken and colleagues will be innovative.by doing a fourth clinical trial in an attempt to find a therapeutic formula which reduces morbidity and mortality from that of the current regimens. one of the more exciting aspects of therapeutic research is the development of newer antiviral agents. for years practitioners have been plagued with the increasing recognition of the viral cause of a variety of diseases and improved methods of diagnosis including rapid identification of many viruses that is not possible with the inability to significantly influence the course; morbidity or mortality associated with these infections. of course the difficulty has been that effective antiviral treatment usually involves interference with viral replication which closely parallels physiologic processes of the normal cell. as a result toxicity as been a severely limiting factor even if the agent was therapeutically effective. a few agents have survived this dilemma and have become useful in clinical practice; the most recent being acyclovir for herpes virus infection. of great promise is that topical and oral forms of this antiviral agent may find a niche in our therapeutic armamentarium. one of the most exciting findings as came to a close was the report that ribvarin was successful in the treatment of respiratory syncytial-virus infections. these promising preliminary findings suggest we can look forward to newer and useful antivirals in . ped inf dis key: cord- -rmtyrbg authors: saad, farouk tijjani; sanlidag, tamer; hincal, evren; sayan, murat; baba, isa abdullahi; kaymakamzade, bilgen title: global stability analysis of hiv+ model date: - - journal: th international conference on theory and application of fuzzy systems and soft computing &#x ; icafs- doi: . / - - - - _ sha: doc_id: cord_uid: rmtyrbg we developed and studied a mathematical model of hiv+. two equilibriums points were found, disease free and endemic equilibrium, and basic reproduction ratio [formula: see text] was also calculated by the use of next generation matrix. global stability analysis of the equilibria was carried out by the use of lyapunov function, and it was shown that the stability of the equilibria depends on the magnitude of the basic reproduction ratio. when [formula: see text] , the disease free equilibrium is globally asymptotically stable, and disease dies out. on the other hand if [formula: see text] , the endemic equilibrium is globally asymptotically stable and epidemics occurs. reported cases of hiv- positive were obtained in the year from ministry of health, turkey (moh). this data is used to present the numerical simulations, which supports the analytic result. [formula: see text] was found to be . , which is bigger than , this shows the threat posed by hiv in turkey. historically, infectious diseases posed a real threat to the human population. although they have been in human population all the time to some extent, the effects of epidemics are the most obvious and noticeable. only in the th century europe, around million out of about million individuals died from the black death [ ] . several diseases were discovered in america which included smallpox, measles, influenza, and typhus, whooping cough, the mumps, and diphtheria. infectious disease was the main reason for the demise of the indians [ ] . in the early 's, some homosexual men in the united states were diagnosed with a type of fungal infection and a tumor called candidiasis and kaposi's sarcoma respectively. paris pasteur institute in detected a virus responsible for those diseases and called it the human immunodeficiency virus (hiv) [ ] . hiv is the virus that causes acquired immunodeficiency syndrome (aids). the virus is responsible for attacking and destroying the immune systems mainly the cd + t-lymphocytes or t-cells [ ] . on a normal basis, these cd + t-lymphocytes or t-cells detect foreign and infected cells, and attack, spread and kill them [ ] [ ] [ ] . hiv is able to infect cd + t-lymphocytes and insert its genome to host genome. this integrated hiv genome may exist in states. they can be either transcriptionally active generating new viruses that can infect other cd + t-lymphocytes or in latent state which may become activated later. in transcriptionally active stage, the infected cd + t-lymphocytes die due to cytopathic effect of the virus. as a result, the number of cd + t-lymphocytes, which are able to recognize foreign and infected cells, declines, and this decrement lead stoper manent and lasting damage to the immune system [ ] . the immune system finally loses its ability to fight and kill infections due to the number of cd + t-lymphocytes count which is so small. when an individual reaches this stage, the person is said to have aids [ ] . the time between getting infected with hiv and advancing to aids is, in general, five years but changes due to many factors. if the cd + t-lymphocytes cells count falls below cells/mm , then the person is considered to be in the "aids phase", otherwise the person is said to be hiv infected [ ] . the mode of transmission of hiv includes heterosexual intercourse, homosexual/bisexual intercourse, intravenous drug use, vertical transmission, and unknown reasons [ ] . since its discovery (hiv/aids), the extensive increase and epidemic continues around the globe. the greatest number in any one year was in , where almost five million individuals became newly infected, with a total of million hiv/aids patients, and almost three million people died from aids in the same year [ ] . to continue its record of one of the most destructive epidemics in history, it killed at least million people by . efforts to improve the use of antiretroviral treatment in some part of the world were still not enough to reduce a significant number of deaths, the hiv/aids epidemic claimed . million lives in , of which about were children (unaids/who [ ] ). the region that suffered most is africa, with sub-saharan africa as the home of the epidemic. in , . million people were newly infected, and . million patients died of aids-related causes across the globe. by the end of , around million individuals were victims of hiv/aids [ ] . china stated that about . million died of aids-related causes in , and there were about . million hiv-infected individuals by the end of . in the year , two patients were diagnosed with aids in turkey, since then, the importance of aids started and still continue to be on the forefront. the number of new cases increases every year, with , , and cases in , , and respectively [ ] . in , the ministry of health (moh) published the total number of hiv patients , of which % are between the ages of to years and sexually active. among these patients, about were aids patients. this is an official data from moh, however, these numbers does not reflect the actual figures of hiv infected individual in turkey, due to insufficiency of the registration system, and the lack awareness and phobia of the patients to attend health centers or hospitals [ ] . at the end of , the ministry stated that the total number of hiv/aids infected people was . it also published in that at least individuals were infected with hiv, and the numbers of newly reported cases in , , and first six months of were , , and respectively. according to a report, poor knowledge of sexually transmitted diseases, poor socio-economic conditions, increase in number of unregistered sex workers, increase in number of homosexuals, and intravenous drug use contributed to the spread of hiv infection in turkey. it was reported that, the main way of transmitting hiv in turkey is via heterosexual sex ( %), then men having sex with men (msm at %), and intravenous drug users (idu at %) among the recorded cases. according to positive living association istanbul, personal communication, hiv/aids will become a major public health issue in turkey in the coming years, as such; it must be regarded as a rising disease for turkey [ ] . the main ways in which hiv/aids is transmitted between individuals are now well understood, but the factors that contribute to the disparities in its prevalence and trends among populations remain an area of interest to scientific researchers. to understand these disparities, it is essential to understand the system, its components and its dynamics. mathematical models of hiv/aids transmission dynamics are important research tool in this category [ , ] . primary purpose of any mathematical model of hiv transmission lies in using individual level inputs to project population level outcomes. some of the important outcomes that can be examined with a model are; the incidence of infection, the prevalence of infection, or the doubling time of the epidemic. more important than these however, is simply the likelihood of an epidemic to occur that is whether there is sufficient transmission potential for a chain of infection to be sustained. this outcome is termed by a simple summary statistic: the reproduction number of the infectious process, r . in a susceptible population, r represents the expected number of secondary infections generated by the first infected individual. if r is equal or greater than an epidemic is expected. if r is less than , the infection is expected to die out [ ] . the magnitude of r is used to measure the risk of an epidemic or pandemic in any emerging infectious disease. it was used for understanding the outbreak and danger of sars. r was also used to characterize bovine spongiform encephalitis (bse), foot and mouth disease (fmd), strains of influenza, and west nile virus [ ] [ ] [ ] [ ] . the incidence and spread of dengue, ebola, and scrapie have also been assessed by r [ ] [ ] [ ] . tropical issues such as the risks of indoor airborne infection, bioterrorism, and computer viruses also depend on this important parameter [ ] [ ] [ ] [ ] . in this paper, we shall first introduce the model involving systems of ode, and then discuss the biological meaning of the parameters involved. we shall study the global stabilities of both disease free and endemic equilibria by the use of lyapunov function. by the use of real data obtained from turkey in , we will conduct numerical simulations to support the analytic result. the organization of the paper is as follows: in sect. , the model is presented and the basic reproduction number is obtained. in sect. , stability of the equilibria are investigated. in sect. , results are obtained by numerical simulations of the real data obtained from turkey in . finally sect. is the discussion and conclusion of the research. the system of ordinary differential equations derived is for the whole turkish population. consider the birth k(t) to the susceptible population per unit time. susceptibles individuals are removed through infection or through natural death. let µ be the natural death rate for the whole population. the removal rate of susceptible individuals through infection is the number of new hiv infections per unit time. we use this rate in calculating hiv incidence which by definition is the number of new infected persons in a specified period of time divided by the number of uninfected persons that were exposed for this same time. let each susceptible have c contacts per unit time. assume that a proportion h/n of these contacts are with infectives and at each of these contacts with infectives, a susceptible has a probability b of becoming infected. let a the incidence rate, then the total probability of one susceptible getting hiv infected from any of their contacts per unit time is ah/n. this is the expression for the force of infection. the force of infection is the probability that a susceptible will get an hiv infection per unit time. therefore in a population of s susceptibles, the number of new hiv infections per unit time is given by ahs/n. infectives are recruited through new hiv infections described above and removed through death at rate v and through natural death at rate µ. hence, /v is the duration spent in the infective stage and /µ is the life expectancy of the population. all these rates are assumed constant in the model. removed cases are recruited either through natural death l or through deaths due to hiv at the rate v. with these assumptions, we arrive at the following system of ode. ( ) can be reduced to it follows from ( ) that, thus the feasible region for ( ) is for the simulation we make further assumptions as follows; (i) s( ) is considered to be the whole population in (ii) we considered homogeneous mixing in the population (iii) v ¼ : is considered (that is averagely years is the life span of hiv+ people) equating the equations in (*) to zero and solving simultaneously we find two equilibrium points. disease free and endemic equilibrium points. this is the number of secondary infections caused by a single infective individual in a completely susceptible population. it is denoted by r . using the next generation of matrix (ngm) method we have, the spectral radius, which is the dominant eigenvalue, is as v þ l hence the basic reproduction ration is; in this section stability analysis of the two equilibrium points is obtained by the use of lyapunov function. the conditions for the global stability of the equilibria in each case depends on the magnitude of the basic reproduction ratio r . hence we have the following theorems and their proofs. theorem : the disease free equilibrium is globally asymptotically stable when r . we construct the following lyapunov function by the relation between geometric and arithmetic means and if as v þ l ð Þ. this implies _ v if r . the endemic equilibrium e is globally asymptotically stable when r [ . proof: we construct the following lyapunov function by the relation between arithmetic and geometric mean and if in this section, results are calculated by simulating the model using the real data obtained from turkey in . here we use the real data obtained from moh, in which there were a total of hiv- positive reported cases in the year , in the year to study and predict the dynamics of hiv in turkey using our model. table presents the values of the parameters as calculated based on the data obtained. since r [ , the disease free equilibrium is not stable and the endemic equilibrium is stable. hence, there is going to be epidemics. simulating the above result, fig. shows the epidemic of hiv/aids in turkey. a mathematical model for hiv+ is constructed and analyzed. two equilibrium points (disease free and endemic) are found and stability of each of the equilibrium point was shown to depend on the magnitude of basic reproduction ratio, using lyapunov function. it was shown that if r ¼ as v þ l is less than one, the disease free equilibrium is globally asymptotically stable. also, if the value is greater than or equals to one the endemic equilibrium is globally asymptotically stable. the turkish population in the year is , and the hiv positive population is . the value of the basic reproduction ratio is . , which is bigger than one. this implies one hiv positive individual in turkey can be able to transfer the disease to almost individuals, hence there is going to be hiv epidemic in turkey. numerical simulations were carried out and the results support the analytic findings. the results in the simulation shows that if appropriate measures are not taken, in years to come, there will be more hiv positive individuals in turkey as there are susceptible individuals. the main limitation to our analysis may be that we did not account for the effect of behavioral change arising both from number of hiv cases in the community as well as awareness by governmental and nongovernmental organizations. secondary, the possible effects of extensive use of antiretroviral drugs (arvs) in terms of method of distributing drugs through public or private health institution or a combination of both could determine whether patients on arvs revert back to the infective class. this together with reduced infectiousness due to lower viral loads for those on treatment was not accounted for. despite the limitations mentioned above, there are several implications of our findings to public health. first, the endemic equilibrium should be brought as low as possible especially during the first wave of the epidemic. this model suggests that this can be achieved by prolonging the lifetime of the hiv patients for as long as possible. second, hiv prevalence at low prevalence levels become less sensitive to changes in the dynamics of hiv epidemic because it is overpowered by demographic changes especially the recruitment of susceptibles. at low prevalence levels, there is hence need to track trends in number of persons infected with hiv than tracking hiv prevalence. a preliminary study of the transmission dynamics of the human immunodeficiency virus (hiv), the causative agent of aids stability analysis of an hiv/aids epidemic model with treatment mathematical epidemiology of infectious diseases: model building, analysis and interpretation stability analysis of an hiv/aids epidemic model with screening stability analysis of an hiv/aids dynamics model with drug resistance analysis of the treatment costs of hiv/aids in turkey global analysis of an hiv/aids epidemic model dynamics of hiv/aids in turkey from to aids knowledge and attitudes in a turkish population. an epidemiology study status hiv/aids epidemic in turkey molecular epidemiology of hiv in a cohort of men having sex with men from istanbul mathematical models for hiv transmission dynamics: tools for social and behavioral science research hiv dynamics and behaviour change as determinants of the impact of sexually transmitted disease treatment on hiv transmission in the context of the rakai trial can population differences explain the contrasting results of the mwanza, rakai, and masaka hiv/sexually transmitted disease intervention trials: a modeling study a simple approximate mathematical model to predict the number of severe acute respiratory syndrome cases and deaths understanding the epidemiology of bse the foot -and -mouth epidemic in great britain: pattern of spread and impact of interventions transmissibility of pandemic influenza an epidemiological model for west nile virus: invasion analysis and control applications uncertainties regarding dengue modeling in rio de janeiro malaria and its possible control on the island of principe the basic ratio number of ebola and the effects of public health measures: the cases of congo and uganda a scrapie epidemic in cyprus risk of indoor airborne infection transmission estimated from carbon dioxide concentration emergence response to small pox attack: the case for mass vaccination role of awareness in controlling hiv/aids: a mathematical model key: cord- -cxn ewfw authors: anderson, virginia title: performing interventions: the politics and theatre of china’s aids crisis in the early twenty-first century date: - - journal: viral dramaturgies doi: . / - - - - _ sha: doc_id: cord_uid: cxn ewfw theatrical productions attest to a radical shift in chinese governmental policy and public awareness of the aids epidemic at the dawn of the twenty-first century; state-subsidised theatre worked directly with the government to contain the transmission of hiv. produced by two of the country’s most elite cultural institutions, the shanghai dramatic arts center and the beijing people’s art theatre respectively, the dying kiss (shengsi zhiwen) in and student zhao ping (zhao ping tongxue) in represented a sea change in the political response to the epidemic while documenting public perceptions towards people living with hiv and aids in china. marking policy change, they reflect experiences that capture a society transitioning from denial to confrontation at the dawn of the twenty-first century. it was sixteen years after china's first aids case was identified that the nation's government made hiv a high national priority by publicly acknowledging the severity of the threat the virus posed to its population in (wu et al. : ) . theatre at high-profile institutions was to serve as a powerful tool for prevention, stigma reduction and national image preservation. government-appointed aids ambassador and stage and screen celebrity pu cunxin communicated a vision for theatre's utility: "we can't leave the arts out of the fight against aids but the arts must disseminate knowledge in an artistically superior waynot just spread education and propaganda. the power of real art is to move people, to reflect people's experiences" (pu ) . these two high profile theatres provided a literal stage for the demonstration of government-sponsored efforts to turn the tide of the epidemic in china. such a partnership was explicitly financial as well as ideological: the dying kiss was co-produced by the shanghai municipal health bureau and the shanghai dramatic arts centre and student zhao ping was coproduced by the china youth fund for the prevention of aids and gobon guilin latex (a point discussed later in this essay). prior to these productions, government officials and the government-controlled media kept the virus separate from promoted views of chinese nationalism, resulting in intense stigma for people living with hiv or aids. with new policies and such visible cultural leadership, a new commitment to hiv and aids prevention and care was palpable in the early twenty-first century. in this chapter, i first establish an historical context for these plays through a discussion of the epidemic's evolution in china through the end of the twentieth century. i then consider the modes of production and the sometimes subtle political content of each play in relation to shifts in governmental policy (with which both content and production are intertwined). rooting my work in historical and dramaturgical analysis as well as interviews with artistic contributors, health workers and activists, i argue for the significance of the dying kiss and student zhao ping as embodiments of government-fueled popular perceptions of hiv and aids in china at the start of the twenty-first century. despite their short runs, these productions established an important precedent for theatre to address stigma and to affect governmental policy and even china's international standing as a leader in the global effort to address the epidemic. early in the new millennium the goal of many theatre artists who addressed the epidemic in china was to alert audiences to its immediacy, to keep them from fearing it and to reduce isolation and shame endured by affected individuals. the need for such goals becomes clear as one considers the cultivation of stigma over the preceding decades. the trajectory of the aids epidemic in china is often divided into three stages (shao ; huang ) . yiming shao, chief expert on aids for the chinese center for disease control and prevention, describes the 'introductory phase' as between roughly and , when a popular perception of aids as a foreign disease was established. during this period, a small number of cases involving foreigners and chinese citizens who had been traveling internationally was identified in coastal cities. yanzhong huang, senior fellow for global health for the council on foreign relations, assesses the impact of these early cases on the perception of the growing crisis: the initial statistics reinforced the myth that hiv/aids was not so much a public health problem as a social ill confined to western countries. like their us counterparts, chinese scientists and public health officials were initially convinced that hiv/aids spread mainly through homosexuality and promiscuity (xinhua july , ) . believing that both behaviors were 'illegal and contrary to chinese morality' and therefore limited in china, senior health officials were confident that the aids epidemic was unlikely to occur within their borders. ( : - ) the second, 'slow' or 'regional' phase of the epidemic, is attributed to the period between and and describes the steady increase in incidence and the appearance of the disease within border regions of the country. it is often marked by the identification of hiv-positive intravenous drug users within china's southwest yunnan province. hiv spread widely during this phase, reaching the majority of china's provinces and adding several hundred cases each year. the geographical site of the next turning point lies in the central henan province, where the practice of selling blood for cash was widespread in the mid- s and hiv infection in the region was recorded at over per cent of the population (rosenthal sept. , a) . by , hiv incidence climbed into the thousands. the third, 'nationwide', phase of the epidemic paved the way for undeniable recognition in the new millennium at about the same time. by , hiv or aids cases were reported in all thirty-one provinces; china documented its first case of mother-to-child transmission, and sexual transmission of the disease had rapidly increased. still, intravenous drug use and commercial blood and plasma donation accounted for the majority of transmissions during this phase, at . per cent and . per cent of the estimated number of hiv infections, respectively (china ministry of health ). the government estimates that in just four years, between and , the number of people living in china with hiv increased from , to , (thompson : ) . during this pivotal period in the first years of the new millennium, theatre artists directly engaged with new governmental policies, cultural identity, and social realities for people living with hiv or aids. their productions serve as time capsules of a radical shift in the nation's response to the epidemic. by world aids day , the chinese news media were covering the epidemic in force. in addition to interviews with people living with hiv and widely-distributed public service announcements, a fictional television 'soap opera about a businessman who contracts the aids virus [sic] after a one-night stand with a prostitute [sic], featuring some of china's most popular actors' called if i have tomorrow aired during prime time on china central tic (cctv) (rosenthal december b) . pan guiyu, vice minister of the sfpc, promoted if i have tomorrow by saying that it 'not only introduces to the public scientific knowledge about aids, but also sets a good example of the correct attitude people should hold toward the aids patients [sic] and their deadly disease. [it] explores the theme of aids from social, family, ethic [sic] and moral perspectives, cautioning people to keep away from aids and calling for social concern for aids patients' (state council ) . foreshadowing the theatre about to emerge, government leaders invested in the power of entertainment to bring issues surrounding hiv to the public's attention. even through this first programme of its kind, conservative morality was linked to a promoted national identity. in a series for the new york times, elisabeth rosenthal documented the direct link between an increase in news media coverage and the government's evolving position on the epidemic, concluding: 'in a country where all news media are state-owned and content is more or less controlled, the burst of interest [in hiv and aids] clearly reflects a government decision to allow greater discussion of an epidemic that is growing rapidly, but has previously received only intermittent attention by the media' ( december b). the changes occurred quickly; in , a short public-service announcement promoting condom use was pulled from television by officials who worried that it was 'too risqué', but only two years later safer sex was openly discussed on the radio. even with more open public discussion, stigma remained and news coverage at the turn of the millennium still reinforced early perceptions of hiv and aids as a problem linked to foreigners; people living with hiv or aids featured on television had generally contracted hiv overseas and concealed their identity by wearing sunglasses or turning their backs to the camera (rosenthal december b) . social discrimination was widespread, manifest through well-documented isolation, the loss of resources and services, verbal stigma, secondary stigma endured by family members and fellow villagers, and even self-discriminating behaviour (cao et al. ; hardee et al. ). despite this increase in reporting, an official shift in policy did not occur until , described by meghan laslocky for pbs as 'the tipping year for china with regard to recognition of aids'. in an iconographic watershed moment, prime minister wen publicly shook the hand of a person living with hiv. laslocky writes: many say it took a televised handshake for china to wake up. on world aids day , prime minister wen jiabao shook the hand of an hivpositive person, and a close-up of their joined hands was broadcast around the country. finally, with by some estimates one million aids victims [sic] in henan province alone, silence was no longer an option, and the country's leaders were scrambling to come up with policies to show that they had a plan. (laslocky ) that year, a new administration headed by president hu jintao, prime minister wen jiabao and vice premier and the then health minister wu yi put the implementation of evidence-based hiv policies high on the national agenda (sun et al. ) and announced a new national aids control policy, 'four frees and one care' (free treatment, free voluntary counseling and testing (vct), free prevention of mother to child transmission (pmct) and free schooling for aids orphans, as well as provision of social relief for hiv patients). however, such high-level policy making could not in and of itself prompt deep cultural change; after a photo of president hu jintao shaking hands with a person living with hiv was published, the man's daughter was expelled from school because of her father's serostatus (wan ) . the impression of government leadership was important, however, and two plays at high-profile state theatres captured this dramatic shift in policy and served as a tool for prevention, stigma reduction and national image preservation. while government spokespeople frequently stated that compassion was needed for all people living with hiv, dramaturgically, the dying kiss is set up to emphasise the protagonist's 'innocence' (in contrast to the 'guilt' of others). even as the play educates audiences about hiv prevention and stigma, protagonist xiao lu is portrayed as a life-saver, a devoted son, a loving brother, a dedicated fiancé and a citizen unfairly discriminated against. for these reasons, producers at the shanghai dramatic arts center were optimistic when they sought funding from the city's board of health to fund additional performances beyond the planned six. nonetheless, the request was denied with the rationale that, with its limited reach, theatre was not a good model for raising awareness (yu ) . the board did, however, supply printed educational materials to distribute to audiences. this act demonstrates conflict among government leaders: while some stress that formal educational materials cannot adequately capture the human dimension of the epidemic (pu ) , not everyone was willing to step away from traditional modes of education and prevention, even during this period of increased awareness and hiv and aids policy reform. nevertheless, the internationally acclaimed theatre is a flagship of modern china's culture and to produce the play on this topic in the first place was a demonstration of commitment to the issue. the banner atop the shanghai dramatic arts center production program for the dying kiss declares the play to be 'the first play about aids in china'. while this description is not quite accurate, the production remains remarkable for its full-length treatment of the emotional experience of a chinese person living with hiv and the embodiment of popular conceptions of hiv and aids. the play, written by li rong and li shengying and directed by terence chang, is based on actual events that were documented by journalist tu qiao in a monthly newspaper column and her subsequent book entitled a century's sorrows ( ) . it depicts the development of a trusting relationship between the journalist and xiao lu, a person living with hiv. the dying kiss is a zhuxuanlu, or main melody play, one that reinforces government-supported values. claire conceison explores the complexity of the 'main melody' campaign in chinese spoken drama, describing a 'complicated dialectic with which the government was able to exert control over theatre workers while at the same time theatre workers were able to manipulate this control to their own advantage' ( ). these nuances are captured within the dying kiss ( fig. . ) . the opening stage directions begin to correct the popular misunderstanding that hiv is an illness coming from beyond china's borders by indicating that taiwanese singer luo dayou's classic love song 'my hand passing through your black hair' plays on set, and 'suddenly brings people to an intangible world that seems far away but is actually very close' (li and li : , emphasis added). the time is now and the location is a corner of the city. journalist xu qian serves as the audience's intended surrogate in the play; through her relationship with xiao lu, the audience member who believes that they are far removed from the virus develops a personal relationship with someone living with hiv. the documentation of early twenty-first century popular understandings of hiv and aids abound from the first moment, sometimes with graphic, ignorant language. upon learning that xu qian is going to interview a person living with hiv, her friend wa wa sets three rules for interaction: she must not shake hands with her interview subject, she must keep three feet away during the interview and she must refrain from talking over forty-five minutes. xu qian responds to her friend's demands with an assurance that includes a grotesque description of the physical manifestation of hiv, in line with popular misconceptions: i understand wa wa, because everyone would have the same reaction. ai zi! wow! the untreatable disease! aids! … it eats your healthy cells, and swallows your entire body. your beauty and figure all turn into rotting meat, a disgusting pile of rotting meat. i am not reading you the poetry of shakespeare, i am interviewing such a person. (li and li : ) although xu qian defies her friend and shakes the hand of xiao lu, who is described as 'a handsome man', afterwards she 'secretly looks at her palm and wipes it on her pants' (ibid.: ). blame and stigma endured by people living with hiv are dominant themes throughout the play. echoing the sentiments of pu cunxin and the government's public stance on hiv and aids, xiao lu addresses his sense of social isolation in stark language and graphic imagery: even if people did get the disease because of their dissolute lifestyle, i do not want you to look at them that way. their lives are already hard enough and now they need to endure everyone's disdainful look. they are like rats curling up in the city's corner waiting to die, and in the morning the cleaner would throw them into the garbage truck. who doesn't want to live healthily and happily? (li and li : ) this vivid and dehumanising comparison to rats contributes to stigma even as the play's producers sought to lessen it. nevertheless, it captures contemporary popular fears. herein lies the complexity of the dying kiss as a signal of governmental change; it calls for compassion, but employs language that underscores fears and revulsion. a nationalistic view of china is reinforced through heroic action, gender dynamics, and echoes of the long-promoted idea that hiv and aids perme-ated china's borders from abroad; much is made of the idea that xiao lu acquired hiv while in thailand. the protagonist is chinese, and national pride is evoked as transmission is portrayed through valiant action: xiao lu saved the life of a co-worker when an industrial sewing machine punctured her hand. when he gallantly freed her, it fell down upon him, puncturing his finger ( - ). the gender dynamics in this scenario are significant. as alicia leung argues ( ) , at the time of this production, china 'maintained a high degree of control over gender construction in order to legitimize its historical achievement of revolution and liberation, … this is derived from the core philosophy confucianism in which human role relations are cultivated and developed within a male-centered world' ( ). therefore, xiao lu was upholding core, nationalist values when he contracted hiv (while overseas) and is thereby presented as one of the play's 'innocent victims'. what the play does manage to achieve is to show discrimination in medical care in china, from references to nurses hiding from people living with hiv ( ) to xiao lu's decision to seek treatment overseas ( ). the play contrasts the blame, social stigma and harsh treatment in china with compassion and care at a treatment centre in thailand. a late scene between xiao lu and his doctor serves as a direct critique of the national response while providing a vision of the future (that aligns with the new governmental policies): director cai: i should apologize to you. … do you remember how i distrusted and doubted you when we met for the first time? xiao lu: that was normal. everyone would think like that. director cai: xiao lu, it is not right to think in that way, especially as medical personnel. no matter how this person got aids, he deserves our sympathy and needs our devoted care. any prejudice would just hurt them more deeply, which fails to help people fight the plague by weakening their fighting capacity. … i wonder why a patient tries so hard to try to prove his innocence? doesn't it reflect prejudice ingrained in our values? while people are suspecting and despising each other, aids becomes increasingly rampant, devouring our land and our lives! i think that only when we create a better recovery? environment and cultural? atmosphere, can we help patients to fight disease and make a miracle. in a sense, every patient is a soldier who fights in the frontline. (li and li : ) as the scene draws to a close, director cai and xu qian (our audience surrogate) reflect on how much they've learned from xiao lu. still, such a critique of china was to be made only within a larger critique of foreign value systems. drawing on this notion of blame and guilt associated with hiv and aids, the play provides an indictment of capitalism and perceived western values while emphasising a commitment to core values of chinese nationalism. perhaps no scene documents this denunciation with greater clarity than a flashback to 'heaven's home', the treatment facility in thailand where xiao lu receives care. making a strong contrast with the hospitals of china, xiao lu describes his new surroundings to the audience: 'here people are absolutely equal. here, the doctors and nurses are kind hearted like angels. they gave me comfort and the newest treatment' ( ). there, xiao lu meets a monk, whose lived buddhist values stand in sharp contrast to xiao lu's father's claimed christianity. the monk's story serves as a critique of capitalist values, further emphasising that some-antinationalist-behaviours make people 'deserve' to have hiv. the monk used to be a government official with a 'loving, sweet wife, a smart son in high school'. he then grew jealous of friends who had more money and beautiful women and quit his government job to go into business: 'at that time, bosses were flying all over the sky, ceos were prevailing on the land. when you yell boss or ceo on the street, nine out of ten people would turn around. it's worth nothing.' he made a lot of money ( ). he reveals that he contracted hiv through infidelity and that, 'without knowing, i brought the disease to my wife' and his son has since cut off contact with him. now, devoted to his spiritual life, he explains: i know i'm going to hell. then why don't i use my last time to make friends and contribute to the society to build a better afterlife? … i will use buddha's great wisdom to light your fire of life, use buddha's endless power to ignite your courage to conquer the disease, and use buddha's forgiveness to make clear that you need to cherish your every day, alive. ( ) this emphasis on society instead of the individual reflects core chinese cultural values. varying degrees of guilt and innocence and a commitment to nationalism emerge through this story. if the monk had not succumbed to capitalist desires, he would still be working for the government with a happy wife and son in further embodiment of cultural values. another play captured nationalistic tensions surrounding hiv and aids at the beginning of the twenty-first century, this time written and directed by one of the leading theatre artists in china, tian qinxin. student zhao ping focuses on the cultural clashes between a younger generation of chinese college students and older, more conservative professors and police officers. its development history captures the conflict between art expressing china's youth culture and official restrictions. in addition to its place in china's official response to the hiv and aids epidemic, student zhao ping is noteworthy within the context of tian's career in that, as she herself observes, it is not like much of her other work (tian a ). the play is left out of most critical discussions of the acclaimed writer/director who is perhaps best known for her passionate and visually inspired presentations of huaju, or spoken drama. the piece began its development when tian was approached by representatives of the china youth development foundation to write a play with themes about the devastating impact of aids and its prevention among young people. tian knew of the prejudice and stigma surrounding hiv and aids and felt as though, for the newest generation, the increasing incidence of hiv was an educational problem, and not only for those who tested positive. she asked; 'who is paying attention to the people who are in fear? i wanted to explore this question. this play looks at the educational problem in this context' (tian a) . brechtian in form and aim, the structure was the rehearsal of a play, calling for actors to play multiple roles even as they shifted between characters and themselves and provided commentary on the action. there were three different levels of interaction: actor to actor, actor to character and character to character, enabling brief moments of audience interaction like that in augusto boal's forum theatre. in these moments, this technique was used for audience empowerment and social change at the grass-roots level. the play begins with the sexual harassment of zhao ping by four western foreigners (played by actors wearing face masks, according to the stage directions; tian b: ) at an international hotel in beijing. presumed to be acting as a sex worker, zhao ping is reported to the police by hotel security. informed of the charge, university faculty and administration debate how prostitution and their (unnamed) university policy could co-exist. police officers join the meeting and share information from their interrogation: zhao ping has multiple boyfriends and 'if she has a foreign boyfriend, she should get her blood tested' ( ). the university officials blame zhao ping's behaviour on her education and her professor xuedong comes under fire. it is revealed to the audience that zhao ping and xuedong have been involved romantically. when zhao ping is convicted of prostitution, university officials fail her final paper, the last requirement for graduation. without telling anyone where she is going, zhao ping then disappears. two months later, a friend of zhao ping tells xuedong that zhao ping had emailed her and shared that one of her boyfriends was diagnosed with aids. concerned about his own status, xuedong goes to the hospital to be tested. following his blood test, he moves 'into another dimension' ( ). tian qinxin pointed to this scene as the crux of the play; as an artist, she was most interested in the emotions surrounding hiv and aids and, for her, 'the most interesting time is the period of waiting for results and the fear people experience. it doesn't matter what the results are, but whoever that person is, they need to have friends supporting them' (tian a) . xuedong describes how he feels 'as if my spirit has left my body'. while unnamed characters offer reassurances about current treatment options and prognoses, zhao ping and her friend express contrary ideas: 'it cannot be cured', 'you would need a huge sum of money. average people cannot afford it,' and 'even flu vaccines change every year. viruses change' (tian b: ) . tian qinxin maintains that the fear xuedong experiences is an opportunity for education ( a); he is enveloped in fear, creating an aura of tension within which the actors switch in and out of character to speak frankly about the disease and risky behaviour directly with the audience through improvisation (tian b: ) . as the educational discussion ends, the audience returns to the fictional world in which a police officer reports that neither the foreigners' claims of prostitution at the hotel nor zhao ping's claims of harassment are considered reliable and, following review of security footage, zhao ping is exonerated. concluding the play, zhao ping, now attending an us university, exchanges emails with xuedong through which she reveals that she does not have aids: she made that up as, indeed, she had made up her boyfriends. her manipulation of authority figures leaves the audience questioning what might be trusted in their own relationships. taken in its entirety, student zhao ping is less a play about hiv and aids and more about generational conflict and gender construction, but this improvised scene, broken out of the fictional narrative, serves an important purpose: ensuring direct, frank conversation about hiv with the audience. that it does so while promoting a specific brand of condoms is an issue i discuss later (fig. . ) . produced by the national theatre company of china, the play was marketed as a fundraiser for aids orphans but tian emphasised its importance for a particular, wider demographic: the rising youth generation within the overall population. the generational divide was captured in the press and described as emotions caught in fierce collision; the construction of gender roles is held up for interrogation and zhao ping's agency stands in sharp contrast with her teacher's view that women are 'born irrational, selfless, and passive' (tian b: ) . theatre critic faye wong observes of the play, 'compared with the physical aspects of the disease, the ideological roots of the virus are more horrible ' ( ) . tian describes how these ideas found manifestation in her process: before making the play, i interviewed some college students and professors about their views on aids. we do not cover drugs or moving scenes of caring for aids patients in this play, because television already tells this aspect of the epidemic extensively and vividly. theatre cannot surpass television on this. we strove to present the collision of thought of people from different ages behind the sexual confusion of aids. (cited in wong ) this emphasis on sexuality and individuality may appear markedly progressive and, certainly, compared to the traditional conservative morality in the dying kiss, it is. however, the play was sponsored by gobon guilin latex, the foremost condom manufacturer in china (see global business ; zou et al. ) , which promoted its brand not only by providing condoms for the audience in a gift bag along with informational brochures, but for conspicuous product placement within the play's final moments: xuedong: i should not preach to the audiences, but people should not have a promiscuous life. zhao ping: if you can't do that, i think, at least be safe. xuedong: the "yezhanpai" is pretty good everyone: we should use "yezhanpai" produced by guilin gaobang. (tian b: ) such a corporation would have a financial interest in promoting (safe) sexual freedom, partnering theatre and industry in efforts to contain the epidemic. furthermore, the market was auspicious: with the increased awareness and action concerning hiv by the government and in the popular media, condom sales were increasing dramatically ('global business' ) . while promoting discussion of hiv, the play was also promoting a new ideology concerning sexual freedom. this cultural shift is apparent within governmental regulation of the play. when tian sought official approval of the script from the cultural bureau in beijing prior to production, she was told that, while the subject of hiv was important, the script's sexual content was a problem. tian was flabbergasted that she had been commissioned to write a play about aids for an increasingly sexually active generation but was not to address sex, a potent means of hiv transmission. she said: 'there's no way we could present this story to this generation without talking about sex' ( a). she sought and found a loophole in the approval system. during my interview with her, she emphasised that this was a time of significant cultural reform; 'there was a socialist system for performance approval and a new, special socialism category' through which the play was finally approved (tian a) . like the dying kiss, tian's play reinforces the idea that hiv and aids are associated with foreigners. indeed, in order to torment her lover, zhao ping plays off the cultural imagination by telling xuedong that she may have contracted hiv from her foreign boyfriend. despite the progressive depiction of zhao ping's sexuality, the play presents the police as a conservative moral authority. while they conclude that zhao ping had not been engaging in prostitution and so should not face punitive actions from the university, therein lies the condemnation of sex workers. similarly, zhao ping had lied about having a foreign lover, suggesting that her own serostatus might be different if in fact she had had a foreign lover. negotiating national identity during an international epidemic both legitimising and challenging the early chinese cultural assignation of aids as a foreign disease, these productions comingle with concurrent policy to acknowledge the reality of the disease in china. the dying kiss and student zhao ping reflected the government's evolving stance concerning the virus. these plays protected the honour of chinese national identity by portraying the disease as something entering chinese society from outside the country's borders. the plays addressed in this study mark policy change, reflecting experiences that capture a society transitioning from denial to confrontation at the dawn of the twenty-first century. since the time these plays were produced few theatrical productions in china have approached the topic of hiv and aids explicitly, while television and feature films continue to offer representation. however, stigma endures (kazar and wang ) and it remains to be seen how the performing arts in china might productively intervene. this research would not have been possible without the generous scholarly support and tireless translation work of dr claire conceison, the financial assistance of the then tufts university provost jamshed barucha, and the enthusiastic research and translation assistance of connecticut college students qingmei (cleo) han and especially shuhan zhang. an early version of this chapter benefitted from generous feedback from participants in the 'theatre and national/ with hiv through such facilities, removed from central society, perhaps most notably the wat phrabat nampu temple, which began as an aids hospice in and continues its service today. see wright et al. ( ) . . notably, one star-studded film, love for life (gu et al. ) , is set in the s instead of contemporary china. documentaries such as the blood of yingzhou district (lennon and yang ) , the epic of central plains (ai ), together (zhao ) understanding hiv-related stigma and discrimination in a "blameless a joint assessment report of hiv/aids prevention, treatment and care in china the main melody campaign in chinese spoken drama companies of the global business coalition on hiv/aids (gbc) announce immediate commitments to fight aids in china hiv and aids stigma and discrimination in china: results from a national survey celebrity philanthropy in china: the political critique of pu cunxin's aids heroism governing health in contemporary china aids demolition brigades" clear path for property developer the spread of aids in china: a slow acknowledgment of the 'capitalism loving disease the blood of yingzhou district feminism in transition: chinese culture, ideology and the development of the women's movement in china xin ru zhi shui shengsi zhiwen beijing: beijing people's art theatre and oly café blood and tears: a chinese family's ordeal in a nation in denial of aids suddenly, aids makes the news in china chinese national identity and national identity gaps in east asia aids epidemic at age and control efforts in china state council information office and the china international publishing group (cipg) evolution of information-driven hiv/aids policies in china hiv carriers stage plays in beijing china confronts aids interview with author (c. conceison, trans.). national theatre company of china zhao ping tongxue = student zhao ping shiji zhitong: zhongguo songfen aizibingren wanquan jilu [a century's sorrows: a complete record of a person with aids from china interview with shuhan zhang discrimination against people with hiv/aids in china modern asian theatre and performance student zhao ping" is a psa for people born in the s hospice and palliative care in southeast asia: a review of developments and challenges in malaysia, thailand and the philippines evolution of china's response to hiv/aids. the lancet together. new york: dgenerate films chinese cultural values and chinese language pedagogy (doctoral dissertation) condom use in china: prevalence, policies, issues and barriers key: cord- -dcdc sqi authors: kimball, am; thant, myo title: “what, me worry?” businesses and aids at davos date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: dcdc sqi nan at the davos summit in february, , the world economic forum released its current survey on businesses and hiv/aids. in , we outlined the case for business in asia to play a pivotal role in preventing the epidemic. at that time, an estimated million people in asia had been infected with hiv. today that number is estimated at · million. aids is a preventable disease. the survey finds an absence of alarm in the business sector which, if true, bodes poorly for success in controlling this epidemic. beyond the tragic human costs, the economic and financial tolls of this epidemic are well known. costs to employers include: increased insurance premiums, larger expenditure on welfare benefits, decline in productivity, and increases in hiring and training costs. loss of skill base, institutional knowledge, and potential conflict in the workplace because of stigmatisation are more difficult to measure. at the macro level, the business environment, including markets and disposable income of consumers, savings rates, interest rates, and general education of the labour force, are put at risk. the findings in the survey from firms worldwide are a subset of global business surveyed annually by the world economic forum. firms appear less concerned this year than last year. this lack of concern is accompanied by conjecture rather than science as a basis for decision-making. informal policies prevail except in high-prevalence areas such as sub-saharan africa. why such complacency? the global epidemic has shown its inexorable nature in community after "what, me worry?" businesses and aids at davos pregnancy to any antiasthmatic drug), there is still much be learned. this need for information is particularly the case for systemic glucocorticosteroids and for recently introduced medications, such as salmeterol, formoterol, and leucotriene-receptor antagonists. one negative point is that, when systemic glucocorticosteroids are administered during the first trimester, the risk of an orofacial cleft is increased by about , although the power of the studies is poor and many confounding factors persist. one positive point is that more than women have been exposed to inhaled corticosteroids (mostly beclomethasone and budesonide) during pregnancy with no increase of outcomes in the infant (including congenital malformations). the higher reported risk of hypertension and pre-eclampsia in steroid-treated pregnant women is not related to the drugs but to uncontrolled asthma. thus, because many clinical trials on inhaled corticosteroids have shown efficacy in pregnant asthmatic women in terms of symptoms, lung function, and reduction of asthma exacerbations, maintaining asthma control during pregnancy is the goal; and, when the indication is clear (eg, severe asthma exacerbation), the benefit of systemic glucocorticosteroids is far greater than the risk. the main message of the update is that it is safer for the asthmatic pregnant woman to be treated with asthma drugs than to suffer from asthma symptoms and exacerbations, and that obstetricians and asthma-care providers should work together. guidelines for asthma during pregnancy should not differ from the guidelines for all asthmatic patients, but fetal toxicity should be monitored and an evidence-based search for drug treatment should be continued. community, country after country; will it now be business after business? in asia, the prospective new epicentre of the epidemic, the efforts of the thailand business coalition on aids and the tata group in india highlight roles business can play: prevention and education for workers; workplace programmes to prevent discrimination; and public-private collaboration and funding for effective programmes. the thailand business coalition on aids offers a range of tools for businesses to assure good-quality programming at all organisational levels. the tata group has focused on a full range of workplace programmes to ensure the sexual health of their employees, including an emphasis on nondiscrimination. leadership at the top of firms, coupled with government commitment, is key. the most populous countries in the global community, china and india, are now in the cross-hairs. projections for india are alarming: - million people living with hiv by , and a potential of million cases by . the epidemic is driven by commercial sex-work, and clients include businessmen who could benefit from education programmes in the workplace. there are peer-to-peer strategies that are effective in condom promotion. thai experience suggests that also addressing the clients ensures success. workplace programmes to secure the safety of the workforce would be a valuable contribution at this critical time. many economies are rural in asia; the effects of hiv on the household level are profound. the health infrastructure in china is crumbling, especially in rural areas, even as market reforms have created unprecedented economic growth. the business sector in china should lead the reinvigoration of preventive and health services. the march summit of the business coalition on aids, in beijing, was a perfect launch. the expansion of access to antiretroviral treatment in asia will not be a panacea. us experience shows that the reprieve from hiv is not forever, efficacy is not %, and people living with hiv face many obstacles in returning to work. from a business perspective, proactive prevention coupled with compassionate policies in the workplace and coverage of treatment through insurance is the wisest choice. there is a gulf between the public and private sectors that must be bridged in the fight against aids and other emerging infections. the urgency of robust public-private partnering is clear in the asia-pacific region, where the threat of new human infections, such as severe acute respiratory syndrome and avian influenza, challenge systems that have not received adequate investment to scale-up to successfully meet these new threats. the economics of intervention by the private sector are not always self-evident. much depends on the ability of the public sector to induce private firms to act for the common good. market incentives, such as tax breaks and subsidies, can lower the cost of training and help businesses provide information and education for workers. the reduction in duties and taxes on imports of equipment and reagents could reduce drug costs. the cornerstone of partnership is for each sector to understand the needs and motivations of the other. the world economic forum's survey is a pioneering work in progress. the kind of information it is positioning itself to capture is very important in the fight against the hiv epidemic. business has brought innovation, energy, and investment in creating value in economies across the globe. the ongoing struggle against hiv and other emergent infections requires no less. in south africa, where less than % of people who need antiretroviral treatment actually get it, private-sector companies are stepping in to fill the need. a growing number are supplying such drugs directly to employees who are hiv-positive or are facilitating access to drugs via third parties such as non-governmental organisations. while businesses in the rest of the world are becoming less concerned about aids, the contradictory trend in south africa is being driven, on the face of it, by two imperatives. the first is heightened social awareness in the postapartheid society. the second is more bankable: an often-compelling economic argument. behind these two driving factors, however, lies the darker reality of the south african government's slow and reluctant concession that it needed to intervene with drugs in the country's aids crisis, and its underperformance in rolling-out treatment with antiretrovirals since being pressed into doing so by, among other things, court rulings. this is where, increasingly, private companies are stepping in. "the corporate sector is shouldering more responsibility for the health of its workforce than it ever has in the past", says bernie clark of the health-care consulting team of alexander forbes, a firm that advises businesses on employee benefits and has helped several companies to develop aids policies (clark b, alexander forbes, johannesburg, south africa, personal communication). about aids, specifically, clark adds: "the perception is that the state is doing precious little to assist the formal work sector to stay at work." so the lesson is that necessity is the mother of drugs' provision. the unadorned bottom-line is that it is cheaper for a firm to supply antiretrovirals than to have an untreated aids patients die while on the payroll. the bottom-line is especially true when the prevalence of hiv positivity runs as high as % -as it does in many of south africa's mining companies which, not surprisingly, have pioneered inhouse aids treatment. for the same reasons of prevalence and financial reckoning, it may be that south african firms are presently leading where others elsewhere in the world will in time follow. a leading example of aids management in asia is thailand, where strong political backing for awareness and prevention campaigns has held the infection rate to · % -compared with south africa's %. in thailand, the thailand business coalition on aids has spawned its own umbrella organisation in the asian business coalition on aids. the coalitions' activities, though, are limited to education and prophylaxis, and do not include inhouse treatment. the most recent survey of the world economic forum's global health initiative shows that awareness by business that aids will affect operations and profits reflects the level of efforts to combat the disease. south african business leaders are well ahead of the rest of the world at % awareness; south and south-east asia, where the thai and asian coalitions are active, lags at %. then the levels fall off even more dramatically: in east asia, where, in china, one of the most worrying prevalences is developing, awareness is at a low %, as it is in latin america. the global health initiative worked with several south african firms to organise case studies, which vividly illustrate the imperatives and benefits for companies offering antiretrovirals to their employees. gold fields, for example, a mining house with mainly low-skilled workers in south africa, calculated that-with one in three of its miners hiv positive-failure to intervene would lead to losses of up to % of earnings by the year . we declare that we have no conflict of interest. global business surveybusiness and aids: commitment and action? world economic forum a role for business in hiv/aids in asia fact sheet: asia modelling hiv/aids epidemics in bostwana and india india's hiv epidemic the economic burden of illness for households in developing countries: a review of studies focusing on malaria, tuberculosis, and human immunodeficiency virus/acquired immunodeficiency syndrome china must prioritise health opportunities for all ministry of health and global business coalition on hiv/aids joint summit on business and aids in china perceived barriers to employment among persons living with hiv/aids key: cord- -cz y u authors: maziarz, eileen k.; perfect, john r. title: cryptococcosis date: - - journal: diagnosis and treatment of fungal infections doi: . / - - - - _ sha: doc_id: cord_uid: cz y u cryptococcosis is an infectious disease caused by the encapsulated fungi cryptococcus neoformans and cryptococcus gattii. once a relatively uncommon cause of human disease, cryptococcal infection can develop in apparently immunocompetent hosts and has emerged as an important opportunistic infection in humans over the past several decades as immunocompromised populations expand in the setting of hiv/aids, organ transplantation, malignancies, and treatment for other conditions. clinical manifestations are myriad but pulmonary and central nervous system (cns) infections are the most common. improvements in diagnostic testing and standardized approaches to antifungal therapy, when available, have made considerable impact in the management of this infection. while the widespread use of highly active antiretroviral therapy (haart) has improved the outcome of cryptococcosis in many hiv-infected patients, cryptococcosis remains an entity of considerable morbidity and mortality in many parts of the world, and restoration of host immunity can present management challenges that require individualized management. as immunocompromised populations continue to expand, it is likely that cryptococcosis will remain an important opportunistic fungal infection of humans requiring ongoing investigation. cryptococcosis is an infectious disease with a wide range of clinical presentations caused by pathogenic encapsulated yeasts in the genus cryptococcus. currently, there are two species of these fungi that commonly cause disease in humans: cryptococcus neoformans, which causes cryptococcosis in both immunocompetent and immunocompromised hosts, and cryptococcus gattii, which is primarily a pathogen in apparently immunocompetent patients but can also cause disease in the immunocompromised. c. neoformans was first identified as a human pathogen in by two german physicians, otto busse and abraham buschke, when they described a circular yeast-like microorganism in a lesion on the tibia of a woman; the microorganism was initially named saccharomyces hominis [ ] . the name c. neoformans has been consistently adopted in both the mycology and medical literature since [ ] . in the mid- s, when kwon-chung discovered two mating types of c. neoformans that produced fertile basidiospores, the organisms were subsequently separated into two varieties, var. neoformans (serotypes a and d) and var. gattii (serotypes b and c). these two varieties were recently separated into two species, c. neoformans and c. gattii, based on their genetic background and phylogenetic diversity, as proposed by kwon-chung in [ ] . it is possible, as more molecular information is gathered from genome sequencing, that c. neoformans var. neoformans (serotype d) and c. neoformans var. grubii (serotype a) will be divided into separate species as well as other cryptic species. the incidence of cryptococcosis began to rise in the late s. early case reports of cryptococcal infections were primarily associated with cancer, autoimmune diseases, organ transplantation, and receipt of corticosteroids as these immunocompromised populations expanded [ ] . a major surge in new cases of cryptococcosis occurred during the first two decades of the hiv pandemic, when cryptococcal infection was an important opportunistic infection (oi) in all parts of the world. furthermore, around , c. gattii strains (previously geographically restricted to tropical and subtropical regions) caused a localized outbreak of cryptococcosis in apparently immunocompetent individuals on vancouver island [ ] . this has increased recognition that these fungi can exploit new geographical environments and cause disease in both immunocompromised and apparently immunocompetent hosts. despite the development of highly active antiretroviral therapy (haart), which has decreased the rate of hiv-related cryptococcosis in developed countries, the burden of cryptococcal infection is still very high in developing countries and in those individuals without access to health care. it has been estimated that there are a million cases per year with more than , deaths due to cryptococcosis worldwide [ ] . the life cycle of c. neoformans and c. gattii involve asexual (yeast) and sexual (basidiospores/hyphae) forms. the asexual form is the encapsulated yeast that reproduces by narrow-based budding and is found most commonly in clinical specimens, whereas the sexual stage, which exists in one of two mating types, "alpha" or "a," is observed only under certain conditions, resulting in meiosis to form basidiospores. the vast majority of clinical infections and environmental isolates are caused by "alpha" mating-type locus strains. since the sexual stage of c. neoformans and c. gattii has been described, their teleomorphs were named filobasidiella neoformans and filobasidiella bacillospora, respectively. c. neoformans and c. gattii usually appear as white-tocream, opaque, and mucoid colonies that grow to several millimeters in diameter on the most routine agar within - h. with some strains, a few colonies occasionally develop sectors with different pigmentation or different morphologies (i.e., wrinkled, smooth, mucoid). both cryptococcal species will grow readily on most fungal culture media without cycloheximide at - °c in aerobic conditions. however, c. neoformans is generally more thermotolerant than c. gattii, and, within this species, serotype a is generally more tolerant than serotype d strains. in addition to their ability to grow at °c, the yeast produce a thick shedding polysaccharide capsule, melanin pigments, and the enzymes urease and phospholipase, which allow cryptococcus to be readily identified from other yeasts. these are also considered to be yeast virulence factors. cryptococcosis was considered an uncommon infection prior to the aids epidemic, associated with malignancies, organ transplantation, and certain immunosuppressive treatments. beginning in the early s, the incidence of cryptococcosis increased significantly and between and % of persons with aids developed cryptococcosis [ , ] . in fact, hiv/aids was found to be associated with % of cryptococcosis cases worldwide. cryptococcal infection is a major oi in hiv-infected patients as the cd + cell count falls below cells/µl. following widespread implementation of haart, the incidence of cryptococcosis among patients with hiv/aids has fallen significantly in most developed nations. the incidence of cryptococcal infection in persons not infected with hiv has remained stable during this time. moreover, in developing nations with limited access to haart, the prevalence of and morbidity and mortality associated with cryptococcosis remains unacceptably high, accounting for up to , deaths per year. besides hiv infection, other risk factors for acquiring cryptococcal infections include many conditions that result in an immunocompromised status (table . ). although both c. neoformans and c. gattii can cause cryptococcosis in apparently normal hosts, the percentage of c. gattii infections causing disease in such patients is significantly higher than for c. neoformans. c. neoformans is found throughout the world in association with excreta from certain birds such as pigeons and in tree hollows. c. gattii is commonly associated with several species of eucalyptus and other trees [ ] . while the link between the environmental source of infection and cryptococcosis cases is not precise, there is evidence to suggest an increased risk of cryptococcosis and asymptomatic cryptococcal antigenemia following intense bird exposures. recently, there has been a strong link between the c. gattii outbreak in humans on vancouver island and common environmental yeast exposures. although these fungi can be detected in endobronchial specimens from humans without disease (colonization), clinicians should be alert for subclinical disease or potential for disease when cryptococcus is isolated from any clinical specimen. approximately % of cryptococcal infections are caused by serotype a strains ( c. neoformans var. grubii) with the remaining - % of infections caused by serotype d ( c. neoformans var. neoformans) or serotype b and c strains ( c. gattii). whereas c. neoformans serotype a is found worldwide, serotypes b and c are found primarily in (table . ) [ ] . in australia and new zealand, serotypes b and c caused up to % of all cases of cryptococcosis cases in one study, but serotype a remains the predominant serotype even in these endemic areas [ ] . to date, only c. gattii strains have been reported to cause a widespread defined outbreak of disease [ ] . cryptococcosis occurs primarily by inhalation of the infectious propagules, either dehydrated (poorly encapsulated) yeasts or basidiospores, into pulmonary alveoli. direct inoculation into tissue due to trauma can be a portal of entry in occasional cases and, potentially, yeast may enter through the gastrointestinal tract. after the yeasts are inhaled into the lungs of a susceptible host, they encounter alveolar macrophages, and other inflammatory cells are recruited through release of cytokines and chemokines such as interleukin (il)- , il- , monocyte chemotactic protein (mcp)- , and macrophage inflammatory protein (mip)- α. cryptococcal infection primarily involves granulomatous inflammation, which is a result of a helper t cell (th ) response with cytokines including tumor necrosis factor, interferon-γ, and il- [ ] . in many circumstances, the yeasts remain dormant (yet viable) in hilar lymph nodes or pulmonary foci of an asymptomatic individual for years and then disseminate outside those complexes when local immunity is suppressed, similar to that which is observed in cases of reactivation tuberculosis or histoplasmosis [ ] . in a patient with severely compromised cellular immunity, the yeasts reactivate and proliferate at the site of infection and then disseminate to other sites causing progressive clinical symptoms. recent advances in the molecular biology of cryptococcus have confirmed several virulence factors. the three classical virulence factors of c. neoformans include: capsule formation, melanin pigment production, and the ability to grow well at °c [ , ] . the prominent antiphagocytic polysaccharide capsule, which is composed of glucuronoxylomannan (gxm), is unique to cryptococcus species and is considered an essential virulence factor that has multiple effects on host immunity. in addition, c. neoformans possesses an enzyme that catalyzes the conversion of diphenolic compounds to form melanin, which may have a biological role to protect the yeasts from host oxidative stresses and which may partially explain the organism's neurotropism. finally, its ability to grow at °c is a basic part of the virulence composite for most of the human pathogenic fungi including cryptococcus, as molecular studies have linked high-temperature growth with certain signaling pathways and enzymes that this yeast has acquired or adapted over time in order to enhance its pathogenicity. other virulence factors include phospholipase and urease production and multiple enzymes associated with protection against oxidative stresses. c. neoformans and c. gattii have a predilection for establishing clinical disease in the lungs and central nervous system (cns). other organs that may be involved in cryptococcosis include skin, prostate, eyes, bone, and blood [ , , , ] . in fact, this yeast may cause disease in any organ of the human body, and widely disseminated cryptococcal infection can affect multiple organs in severely immunosuppressed patients (table . ). the respiratory tract serves as the most important portal of entry for this yeast, and thus there are many clinical manifestations of pulmonary cryptococcosis, ranging from asymptomatic transient or chronic colonization of the airways or simply a pulmonary nodule on radiograph to life-threatening fungal pneumonia with acute respiratory distress syndrome (ards) [ , ] . in a normal host with cryptococcal infection, asymptomatic pulmonary cryptococcosis can occur in about one third of patients with pulmonary infection and patients may present to care with only an abnormal chest radiograph. the most common radiologic findings of cryptococcosis include well-defined single or multiple noncalcified nodules ( fig. . ) and pulmonary infiltrates ( fig. . ), but other less frequent radiographic findings include pleural effusions, hilar lymphadenopathy, and lung cavitation. patients with pulmonary cryptococcosis can present with symptoms of acute onset of fever, productive cough, respiratory distress, chest pain, and weight loss [ ] . the outbreak of c. gattii infections in vancouver island included several cases of severe symptomatic pulmonary cryptococcosis in apparently immunocompetent individuals. in an immunocompromised patient, especially those with hiv infection, cryptococcal pneumonia is usually symptomatic and can progress rapidly to ards, even in the absence of cns involvement. most immunocompromised patients with cryptococcal in-fection, however, present with cns rather than pulmonary symptoms. in fact, more than % of hiv/aids patients with cryptococcal infection already have cns cryptococcosis at the time of diagnosis, many of whom will have a paucity of respiratory complaints. the findings in chest radiographs of immunocompromised patients with pulmonary cryptococcosis are the same as those in immunocompetent patients, but alveolar and interstitial infiltrates tend to be more frequent and imaging can mimic pneumocystis pneumonia. accelerated presentations of cryptococcal pneumonia are more common among immunocompromised patients. in pulmonary cryptococcosis, if the infection is confined to the lung, serum cryptococcal polysaccharide antigen is usually negative. however, while a positive serum polysaccharide antigen may indicate the dissemination of the yeast from the lung, it does not confirm cns involvement. in immunocompromised individuals with pulmonary cryptococcosis, a lumbar puncture to rule out cns disease should be considered regardless of the patient's symptoms or serum polysaccharide antigen test results. the only setting in which screening a lumbar puncture may not necessarily need to be performed in a patient with cryptococcus isolated from the lung is in the asymptomatic, immunocompetent patient with disease that appears to be limited to the lungs. clinical manifestations of cns cryptococcosis include headache, fever, cranial neuropathy, alteration of consciousness, lethargy, memory loss, and signs of meningeal irritation [ , ] . these findings are usually present for several weeks and therefore cause a clinical syndrome of subacute meningitis or meningoencephalitis. however, on some occasions, patients can present more acutely or lack typical features including headache. in hiv-infected patients with cns cryptococcosis, the burden of fungal organisms in the cns is usually high. therefore, these patients may have a shorter onset of signs and symptoms, higher cerebrospinal fluid (csf) polysaccharide antigen titers and intracranial pressures (icps), and slower csf sterilization after starting antifungal treatment. different species may produce differences in clinical manifestations. for instance, one species may have a predilection to cause disease in brain parenchyma rather than the meninges. in certain areas of the world, c. gattii tends to cause cerebral cryptococcomas ( fig. . ) and/or hydrocephalus with or without large pulmonary mass lesions more frequently than c. neoformans. these patients with brain parenchymal involvement usually have high icp and cranial neuropathies, and respond poorly to antifungal therapy. cutaneous infections are the third most common clinical manifestations of cryptococcosis. patients can manifest several types of skin lesions. one common skin lesion is a papule or maculopapular rash with central ulceration that may be described as "molluscum contagiosum-like." these lesions are indistinguishable from those due to other fungal infections including histoplasma capsulatum, coccidioides immitis, and penicillium marneffei. other cutaneous lesions of cryptococcosis include acneiform lesions, purpura, vesicles, nodules, abscesses, ulcers ( fig. . ) , granulomas, pustules, plaques, draining sinus, and cellulitis. because there are many skin manifestations in cryptococcosis that mimic other infectious as well as malignant conditions, skin biopsy with culture and histopathology are essential for definitive diagnosis. skin lesions of cryptococcosis usually represent disseminated cryptococcal infection. primary cutaneous cryptococcosis is very rare and is usually associated with skin injury and direct inoculation of the yeasts. solid organ transplant (sot) recipients on tacrolimus seem to be more likely to develop skin, soft-tissue, and osteoarticular infections due to cryptococcus [ ] . tacrolimus has anti-cryptococcal activity at high temperatures, but loses this activity as environmental temperatures decrease; this may in part explain the increased frequency of cutaneous cryptococcosis in these patients. despite this series of patients, however, the most common site of disseminated infection in sot recipients still remains the cns, including patients receiving tacrolimus. prostatic cryptococcosis is usually asymptomatic, and the prostate gland is considered to be a sanctuary site for this yeast. the prostate may serve as an important reservoir for relapse of cryptococcosis in patients with a high fungal burden [ ] . latent c. neoformans infection has even been recognized to disseminate to the bloodstream during urological surgery on the prostate [ ] . cultures of urine or seminal fluid may still be positive for cryptococcus after initial antifungal treatment of cryptococcal meningitis in aids patients [ ] , strongly supporting the need for prolonged antifungal treatment to clear the prostate in these severely immunocompromised patients. in the early reports of cryptococcal meningitis before the aids epidemic, ocular signs and symptoms were noted in approximately % of cases [ ] . the most common manifestations were ocular palsies and papilledema. in the present hiv era, several other manifestations of ocular cryptococcosis have been identified, including the presence of extensive retinal lesions with or without vitritis, which can lead to irreversible blindness. furthermore, catastrophic loss of vision without evidence for endophthalmitis has also been reported [ ] . visual loss may be due to one of two pathogenic processes. the first is caused by infiltration of the optic nerve with the yeasts, producing rapid visual loss with few effective treatments. the second is due to increased icp and compression of the ophthalmic artery. in this setting, patients have slower visual loss and treatment with serial lumbar punctures or ventricular shunts can prevent or slow down visual loss. in addition to lung, cns, skin, prostate, and eye, c. neoformans can cause disease in many other organs (table . ). cryptococcemia can occur in severely immunosuppressed patients but rarely causes endocarditis. bone involvement of cryptococcosis typically presents as one or more circumscribed osteolytic lesions in any bone of the body, occasionally associated with "cold" soft-tissue abscesses, and has been associated with sarcoidosis. bone marrow infiltration can be observed in severely immunocompromised hosts. cryptococcal peritonitis [ ] and cryptococcuria are also reported in several case series. any organ of the human body can be a site of cryptococcal infections. there are several methods used for the diagnosis of cryptococcosis. these techniques include direct examination of the fungus in body fluids, histopathology of infected tissues, serological studies, and culture of body fluids or tissues. molecular methods, while available, are not currently used in routine clinical practice. the most rapid method for diagnosis of cryptococcal meningitis is direct microscopic examination for encapsulated yeasts by an india ink preparation of csf. cryptococcus can be visualized as a globular, encapsulated yeast cell with or without budding, ranging in size from to µm in diameter. it is easily distinguished in a colloidal medium of india ink when mixed with csf ( fig. . ). approximately - ml of specimen is recommended for use in the india ink preparation. india ink examination can detect encapsulated yeasts in a csf specimen with a threshold between and colony-forming units of yeasts/ml of fluid. the sensitivity of the india ink preparation technique is - % in non-aids-related cryptococcal meningitis and up to % in aids-related disease. some false-positive results can be found from intact lymphocytes, myelin globules, fat droplets, and other tissue cells. also, dead yeast cells can remain in the csf and be visualized by india ink preparation for varying periods of time during and after appropriate antifungal treatment. this is a limitation of direct microscopy of csf during the management of cryptococcal meningitis [ ] . cryptococcus can be identified by histological staining of tissues from lung, skin, bone marrow, brain, or other organs [ ] . histopathological staining of centrifuged csf sediment is more sensitive for rapid diagnosis of cryptococcal meningitis than the india ink method [ ] . peritoneal fluid from chronic ambulatory peritoneal dialysis, seminal fluid, bronchial wash, or bronchoalveolar lavage fluid can also be used for cytology preparations in the diagnosis of cryptococcal infections, whereas india ink preparations from these body fluids are difficult to interpret [ , ] . fine needle aspiration for cytology of peripheral lymph nodes, adrenal glands, or vitreous aspiration; percutaneous transthoracic biopsy under real-time ultrasound guidance; or video-assisted thoracoscopic lung biopsy on pulmonary nodules, masses, or infiltrative lesions can be used for obtaining tissues for cytology/histopathology [ ] . a variety of positive staining methods have been described to demonstrate the yeast cells in tissue or fluids, ranging from the nonspecific papanicolaou or hematoxylin and eosin stains to the more specific fungal stains such as calcofluor, which binds fungal chitin, or gomori methenamine silver (gms), which stains the fungal cell wall [ , ] ( fig. . ). several stains can identify the polysaccharide capsular material surrounding the yeasts. these stains can be especially useful in presumptively identifying cryptococcus when the organism does not grow or cultures are not obtained. they include mayer's mucicarmine, periodic acid-schiff (pas), and alcian blue stains [ ] . the fontana-masson stain appears to identify melanin in the yeast cell wall. the fungus is observed as a yeast that reproduces by formation of narrow-based budding with a prominent capsule. gram stain is not optimal for identification of this yeast, but may show diagnosis of cryptococcosis has improved significantly over the past several decades with the development of serological tests for cryptococcal polysaccharide antigen and/ or antibody. use of serum cryptococcal antibodies for diagnosis of cryptococcosis has not been adopted. in contrast, detection of cryptococcal capsular polysaccharide antigen in serum or body fluids by a latex agglutination (la) technique has been robust in its performance and is considered the gold standard diagnostic test for serological diagnosis of cryptococcosis. this test uses latex particles coated with polyclonal cryptococcal capsular antibodies or anti-gxm monoclonal antibodies and has overall sensitivities and specificities of - % and - %, respectively [ , ] . the false-positive rate of cryptococcal capsular polysaccharide antigen testing is - . % [ ] . the majority of false-positive results can be explained by technical error (improper boiling/treatment), presence of rheumatoid factor or interference proteins, and infections with trichosporon beigelii [ ] or some bacterial species [ ] . however, most of the false-positive results of la testing for cryptococcal polysaccharide antigen have initial reciprocal titers of or less [ ] . therefore, results of such low titers must be carefully interpreted within the clinical context. falsenegative results of the la test for cryptococcal polysaccharide antigen in cryptococcal meningitis are unusual but can be seen due to a prozone effect, and, therefore, high-risk negative specimens should be diluted and retested [ ] . low fungal burden, as in chronic low-grade cryptococcal meningitis or in the very early stages of cryptococcal infection, and improper storage of patient sera can also cause false-negative results in la cryptococcal polysaccharide antigen tests [ ] . enzyme immunoassays (eias) for detection and quantification of cryptococcal polysaccharide antigen of all four serotypes of c. neoformans in sera and csf have been developed to detect the major component of the polysaccharide capsule, gxm, with sensitivities and specificities of . - and %, respectively [ , ] . this methodology is automated and overcomes some of the practical limitations of la testing. previous studies have compared eia and la assays and revealed no significant difference between these testing methods. eia for cryptococcal polysaccharide antigen does not give discrepant results with rheumatoid factor or serum macroglobulins and is not affected by prozone reactions. both la and eia testing have been rigorously studied and are recommended for use in both serum and csf samples. recently, a lateral flow assay (lfa) was introduced in the diagnostic repertoire for cryptococcal infection and is food and drug administration (fda) approved for use in serum and csf. the semiquantitative lfa offers many advantages over other serological methods, including rapid turnaround (approximately minutes), minimal requirements for specialized laboratory infrastructure, stability at room temperature, and low cost [ ] . the lfa has been evaluated against both eia and culture, with sensitivities of - % for serum and plasma and - % for urine samples [ ] [ ] [ ] [ ] . this assay has good performance across a broad range of clinical settings, including resource-limited settings and among cohorts with low burden of hiv infection and high rates of c. gattii infection, for which some eia and la tests are known to be insensitive [ ] [ ] [ ] [ ] [ ] . the satisfactory performance of lfa combined with established cost-effectiveness and practical advantages of this approach support its use as a point-of-care testing (including preemptive screening of high-risk patients) in resource-limited settings [ , , ] . although the presence of cryptococcal polysaccharide antigen in serum is undoubtedly suggestive for dissemination of cryptococcal infection outside the lung, the precise value of cryptococcal polysaccharide antigen for diagnosis of nondisseminated pulmonary cryptococcosis remains less certain. generally speaking, detectable cryptococcal antigen in serum should make clinicians consider that infection is now also located outside the lung. in a high-risk patient with clinical symptoms suggestive of meningitis, identification of cryptococcal antigen in csf or serum is rapid, specific, noninvasive, and virtually diagnostic of meningoencephali- tis or disseminated cryptococcosis even when the india ink examination or culture is negative [ , ] . the la test for serum cryptococcal polysaccharide antigen is widely used for detecting cryptococcal infection in patients with aids, as an initial screening test for those with fever of unclear etiologies or neurological symptoms. in some patients, it may represent the only means of achieving an etiologic diagnosis of invasive cryptococcosis or early diagnosis prior to cns involvement. likely because of its sensitivity, the detection of cryptococcal polysaccharide antigen in the serum may precede clinically obvious disseminated cryptococcal disease ("isolated cryptococcal polysaccharidemia") in severely immunosuppressed patients [ ] [ ] [ ] . the management of these cases, in which there is a positive serum antigen and other nonspecific clinical findings in hiv-infected patients with negative fluid or tissue cultures, is uncertain. persons of high risk with isolated cryptococcal antigenemia probably do benefit from antifungal therapy to prevent or delay the development of overt cryptococcosis [ ] . generally, positive serum antigen tests at titers of : or more strongly suggest cryptococcal infections in these patients. baseline cryptococcal polysaccharide antigen titers in serum and csf may carry prognostic significance in patients with cryptococcal meningitis [ ] . a study in hiv-related acute cryptococcal meningitis indicated that a baseline titer of csf cryptococcal polysaccharide antigen of : or greater was a predictor of death during systemic antifungal treatment [ ] . after initiation of systemic antifungal therapy, patients may respond to treatment and titers of cryptococcal polysaccharide antigen fall. similarly, a rise in csf cryptococcal polysaccharide antigen titers during suppressive therapy has been associated with relapse [ ] . however, it is important to emphasize that the use of changing antigen titers to make therapeutic decision should be done with caution, as titers may not be equivalent across different serological modalities [ ] . the kinetics of polysaccharide elimination remains unclear and, despite the accuracy of commercial kits for general diagnosis, the accuracy of specific titers can vary from kit to kit even from the same clinical specimen. cryptococcus can be easily grown from biologic samples such as csf, sputum, and skin biopsy on routine fungal and bacterial culture media. colonies can usually be observed on solid agar plates after - h of incubation at - °c in aerobic conditions. antibacterial agents, preferably chloramphenicol, can be added to the media when bacterial contamination is considered. the yeast, however, do not grow in the presence of cycloheximide at the con-centration used in selective fungal isolation media ( µg/ ml). despite relatively rapid growth for most strains, cultures should be held for - weeks before discarding, particularly for patients already receiving antifungal treatment. conversely, cultures may be negative despite positive microscopic examinations (india ink) due to nonviable yeast cells, which may persist for a prolonged period of time at the site of infection. positive blood cultures are frequently reported in aids patients and may actually be the first positive test for cryptococcal infection in a febrile high-risk patient. c. neoformans colonies will appear on routine fungal media as opaque, white, creamy colonies that may turn orange-tan or brown after prolonged incubation. the mucoid appearance of the colony is related to the capsule size around the yeasts. cryptococcus does not routinely produce hyphae or pseudohyphae, or ferment sugars, but is able to assimilate inositol and hydrolyze urea [ ] . c. neoformans and c. gattii have the ability to use galactose, maltose, galactitol, and sucrose [ ] . there are special media such as canavanine-glycine-bromthymol blue (cgb) agar that can be used to differentiate c. gattii strains from c. neoformans strains [ ] . a number of molecular techniques have been developed for identification of cryptococcal species from biological specimens including single and multiplex polymerase chain reaction (pcr) fingerprinting, random amplified polymorphic dna (rapd), pcr restriction fragment length polymorphism (rflp) analysis, multi-locus sequence typing (mlst), and matrix-assisted laser desorption ionization time-of-flight (maldi-tof) mass spectrometry [ ] [ ] [ ] [ ] [ ] [ ] [ ] . these highly sensitive and specific methods have been evaluated with a variety of biologic samples [ ] and can rapidly identify to the species and subspecies/genotypic level, including identification of recognized and novel strains within geographical niches [ ] . while the expense and specialized techniques required of these methods preclude widespread use in clinical practice, their use in larger-scale investigations will continue to enhance our understanding of the epidemiology, pathogenesis, and nuances of antifungal management, as well as identify microevolution of different strains [ ] . the infectious diseases society of america clinical practice guidelines for the management of cryptococcal disease (summarized in tables . , . ), updated in , provide a suitable framework for therapeutic decision making [ ] . the updated guidelines provide detailed recommendations for specific "at-risk" populations and address different management strategies based on host, site of infection, and potential complications of cryptococcal infection. while subtle nuances exist based on host and site of infection, general principles for the management of cryptococcal infection can provide the cornerstone of a treatment plan in most cases. primary regimen ambd ( . - mg/kg/day) plus flucytosine ( -fc; mg/kg/day) weeks liposomal amb ( - mg/kg/day) or amb lipid complex (ablc; mg/kg/day) pls -fc( mg/kg/day) for patients predisposed to renal dysfunction weeks alternative regimens b - weeks ambd ( . - mg/kg/day) or liposomal amb c ( - mg/kg/day) or ablc ( mg/kg/day) if flucytosine-intolerant weeks ambd ( . - mg/kg/day) plus fluconazole ( mg/day) weeks fluconazole (> mg/day, preferably mg/day) plus -fc ( mg/kg/day) - months ablc amb lipid complex, amb amphotericin b, -fc flucytosine a initiate haart - weeks after beginning antifungal regimen. shorter duration (i.e., weeks) of induction therapy can be considered for certain low-risk patients b can be considered as alternative regimen in circumstances in which primary regimen not available but are not encouraged as equivalent substitutes c liposomal amphotericin can be safely administered in doses as high as mg/kg/day d after year of therapy, if successful response to arvs (cd count > and viral load low or undetectable for > months), discontinuation of antifungal therapy can be considered. consider reinstitution if cd count falls below e consider stepwise de-escalation of immunosuppressive regimen if allograft function permits f if csf culture remains positive at weeks of therapy or initial presentation with neurologic complications, longer therapy preferred g caution due to concomitant calcineurin inhibitor use amphotericin b deoxycholate (ambd) remains the foundation of treatment for disseminated cryptococcosis and severe cryptococcal infection. a standard induction dose of . - mg/kg/day is recommended. liposomal amphotericin b (ambisome) at - mg/kg/day has become a preferred alternative treatment with similar outcomes to that of ambd but with less nephrotoxicity and is specifically recommended for primary induction in organ transplant patients as well as patients at risk for renal dysfunction [ ] [ ] [ ] . higher doses of ambd have been shown to be more rapidly fungicidal [ , ] . flucytosine ( -fc) is primarily used in combination therapy with ambd for first-line therapy in cryptococcal meningitis or severe pulmonary cryptococcosis at a dosage of mg/kg/day in divided doses in patients with normal renal function [ , ] . the combination of ambd and -fc represents the most potent fungicidal regimen with more rapid sterilization of csf cultures at weeks as demonstrated by multiple studies [ , , ] . early studies from hiv infection demonstrated increased rates of csf sterilization and fewer relapses with the combination of ambd and -fc followed by itraconazole maintenance [ ] . this initial combination regimen has since been compared against multiple alternatives, with the superiority of its fungicidal activity consis-tently confirmed [ ] . similar results have been observed among the most severe cases of cryptococcal infection [ , ] . early mycological failure (as defined by persistently positive csf cultures at day ) has for many years been associated with late treatment failure and poor outcome [ ] , and lack of -fc has been independently associated with both early [ ] and late [ ] mycological failure. the improved fungicidal activity of combination therapy with ambd plus -fc has been shown to translate into a direct survival benefit compared with ambd monotherapy, with improved survival at weeks lasting up to months [ ] . -fc should be dose-adjusted for renal dysfunction, with therapeutic monitoring performed - days after initiation of therapy, to maintain -h post-dose levels under µg/ml (goal , to reduce its primary side effect of bone marrow suppression [ ] . though combination induction therapy with ambd and -fc remains the recommended standard of care for severe cryptococcosis including cryptococcal meningitis, limited availability of -fc in resource-limited settings presents significant challenges for managing patients in areas where the disease burden and mortality rates are highest. alternative combination therapies have been investigated, the most efficacious of which has been ambd ( . mg/kg/day) plus fluconazole ( mg/day), which has demonstrated improved rates of a composite end point of csf culture negativity, neurological improvement, and survival compared with ambd alone or in combination with lower doses of fluconazole [ ] . fluconazole (at doses of - mg/ day) in combination with ambd (standard dosing) has been shown to demonstrate similar rates of fungal clearance from csf as standard ambd plus -fc in a randomized study performed in hiv-infected patients in south africa [ ] and offers a potential viable option for effective initial therapy in settings where access to -fc is limited. whether the survival benefit observed with ambd plus -fc will be observed with this regimen remains uncertain. additional alternative regimens for primary therapy are available in the guidelines but their use is not encouraged based on limited data on the success of these regimens [ ] . use of fluconazole in the absence of a polyene is not recommended given the fungistatic nature of this drug, poor success, higher relapse rates, and increased resistance in relapse when used as monotherapy for induction [ , ] . however, in areas without access to ambd, high doses ( mg/day) of fluconazole should be commenced. csf sampling should be performed to rule out cns involvement b csf sampling can be considered but not required in the absence of neurological symptoms or high serum cryptococcal antigen c if successful response to arvs (cd count > and viral load low or undetectable for > months) and stable serum cryptococcal antigen, can consider discontinuation of antifungal therapy after months of therapy a three-stage regimen of induction/consolidation/maintenance is employed in the treatment of cryptococcal meningitis in all patients, irrespective of host risk factors [ , ] . in hiv-infected patients, the initial induction treatment usually begins with combination therapy with ambd plus -fc for at least weeks as above, followed by consolidation treatment with fluconazole - mg/day for weeks in patients who have demonstrated favorable response. following consolidation, a long-term suppressive/maintenance phase is commenced with oral fluconazole, - mg given once daily. this has been demonstrated to effectively reduce rates of relapse from ~ % to less than % in the pre-haart era [ ] . secondary prophylaxis can be discontinued after - years of antifungal therapy in patients who respond to haart with rise in cd + cell counts to greater than cells/µl and decline in viral load (hiv rna) to undetectable levels for at least months [ , , ] . itraconazole can be used as an alternative consolidation treatment for cryptococcosis, but first-line therapy is with fluconazole. despite its poor csf penetration and inconsistent oral bioavailability, itraconazole has been successfully used in the treatment of cryptococcal meningitis [ ] ; however, it has been shown to be inferior to fluconazole during the suppression phase [ ] and requires therapeutic drug monitoring due to its poor bioavailability. newer triazoles including posaconazole and voriconazole are not specifically incorporated into practice guidelines but are active against cryptococcal isolates in vitro and have been shown to demonstrate moderate efficacy in patients with refractory disease [ , ] . in patients with hiv-associated cryptococcal infection, haart has a major impact on long-term prognosis. however, given concerns regarding immune reconstitution inflammatory syndrome (iris), the optimum timing for haart initiation in the setting of ois has been a subject of much debate. early retrospective studies suggested an increased risk of iris among hiv-infected patients initiated on haart early after the diagnosis of an oi [ , ] . more contemporary studies have demonstrated conflicting results regarding outcomes of cryptococcal infection based on timing of haart initiation [ ] [ ] [ ] [ ] [ ] . the cryptococcal optimal art timing (coat) study provides the best evidence for current recommendations regarding timing of haart initiation in patients with cryptococcal meningitis [ ] . haart-naïve patients were randomized to receive immediate (within h) or deferred (greater than four weeks) haart following a minimum of days of antifungal therapy with ambd and high-dose fluconazole. this trial was stopped early after interim analyses suggested poorer early survival among patients receiving immediate haart ( % vs. %, p = . ), particularly among patients with altered mentation and low csf white blood cell count. although a trend toward increased rates of and earlier iris was observed in the immediate haart group, this was not statistically significant. the above data support recommendations to delay initiation of haart in patients with cryptococcal meningitis for a minimum of weeks after starting antifungal therapy (potentially longer if the primary regimen does not include ambd) and after demonstration of a sustained clinical response to antifungal therapy [ , ] . interruption of haart and/or corticosteroid treatment may be used to control symptoms if severe cryptococcal iris occurs. organ transplant recipients with cns cryptococcal infection are managed similar to hiv-infected patients, with the exception of preferential use of lipid formulations of amphotericin b to limit nephrotoxicity [ ] . the principles of induction, consolidation, and maintenance therapy remain the same. repeat csf sampling at weeks is recommended in this population and a longer course of induction therapy should be pursued if csf cultures remain positive at weeks, as this scenario is associated with increased -month mortality [ ] . unlike hiv-infected patients, relapse rates among organ transplant recipients are quite low (~ . %), such that a shorter course of maintenance therapy with fluconazole ( - months) can be pursued following standard consolidation [ , ] . drug interactions between fluconazole and immunosuppressive agents should be anticipated due to fluconazole-induced cyp a inhibition, and preemptive adjustment (reduction) in calcineurin inhibitors should be made. management of immunosuppression in the setting of cryptococcal infection requires recognition of the increased risk of iris associated with abrupt withdrawal or reduction of immunosuppression in organ transplant recipients with increased rates of allograft loss reported in some patients [ ] [ ] [ ] . stepwise reduction in immunosuppression is recommended, though the approach should be individualized for each patient. screening for hiv and cd lymphopenia is recommended among patients who present with cryptococcosis without apparent risk factors [ ] . very little prospective data are available on the management of cryptococcal infection among this heterogeneous group of "apparently immunocompetent" patients lacking classical risk factors for cryptococcosis. what is known is based on early studies that included a heterogeneous mix of patients and were performed prior to acceptance of the standard algorithm of induction, consolidation, and maintenance therapy and higher-dose polyene therapy [ ] . recommendations for longer induction therapy ( weeks or more) in this population are based on the recognition of poorer outcomes and higher mortality rates in this group of patients in both early [ , ] and contemporary [ ] studies. an additional weeks of therapy should be considered if -fc is not included in the induction regimen [ ] . recommendations for consolidation and maintenance parallel those for hiv-infected and transplant patients, and reflect early reports of relapse rates approaching % within the st year prior to introduction of consolidation and maintenance antifungal therapy [ , ] . criteria for stopping treatment in these patients include resolution of symptoms, generally following at least year of suppressive therapy. patients may have prolonged positive cryptococcal polysaccharide antigen tests and/or slightly abnormal csf findings for months during successful therapy, and if there are concerns about cure, follow-up csf culture should be considered. just as host factors influence management approaches for cryptococcal infection, site of infection also matters. airway colonization in a nonimmunosuppressed individual poses a low risk for invasive pulmonary infection (and dissemination) and treatment can be deferred. some experts would still favor treatment with fluconazole in this scenario, given the relative benign nature of this therapy. however, among immunocompromised patients with isolated pulmonary cryptococcosis, treatment is recommended to prevent dissemination [ ] . it should be emphasized that a thorough evaluation to rule out systemic disease/dissemination is warranted in this group of patients to provide optimal treatment. this includes blood and csf cultures as well as serum and csf cryptococcal antigen testing. if the results of the above evaluation are negative, symptoms are mild, and there is no evidence of diffuse pulmonary infiltrates or ards, oral fluconazole ( mg/day) is recommended for - months. however, in any patient in whom cryptococcemia is identified, symptoms are severe, ards is present, or csf examination reveals asymptomatic cns involvement, treatment for cryptococcal meningitis is recommended [ ] . cerebral cryptococcomas often can be managed with prolonged antifungal therapy without need for surgical removal unless mass effect or other evidence of obstruction is identified. at least weeks of induction therapy with ambd plus -fc, followed by - months of consolidation therapy with fluconazole ( - mg/day), is recommended for management. surgery should be considered for large lesions (> cm) or the presence of obstructive hydrocephalus [ ] . localized infection of extrapulmonary nonmeningeal sites can occasionally occur with direct inoculation, but more commonly represents disseminated infection. suspicion for the latter must be maintained when cryptococcus is identified from a sterile body site, as management strategies will differ if disseminated disease is present. consultation with ophthalmology is indicated in cases of cryptococcal eye disease [ ] . restoration of pathogen-specific immunity as a result of haart or following reduction of immunosuppression in sot recipients can result in a destructive inflammatory response known as the immune reconstitution inflammatory syndrome (iris). iris is best characterized in association with c. neoformans infection of the cns, particularly among hiv-infected patients, and is associated with significant morbidity and mortality [ , , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . proposed criteria for iris include onset of symptoms within months of haart initiation (with concomitant cd + recovery) [ ] . in addition, iris is estimated to occur in - % of sot recipients with cryptococcal infection and has been associated with an increased risk of allograft failure [ , [ ] [ ] [ ] [ ] [ ] ; cryptococcal iris may also be observed in non-hiv-infected, nontransplant patients [ ] . clinical features of cryptococcal iris are similar to cryptococcal infection, most commonly presenting as cns disease, although lymphadenitis, pneumonitis, multifocal disease, soft-tissue involvement, and mediastinitis have all been reported [ , ] . meningeal disease is the most frequent and most serious presentation [ ] ; aseptic meningitis with associated intracranial hypertension and csf pleocytosis is most commonly observed [ , , , , , ] . a hallmark histopathologic finding is suppurative or necrotic granulomatous inflammation with yeast seen in tissues despite negative tissue cultures [ , , , ] . the presence of a positive csf culture in cases of suspected cryptococcal iris should raise suspicion for direct antifungal failure or resistance, particularly in settings where fluconazole therapy is widely used as the standard of care [ ] . cryptococcal iris represents unchecked reversal of a th (anti-inflammatory) to th (pro-inflammatory) immune response in the setting of immune reconstitution [ ] . prospective cohort studies of haart-naïve individuals indicate that an ineffectual host immune response to initial infection is associated with a greater likelihood of future iris [ ] . a three-phase theory of cryptococcal immune reconstitution has been postulated, marked by: ( ) failure of antigen clearance due to inappropriate th response; ( ) lack of effector response despite inflammatory signaling; and, ultimately, ( ) vigorous pro-inflammatory responses (both th and th ) to residual antigen, recognized clinically as iris [ ] . there are no reliable diagnostic tests for iris, and establishing the diagnosis presents a considerable challenge [ , ] . the differential diagnosis includes progressive disease due to persistent immune deficiency, failure of antimicrobial therapy (due to resistance or nonadherence), coinfection with other ois, and drug toxicity. a high index of suspicion is necessary for recognizing atypical presentations or manifestations at distant sites. nevertheless, distinguishing between disease progression related to ongoing immune deficiency and clinical deterioration due to restoration of host immunity has important management implications. csf analyses and biomarkers may be useful in distinguishing between relapse and iris. prospective studies have demonstrated that csf opening pressure [ ] and wbc count [ , ] at the time of an iris event are significantly higher than baseline values for individual patients, and higher csf opening pressures can distinguish iris from relapsed infection [ ] . treatment options for cryptococcal iris are based largely on expert opinion [ ] . implicit in management is ensuring the efficacy of antifungal therapy, particularly in settings where access to ambd may be limited and fluconazole resistance may account for recurrent meningitis episodes [ , ] . in the absence of disease relapse or direct antifungal resistance, modification of antimicrobial therapy is not indicated [ ] . once the diagnosis of iris is suspected, consideration of disease severity is warranted. a significant proportion of minor cases will improve without specific treatment [ , , ] . corticosteroids have been shown to reduce the need for hospitalization and to improve short-term quality of life and functional status without increased risk of complications in paradoxical tuberculosis (tb)-associated iris [ ] ; the role of corticosteroids in cryptococcal iris, however, is not as well established and should be reserved for life-threatening cases, particularly in light of their association with increased mortality in one study [ ] . other antiinflammatory agents have been used in cryptococcal iris, but the number of patients treated with any of these agents is too small to draw substantive conclusions [ , , ] . other management strategies, including therapeutic lumbar drainage in the setting of intracranial hypertension [ , , ] and, at times, surgical drainage of suppurative lymph nodes [ , ] , are important adjunctive therapies that may be considered in severe disease. although no controlled studies have been performed, continuation of haart in the setting of iris is recommended and has been performed safely without adverse effects in several studies [ , , , , ] . similarly, withdrawal or reduction of immunosuppressive agents is standard practice in managing infectious complications in sot recipients [ ] . given the putative risk of iris with abrupt withdrawal or discontinuation of immunosuppressive agents in these patients, gradual de-escalation during the initiation of antifungal therapy is advised to reduce the risk of future iris [ , , ] . persistent and relapsed infection must be distinguished from iris, as management strategies will differ significantly. persistent disease can be defined as persistently positive csf cultures after month of antifungal therapy, whereas relapse requires new clinical signs and symptoms and repeat positive cultures (at same or distant sites) after initial improvement and fungal sterilization [ ] . surrogate markers, including biochemical parameters, india ink staining, and cryptococcal antigen titers, are insufficient to define relapse or alter antifungal therapy. general recommendations for management in these cases include resumption of induction therapy, often for a longer duration and at increased dosages, if tolerable, and pursuance of antifungal susceptibility testing [ ] . while routine in vitro susceptibility testing of cryptococcal isolates at the time of initial therapy is not recommended, there is a role for testing in cases of suspected relapse or persistent infection [ ] . it is generally recognized that primary antifungal resistance to most agents is rare, although reduced susceptibility to -fc has been observed in untreated patients [ ] and echinocandins have no reliable activity against this yeast. reduced susceptibility to fluconazole has been described in cases of culture-positive relapsed cryptococcal meningitis associated with prior fluconazole therapy [ , , ] (table . ). along with the optimization of antifungal therapy, management of increased icp is critically important. elevated icp is correlated with overall fungal burden, and is thought to be due to csf outflow obstruction by clumped yeast forms [ ] . an icp of mm h o or greater is considered elevated and is associated with increased morbidity and mortality [ ] . persistently elevated icp after weeks of treatment is associated with poorer clinical responses among patients with hiv-associated cryptococcal meningitis [ ] . intracranial imaging should be performed prior to lumbar puncture if impaired mentation or focal neurologic deficits are present. a baseline measurement of csf pressure should be obtained in all patients with suspected cryptococcal meningitis. aggressive attempts to control increased icp should occur, if elevated and if there are signs/symptoms to suggest increased icp (headache, mental status changes, and new focal neurological findings). treatment options for managing acutely elevated icp include repeated lumbar punctures (daily until pressure and symptoms are stable for > days), lumbar drain insertion, ventriculostomy, or ventriculoperitoneal (vp) shunt (table . ) [ ] . medical treatments such as corticosteroids (unless there is a component of iris), mannitol, and acetazolamide have been used in some cases, but are generally not recommended for use in management of increased icp in cryptococcal meningitis [ ] . some patients may develop symptoms of obstructive hydrocephalus necessitating the placement of a permanent vp shunt during the first - years of treatment, and occasionally at initial presentation. sterilization of csf is not required prior to placement of a vp shunt, which can be inserted once a patient is receiving the appropriate antifungal therapy [ ] . prevention of cryptococcal disease can be achieved by use of haart in hiv-infected patients. fluconazole prophylaxis has been shown to be effective for preventing cryptococcosis in aids patients with persistently low cd + cell counts (below cells/µl) [ , ] , but due to concerns regarding antifungal resistance, this approach is not currently recommended, and haart remains the best strategy for the prevention of cryptococcal disease in this population. routine screening for cryptococcal infection and/or prophylaxis are not recommended in sot recipients, even when immunosuppression is augmented in patients with previously (appropriately) treated infection [ ] . although cryptococcal gxm-tetanus toxoid conjugate vaccine and specific monoclonal antibodies to cryptococci have been developed, clinical trials have not been initiated to determine their usefulness in human subjects [ , ] . one hundred years ago: the history of cryptococcosis in greifswald. medical mycology in the nineteenth century cryptococcus neoformans proposal to conserve the name cryptococcus gattii against c. hondurianus and c. bacillisporus cryptococcosis in the era of aids- years after the discovery of cryptococcus neoformans a rare genotype of cryptococcus gattii caused the cryptococcosis outbreak on vancouver island (british columbia, canada) estimation of the current global burden of cryptococcal meningitis among persons living with hiv/aids cryptococcosis: population-based multistate active surveillance and risk factors in human immunodeficiency virus-infected persons. cryptococcal active surveillance group genetics of cryptococcus neoformans dolin r, editors. mandell, douglas, and bennett's principles and practice of infectious diseases epidemiology and host-and variety-dependent characteristics of infection due to cryptococcus neoformans in australia and new zealand. australasian cryptococcal study group cryptococcus neoformans: a sugar-coated killer with designer genes the wide spectrum of cryptococcal infections the spectrum of pulmonary cryptococcosis clinical spectrum of invasive cryptococcosis in liver transplant recipients receiving tacrolimus richman dd. persistent cryptococcus neoformans infection of the prostate after successful treatment of meningitis. california collaborative treatment group disseminated cryptococcosis after transurethral resection of the prostate persistence of cryptococcus neoformans in seminal fluid and urine under itraconazole treatment. the urogenital tract (prostate) as a niche for cryptococcus neoformans ophthalmologic complications of cryptococcal meningitis catastrophic visual loss due to cryptococcus neoformans meningitis cryptococcus neoformans peritonitis in a patient with alcoholic cirrhosis: case report and review of the literature prognostic factors in cryptococcal meningitis. a study in cases histopathology of cryptococcosis and other fungal infections in patients with acquired immunodeficiency syndrome rapid diagnosis of cryptococcal meningitis by microscopic examination of centrifuged cerebrospinal fluid sediment cytologic diagnosis of cryptococcus neoformans in hiv-positive patients utility of bronchoscopic sampling techniques for cryptococcal disease in diagnosis of pulmonary cryptococcosis by ultrasound guided percutaneous aspiration comparison of commercial kits for detection of cryptococcal antigen comparison of three commercial cryptococcal latex kits for detection of cryptococcal antigen detection of cryptococcal antigen. comparison of two latex agglutination tests detection of a trichosporon beigelii antigen cross-reactive with cryptococcus neoformans capsular polysaccharides in serum from a patient with disseminated trichosporon infection cross-reactivity between stomatococcus mucilaginosus and latex agglutination for cryptococcal antigen false-negative cryptococcal antigen test detection of cryptococcus neoformans antigen in body fluids by latex particle agglutination comparison of the premier cryptococcal antigen enzyme immunoassay and the latex agglutination assay for detection of cryptococcal antigens evaluation of a novel pointof-care cryptococcal antigen test on serum, plasma and urine from patients with hiv-associated cryptococcal meningitis evaluation of a newly developed lateral flow immunoassay for the diagnosis of cryptococcus clinical utility of the cryptococcal antigen lateral flow assay in a diagnostic mycology laboratory comparison of four assays for the detection of cryptococcal antigen large-scale evaluation of the immuno-mycologics lateral flow and enzyme-linked immunoassays for detection of cryptococcal antigen in serum and cerebrospinal fluid cost effectiveness of cryptococcal antigen screening as a strategy to prevent cryptococcal meningitis in south africa infections with cryptococcus neoformans in the acquired immunodeficiency syndrome cryptococcal meningitis in non-hiv-infected patients serum cryptococcal antigen in patients with aids systematic screening of cryptococcal antigenemia in hiv-positive adults in uganda screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in south africa serology of human cryptococcosis comparison of amphotericin b with fluconazole in the treatment of acute aids-associated cryptococcal meningitis. the niaid mycoses study group and the aids clinical trials group measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of aids-associated cryptococcal meningitis philadelphia: churchill livingstone the biochemical basis for the distinction between the two cryptococcus neoformans varieties with cgb medium cryptococcus species identification by multiplex pcr development of a singleplex pcr assay for rapid identification and differentiation of cryptococcus neoformas var. grubii, cryptococcus neoformans var. neoformans, cryptococcus gattii, and hybrids identification by random amplification of polymorphic dna (rapd) of a common molecular type of c. neoformans var. neoformans in patients with aids or other immunosuppressive conditions simultaneous identification of molecular and mating types within the cryptococcus species complex by pcr-rflp analysis consensus multi-locus sequence typing scheme for cryptococcus neoformans and cryptococcus gattii maldi-tof ms enables the rapid identification of the major molecular types within the cryptococcus neoformans/c. gattii species complex matrixassisted laser desorption ionization-time of flight mass spectrometry-based method for discrimination between molecular types of cryptococcus neoformans and cryptococcus gattii detection of cryptococcus by conventional and molecular methods multilocus sequence typing reveals three genetically distinct subpopulations of cryptococcus neoformans var. grubii (serotype a), including a unique population in botswana genotyping and antifungal susceptibility testing of cryptococcus neoformans isolates from cameroonian hiv-positive adult patients clinical practice guidelines for the management of cryptococcal disease: update by the infectious disease society of america liposomal amphotericin b (ambisome) compared with amphotericin b both followed by oral fluconazole in the treatment of aids-associated cryptococcal meningitis comparison of doses of liposomal amphotericin b and conventional amphotericin b deoxycholate for treatment of aids-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety high-dose amphotericin b with flucytosine for the treatment of cryptococcal meningitis in hiv-infected patients: a randomized trial combination antifungal therapy for cryptococcal meningitis treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. national institute of allergy and infectious diseases mycoses study group and aids clinical trials group treatment of cryptococcal meningitis with combination amphotericin b and flucytosine for four as compared with six weeks combination antifungal therapies for hiv-associated cryptococcal meningitis: a randomised trial major role for amphotericin-flucytosine combination in severe cryptococcosis early mycological treatment failure in aids-associated cryptococcal meningitis determinants of disease presentation and outcome during cryptococcosis: the crypto a/d study antimicrobial therapy and vaccines a phase ii randomized trial of amphotericin b alone or combined with fluconazole in the treatment of hiv-associated cryptococcal meningitis comparison of the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin b for the treatment of hiv-associated cryptococcal meningitis combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in malawi symptomatic relapse of hiv-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution a placebo-controlled trial of maintenance therapy with fluconazole after treatment for cryptococcal meningitis in the acquired immunodeficiency syndrome discontinuation of secondary prophylaxis for cryptococcal meningitis in human immunodeficiency virus-infected patients treated with haart: a prospective, multicenter, randomized study discontinuation of maintenance therapy for cryptococcal meningitis in patients with aids treated with haart: an international observational study itraconazole therapy for cryptococcal meningitis and cryptococcosis a comparison of itraconazole versus fluconazole as maintenance therapy for aidsassociated cryptococcal meningitis. national institute of allergy and infectious diseases mycoses study group voriconazole treatment for less-common, emerging or refractory fungal infections activity of posaconazole in the treatment of central nervous system fungal infections incidence and risk factors for immune reconstitution inflammatory syndrome during haart incidence and risk factors of immune reconstitution inflammatory syndrome complicating hiv-associated cryptococcosis in france early haart reduces aids progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial immune reconstitution inflammatory syndrome in hiv-associated cryptococcal meningitis: a prospective study cryptococcal immune reconstitution inflammatory syndrome after haart in aids patients with cryptococcal meningitis: a prospective multicenter study mbuagbaw l optimal timing for haart initiation in patients with hiv infection and concurrent cryptococcal meningitis early versus delayed initiation of haart for concurrent hiv infection and cryptococcal meningitis in sub-saharan africa haart initiation within the first weeks of cryptococcal meningitis is associated with higher mortality: a multisite randomized trial world health organization. rapid advice: diagnosis, prevention and management of cryptococcal disease in hiv-infected adults, adolescents and children. geneva: world health organization antifungal management practices and evolution of infection in organ transplant recipients with cryptococcus neoformans infection allograft loss in renal transplant recipients with cryptococcus neoformans associated immune reconstitution syndrome an immune reconstitution syndrome-like illness associated with cryptococcus neoformans infection in organ transplant recipients cellulitis revealing a cryptococcosis-related immune reconstitution inflammatory syndrome in a renal allograft recipient a comparison of amphotericin b alone and combined with flucytosine in the treatment of cryptococcal meningitis comparison of temporal trends of three groups with cryptococcosis: hivinfected, solid organ transplant and hiv-negative/non-tranpslant clinical features and serum biomarkers in hiv immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus case definitions in a south african cohort the role of immune reconstitution inflammatory syndrome in aids-related cryptococcus neoformans disease in the era of haart timing of cryptococcal immune reconstitution inflammatory syndrome after haart in patients with aids and cryptococcal meningitis outcomes of cryptococcal meningitis in uganda before and after the availability of haart paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome immune reconstitution inflammatory syndrome (iris) associated with cryptococcus neoformans infection in aids patients intramedullary abscess resulting from disseminated cryptococcosis despite immune restoration in a patient with aids cryptococcal immune reconstitution inflammatory syndrome: report of four cases in three patients and review of the literature cryptococcal immune reconstitution inflammatory syndrome in hiv- -infected individuals: proposed clinical case definitions th cells and il- receptor signaling are essential for mucosal host defense against oral candidiasis opportunistic infection-associated immune reconstitution syndrome in transplant recipients cellulitis revealing a cryptococcosis-related immune reconstitution inflammatory syndrome in a renal allograft recipient immune reconstitution syndrome after voriconazole treatment for cryptococcal meningitis in a liver transplant recipient novel immune regulatory pathways and their role in immune reconstitution syndrome in organ transplant recipients with invasive mycoses the poor prognosis of central nervous system cryptococcosis among nonimmunosuppressed patients: a call for better disease recognition and evaluation of adjuncts to antifungal therapy mediastinitis due to cryptococcal infection: a new clinical entity in the haart era hiv combination therapy: immune restitution causing cryptococcal lymphadenitis dramatically improved by anti-inflammatory therapy immunological profiles of immune restoration disease presenting as mycobacterial lymphadenitis and cryptococcal meningitis tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings symptomatic relapse of hiv-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution independent association between rate of clearance of infection and clinical outcome of hiv-associated cryptococcal meningitis: analysis of a combined cohort of patients randomized placebocontrolled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome diagnosis and management of increased intracranial pressure in patients with aids and cryptococcal meningitis. the niaid mycoses study group and aids cooperative treatment groups cryptococcal immune reconstitution syndrome during steroid withdrawal treated with hydroxychloroquine treatment of hiv-related inflammatory cerebral cryptococcoma with adalimumab paradoxical immune reconstitution inflammatory syndrome associated with previous cryptococcus neoformans infection in an hiv-positive patient requiring neurosurgical intervention aids: immune reconstitution inflammatory syndrome: a reappraisal flucytosine primary resistance in candida species and cryptococcus neoformans correlation of in vitro azole susceptibility testing with in vivo response in a murine model of cryptococcal meningitis correlation of fluconazole mics with clinical outcome in cryptococcal infection elevated cerebrospinal fluid pressures in patients with cryptococcal meningitis and acquired immunodeficiency syndrome a randomized, double-blind, placebo-controlled trial of acetazolamide for the treatment of elevated intracranial pressure in cryptococcal meningitis treatment of hydrocephalus secondary to cryptococcal meningitis by use of shunting primary prophylaxis with fluconazole against systemic fungal infections in hiv-positive patients a multicentre, randomized, double-blind, placebo-controlled trial of primary cryptococcal meningitis prophylaxis in hiv-infected patients with severe immune deficiency cryptococcosis in solid organ transplant recipients: current state of the science cryptococcus neoformans serotype a glucuronoxylomannan protein conjugate vaccines: synthesis, characterization, and immunogenicity therapeutic efficacy of monoclonal antibodies to cryptococcus neoformans glucuronoxylomannan alone and in combination with amphotericin b. antimicrob agents chemother suggested reading casadevall a, perfect jr. cryptococcus neoformans combination antifungal therapy for cryptococcal meningitis large-scale evaluation of the immuno-mycologics lateral flow and enzyme-linked immunoassays for detection of cryptococcal antigen in serum and cerebrospinal fluid a rare genotype of cryptococcus gattii caused the cryptococcosis outbreak on vancouver island (british columbia, canada) evaluation of a newly developed lateral flow immunoassay for the diagnosis of cryptococcus cryptococcosis in the era of aids- years after the discovery of cryptococcus neoformans discontinuation of maintenance therapy for cryptococcal meningitis in patients with aids treated with haart: an international observational study dolin r, editors. mandell, douglas, and bennett's principles and practice of infectious diseases clinical practice guidelines for the management of cryptococcal disease: update by the infectious disease society of america measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of aids-associated cryptococcal meningitis comparison of amphotericin b with fluconazole in the treatment of acute aids-associated cryptococcal meningitis. the niaid mycoses study group and the aids clinical trials group key: cord- -js vvsud authors: hayes, anna marie title: human insecurity in the people’s republic of china: the vulnerability of chinese women to hiv/aids date: - - journal: human security doi: . / - - - - _ sha: doc_id: cord_uid: js vvsud hiv/aids has become one of the world’s leading causes of human insecurity for both men and women. in addition to physiological factors, women’s vulnerability to hiv transmission is primarily fuelled by gender inequality and gender-based discrimination and violence. therefore, women’s vulnerability to hiv transmission is closely linked to issues of empowerment and gender-based power relations. even with this realization however, women are still sometimes overlooked in many hiv/aids prevention and treatment campaigns, such as those in the people’s republic of china (prc), and responses to hiv/aids do not always actively seek to empower women. therefore, a deficiency in women’s human security increases their hiv/aids vulnerability. this chapter examines the intersection of gender inequality and hiv vulnerability as it applies to women in the prc. the unequal status of many women in china, and the privileged position accorded to chinese men, strongly indicates that chinese women face a heightened vulnerability to hiv transmission. while many of these vulnerabilities are similar to women elsewhere in the world and certainly are not unique to china, by overlooking the many social, cultural, economic and political factors that contribute to hiv/aids vulnerability and transmission of the virus, particularly those faced by women, china has a long way to go before chinese women are protected from hiv transmission. given that hiv/aids heightens human insecurity, the stage is set for chinese women (and men) to face an insecure future if the chinese government does not fully implement international best practice, meaning a gendered response, into its overall hiv/aids response. for the purposes of this chapter, the defi nition of human security is aligned closely with that of the united nations which states that human security is both 'freedom from fear' and 'freedom from want', incorporating components such as economic, food, health, environmental, personal, community and political security. this defi nition challenges the more restricted notions of human security and is centred on the principles that human security is a universal concern, its components are interdependent, that it is best achieved through prevention rather than intervention and that it is people-centred (undp : - ) . figures from the ministry of health (moh) show sexual transmission is now the main mode of hiv transmission in the prc, signalling that china has moved into the 'growth period' of its hiv/aids epidemic. at the close of , it was reported that % of the total number of hiv/aids cases in china were caused by sexual transmission, with heterosexual transmission accounting for . % of those infections and homosexual transmission accounting for . % (ministry of health of the people's republic of china : ) . of the total reported number of hiv/aids cases, . % of plwha in the prc are women demonstrating the vulnerability of women to hiv transmission and increasing the concerns that the country is in a growth period (scawco and unaids : ) . also concerning is that since , sexual transmission has been the fastest growing mode of hiv transmission in china (hong et al. ) . further evidence of china's hiv epidemic moving into its growth period are the country's fi gures on mother-to-child-transmission (mtct). since , it has estimated that mtct of hiv accounted for approximately . - . % of the total number of new hiv cases (national center for aids/std prevention and control : ; ministry of health of the people's republic of china : ). according to the united nations joint program on hiv/aids (unaids) mtct rates in excess of % demonstrate that a hiv/aids epidemic meets the criteria for the categorization of a 'generalized epidemic' as mtct highlights rates of hiv among women in the general population who do not belong to any particular high-risk group (gill et al. ) . therefore, the above results are further evidence that china's overall hiv/aids epidemic has moved into its growth period . if effective prevention and control measures are not introduced prior to or during the growth period, and the country's hiv/ aids epidemic moves into the 'rampant prevalence period', large scale hiv transmission is inevitable. although rates of hiv among the general population remain low in the prc, with rates believed to be between . % and . % (ministry of health of the people's republic of china : ), the spread of hiv through heterosexual intercourse among the general population is very much a warning that the numbers of plwha may soon explode across the country. if this occurs, it would make the epidemic very diffi cult to prevent and control and chinese women's vulnerability to hiv transmission will increase substantially, particularly because the prevalence rate of hiv among the general population would increase rapidly. physiologically, women are two to four times more vulnerable to hiv transmission than their male counterparts when engaging in unprotected vaginal intercourse (unaids : ) . in addition to physiological risks, women worldwide face a number of vulnerabilities to hiv/aids, deriving from a variety of social, cultural, economic and political factors. a society's gender roles have considerable infl uence on three main areas of hiv/aids vulnerability; accurate sexual and reproductive health knowledge, sexual passivity and aggression, and promiscuity. in addition, 'enabling environments' such as social, cultural, political and economic environments, can all fuel hiv vulnerability among women and these vulnerabilities are largely the result of gender inequality (feinstein and prentice ) . thus, in order for a state's hiv/aids response to be effective it must include gender-specifi c factors. therefore, women must be recognized as a vulnerable group. however, when asked whether she believed chinese women were particularly vulnerable to hiv transmission, interviewee d ( , pers. comm., august) , who was the director of a government organization that played a key role in hiv/ aids prevention and treatment, responded that she believed 'women are less vulnerable [than men] to hiv/aids' and that women's vulnerability to hiv/aids largely depended on whether a woman was a sex worker, an intravenous drug user (idu), if she had donated her blood, had a blood transfusion or had used other blood products (interviewee d , pers. comm., august) . this point of view was supported by another interviewee, who was the national programme offi cer for an international non-governmental organization (ingo) responsible for hiv/aids prevention and treatment. in response to the same question, this interviewee stated that 'gender does not play any role [in its hiv/aids policies], and it is not part of mainstream discussions' (interviewee c , pers. comm., august) . these responses are alarming because they ignore the patterns of hiv transmission to women in much of the rest of the world, whereby women in the general population have been found to be extremely vulnerable to hiv transmission in areas with high rates of hiv/aids. however, while interviewee c's organization did not incorporate a gendered response into its overall hiv prevention and treatment programs, her responses indicated that the intersection of gender and hiv vulnerability was being considered ( , pers. comm., august) . interviewee c believed that gender and economics were important issues in hiv/aids prevention and treatment, even though they were not yet widely recognized or were a part of china's offi cial hiv/aids response and policies. on the issue of what factors increased female vulnerability to hiv transmission, she said: women are vulnerable… for a number of reasons. these include the status of womenpolitical, economic and social status of women. also, the educational level of women is lower than their male counterparts, and unemployment rates are a great deal higher. this has a lot to do with remaining views on the role of women, which follow closely with the traditional stereotypes of women as wives, devoted to house and raising children. they are still seen in this caregiver role. women are also restricted in their access to information, so this also makes them vulnerable because they don't know what hiv/aids is or how to prevent it (interviewee c , pers. comm., august). responses from other interviewees also demonstrated that organizations were aware of the links between gender and hiv vulnerability. when asked what factors he believed increased chinese women's vulnerability to hiv/aids, interviewee e ( , pers. comm., august), a health specialist for an ingo that included hiv/ aids in its health framework, responded that he felt unemployment and low education levels were key factors because they led to economic insecurity that could lead women to prostitution. he stated that particularly in rural china, female school enrolments were much lower than those of males, and that this adversely affected women's employment opportunities. he also stated that women were further disadvantaged because they were not paid the same as men for equal work. also, because many women had been laid-off from their jobs in northeast china, due to factory closures and cutbacks, many of these women had been forced to enter the sex industry as a means of survival (interviewee e , pers. comm., august) . hence, while both interviewees c and e were aware of the effects gender has on hiv/aids vulnerability, neither their particular organizations, nor any other organizations responsible for hiv/aids prevention and treatment campaigns at the time, incorporated gender into their programmes or education campaigns. interviewee a, who was a senior programme offi cer for an overseas aid agency ( , pers. comm., august) , offered two possible reasons for this oversight. firstly, she believed a gendered response was not a major component of china's hiv/aids strategy because 'gender issues are generally addressed by the all china women's federation (acwf) or the regional women's commission (rwc)' (interviewee a , pers. comm., august) . secondly, at the time of fi eldwork, ordinary chinese women among the general population were not widely recognized or targeted as being vulnerable to hiv transmission (interviewee a , pers. comm., august). therefore, according to interviewee a, because women among the general population were not regarded as a vulnerable group it made little sense to organizations such as hers to engender their hiv/aids prevention strategies. however, if we consider interviewee a's fi rst response, it would appear that the acwf and rwc have unintentionally 'marginalized' women in discussions on hiv/aids vulnerability among organizations responsible for hiv/aids prevention and treatment campaigns because these organizations do not want to interfere with the role of the acwf and the rwc. this reluctance could in part be because of the historical background of the acwf. this organization was one of the fi rst mass organizations formed by the chinese communist party following the liberation and was the impetus for the social, legislative and policy changes aimed at improving the status of women in the s. while it was temporarily disbanded during the cultural revolution , the organization was fully reformed in and since that time it has continued its earlier work on improving the status of women in china through legislative and social change (howell ) . therefore, the acwf has had a monopoly on women's issues in china for much of china's post-liberation period. while there has been an expansion of women's groups and organizations since the reform and opening of china in , it is signifi cant to note that the acwf has remained an important ally for these groups (lee and regan ) , and the strongest women's organization in china due to its political legitimacy and sway in the political structure (howell ) . therefore, interviewee a's reasons for the lack of consideration of gender in offi cial responses to hiv/aids in china demonstrates that there are serious impediments which need to be addressed. it would seem there is a reluctance to either tackle gender issues by non-acwf organizations as they may perceive a turf war confl ict, or simply because they feel that such issues are best handled by the acwf. whatever the reason, because such organizations are reluctant to incorporate gendered responses into their hiv/aids prevention and treatment campaigns women have been marginalized in the mainstream responses to hiv/aids in china even though international experience has repeatedly demonstrated that if they are left unresolved, gender vulnerabilities to hiv transmission fuel hiv epidemics. however, interviewee a did state that should the epidemic move into the 'rampant prevalence' period, these groups (meaning women in the general population not belonging to any of the traditional 'high-risk' groups) would receive more attention from organizations like hers. thus, it would appear some organizations do believe gendered responses may be necessary in the future. nonetheless, the reluctance of international organizations like interviewee a's to incorporate gendered responses was concerning as in many aids-stricken countries, especially those in sub-saharan africa, women among the general population have been found to be at substantial risk of contracting hiv through non-commercial heterosexual intercourse (unaids, unfpa and unifem : - ). as stated above, much of this vulnerability stems from social, cultural, economic and political factors that often refl ect gender inequality and this chapter now turns to an examination of these in the context of women in the prc. accurate knowledge about hiv/aids, including the prevention and transmission of hiv, is an essential part of an adequate response to hiv/aids. however, surveys conducted by some ingos have revealed that as much as - % of china's population has no knowledge of hiv/aids at all (park : ; unaids : ) . while recent fi gures suggest this has changed and that 'basic' hiv/aids awareness is in the vicinity of between . % and . % for urban and rural residents and migrant workers, there still remain pockets of the population who lack accurate hiv/aids knowledge and awareness (ministry of health of the people's republic of china : ). one of the reasons often cited for this lack of knowledge is that due to china's size and regional variances in language dialects, country-wide hiv/ aids education campaigns are diffi cult to conduct. interviewee f ( , pers. comm., september) , the division director of a government organization that examines hiv/aids related issues, confi rmed this when she stated 'because china is so large… not everyone knows about aids [and] the information has not spread to very remote areas, [therefore] more work will be done there'. these factors seriously complicate the dispersal of accurate hiv/aids knowledge, and are a key area that the chinese government must overcome to effectively respond to china's growing hiv/aids epidemic. however, there also exists a range of other reasons for the poor levels of hiv/aids knowledge in china. the reform and opening period , which began in the late s, loosened societal attitudes and views on sexual issues in china, and this resulted in an increase in premarital sex and societal acceptance of premarital sex (qian et al. ; wu et al. ) . a study by the sex sociology institute of the people's university of china found that in people over years of age, . % of men and . % of women reported they had engaged in premarital sex . however, for the - year old age bracket, rates were signifi cantly higher with . % of men and . % of women reporting they had engaged in premarital sex (xia : ) . even though premarital sex is occurring, sex education and the supply of contraceptive devices to young, unmarried people remains a contentious issue. interviewee c ( , pers. comm., august) stated that sex education was an important topic in china and that there had been much debate over when young people should be taught about sexual health, with some sections of chinese society arguing that the university level was the most appropriate time for formalized sex education . there was also growing debate over abstinence-based sex education as opposed to sex education that promotes 'safer sex', such as using condoms, with the proponents of the abstinence-based sex education style hoping to see a return to 'traditional morality' (xia : ) . in the meantime, no real steps have been made in implementing a comprehensive sex education curriculum into chinese schools. as a result, many university students in the prc have 'alarmingly low' levels of aids knowledge and self-perceived risk (wu et al. : ) , refl ecting the need for a national sex education curriculum. this is concerning as hiv in china is most prevalent among people in the - year old age bracket, with this group accounting for % of china's overall hiv/aids cases (ma et al. : ) . however, these rates of infection are unsurprising when one considers that surveys of university students have found that only % of those who were sexually active reported % condom use in their sexual encounters during the year prior to the study (ma et al. : ) . for many young unmarried people in china, the lack of accurate knowledge on 'safer sex' has been a contributing factor in them engaging in unprotected sex, which easily facilitates the transmission of stis, including hiv, as well as increasing rates of unintended pregnancy. although young unmarried people can access contraceptive services in china, information and advice about contraception is somewhat limited. this is because the national family planning programme only targets married couples for the delivery of contraception information and devices. furthermore, studies conducted in rural and urban shanghai found that when premarital sex resulted in pregnancy, most pregnancies were unintended, and were usually because the couple had not used contraceptives (qian et al. ) . surveys conducted on confi dence levels when purchasing condoms found that only . % of women compared to . % of men felt confi dent buying condom s (ma et al. : ) . clearly, even though premarital sex has become more commonplace and generally more acceptable, a comprehensive sex education programme and easy, more accepted access to reliable barrier methods of contraception are needed if optimum health outcomes are to be achieved. another key factor in this discussion is how condoms are perceived by chinese society. with the resurgence of stis in china, and the need to promote condoms effectively as a means of preventing stis, condoms have undergone a name change from bi yun tao , or 'avoid pregnancy sheath', to an quan tao , or 'safety sheath'. the change refl ects the dual role of condoms in preventing conception, but also as a means of preventing the transmission of stis/hiv (yuan et al. : ) . interviewee f acknowledged this change, adding that her organization stressed '…using condoms is benefi cial for men and women, from the point of view of health, because men and women will both benefi t from the[ir] use ' ( , pers. comm., september) . however, a recent study has reinforced that condoms are still primarily perceived by some university students as pregnancy prevention rather than protection against stis/hiv. the study found that % of respondents identifi ed condoms as protection against pregnancy while only - % regarded them as protection against stis/hiv (ma et al. : ) . clearly, condoms are a necessary part of an effective hiv prevention strategy so it is imperative that their role in sti prevention is stressed and encouraged in the chinese situation. thus, even with the name change, condom use in china remains low. this is alarming to epidemiologists because of the role of condoms in preventing stis/hiv, particularly for women. a study by xia in found that . % of male respondents were unwilling to use condoms in their sexual relations because they found them to be 'troublesome', to decrease male sexual pleasure, as well as too expensive. in addition, many unmarried men preferred not to use condoms because they felt their 'sexual and reproductive ability' was proven if their partners became pregnant ( : ). furthermore, many men continue to view their sexual relationship with their wife as procreation, whereas sexual pleasure is derived from commercial sex workers. therefore, condoms within marriage are not considered appropriate and they are rarely used, regardless of some men having multiple sexual partners (chen ) . interviewee b ( , pers. comm., august), a programme offi cer for an overseas aid agency, believed that women could be vulnerable to stis from their partners because 'there is no such dialogue [safer sex] between husband and wife or partners'. furthermore, she concluded that in south-west china for instance, promotion of condom use in sexual relationships was absolutely necessary because the main route of hiv infection for men there has been idu and for women, it was through heterosexual intercourse 'within the family, within marriage, it's not through commercial sex workers' (interviewee b , pers. comm., august) . increasing condom usage rates among the general population is further complicated because many chinese women use intra-uterine devices (iuds) or have had surgeries such as tubal ligation or hysterectomies to avoid further pregnancies, causing condoms to be viewed as unnecessary. therefore, interviewee b believed that it was imperative condoms be promoted as a sexual health device within marriage and committed relationships in addition to persons engaging in premarital sex or infi delity. while promoting condom use among the general population was also identifi ed as a necessity by interviewees d and c, work is needed on promoting % condom use among commercial sex worker s in both their commercial and noncommercial sexual relations. in china, condom use among sex workers is also extremely low with only % of sex workers surveyed at various locations reporting that they always used condoms, and close to % of sex workers reporting that they had never used a condom with a client (kanabus ) . this is not surprising considering many sex workers lack adequate hiv/aids information in the fi rst instance and secondly because condom use in sexual exchange generally involves a 'discount' due to both decreased sensitivity and male sexual pleasure. therefore, the economic burden faced when insisting on condom use in the commercial sex exchange means that for many sex workers condom use is not a viable or desirable economic option. in addition, low rates of hiv/aids and sti knowledge has meant that many sex workers do not believe they are at risk of contracting hiv. this clearly indicates a continuing lack of hiv prevention knowledge in an important 'high-risk' group, which increases the likelihood of the transmission of hiv among sex workers and their clients (kanabus ) . furthermore, other sex workers who wanted to use condoms in the commercial sexual exchange were prevented from doing so because they lacked 'the power to insist on the use of condom s with their clients' . in most instances, it is the client who decides whether or not a condom is used in commercial sexual exchange, again refl ecting the disempowered status sex workers face (kanabus ) . hence, poor hiv/aids awareness and female disempowerment facilitates such 'high-risk' behaviour, and this situation reinforces the need for widespread public education campaigns to better educate the entire chinese population on hiv/aids prevention and risk. this is particularly pressing considering that commercial sex is the leading contributing factor for the transmission of hiv through heterosexual intercourse (hong et al. ) . however, such an education campaign must contain accurate and appropriate messages about hiv/ aids and hiv prevention. early state media representations of hiv/aids negatively affected hiv/aids knowledge in china, and how plwha were received by society and by the medical profession. interviewee d ( , pers. comm., august) stated that when the state media initially discussed hiv/aids, it was portrayed as 'the enemy' and that media reports were largely focused on scaring people about the virus. furthermore, interviewee d believed that these early representations greatly contributed to the stigma and discrimination of plwha in china. this argument was reinforced by dikötter, who claimed that aids was initially described in offi cial discourse as an 'evil from abroad', and that it was widely believed that the 'superior immune system' of the chinese, combined with their 'neo-confucian values', would mean that hiv/aids would not infect the general population but would largely remain limited to homosexual men and sex workers who serviced foreign clients ( : - ). such beliefs became accepted by chinese society and have infl uenced how both the virus and plwha are perceived. in addition to stigma and discrimination , these early representations of hiv/ aids have also led to many people falsely believing that they are not at risk from contracting hiv if they do not belong to one of the above-mentioned groups. this false sense of security was refl ected in the section on 'self-perceived risk of contracting hiv/aids' in a study conducted by the futures group ( : ) . this study explored the levels of hiv/aids knowledge among respondents and their attitudes and behaviours towards aids related issues. the study found that % of those surveyed believed themselves to be at 'low-risk' of contracting hiv/aids, and that the main reason for such a belief was because very few of the respondents ( %) reported that they knew of a plwha or a person who had died from aids. therefore, because they themselves had not known anyone affected by hiv/aids, their perception of the virus was that it is something that affects the 'other' or that it only affected 'degraded people' (futures group : ) . consequently, because they did not fi t either category, they believed themselves to be of little risk of contracting hiv/aids. self-perceived risk has also been skewed by the government's hiv/aids prevention policies, which have long been focused on 'high-risk' groups. it can be argued that current prevention strategies actually put women at risk because they stress partner reduction over condom use as an effective way to avoid hiv transmission. the 'one partner' or 'faithfulness' prevention messages, which teach both men and women to protect themselves against hiv transmission by limiting the number of partners they have to one, has been described by unaids as lulling people into a 'false safety' (unaids : ) . surveys that have been conducted in china among traditional 'low-risk' groups such as married women, who do not engage in any of the traditionally recognized 'risky practices' conducive to hiv transmission, have found that most women believe that limiting the number of partners they have to one is much better protection against hiv transmission than using condom s (unaids : ) . however, such a measure is dependent upon their spouse having a negative status upon the commencement of the relationship, and not engaging in practices that may cause them to contract hiv for the duration of the sexual relationship. furthermore, the 'one partner' campaign ignores the fact that for many women in the developing world who have contracted hiv/aids through heterosexual intercourse, the source of their transmission was their only sexual partner, usually their husband. often these women were unaware of their husband's hiv+ status, and in other cases, whereby they knew their husband was hiv+, they were unable to say no to sex or insist on condom use due to the unequal gender-based power relations within the relationship. in a study of chinese women who contracted hiv from their husbands, none of the women interviewed were aware of their husband's hiv+ status prior to their own diagnoses. in addition, one husband commented that he felt women 'had little choice if their husbands insisted they do so [have sex], inasmuch as the fact that "we are still married" legitimized their sex' (cited in zhou : ). therefore, the government sponsored campaigns in china that primarily focus on individuals reducing 'risky practices' or limiting the number of sexual partners they have to one, are out of step with reality. instead, hiv/aids prevention campaigns also need to focus on providing easily accessible sexual and reproductive health information for both men and women, and making condoms available and accessible to all sexually active persons. they should also aim to empower women and challenge the negative gender stereotypes and biases attributed to both men and women that heighten their vulnerability to hiv transmission. worldwide, women's vulnerability to hiv/aids is further heightened in societies where women are expected to be passive towards sex. while china was, traditionally, very much a society whereby passivity was expected of women in sexual matters, after this situation was widely believed to have altered because of mao's proclamations about female equality as well as the belief that the 'smashing' of class surveys conducted in africa reveal that - % of hiv positive women, who contracted hiv from sexual intercourse, reported that their only sexual partner was their husband. another study, which was conducted in india, another region where hiv/aids is growing at an alarming rate, reveals that % of hiv positive women surveyed, who had contracted hiv from sexual intercourse, also reported that their only sexual partner was their husband (feinstein and prentice : ) . these fi ndings support the results of an earlier study conducted in which also found the majority of hiv positive women who had contracted hiv through heterosexual intercourse, had also contracted hiv/aids from their only sexual partner, their husband. the researchers in this instance concluded that often 'condom use was more effective in preventing hiv infection than was limiting the number of partners' (berger and vizgirda : ). difference would lead to the eradication of outdated sexual stereotypes regarding men and women. however, patriarchal views still permeate chinese society and overall chinese men retain their position of gender privilege, often refl ected in the power dynamics of heterosexual relationships. the one child policy is one of the main factors in increasing female insecurity in contemporary china, particularly within the marital unit. since its introduction, there has been a strong resurgence in son preference , especially in the rural areas where sons play an important role in continuing the family lineage, contributing to the family labour force and their fi lial duty to provide for their parents in old age ( croll et al. ; croll ; chan et al. ) . in some areas of china, the reemergence of son preference has caused there to be strong pressure on women to give birth to a son and failure to do so can lead to domestic violence and even divorce. this is because women are wrongfully blamed over the sex of the child due to poor knowledge on the biological determinants of the sex of the fetus and also because it is believed to be 'the duty of a chinese wife to bear a son to continue the family name' (chan et al. : ) . in her discussion of son preference and the resultant violence against women who give birth to daughters, croll provided several accounts of incidences whereby a husband committed acts of domestic violence against his wife after she bore a daughter ( : - ). the acwf has found that reported cases of domestic violence occur in approximately % of chinese families, with . % of abused women being beaten around four times per month (xinhua ) . female suicide rates are also high in the prc, refl ecting female insecurity there. of the total number of female suicides worldwide, % occurred in china (renwick : ) . in addition, while the urban rate of female suicide is estimated to be in the vicinity of . per , women, in rural areas the fi gures have reached . per , women, clearly demonstrating a rural/urban divide in female suicide rates in china (hric, cited in renwick : ) . a report by the bbc echoed these fi ndings, and stated that many rural women are highly successful in their suicide attempts because they used pesticides and rat poisons to commit suicide (bbc ) . if gender-based violence such as domestic violence is viewed as an acceptable factor in preserving gender relations in the home, it can substantially increase women's vulnerability to hiv transmission. in societies where there exists 'a cultural ethos that violence is a valid means of solving inter-personal disputes' (whelan : ) , such as in the domestic spheres, women may avoid discussing the use of condoms or fi delity issues with their partners for fear of violent response. the fear of violent retribution was identifi ed by women from a range of countries such as guatemala, jamaica and papua new guinea as being the reason why they did not try to negotiate condom usage with their sexual partners (feinstein and prentice : ) . women's vulnerability to hiv/aids is heightened by male aggression because it can often be linked to the occurrence of sexual coercion, non-consensual sex and sexual violence against women. for many women, decisions about their sexual behaviour are denied to them because they are forced into sexual intercourse against their will. this is applicable both inside and outside of relationships. in such instances, condom usage is unlikely, so women's vulnerability to hiv transmission is increased (irwin et al. : ) . therefore, the accounts given above of high rates of domestic violence and female suicide demonstrate that there are a great number of women in the general population who are facing increased hiv vulnerability due to their unhealthy domestic environment. the traffi c of women in china is also fuelling female vulnerability to hiv transmission, and is most prolifi c in sichuan and guizhou. interviewee a ( , pers. comm., august) attributed this to the fact that these two provinces 'have a high number of poor farmers and unemployed' so they sell women for fi nancial rewards. interviewee a also stated that the 'traffi c of women in china is generally restricted to marriage, whereas traffi cking outside of china is generally for prostitution'. in saying this, the interviewee believed that the traffi c of women , while bad, would not increase the likelihood of hiv transmission because the women were sold as 'brides', not sex workers (interviewee a , pers. comm., august) . the belief that traffi cked 'brides' are not particularly vulnerable to hiv transmission was also shared by interviewee e ( , pers. comm., august) . however, this belief demonstrates a serious lack of understanding of human traffi cking as members of the traffi cking gangs sometimes rape the women, regardless of them being traffi cked as 'brides' or as sex workers . furthermore, prospective husbands are sometimes allowed to have intercourse with the women before purchasing them, in order to decide which woman will become their 'bride' and also so that they can bargain the price of the woman ( south china morning post , cited in jaschok and miers : ) . clearly, the rape of these women by numerous men, including their 'husband', increases their vulnerability to hiv transmission. in addition, the likelihood that their 'husband' will contract hiv from them or from other women he 'sampled' is also heightened if he does not already carry the virus. hence, it is a very serious misconception that the traffi c of women in china as 'brides' will have little impact on the hiv/aids epidemic there. equally alarming is the view held by some segments of chinese society that 'as long as they [men] have the money, buying a wife or child is their own affair' (li zhongxiu, cited in jaschok and miers : ) . again, this kind of attitude illustrates the low status that many women (and children) continue to occupy in chinese society and the patriarchal factors that heighten their vulnerability to hiv/aids. in addition, it is widely predicted that the sale of women in china is set to continue to expand because from a purely economic standpoint, buying a traffi cked bride can be far cheaper than paying a dowry (song, cited in jaschok and miers : ) . also, the skewed sex ratios that have resulted from the introduction of the one child policy and resultant resurgence of son preference have seen men far outnumber women in many areas of china (edwards : ) . it has been estimated that by , there will be million more males than females in the - year age bracket due to sex selective abortion and the neglect of girl children in china (chan et al. : ) . due to the gender imbalance it is unlikely that these men will be able to fi nd a bride to marry legally and they will increasingly turn to bride traffi cking as the solution, making it a crime that is likely to soar over the next few decades, alongside prostitution. while the chinese government has not ignored this situation, and the public security bureau often detects and arrests human traffi ckers , traffi cking is diffi cult to police as the number of women traffi cked yearly is believed to be in the vicinity of tens of thousands. they are primarily abducted from poor regions in guizhou, sichuan and yunnan provinces (woodman and ho, cited in hughes et al. ) . further complicating this issue is the fact that many women who have escaped their 'husbands' have not received assistance because some authorities also have sympathy toward men who have been unable to fi nd brides. as a result, women who escape their situation are often returned to their 'husbands' by authorities. villagers also assist in the traffi cking of women either by ignoring the problem, or by helping to buy women. in fact, it has been reported that one remote village collectively purchased women with the intention of soliciting them from their homes (woodman and ho, cited in hughes et al. ) . the traffi c of women constitutes a serious potential bridge for hiv transmission to the general population and again refl ects a heightened vulnerability, in terms of both hiv transmission and human insecurity, for chinese women. another factor identifi ed by interviewee c as compounding the situation of women's vulnerability to hiv transmission was the migration of rural workers to the cities for work. she stated that although many male migrant workers are married, they leave their wives behind and often engage in 'risky practices' in the cities, such as idu, procuring sex workers, and infi delity. generally, the men return to their homes once a year, during which they engage in sexual activity with their spouse, usually without using condoms. the interviewee further stated that even if the woman may suspect her spouse of having engaged in 'risky practices' while away, many women are unable to insist that their spouse use a condom (interviewee c , pers. comm., august) . in addition, for many rural women, labour migration can heighten their vulnerability to hiv transmission because it removes them from the economic support and protection nets that exist in their home villages, making them easy targets to be lured or forced into prostitution. in fact, a large number of china's sex workers are migrant women (thompson ) and they sometimes display higher risk behaviour than non-migrant sex workers, in part due to low education levels and poor hiv/aids awareness, which increases their likelihood of contracting hiv (hong et al. ) . many migrant women have also become the victims of sexual harassment and sexual violence, which also increases their vulnerability to hiv transmission. while conservative estimates suggest the number of sex workers in china is approximately three million to four million (harding ) , scholars such as professor pan of people's university of beijing believe the fi gure to be much higher when the numbers of women who engage in 'casual or infrequent transactional sex' are included (cited in . it has also been reported by unaids that the public security bureau estimates the number of sex workers in china could be as high as six million (unaids : ) . jeffreys states that government authorities in china have called prostitution a 'widespread and growing problem ' ( : ) . thus, a conservative estimate of four million sex workers demonstrates that a considerable number of chinese women are vulnerable to hiv infection through prostitution. the illegal nature of prostitution in china is a major barrier to hiv/aids advocacy for sex workers and continues to exacerbate the vulnerable status of sex workers. interviewee d ( , pers. comm., august) stated that organizations like hers could give hiv prevention information to sex workers, without arresting them, because it was not a government organization. if workers from the government organizations identifi ed sex workers, she stated that they were required to report them because of the illegality of prostitution. after being reported, the identifi ed sex worker would then face detention in a rehabilitation centre. while there are debates in china as to whether or not prostitution should be decriminalized or legalized so as to allow ingos, ngos and government organizations to legally provide sti prevention knowledge and services to sex workers, the rehabilitation system does currently offer an opportunity to reach this vulnerable group with hiv/aids prevention information. however, interviewee d ( , pers. comm., august) stated that this was not occurring, even though the organization she worked for had been trying to launch programs that linked 'hiv/aids prevention education into the rehabilitation programs of these centres'. furthermore, without adequate help to overcome their economic insecurity, upon release from these centres many women actually returned to prostitution. thus, she stated, an important opportunity was being missed. there is concern however, over the contradiction in the government's response to prostitution, which sees sex workers targeted by interventionist programs, not those soliciting the prostitutes. this obvious gender bias is in part fuelled by the extant view in china that those selling sex always come before those buying sex. this view is problematic in that one could argue that it is demand that drives provision; however at a very basic level it punishes the sex worker as the guilty party in the commercial sex exchange and not the solicitor. it also means that many of the men who solicit prostitutes are left out of the targeted commercial sex hiv prevention strategies although they are clearly a 'high-risk' group (chen ) . if they are married or have other sexual encounters outside of the commercial sexual exchange, they are also a possible 'bridge' population who have the potential to transmit hiv into the general population. chen ( ) argues that the failure of the chinese government to adequately respond to this contradiction refl ects that there is an urgent need in china for recognition of the important role men play in safer sexual practice, a responsibility that is continually being thrust onto women. in fact, recent campaigns by the acwf reportedly 'exposed' . million women across china to hiv/aids prevention and awareness knowledge. however, there was no discussion of if/how men were also given this important knowledge or if they were made aware of how their actions can impact on the hiv vulnerability of their spouses (scawco and unaids ) . considering the unequal gender-based power relations discussed above, it is unlikely that these types of measures will have much success as men and women both need to be involved in such advocacy programs. to neglect the involvement and importance of men serves to increase women's vulnerability while at the same time proportioning responsibility to women for their own hiv safety, something that is simply unachievable for many women. the failure of the rural health system is also exacerbating the vulnerability of chinese women to hiv/aids. approximately % of rural women are now showing symptoms of having untreated rtis or stis (interviewee c , pers. comm., august), both of which increase their susceptibility to hiv through sexual transmission ( jolly and ying : ) . the fi gures on stis clearly indicate that behaviours conducive to the transmission of hiv/aids, such as unprotected intercourse, are becoming more widespread. however, rural healthcare facilities continue to be inadequate, and therefore information on hiv/aids and prevention of the virus is not reaching rural men and women (interviewee c , pers. comm., august) . in addition, many rural women are not targeted for information dissemination due to the offi cial belief that these women fall into the 'low-risk' category due to their marital status and individual behaviour. in light of the discussion above, this overly simplistic classifi cation of who is or is not 'at risk' is substantially heightening women's vulnerability to hiv. considering the changing face of china's hiv/aids epidemic in the current era, the failure of the government to have a comprehensive gendered response to the burgeoning aids epidemic in the prc may result in the government ineffectively responding to hiv/aids. chen ( ) warns that this could lead to an increase in stigma and discrimination against women as their hiv+ rates increase and may further exacerbate women's insecurity. when critiquing the privatization of health care in china, interviewee d ( , pers. comm., august) stated that prior to the s, the health system in rural china was much better because 'bare foot doctors and health workers were active in even the most remote areas'. however, after the dismantling of government sponsorship, the rural healthcare system was left in ruins, with only expensive private doctors available to meet the health care needs of the rural population. another problem with the provision of health care is that the government does not regulate sti facilities. in fact, some sti clinics are now being rented out to private practitioners. while this can benefi t plwha, because it reduces the possibility of their hiv+ status being leaked, it also causes prices to rise and patient care tends to decline (interviewee c , pers. comm., august) . therefore, the privatization of essential services such as the health industry has seen medical services fall out of the economic reach of many poorer families or individuals. this compounds chinese women's vulnerability to hiv because it limits the ability of both men and women to manage their sexual and reproductive health. another diffi culty identifi ed by interviewee d ( , pers. comm., august) was that organizations like hers lacked adequate funding both to run programs as well as to support plwha. she stated that because most plwha in china are rural poor, education on lifestyle, proper diet and medication was in vain as 'many [patients] can't follow these instructions because they live in poor conditions in rural china, where their income is just enough to feed their families'. however, with better funding, hiv/aids prevention and treatment campaigns could help plwha with the costs of living and medications, making their lives better (interviewee d , pers. comm., august). interviewee f ( also identifi ed funding as a problem for hiv/aids prevention and treatment. she stated that sometimes her organization wanted to carry out pilot projects, but because they were given insuffi cient funding they were unable to run the projects. clearly, without the funding to properly test pilot programmes or institute nation-wide campaigns, hiv/aids prevention in china will continue to be hindered. on the other hand, the introduction of the 'four frees and one care ' policy in has seen a positive change in the government's funding response to china's aids epidemic. the 'four frees' provided by the policy include government funded schooling for aids orphans, drug therapy for plwha, prevention of mtct and voluntary counseling and testing (vct). the 'one care' component refers to care and economic assistance for people affl icted with or affected by hiv/aids (cao et al. : ) . however, by the government's own admission, the implementation of this policy has been uneven (national center for aids/std prevention and control : ii), so while it is certainly a step in the right direction, it is not fully operational as it will require a great deal of cooperation between all levels of government and assistance by civil society before it can really meet its objectives. it should be acknowledged that china has been injecting more funds into hiv/aids prevention and treatment strategies since . the update by unaids and the world health organization reported that there had been a threefold increase in funding by china in the period between and demonstrating stronger commitment from the government (unaids and who ) . the incorporation of civil society into hiv/aids prevention was an issue also identifi ed by interviewee b ( , pers. comm., august) . she stated that the solitary nature of the moh in combating hiv/aids in china means that it is effectively tackling hiv/aids by itself. while the enabling environments for hiv transmission include diverse fi elds such as employment and public security, interviewee b stated that there was no cooperation between the ministry of public security (mps) and the moh, a point which chen believes has led to; tensions, and sometimes contradictions, between the goals of public policies and the methods of policy practice, such as the confl ict between public security (law enforcement) policies relating to sex work and public health policies for the prevention of hiv/aids ( : ). furthermore, issues pertaining to commercial sex workers and idus, which were handled by the mps, also did not involve input from the moh. this is quite possibly the reason why hiv/aids prevention advocacy programs have still not been uniformly implemented in all rehabilitation centres for idus and sex workers . interviewees c and f both believed that education campaigns aimed at the general population could be a valuable way to disperse hiv/aids information. they stated that efforts like the severe acute respiratory syndrome (sars) mass media education campaigns would be a major step in changing people's beliefs about hiv/ aids and increasing knowledge and public awareness of the virus and how it is transmitted. after the cessation of sars, the chinese government did shift its focus to hiv/aids, and education campaigns on hiv/aids have been undertaken. therefore, unlike previous efforts, top leaders in government have demonstrated they are serious in their response to hiv/aids. while this signals a positive change, unfortunately the gender issues that contribute to hiv/aids vulnerability do not appear to be an integral component of these campaigns, so their overall effectiveness is doubtful. in addition, gender inclusive campaigns would also need to be supported with active steps at both the government and grassroots level to reverse the continuing unequal social, political and economic structures that disempowered chinese women, which have been shown to heighten their vulnerability to hiv/ aids. however, beijing's reluctance to support the development of an unrestrained civil society in china makes this unlikely. in the united nations report hiv/aids: china's titanic peril ( ) , china's political system was identifi ed as possibly the most sensitive obstacle to tackling hiv/aids in the prc. this was because the central government has long appeared uncomfortable with the emergence of organizations that are independent of the government and especially the free fl ow of information that such organizations may facilitate (unaids : - ). yet, while the central government may fear that the emergence of civil society could contribute to a breakdown in the chinese communist party's authority in china, civil society participation and the free fl ow of information are not only good governance when responding to hiv/ aids epidemics, but international experience has proven them to be essential elements in a state's response to hiv/aids. therefore, until the central government is willing to allow greater autonomy among the various ngos and ingos operating in china, it is unlikely that the chinese response to hiv/aids will make any real inroads in the prevention of hiv transmission -and even less so in terms of gender-specifi c issues such as the human insecurities that increase women's vulnerability to hiv/aids. when determining women's vulnerability to hiv transmission, female human security , or more aptly their 'insecurity', is an important factor. the status of many women in china, and the privileged position accorded to chinese men, strongly indicates that chinese women face a heightened vulnerability to hiv transmission. while many of these vulnerabilities are similar to women elsewhere in the world and certainly are not unique to china, they attest to the interplay of the unequal status accorded many chinese women due to their sex, their disempowered status within society, unequal gender-based power relations both within the domestic and public arenas, and the patriarchal norms and attitudes that infl uence all of the above. by overlooking the many social, cultural, economic and political factors that contribute to hiv/aids vulnerability and transmission of the virus, particularly those faced by women, china has a long way to go before chinese women are protected from hiv transmission. given that hiv/aids heightens human insecurity, the stage is set for chinese women (and men) to face an insecure future if the chinese government does not fully implement international best practice, meaning a gendered response, into its overall hiv/aids response. hiv hits women hardest prevention of hiv infection in women and children understanding hiv-related stigma and discrimination in a "blameless gender selection in china: its meanings and implication gendering china's strategy against hiv/aids: findings from a research project in guangdong province endangered daughters: discrimination and development in asia china's one-child family policy sex, disease and society: a comparative history of sexually transmitted diseases and hiv/aids in asia and the pacifi c women in the people's republic of china: new challenges to the grand gender narrative gender and aids almanac aids crisis impending: research on knowledge, attitudes and behaviours related to hiv/aids in china demography of hiv/aids in china: a report of the task force on hiv/aids center for strategic and international studies india is new loser in asian aids epidemic aids, bloodheads and cover-ups: the "abc" of henan's aids epidemic hiv/aids-related sexual risks and migratory status among female sex workers in a rural chinese country women's organizations and civil society in china the factbook on global sexual exploitation global aids: myths and facts. tools for fi ghting the aids pandemic women and chinese patriarchy: submission, servitude and escape feminist prostitution debates: are there any sex workers in china? key issues on gender and hiv/aids in china hiv & aids in china why develop and support women's organizations in providing legal aid in china? women's rights, women's organization and legal aid in china behavioural and psychosocial predictors of condom use among university students in eastern china update on the hiv/aids epidemic and response in china china's secret plague: how one us scientist is struggling to help the government face up to an exploding aids crisis unintended pregnancy and induced abortion among unmarried women in china: a systematic review the 'nameless fever': the hiv/aids pandemic and china's women a joint assessment of hiv/aids prevention, treatment and care in china hiv/aids epidemic in china spreads into the general population china's growing aids epidemic increasingly affects women hiv/aids: china's titanic peril women and hiv/aids: confronting the crisis aids epidemic update redefi ning security: the human dimension gender and hiv/aids: taking stock of research and programmes evolution of china's response to hiv/aids hiv/aids in china ban on family violence urged in china modelling the impact of the legal and policy environment on hiv/aids in china quality of care of reproductive health in china today endangered womanhood: women's experiences with hiv/aids in china the author would like to thank professor donald mcmillen, dr rosemary roberts and an anonymous reviewer for their insightful comments and suggestions. key: cord- -tpqsjjet authors: nan title: section ii: poster sessions date: - - journal: j urban health doi: . /jurban/jti sha: doc_id: cord_uid: tpqsjjet nan food and nutrition programs in large urban areas have not traditionally followed a systems approach towards mitigating food related health issues, and instead have relied upon specific issue interventions char deal with downstream indicators of illness and disease. in june of , the san francisco food alliance, a group of city agencies, community based organizations and residents, initiated a collahorarive indicator project called rhe san francisco food and agriculture assessment. in order to attend to root causes of food related illnesses and diseases, the purpose of the assessment is to provide a holistic, systemic view of san francisco\'s food system with a focus on three main areas that have a profound affect on urban public health: food assistance, urban agriculture, and food retailing. using participatory, consensus methods, the san francisco food alliance jointly developed a sec of indicators to assess the state of the local food system and co set benchmarks for future analysis. members collected data from various city and stare departments as well as community based organizations. through the use of geographic information systems software, a series of maps were created to illustrate the assets and limitations within the food system in different neighborhoods and throughout the city as a whole. this participatory assessment process illustrates how to more effectively attend to structural food systems issues in large urban areas by ( t) focusing on prevention rather than crisis management, ( ) emphasizing collaboration to ensure institutional and structural changes, and ( ) aptly translating data into meaningful community driven prevention activities. to ~xplore the strategies to overcome barriers to population sample, we examined the data from three rapid surveys conducted at los angeles county (lac). the surveys were community-based partic· patory surveys utilizing a modified two-stage cluster survey method. the field modifications of the method resulted in better design effect than conventional cluster sample survey (design effect dose to that if the survey was done as simple random sample survey of the same size). the surveys were con· ducte~ among parents of hispanic and african american children in lac. geographic area was selected and d .v ded int.o small c~usters. in the first stage, clusters were selected with probability proportionate to estimated size of children from the census data. these clusters were enumerated to identify and develop a list of households with eligible children from where a random sample was withdrawn. data collectmn for consented respondents involved - minutes in-home interview and abstraction of infor· ma~ion from vaccine record card. the survey staff had implemented community outreach activities designed to fost~r an~ maintain community trust and cooperation. the successful strategies included: developing re.lat on .w. th local community organizations; recruitment of community personnel and pro· vide them with training to conduct the enumeration and interview; teaming the trained community introduction: though much research has been done on the health and social benefits of pet ownership for many groups, there have been no explorations of what pet ownership can mean to adults who are marginalized, living on fixed incomes or on the street in canada. we are a community group of researchers from downtown toronto. made up of front line staff and community members, we believe that community research is important so that our concerns, visions, views and values are presented by us. we also believe that research can and should lead to social change. method: using qualitative and exploratory methods, we have investigated how pet ownership enriched and challenged the lives of homeless and transitionally housed people. our research team photographed and conducted one-on-one interviews with pet owners who have experienced home· lessncss and live on fixed incomes. we had community participation in the research through a partnership with the fred vicror centre camera club. many of the fred victor centre camera club members have experienced homelessness and being marginalized because of poverty. the members of the dub took the photos and assisted in developing the photos. they also participated in the presenta· tion of our project. results: we found that pet ownership brings important health and social benefits to our partici· pants. in one of the most poignant statements, one participant said that pet ownership " ... stops you from being invisible." another commented that "well, he taught me to slow down, cut down the heavy drugs .. " we also found that pet ownership brings challenges that can at times be difficult when one is liv· ing on a fixed income. we found that the most difficult thing for most of the pet owners was finding affordable vet care for their animals. conclusion: as a group, we decided that research should only be done if we try to make some cha.nges about what we have learned. we continue the project through exploring means of affecting social change--for example, ~eti.tions and informing others about the result of our project. we would like to present our ~mdmgs and experience with community-based participatory action resea.rch m an oral. presentarton at yo~r conference in october. our presentation will include com· mumty representation ~f. both front-hne staff and people with lived experience of marginalization and homdessness. if this is not accepted as an oral presentation, we are willing to present the project m poster format. introduction the concept of a healthy city was adopted by the world health organization some time ago and it includes strong support for local involvement in problem solving and implementation of solutions. while aimed at improving social, economic or environmental conditions in a given community, more significantly the process is considered to be a building block for poliq reform and larger scale 'hange, i.e. "acting locally while thinking globally." neighbourhood planning can he the entry point for citizens to hegin engaging with neighbours on issues of the greater common good. methods: this presentation will outline how two community driven projects have unfolded to address air pollution. the first was an uphill push to create bike lanes where car lanes previously existed and the second is an ongoing, multi-sectoral round table focused on pollution and planning. both dt•monstrate the importance of having support with the process and a health focus. borrowing from traditions of "technical aid"• and community development the health promoter /planner has incorporated a range of "determinants of health" into neighbourhood planning discussions. as in most urban conditions the physical environment is linked to a range of health stressors such as social isolation, crowding, noise, lack of open space /recreation, mobility and safety. however typical planning processes do not hring in a health perspective. health as a focus for neighbourhood planning is a powerful starti_ng point when discussing transportation planning or changing land-uses. by raising awareness on determmants of health, citizens can begin to better understand how to engage in a process and affect change. often local level politics are involved and citizens witness policy change in action. the environmental liaison committee and the dundas east hike lanes project resulted from local level initiatives aimed at finding solutions to air pollution -a priority identified hy the community. srchc supported the process with facilitation and technical aid. _the processs had tangible results that ultimately improve living conditions and health. •tn the united kmgdom plannm in the 's established "technical aid" offices much like our present day legal aid system to provide professional support and advocacy for communities undergoing change. p - (c) integrating community based research: the experience of street health, a community service agency i.aura cowan and jacqueline wood street health began offering services to homeless men and women in east downtown ~oronto in . nursing stations at drop-in centres and shelters were fo~lowed by hiv/aids prevent ~, harm reduction and mental health outreach, hepatitis c support, sleeping bag exchange, and personal tdennfication replacement and storage programs. as street health's progi;ams expanded, so to~ did the agency:s recognition that more nee~ed t~ be done to. address the underl~ing causes of, th~ soct~l and economic exclusion experienced by its clients. knowing t.h~t. a~voca~y ts. helped by . evtd~nce , street he.alt~ embarked on a community-based research (cbr) initiative to dent fy commumty-dnven research priorities within the homeless and underhoused population. methods: five focus groups were conducted with homeless people, asking participants to identify positive and negative forces in their lives, and which topics were important to take action on and learn more about. findings were validated through a validation meeting with participants. results: participants identified several important positive and negative forces in their lives. key positive forces included caring and respectful service delivery, hopefulness and peer networks. key negative forces included lack of access to adequate housing and income security, poor service delivery and negative perceptions of homeless people. five topics for future research emerged from the process, focusing on funding to address homelessness and housing; use of community services for homeless people; the daily survival needs of homeless people and barriers to transitioning out of homelessness; new approaches to service delivery that foster empowerment; and policy makers' understanding of poverty and homelessness. conclusions: although participants expressed numerous issues and provided much valuable insight, definitive research ideas and action areas were not clearly identified by participants. however, engagement in a cbr process led to some important lessons and benefits for street health. we learned that the community involvement of homeless people and front-line staff is critical to ensuring relevance and validity for a research project; that existing strong relationships with community parmers are essential to the successful implementation of a project involving marginalized groups; and that an action approach focusing on positive change can make research relevant to directly affected people and community agency staff. street health benefited from using a cbr approach, as the research process facilitated capacity building among staff and within the organization as a whole. p - (c) a collaborative process to achieve access to primary health care for black women and women of colour: a model of community based participartory research notisha massaquoi, charmaine williams, amoaba gooden, and tulika agerwal in the current healthcare environment, a significant number of black women and women of color face barriers to accessing effective, high quality services. research has identified several issues that contribute to decreased access to primary health care for this population however racism has emerged as an overarching determinant of health and healthcare access. this is further amplified by simultaneous membership in multiple groups that experience discrimination and barriers to healthcare for example those affected by sexism, homelessness, poverty, homophobia and heterosexism, disability and hiv infection. the collaborative process to achieve access to primary health care for black women and women of colour project was developed with the university of toronto faculty of social work and five community partners using a collaborative methodology to address a pressing need within the community ro increase access to primary health care for black women and women of colour. women's health in women's hands community health centre, sistering, parkdale community health centre, rexdale community health centre and planed parenthood of toronto developed this community-based participatory-action research project to collaboratively barriers affecting these women, and to develop a model of care that will increase their access to health services. this framework was developed using a process which ensured that community members from the target population and service providers working in multiculrural clinical settings, were a part of the research process. they were given the opportunity to shape the course of action, from the design of the project to the evaluation and dissemination phase. empowerment is a goal of the participatory action process, therefore, the research process has deliberately prioritized _ro enabling women to increase control over their health and well-being. in this session, the presenters will explore community-based participatory research and how such a model can be useful for understanding and contextualizing the experiences of black women and women of colour. they will address. the development and use of community parmerships, design and implementation of the research prorect, challenges encountered, lessons learnt and action outcomes. they will examine how the results from a collaborative community-based research project can be used as an action strategy to poster sessions v address che social determinants of women health. finally the session will provide tools for service providers and researchers to explore ways to increase partnerships and to integrate strategies to meet the needs of che target population who face multiple barriers to accessing services. lynn scruby and rachel rapaport beck the purpose of this project was ro bring traditionally disenfranchised winnipeg and surrounding area women into decision-making roles. the researchers have built upon the relationships and information gachered from a pilot project and enhanced the role of input from participants on their policy prioriries. the project is guided by an advisory committee consisting of program providers and community representatives, as well as the researchers. participants included program users at four family resource cencres, two in winnipeg and two located rurally, where they participated in focus groups. the participants answered a series of questions relating to their contact with government services and then provided inpuc as to their perceptions for needed changes within government policy. following data analysis, the researchers will return to the four centres to share the information and continue che discussion on methods for advocating for change. recommendations for program planning and policy development and implementation will be discussed and have relevance to all participants in the research program. women's health vera lefranc, louise hara, denise darrell, sonya boyce, and colleen reid women's experiences with paid and unpaid work, and with the formal and informal economies, have shifted over the last years. in british columbia, women's employability is affected by government legislation, federal and provincial policy changes, and local practices. two years ago we formed the coalition ior women's economic advancement to explore ways of dealing with women's worsening economic situations. since the formation of the coalition we have discussed the need for research into women's employabilicy and how women were coping and surviving. we also identified how the need to document the nature of women's employability and reliance on the informal economy bore significanc mechodological and ethical challenges. inherent in our approach is a social model of women's health that recognizes health as containing social, economic, and environmental determinants. we aim to examine the social contexc of women's healch by exploring and legitimizing women's own experiences, challenging medical dominance in understandings of health, and explaining women's health in terms of their subordination and marginalizacion. through using a feminist action research (far) methodology we will explore the relationship between women's employability and health in communities that represent bricish columbia's social, economic, cultural/ethnic, and geographic diversities: skidegate, fort st . .john, lumhy, and surrey. over the course of our year project, in each community we will establish and work with advisory committees, hire and train local researchers, conduct far (including a range of qualitative methods), and support action and advocacy. since the selected communities are diverse, the ways that the research unfolds will ·ary between communities. expected outcomes, such as the provision of a written report and resources, the establishment of a website for networking among the communities, and a video do.:umentary, are aimed at supporting the research participants, coalition members, and advisory conuniuces in their action efforts. p t (c) health & housing: assessing the impact of transitional housing for people living with hiv i aids currently, there is a dearth of available literature which examines supporrive housing for phas in the canadian context. using qualitative, one-on-one interviews we investigace the impact of transitional housing for phaswho have lived in the up to nine month long hastings program. our post<'r pr<·senta-t on will highlight research findings, as well as an examination of transitional housing and th<· imp;kt it has on the everyday lives of phas in canada. this research is one of two ground breaking undertakings within the province of ontario in which fife house is involved. p - (c) eating our way to justice: widening grassroots approaches to food security, the stop community food centre as a working model charles l.evkoe food hanks in north america have come co play a central role as the widespread response to growing rates of hunger. originally thought to be a short term-solution, over the last years, they have v poster sessions be · · · · d wi'thi'n society by filling the gaps in the social safety net while relieving govemcome mst tut ona ze . . . t f the ir responsibilities. dependent on corporate donations and sngmauzmg to users, food banks men so th' . · i i . are incapable of addressing the structural cause~ of ~u~ger. s pres~ntation w e~~ ore a ternanve approaches to addressing urban food security while bmldmg more sustamabl.e c~mmumt es. i:nrough the f t h st p community food centre, a toronto-based grassroots orgamzanon, a model is presented case e h'l k' b 'id · b that both responds to the emergency food needs of communities w e wor mg to. u ~ sustama le and just food system. termed, the community food centre model. (cfc), ~he s~op is worki?g to widen its approach to issues of food insecurity by combining respectful ~ rect service wit~ com~~mty ~evelop ment, social justice and environmental sustainability. through this approach, various critical discourses around hunger converge with different strategic and varied implications for a~ion. as a plac~-based organization, the stop is rooted within a geographical space and connected directly to a neighbourhood. through working to increase access to healthy food, it is active in maintaining people's dignity, building a strong and democratic community and educating for social change. connected to coalitions and alliances, the stop is also active in organizing across scales in connection with the global food justice movement. inner city shelter vicky stergiopoulos, carolyn dewa, katherine rouleau, shawn yoder, and lorne tugg introduction: in the city of toronto there are more than , hostel users each year, many with mental health and addiction issues. although shelters have responded in various ways to the health needs of their clients, evidence on the effectiveness of programs delivering mental health services to the home· less in canada has been scant. the objective of this community based research was to provide a forma· tive evaluation of a multi-agency collaborative care team providing comprehensive care for high needs clients at toronto's largest shelter for homeless men. methods: a logic model provided the framework for analysis. a chart review of clients referred over a nine month period was completed. demographic data were collected, and process and outcome indicators were identified for which data was obtained and analyzed. the two main outcome measures were mental status and housing status months after referral to the program. improvement or lack of improvement in mental status was established by chart review and team consensus. housing outcomes were determined by chart review and the hostel databases. results: of the clients referred % were single and % were unemployed. forty four percent had a psychiatric hospitalization within the previous two years. the prevalence of severe and persistent men· tal illness, alcohol and substance use disorders were %, % and % respectively. six months after referral to the program % of clients had improved mental status and % were housed. logistic regression controlling for the number of general practitioner and psychiatrist visits, presence of person· ality or substance use disorder and treatment non adherence identified two variables significantly associ· ated mental status improvement: the number of psychiatric visits (or, . ; % ci, . - . ) and treatment non adherence (or, . ; % ci, . - . ). the same two variables were associated with housing outcomes. history of forensic involvement, the presence of a personality or substance use disorder and the number of visits with a family physician were not significantly associated with either outcome. conclusions: despite the limitations in sample sire and study design, this study can yield useful informa· tion to program planners. our results suggest that strategies to improve treatment adherence and access to mental health specialists can improve outcomes for this population. although within primary care teams the appropriate collaborative care model for this population remains to be established, access to psychiatric follow up, in addition to psychiatric assessment services, may be an important component of a successful program. mount sinai hospital (msh) has become one of the pre-eminent hospitals in the world by contributing to the development of innovative approaches to effective health care and disease prevention. recently, the hospital has dedicated resources towards the development of a strategy aimed at enhancing the hospital's integration with its community partners. this approach will better serve the hospital in the current health care environment where local health integration networks have been struck to enhance and support local capacity to plan, coordinate and integrate service delivery. msh has had early success with developing partnerships. these alliances have been linked to programs serving key target populations with _estabhshe~. points of access to msh. recognizing the need to build upon these achievements to remain compe~mve, the hospital has developed a community integration strategy. at the forefront of this strategy is c.a.r.e (community advisory reference engine): the hospital's compendium of poster sessions v community partners. as a single point of access to community partner information, c.a.r.e. is more than a database. c.a.r.e. serves as the foundation for community-focused forecasting and a vehicle for inter and intra-organizational knowledge transfer. information gleaned from the catalog of community parmers can be used to prepare strategic, long-term partnership plans aimed at ensuring that a comprehensive array of services can be provided to the hospital community. c.a.r.e. also houses a permanent record of the hospital's alliances. this prevents administrative duplication and facilitates the formation of new alliances that best serve both the patient and the hospital. c.a.r.e. is not a stand-alone tool and is most powerful when combined with other aspects of the hospital's community integration strategy. it iscxpected that data from the hospital's community advisory committees and performance measurement department will also be stored alongside stakeholder details. this information can then be used to drive discussions at senior management and the board, ensuring congruence between stakeholder, patient and hospital objectives. the patient stands to benefit from this strategy. the unique, distinct point of reference to a wide array of community services provides case managers and discharge planners with the information they need to connect patients with appropriate community services. creating these linkages enhances the patient's capacity to convalesce in their homes or places of residence and fosters long-term connections to neighborhood supports. these connections can be used to assist with identifying patients' ongoing health care needs and potentially prevent readmission to hospital. introduction: recruiting high-risk drug users and sex workers for hiv-prevention research has often been hampered by limited access to hard to reach, socially stigmatized individuals. our recruitment effom have deployed ethnographic methodology to identify and target risk pockets. in particular, ethnographers have modeled their research on a street-outreach model, walking around with hiv-prevention materials and engaging in informal and structured conversations with local residents, and service providers, as well as self-identified drug users and sex workers. while such a methodology identifies people who feel comfortable engaging with outreach workers, it risks missing key connections with those who occupy the margins of even this marginal culture. methods: ethnographers formed a women's laundry group at a laundromat that had a central role as community switchboard and had previously functioned as a party location for the target population. the new manager helped the ethnographers invite women at high risk for hiv back into the space, this time as customers. during weekly laundry sessions, women initiated discussions about hiv-prevention, sexual health, and eventually, the vaccine research for which the center would be recruiting women. ra.its: the benefits of the group included reintroducing women to a familiar locale, this time as customers rather than unwelcome intruders; creating a span of time (wash and dry) to discuss issues important to me women and to gather data for future recruitment efforts; creating a location to meet women encountered during more traditional outreach research; establishing the site as a place for potential retention efforts; and supporting a local business. women who participated in the group completed a necessary household task while learning information that they could then bring back to the community, empowering them to be experts on hiv-prevention and vaccine research. some of these women now assist recruitment efforts. the challenges included keeping the group women-only, especially after lunch was provided, keeping the membership of the group focused on women at risk for hiv, and keeping the women in the group while they did their laundry. conclusion: public health educators and researchers can benefit from identifying alternate congregation sites within risk pockets to provide a comfortable space to discuss hiv prevention issues with high-risk community members. in our presentation, we will describe the context necessary for similar research, document the method's pitfalls and successes, and argue that the laundry group constitutes an ethical, respectful, community-based method for recruitment in an hiv-prevention vaccine trial. p - t (c) upgrading inner city infrastructure and services for improved environmental hygiene and health: a case of mirzapur in u.p. india madhusree mazumdar in urgency for agricultural and industrial progress to promote economic d.evelopment follo_wing independence, the government of india had neglected health promotion and given less emphasis on infrastructure to promote public health for enhanced human pro uct v_ity. ong wit r~p m astrucrure development, which has become essential if citie~ are to. act ~s harbmger.s of econ~nuc ~owth, especially after the adoption of the economic liberalization policy, importance _is a_lso ~emg g ve.n to foster environmental hygiene for preventive healthcare. the world health orga~ sat ~ is also trj:' ! g to help the government to build a lobby at the local level for the purpose by off~rmg to mrroduce_ its heal.thy city concept to improve public health conditions, so as to reduce th_e disease burden. this pape~ s a report of the efforts being made towards such a goal: the paper descr~bes ~ c~se study ?f ~ small city of india called mirzapur, located on the banks of the nver ganga, a ma or lifeline of india, m the eastern part of the state of uttar pradesh, where action for improvement began by building better sanitation and environmental infrastructure as per the ganga action plan, but continued with an effort to promote pre· ventive healthcare for overall social development through community participation in and around the city. asthma physician visits in toronto, canada tara burra, rahim moineddin, mohammad agha, and richard glazier introduction: air pollution and socio-economic status are both known to be associated with asthma in concentrated urban settings but little is known about the relationship between these factors. this study investigates socio-economic variation in ambulatory physician consultations for asthma and assesses possible effect modification of socio-economic status on the association between physician visits and ambient air pollution levels for children aged to and adults aged to in toronto, canada between and . methods: generalized additive models were used to estimate the adjusted relative risk of asthma physician visits associated with an interquartile range increase in sulphur dioxide, nitrogen dioxide, pm . , and ozone, respectively. results: a consistent socio-economic gradient in the number of physician visits was observed among children and adults and both sexes. positive associations between ambient concentrations of sul· phur dioxide, nitrogen dioxide and pm . and physician visits were observed across age and sex strata, whereas the associations with ozone were negative. the relative risk estimates for the low socio-«onomic group were not significantly greater than those for the high socio-economic group. conclusions: these findings suggest that increased ambulatory physician visits represent another component of the public health impact of exposure to urban air pollution. further, these results did not identify an age, sex, or socio-economic subgroup in which the association between physician visits and air pollution was significantly stronger than in any other population subgroup. eco-life-center (ela) in albania supports a holistic approach to justice, recognizing the environ· mental justice, social justice and economic justice depend upon and support each other. low income cit· izens and minorities suffer disproportionately from environmental hazards in the workplace, at home, and in their communities. inadequate laws, lax enforcement of existing environmental regulations, and ~ea.k penalties for infractions undermine environmental protection. in the last decade, the environmental ust ce m~ve~ent in tirana metropolis has provided a framework for identifying and exposing the links ~tween irrational development practices, disproportionate siting of toxic facilities, economic depres· s on, and a diminished quality of life in low-income communities and communities of color. the envi· ~onmental justice agenda has always been rooted in economic, racial, and social justice. tirana and the issues su.rroun~ing brow~fields redevelopment are crucial points of advocacy and activism for creating ~ubstantia~ social chan~~ m low-income communities and communities of color. we engaging intensively m prevcnnng co'.' mumnes, especially low income or minority communities, from being coerced by gov· ernmenta~ age_nc es or companies into siting hazardous materials, or accepting environmentally hazard· ous_ practices m order to create jobs. although environmental regulations do now exist to address the environmental, health, and social impacts of undesirable land uses, these regulations are difficult to poster sessions v enforce because many of these sites have been toxic-ridden for many years and investigation and cleanup of these sites can be expensive. removing health risks must be the main priority of all brown fields action plans. environmental health hazards are disproportionately concentrated in low-income communities of color. policy requirements and enforcement mechanisms to safeguard environmental health should be strengthened for all brownfields projects located in these communities. if sites are potentially endangering the health of the community, all efforts should be made for site remediation to be carried out to the highest cleanup standards possible towards the removal of this risk. the assurance of the health of the community should take precedence over any other benefits, economic or otherwise, expected to result from brownfields redevelopment. it's important to require from companies to observe a "good neighbor" policy that includes on-site visitations by a community watchdog committee, and the appointment of a neighborhood environmentalist to their board of directors in accordance with the environmental principles. vancouver - michael buzzelli, jason su, and nhu le this is the second paper of research programme concerned with the geographical patterning of environmental and population health at the urban neighbourhood scale. based on the vancouver metropolitan region, the aim is to better understand the role of neighbourhoods as epidemiological spaces where environmental and social characteristics combine as health processes and outcomes at the community and individual levels. this paper builds a cohort of commensurate neighbourhoods across all six censuses periods from to , assembles neighbourhood air pollution data (several criterion/health effects pollutants), and providing an analysis to demonstrate how air pollution systematically and consistently maps onto neighbourhood socioeconomic markers, in this case low education and lone-parent families. we conclude with a discussion of how the neighbourhood cohort can be further developed to address emergent priorities in the population and environmental health literatures, namely the need for temporally matched data, a lifecourse approach, and analyses that control for spatial scale effects. solid waste management and environment in mumbai (india) by uttam jakoji sonkamble and bairam paswan abstract: mumbi is the individual financial capital of india. the population of greater mumbai is , , and sq. km. area. the density of population , per sq. km. the dayto-day administration and rendering of public services within gr. mumbai is provided by the brihan mumbai mahanagar palika (mumbai corporation of gr. mumbai) that is a body of elected councilors on a -year team. mumcial corporation provides varies conservancy services such as street sweeping, collection of solid waste, removal and transportation, disposal of solid waste, disposal of dead bodies of animals, construction, maintance and cleaning of urinals and public sanitary conveniences. the solid waste becoming complicated due to increase in unplanned urbanization and industrialization, the environment has deteriorated significantly due to inter, intra and international migration stream to mumbai. the volume of inter state migration to mumbai is considerably high i.e. . lakh and international migrant . lakh have migrated to mumbai. present paper gives the view on solid waste management and its implications to environment and health. pollution from a wide varity of emission, such as from automobiles and industrial activities, has reached critical level in mumbai, causing respiratory, ocular, water born diseases and other health problems. sources of generation of waste are -household waste, commercial waste, institutional waste, street sweeping, silt removed from drain/nallah/cleanings. disposal of solid waste in gr. mumbai done under incineration . processing to produce organic manure. . vermi-composting . landfill the study shows that the quantity of waste disposal of through processing and conversion to organic ~anure is about - m.t. per day. the processing is done by a private agency m/s excel industries ltd. who had set up a plant at the chincholi dumping ground in western mumbai for this purpose. the corporation is also disposal a plant of its waste mainly market waste through the environment friendly, natural pro-ces~ known as vermi-composing about m.t. of market waste is disposed of in this manner at the various sites. there are four land fill sites are available and percent of the waste matter generated m mumbai is disposed of through landfill. continuous flow of migrant and increa~e in slum population is a complex barrier in the solid waste management whenever community pamc pat on work strongly than only we can achieved eco-friendly environment in mumbai. persons exposed to residential craffic have elevated races of respiratory morbidity an~ ~ortality. since poverty is an important determinant of ill-health, some h~ve argued that t~es~ assoc at ons may relate to che lower socioeconomic status of those living along ma or roads. our ob ect ve was to evaluate the association between traffic intensity at home and hospital admissions for respiratory diagnoses among montreal residents older than years. morning peak traffic estimates from the emmej montreal traffic model (motrem ) were used as an indicator of exposure to road traffic outside the homes of those hospitalised. the influence of socioeconomic status on the relationship between traffic intensity and hospital admissions for respiratory diagnoses was explored through assessment of confounding by lodging value, expressed as the dollar average over road segments. this indicator of socioeconomic status, as calculated from the montreal property assessment database, is available at a finer geographic scale than socioeconomic information accessible from the canadian census. there was an inverse relationship between traffic intensity estimates and lodging values for those hospitalised (rho - . , p vehicles during che hour morning peak), even after adjustment for lodging value (crude or . , cl % . - . ; adjusted or . , cl % . - . ). in montreal, elderly persons living along major roads are at higher risk of being hospitalised for respiratory illnesses, which appears not simply to reflect the fact that those living along major roads are at relative economic disadvantage. the paper argues that human beings ought to be at the centre of the concern for sustainable development. while acknowledging the importance of protecting natural resources and the ecosystem in order to secure long term global sustainability, the paper maintain that the proper starting point in the quest for urban sustainability in africa is the 'brown agenda' to improve che living and working environment of che people, especially che urban poor who face a more immediate environmental threat to their health and well-being. as the un-habitat has rightly observed, it is absolutely essential "to ensure that all people have a sufficient stake in the present to motivate them to take part in the struggle to secure the future for humanity.~ the human development approach calls for rethinking and broadening the narrow technical focus of conventional town planning and urban management in order to incorporate the emerging new ideas and principles of urban health and sustainability. i will examine how cities in sub-saharan africa have developed over the last fifty years; the extent to which government policies and programmes have facilitated or constrained urban growth, and the strategies needed to achieve better functioning, safer and more inclusive cities. in this regard i will explore insights from the united nations conferences of the s, especially local agenda of the rio summit, and the istanbul declaration/habitat agenda, paying particular attention to the principles of enablement, decentralization and partnership canvassed by these movements. also, i will consider the contributions of the various global initiatives especially the cities alliance for cities without slums sponsored by the world bank and other partners; che sustainable cities programme, the global campaigns for good governance and for secure tenure canvassed by unhabit at, the healthy cities programme promoted by who, and so on. the concluding section will reflect on the future of the african city; what form it will take, and how to bring about the changes needed to make the cities healthier, more productive and equitable, and better able to meet people's needs. heather jones-otazo, john clarke, donald cole, and miriam diamond urban areas, as centers of population and resource consumption, have elevated emissions and concentrations of a wide range of chemical contaminants. we have developed a modeling framework in which we first ~stimate the emissions and transport of contaminants in a city and second, use these estimates along with measured contaminant concentrations in food, to estimate the potential health risk posed by these che.micals. the latter is accomplished using risk assessment. we applied our modeling framework to consider two groups of chemical contaminants, polycyclic aromatic hydrocarbons (pah) a.nd the flame re~ardants polybrominated diphenyl ethers (pbde). pah originate from vehicles and stationary combustion sources. ~veral pah are potent carcinogens and some compounds also cause noncancer effects. pbdes are additive flame retardants used in polyurethane foams (e.g., car seats, furniture) fer sessions v and cl~ equipm~nt (e.g., compute~~· televisio~s). two out of three pbdes formulations are being voluntarily phased by mdustry due to rmng levels m human tissues and their world-wide distribution. pbdes have been .related to adv.erse neurological, developmental and reproductive effects in laboratory ijlimals. we apphed our modelmg framework to the city of toronto where we considered the southcattral area of by km that has a population of . million. for pah, local vehicle traffic and area sources contribute at least half of total pah in toronto. local contributions to pbdes range from - %, depending on the assumptions made. air concentrations of both compounds are about times higher downtown than km north of toronto. although measured pah concentrations in food date to the s, we estimate that the greatest exposure and contribution to lifetime cancer risk comes from ingestion of infant formula, which is consistent with toxicological evidence. the next greatest exposure and cancer risk are attributable to eating animal products (e.g. milk, eggs, fish). breathing downtown air contributes an additional percent to one's lifetime cancer risk. eating vegetables from a home garden localed downtown contributes negligibly to exposure and risk. for pbdes, the greatest lifetime exposure comes through breast milk (we did not have data for infant formula), followed by ingestion of dust by the toddler and infant. these results suggest strategies to mitigate exposure and health risk. p - (a) immigration and socioeconomic inequalities in cervical cancer screening in toronto, canada aisha lofters, rahim moineddin, maria creatore, mohammad agha, and richard glazier llltroduction: pap smears are recommended for cervical cancer screening from the onset of sexual activity to age . socioeconomic and ethnoracial gradients in self-reported cervical cancer screening have been documented in north america but there have been few direct measures of pap smear use among immigrants or other socially disadvantaged groups. our purpose was to investigate whether immigration and socioeconomic factors are related to cervical cancer screening in toronto, canada. methods: pap smears were identified using fee codes and laboratory codes in ontario physician service claims (ohip) for three years starting in for women age - and - . all women with any health system contact during the three years were used as the denominator. social and economic factors were derived from the canadian census for census tracts and divided into quintiles of roughly equal population. recent registrants, over % of whom are expected to be recent immigrants to canada, were identified as women who first registered for health coverage in ontario after january , . results: among , women age - and , women age - , . % and . %, rtspcctively, had pap smears within three years. low income, low education, recent immigration, visible minority and non-english language were all associated with lower rates (least advantaged quintile:most advantaged quintile rate ratios were . , . , . , . , . , respectively, p < . for all). similar gradients were found in both age groups. recent registrants comprised . % of women and had mm;h lower pap smear rates than non-recent registrants ( . % versus . % for women age - and . % versus . % for women age - ). conclnsions: pap smear rates in toronto fall well below those dictated by evidence-based practice. at the area level, immigration, visible minority, language and socioeconomic characteristics are associated with pap smear rates. recent registrants, representing a largely immigrant group, have particularly low rates. efforts to improve coverage of cervical cancer screening need to be directed to all ~omen, their providers and the health system but with special emphasis on women who recently arrived m ontario and those with social and economic disadvantage. challeges faced: a) most of the resources are now being ~pent in ~reventing the sprea.d of hiv/ aids and maintaining the lives of those already affected. b) skilled medical ~rs~nal are dymg under· mining the capacity to provide the required health care services. ~) th.e comphcat o~s of hiv/aids has complicated the treatment of other diseases e.g. tbs d) the ep dem c has led. to mcrease number of h n requiring care and support. this has further stretched the resources available for health care. orp a s d db . . i methods used on our research: . a simple community survey con ucte y our orgamzat on vo · unteers in three urban centres members of the community, workers and health care prov~ders were interviewed ... . meeting/discussions were organized in hospitals, commun.ity centre a~d with government officials ... . written questionnaires to health workers, doctors and pohcy makers m th.e health sectors. lessors learning: • the biggest-health bigger-go towards hiv/aids prevention • aids are spreading faster in those families which are poor and without education. •women are the most affected. •all health facilities are usually overcrowded with hiv/aids patients. actions needed:• community education oh how to prevent the spread of hiv/aids • hiv/aids testing need to be encouraged to detect early infections for proper medical cover. • people to eat healthy • people should avoid drugs. implications of our research: community members and civic society-introduction of home based care programs to take care of the sick who cannot get a space in the overcrowded public hospitals. prl-v a te sector private sector has established programs to support and care for the staff already affected. government provision of support to care-givers, in terms of resources and finances. training more health workers. introduction: australian prisons contain in excess of , prisoners. as in most other western countries, reliance on 'deprivation of liberty' is increasing. prisoner numbers are increasing at % per annum; incarceration of women has doubled in the last ten years. the impacts on the community are great - % of children have a parent in custody before their th birthday. for aboriginal communities, the harm is greater -aboriginal and/or torres strait islanders are incarcerated at a rate ten times higher than other australians. % of their children have a parent in custody before their th birthday. australian prisons operate under state and territory jurisdictions, there being no federal prison system. eight independent health systems, supporting the eight custodial systems, have evolved. this variability provides an unique opportunity to assess the capacity of these health providers in addressing the very high service needs of prisoners. results: five models of health service provision are identified -four of which operate in one form or another in australia: • provided by the custodial authority (queensland and western australia)• pro· vided by the health ministry through a secondary agent (south australia, the australian capital territory and tasmania) • provided through tendered contract by a private organization (victoria and northern territory) • provided by an independent health authority (new south wales) • (provided by medics as an integral component of the custodial enterprise) since the model of the independent health authority has developed in new south wales. the health needs of the prisoner population have been quantified, and attempts are being made to quantify specific health risks /benefits of incarceration. specific enquiry has been conducted into prisoner attitudes to their health care, including issues such as client information confidentiality and access to health services. specific reference will be made to: • two inmate health surveys • two inmate access surveys, and • two service demand studies. conclusions: the model of care provision, with legislative, ethical, funding and operational independence would seem provide the best opportunity to define and then respond to the health needs of prisoners. this model is being adopted in the united kingdom. better health outcomes in this high-risk group, could translate into healthier families and their communities. p - (a) lnregrated ethnic-specific health care systems: their development and role in increasing access to and quality of care for marginalized ethnic minorities joshua yang introduction: changing demographics in urban areas globally have resulted in urban health systems that are racially and ethnically homogenous relative to the patient populations they aim to serve. the resultant disparities in access to and quality of health care experienced by ethnic minority groups have been addressed by short-term, instirutional level strategies. noticeably absent, however, have been structural approaches to reducing culturally-rooted disparities in health care. the development of ethnic-specific h~alth car~ systems i~ a structural, long-term approach to reducing barriers to quality health care for eth· me mmonty populations. methods: this work is based on a qualitative study on the health care experiences of san francisco chinatown in the united states, an ethnic community with a model ethnic-specific health care infrastrucrure. using snowball sampling, interviews were conducted with key stakeholders and archival research was conducted to trace and model the developmental process that led to the current ethnic-specific health care system available to the chinese in san francisco. grounded theory was the methodology ijltd to analysis of qualitative data. the result of the study is four-stage developmental model of ethnic-specific health infrastrueture development that emerged from the data. the first stage of development is the creation of the human capital resources needed for an ethnic-specific health infrastructure, with emphasis on a bilingual and bicultural health care workforce. the second stage is the effective organization of health care resources for maximal access by constituents. the third is the strengthening and stability of those institutional forms through increased organizational capacity. integration of the ethnic-specific health care system into the mainstream health care infrastructure is the final stage of development for an ethnic-specific infrastructure. conclusion: integrated ethnic-specific health care systems are an effective, long-term strategy to address the linguistic and cultural barriers that are being faced by the spectrum of ethnic populations in urban areas, acting as culturally appropriate points of access to the mainstream health care system. the model presented is a roadmap to empower ethnic communities to act on the constraints of their health and political environments to improve their health care experiences. at a policy level, ethnic-specific health care organizations are an effective long-term strategy to increase access to care and improve qualiiy of care for marginalized ethnic groups. each stage of the model serves as a target area for policy interventions to address the access and care issues faced by culturally and linguistically diverse populations. users in baltimore md: - noya galai, gregory lucas, peter o'driscoll, david celentano, david vlahov, gregory kirk, and shruti mehta introduction: frequent use of emergency rooms (er) and hospitalizations among injection drug users (idus) has been reported and has often been attributed to lack of access to primary health care. however, there is little longitudinal data which examine health care utilization over individual drug use careers. we examined factors associated with hospitalizations, er and outpatient (op) visits among idus over years of follow-up. methods: idus were recruited through community outreach into the aids link to lntravenous experience (alive) study and followed semi-annually. , who had at least follow-up visits were included in this analysis. outcomes were self-reported episodes of hospitalizations and er/op visits in the prior six months. poisson regression was used accounting for intra-person correlation with generalized estimation equations. hits: at enrollment, % were male, % were african-american, % were hiv positive, median age was years, and median duration of drug use was years. over a total of , visits, mean individual rates of utilization were per person years (py) for hospitalizations and per py for er/op visits. adjusting for age and duration of drug use, factors significantly associated with higher rates of hospitalization included hiv infection (relative incidence [ri(, . ), female gender (ri, . ), homelessness (ri, . ), as well as not being employed, injecting at least daily, snorting heroin, havmg a regular source of health care, having health insurance and being in methadone mainte.nance treatment (mmt). similar associations were observed for er/op visits except for mmt which was not associated with er/op visits. additional factors associated with lower er/op visits were use of alcohol, crack, injecting at least daily and trading sex for drugs. % of the cohort accounted for % of total er/op visits, while % of the cohort never reported an op visit during follow-up. . . . lgbt) populations. we hypothesized that prov dmg .appomtments .for p~t ~nts w thm hours would ensure timely care, increase patient satisfaction, and improve practice eff c ency. further, we anticipated that the greatest change would occur amongst our homeless patients.. . methods: we tested an experimental introduction of advanced access scheduling (usmg a hour rule) in the primary care medical clinic. we tracked variables inclu~ing waiting ti~e fo~ next available appointment; number of patients seen; and no-show rates, for an eight week penod pnor to and post introduction of the new scheduling system. both patient and provider satisfaction were assessed using a brief survey ( questions rated on a -pt scale). results and conclusion: preliminary analyses demonstrated shorter waiting times for appointments across the clinic, decreased no-show rates, and increased clinic capacity. introduction of the advanced access scheduling also increased both patient and provider satisfaction. the new scheduling was initiated in july . quantitative analyses to measure initial and sustained changes, and to look at differential responses across populations within our clinic, are currently underway. introduction: there are three recognized approaches to linking socio-economic factors and health: use of census data, gis-based measures of accessibility/availability, and resident self-reported opinion on neighborhood conditions. this research project is primarily concerned with residents' views about their neighborhoods, identifying problems, and proposing policy changes to address them. the other two techniques will be used in future research to build a more comprehensive image of neighborhood depri· vation and health. methods: a telephone survey of london, ontario residents is currently being conducted to assess: a) community resource availability, quality, access and use, b) participation in neighborhood activities, c) perceived quality of neighborhood, d) neighborhood problems, and e) neighborhood cohesion. the survey instrument is composed of indices and scales previously validated and adapted to reflect london specifically. thirty city planning districts are used to define neighborhoods. the sample size for each neighborhood reflects the size of the planning district. responses will be compared within and across neighborhoods. data will be linked with census information to study variation across socio-eco· nomic and demographic groups. linear and gis-based methods will be used for analysis. preliminary results: the survey follows a qualitative study providing a first look at how experts involved in community resource planning and administration and city residents perceive the availability, accessibility, and quality of community resources linked to neighborhood health and wellbeing, and what are the most immediate needs that should be addressed. key-informant interviews and focus groups were used. the survey was pre-tested to ensure that the language and content reflects real experiences of city residents. the qualitative research confirmed our hypothesis that planning districts are an acceptable surrogate for neighborhood, and that the language and content of the survey is appropriate for imple· mentation in london. scales and indices showed good to excellent reliability and validity during the pre· test (cronbach's alpha from . - . ). preliminary results of the survey will be detailed at the conference. conclusions: this study will help assess where community resources are lacking or need improve· ment, thus contributing to a more effective allocation of public funds. it is also hypothesized that engaged neighborhoods with a well-developed sense of community are more likely to respond to health programs and interventions. it is hoped that this study will allow london residents to better understand the needs and problems of their neighborhoods and provide a research foundation to support local understandmg of community improvement with the goal of promoting healthy neighborhoods. p - (a) hiv positive in new york city and no outpatient care: who and why? hannah wolfe and victoria sharp introduction: there are approximately million hiv positive individuals living in the united sta!es. about. % of these know their hiy status and are enrolled in outpatient care. of the remaining yo, approx~mately half do not know their status; the other group frequently know their status but are not enrolled m any .sys~em of outpatient care. this group primarily accesses care through emergency departments. when md cated, they are admitted to hospitals, receive acute care services and then, upon poster sessions v di 'harge, disappear from the health care system until a new crisis occurs, when they return to the emergency department. as a large urban hiv center, caring for over individuals with hiv we have an active inpatient service ".'ith appr~xi~.ately discharges annually. we decided to survey our inpatients to better charactenze those md v duals who were not enrolled in any system of outpatient care. results: % of inpatients were not enrolled in regular outpatient care: % at roosevelt hospital and % at st.luke\'s hospital. substance abuse and homelessness were highly prevalent in the cohort of patients not enrolled in regular outpatient care. % of patients not in care (vs. % of those in care) were deemed in need of substance use treatment by the inpatient social worker. % of those not in care were homeless (vs. % of those in care.) patients not in care did not differ significantly from those in me in terms of age, race, or gender. patients not in care were asked "why not:" the two most frequent responses were: "i haven't really been sick before" and "i'd rather not think about my health. conclusions: this study suggests that there is an opportunity to engage these patients during their stay on the inpatient units and attempt to enroll them in outpatient care. simple referral to an hiv clinic is insufficient, particularly given the burden of homelessness and substance use in this population. efforts are currently underway to design an intervention to focus efforts on this group of patients. p .q (a) healthcare availability and accessibility in an urban area: the case of ibadan city, nigeria in oder to cater for the healthcare need of the populace, for many years after nigeria's politicl independence, empphasis was laid on the construction of teaching, general, and specialist hospital all of which were located in the urban centres. the realisation of the inadequacies of this approach in adequately meeting the healthcare needs of the people made the country to change and adopt the primary health care (phc) system in . the primary health care system which is in line with the alma ata declaration of of , wsa aimed at making health care available to as many people as possible on the basis of of equity and social justice. thus, close to two decades, nigeria has operated primary health care system as a strategy for providing health care for rural and urban dwellers. this study focusing on urban area, examimes the availabilty and accessibility of health care in one of nigeria's urban centre, ibadan city to be specific. this is done within the contest of the country's national heath policy of which pimary health care is the main thrust. the study also offers necessary suggestion for policy consideration. in spite of the accessibility to services provided by educated and trained midwifes in many parts of fars province (iran) there are still some deliveries conducted by untrained traditional birth attendants in rural parts of the province. as a result, a considerable proportion of deliveries are conducted under a higher risk due to unauthorised and uneducated attendants. this study has conducted to reveal the pro· portion of deliveries with un-authorized attendants and some spatial and social factors affecting the selection of delivery attendants. method: this study using a case control design compared some potentially effective parameters indud· ing: spatial, social and educational factors of mothers with deliveries attended by traditional midwifes (n= ) with those assisted by educated and trained midwifes (n= ). the mothers interviewed in our study were selected from rural areas using a cluster sampling method considering each village as a cluster. results: more than % of deliveries in the rural area were assisted by traditional midwifes. there are significant direct relationship between asking a traditional birth attendant for delivery and mother age, the number of previous deliveries and distance to a health facility provided for delivery. significant inverse relationships were found between mother's education and ability to use a vehicle to get to the facilities. conclusion: despite the accessibility of mothers to educated birth attendants and health facilities (according to the government health standards), some mothers still tend to ask traditional birth attendants for help. this is partly because of unrealistic definition of accessibility. the other considerable point is the preference of the traditional attendants for older and less educated mothers showing the necessity of changing theirs knowledge and attitude to understand the risks of deliveries attended by traditional and un-educated midwifes. p - (a) identification and optimization of service patterns provided by assertive community treatment teams in a major urban setting: preliminary findings &om toronto, canada jonathan weyman, peter gozdyra, margaret gehrs, daniela sota, and richard glazier objective: assertive community treatment (act) teams are financed by the ontario ministry of health and long-term care (mohltc) and are mandated to provide treatment, rehabilitation and support services in the community to people with severe and persistent mental illness. there are such teams located in various regions across the city of toronto conducting home visits - times per week to each of their approximately respective clients. each team consists of multidisciplinary health professionals who assist clients to identify their needs, establish goals and work toward them. due to complex referral patterns, the need for service continuity and the locations of supportive housing, clients of any one team are often found scattered across the city which increases home visit travel times and decreases efficiency of service provision. this project examines the locations of clients in relation to the home bases of all act teams and identifies options for overcoming the geographical challenges which arise in a large urban setting. methods: using geographic information systems (gis) we geocoded all client and act agency addresses and depicted them on location maps. at a later stage using spatial methods of network analysis we plan to calculate average travel rimes for each act team, propose optimization of catchment areas and assess potential travel time savings. resnlts: initial results show a substantial scattering of clients from several act teams and substan· rial overlap of visit travel routes for most teams. conclusions: reallocation of catchment areas and optimization of act teams' travel patterns should lead to substantial savings in travel times, increased service efficiency and better utilization of resourc_~· ~e l'<!tenri~i modifications to catchment areas must be conducted with appropriate attention to specific clients servtce needs, service continuity and applicable regulations by the mohl tc. venice lido is a popular island within and outside italy because it hosts the international cinema festival yearly. only few people remember the island for its hospital, which, in the fifties, was one of the most important hospitals in italy and in europe, being a modern center for wind-, sun-and thermal-therapy. since the sixties, its fame became to drop away, since its structure was no longer adequate for the evolving medicine science. at the end of the seventies all the wards were moved into a new big building in the same area. at present the hospital is made up by about forty 'pavilions' (mostly partially used or empty) and a big building, disseminated in a hectares area, on the sea front, on the m long beach. the aim of my research is to suggest a realistic solution, sustainable on the functional use of the area according to basic local needs and economically realizable. i used a philological and multi-disciplinary method, more in detail: -from historical documents, i found what was the very first call of the property and how it adapted to the needs of the demographic development and the sanitary supply over time; -by contacting some operators from different fields, i realized which functions were suitable to the buildings in existence, to the population's needs and to the present sanitary supply. moreover the planning idea considers: -the debate going on between local people who strongly want to preserve the property, and die ones who want to renew it by different new opportunities; and -the regional sanitary politics, aiming at rationalizing the regional hospitals dislocation, and the budget needs. this plan analyzes and proposes some new alternative solutions to satisfy different needs. the different activities will be dealt out and the environmental fall will be limited as much as possible. after having analyzed its basic call, considered its environmental peculiarities and its position, verified the emerging needs of the local population, the plan proposes different activities: the hospital; the social-rehabilitation center; the elderly house; the thermal center; the residential center; and other activities. such a plan wants to share in the solution of a basic problem by giving architectonic and functional dignity to an historical completely degraded area and by starting again a social-economical broken off process, by bringing in venice lido some fresh necessary elements for its so wished new throw. p - (c) dilemma of free health care in spokane, wa david bunting introduction: the paper reports on the activities of project access spokane [pas], a physician sponsored initiative to provide uncompensated health care to low income, uninsured residents of spokane county wa. program providers included all county hospitals, over physicians, other medical professionals, and specialized clinics. each prescription requires only a $ co-payment. sponsored and administered by the county medical society, pas is funded by local and national foundations, private corporations, municipalities, civic organizations and individuals. method: the paper is based on a first year assessment report funded by pas, using hcfa [health care financing administration] insurance claim data documenting utilization rates, disease categories and donated charge information and patient cares [centralized applications, referrals and enrollment status) data. results: while essentially free for enrollees, the program involved real costs. an administrative organization to refer over patients to any of over providers had to be developed and staffed, using both paid and unpaid personnel. methods to identify potential patients and veri.fy eligibility. had to ~devised. patient appointments and transportation had to be scheduled and monitored. pu~hc relanons, provider solicitations and fundraising activities were continuous. information requirements regarding program operation were also significant. data reporting the volume. ~nd value of dona~ed medical services were necessary to demonstrate accomplishments and attr~ct addmon~l support. providers required assurances their contributions were both significant and eqmtable. funding sources sought evidence that their support had important consequences. however, generating this ~~ta proved difficult. many providers failed to submit appropriate insurance claims forms because .of a~dmonal donated effort and administrative cost, thereby not only reducing their own apparent conmbut ons but also the overall significance of the program. conclusions: during its initial year, the estimated cost to deliver free health care was ~bout per enrollee. the lesson is that without an elaborate administrative structure and record keeping s.yst~~· efforts to provide free health care probably will fail. eligible enrollees c~n not be ~parated from in~hgi ble ones, care will not be accessed or delivered in an efficient manner, neither fundmg nor ~upport "". be offered without evidence of tangible benefits, and providers will withdraw if they perceive mequ table tteannent. v p - s (c) mobility in prostitution and the impact of health therese van der helm and henk sulman poster sessions introduction: many of the estimated . commer~ial ~ex wor~ers (c~w)in a'.' ~terdam ~~me from developing countries and eastern europe. to gain ins~ght mto their workmg and_ hvmg condinons the intermediary project (ip) at the municipal health serv ~e _contacts these women via ?utreach work on regular basis. since the new brothel law in october s ~troduc~d, ~sw ~rom outside the eu and who have no dutch residence permit are not allowed to work m prost tut n. smee then, many of these csw therefore have gone "underground." the consequences of the new law in the netherlands will be discussed with regard to the accessibility of csw and their risk for stl/hiv acquisition and unplanned pregnancies. methods: topics during outreach work are the interventions to increase the knowledge of safe sex and birth control for csw. written information is handed out in relevant languages and with addresses of health and social services. in conversations with the women, it appeared that many are not aware of these services. to provide easier access to health care for women, staff of the ip carries out free sti control csw working places, in windows brothels and sex houses. also, women are offered vaccination against hepatitis b (hbv). results: from january till july we approached csw for first contact. one third was dutch; others were from developing countries, other eu countries and eastern europe. sti consul· rations were done among non-iv drug using sex workers, of whom % was dutch. of these, % was diagnosed with syphilis, % with gonorrhea, and % with chlamydia. of women tested for hiv, none were infected. due to the high turnover of csw in .brothels, most wnmen were tested only once. among csw tested for hbv -of whom one third is dutch - % had antibodies for hbv, were carrier of hbv, most of whom came from hbv endemic areas. conclusions: sti control and hbv vaccination in brothels is an important support in health care. our findings suggest that csw do not play an important role in the transmission of sti. many csw are highly mobile and often not aware of the existing health and social services. continuous outreach is important to remain in contact with this mobile population. regulations in the new brothel law should not hamper contacts with (illegal) csw. heart disease (cho) is projected to become the leading cause of death. studies conducted in europe and the united states have proven a higher rate of cho in south asians who have migrated from south asia, most notably india, pakistan and bangladesh. approximately % of all heart attacks among south asian men occur under the age of ; % of them occur under the age of -unheard of in any other population. associated risk factors such as diabetes, high blood pressure and cholesterol are also com· mon in this group. the population of south asians residing in nyc has more than doubled over the past decade to over , , the majority being young, working-class and with limited health care access. many south asian men are employed as taxi drivers ( out of nyc taxi drivers are from south asial, working daily hour plus shifts. methods: acknowledging that this vulnerable, at-risk group was unavailable for outreach through conventional venues, three of the hospitals of the new york city health and hospital corporation, (elmhurst, queens and bellevue) conducted a one day outreach effort at nyc's jfk international air· ~rt's taxi holdin~ ar~a, ~here over one thousand taxis regularly assemble. bringing an outreach event directly to the taxi dnvers workplace, a tent was set up where cardiovascular-related health screenings, in~luding bl~ pressure, sugar, cholesterol, body mass index (bmi), were provided. results were shared with and explamed to the drivers and each participant received a south asian health education brochure. a total of taxi drivers who identified as south asian were involved. rau/ts: participants were all male, ranging from to years; mean age, . . screenings revealed % hypertensive; % had cholesterols over ; % blood glucose over ; % had a bmi greater than . conc~on: a unique outreach activity, adapting to logistical, occupational limitations, is pre· se~ted. on-site f~back and explanation of results, reiterating and reinforcing the concern that south asia~. men are at mcreased danger for early coronary heart disease, and the dissemination of a culturally sensmve and r~levant brochure, may heighten awareness of prevailing cardiac risk factors in this immi· grant community. p - (c) the community-hospital integration program framework: community-hospital panoenhips to improve the population's health john stevenson, richard blickstead, ann-marie marcolin, and sandi kendal v introduction: st. josephs health centre is a catholic community teaching hospital located in the heart of southwest toronto. st. joseph\'s was founded from a community-expressed need for hospital services, and since then has stayed committed to fostering a healthy community through collaboration and parmership. st. joseph's has developed an innovative model, the community-hospital integration program (chip), to strengthen st. joseph's partnerships with community stakeholders, and facilitates the building of links between community needs, service provision, and public policy outcomes to improve the health and wellness of the diverse neighbourhoods they together serve. methods: development of the chip framework st. joseph's health centre developed the chip framework through a multidisciplinary approach that included extensive international literature reviews, consultations, and key informant interviews with community service agencies and academics. to ensure active community voice, st. joseph's has hosted a number of community consultations including a community outreach forum attended by over ninety representatives from community partners. results: the chip framework the chip framework aims to improve the health and wellness of the urban communities served by st. josephs health centre through four intersecting pillars: • raising community voices provides an infrastructure and process that supports community stakeholder input into health care service planning, decision-making, and delivery by the hospital and across the continuum of care; • sharing reciprocal capacity promotes healthy communities through the sharing of our intellectual and physical capacity with our community partners; • cultivating integration initiatives facilitates vertical, horizontal, and intersectoral integration initiatives in support of community-identified needs and gaps; and • facilitating healthy exchange develops best practices in community integration through community-based research, and facilitates community voice in informing public policy. the chip framework drives the complex inter-relationships between community-hospital engagement, reciprocal capacity-building, integration initiatives, and community-based research and evaluation, to create an interconnected network of health care services. the fluidity and simplicity of this framework, and its dedication to balancing community needs and hospital mandate, posits the st. josephs health centre's chip model as an integral component in building healthy and thriving communities. p - (c) home based care promotion: improving acess to quality services and livelihood in the face of aids home based care is a service provided to persons affected/living with hiv/aids, a menu of care/support services at home/community. it is a prominent alternative approach. in uganda, hospital bed ocupacny is high, patient health care worker ratio deteriorating. empowering communities offers solutions to the problems; adressing cost, effectiveness of care. hiv/aids demands changes in attitudes, behaviour, approaches which is enhanced in home/community settings. for example art requires high levels of adherecnce, which medical workers have vety little opportunity to enforce. it also demands other support mechanisims in terms of nutrition, personal displine, etc which work best in stigma free environments. hence the relevance of home based care. this paper highlights the gaps that call for increased action in terms of home based care, examples of whre it has worked key challenges and recommendations for the future. p - (c) health care for one ... health care for alli katharina kovacs burns introduction: at the surface, it appears that every person in canada _has. ~ccess to a publicly funded health care system. those living in urban centers should have the best ava l~b hty, chmce, and access to a variety of health care services because of the distribution of health care services, fac lmes, and health professionals in concentrated in urban centers. this is not true for everyone -people with low income or who are homeless experience the challenges of social exclusion and being marginalized: there are many factors at play making it difficult for the latter group of people to access health care. service they need,.when they need them. health care is not as accessible or inclusive as intended. the quesuon to be explore.cl ~: if health care is available and accessible to one person, what makes it not available to all people? the ~ gmfic~nce of having marginalized people accessing health care and other services includes e~hanced quality of hfe and decreased risks associated with being homeless, and cost savings in ion~ ter~ w rh acute health care. methodology: community-based participatory research is applied m a case study on health care access and challenges experienced by low income and homeless people in one urban centre, edmonton, edmonton, and their challenges. the data is being gathered and ana_lyzed usmg basic m x~d methods. results: the results will focus on how services can be more mtegrated and accessible to all people with low income and who are homeless. there will also be discussion about specific perceptions of not only the service providers but also of people with low income an~ who are homeless~ and vario~s decision makers. the results will be compared to the literature regardmg health care services access mother urban centers in canada and elsewhere. conclusions: recommendations will need to address social exclusion and other factors which can make health care and other services more available to all people in the community. the implications for health care will also be discussed. additional information will be gathered in the next phases of the study to develop a community services access model. p - (c) availability and access exemplified: a case study beth hayhoe and ruth ewert introduction: access to health care in canada requires either the correct documentation or money. street youth have neither. in addition, health services in canada are designed by adults for adults. youth in general are often wary of having trust in adults with respect to their health concerns and frequently feel misunderstood. street youth are even more mistrustful of adults and public organizations, making their contact with health care professionals minimal. this combined with their risky behaviours and dangerous environment creates a population at risk for numerous health issues but with no place to have them investi· gated. at our non-government, not for profit health service designed specifically to provide a broad range of health care to street youth, professional services are provided almost entirely by volunteers. methods: using a retrospective analysis of the years of data gathered from this organization and reviewing the initial reasons gathered from youth about their needs, the success of the health centre was examined. results: all the things youth had listed as being important in a health centre have been implemented, and even more things have been added to improve the breadth and quality of services offered. the use of the health centre has increased by more than six times since its opening in . in addition, tens of thousands of visits have been paid to the health centre, costing the government and taxpayers nothing. as far as we know there is nothing else in canada that offers so many diverse and innovative services to youth in need. conclusion: it is clear from this case, that health care targeted at the needs of specific disadvan· taged populations can successfully provide them with appropriate health care. a model of accessible health care for marginalized populations can easily be developed for high impact and low cost from this successful case. toronto is one of the most ethno-racially diverse cities in the world of the estimated , , toronto residents, % ( , ) live in scarborough population growth in scarborough is faster than toronto. scarborough's population increased by % from to while toronto increased only by %. toronto's population is projected to increase by % ( ) in while scarbor· ough's will increase by %. (census canada ) low income, pove;ty, seniors, hidden homeless, new~omers to canada, the uninsured, are just a few of the issues concerning health care in our community. health care needs in scarborough are greatly impacted by diversity of ethnic and racial groups, poverty and settlement issues. this paper will share how the scarborough hospital (tsh) an urb~n communir_y hospital cares f~~ it~ community. tsh recognizes: •the changing community• b_arriers t~ accessing care • lnequalmes m health care the hospital in caring for its community pro· v ~es services that '!'e~e cu~turally, racially, and linguistically sensitive to our community. the paper will share the hospitals unique program on access and equity. the paper will share the needs in scar· borough and tsh's response to these needs: working in partnership with the local health committee, i:ne scarborough homeless co.mminee, the scarborough network of immigrant services organiza· nons a~d others. :' e paper will also share the many initiatives this urban community hospital has taken viz. community and home programs in service areas such as mental health, haemodialysis day care, t~~ home oxyg~n program, the palliative at-home program, and above all support for the volunteer clinic for the uninsured. j"'" tllu:lion: in canada's universal health care system it is generally assumed that everyone has equal access to health care. however, some immigrant groups in canada have historically been uninswed. these groups include failed refugee claimants, those overstaying their visas, and new immigrants in transition who are waiting to become eligible for health insurance. some estimates have suggested that at the present time there may be as many as one hundred thousand undocumented and thus uninsured immigrants in toronto alone. understandably, information on the characteristics of this marginalized population is very limited, since undocumented immigrants tend to have little contact with formal institutions. knowledge of the demographic characteristics of this population may aid in the development of health and social programs to better identify and meet the needs of undocumented immigrants in toronto. we conducted a review of all undocumented, uninsured patients, years of age or older at access alliance multicultural community health centre (aamchc) between and . demographic information such as age, gender, preferred language, length of time living in canada, selfreported education level and household income were recorded. rmdts: % of all adult patients at access alliance were undocumented and uninsured. % were under years of age (with a median age of years), % were women and only % spoke english. this group lived in canada for an average period of . years before they were first seen at aamchc. % of undocumented clients reported having completed at least a secondary or post-secondary education. % had self-reported household incomes of less than , $/year, while % of households reported earning less than $ , /year. the mean income per person in an average household was $/month. conchuions: uninsured individuals at aamchc were predominantly young females with limited knowledge of the english language. despite having attained a high level of education most were living well below the poverty line. recognition of these characteristics may assist in the development of health and social programs that are better adapted to meet the needs of undocumented immigrants. p - (c) sharing expertise: a role for the hospital lactation consultant in the community. badrgrmuul: st. michael's hospital is a tertiary care hospital that serves a large inner city population in downtown toronto. in order to provide care to this population, the hospital has developed a number of unique outreach roles. one such role was developed to work with pregnant and breastfeeding women living in regent park, a social housing complex located near the hospital. the population of regent park includes new immigrants, refugees and the socially disadvantaged. approach: the outreach lactation consultant provides care, as part of the canada prenatal nutrition program, in the community prenatally, in the hospital during their inpatient stay and postnatally when they return to the community. the continuity of care enhances the probability of long term successful breastfeeding. aside from the health benefits of breastmilk, breastfeeding is especially important for women who are financially needy and must depend on food banks for formula. . . lason learned: aher two years of partnership, the relationship between the an-hospital ~stpar tum experience for breastfeeding mothers and the community postpartum support, the breastfeeding rate ~thin this community is high. the professional support and visibility of the : ctation consultant, both m the hospital and in the community, contributes to the support of breastfee~m~.. . in light of ongoing funding constraints, this ha son between hospital and community could be at risk and discontinued. in light of the benefits to the mother/baby dyad, the lactation consultant as a community partner in the canada prenatal nutrition program should be safeguarded. . lldpodiu:tion: although the importance of adequate health care in pregna~cy is well recognised, ethnic disparities in utilization of prenatal care still exist in many western coun~~es. a fun~amental factor in these disparities may be language proficiency, as it influences women's ab hty. to ob~m and understand health information, to find the way in the health care system and to communicate with health care v poster sessions providers. we investigated the role of language proficiency in use and knowledge of folic acid as aspect of prenatal care in an urban multi-ethnic pregnancy c?hort. . . design: prospective cohort study. setting and parnc pants: amsterdam ~regnant women attending obstetric care providers for their first antenatal visit (n= ). country of birth defined ethnicity: the netherlands, surinam, antilles, turkey, morocco, ghana, other non-~est~m (nw) and other western (w) country. main outcome measures: knowledge about and use of.fohc a~d (fa) supplements in pregnancy, and determinants of these in diffe~~t ethnic ~~ups. deterrrunants mcl~ded age, ed~ tion, parity, pregnancy intention and dutch prof c ency. stansncs: ~ to co~p~re e~c groups, stranfied logistic regression (forward stepwise method) to explore determmants "'.'thm ethmc groups .. use of fa supplements was significantly lower among ghanaian, moroccan, turkish and other nw women ( %to %) than among dutch ( %) or other w women ( %). use amongsurinames and antillean women was intermediate ( %and %). ethnic differences in fa knowledge were similar. knowledge was the strongest determinant of use in all ethnic groups, with odds ratios (ors) ranging from . to . . language proficiency was the strongest determi~a~t of kno~ledge in ethnic groups with a mother tongue different from dutch (ors good vs. low proficiency ranging from . ro . ). educational level had a modifying role, as shown by an interaction effect between education and language proficiency in the nw group. here, the odds of having fa knowledge given a high education and good dutch proficiency was times the odds given a good proficiency but low education. conclusions: appropriate periconceptional use of folic acid supplements in non-western ethnic groups is low, reflecting an absence of knowledge that is largely determined by the inability to speak and understand the language of the habitual country. tailored interventions using communication channels most likely to address (pregnant) women from ethnic minority groups are necessary. apan from specific interventions, our results are in support of strong incentives on language education despite current political debate. introduction: recent research suggests living in an economically disadvantaged neighborhood is asso· ciated with decreased likelihood of undergoing mammography and increased risk of late-stage breast can· cer diagnosis. long distances and travel times to facilities offering low-or no-cost mammography may be imponant barriers to adherence to mammography screening recommendations for residents of economically disadvantaged neighborhoods. the purpose of this study was to examine whether facilities providing low-and no-cost screening mammography were less spatially accessible in low-income neighborhoods in chicago, and the extent to which the relationship between neighborhood income and the spatial accessibility of facilities varied by the proponion of african-american residents in the neighborhood. methods: the sample consisted of chicago neighborhoods. for each neighborhood, we con· structed three measures of the spatial accessibility of facilities: street network distance to the nearest facility, public transportation travel time to the nearest facility, and shortest automobile travel time to a facility. using decennial census data, we characterized the neighborhoods according to proportion of residents with incomes below the poverty line, proportion of residents in each of four raciavethnic groups (african-american, latino, white, and other), and population density. we used ordinary least squares (ols) and spatial exogenous lag regression to examine relationships. model estimated the relationship between neighborhood poverty and the spatial accessibility of facilities, adjusting for raciaveth· nic composition and population density. model added a multiplicative interaction term between neighborhood poverty and african-american. restllts: we identified deven facilities that provided low-or no-cost screening mammography to chicago residents in . we found that the distance and travel times via automobile and public trans· portation to facilities generally decreased as neighborhood poveny increased. however, we also found that the ~egative associations between neighborhood poverty and two of the spatial accessibility mea· sures -distance and public transportation travel time -were less strong in neighborhoods with the highest proponions of african-american residents. among neighborhoods in the highest tertile for poveny, th~ mean distance and mean public transportation travel time to facilities were over twice as long in neighborhoods in the highest tertile than in those in the lowest tenile of african-american residents. . ~ persistent socioeconomic and racial/ethnic disparities in breast cancer stage at diagno-s ~nd su~ val suggest that ensuring an equitable distribution of affordable mammography is a worth-w~e policy .goal. the ~~dy sugges~ that ~ture investigations should consider both neighborhood soc oecono d c charactensbes and rac avethmc composition when examining the spatial distribution of health resources. , ) . epidemiological data suggest tha~ hiv prevalence among msm is over % in some metropolitan cities, such .as beijing (ibid.). due to widespread homophobia in chinese society, however, this population remains invisible within current health/social services. lack of research on sexuality, specifically homosexuality, has impaired our understanding of health and health practices of chinese msm. focusing on the illness experiences of chinese msm with hiv/aids, this paper explores the socio-cultural impacts of hiv/ aids on this group. the data used for this paper were collected through semi-constructed in-depth face-toiace interviews with adult plwhas (including msm) in beijing, china. with the permission of the participants, the interviews were audio-taped or recorded in notes. the transcribed interviews and interview notes were analyzed by using n-vivo, a software program for qualitative data analysis. this phenomenological study aimed to understand the experiences chinese plwhas (including msm) from their own perspectives. results: it is found that the illness experiences of chinese msm with hiv/aids are profoundly shaped by the socio-cultural meanings of homosexuality, which are further complicated by the dominant discourses on hiv/aids in china. at a macro level, homophobia in the larger society has decreased the capability of this group to respond to this epidemic in a more efficient way. at a meso level, aids-phobia within the chinese msm circuits has prevented this group from openly confronting this disease and offering support to those who are already affected by it. at a micro level, however, these hiv-infected/ affected msm have tried their best to locate spaces to live and to construct hope for their future lives despite various barriers within family, community, and the larger society. this study suggests that facilitating chinese msm's response to the aids crisis urgently requires bridging awareness, commitment, knowledge and resources both within and without this group. it also illustrates the importance of understanding homosexuality in the local context of hiv i aids, which will be helpful for developing culturally sensitive hiv/aids programs for this population on the community, national and international levels. introduction: having a regular family doctor (rfd) is known to be positively correlated with a good medical follow up, including access to preventive and/or chronic care. inversely, a lack of primary care may lead to high rates of avoidable hospitalizations, especially among poor people and/or in underserved neighbourhoods. in such a matter, a recent comparative study showed that paris was better ranged than other cities, such as nyc, tokyo or london. nevertheless, despite a quasi universal health insurance and a high density of general practitioners, a noticeable fraction of the paris population does not have any regular physician and we aimed to understand who they are and for what reasons rhey don't have any rfd. mdbods: cross sectional population survey among a random sample of households in ~nderpriv ileged neighbourhoods in paris inner city, performed in , using a face-to-face quest nna re collecr- ng more than social and health characteristics. ruults: a quarter ( . %) of rhe study popularion did not have any rfd. this proporrion was iignificantly higher among male (or= . , %ci = [ . - . ), younger (e.g. or - /> .s l _= ._oo, " .ci = ( . - . )), and/or unemployed (or = . , %ci = ij . - . _ people. in multtvanate analysis, after a full adjustment on gender, age, health status, health insura~ce, income, occupat n and tducation level, we observed significant associations between having no rfd and: ~arrtal and_ pare~t hood status (e.g. or single no kids/in couple+kids = . , %ci = ( . - . ()~ quality of relattonsh ps with neighbours (or bad/good= . , %ci = [ . - . )), and length of residence m the neighbourhood (with a dose/effect statistical relationship). . co clusion: gender, age, employment status, mariral and parenthood stat~s as well as ~e gh bourhood anchorage seem to be major predictors of having a rfd, even when um.versa! health i~sur ance has reduced most of financial barriers. in urban contexts, where residential migrattons and single lift (or family ruptures) are frequent, specific information may be conducted to encourage people to ket rfd. :tu~y tries to assess the health effects and costs and also analyse the availability and accessibility to health care for poor. . methods: data for this study was collected by a survey on households of the local community living near the factories and households where radiation hazard w~s n?~ present. ~~art from mor· bidity status and health expenditure, data was collected ~n access, a~ail~b .hty and eff c ency of healrh care. a discriminant analysis was done to identify the vanables that d scnmmate between the study and control group households in terms of health care pattern. a contingent valuation survey was also undertaken among the study group to find out the factors affecting their willingness to pay for health insurance and was analysed using logit model. results: the health costs and indebtedness in families of the study group was high as compared to control group households and this was mainly due to high health expenditure. the discriminant analysis showed that expenditure incurred by private hospital inpatient and outpatient expenditure were significant variables, which discriminated between the two types of households. the logit analysis showed !hat variables like indebtedness of households, better health care and presence of radiation induced illnesses were significant factors influencing willingness to pay for health insurance. the study showed that study group households were dependent on private sector to get better health care and there were problems with access and availability at the public sector. conclusion: the study found out that the quality of life of the local community is poor due to health effects of radiation and the burden of radiation induced illnesses are so high for them. there is an urgent need for government intervention in this matter. there is also a need for the public sector to be efficient to cater to the needs of the poor. a health insurance or other forms of support to these households will improve the quality for health care services, better and fast access to health care facilities and reduces the financial burden of the local fishing community. the prevalence of substance abuse is an increasing problem among low-income urban women in puerto rico. latina access to treatment may play an important role in remission from substance abuse. little is known, however, about latinas' access to drug treatment. further, the role of social capital in substance abuse treatment utilization is unknown. this study examines the relative roles of social capital and other factors in obtaining substance abuse treatment, in a three-wave longitudinal study of women ages - living in high-risk urban areas of puerto rico, the inner city latina drug using study (icldus). social capital is measured at the individual level and includes variables from social support and networks, familism, physical environment, and religion instruments of the icdus. the study also elucidates the role of treatment received during the study in bringing about changes in social capital. the theoretical framework used in exploring the utilization of substance abuse treatment is the social support approach to social capital. the research addresses three main questions: ( t) does social capital predict parti~ipating in treatment programs? ( ) does participation in drug treatment programs increase social capital?, and ( ) is there a significant difference among treatment modalities in affecting change in ~ial capital? the findings revealed no significant association between levels of social capital and gettmg treatment. also, women who received drug treatment did not increase their levels of social capital. the findings, however, revealed a number of significant predictors of social capital and receiving drug ~buse treatment. predictors of social capital at wave iii include employment status, total monthly mcoi:rie, and baseline social capital. predictors of receiving drug abuse treatment include perception of physical health and total amount of money spent on drugs. other different variables were associated to treatment receipt prior to the icldus study. no significant difference in changes of social capital was found among users of different treatment modalities. this research represents an initial attempt to elucidate the two-way relationship between social capital and substance abuse treatment. more work is necessary to unden~nd. ~e role of political forces that promote social inequalities in creating drug abuse problems and ava lab hty of treatment; the relationship between the benefits provided by current treatment poster sessions v sctrings and treatment-seeking behaviors; the paths of recovery; and the efficacy and effectiveness of the trtaanent. and alejandro jadad health professionals in urban centres must meet the challenge of providing equitable care to a population with diverse needs and abilities to access and use available services. within the canadian health care system, providers are time-pressured and ill-equipped to deal with patients who face barriers of poverty, literacy, language, culture and social isolation. directing patients to needed supportive care services is even more difficult than providing them with appropriate technical care. a large proportion of the population do not have equitable access to services and face major problems navigating complex systems. new approaches are needed to bridge across diverse populations and reach out to underserved patients most in need. the objective of this project was to develop an innovative program to help underserved cancer patients access, understand and use needed health and social services. it implemented and evaluated, a pilot intervention employing trained 'personal health coaches' to assist underserved patients from a variety of ethno-linguistic, socio economic and educational backgrounds to meet their supportive cancer care needs. the intervention was tested with a group of underserved cancer patients at the princess margaret hospital, toronto. personal coaches helped patients identify needs, access information, and use supportive care services. triangulation was used to compare and contrast multiple sources of quantitative and qualitative evaluation data provided by patients, personal health coaches, and health care providers to assess needs, barriers and the effectiveness of the coach program. many patients faced multiple barriers and had complex unmet needs. barriers of poverty and language were the easiest to detect. a formal, systematic method to identify and meet supportive care needs was not in place at the hospital. however, when patients were referred to the program, an overwhelming majority of participants were highly satisfied with the intervention. the service also appeared to have important implications for improved technical health care by ensuring attendance at appointments, arranging transportation and translation services, encouraging adherence to therapy and mitigating financial hardship -using existing community services. this intervention identified a new approach that was effective in helping very needy patients navigate health and social services systems. such programs hold potential to improve both emotional and physical health out· comes. since assistance from a coach at the right time can prevent crises, it can create efficiencies in the health system. the successful use of individuals who were not licensed health professionals for this purpose has implications for health manpower planning. needle exchange programs (neps) have been distributing harm reduction materials in toronto since . counterfit harm reduction program is a small project operated out of a community health centre in south-east toronto. the project is operated by a single full-time coordinator, one pan-rime mobile outreach worker and two peers who work a few hours each week. all of counterfit's staff, peers, and volunteers identify themselves as active illicit drug users. yet the program dis~rib utes more needles and safer crack using kits and serves more illicit drug u~rs t~an the comb ~e~ number of all neps in toronto. this presentation will discuss the reasons behind this success, .s~ f cally the extended hours of operation, delivery models, and the inclusion of an. extremely marg ~ahzed community in all aspects of program design, implementation and eva.luat ?n. ~ounterfit was recently evaluated by drs. peggy milson and carol strike, two leading ep dem olog st and researchers in the hiv and nep fields in toronto and below are some of their findings: "the program has experienced considerable success in delivering a high quality, accessible and well-used program .... the pro· gram has allowed (service users) to become active participants in providing. services to others and has resulted in true community development in the best sense. " ... counterf t has ~~n verr succe~sful attracting and retaining clients, developing an effective peer-based model an.d assisting chen~s ~ th a vast range of issues .... the program has become a model for harm red~ctmn progr~ms withm the province of ontario and beyond." in june , the association of ?ntano co~mumty heal~~ <:en· ires recognized counterfit's acheivements with the excellence m community health initiatives award. in kenya, health outcomes and the performance of government health service~ have det~riorated since the late s, trends which coincide with a period of severe resource constramts necessitated by macro-economic stabilization measures after the extreme neo-liberalism of the s. when the govern· ment withdrew from direct service provision as reform trends and donor advocacy suggested, how does it perform its new indirect role of managing relations with new direct health services providers in terms of regulating, enabling, and managing relations with these health services providers? in this paper therefore, we seek to investigate how healthcare access and availability in the slums of nairobi has been impacted upon by the government's withdrawal from direct health care provision. the methodology involved col· leering primary data by conducting field visits to health institutions located in the slum areas of kibera and korogocho in nairobi. purposive random sampling was utilized in this study because this sampling technique allowed the researcher(s) to select those health care seekers and providers who had the required information with respect to the objectives of the study. in-depth interviews using a semi-structured ques· tionnaire were administered ro key informants in health care institutions. this sought to explore ways in which the government and the private sector had responded and addressed in practical terms to new demands of health care provision following the structural adjustment programmes of the s. this was complemented by secondary literature review of publications and records of key governmental, bilateral and multilateral development partners in nairobi. the study notes a number of weaknesses especially of kenya's ministry of health to perform its expected roles such as managing user fee revenue and financial sustainability of health insurance systems. this changing face of health services provision in kenya there· fore creates a complex situation, which demands greater understanding of the roles of competition and choice, regulatory structures and models of financing in shaving the evolution of health services. we rec· ommend that the introduction of user fees, decentralization of service provision and contracting-out of non-clinical to private and voluntary agencies require a new management culture, and new and clear insri· tutional relationships. experience with private sector involvement in health projects underlines the need not only for innovative financial structures to deal with a multitude of contractual, political, market and risks, but also building credible structures to ensure that health services projects are environmentally responsive, socially sensitive, economically viable, and politically feasible. purpose: the purpose of this study is to examine the status of mammography screening utilization and its predictors among muslim women living in southern california. methods: we conducted a cross-sectional study that included women aged ::!: years. we col· leered data using a questionnaire in the primary language of the subjects. the questionnaire included questions on demography; practices of breast self-examination (bse) and clinical breast examination (cbe); utilization of mammography; and family history of breast cancer. bivariate and multiple logistic regression analyses were performed to estimate the odds ratios of mammography use as a function of demographic and other predictor variables. . results: among the women, % were married, % were - years old, and % had family h story of breast cancer. thirty-two percent of the participating women never practiced bse and % had not undergone cbe during the past two years. the data indicated that % of the women did not have mammography in the last two years. logistic regression analysis showed that age ( r= . , % confi· dcnc~ interval (cl)=l. - . ), having clinical breast examination ( r= . , % cl= . - . ), and practtce of self-breast examination ( r= . , % cl= . - . ), were strong predictors of mammography use . . conclusions: the data point to the need for intervention targeting muslim women to inform and motivate th.cm a~ut practices for early detection of breast cancer and screening. further studies are needed to investigate the factors associated with low utilization of mammography among muslim women population in california. we conducted a review of the scientific literature and° government documents to describe ditnational health care program "barrio adentro" (inside the neighborhood). we also conducted qualiurivt interviews with members of the local health committees in urban settings to descrihe the comm unity participation component of the program. rtsmlts: until recently, the venezuelan public health system was characterized by a lack or limited access w health care ( % of the population) and long waiting lists that amounted to denial of service. moit than half of the mds worked in the five wealthiest metropolitan areas of the country. jn the spring oi , a pilot program hired cuban mds to live in the slums of caracas to provide health care to piople who had previously been marginalized from social programs. the program underwent a massive expansion and in only two years , cuban and , venezuelan health care providers were working acmss the country. they provide a daily average of - medical consultations and home visits, c lly out neighborhood rounds, and deliver health prevention initiatives, including immunization programs. they also provide generic medicines at no cost to patients, which treat % of presenting ill-ij!m, barrio adentro aims to build , clinics (primary care), , diagnostic and rehabilitation ctnrres (secondary care), and upgrade the current hospital infrastructure (tertiary care). local health committees survey the community to identify needs and organize a variety of lobby groups to improve dit material conditions of the community. last year, barrio adentro conducted . times the medical visits conducted by the ministry of health. the philosophy of care follows an integrated approach where btalrh is related to housing, education, employment, sports, environment, and food security. conclusions: barrio adentro is a unique collaboration between low-middle income countries to provide health care to people who have been traditionally excluded from social programs. this program shows that it is possible to develop an effective international collaboration based on participatory democracy. low-income americans are at the greatest risk of being uninsured and often face multiple health concerns. this evaluation of the neighborhood health initiative (nh!), an organization which uses multiple programmatic approaches to meet the multiple health needs of clients, reflected the program's many activities and the clients' many service needs. nh! serves low-income, underserved, and hard-to-reach residents in the des moines enterprise community. multiple approaches (fourth-generation evaluation, grounded theory, strengths-and needs-based) and methods (staff and client interviews, concept mapping, observations, qualitative and quantitative analysis) were used to achieve that reflection. results indicate good targeting of residents in the zip code and positive findings in the way of health insurance coverage and reported unmet health needs of clients. program activities were found to match client nttds, validating the organization\'s assessment of clients. important components of nhi were the staff composition and that the organization had become part of both the formal and informal networks. nhi positioned as a link between the target population and local health and social sc:rvice agencies, working to connect residents with services and information as well as aid local agencies in reaching this underserved population. p - (c) welfare: definition by new york city maribeth gregory for an individual who resides in new york city, to obtain health insurance under the medicaid policy one must fall under certain criteria .. (new york city's welfare programs ) if the individual _is on ssi or earns equal to or less than $ per month, he is entitled to receive no more than $ , m resources. a family the size of two would need to earn less than $ per month to qualify for no greater than ss, worth of medicaid benefits. a family of three would qualify for $ , is they earned less than $ per month and so on. introduction: the vancouver gay communiry has a significant number of asian descendan!l. because of their double minority status of being gay and asian, many asian men who have sex with men (msm) are struggling with unique issues. dealing with racism in both mainstream society and the gay communiry, cultural differences, traditional family relations, and language challenges can be some of their everyday srruggles. however, culturally, sexually, and linguistically specific services for asian msm are very limited. a lack of availability and accessibiliry of culturally appropriate sexual health services isolates asian msm from mainstream society, the gay community, and their own cultural communities, deprives them of self-esteem, and endangers their sexual well-being. this research focuses on the qualita· tive narrative voices of asian msm who express their issues related to their sexualiry and the challenges of asking for help. by listening to their voices, practitioners can get ideas of what we are missing and how we need to intervene in order to reach asian msm and ensure their sexual health. methods: since many asian msm are very discreet, it is crucial to build up trust relationships between the researcher and asian msm in order to collect qualitative data. for this reason, a community based participatory research model was adopted by forming a six week discussion group for asian msm. in each group session, the researcher tape recorded the discussion, observed interactions among the participants, and analyzed the data by focusing on participants' personal thoughts, experiences, and emotions for given discussion topics. ra lts: many asian msm share challenges such as coping with a language barrier, cultural differ· ences for interpreting issues and problems, and westerncentrism when they approach existing sexual health services. moreover, because of their fear of being disclosed in their small ethnic communities, a lot of asian msm feel insecure about seeking sexual health services when their issues are related to their sexual orientation. conclflsion: sexual health services should contain multilingual and multicultural capacities to meet minority clients' needs. for asian msm, outreach may be a more effective way to provide them with accessible sexual health services since many asian msm are closeted and are therefore reluctant to approach the services. building a communiry for asian msm is also a significant step toward including them in healthcare services. a communiry-based panicipatory approach can help to build a community for asian msm since it creates a rrust relationship between a worker and clients. p - (c) identifying key techniques to sustain interpretation services for assisting newcomers isolated by linguistic and cultural barriers from accessing health services s. gopi krishna lntrodaetion: the greater toronto area (gta) is home to many newcomer immigrants and other vulnerable groups who can't access health resources due to linguistic, cultural and systemic barriers. linguistic and cultural issues are of special concern to suburbs like scarborough, which is home to thousands of newcomer immigrants and refugees lacking fluency in english. multilingual community ~nterpreter. service~ (mcis) is a non-profit social service organization mandated to provide high quality mterpretanon services. to help newcomers access health services, mcis partnered with the scarborough network of immigrant serving organizations (sniso) to recruit and train volunteer interpreters to accompany clienrs lacking fluency in english and interpret for them to access health services at various locati?ns, incl~~ing communiry ~c:-lth centres/social service agencies and hospitals. the model envisioned agencies recruin~ and mcis ~.mm.g and creating an online database of pooled interpreter resources. this da.tabase, acces& bl~ to all pama~~g ?rganization is to be maintained through administrative/member · ship fees to. be ~ d by each parnapanng organization. this paper analyzes the results of the project, defines and identifies suc:cases before providing a detailed analysis for the reasons for the success . . methods:. this ~per~ q~ntitative (i.e. client numben) and qualitative analysis (i.e. results of key •~ormant m~rv ews with semce ~sers and interpreters) to analyze the project development, training and mplementanon phases of the project. it then identifies the successes and failures through the afore· mentioned analysis. poster sessions vss resljts: the results of the analysis can be summarized as: • the program saw modest success both ia l?lllls of numbers of clients served as well as sustainability at various locations, except in the hospital iririog. o the success of the program rests strongly on the commitment of not just the volunteer interprmr, but on service users acknowledgments through providing transponation allowance, small honororia, letter of reference etc. • the hospital sustained the program better at the hospital due to the iolume and nature of the need, as well as innate capacity for managing and acknowledging volunceers. collc/llsion: it is possible to facilitate and sustain vulnerable newcomer immigrants access to health !ul'ices through the training and commitment of an interpreter volunteer core. acknowledging volunteer commitment is key to the sustenance of the project. this finding is important to immigration and health policy given the significant numbers of newcomer immigrants arriving in canada's urban communities. nity program was established in to provide support to people dying at home, especially those who were waiting for admission to the resi<lential hospice. with the advent of haart and corresponding challenges for people living with hiv/aids in the community, the community program has developed a unique case management approach. this model features an interdisciplinary team providing a clientdrivcn service. the case manager provides continuity of care to clients in a variety of settings both within and outside of the health care system. a case study is used to demonstrate how formal and informal networks of support facilitate efficient and appropriate resource utilization to promote client health. this case study demonstrates the value of consistent coordination with a client who has complex physical, spiritual, substance use and mental health needs. the authors will show how they liaised with the housing authority, police, social services as well as the family physician, clinic staff and a hospital emergtncy room to ensure this client did not fall between the cracks. tarek hussain recognition of the importance of community involvement and sectoral cooperation in health and !ocial services, formalized in alma-ata declaration in , was reinforced at riga meeting held at the mid·point between alma-ata and the year . then at the th anniversary of alma-ata declaration, ir was declared that 'primary health care is everybody's business'. health does not exist in isolation. health cannot be defined only as an outcome of 'medical care' but also as one of 'social action'; the responsibility of disease prevention and health promotion rests not only on governments, but also with don·govemmentorgan izations, the community, and individuals. the major accomplishment to date may be that rhere is growing realization in the health sector that community involvement is more than a political right-it is absolute necessary. lessons have learned during the implementation of disease-specific l'cltical programmes, such as cdd, ari, and epi; first, integrated and holistic approaches to childcare art needed, and second, the need for community involvement has become evident. imc! is a broad inte-gra ed strategy with an overall objective contributing to reducing child morbidity and mortality in developing countries. and one of the imci components, 'community !mci', which is now broadening ~s an entry point for child-focused community development initiatives. community jmcl/c~ ld health is ~n mtcgrated approach to the promotion of key family and community practices that have impact on: child growth and development, disease prevention, home care for sick, malnourished child~en, a.nd care-seekmg behavior and compliance with advice and treatment. the presentation addres~es, m brief, the ~evel opinent of community !mci, operational aspect of community/im cl, key strategies and tools ava la~le for implementation of c/imci. the paper draws some successful programme examples on working logether for imc! with the community in various countries which had substantial benefns on programme outcomes. p - t (c) healthy child screening: an innovative service initiative ann-marie marcolin and joyce allen . introduction: with mounting attention for creative and integrated models of c~re .that are populallon and community focused, the healthy child screening initiative achiev.es t~ese pnncipl~s and more! . • parkdale high park rotary (sponsorship) the heal~h ~h ld scree? ?g is a ~opl~-centred model of care. agency and professional sector-specific silos are ehmmated, ~rov dmg f~~ hes wit~ one-sto~ access to primary prevention services in a local school gym! children at nsk are rece vmg early mtervent n and appropriate referrals to the right care provider, at the right time a~d in t~e right place. further, with a complimentary focus on prevention, the program serves to keep at nsk children healthy. healthy child screening results: the service model is developed around four distinct phases: ) planned outreach; ) coordinated intake and registration; ) interdisciplinary screening; and ) targeted referral. since the fall and through six collaborative healthy child screenings children ranging in age from to have benefited from this unique service model of care. conclusion: the presentation will provide practical information on the development and implementation of the model. there will also be a focus on lessons learned in building community service provider-hospital relationships. according to statistics canada ( ) % of the toronto population was born outside of canada and % were new immigrants. immigrants often arrive in canada in superior health compared to the canadian born population, but they lose this health advantage over time. changes in immigrant health status over time may be attributed to a variety of factors including barriers to accessing and receiving care as well as limitations in the mainstream health service organizations and their approaches to health care delivery (hyman, ) . for example, immigrant women are less likely to receive pap tests, which places them at a greater risk for developing cervical cancer. similarly, immigrant women receive less mammography screening than their canadian counterparts. the immigrant women's health centre mobile health unit (mhu) was created as an alternative care delivery model to address the need for increased accessibility as well as culturally and linguistically appropriate reproductive health care. toronto western hospital and the immigrant women's health centre have formed a collaborative partnership which incorporates a primary care nurse practitioner and lay ethnocultural counselors providing care on the mhu. currently, a qualitative ethnonursing study is underway to understand the unique experiences of women using the mhu for their reproductive health care as well as the perspectives of the mhu health care providers. based on a literature review and preliminary findings from provider and participant interviews, the proposed presentation will address the themes of health status for immigrant and refugee women, accessibility issues as well strategies to improve their reproductive health care. we will discuss benefits as well as limitations to health care provision using this alternative service delivery model. michael carden, brian edlin, andrew talal, elizabeth getter, and marla shu lntrod.ction: to date most active drug users have not had access to treatment for hepatitis c virus (hcv) infection and substantial barriers continue to exist that interfere with treatment availability for this population. methods: active illicit drug users interested in pursuing hcv care and treatment were recruited in partnership w~th co~munity-based organizations (cbo's) in new york city. baseline data were collected on quahty of hfe, substance use patterns, depression, health care utilization, hcv health beliefs and other relev.ant variables. medical evaluations were conducted, including liver biopsy when indicated, an~ treatment ts ~ffered when no contraindications are present. participants also receive psychiatric evaluahons to determme the appropriateness of interferon treatment. renlts: fifteen individuals have been recruited to date and received an initial medical evaluation. the mean age was years and _the average age of initial heroin or cocaine use was . . eight ( %) ha~ been homeless at least once m the last months and s ( %) were homeless for most or all of this penod. fourteen ( %) had a history of injection drug use with the mean age at first injection being s frsewons v ,an. elrven persc.!ns ( %) reported inje~~ng .heroin or cocaine within the last days while the .wing four ( l'o) reported regular non-m ect on use of cocaine and street-obtained benzodiazepines. sijiy seven percent of the sample (n= ) reported ever being referred to hcv treatment while ( t % ) ftponeddiattreann~nt had been offered by~ ~e.dical provider. none had ever received a liver biopsy or araanent. most believed that hcv was a s gmf cant threat to their health ( %) and that there was a pm)dchance they would eventually die if their hepatitis c was not treated ( %). though individuals % believed that there was no cure for hcv, ( %) reported that they would initiate treatment if i was recommended by their doctor. thirteen ( %) had a current psychiatric diagnosis including «pmsion, anxiety disorder, schizophrenia, schizoaffective disorder, and borderline and antisocial persooaliry disorders. among eight individuals who had the beck depression inventory administered, the mean score was . . attendance rates were % ( / ) at scheduled medical and psychiatric ppointments and % ( / ) at liver biopsy. <andtuions: active drug users, despite experiencing multiple psycho-social problems, can be mgaged in hcv care using a multidisciplinary approach, but require intensive follow-up support. hcv aunnent of active drug users should not be dismissed. n- (c) antiretroviral therapy in mv infected infants: when to initiate therapy an african experience kingsley okonkwo, ademola adeyemo, israel sokeye, and nwaife umeike /""°""ction: as technology for early diagnosis of human immunodeficiency virus [hiv] improves, m to commence highly active antiretroviral therapy [haarn is yet to be fully evaluated. this prospective study describes our initial experience with early haart in hiv infected nigerian infants and rqions the outcome. we also analyzed the socioeconomic implications of early haart therapy in infants in the african setting. method: hiv infected infants were started on haart before months and followed up at mkly intervals.we monitored baseline and monthly cd . conclusion: initial results suggest early haart before months resulted. in improv~d out~ome in african children. treatment appears to be as effective as in developed counmes. in. a~nca as. m most developing countries with limited resources it is possible and effective to use haart m ~~ants if p~oper llloniroring facilities are available. however the occurrence of long-term drug related tox c ty and mk of emergence of resistant viral strains create need for further evaluation of haart in infants. background: most risk factors for cardiovascular disease (cvd) can be mitigated through ~th clinical interventions and lifestyle change. we used data from a telephone survey of new york city (nyc) adults to characterize health care access and healthy behavior among those with three or more cvd risk factors. methods: the study population included respondents to the nyc community health survey (n= , ) self-reporting~ of the following: smoking, diabetes, high cholesterol level, high blood pres· sure, body mass index > , and age > (males) or > (females) (n= , ). results: based on self-report, an estimated . , ( %) of nyc adults have~ or more cvd risk factors. this population is % male, % white, % black, and % with s years of education. most report good access to health care, indicated by having health insurance ( %), regular doctor ( %), their blood pressure checked within last months ( %), and their choles· terol checked within the past year ( % ). only % reported getting at least minutes of exercise ~ times per week and only % eating ~ servings of fruits and vegetables the previous day. among current smokers, % attempted to quit in past months, but only % used medication or counseling. implications: these data suggest that most nyc adults known to be at high risk for cvd have access to regular health care, but most do not engage in healthy lifestyle or, if they smoke, attempt effective quit strategies. more clinic-based and population-level interventions are needed to support lifestyle change among those at high risk of cvd. introduction: recently, much interest has been directed at "obesogenic" (obesity-promoting) (swinburn, egger & raza, ) built environments, and at geographic information systems (gis) as a tool for their exploration. a major geographical concept is accessibility, or the ease of moving from an origin to a destination point, which has been recently explored in several health promotion-related stud· ies. there are several methods of calculating accessibility to an urban feature, each with its own strengths, drawbacks and level of precision that can be applied to various health promotion research issues. the purpose of this paper is to describe, compare and contrast four common methods of calculating accessibility to urban amenities in terms of their utility to obesity-related health promotion research. practical and conceptual issues surrounding these methods are introduced and discussed with the intent of providing health promotion researchers with information useful for selecting the most appropria e accessibility method for their research goal~ ~ethod: this paper describes methodological insights from two studies, both of which assessed the neighbourhood-level accessibility of fast-food establishments in edmonton, canada -one which used a relatively simple coverage method and one which used a more complex minimum cos method. res.its: both methods of calculating accessibility revealed similar patterns of high and low access to fast-food outlets. however, a major drawback of both methods is that they assume the characteristics of the a~e~ities and of the populations using them are all the same, and are static. the gravity potential method is introduced as an alternative, since it is ·capable of factoring in measures of quality and choice. a n~mber of conceptual and pr~ctical iss~es, illustrated by the example of situational influences on food choice, make the use of the gravity potential model unwieldy for health promotion research into sociallydetermined conditions such as obesity. co.nclusions: i~ ~ommended that geographical approaches be used in partnership with, or as a foun~ation for, ~admonal exploratory methodologies such as group interviews or other forms of commumty consultation that are more inclusive and representative of the populations of interest. qilhl in los angeles county ,,..ia shaheen, richard casey, fernando cardenas, holman arthurs, and richard baker ~the retinomax autorefractor has been used for vision screening of preschool age childien. ir bas been suggested to be used and test school age children but not been validated in this age poup. ob;taiw: to compare the results of retinomax autorefractor with findings from a comprehensive i!' examination using wet retinoscopy for refractive error. mllhods: children - years old recruited from elementary schools at los angeles county were iaml with snellen's chart and the retinomax autorefractor and bad comprehensive eye examination with dilation. the proportion of children with abnormal eye examination as well as diesensitiviry and specificity of the screening tools using retinomax autorefractor alone and in combinalion wirh snellen's chart. results of the children enrolled in the study (average age= . ± . years; age range, - years), ?% had abnormal eye examination using retinoscopy with dilation. for the lerinomax, the sensitivity was % ( % confidence interval [ci] %- %), and the specificity was % ( % ci, %- o/o). simultaneous testing using snellen's chart and retinomax resulted in gain in sitiviry ( %, % cl= , ), and loss in specificity ( %, % cl= %- %). the study showed that screening school age children with retinomax autorefractor could identify most cases with abnormal vision but would be associated with many false-positive results. simuhaneous resting using snellen's chart and retinomax maximize the case finding but with very low specificiry. mdhotjs: a language-stratified, random sample of members of the college of family physicians of canada received a confidential survey. the questionnaire collected data on socio-demographic characteristics, medical training, practice type, setting and hcv-related care practices. the self-adminisratd questionnaire was also made available to participants for completion on the internet. batdti: response proportion was %. median age was years ( % female) and the proporlionoffrench questionnaires was %. approximately % had completed family medicine residency lllining in canada; median year of training completion was . sixty-seven percent, % and % work in private offices/clinics, community hospitals and emergency departments, respectively. regarding ~practices, % had ever requested a hcv test and % of physicians had screened for hcv iafrction in rhe past months· median number of tests was . while % reported having no hcv-uaed patients in their practic~, % had - hcv-infected patients. regarding the level of hcv care provided, . % provide ongoing advanced hcv care including treatment and dose monitoring for ctmduions: in this sample of canadian family physicians, most had pro~ided hcv screening. to •least one patient in the past year. less than half had - hcv-infected patients and % provide ~:relared care the role of socio-demographic factors, medical training as wel_i as hcv ca~e percep-lldas rhe provision of appropriate hcv screening will be examined and described at the time of the canference. ' - (c) healthcare services: the context of nepal meen poudyal chhetri """ tl.ction healthcare service is related with the human rights and fundamental righ~ of the ci~ ciaaiuntry. however, the growing demand foi health care services, quality heal~care service, accessib b~ id die mass population and paucity of funds are the different but interrelated issues to .be ~ddressed. m nepat. n view of this context, public health sector in nepal is among other sectors, which is struggling -.i for scarce resources. . . . nepal, the problems in the field of healthcare servic~s do not bnut ~o the. paucity of faads and resources only, but there are other problems like: rural -urban imbalance, regional unbalance, poster sessio~ f the ll ·m ·ted resources poor healthcare services, inequity and inaccessibility of the poor management o , . poor people of the rural, remote and hilly areas for the healthcare services and so on.. . . . · . i f ct the best resource allocation is the one that max m zes t e sum o m ivi ua s u · ea t services. n a , · h d' ·b · · · h . ·t effi.ciency and efficient management are correlated. it might be t e re istn utmn of mes. ence, equi y, . . . . . income or redistribution of services. moreover, maximizanon of available resources, qua tty healthcare services and efficient management of them are the very important and necessary tools and techmques to meet the growing demand and quality healthcare services in nepal. p - (a) an jn-depth analysis of medical detox clients to assist in evidence based decision making xin li, huiying sun, ajay puri, david marsh, and aslam anis introduction: problematic substance use represents an ever-increasing public health challenge. in the vancouver coastal health (vch) region, there are more than , individuals having some probability of drug or alcohol dependence. to accommodate this potential demand for addiction related services, vch provides various services and treatment, including four levels of withdrawal management services (wms). clients seeking wms are screened and referred to appropriate services through a central telephone intake service (access i). the present study seeks to rigorously evaluate one of the services, vancouver detox, a medically monitored -bed residential detox facility, and its clients. doing so will allow decision makers to utilize evidence based decision-making in order to improve the accessibility and efficiency of wms, and therefore, the health of these clients. methods: we extract one-year data (october , -september , from an efficient and comprehensive database. the occupancy rate of the detox centre along with the clients' wait time for service and length of stay (los) are calculated. in addition, the effect of seasonality on these variables and the impact of the once per month welfare check issuance on the occupancy rate are also evaluated. results: among the clients (median age , % male) who were referred by access! to vancouver detox over the one-year period, were admitted. the majority ( %) of those who are not admitted are either lost to follow up (i.e., clients not having a fixed address or telephone) or declined service at time of callback. the median wait time was day [q -ql: - ], the median los was days iq -qt: - ], and the average bed occupancy rate was %. however, during the threeday welfare check issue period the occupancy rate was lower compared to the other days of the year % vs. %, p conclusion: our analysis indicates that there was a relatively short wait time at vancouver detox, however % of the potential clients were not served. in addition, the occupancy rate declined during the welfare check issuance period and during the summer. this suggests that accessibility and efficiency at vancouver detox could be improved by specifically addressing these factors. background: intimate partner violence (ipv) is associated with acute and chronic physical and men· tal health outcomes for women resulting in greater use of health services. yet, a vast literature attests to cultural variations in perceptions of health and help-seeking behaviour. fewer studies have examined differences in perceptions of ipv among women from ethnocultural communities. the recognition, definition, and understanding of ipv, as well as the language used to describe these experiences, may be different in these communities. as such, a woman's response, including whether or not to disclose or seek help, may vary according to her understanding of the problem. methods: this pilot study explores the influence of cultural factors on perceptions of and responses to ipv among canadian born and immigrant young women. in-depth focus group interviews were con· ducted with women, aged to years, living in toronto. open-ended and semi-structured interview questions were designed to elicit information regarding how young women socially construct jpv and where they would go to receive help. interviews were transcribed, then read and independently coded by the research team. codes were compared and disagreements resolved. qualitative software qsr n was used to assist with data management. . ruu~ts_: res~nses_abo~t what constitutes ipv were similar across the study groups. when considering specific ab.us ve ~ tuanons and types of relationships, participants held fairly relativistic views about ipv, especially with regard to help-seeking behaviour. cultural differences in beliefs about normaive m;ile/femal~ relations. familial.roles, and customs governing acceptable behaviours influenced partictpants perceptions about what n ght be helpful to abused women. interview data highlight the social l ter srnfons v suucrural _impact these factors ha:e on you?g women and provide details regarding the dynamics of cibnocultur~ m~uences on help-~eekmg behav ur: t~e ro~e of such factors such as gender inequality within rtlaoo?sh ps and t_he ~erce ved degree of ~oc al solat on and support nerworks are highlighted. collc~ the~ findmgs unde~score the _ mporta_nc_e of understanding cultural variations in percrprions of ipv ~ relanon to ~elp-seekmg beha~ ':'ur. th s_mformation is critical for health professionals iodiey may connnue developmg culturally sensmve practices, including screening guidelines and protorol s. ln addition, _this study demonstr~tes that focus group interviews are valuable for engaging young romen in discussions about ipv, helpmg them to 'name' their experiences, and consider sources of help when warranted. p -s (a) health problems and health care use of young drug users in amsterdam .wieke krol, evelien van geffen, angela buchholz, esther welp, erik van ameijden, and maria prins / trod ction: recent advances in health care and drug treatment have improved the health of populations with special social and health care needs, such as drug users. however, still a substantial number dots not have access to the type of services required to improve their health status. in the netherlands, tspccially young adult drug users (yad) whose primary drug is cocaine might have limited access to drugrreatment services. in this study we examined the history and current use of (drug associated) treatmmt services, the determinants for loss of contact, and the current health care needs in the young drug mm amsterdam study (yodam). methods: yodam started in and is embedded in the amsterdam cohort study among drug mm. data were derived from y ad aged < years who had used cocaine, heroin, ampheramines and i or methadone at least days a week during the months prior to enrolment. res lts:of yao, median age was years (range: - years), % was male and % had dutch nationality at enrolment. nearly all participants ( %) reported a history of contact with drug llt.lnnent services (methadone maintenance, rehabilitation clinics and judicial treatment), mental health car? (ambulant mental care and psychiatric hospital) or general treatment services (day-care, night-care, hdp for living arrangements, work and finance). however, only % reported contact in the past six l!xlllths. this figure was similar in the first and second follow-up visit. among y ad who reported no current contact with the health care system, % would like to have contact with general treatment serl' icts. among participants who have never had contact with drug treatment services, % used primarily cocaine compared with % and % among those who reported past or current contact, respectively. saied on the addiction severity index, % reported at least one mental health problem in the past days, but only % had current contact with mental health services. concl sion: results from this study among young adult drug users show that despite a high contact rm with health care providers, the health care system seems to lose contact with yao. since % indicatt the need of general treatment services, especially for arranging house and living conditions, health m services that effectively integrate general health care with drug treatment services and mental health care might be more successful to keep contact with young cocaine users. mtthods: respondents included adults aged and over who met dsm-iv diagn?snc criteria for an anxiety or depressive disorder in the past months. we performed two sets of logisnc regressmns. thtdichotomous dependent variables for each of the regressions indicated whether rhe respondenr_vis-ud a psychiatrist, psychologist, family physician or social worker in the _past_ months. no relationship for income. there was no significant interaction between educatmn an mco~:· r: ::or respondents with at least a high school education to seek help ~rom any of the four servic p were almost twice that for respondents who had not completed high school. th . d ec of analyses found che associacion becween educacion and use of md-provided care e secon s · · be d · · ·f· ly ·n che low income group for non-md care, the assoc anon cween e ucatlon and was s gm icant on -· . . . . use of social workers was significant in both income groups, but significant only for use of psychologists in che high-income group. . . . conclusion: we found differences in healch service use by education level. ind v duals who have nor compleced high school appeared co use less mental he~lt~ servi~es provided ~y psyc~iatrists, psycholo· gists, family physicians and social workers. we found limited e.v dence _suggesting the influence of educa· tion on service use varies according to income and type of service provider. results suggesc there may be a need to develop and evaluate progr~ms.designe~ to deliver targeted services to consumers who have noc completed high school. further quahtanve studies about the expen· ence of individuals with low education are needed to clarify whether education's relationship with ser· vice use is provider or consumer driven, and to disentangle the interrelated influences of income and education. system for homeless, hiv-infected patients in nyc? nancy sahler, chinazo cunningham, and kathryn anastos introduction: racial/ethnic disparities in access to health care have been consistently documented. one potential reason for disparities is that the cultural distance between minority patients and their providers discourage chese patients from seeking and continuing care. many institucions have incorporated cultural compecency craining and culturally sensicive models of health care delivery, hoping co encourage better relacionships becween patients and providers, more posicive views about the health care system, and, ulcimacely, improved health outcomes for minority patients. the current scudy tests whether cultural distance between physicians and patients, measured by racial discordance, predicts poorer patient attitudes about their providers and the health care system in a severely disadvantaged hiv-infected population in new york city that typically reports inconsistent patterns of health care. methods: we collected data from unscably housed black and latino/a people with hiv who reported having a regular health care provider. we asked them to report on their attitudes about their provider and the health care system using validated instruments. subjects were categorized as being racially "concordant" or "discordant" with their providers, and attitudes of these two groups were compared. results: the sample consisted of ( %) black and ( %) latino/a people, who reported having ( %) black physicians, ( %) latino/a physicians, ( %) white physicians, and ( %) physicians of another/unknown race/ethnicity. overall, ( %) subjects had physicians of a different race/ethnicity than their own. racial discordance did not predict negative attitudes about rela· tionship with providers: the mean rating of a i-item trust in provider scale (lo=high and o=low) was . for both concordant and discordant groups, and the mean score in -icem relationship with provider scale ( =high and !=low) was . for both groups. however discordance was significantly associated with distrust in che health care syscem: che mean score on a -icem scale ( =high discrust and l=low distrust) was . for discordant group and . for che concordant group (t= . , p= . ). we further explored these patterns separacely in black and lacino/a subgroups, and using different strategies ro conceptualize racial/ethic discordance. conclusions: in this sample of unscably housed black and latino/a people who receive hiv care in new york city, having a physician from the same racial/ethnic background may be less important for developing a positive doctor-patient relationship than for helping the patients to dispel fear and distrust about the health care system as a whole. we discuss the policy implications of these findings. ilene hyman and samuel noh . .abstract objectiw: this study examines patterns of mental healthcare utilization among ethiopian mm grants living in toronto. methods: a probability sample of ethiopian adults ( years and older) completed structured face-to-face interviews. variables ... define, especially who are non-health care providers. plan of analysis. results: approximately % of respondents received memal health services from mainstream healthcare providers and % consulted non-healthcare professionals. of those who sought mental health services from mainstream healthcare providers, . % saw family physicians, . % visited a psychiatrist. and . % consulted other healthcare providers. compared with males, a significantly higher proportion gsfer sessions v ri ftlnales consulted non-healthcare_ professionals for emotional or mental health problems (p< . ). tlbile ethiopian's overall use of mamstream healthcare services for emotional problems ( %) did not prlydiffer from the rate ( %) of the general population of ontario, only a small proportion ( . %) rjerhiopians with mental health needs used services from mainstream healthcare providers. of these, !oj% received family physicians' services, . % visited a psychiatrist, and . % consulted other healthll/c providers. our data also suggested that ethiopian immigrants were more likely to consult tradioooal healers than health professionals for emotional or mental health problems ( . % vs. . % ). our bivariate analyses found the number of somatic symptoms and stressful life events to be associated with an increased use of medical services and the presence of a mental disorder to be associated with a dfcreased use of medical services for emotional problems. however, using multivariate methods, only die number of somatic symptoms remained significantly associated with use of medical services for emooonal problems. diu#ssion: study findings suggest that there is a need for ethnic-specific and culturally-appropriate mrcrvention programs to help ethiopian immigrants and refugees with mental health needs. since there ~a strong association between somatic symptoms and the use family physicians' services, there appears robe a critical role for community-based family physicians to detect potential mental health problems among their ethiopian patients, and to provide appropriate treatment and/or referral. the authors acknowledge the centre of excellence for research in immigration and settlement (ceris) in toronto and canadian heritage who provided funding for the study. we also acknowledge linn clark whose editorial work has improved significantly the quality of this manuscript. we want to thank all the participants of the study, and the ethiopian community leaders without whose honest contributions the present study would have not been possible. this paper addresses the impact of the rationalization of health-care services on the clinical decision-making of emergency physicians in two urban hospital emergency departments in atlantic canada. using the combined strategies of observational analysis and in-depth interviewing, this study provides a qualitative understanding of how physicians and, by extension, patients are impacred by the increasing ancmpts to make health-care both more efficient and cost-effective. such attempts have resulted in significantly compromised access to primary care within the community. as a consequence, patients are, out of necessity, inappropriately relying upon emergency departments for primary care services as well as access to specialty services. within the hospital, rationalization has resulted in bed closures and severely rmricted access to in-patient services. emergency physicians and their patients are in a tenuous position having many needs but few resources. furthermore, in response to demands for greater accountability, physicians have also adopted rationality in the form of evidence-based medicine. ultimately, ho~ever, rationality whether imposed upon, or adopted by, the profession significantly undermines physu.: ans' ability to make decisions in the best interests of their patients. johnjasek, gretchen van wye, and bonnie kerker introduction: hispanics comprise an increasing proportion of th.e new york city (nyc) populanon !currently about %). like males in the general population, h spamc males (hm) have a lower prrval,nce of healthcare utilization than females. however, they face additional access barriers such as bnguage differences and high rates of uninsurance. they also bear a heavy burden of health problems lllehasobesity and hiv/aids. this paper examines patterns of healthcare access and ut hzat on by hm compared to other nyc adults and identifies key areas for intervention. . . . and older are significantly lower than the nhm popu anon . v. . , p<. ), though hi\' screening and immunizations are comparable between the two groups. conclusion: findings suggest that hm have less access t? healthcare than hf or nhm. hown r, hm ble to obtain certain discrete medical services as easily as other groups, perhapsdueto!rtor are a hm. i i . subsidized programs. for other services, utilization among s ower. mprovmg acc~tocareinthis group will help ensure routine, quality care, which can lead to a greater use of prevennve services iii! thus bener health outcomes. introduction: cancer registry is considered as one of the most important issues in cancer epidemiology and prevention. bias or under-reporting of cancer cases can affect the accuracy of the results of epidemiological studies and control programs. the aim of this study was to assess the reliability of the regional cancer report in a relatively small province (yasuj) with almost all facilities needed for c llcll diagnosis and treatment. methods: finding the total number of cancer cases we reviewed records of all patients diagnoicd with cancer (icd - ) and registered in any hospital or pathology centre from until i n yasuj and all ( ) surrounding provinces. results: of patients who were originally residents of yasui province, . % wereaccoulll!d for yasuj province. the proportion varies according to the type of cancer, for exarnplecancetsofdiglstive system, skin and breast were more frequently reported by yasuj's health facilities whereas cancmoi blood, brain and bone were mostly reported by neighbouring provinces. the remaining cases ( . % were diagnosed, treated and recorded by neighbouring provinces as their incident cases. this is partly because of the fact that patients seek medical services from other provinces as they believed that the facil. ities are offered by more experienced and higher quality stuffs and their relative's or temporary acooiii' modation addresses were reported as their place of residence. conclusion: measuring the spatial incidence of cancer according to the location of report ortht current address affected the spatial statistics of cancer. to correct this problem recording the permanm! address of diagnosed cases is important. p - (c). providing primary healthcare to a disadvantaged population at a university-run commumty healthcare facility tracey rickards the. c:ommuni~y .h~alth ~linic (chc) is a university sponsored nurse-managed primary bealthwt (p~c:l clime. the clm c is an innovative model of healthcare delivery in canada that has integrated tht principles of phc ser · · h' . vices wit ma community development framework. it serves to provide access to phc services for members of th · · illi · dru is ii be . . e community, particularly the poor and those who use or gs, we mg a service-learning facil'ty f d · · · · · · d rionll h . . .,m.:. · t · . meet c ient nee s. chmc nursing and social work staff and srudents r·--· ipa em various phc activities and h .l.hont" less i . f . outreac services in the local shelters and on the streels to'"" popu auon o fredericton as well th chc · model iii fosterin an on oi : . • e promotes and supports a harm reduction . · local d!or an~ h ng ~art:ersh p with aids new brunswick and their needle exchange program, w tha ing condoms and :xu:t h:~~~e e~aint~nance therapy clients, and with the clie~ts themselves ~_r; benefits of receiving health f ucation, a place to shower, and a small clothing and food oai~· care rom a nurse p · · d d · --""~'i"· are evidenced in th r research that involved needsaans mvo ves clients, staff, and students. to date the chc has unacn- · sessment/enviro i . d ; •• '"""" ll eva uanon. the clinic has also e . d nmenta scan, cost-benefit analysis, an on-go...,, "".'i'~ facility and compassionate lea x~mme the model of care delivery' focusing on nursing roles wi~ cj rmng among students. finally, the clinic strives to share the resu•p v . -arch with the community in which it provides service by distributing a bi-monthly newsletter, and plllicipating in in-services and educational sessions in a variety of situations. the plan for the future is coolinued research and the use of evidence-based practice in order to guide the staff in choosing how much n~ primary healthcare services to marginalized populations will be provided. n- (c) tuming up the volume: marginalized women's health concerns tckla hendrickson and betty jane richmond bdrotbu:tion: the marginalization of urban women due to socio-economic status and other determinants negatively affects their health and that of their families. this undermines the overall vitaliry of urban communities. for example, regarding access to primary health care, women of lower economic surus and education levels are less likely to be screened for breast and cervical cancer. what is not as widely reported is how marginalized urban women in ontario understand and articulate their lack of access to health care, how they attribute this, and the solutions that they offer. this paper reports on the rnults of the ontario women's health network (owhn) focus group project highlighting urban women's concerns and suggestions regarding access to health care. it also raises larger issues about urban health, dual-purpose focus group design, community-based research and health planning processes. mdhods: focus group methodology was used to facilitate a total of discussions with urban and rural women across ontario from to . the women were invited to participate by local women's and health agencies and represented a range of ages, incomes, and access issues. discussions focussed on women's current health concerns, access to health care, and information needs. results were analyzed using grounded theory. the focus groups departed from traditional focus group research goals and had two purposes: ) data collection and dissemination (representation of women's voices), and ) fostering closer social ties between women, local agencies, and owhn. the paper provides a discussion and rationale for a dual approach. rax/ts: the results confirm current research on women's health access in women's own voices: urban women report difficulty finding responsive doctors, accessing helpful information such as visual aids in doctors' offices, and prohibitive prescription costs, in contrast with rural women's key concern of finding a family doctor. the research suggests that women's health focus groups can address access issues by helping women to network and initiate collective solutions. the study shows that marginalized urban women are articulate about their health conctrns and those of their families, often understanding them in larger socio-economic frameworks; howtver, women need greater access to primary care and women-friendly information in more languages and in places that they go for other purposes. it is crucial that urban health planning processes consult directly with women as key health care managers, and turn up the volume on marginalized women's voices. women: an evaluation of awareness, attitudes and beliefs introduction: nigeria has one of the highest rates of human immunodeficiency virus ihivi seroprrvalence in the world. as in most developing countries vertical transmission from mother to child account for most hiv infection in nigerian children. the purpose of this study was ro. determine the awareness, attitudes and beliefs of pregnant nigerian women towards voluntary counseling and testing ivct! for hiv. mnbod: a pre-tested questionnaire was used to survey a cross section '.>f. pregnant women ~t (lrlleral antenatal clinics in awka, nigeria. data was reviewed based on willingness to ~c~ept or re ect vct and the reasons for disapproval. knowledge of hiv infection, routes of hiv transm ssmn and ant rnroviral therapy iart) was evaluated. hsults: % of the women had good knowledge of hiv, i % had fair knowledge while . % had poor knowledge of hiv infection. % of the women were not aware of the association of hreast milk feeding and transmission of hiv to their babies. majority of the women % approved v~t while % disapproved vct, % of those who approved said it was because vct could ~educe risk of rransmission of hiv to their babies. all respondents, % who accepted vc.i ~ere willing to be tnted if results are kept confidential only % accepted to be tested if vc.t results w. be s~ared w .th pinner and relatives % attributed their refusal to the effect it may have on their marriage whale '-gave the social 'and cultural stigmatization associated with hiv infection for their r~fusal.s % wall accept vct if they will be tested at the same time with their partners. ~ of ~omen wall pref~r to breast feed even if they tested positive to hiv. women with a higher education diploma were times v more likely to accept vct. knowledge of art for hiv infected pregnant women as a means of pre. vention of maternal to child transmission [pmtct) was generally poor, % of respondents wm aware of art in pregnancy. conclusion: the acceptance of vct by pregnant women seems to depend on their understanding that vct has proven benefits for their unborn child. socio-cultur al factors such as stigmatizationof hiv positive individuals appears to be the maj_or impedi~ent towards widespread acceptanee of ycr in nigeria. involvemen t of male partners may mpro~e attitudes t~wa~ds vct:the developmentofm novative health education strategies is essential to provide women with mformanon as regards the benefits of vct and other means of pmtct. p - (c) ethnic health care advisors in information centers on health care and welfare in four districts of amsterdam arlette hesselink, karien stronks, and arnoud verhoeff introduction : in amsterdam, migrants report a "worse actual health and a lower use of health care services than the native dutch population. this difference might be partly caused by problems migrants have with the dutch language and health care and welfare system. to support migrants finding their way through this system, in four districts in amsterdam information centers on health care and welfare were developed in which ethnic health care advisors were employed. their main task is to provide infor· mation to individuals or groups in order to bridge the gap between migrants and health care providers. methods: the implementat ion of the centers is evaluated using a process evaluation in order to give inside in the factors hampering and promoting the implementat ion. information is gathered using reports, attending meetings of local steering groups, and by semi-structu red interviews with persons (in)directly involved in the implementat ion of the centers. in addition, all individual and groupcontaets of the health care advisors are registered extensively. results: since four information centers, employing ethnic health care advisors, are implemented. the ethnicity of the health care advisors corresponds to the main migrant groups in the different districts (e.g. moroccan, turkeys, surinamese and african). depending on the local steering groups, the focus of the activities of the health care advisors in the centers varies. in total, around individual and group educational sessions have been registered since the start. most participants were positive about the individual and group sessions. the number of clients and type of questions asked depend highly on the location of the centers (e.g. as part of a welfare centre or as part of a housing corporation). in all districts implementa tion was hampered by lack of ongoing commitment of parties involved (e.g. health care providers, migrant organization s) and lack of integration with existing health care and welfare facilities. discussion: the migrant health advisors seem to have an important role in providing information on health and welfare to migrant clients, and therefore contribute in bridging the gap between migrants and professionals in health care and welfare. however, the lack of integration of the centers with the existing health care and welfare facilities in the different districts hampers further implementation . therefore, in most districts the information centres will be closed down as independent facilicities in the near future, and efforts are made to better connect the position of migrant health advisor in existing facilities. the who report ranks the philippines as ninth among countries with a high tb prevalence. about a fourth of the country's population is infected, with majority of cases coming from the lower socioeconomic segments of the community. metro manila is not only the economic and political capital of the philippines but also the site of major universities and educational institutions. initial interviews with the school's clinicians have established the need to come up with treatment guidelines and protocols for students and personnel when tb is diagnosed. these cases are often identified during annual physical examinations as part of the school's requirements. in many instances, students and personnel diagnosed with tb are referred to private physicians where they are often lost to follow-up and may have failure of treatment due to un monitored self-administered therapy. this practice ignores the school clinic's great potential as a tb treatment partner. through its single practice network (spn) initiative, the philippine tuberculosis initiatives for the private sector (philippine tips), has established a model wherein school clinics serve as satellite treatment partners of larger clinics in the delivery of the directly observed treatment, short course (dots) protocol. this "treatment at the source" allows school-based patients to get their free government-suppl ied tb medicines from the clinic each day. it also cancels out the difficulty in accessing medicines through the old model where the patient has to go to the larger clinic outside his/her school to get treatment. the model also enables the clinic to monitor the treatment progress of the student and assumes more responsibility over their health. this experience illustrates how social justice in health could be achieved from means other than fund generation. the harnessing of existing health service providers in urban communities through standardized models of treatment delivery increases the probability of treatment success, not only for tb but for other conditions as well. p - (c) voices for vulnerable populations: communalities across cbpr using qualitative methods martha ann carey, aja lesh, jo-ellen asbury, and mickey smith introduction: providing an opportunity to include, in all stages of health studies, the perspectives and experiences of vulnerable and marginalized populations is increasingly being recognized as a necessary component in uncovering new solutions to issues in health care. qualitative methods, especially focus groups, have been used to understand the perspectives and needs of community members and clinical staff in the development of program theory, process evaluation and refinement of interventions, and for understanding and interpreting results. however, little guidance is available for the optimal use of such information. methods: this presentation will draw on diverse experiences with children and their families in an asthma program in california, a preschool latino population in southern california, a small city afterschool prevention program for children in ohio, hiv/aids military personnel across all branches of the service in the united states, and methadone clinic clients in the south bronx in new york city. focus groups were used to elicit information from community members who would not usually have input into problem definitions and solutions. using a fairly common approach, thematic analysis as adapted from grounded theory, was used to identify concerns in each study. next we looked across these studies, in a meta-synthesis approach, to examine communalities in what was learned and in how information was used in program development and refinement. results: while the purposes and populations were diverse, and the type of concerns and the reporting of results varied, the conceptual framework that guided the planning and implementation of each study was similar, which led to a similar data analysis approach. we will briefly present the results of each study, and in more depth we will describe the communalities and how they were generated. conclusions: while some useful guidance for planning future studies of community based research was gained by looking across these diverse studies, it would be useful to pursue a broader examination of the range of populations and purposes to more fully develop guidance. background: the majority of studies examining the relationship between residential environments and cardiovascular disease have used census derived measures of neighborhood ses. there is a need to identify specific features of neighborhoods relevant to cardiovascular disease risk. we aim to ) develop methods· data on neighborhood conditions were collected from a telephone survey of s, fesi· dents in balth:.ore, md; forsyth county, nc; and new york, ny. a sample of of the i.ni~~l l'elpondents was re-interviewed - weeks after the initial interview t~ measure the tes~-~etest rebab ~ ty of ~e neighborhood scales. information was collected across seven ~e ghborho~ cond ~ons (aesth~~ ~uah~, walking environment, availability of healthy foods, safety, violence, social cohesion, and acnvmes with neighbors). neighborhoods were defined as census tracts or homogen~us census tra~ clusters. ~sycho metric properties.of the neighborhood scales were accessed by ca~cu~~.ng chronba~h s alpha~ (mtemal consistency) and intraclass correlation coefficients (test-r~test reliabilmes) .. pear~n s .corre~anons were calculated to test for associations between indicators of neighborhood ses (tncludmg d mens ons of race/ ethnic composition, family structure, housing, area crowding, residential stability, education, employment, occupation, and income/wealth) and our seven neighborhood scales. . chronbach's alphas ranged from . (walking environment) to . (violence). intraclass correlations ranged from . (waling environment) to . (safety) and wer~ high~~~ . ~ for ~urout of the seven neighborhood dimensions. our neighborhood scales (excluding achv hes with neighbors) were consistently correlated with commonly used census derived indicators of neighborhood ses. the results suggest that neighborhood attributes can be reliably measured. further development of such scales will improve our understanding of neighborhood conditions and their importance to health. childhood to young adulthood in a national u.s. sample jen jen chang lntrodfldion: prior studies indicate higher risk of substance use in children of depressed mothers, but no prior studies have followed up the offspring from childhood into adulthood to obtain more precise estimates of risk. this study aimed to examine the association between early exposure to maternal depl'elsive symptoms (mds) and offspring substance use across time in childhood, adolescence, and young adulthood. methods: data were obtained from the national longitudinal survey of youth. the study sample includes , mother-child/young adult dyads interviewed biennially between and with children aged to years old at baseline. data were gathered using a computer-assisted personal interview method. mds were measured in using the center for epidemiologic studies depression scale. offspring substance use was assessed biennially between and . logistic and passion regression models with generalized estimation equation approach was used for parameter estimates to account for possible correlations among repeated measures in a longitudinal study. rnlllta: most mothers in the study sample were whites ( %), urban residents ( %), had a mean age of years with at least a high school degree ( %). the mean child age at baseline was years old. offspring cigarette and alcohol use increased monotonically across childhood, adolescence, and young adulthood. differential risk of substance use by gender was observed. early exposure to mds was associated with increased risk of cigarette (adjusted odds ratio (aor) = . , % confidence interval ( ): . , . ) and marijuana use (aor = . , % ci: . , . ), but not with alcohol use across childhood, adolescence, and young adulthood, controlling for a child's characteristics, socioeconomic status, ~ligiosity, maternal drug use, and father's involvement. among the covariates, higher levels of father's mvolvement condluion: results from this study confirm previous suggestions that maternal depressive symptoms are associated with adverse child development. findings from the present study on early life experi-e~ce have the potential to inform valuable prevention programs for problem substance use before disturbances become severe and therefore, typically, much more difficult to ameliorate effectively. the ~act (~r-city men~ health study predicting filv/aids, club and other drug transi-b~) study a multi-level study aimed at determining the association between features of the urban enyjronment mental health, drug use, and risky sexual behaviors. the study is randomly sampling foster sessions v neighborhood residents and assessing the relations between characteristics of ethnographically defined urban neighborhoods and the health outcomes of interest. a limitation of existing systematic methods for evaluating the physical and social environments of urban neighborhoods is that they are expensive and time-consuming, therefore limiting the number of times such assessments can be conducted. this is particularly problematic for multi-year studies, where neighborhoods may change as a result of seasonality, gentrification, municipal projects, immigration and the like. therefore, we developed a simpler neighborhood assessment scale that systematically assessed the physical and social environment of urban neighborhoods. the impact neighborhood evaluation scale was developed based on existing and validated instruments, including the new york city housing and vacancy survey which is performed by the u.s. census bureau, and the nyc mayor's office of operations scorecard cleanliness program, and modified through pilot testing and cognitive testing with neighborhood residents. aspects of the physical environment assessed in the scale included physical decay, vacancy and construction, municipal investment and green space. aspects of the social environment measured include social disorder, social trust, affluence and formal and informal street economy. the scale assesses features of the neighborhood environment that are determined by personal (e.g., presence of dog feces), community (e.g., presence of a community garden), and municipal (e.g., street cleanliness) factors. the scale is administered systematically block-by-block in a neighborhood. trained research staff start at the northeast corner of an intersection and walk around the blocks in a clockwise direction. staff complete the scale for each street of the block, only evaluating the right side of the street. thus for each block, three or more assessments are completed. we are in the process of assessing psychometric properties of the instrument, including inter-rater reliability and internal consistency, and determining the minimum number of blocks or street segments that need to be assessed in order to provide an accurate estimate of the neighborhood environment. these data will be presented at the conference. obj«tive: to describe and analyze the perceptions of longterm injection drug users (idus) about their initiation into injecting. toronto. purposive sampling was used to seek out an ethnoculturally diverse sample of idus of both genders and from all areas of the city, through recruitment from harm reduction services and from referral by other study participants. interviews asked about drug use history including first use and first injecting, as well as questions about health issues, service utilization and needs. thematic analysis was used to examine initiation of drug use and of injection. results: two conditions appeared necessary for initiation of injection. one was a developed conception of drugs and their (desirable) effects, as suggested by the work of becker for marijuana. thus virtually all panicipants had used drugs by other routes prior to injecting, and had developed expectations about effects they considered pleasureable or beneficial. the second condition was a group and social context in which such use arose. no participants perceived their initiation to injecting as involving peer pressure. rather they suggested that they sought out peers with a similar social situation and interest in using drugs. observing injection by others often served as a means to initiate injection. injection served symbolic purposes for some participants, enhancing their status in their group and marking a transition to a different social world. concl ion: better understanding of social and contextual factors motivating drug users who initiate injection can assist in prevention efforts. ma!onty of them had higher educational level ( %-highschool or higher).about . yo adffiltted to have history of alcohol & another . % had history of smoking. only . % people were on hrt & . % were receiving steroid. majority of them ( . ) did not have history of osteoporosis. . % have difficulty in ambulating. only . % had family history of osteoporosis. bmd measurements as me~sured by dual xray absorptiometry (dexa) were used for the analysis. bmd results were compare~ w ~ rbc folate & serum vitamin b levels. no statistical significance found between bmd & serum v taffiln b level but high levels of folate level is associated with normal bmd in bivariate and multivariate analysis. conclusion: in the studied elderly population, there was no relationship between bmd and vitamin b ; but there was a significant association between folate levels & bmd. introduction: adolescence is a critical period for identity formation. western studies have investigated the relationship of identity to adolescent well-being. special emphasis has been placed on the influence of ethnic identity on health, especially among forced migrants in different foreign countries. methodology: this study asses by the means of an open ended question identity categorization among youth in three economically disadvantaged urban communities in beirut, the capital of lebanon. these three communities have different histories of displacement and different socio-demographic makeup. however, they share a history of displacement due to war. results and conclusion: the results indicated that nationality was the major category of identification in all three communities followed by origin and religion. however, the percentages that self-identify by particular identity categories were significantly different among youth in the three communities, perhaps reflecting different context in which they have grown up. mechanical heart valve replacement amanda hu, chi-ming chow, diem dao, lee errett, and mary keith introduction: patients with mechanical heart valves must follow lifelong warfarin therapy. war· farin, however, is a difficult drug to take because it has a narrow therapeutic window with potential seri· ous side effects. successful anticoagulation therapy is dependent upon the patient's knowledge of this drug; however, little is known regarding the determinants of such knowledge. the purpose of this study was to determine the influence of socioeconomic status on patients' knowledge of warfarin therapy. methods: a telephone survey was conducted among patients to months following mechan· ical heart valve replacement. a previously validated -item questionnaire was used to measure the patient's knowledge of warfarin, its side effects, and vitamin k food sources. demographic information, socioeconomic status data, and medical education information were also collected. results: sixty-one percent of participants had scores indicative of insufficient knowledge of warfarin therapy (score :s; %). age was negatively related to warfarin knowledge scores (r= . , p = . ). in univariate analysis, patients with family incomes greater than $ , , who had greater. than a grade education and who were employed or self employed had significantly higher warfarm knowledge scores (p= . , p= . and p= . respectively). gender, ethnicity, and warfar~n therapy prior to surgery were not related to warfarin knowledge scores. furthermore, none of t~e. m-hospital tea~hing practices significantly influenced warfarin knowledge scores. however, panic ~ants who _rece v~d post discharge co~unity counseling had significantly higher knowledge scores tn comp~r son with those who did not (p= . ). multivariate regression analysis revealed that und~r~tandmg the ~oncept of ?ternational normalized ratio (inr), knowing the acronym, age and receiving ~ommum !' counseling after discharge were the strongest predictors of warfarin kn~wledge. s~ oeconom c status was not an important predictor of knowledge scores on the multivanate analysis. poster sessions v ~the majority of patients at our institution have insufficient knowledge of warfarin therapy.post-discharge counseling, not socioeconomic status, was found to be an important predictor of warfarin knowledge. since improved knowledge has been associated with improved compliance and control, our findings support the need to develop a comprehensive post-discharge education program or, at least, to ensure that patients have access to a community counselor to compliment the in-hospital educatiop program. brenda stade, tony barozzino, lorna bartholomew, and michael sgro lnttotl#ction: due to the paucity of prospective studies conducted and the inconsistency of results, the effects of prenatal cocaine exposure on functional abilities during childhood remain unclear. unlike the diagnosis of fetal alcohol spectrum disorder, a presentation of prenatal cocaine exposure and developmental and cognitive disabilities does not meet the criteria for specialized services. implications for public policy and services are substantial. objective: to describe the characteristics of children exposed to cocaine during gestation who present to an inner city specialty clinic. mnbods: prospective cohort research design. sample and setting: children ages to years old, referred to an inner city prenatal substance exposure clinic since november, . data collection: data on consecutive children seen in the clinic were collected over an month period. instrument: a thirteen ( ) page intake and diagnostic form, and a detailed physical examination were used to collect data on prenatal substance history, school history, behavioral problems, neuro-psychological profile, growth and physical health of each of the participants. data analysis: content analysis of the data obtained was conducted. results: twenty children aged to years (mean= . years) participated in the study. all participants had a significant history of cocaine exposure and none had maternal history or laboratory (urine, meconium or hair) exposure to alcohol or other substances. none met the criteria of fetal alcohol spectrum disorder. all were greater than the tenth percentile on height, weight, and head circumference, and were physically healthy. twelve of the children had iqs at the th percentile or less. for all of the children, keeping up with age appropriate peers was an ongoing challenge because of problems in attention, motivation, motor control, sensory integration and expressive language. seventy-four percent of participants had significant behavioral and/or psychological problems including aggressiveness, hyperactivity, lying, poor peer relationships, extreme anxiety, phobias, and poor self-esteem. conclusion: pilot study results demonstrated that children prenatally exposed to cocaine have significant learning, behavioural, and social problems. further research focusing on the characteristics of children prenatally exposed to cocaine has the potential for changing policy and improving services for this population. methods: trained interviewers conducted anonymous quantitative surveys with a random sample (n= ) of female detainees upon providing informed consent. the survey focused on: sociodemographic background; health status; housing and neighborhood stability and social resource availability upon release. results: participants were % african-american, % white, % mixed race and % native american. participants' median age was , the reported median income was <s , year, and % reported receiving a high school diploma or equivalent. women reported a number of health conditions rypical of underserved populations, including asthma ( %), sexually transmitted infections ( %), high blood pressure ( %), hcv ( %), diabetes ( %) and hiv ( %). nearly half ( %) did not anticipate having a place to stay for at least days upon release. factors significantly associated housing stability upon release were: high family support score (adjusted odds ratio [aor) . ; % confidence interval ( % cl) . , . ), high neighborhood stability score (aor . ; % cl . , . ), wanting a commercial sex worker (csw) support group (aor . ; % cl . , . ); and identifying as bisexual (aor . ; % cl . , . ). women desired employment ( %), housing ( %), education ( %), drug treattnent ( %), help with custody of children ( %), childcare ( %), and domestic violence suppon ( %) services. conclusions: female detainees represent one of urban centers' most marginalized pcjpwatioos. short periods of detention represent a unique opportunity for _interven?~ns bri~ co~s and public health institutions. service providers should collaborate ~ th local ~ails to .p~de a con uwnof care for female detainees upon release that includes transportation , housing, residential drug treallllcnt, employment, education, family reunification, childcare and domestic viol~nce su~rt. ~pecial attenlion is warranted to lesbian and bisexual women and csws, who may be especially margmalized &om family and service-based support networks. introduction: "health care and ethnic minority immigrants" examines how health care policy dil· ferences between canada and the united states impact the health-related hardships, access and use of preventative care, and health outcomes of urban ethnic minority immigrants in both countries. methods: the findings of this paper build on the results of my qualitative comparative study of hotel workers in vancouver, bc and seattle, wa that revealed greater health related hardships for similarly matched employees in seattle compared to vancouver. in this paper, i examine the generalizability of these findings at the cross-national level for similar ethnic minority immigrant groups. i compare the impact of health care policy differences on specific groups that have emigrated to cities in both canada and the united states. these include immigrants from china, viemam, philippines, west indies, africa, sri lanka, pakistan, and latin america. comparative statistical analysis -utilizing rel· evant data from statistics canada and the u.s. census -reveal the extent to which health policy differ· ences help explain how current health policy in the united states disadvantages urban ethnic minority immigrants. results: many ethnic minority immigrants are a part of the working poor, a group which disproportionately lacks health insurance coverage in the united states. their position in the labour market makes them most vulnerable to exclusion from health care services. the data reveals how current u.s. health policy creates barriers for recently arrived ethnic minority immigrants to access health insurance and care. it remains difficult to ascribe health outcome differences directly to policy differences because of the challenge in disentangling the complex interacting interventing variables, including income inequality, that determine health outcomes. yer suggestive evidence suggests that health policy in the united states is harming the health of urban ethnic minority immigrants. the current health policy regime in the united states harms the health access, care, and outcomes of urban ethnic minority immigrants. comparing the fortunes of similar immigrants in cana· dian and u.s. cities reveals these patterns of disadvantage and some of their consequences. these barriers are an understudied factor in the sociological literature on "segmented assimilation" and social exclu· sion. the paper ends with policy recommendatio ns to improve access to health care among ethnic minor· ity immigrants in both countries, with the goal of reducing health related hardships, and improving health outcomes. mass index deyu pan, richard baker, and keith norris badtgrou~ over the past decades, there has been dramatic increase in prevalence of obesity in the us population. however, the relationship between obesity and the prevalence of cardiovascular dis· ease (cv~) risk factors in different race/ethnic groups over time is not well known. . ik~rgn: _we use cross-sectional , nationally representative surveys: national health and nutri· t nal examination survey (nhanes iii - (n= ) and nhanes nhanes - , including white, black, and hispa~ic races who were no~preg~ant, aged to years. res lt : the preval~nce of high cholesterol level (~ mg/dl), untreated high blood pressure ( : l / mm hg) an~ diabetes were calculated according to bmi group (lean, < ; overweight, - ; and obese, : ) for different race/ethnicity groups. over the approximately years period (from l ~ ~o [ ] [ ] [ ] [ ] , reducrion in cvd risk factors in non-hispanic white has been observed. for mmonty race/~hnicity groups, black and hispanic, there had been increases in prevalence in high blood fa pressure and diabetes. the lean group experienced larger increase in prevalence of those cvd risk ctors. . fo~~ the prevalence in cvd risk factors over time had reduced in most of the bmi ca egoes r t e w ~~e population. however, for black and hispanic, prevalence of of cvd risk factors ave generauy uncreased, especially in overweight and obese groups. methods: strategies identified to achieve these goals include: developing meaningful neighbourhood and district boundaries for comparing health information, providing free access to neighbourhood health profiles (including relevant data at the smallest level for which valid rates could be calculated); mapping relationships of inequality at a variety of nested levels; providing a range of formats (maps, tables) to meet the needs of users; providing technical support; seeking user input to advance and improve the site; and conducting workshops to foster access and use of data for decision-making , advocacy and collaboration. an evaluation strategy is being developed to assess the efforts and impact of these strategies. a preliminary assessment of the results of the first six months of activity will be completed in october . results: significant differences in health are shown at all the geographic levels indicating success in developing the boundaries. results tabulated for the first six months use of the site include: site visits; media use; reference/acknow ledgement of the site in other documents; number of contacts through presentations and workshops; feedback from users identifying strengths and limitations; and, response from health decision makers. members of the partnership are identifying additional tools and services to further support actions that reduce health inequalities. the assessment will be used to develop more specific goals, targets and monitoring mechanisms. conclusions: our experience with paper-based health profiles indicates that they have been used extensively for program planning and advocacy. the greater availability of information in a publiclyavailable web-based format is expected to translate into even greater usefulness and wider application. the web site has had considerable usage to date, extensive media coverage. site users and workshop participants have provided positive feedback and suggestions for next steps. the six month review will be available in october . in india, more than and a half people are hiv-positive and half a million have aids. india currently has the largest number of positive people in the world, oumumbering south africa and accounting for nearly one tenth of the global hiv/aids prevalence. the world bank predicts that by , there will be million hiv/aids cases in india. the central challenge facing hiv prevention efforts in south asia today is learning how to respond to the societal determinants of vulnerability to hiv. hiv/aids is an issue largely engulfed by social stigma. stigma and discrimination are often considered the foremost barriers to effective poster sess ns v prevention and care initiatives. stigma can make a person afraid of disclosing their status~ ~yone el se, and may make them feel depressed or alone. stigma can .also le~d to poor adherence to medicanon, ~ likelihood to access health and social services, and less desire to hve. hiv+ men and women may beafraidtotd! their co-workers that they have hiv for fear of their reactions or for fear of losing their jobs. in a study conducted of people living with hiv/aids in delhi, india ov~r. -~, many respo~ts shared their experiences of discrimination in their families, in their communmes, an~ m health ~e settmgs. these findings will be shared in the workshop, and will be compa~ed to m~ ex~nences workmg as an ~ co~l~ at the center for aids prevention studies in san francisco, cahforma and congreso de lannos unidos m philadelphia, pennsylvania. the workshop will include an overview of hiv/aids in urban contexts in tht united states (los angeles, san francisco, new york, philadelphia) and south asia (delhi, hyderabad, chennai). differences in methods for outreach, prevention and treatment efforts between devdoped world and developing world contexts will be discussed. a large portion of the workshop will be centered on discussion. participants will engage in an exercise to categorize their ideas of stigma. the workshop will also include a powerpoint presentation on the quantitative data gathered from the survey. the number of homeless and runaway youth is increasing in toronto, which is currently home to out of youth in the gt a who live alone, and it is the preferred locale for the street-involved and homeless youth. the city's youth population is expected to grow by nearly % by , the school dropout rate is rising, and there are is a paucity of empirical data on what works with these at-risk youth. over a two-year period, ( ) ( ) ( ) , youthlink-inner city, conducted an evaluation of the impact of a harm reduction program aimed at reducing street youth's risk of contracting/infecting others with the hep c virus, which has both short-term and long-term deleterious effects. demographic data from street-youth, along with resources/services used, employment methods, type and frequency of drug use, health status, police contacts, and their views of program impact were analyzed using a standardized sur· vey. additionally, focus groups with youth, agency staff and community key informants were conducted, as well as in-depth interviews with three youth, over a sixth-month period. this paper details study results, which both inform both practice and future study about what works, why it works, and how best to work with these vulnerable youth. sho~ed .that the wasteland in this area was contaminated by as cd zn pb cu simultaneously. the con-ta~matton of as ~d was quit significant. the contamination problems and environmental issues in this region are very. serious. the awareness on environmental and health issues was investigated by spot survey and analysis. overall awareness among the residents in the region is very poor. the measures must be taken to assu~e t~e .sustainable economy development by local and central gorvernments. keywords nandan guangx ; mmmg area; environmental awareness. concern like, epileptic fits, vision problems, earache, cough of more than weeks and urinary problems. ninety-five subjects did not take bath regularly and were exposed to sex. the health problems identified are only of a particular point of time and it may be difficult to interpret the depth of "iceberg" of the street children's world also draw the health-illness continuum. periodic interaction and follow-up is very difficult as they generally disappear from the research setting due to their frequent mobility for survival measures. as per the prediction of the iceberg theory, only some problems may have been identified, larger problems in respect to their health may not have been identified. in spite of various limitations, this attempt had proven that, it is possible to enter the street children world, explore the iceberg of illnesses, and establish data of health-illness continuum through an effective nursing agency. it is recommended to deworm these children, provide nutritional education, establish "condom corners" and "street children help line" in the city and urban slum areas and undertake action research on their health. malnutrition is a serious problem in developing countries like bangladesh. malnutrition causes a great deal of child suffering. malnutrition is one of the major causes of morbidity and mortality among the child. the aim of present study was to investigate the nutritional status and its relation to socioeconomic conditions of urban disadvantaged child of under five years age. nutritional status was determined by anthropoemetric measurement(heig ht, weight, mid-arm circumference etc.). determination of total protein and serum albumin were done for biochemical examination. haematological examination was done by blood haemoglobin profile estimation by cynmethhaemoglob in method and determination of haematocrit value or packed cell volume (pcv). stool examination for ova of hook worm, round worm, trichuris species and other species were also done. relevant information on socioeconomic characteristics was recorded by interviewing the house hold head using pretested questionnaire. our study demonstrated that nutritional status of the children are positively correlated with family income, parents level of formal education and negatively related to the family size. the effect of family income on the nutritional status, haematological and biochemical indices of urban disadvantaged child under five will be discussed in detail which will help us to determine proper way of utilization of health care facilities exists in developing countries. introduction: with the increase in morbidity and reduction in mortality and with the introduction of highly active antiretroviral therapy (haart), there is increasing focus on the determinants of healthrelated quality of life (hrqol) in hiv-infection. the focus on the present study is to examine the relationship between social support, depression, and hiv disease severity, and the extent to which these variables impact on hrqol in adult men with hiv-infection. methods: as part of a larger ongoing natural history study focusing on the neurobehavioural complications of hiv and aids, we administered questionnaires to assess depression (beck depression inventory), social support, and hrqol (mos-hiv) to adult men with hiv-infection. a structured interview was used to collect health information and data on hiv disease severity. physical and mental health summary scores (phs and mhs) were derived through principal components analysis. participants were grouped according to level of social support: "well supported" (n= ), "moderately supported" (n= ), "little or ineffective support" (n= ). analysis of variance was conducted to assess the effects of three levels of perceived social support, depression status (present vs absent), and hiv disease severity (aids vs non-aids) on mental and physical health dimensions of hrqol. potential interaction effects were also evaluated. results: social support was found to have a significant effect on both mhs and phs. presence of depression was found to have a significant effect on mhs but not phs. hiv disease severity (presence of aids diagnosis) was found to have a significant effect on phs but not mhs. manov a analyses revealed no significant interactions effects. conclusions and implications: level of social support, presence of depression and hiv disease severity were shown to have independent effects on hrqol. feeling "well supported" appears to have significant benefits for mental and physical health. biological indicators of hiv disease appear to have a selective impact on physical health while presence of depression is related to significant reductions in mental health. the development and evaluation of behavioural interventions to improve perceived social support network and depression will likely result in significant improvements in health outcomes of adults with hiv and aids. introduction: ongoing medical advances have greatly enhanced the longevity of penons living with aids (plwa). however, for certain subgroups living with hiv/aids, including, members of minority groups, women and the economically underprivilege d, aids outcomes have not changed so favorably. one obvious factor to consider when explaining disparities in aids outcomes is the environ· ment within which an individual resides. few studies of aids outcomes have focused on how commu· nity setting influences the effectiveness of care delivery. the principle research questions were: ) what is the relationship between the locations of areas with concentrations of pl wa and the distribution of both primary and ancillary service providers? ) how has the widespread availability of haart (after ) impacted aids outcomes at the community level? ) how do aids mortality and fatality rates vary when related community characteristics, such as household income, ethnic mix, and geographic access to primary and ancillary hiv/aids services are considered? we examine this issue across residential communities in the los angeles area. methods: los angeles county's comprehensive aids service providers database (compiled and maintained by aids project los angeles) was geo-referenced and distances between weighted mean population centers and the nearest hiv/aids service providers were calculated to provide a measure of access which was then merged with aids diagnosis and mortality data along with relevant socioeconomic and population indicators and for analysis using bivariate and multivariate statistics at the zip code level. results: there is a growing disparity in hiv/aids outcomes between low-income minority areas and affluent non-minority areas in the post-haart era (p = . ). ancillary aids services such as case management and counseling and testing are located near the places where low income hiv/aids service consumers are likely to live (p =. ). in spite of having more access to ancillary services low income areas continue to be associated with smaller decreases post-haart aids mortality rates (p= . ). conclusions: given the increasing disparities in aids outcomes between lower and upper income communities in the post -haart era, more specific research into the capacities of aids services providers and the efficiency of their interventions is required. although it is clear that ancillary services are operating in the areas of greatest need, their effectiveness remains limited. understanding the reasons for t~is, be they lack of adequate resources for inner city service providers, failure to reach target popula· tmns or other causes, requires additional research. in ? , y.out~ who were able to speak either french or english and had been absent from their parent's/ c~regivers ~es. dence for at least three consecutive nights took part in the survey which consisted of inter· viewer-adm ms tered question~aires. p.arti~i~an~s were recruited from drop in centres in cities across <?-nada.y~uth self-report as either using in ect on or non-injection drugs. statistical analyses were car· r ed out using sas version . the 'home' is a contested site for many women living in urban areas. women living in poverty and using illicit drugs are largely excluded from participation in dominant 'home-base' gender roles of wife and mother because of economic disadvantage. they thus 'make home' in ways that are specific to their everyday experiences. while research has established links between housing, health and drug use, this literature does not tend to consider the meanings that home may have within the lives of women who lack access to adequate tenured living spaces. this presentation reports the findings of my master's thesis work. using grounded theory methodology within a poststructuralist feminist conceptual framework, i conducted in-depth, open-ended interviews with women living in the toronto area. the women were recruited from within the community through posters at different social service agencies (e.g., drop-in centres, community health centres). they were asked to describe their housing experiences and what home meant to them over the course of their lives. through the data analysis process, a substantive theory of 'making home' for women living in poverty and using illicit drugs emerged. the central concept of making home is a continual process of learning about and interacting with the environment. the process of making home entails different subprocesses: finding home (knowing what is available and accessible, and accessing home), adaptation, and leaving home. the different meanings of home that women developed from their experiences and knowledge emerged as critical components for the process of making home. the women i interviewed were very mobile and experienced constant change with regards to home. home was not considered only in relation to physical living space. home could be made within a relationship or with regards to a possession. while dominant meanings of home relation to tenured living spaces are generally positive, my research indicated that home could also be a negative context. the presentation will describe my research process and findings as well as the theoretical and policy implications of my results. in the western democracies, social citizenship bundles the right to social provision (defined as a share of the social good, not necessarily proportionate to the market value of a citizen's contribution) with participation in the paid labour force. for this reason, social citizenship rights, which usually involve some kind of redistributive measures, are a key mechanism by which states ensure economic equality, or at least, economic equality of opportunity, but are also a mechanism of social exclusion. social rights are inscribed around a single kind of relationship, that which exists between a male family breadwinner and the paid labor market; those who make economic contributions that fall outside this relationship -such as unpaid care-work, or, work that occurs in shadow or underground economiesare to a greater or lesser degree barred from accessing citizen-based social provisions. furthermore, social provision that occurs outside of the breadwinner/market-eco nomy dyad is very often meanstested and is accompanied by regulatory state apparatuses (this includes a range of social services, from welfare payments, to child-care subsidies, to disability pensions). social citizenship is thus stratified; the legal relationship that is at the heart of social citizenship acts as a form of social closure against claims for a share of the social good made by those who are 'lesser' citizens than others. of particular interest in this paper is how citizenship inequalities translate into inequalities in the social provisions that emerge from economic participation: the right to safety on the job, protection from employer harassment, protection from the vagaries of the market as well the right to adequate, comprehensive, and appropriate health services. drawing on mixed methods, longitudinal data from adult sex workers (n= ) located in two research sites with different social welfare regimes -one in canada and one in the u.s. -we examine the consequences of working in a "shadow" or "underground" economy on various facets of health and access to health services, taking into consideration the mediating role that citizenship constructs and social welfare regimes play in accessing other key social and economic determinants of health. methods: the study population included methadone patients (re)admitted at the mhs in the period from / / to / / , born in the netherlands, morocco, surinam, dutch antilles or turkye, and officially registered in the population register of amsterdam. the population register was used to ascer· rain the vital status. causes of death were provided by the central bureau of statistics. mortality was categorised as hiv related, directly drug related (overdose) and other.mortality. results: the methadone patients had the following characteristics: years of age at entry; % male; % ethnic minority; % ever injected. in total, personyear (py) of observation time and deaths ( % hiv related, % overdose; % other) were observed. hence, the crude mortality rate was / py ( % ci - / py). the percentage of (ever) injectors was higher among the native dutch than among the ethnic minorities, % and % respectively. higher rates were observed among native dutch drug users compared to those belonging to an ethnic minority (age adjusted hazard ratio (hr) . ( % ci . - . ). the age adjusted hr of (ever) injecting drug users versus non injecting users was . ( % cl . - . ). after additional adjustment for route of administration a non significant difference between the dutch and ethnic minorities remained (hr . , % cl . - . , p-value . . conclusion: the mortality rate among the heroin users in amsterdam is strongly affected by the high prevalence of non-injecting drug use. moreover, this study confirms that differences in mortality between the native dutch and the ethnic minorities is related to differences in route of administration. the ongoing reduction of injecting drug use (due tot selctieve mortality, and switching route ofadministration and popularity of crack cocaine) may lead to a further reduction of mortality rates among heroin users in amsterdam. interventions preventing the initiation of injecting should be encouraged. . introduction: food insecurity is an inequality that is central in the lives of many low-income cana· d ans. people lack food security when regular access to nutritious food is limited or variable due to high prices'. low income, lack of transportation or inadequate food distribution, or they become disadvan· taged m other w~ys through the acquisition of food. a group comprising academics, health profession· als, and commumty workers who have experience in food insecurity, developed a pilot study in ottawa that sought to und~rstand the lived experience of food insecurity. the study also used the united states department of agriculture (usda) community food security module. methods: a series of group meetings determined the best research approaches; questionnaires and consent forms were developed by a working group. twenty-three self-identified food insecure respon· dents were interviewed. the data were analysed using frequency distributions· the food security module was coded according to the usda coding guide, and open-ended responses w~re coded using a grounded approach. renlts: preliminary results from our pilot study have given the research team cause for considerable concern. out of households without children, experienced food insecurity with hunger; ~ere at the severe l~vel. out of households with children, experienced food insecurity with hunger. ~•rst person reflecnons commonly featured feelings of depression low self-esteem and despair. participants' account tha d . an cu ty gettmg to the store, severely limited putting knowledge and skills mto practice. l'oster sessions v conclusion: based on these early findings, our research team is looking to challenge what appear to be assumptions about poverty and food insecurity and for best ways to use this information. some policy approaches and interventions that encourage people to eat better and exercise more, may be missing the mark for low-income individuals, and may serve to maintain food insecurity. future research will build on this pilot. with methods augmentation, and a comprehensive knowledge dissemination plan, we hope co contribute to research and policy frameworks at all levels. ps- (a) mental health and the corrections system: population-based analyses in urban, semi-urban, and rural settings julian somers, robert watts, and michelle patterson introduction: according to recent epidemiological research, rates of mental disorders vary considerably across countries and across regions within countries. nevertheless, rates of mental disorders (including substance use disorders) are consistently higher in populations involved in the corrections sys- em. courts have long recognized the heavy burden of mental illness within their purview, and have developed innovative programs to better manage the needs of such individuals. the majority of these innovations (e.g., specialized courts) exist in urban settings. however, few studies have examined the degree of variability in rates of different mental disorders between courts in urban and other settings (e.g., semi-urban, rural). variability between courts in different settings, if present, holds implications for needs-based resource planning. the present study was conducted as part of a long-term inter-ministerial collaboration in british columbia (bc). analyses were conducted on linked administrative data regarding population health and correctional services. a database was constructed including all individuals sentenced in bc in a single year (n= , ). corrections records were matched to records of health services utilization (hospital and outpatient services) for mental disorders and substance use disorders in the years preceding sentencing. services for mental health and substance-related problems were aggregated into three groups: severe mental illness (smi); less-severe mental illness (lsmi); alcohol/other drug (ad). courts were grouped, based on their annual volumes, inro three categories: "urban"; "semi-urban" and "rural." rates of service use for mental disorders were compared between groups for -year and -years preceding sentencing. results: there were significant differences in the rates of mental disorders in courts of different size (urban, semi-urban, rural) . however, differences between the rates of disorders within each of these groups exceeded the discrepancies between groups. comparatively high and low rates of disorders were observed in courts of each size. moreover, the courts with the highest rates of certain disorders (e.g., ad) did not have the highest rates of other types of mental disorders (e.g., smi). conclusions: rates of mental disorders differed significantly among the annual populations sentenced across courts in bc. urban courts (which process comparatively large numbers of people) have implemented services to address the needs of the mentally ill. the present analyses strongly suggest that program development should be closely linked to the demonstration of need. the results caution that a uniform approach to court programs for the mentally ill is likely to be inefficient, over-supplying services in some settings and underestimating need in others. results: public settings used for injection are characterized by highly unhygienic conditions, the presence of unsafely disposed syringes, limited availability of sterile syringes and a lack of sterile water for injecting. a number of unsafe injection practices observed were common among public injectors. the presence of police officers nearby and the potential of assault by street predators fostered rushed injecting among those consuming drugs in public spaces. the ecological features of these environments encourage unhygienic and unsafe injecting practices, heighten risk for overdose and the transmission of blood borne viruses. introduction: approximately % of women experience depression in the first weeks or months after giving birth. although it has been argued that postpartum depression (ppd) is a culture-bound p~ nomenon, experienced only in western, industrialized countries, recent international research studies have confirmed that the prevalence of ppd is similar around the world. however, little is known about variables that may influence the experience of ppd in women from diverse cultures and immigrant women. research is needed to identify the role culture may play in the presentation of ppd (i.e., types of symptoms most commonly reported), how women from various racial, ethnic and cultural backgrounds perceive and attribute their symptoms of ppd, and finally, how culture can be appropriately addressed in ppd treatment programs. method: to examine the role of culture in ppd, semi-structured interviews and self-report question· naires were administered to clients of the women's health centre of st. joseph's health centre, tor· onto. participants were identified as either first generation canadians (relative newcomen) (n= ) or second generation canadian (parents were immigrants to canada) (n= ). data were collected qd these two groups of women based on: severity of depression, symptom presentation, perceived role of social supports and culturally-specific traditions, and barriers and responses to treatment. the interview data were analyzed using qualitative methods (thematic content analysis), and the following themes were identified: ) stress about passing on their culture to their children, ) lack of social support and feelings of isolation, ) perceived importance or lack of importance of cultural based tra· ditions, ) conflicts with family members. about cultural traditions and beliefs, ) mental health stigma within ethnic communities and beyond, ) race-and sex-based discrimination, and ) language barriers. conclrllion: identifying the role culture plays in the presentation of ppd, and how women from diverse backgrounds perceive and attribute their symptoms of ppd, is critical in order to establishcultur· ally appropriate guidelines for treatment options. furthermore, information gathered from this study can be used to develop policies and resources for delivering culturally competent care for newcomer wo~ who are dealing with ppd as well as the issues around acculturation (i.e., language barriers, racism). llus is of particular importance for urban health centers which provide postpartum care to diverse groups of women, and particularly recent immigrants or newcomers. ps-~ (al. contaminated 'therapeutic landscape': perceptions of the aamjiwnaang fint nation keyln smith and isaac luginaah . in~: this. paper pres;ents the findings of an ongoing study among the aamjiwnaang f!rst nanon. aam wnaang is located m the heart of samia's 'chemical valley', surrounded by cherrucal ~(ants such as esso, imperial oil, shell, suncor energy, and canada's largest hazardous waste disposal sate. safety kleen. this fint nation community is located within the st. clair river •area of concem'. as destgna~ by health canada for the population of samia and the surrounding region. although this comm_umty, by way of. its proximity to the numerous chemical plants is already exposed to high levels pollu~on, recent che?ucal dumping in ~mjiwnaang, as well as a failed proposal for another ethanol plant m the community, only helped to mtensify community concerns about potential health impacts of exposure. research on the cultural beliefs and traditions of first nation communities has established that th~ ~isting rel~tionship between first nations people and 'mother earth' is not only physical, but also_ spmtual. in this study we explore how the complex relationship between the aamjiwnaang first naaon and 'mother earth' be ha · · · i .. may c ngmg a contammated 'therapeutic' landscape. the study a so ~lores h?w aam wnaang residents are coping with these changes and with the probable conramina· boa of their community. ra!jts: aamjiwnaang residents acknowledge that they are living in a contaminated environment and are being impacted by emissions from the surrounding 'chemical valley' especially for future generations, and have expressed concerns that members of the community and mother earth are 'sick' as a result of this exposure. while moving from that 'place' has been discussed, residents have strong personal and generational connections to the land and insist however, that aamjiwnaang is their 'home' and will remain that way despite growing community concerns about the impact from industry. the contribution of this study lies in the direct involvement of community leadership in designing and conducting this research and distributing the results to further local policy development regarding community concerns on the reserve. background: truck driver are at very high risk for drug abuse because the factor contributing to drug abuse among driver are multiple. it is important to gain an understanding of the key factors that contributing to drug abuse among truck drivers. methods: seventy-truck driver aged - years were conveniently selected from the population. all the participants were male. an interview schedule was developed in the light of literature data and data were collected by personal interview with informed consent in selected urban area of eastern part of nepal. results: a considerable percentage of truck driver have less knowledge about drug abuse, its effect on body and their complication. majority of the participants ( %) explained that lack of education, financial crisis were leading factors of drug abuse. the average numbers of respondents were believed that lack of meaning in life, marital disharmony. friendship with drug abuser, stress, tiredness, modernization of life pattern and freedom from the home pressure were the influencing risk factors to drug abuse. conchuion: this study reveals those truck drivers are at risk in urban area for developing drugs abuse, mostly influenced by social and environmental factors. hence, these groups should undergo certain educational programme to prevent not only drug abuse, but also prevent transmission of infectious disease among these groups. introduction: food insecurity is an inequality that is central in the lives of many low-income canadians. our group of university researchers, health professionals, and community developers conducted a study in ottawa with community workers who work with people identified as food insecure. the purpose of the study was to understand the nature of their work, and their perspectives, perceptions and experiences of the causes and consequences of food insecurity. (a parallel study was conducted with food insecure participants). methods: sampling was through local knowledge of organizations involved in the provision of food to community members. written permission for the researchers to contact workers in confidence was obtained from each organization. thirteen in-depth interviews were conducted. the interviews consisted of a number of open-ended questions. the data were collated, and analysed using a grounded approach. results: workers interviewed represented organizations that offered diverse programming and methods of food distribution intended to address the needs of the community. the provision of food was seen as a necessary response to address hunger that arose for the majority from poverty caused by low income, or levels of government income support and safety nets that were insufficient to support food requirements. workers reported that food requirements varied according to different. ethnic backgrounds, ages of recipients and family configurations, and with food preferences, and d'.etary (health) requirements. workers' observations of the effects of insufficient food on adults and children such as depression, low energy and non-participation or social disengagement matched those of food insecure respondents. food insecurity was cited as "another srressor among the mountain of problems." overall, workers presented a picture of a silent, stigmatized, poor population including children, and a lack of advocacy to address the issues. be tha th · ·ty the results suggest that workers and organizations, like the commuruty mem rs t ey msecun • · · · · f ilab'l' f food · t d ·n thei·r ab 'l 'ty to address food insecurity. l m tanons m terms o ava ty o , serve, are restnc e . . funding, and donations appeared to set the para? eters of pr~g:am r.espon~ to commuruty food msecurity. workers were concerned with program des g": and a~m mstranon that m general addr~d hunger on an emergency short-term basis, although food msecunty was long-ter_m for ~any. sustainable solutions that include knowledge translation strategies, and health and social pohcy responses were suggested and will be explored in future research that hopes to build on this pilot. background: socioeconomic deprivation as well as low levels of soc!al s.uppoi:r have .been associated with poor outcomes following cardiac surgery. pre-operative depression m ~anents with coron~ry artery disease awaiting cabg ranges from - % and is an independent predictor of post-operanve mortality. since st. michael's hospital has a large inner city population, this study was designed to determine the both the prevalence of depressive symptomatology (ds) in patients awaiting cabg as well as its relationship with socioeconomic status (ses) and social support. methods: consecutive patients referred for isolated cabg were invited to complete the centre for epidemiological studies depression scale (ces-d) as well as a social support scale and a life stressors inventory. a ces-d score of : represents mild ds and a score of : represents moderate to severe ds. participants also recorded information on functional status, perceived progression of heart failure, demographic and ses variables. all participants with ces-d scores : were considered to have ds. results: of the patients ( %) who returned the survey, ( . %) of participants had a ces-d score : with ( . %) of those having scores suggestive of severe depression. females and those with ongoing medical concerns tended to have more ds (p= . and p= . respectively). age was not related to ds. perceived worsening of symptoms and increased ccs angina class were significantly related to the presence of ds (p= . and p= . respectively) but not the number of diseased heart vessels. satisfaction with personal relationships including having someone to confide in (p= . ), feeling lonely (p= . ) and not having a partner (p= . ) were significantly related to ds. being very upset by a recent breakup in the immediate family was also significantly related to ds (p= . ). having greater than a grade education was the only ses variable related to ds (p= . ). multivariate logistic regression suggested that not being partnered and having low education were the most significant predictors of ds. conclnsion: pre-operative depression is present in at least one quarter of patients referred for cabg. since ds is related to poor outcomes following cabg, single patients with few social supports and low education should be considered at high risk for ds. these findings support the need for the development of supportive interventions in patients at risk in order to decrease post-operative morbidity. this study examines the relationship between childhood sexual abuse, sexual assault during adolescence, and hiv-risk-related behaviours in a sample of homeless youths. over the past decade, there has been increasing research devoted to the impact of childhood sexual abuse. some studies have suggested that the experience of childhood sexual abuse is associated with substance use and abuse, at· risk sexual behaviour and subsequent higher rates of hiv infection (ompad et al., ; cinq-mars et al., ; brown et al., ) . other studies have found that childhood abuse, especially sexual abuse, is c_o~n among stree~ youth (noell et al. ). this study compares sexually abused males and females livtng on the street ~th non-sexually abused street youth, with regards to unsafe sexual behaviours and e~ures to potmnal t:dv sources (e.g., tattooing, body piercing and injection drug use). the hypothe-sis oft~ ~nt study is that the prevalence of hn-risk-related behaviours will be higher among street youth vtctuns of sexual abuse than those who have not been sexually abused. the sample includes youths aged to who met specific criteria's for itinerancy ( male and female, with a mean ~of . y· and a standard deviation of . ). they were recruited through five organisations working ~th~ you~ and were~ of an ongoing cohort study. all youth completed a to minute ques· ~onnaue on their sexual behaviours, use of drugs and alcohol and other hiv risk behaviours. oral spec· unens for hiv testing were. also collected. a total of ( . %) youth reported at least one incident of ~i •~use/assault ( ~ girls ( . % of all the girls) and boys ( . % of all the boys]). preliminary descnpnve analyses pomt to sexually abused/assaulted youth showing the highest prevalence of sexual poster sessions v at-risk behaviours. for example, . % of sexual abuse/assault victims have engaged in prostitution in their lives compared with . % in the non-sexually abused/assaulted group. in addition, . % of sexual abuse/assault victims reported having injected drugs, compared with . % in the non-sexually abused/assaulted group. more statistical analyses will bring other significant factors to light, especially when we analyze separately those victim of childhood sexual abuse as compare to those victim of sexual assault after childhood. elucidating the risk factors for getting involved in hiv-risk-related behaviours is important for the development of comprehensive and appropriate prevention and treatment intervention strategies. introduction: new immigrants and refugees to canada frequently emigrate from regions of the world where intestinal parasitic infections with worms are endemic. of note, some of these parasites area capable of surviving for years to decades within a given host and can have life threatening consequences many years after initial infection. thus, early diagnosis and treatment of intestinal parasitic worms is considered important in high risk immigrant populations, however there remains a lack of consensus regarding the best method of accomplishing this. diagnosing worm infections through stool examinations is costly and has limited sensitivity, while presumptive treatment of all immigrants, although advocated by some, is expensive and results in healthy individuals being unnecessarily treated. herein, we examine the utility of a hematologic marker (i.e. peripheral blood eosinophilia) as a screening instrument to identify parasitic worm infections in new immigrants to toronto. we identified adults, years of age or older, who were screened for intestinal parasitic infections by stool examination as part of a recently developed screening protocol at a downtown toronto community health centre. we examined the prevalence of infections with worms and subsequently evaluated the impact of several demographic factors on the presence of worm infections. we also determined the sensitivity and specificity of peripheral blood eosinophilia (defined as greater than eosinophils per ml) as a marker for intestinal parasitic worm infections. results: overall, % of the immigrants tested had evidence of at least one worm infection on a single stool examination, while % of such individuals bad infections with multiple worms concurrently. age did not appear to be associated with the presence of worms, however % of males had evidence of worm infections compared with % of females (p= . ). immigrants from asia, sub-saharan africa, and central america had the highest burden of overall infection. the sensitivity and specificity of peripheral blood eosinophilia for worm infections was % and % respectively. conclusions: one in five recent immigrants presenting to a community health centre in downtown toronto had evidence of at least one intestinal parasitic worm infection. the highest burden of illness was in men and in those emigrating from less developed regions of the world. peripheral blood eosinophilia is a poor screening test for worm infections however its presence is highly suggestive of the existence of worms in new immigrants. more than a decade ago, the journal of american college health recommended that a national study be conducted to measure the health status of african american college students, 'both health disparities and [their] positive healthful behaviors' (fennell, ) . it was later decided that when exploring the level of health risk behaviors for african american students, gender is an important variable and should be included in the research (fennell, ) . at historically black college and universities (hbcus) college health researchers must tackle gender disparities through highly-effective health promotion and disease prevention programs. the purpose of this review is to examine the literature that addresses the overarching health behaviors (i.e. risky sexual behavior, poor diet, smoking, physical inactivity, etc.) of african american men who attend hbcus. despite the various social, cultural, and academic benefits of african american students who attend hbcus, the number of research studies that adequately address their health and health behaviors is limited. studies indicate that african american men who attend hbcus are actively engaged in poor health behaviors. compared to females at hbcus, african american men are more likely to behave in ways that could result in injuries and the use tobacco, alcohol, and ~ther dru~. the city of toronto has recently proposed to conduct a street count of the homeless. like proposals that have come before, this most recent proposal is controversial among many homeless advocates and service providers because it is perceived as intrusive, likely to undercount the target population, and unnecessary for addressing the problem. advocates of the count view it as necessary to gauge the scope of the problem and advise city leaders about how to most effectively direct resources ro.the various homeless services. this paper first reviews the history of efforts to count homeless populat ns m toronto, describing the motivations and arguments of people on both sides of the issue. second, the paper reviews the methodological complexities of counting homeless populations, describing approaches that use shelter-counts, administrative data and street observations. those interested in counts for toronto and elsewhere can benefit from this review of approaches that have been proposed and carried out in other municipalities. third, the paper proposes a new community-base d strategy that joins the skills of methodologists, local experts, and service providers to ensure a fair and accurate count. the method of systematic social observation avoids some of the problems of early counts by utilizing a repeated identification approach to minimize undercount bias. the method also has the advantage of involving and compensating homeless individuals for assisting with the street count estimates. the estimation approach can be implemented on a rolling basis throughout the year. drug transitions) is a multi-level study aimed at examining the associations between features of the urban environment and mental health, drug use, and risky sexual behaviors. research participants are being recruited in new york city (nyc) neighborhoods. an essential first step in the implementation of this study was to delineate boundaries for each target neighborhood that could then be used to establish sampling frames and as key units of analytic interest. although many neighborhood studies rely on pre-established definitions (e.g. those used for the census or administrative purposes), such definitions do not always reflect contemporary settlement patterns. we felt that street level observations were a neces· sary component of the definition process. methods: the procedures used to delineate neighborhoods were: ( ) development of census block maps of targeted areas; ( ) review of land use maps and census tract data to ensure, prior to going into the field, tha.t particular blocks are residential and likely to have sufficient population for recruitment purposes; and ( ) field vislts and observation in each of the targeted areas. field observations focused on: housing characteristics, including housing type and condition; characteristics of commercial areas, such as likely customer base (e.g. local or no~, socio-economic status and ethnicity of customers); pedestrian volume (including con· gregauons of people m parks and outside stores or residences); obstructions to pedestrian traffic (e.g. ma or thoroughfares, multi-block industry or institutions); and maintenance and use of open spaces. results: in making the final decisions regarding neighborhood boundaries and the inclusion or exclusion of particular. blocks, we considered a broad range of factors including evidence of homogeneity an~ heterogeneity (socmeconomic, ethnic, housing type, environmental) across blocks within and blocks ad acent to a nei.ghborhood, and across the sample neighborhoods; the potential for efficient recruit· ment of appropriate particip.ants (i.e. sufficient local pedestrian traffic); and boundaries used in reporting census data (s? that population data can be used in our analysis). . altho~gh utilization of field observations for neighborhood definitions is relatively time consuming (ap~~ox mately hours for a block area, with more diverse neighborhoods taking even longer), we annc p~t~ that it will substantially improve the quality and consistency of our data gath· ~rmg ~nd analyse~. spec f c e?'amples from neighborhoods defined through this process will be given dur· m~ this presentatmn. we will also discuss the merits and limitations of characterizing neighborhoods usmg street level observations. has been no consideration for how social networks are associated with sse. the objective of this study was to identify personal and social network characteristics associated with being a recipient of sse. in this cross-sectional study, idus who injected in the past months were recruited from syringe exchange programs in montreal, canada, between april and january . information on each participant and on the persons with whom contact had occurred in the past month were elicited using a structured, interviewer-administe red questionnaire. participants provided detailed demographic and drug use information on up to idu members with whom drugs or injecting materials were shared. using logistic regression, personal and network characteristics were examined in relation to receipt of sterile syringes. res.its: of idus, % reported receiving sterile syringes in the past month from another idu. the sample mean age was years (range - ), % male, % caucasian, and % cocaine injectors. in multivariate analyses adjusted for age and gender, recipients of sterile syringes were more likely than non-recipients to share drugs after preparation ( r= . ( . - . )), to require help or to have helped inject another idu (or= . ( . - . )), to have asked someone to get sterile syringes from a syringe exchange program (or= . [ . - . )), to lend syringes (or= . [ . - . ) ) and to use drug preparation water that was previously used by another iou ( r= . ( . - . ) ) during the past months. recipients also had a higher rate of change (p= . ) of idus in their drug injecting network during the past month. with respect to social networks, % ( / ) of idu network members were providers of sterile syringes and were more likely than non-providers to inject everyday (or= . ( . - . )). when stratified by their role as a sexual partner or as someone who provides support (e.g. friend, family member), further risk behaviours were observed in relation to sharing injecting materials with the participant. conclusion: recipients of sterile syringes and their idu network members had several high-risk behaviours for infection with bloodborne diseases. sse may afford an opportunity for the dissemination of other salutary behaviours such as information sharing on safe injecting practices between recipients and distributors. furthermore, drug injecting networks may be an avenue to reach idus who may not otherwise be exposed to preventive measures. there are numerous sources of stigma and labelling of mental and physical illness. first, the sociocultural dimension to stigma and labelling clearly influences patients, families, health care professionals and society's perception and treatment of illness. this creates multiple challenges related to illness identification and recovery, particularly in culturally diverse societies. second, the media is a major source of stigma and stereotyping with regard to a variety of mental and physical illnesses. despite increased public knowledge of many illnesses, studies have shown that stigma has intensified over the years in certain cases. a third element of stigma and labels appears with the use of diagnosis as a solution to human problems with the result that difficult to treat patients are repudiated and social issues are unaddressed. this presentation will serve to outline the development of stigma, various expressions of stigma, and consequences of stigma. it will provide some practical recommendations for the reduction of stigma related to mental and physical illness. purpose: to assess the knowledge, attitude, and practice about immunization for parent of - years old hispanic and african american children in los angeles county (lac). methods: we conducted two cluster surveys in lac. the sample was selected with probability proportionate to estimated size at the first stage and simple random sample of children at the second stage. data were collected through interview. we absuacted vaccine coverage data from immunization record card (irc) at home or from clinic records. the participation was % in hispanics and % in african americans populations. irc was not available at home for % of african american and % of hispanic children. results: all parents perceived their children got all necessary vaccine~. fa~orable attitudes to.w~rd immunization were reported by % of african american and % of h s?amc parents. '.he m~ ority of the parents ( % african american and % hispanic) agreed that vaccines prevent senous d se~ses among children. regarding vaccine safety, significantly more hispanic parents ( %) than african american parents ( %) mentioned that vaccines are safe. introduction: cervical cancer has been shown to be preventable by papanicolau tests in heterosexual women; however, the utility of papanicolau test in lesbians is controversial. cervical cancer is caused by the human papillomavirus (hpv) which is transmitted by sexual _intercourse; howev_er, its' transmission by homosexual intercourse is also controversial. the goal of this study was to review the evidence for papanicolau tests in lesbians. methods: a pub med, ovid ( ovid ( to , and cochrane library search was performed using the mesh headings "homosexuality , female," "vaginal smears," and "papillomavirus, human." in pub med, the clinical queries feature was used with "diagnosis" and "broad, sensitive" filters. a google advanced search of the internet was conducted with the terms "lesbian," "cervical cancer," and "pap rest." the url was limited to ".ca," ".edu," or ".gov." results: the search yielded original articles and reviews, but no cochrane reviews. none of the publications were canadian. website hits were found and selected websites were reviewed. studies showed that lesbians have fewer papanicolau tests than heterosexual women; however, many reported risk factors for cervical cancer, including multiple past or current sexual partners (male and female), early age of first coitus, history of sexually transmitted diseases, and cigarette smoking. hpv has been detected in - % of lesbians and - % of lesbians who have never had sex with men. case studies of abnormal papanicolau tests in lesbians who have never had sex with men have also been reponed. sexual transmission of hpv among lesbians can be explained by several factors: ) - % of lesbians have had sex with men and - % of lesbians continue to have sex with men. ) hpv may be transmitted by sexual behaviours among women, like digital-vaginal sex, digital-anal sex, oral sex, and the use of insertive sex toys. ) hpv transmission requires only skin-to-skin contact. genital hpv has been identified on human fingers. some professional organizations, like the society of obstetricians and gynecologists of canada and the american cancer society, recognize the need for papanicolau tests in lesbians. other organizations, like the canadian cancer society, do not have official policy statements. the current ontario cervical screening program does not specifically address lesbians. conclusion: although the data was limited, most studies recommended that lesbians should receive papanicolau tests. the frequency of these tests was controversial. policy makers and professional organizations should address the needs of this special population and make specific recommendations . monique chaaya, ahia sibai, hiam chemaitelly, and zana el roueiheb . literature concerning the mental and physical effect of work at an old age is contradictory. in addinon, urban environments are physically and socially harsh with reduced potential for income generation and employment and increased potential for depression. the present paper is an attempt to study how do work, or lack of work, link to the experience of depression among older adults in underprivileged lebanese urban communities. the data comes from a cross-sectional survey, where elderly residing in underprivileged communities in beirut, including a palestinian refugee camp, were successfully inter-v ewed through face-to-face interviews. logistic regression was performed to assess the effect of work on depression ad_justing for many other covariates. data showed that . % of people aged years and more were still workmg. there was a highly protective effect of work on depression in elderly males (or= . , % cl= . - . ). the current study is the first of its kind in the arab region and more work shou_ld be _don_e in this area. it is important for the lebanese government to consider elderly rights for social mclus n m terms of employment opportunities. amam nuru-jeter, nancy adler, and burton singer . l~u~on:_ the socioeconomic gradient is perhaps the most persistent and significant finding in social epidem ological research. the insistent nature of the ses effect is evidenced by its significance after acc?untmg for ~umerous confounds. the significance and magnitude of the effect, however, varies by ::•al group. evidence_ o_f the relative effect of race and ses is inconclusive. further, less attention has f ~ ptid to the specific interactions of race and ses than to examinations of which is a better predictor d ~ th. ~sues are further complicated by the explanatory complexity of the various measures of ses anl . owht ey relate to the health of various social groups. understanding the specific nature of these re a ons ips s necessary for guiding he ith d · i · · h a an soc a po mes and programs aimed at improving t e poster sessions v health of our most disadvantaged groups, and therefore population health, overall. this study examines the synergistic effects of ses with both race and gender in predicting group differences in mortality. methods: analyses use data from the national longitudinal mortality survey (n= , ) for the years , , and - ; and were linked to the national death index for deaths occurring through . results were confirmed using data from the national mortality followback survey for people who died in (n= , ) and the national health interview survey (denominator). we used correlation analysis and the standardized mortality ratio to examine ses (education and income), race, and gender as predictors of group differences in changes in mortality. results: for the total population, analyses support the income gradient showing significant declines in mortality ratios from low to high income along the income strata. education shows a significant drop in mortality with completion of high school and completion of college, exhibiting a threshold rather than a gradient effect. compared to whites, blacks receive diminishing health returns for each subsequent level of income and education; with whites closely mirroring the total population in ses thresholds. similarly, compared to men, women do not experience the same health gains at comparable ses levels. for education, black men and women only show significant mortality declines upon completion of high school. the ses gradient operates differently among race and gender subgroups. threshold effects suggest resource gains in life opportunities at particular milestones along the ses gradient. further, ses matters less for blacks and women compared to whites and men suggesting differing implications for health and social policy aimed at reducing disparities. objective: we assessed the impact of diabetes in a large puerto rican community of chicago by measuring the prevalence of diagnosed diabetes and calculating the diabetes mortality rate. methods: we analyzed data from a comprehensive health survey conducted in randomly selected households in community areas. questions on diagnosed diabetes and selected risk factors were asked. in addition, mortality data were analyzed in order to calculate the age-adjusted diabetes mortality rate. when possible, rates were compared to those found in other studies. results: the diabetes prevalence located in this community ( . %: % cl= . %- . %) is one of the highest ever reported for puerto ricans. for instance, it is more than three times higher than the prevalence for the us ( . %) and twice the prevalence for puerto ricans in new york ( . %) and puerto rico ( . %- . %). diagnosed diabetes was found to be significantly associated with obesity (p= . ). the prevalence was particularly high among older people, females, those horn in the us, and those with a family history. the diabetes mortality rate ( . per , population) was more than twice the rate for all of chicago ( . ) and the us ( . ). conclusions: understanding why the diabetes and mortality rates for puerto ricans in this commu· nity are so much higher than those of other communities is imperative. collaboration between researchers, service providers and community members can help address the issues of diabetes education, early screening and diagnosis and effective treatment needed in this community. introduction: sars is a respiratory illness that is spread from person to person through dose contact. this infectious disease outbreak was unusual due to the high rate of infection among health care workers. the aim of the study is to explore the demographic and attitudinal determinants of psychological distress due to sars among health care workers of a toronto hospital. methods: a total of adult participants completed questionnaires co assess psychological distress (impact of event scale -jes) and attitudes to sars. of these, participants completed the questionnaire during the sars i outbreak, and participants completed the questionnaire during the sars ii outbreak. participants also provided information on demographic variables, including occupation and exposure to sars. principal components analysis was used to derive eight attitudinal scales: fear: system, protection, prevention, job stress, stigma, instrumental coping, and psychological copm~. l ear regression analyses were applied to evaluate the associations of the demographic and amtudmal variables, as well as time, with psychological distress. . . regression analyses showed that time and higher scores on fear, ob stress, stigma'. and instrumental coping were associated with a higher total ies score: (r =. ). contrary to expectations, none of the demographic variables was associated with total ies score. conclusion: the presence of psychological distress in health care workers is indicative of intrusive or avoidant responses to thoughts, feelings, and memories associated with the sars outbreak. this study shows that ( ) fear for one's health and the he~lth of.others, ( ) ex~erien~in~ job stress, ( )_tbe per· ception of stigma, ( ) usage of instrumental copmg skills, ~n~ ( ) t m_e s grufi~an~ly c~nmb~te to increased psychological distress in health care workers. potential mterventmns during mfecttous diseaie outbreaks in health care settings should be targeted to minimize the impact of these factors. purpose: the purpose of this study was to expand knowledge regarding feeding practices, know!· edge and nutritional beliefs of mothers currently residing in the dominican republic (dr). the rising incidence of obesity in children is a major national health concern and obesity in first and second-generation immigrant children also continues to rise. we know that parents (particularly mothers) shape children's early diet patterns and that immigrant mothers experience additional challenges related to acculturation and assimilation into a new culture, however there is a paucity of literature concerning the effect of immigrant adaptation to american culture on the nutrition of children. in addition, new immigrant knowledge about the causes of obesity and the resulting health implications for childhood obesity has not been assessed and reported. this qualitative study used focus group methodology to discuss views and practices related to the introduction of food for infants and feeding practices for young children, along with a discussion on knowledge and beliefs related to the causes and health implications of child· hood obesity. ten dominican mothers' of young children (birth to years old) who reside in a small town in the western frontier area of the dr were participants in the focus group. results from this srudy will be compared to results from an identical study that will be conducted in fall with new immi· grant mothers from the dr to the boston area. we will compare feeding practices, beliefs and knowledge about nutrition for young children between these two groups. methods: using participatory principles, a focus group design was used to interview a group of mothers in the dr. the investigator along with a bilingual translator conducted the focus group. the session was tape recorded and is currently in the process of being transcribed and translated. transcribed data will be systematically analyzed themes will be identified. a qualitative data analysis software will be used to organize and code the data according to the specific aims of the study. supporting quotations will be selected to substrate each theme. lmpli~tions for urban health practice: an ultimate goal of this study is to lay a foundation for understanding the process of acculturation on feeding practices of mothers when they immigrate to the us. understanding beliefs, knowledge and feeding practices that mothers use with young children will help m ~he ~evelopment of culturally and linguistically appropriate educational strategies and materials for use m primary prevention of pediatric obesity. in canada more than seventy-five percent of immigrants choose to stay in three major urban centers of toronto, montreal and vancouver. approximately fifty percent of the immigrants eventually set· tie m ~~e greater tor<_>nto area. there is mounting evidence that the increasing immigrant population has a_ sigmfic~nt health disadvantage over canadian-born residents. this health disadvantage manifests particularly m the ma "ority of "mm "gr t h h d be · · h . . . . an s w o a en m canada for longer than ten years. this group as ~n associ~te~ with higher risk of chronic disease such as cardiovascular diseases. this disparity twccb n ma onty of the immigrant population and the canadian-born population is of great importance to ur an health providers d" · i i · b as isproporttonate y arge immigrant population has settled in the ma or ur an centers. generally the health stat f · · · · · · h h been . us most mm grants s dynamic. recent mm grants w o av_e ant •;ffca~ada _for less ~han ~en years are known to have a health advantage known as 'healthy imm • ~ants r::r · ~:s eff~ ~ defined by the observed superior health of both male and female recent immi- immigrant participation in canadian society particularly the labour market. a new explanation of the loss of 'healthy immigrant effect' is given with the help of additional factors. lt appears that the effects of social exclusion from the labour market leading to social inequalities first experienced by recent immigrant has been responsible for the loss of healthy immigrant effect. this loss results in the subsequent health disadvantage observed in the older immigrant population. a study on patients perspectives regarding tuberculosis treatment by s.j.chander, community health cell, bangalore, india. introduction: the national tuberculosis control programme was in place over three decades; still tuberculosis control remains a challenge unmet. every day about people die of tuberculosis in india. tuberculosis affects the poor more and the poor seek help from more than one place due to various reasons. this adversely affects the treatment outcome and the patient's pocket. many tuberculosis patients become non-adherence to treatment due to many reasons. the goal of the study was to understand the patient's perspective regarding tuberculois treatment provided by the bangalore city corporation. (bmc) under the rntcp (revised national tuberculosis control programme) using dots (directly observed treatment, short course) approach. bmc were identified. the information was collected using an in-depth interview technique. they were both male and female aged between - years suffering from pulmonary and extra pulmonary tuberculosis. all patients were from the poor socio economic background. results: most patients who first sought help from private practitioners were not diagnosed and treated correctly. they sought help form them as they were easily accessible and available but they. most patients sought help later than four weeks as they lacked awareness. a few of patients sought help from traditional healers and magicians, as it did not help they turned to allopathic practitioners. the patients interviewed were inadequately informed about various aspect of the disease due to fear of stigma. the patient's family members were generally supportive during the treatment period there was no report of negative attitude of neighbours who were aware of tuberculosis patients instead sympathetic attitude was reported. there exists many myth and misconception associated with marriage and sexual relationship while one suffers from tuberculosis. patients who visited referral hospitals reported that money was demanded for providing services. most patients had to borrow money for treatment. patients want health centres to be clean and be opened on time. they don't like the staff shouting at them to cover their mouth while coughing. conclusion: community education would lead to seek help early and to take preventive measures. adequate patient education would remove all myth and conception and help the patients adhere to treatment. since tb thrives among the poor, poverty eradiation measures need to be given more emphasis. mere treatment approach would not help control tuberculosis. lntrod#ction: the main causative factor in cervical cancer is the presence of oncogenic human papillomavitus (hpv). several factors have been identified in the acquisition of hpv infection and cervical cancer and include early coitarche, large number of lifetime sexual partners, tobacco smoking, poor diet, and concomitant sexually transmitted diseases. it is known that street youth are at much higher risk for these factors and are therefore at higher risk of acquiring hpv infection and cervical cancer. thus, we endeavoured to determine the prevalence of oncogenic hpv infection, and pap test abnormalities, in street youth. ~tbods: this quantitative study uses data collected from a non governmental, not for profit dropin centre for street youth in canada. over one hundred females between the ages of sixteen and twentyfour were enrolled in the study. of these females, all underwent pap testing about those with a previous history of an abnormal pap test, or an abnormal-appearing cervix on clinical examination, underwent hpv-deoxyribonucleic (dna) testing with the digene hybrid capture ii. results: data analysis is underway. the following results will be presented: ) number of positive hpv-dna results, ) pap test results in this group, ) recommended follow-up. . the results of this study will provide information about the prevalence of oncogemc hpv-dna infection and pap test abnormalities in a population of street youth. the practice implic~ tions related to our research include the potential for improved gynecologic care of street youth. in addition, our recommendations on the usefulness of hpv testing in this population will be addressed. methods: a health promotion and disease prevention tool was developed over a period of several years to meet the health needs of recent immigrants and refugees seen at access alliance multicultural community health centre (aamchc), an inner city community health centre in downtown toronto. this instrument was derived from the anecdotal experience of health care providers, a review of medical literature, and con· sultations with experts in migration health. herein we present the individual components of this instrument, aimed at promoting health and preventing disease in new immigrants and refugees to toronto. results: the health promotion and disease prevention tool for immigrants focuses on three primary health related areas: ) globally important infectious diseases including tuberculosis (tb), hiv/aids, syphilis, viral hepatitis, intestinal parasites, and vaccine preventable diseases (vpd), ) cancers caused by infectious diseases or those endemic to developing regions of the world, and ) mental illnesses includiog those developing among survivors of torture. the health needs of new immigrants and refugees are complex, heterogeneous, and ohen reflect conditions found in the immigrant's country of origin. ideally, the management of all new immigrants should be adapted to their experiences prior to migration, however the scale and complexity of this strategy prohibits its general use by healthcare providers in industrialized countries. an immigrant specific disease prevention instrument could help quickly identify and potentially prevent the spread of dangerous infectious diseases, detect cancers at earlier stages of development, and inform health care providers and decision makers about the most effective and efficient strategies to prevent serious illness in new immigrants and refugees. lntrodmction: as poverty continues to grip pakistan, the number of urban street children grows and has now reached alarming proportions, demanding far greater action than presently offered. urbanization, natural catastrophe, drought, disease, war and internal conflict, economic breakdown causing unemployment, and homelessness have forced families and children in search of a "better life," often putting children at risk of abuse and exploitation. objectives: to reduce drug use on the streets in particular injectable drug use and to prevent the transmission of stds/hiv/aids among vulnerable youth. methodology: baseline study and situation assessment of health problems particularly hiv and stds among street children of quetta, pakistan. the program launched a peer education program, including: awareness o_f self and body protection focusing on child sexual abuse, stds/hiv/aids , life skills, gender and sexual rights awareness, preventive health measures, and care at work. it also opened care and counseling center for these working and street children ar.d handed these centers over to local communities. relationships among aids-related knowledge and bt:liefs and sexual behavior of young adults were determined. rea.sons for unsafe sex included: misconception about disease etiology, conflicting cultural values, risk demal, partner pressur~, trust and partner significance, accusation of promiscuity, lack of community endorsement of protecnve measures, and barriers to condom access. in addition socio-economic pressure, physiological issues, poor community participation and anitudes and low ~ducation level limited the effectiveness of existing aids prevention education. according to 'the baseline study the male children are ex~ to ~owledge of safe sex through peers, hakims, and blue films. working children found sexual mfor~anon through older children and their teachers (ustad). recommendation s: it was found that working children are highly vulnerable to stds/hiv/aids, as they lack protective meas":res in sexual abuse and are unaware of safe sexual practices. conclusion: non-fatal overdose was a common occurrence for idu in vancouver, and was associated with several factors considered including crystal methamphetamine use. these findings indicate a need for structural interventions that seek to modify the social and contextual risks for overdose, increased access to treatment programs, and trials of novel interventions such as take-home naloxone programs. background: injection drug users (idus) are at elevated risk for involvement in the criminal justice system due to possession of illicit drugs and participation in drug sales or markets. the criminalization of drug use may produce significant social, economic and health consequences for urban poor drug users. injection-related risks have also been associated with criminal justice involvement or risk of such involvement. previous research has identified racial differences in drug-related arrests and incarceration in the general population. we assess whether criminal justice system involvement differs by race/ethnicity among a community sample of idus. we analyzed data collected from idus (n = , ) who were recruited in san francisco, and interviewed and tested for hiv. criminal justice system involvement was measured by arrest, incarceration, drug felony, and loss/denial of social services associated with the possession of a drug felony. multivariate analyses compared measures of criminal justice involvement and race/ethnicity after adjusting for socio-demographic and drug-use behaviors including drug preference, years of injection drug use, injection frequency, age, housing status, and gender. the six-month prevalence of arrest was highest for whites ( %), compared to african americans ( %) and latinos ( % ), in addition to the mean number of weeks spent in jail in the past months ( . vs. . and . weeks). these differences did not remain statistically significant in multivariate analyses. latinos reported the highest prevalence of a lifetime drug felony conviction ( %) and mean years of lifetime incarceration in prison ( . years), compared to african americans ( %, . years) and whites ( %, . years). being african american was independently associated with having a felony conviction and years of incarceration in prison as compared to whites. the history of involvement in the criminal justice system is widespread in this sample. when looking at racial/ethnic differences over a lifetime including total years of incarceration and drug felony conviction, the involvement of african americans in the criminal justice system is higher as compared to whites. more rigorous examination of these data and others on how criminal justice involvement varies by race, as well as the implications for the health and well-being of idus, is warranted. homelessness is a major social concern that has great im~act on th~se living.in urban commu?ities. metro manila, the capital of the philippines is a highly urbanized ar~ w. t~ the h gh~st concentration of urban poor population-an estimated , families or , , md v duals. this exploratory study v is the first definitive study done in manila that explores the needs and concerns of street dwdlent\omc. less. it aims to establish the demographic profile, lifestyle patterns and needs of the streetdwdlersindit six districts city of manila to establish a database for planning health and other related interventions. based on protocol-guid ed field interviews of street dwellers, the data is useful as a template for ref!!. ence in analyzing urban homelessness in asian developing country contexts. results of the study show that generally, the state of homelessness reflects a feeling of discontent, disenfranchisem ent and pow!!· lessness that contribute to their difficulty in getting out of the streets. the perceived problems andlar dangers in living on the streets are generally associated with their exposure to extreme weather condirioll! and their status of being vagrants making them prone to harassment by the police. the health needs of the street dweller respondents established in this study indicate that the existing health related servias for the homeless poor is ineffective. the street dweller respondents have little or no access to social and health services, if any. some respondents claimed that although they were able to get service from heallh centers or government hospitals, the medicines required for treatment are not usually free and are beyond their means. this group of homeless people needs well-planned interventions to hdp them improve their current situations and support their daily living. the expressed social needs of the sucet dweller respondents were significantly concentrated on the economic aspect, which is, having a perma· nent source of income to afford food, shelter, clothing and education. these reflect the street dweller' s need for personal upliftment and safety. in short, most of their expressed need is a combination of socioeconomic resources that would provide long-term options that are better than the choice of living on the streets. the suggested interventions based on the findings will be discussed. . methods: idu~ aged i and older who injected drugs within the prior month were recruited in usmg rds which relies on referral networks to generate unbiased prevalence estimates. a diverse and mon· vated g~o~p of idu "seeds." were given three uniquely coded coupons and encouraged to refer up to three other ehgibl~ idu~, for which they received $ usd per recruit. all subjects provided informed consent, an anonymous ~t erv ew and a venous blood sample for serologic testing of hiv, hcv and syphilis anti~!· results. a total of idus were recruited in tijuana and in juarez, of whom the maion!)' were .male < .l. % and . %) and median age was . melhotls: using the data from a multi-site survey on health and well being of a random sample of older chinese in seven canadian cities, this paper examined the effects of size of the chinese community and the health status of the aging chinese. the sample (n= , ) consisted of aging chinese aged years and older. physical and mental status of the participants was measured by a chinese version medical outcome study short form sf- . one-way analysis of variance and post-hoc scheffe test were used to test the differences in health status between the participants residing in cities representing three different sizes of the chinese community. regression analysis was also used to examine the contribution of size of the chinese community to physical and mental health status. rmdts: in general, aging chinese who resided in cities with a smaller chinese population were healthier than those who resided in cities with a larger chinese population. the size of the chinese community was significant in predicting both physical and mental health status of the participants. the findings also indicated the potential underlying effects of the variations in country of origin, access barriers, and socio-economic status of the aging chinese in communities with different chinese population size. the study concluded that size of an ethnic community affected the health status of the aging population from the same ethnic community. the intra-group diversity within the aging chinese identified in this study helped to demonstrate the different socio-cultural and structural challenges facing the aging population in different urban settings. urban health and demographic surveillance system, which is implemented by the african population & health research center (aphrc) in two slum settlements of nairobi city. this study focuses on common child illnesses including diarrhea, fever, cough, common cold and malaria, as well as on curative health care service utilization. measures of ses were created using information collected at the household level. other variables of interest included are maternal demographic and cultural factors, and child characteristics. statistical methods appropriate for clustered data were used to identify correlates of child morbidity. preliminary ratdts: morbidity was reported for , ( . %) out of , children accounting for a total of , illness episodes. cough, diarrhoea, runny nose/common cold, abdominal pains, malaria and fever made up the top six forms of morbidity. the only factors that had a significant associ· ation with morbidity were the child's age, ethnicity and type of toilet facility. however, all measures of socioeconomic status (mother's education, socioeconomic status, and mother's work status) had a significant effect on seeking outside care. age of child, severity of illness, type of illness and survival of father and mother were also significantly associated with seeking health care outside home. the results of this study have highlighted the need to address environmental conditions, basic amenities, and livelihood circumstances to improve child health in poor communities. the fact that socioeconomic indicators did not have a significant effect on prevalence of morbidity but were significant for health seeking behavior, indicate that while economic resources may have limited effect in preventing child illnesses when children are living in poor environmental conditions, being enlightened and having greater economic resources would mitigate the impact of the poor environmental conditions and reduce child mortality through better treatment of sick children. inequality in human life chances is about the most visible character of the third world urban space. f.conomic variability and social efficiency have often been fingered to justify such inequalities. within this separation households exist that share similar characteristics and are found to inhabit a given spatial unit of the 'city. the residential geography of cities in the third world is thus characterized by native areas whose core is made up of deteriorated slum property, poor living conditions and a decayed environment; features which personify deprivation in its unimaginable ma~t~de. there are .eviden~es that these conditions are manifested through disturbingly high levels of morbidity and mortality. ban · h h d-and a host of other factors (corrupt n, msens t ve leaders p, poor ur ty on t e one an , . · f · · · th t ) that suggest cracks in the levels and adherence to the prmc p es o socta usnce. ese governance, e c . . . . . ps £factors combine to reinforce the impacts of depnvat n and perpetuate these unpacts. by den· grou o . · "id . . bothh tifying health problems that are caused or driven by either matena _or soc a e~nvanon or , t e paper concludes that deprivation need not be accepted as a way. of hfe a~d a deliberate effon must be made to stem the tide of the on going levels of abject poverty m the third world. to the extent that income related poverty is about the most important of all ramifications of po~erty, efforts n_iu_st include fiscal empowerment of the poor in deprived areas like the inner c~ty. this will ~p~ove ~he willingness of such people to use facilities of care because they are able to effectively demand t, smce m real sense there is no such thing as free medical services. ). there were men with hiv-infection included in the present study (mean age and education of . (sd= . ) and . (sd= . ), respectively). a series of multiple regressions were used to examine the unique contributions of symptom burden (depression, cognitive, pain, fatigue), neuropsychologic al impairment (psychomotor efficiency), demographics (age and education) and hiv disease (cdc- staging) on iirs total score and jirs subscores: ( ) activities of daily living (work, recreation, diet, health, finances); ( ) psychosocial functioning (e.g., self-expression, community involvement); and ( ) intimacy (sex life and relationship with partner). resnlts: total iirs score (r " . ) was associated with aids diagnosis (ii= . , p < . ) and symptoms of pain (ii= - . , p < . ), fatigue (ji = - . , p < . ) and cognitive difficulties (p = . , p < . ). for the three dimensions of the iirs, multiple regression results revealed: ( ) activities of daily living (r = . ) were associated with aids diagnosis (ii = . , p < . ) and symptoms of pain <p =- j , p < . ), fatigue (ji = - . , p < . ) and cognitive difficulties (ji = . , p < . ); ( ) psychosocial functioning (r = . ) was associated with was associated with symptoms of fatigue (ii= - . , p < . ) and cognitive difficulties <ii = . , p < . ); and ( ) intimacy (r = . ) was related to was associated with symptoms of fatigue (ij = - . , p < . ) and cognitive difficulties (ii= . , p < . ). methods: the sif evaluation methodology involves a comprehensive database located at the sif, a randomly selected p~o.spective coh~rt of sif users, and two pre-existing external control cohorts. . . ~ts: in addmon to reporting process data and descriptions of the sif users, we report on data indicating that the establishment of the sif has been independently associated with reductions in public ~':°g ~ (p <?. ), and syringe sharing (aor = . [ %ci: . _ . ); p = . ) and other unsafe m ecnon pract _ces_ (p ~ . ), and increased uptake of detox services (log-rank p = . ). as well, we report on da~ md cat ng that the sif has not prompted adverse changes in community drug use patterns. the vancouver sif has been well accepted by the target population, and while adve~ events s~c~ as overdoses have occurred, these events have been successfully managed. externally compiled data indicate that the sif has been associated with substantial declines in public disorder !'oster sessions v associated with injection drug use, syringe sharing, and increased uptake of detox services. as well, the establishment of the sif has not exacerbated community drug use patterns. ongoing evaluation activities wiu involve assessing the impact of the sif on a variety of outcomes, including infectious disease transmission, fatal overdose, and utilization of health and social services. city, brazil, - maria cristina almeida, waleska caiaffa, renato assum;iio, and fernando proietti dengue cases were described according to time, space, intensity, age, gender, onset of symptoms, residence address and census tract. spatial distribution of two groups (children and women over years old and men aged - ) were compared, under assumption that they have distinct behaviors regarding their displacement around the city. analysis included local moran index, ripley\\'s k function and recurrence of census areas over time. about , cases were identified in seven epidemic waves. concentration of cases in small areas, followed by a spread either in space or time suggested endemic patterns. regarding age-gender groups, distinct patterns suggested that residence might not be a good proxy in determining the local of infection for men aged - . dengue is shifting to endemic pattern in this city and transmission may not be sole related to home environment, suggesting that additional spatial information must be couected aiming efficient control measures. murukan kandamuthan and subodh kandamuthan lnl uduction: illness or disablement of a child may affect the economic functioning of a family as it alters the employment pattern and earnings of parents this paper tries to assess the health status and the quality of life of disabled children, and how generally, severe disablement in a child affected their fami-lies\' finances, and to quantify any such effects the problems faced by children in their home and to provide information relevant to the formation of criteria for new or increased cash support. methods: a case-control study was done in the thiruvananthapuram district, capital city of kerala by selecting a random sample of families with severely disabled children below years and a random sample of normal children matched for age and occupation of the parents. comparative and subjective data were collected. money spent on children\'s medical care, loss of earnings of the parents, and other economic burden to the family due to the disability of the child in the family. a discriminant analysis along with univariate analysis was done to assess the factors that mostly differentiate the disabled and normal children. the mean expenditure of the families with a disabled child was rs. /-per month, which is significantly higher than the corresponding expenditure of rs. /-per month of families with normal child, (t= . , p <. ). of the disabled children, % were not getting any social security payments and % had no special concessions for medical and other educational purposes. the analysis of income and expenditure pattern indicated that financial impact of disablement in a child on the family is significant. the discriminant model results revealed that medical expenditure was a significant variable that differentiated the disabled and normal child. the study found that the health status and quality of life of the disabled children were far from satisfactory. this in fact affected the economic status of the disabled children. in addition to reduced earnings, there are extra costs for disabled children for travel, domestic help, medical care, and health care expenditures (hospital care, physician services, dentistry, drugs and others) for disabled individuals. a strong case can be made for their long-term care by improving the financial support to such families possibly through the introduction of an allowance specially to compensate for the earnings lost by parents due to the disability of their children. widows in india are considered disadvantage group of population. because they are characterized by pangs of separation from spouse, and consequently they go through mental agony, social ~s?lation, and economic dislocation. in addition to these, poverty, landlessness, homelessness, malnutr non etc. endure serious deterioration of their health. according to census , there are million women are widowed and one fourth live in urban areas. there is a noticeable increase of urban widows from the previous census (almost half). the paper examines the type of disability and chronic ailment borne among elderly widows ( years and above). fifty second round of national sample survey aske~ the individuals three sets of questions regarding their health: their status of health, whether they are physically poster sessions v immobile, and whether or not they have had any specific chronic illnesses. although health infrastruc- · ble ·n urban setting in india as compared to rural counterpart, prevalence of tures are arge y ava a . . . . . h · · · h h"gher "n urban areas analysis shows omt problems m old age qmte common c romc ness is muc • . . and nearly percent elderly widows are suffering from this ail'. ent in urban areas. one-fifth of widows are suffering from high/low bp. heart disease, diabetes and urinary problems are much ~ore pre~alent in urban areas though disabilities is comparatively lower in urban areas. however, the d~fference is not statistically significant. disability with respect to vision is more pronounced and one third_ of the total respondents have problems regarding eyesight. one fifths ofdderly widows are _ha.rd of hearing. though disability increases with age, similar trend is not observed with respect to chr~mc illness. the percepnon of self-health among elderly becomes poorer as their age increases. the perceived health status need not be always corrected to objective indicators of health. it is noted that around per~en~ of those perceived their health as "excellenr" or "very good" are found to be suffering from chrome disease of omts and percent have visual disability. to conclude an elderly widow living in urban areas have similar health problems as she jives in rural areas. this can be easily explained, as they were not made aware to seek treatment from health facility. in addition, the study shows that the economic conditions are deterrent factors for their illness. it is essential that intervention should be taken up improving their economic conditions so that wellbeing of this most vulnerable group of the society can be taken care of. heart failure is a disease that affects nearly million people world wide. the united states alone accounts for one third of this population. blacks are stricken with heart failure twice as often as whites. men are more likely to develop chf than women, however since the majority of the chf population are seniors, there are actually more women than men. congestive heart failure (chf) has become a pandemic. as the baby boomer generation ages, the number of chf cases will rise dramatically. (young, j. & mills, r., ). after the age of , each proceeding decade doubles the incidence level of chf. the average person has a in chance of developing heart failure within their lifespan according to the framingham study (nih.gov). individuals aging or older compose over half of the entire documented heart failure population. in this age group, chf is the leading cause of hospitalization. many patients are continuously readmitted. it is estimated that the chf population will increase by one million within the next years. mortality was at % for a two year period and % for five years (young, j. & mills, r., ). data from: aha as technology evolves, the understanding of the nature of heart failure has become clearer. in the beginning of the th century heart failure was diagnosed as a condition that presented with edema (swelling) in the extremities caused by water retention. treatment in the beginning of the past cenrury was limited to abdominal drainage and diuretics. the discovery of the heart's insufficient pumping ability in heart failure patients lead to new surgeries and devices such as heart transplants and ventricular assist devices (bridge until transplant is available). ventricular hypertrophy often occurs before the development of heart failure. hypertrophy is the term given for cardiac remodeling. cardiac remodeling also includes chamber dilation (young, j. & mills, r., ) . chf financial burden the us healthcare financing administration has ranked chf as the highest cost illness in the diagnose-related area. direct costs related to chf in the us for were nearly $ billion. these costs included hospital admissions, physician fees, home health aids and medications. indirect costs were over $ billion in . loss of jobs or death due to chf was the criteria for this category (young, j. & mills, r., ). . introduction: the injection drug user quality of life scale (iduqol) is a relatively new scale ~es gned to capture the unique and individual circumstances that determine quality of life among injection drug users (idus). the life areas comprising the instrument were based on the research literature an~ ~ocus group discussions with idus. the purpose of the present study was to evaluate the content validity of t.h~ iduqol using judgmental methods based on subject matter experts' (smes) ratings. content vah~ ty refers to the de~ee to which elements of an assessment tool are representative of the construct of interest and appropnate for a given population. methods: data were obtained from six smes, from the field of idu research and practice, who ~ere. asked t.o evaluate various aspects of the iduqol, including the title of the instrument, administraon instruchons, clarity of the names and descriptions of each life area, response format, scoring instruc-no~s and examples, record form and whether each life area should be included in the instrument. sme ratings were made using either or point scales. sm es were also given the opportunity to comment on poster sessions v each section and to suggest whether important life areas had been overlooked, were redundant, not relevant, or in need of revision. (cvi) and the ~v.erage ~eviation index (ad) were used to evaluate smes' agreement on ratings of the content vahd ty vanables. both measures provided support for the content validity of various aspects of the iduqol, although results from the stricter ad index noted some areas of disagreement, including the description of particular life areas (e.g., being useful, drugs, sex), the inclusion of some life areas (e.g., drug treatment, education, independence and free choice), and the ease of the scoring instructions. the findings from this study provide (a) content validity evidence to support the use of the iduqol as well as (b) recommendations to suengthen both the instrument (e.g., improved descriptions for some items) and the accompanying administration and scoring manual (e.g., an easier scoring template). changes made to the instrument and its manual make the iduqol even easier for researchers, practitioners, and program evaluators to use as a way of assessing, and tracking changes over time or as a result of interventions in, quality of life in injection drug users. introduction: strict adherence to prescribed regimens is required to derive maximal benefit from highly active antireuoviral therapy (haart) in persons living with hiv/aids (phas). adherence is a key determinant of the degree and durability of viral suppression. adherence is also essential in reducing the spread of hiv and ensuring that today's treatments remain effective for as long as possible. the objective of this study is to conduct a systematic review of the research literature on the effectiveness of education and patient support strategies for improving adherence to haart. methods: a systematic search of the core databases was performed from january until may . randomized controlled trials examining the effectiveness of education and patient support interventions to improve the adherence to haart were considered for inclusion. only those studies that measured adherence at a minimum of six weeks were included. study selection, quality assessments, and data abstraction were performed independently by two reviewers. results: study heterogeneity with respect to differing populations, interventions, outcomes, and length of follow-up did not allow for meta-analysis. we included studies involving , ph as. sample sizes ranged from to . study duration ranged from a single session to a variable number of sessions delivered over one year. many of the interventions involved the provision of an educational component to improve adherence and often addressed strategies to overcome barriers to adherence and the development of problem-solving skills. they ranged from simple interventions (e.g., the provision of reminder devices) to complex interventions (e.g., cognitive-behavioural therapy delivered by licensed psychologists). eleven of the studies demonstrated a statistically significant advantage associated with the described adherence intervention. the advantage associated with adherence outcomes does not seem to translate into the more clinically relevant outcome of viral suppression. only out of studies that reported virological or immunological results found a significant effect associated with the intervention. the studies had several methodological shortcomings. conclusions: there is a need for standardization and methodological rigour in the conduct of adherence trials. some interventions may have a significant impact on improving adherence. further research is required before any specific adherence improving strategy can confidently be incorporated into standard clinical practice. focus groups were used to collect data from a purposive sample of treatmentexperienced participants. focus group data were analyzed using a grou~ded t~eory appr~ach. i:ne themes identified from the interviews were used to identify the effects of ant rerrov rals on quality of hfe. the content of the mos-hiv was appraised against the themes identified from our analysis. participants also completed the mos-hiv survey and were asked whether the survey covered all important aspects of quality of life on antiretroviral medications. results: five key informant interviews and five focus groups with participants were used to identify effects on quality of life that are not directly ~aptu~ed by_ the mos-hiv health survey. our~~ showed that our participants described quality of hfe as mvol~mg_ a set of ~rsonal trad~ffs ~stay alive. in most cases, worsened quality of life was traded-off for gams ~ longevlty from ~~canon use. these eff~'ts or tradeoffs included: ( ) downstream consequences of side effects and toxlanes; ( ) loss of lrufe. pende~t decision-making privileges, ( ) having to choose drugs over ~areer; (~)burden of medication-taking responsibilities; and ( ) living life under a pretense and havmg to hide-the net effect of the tradeoffs, or "prices" to pay led to what was described as "longevity with hn without hope and future~. conclusion: our study highlights five major themes summarizing the impact of haart on quality on life, and suggests that currently used scales for measuring quality of life do not a~atd~ cap~e these findings and the associated consequences. the conceptual framework for measuring quality of bfe in hiv should be reconsidered in order to better capture the important effects of the medications on quality of life. this may involve widening the boundaries of the definition of health-related quality oflife to include aspects such as finances, employment, and housing. we should further consider the development of a haart adverse effect specific instrument, using a broad definition of adverse effect in order to capture all types of adverse impacts of hiv treatments on quality of life. introduction: measles (rubeola) is the most contagious vaccine preventable disease of humans. while cases of measles are uncommon in canada today, the disease continues to be a leading cause of morbidity and death in the developing world. as a result of human migration, measles cases still occur in canada, primari~ among immigrants, returning travelers, and other susceptible groups. canada's national advisory council on immunizations (naci) recommends that immigrants without records of measles immunization be considered for vac:cination since these individuals may not have been appropriately vaccinated in their native country. on rhe other hand, natural immunity to measles in immigrants is likely to be high given the high incidence of disease in developing parts of rhe world. thus it remains unclear if the most efficient strategy to achieve high levels of measles immunity in immigrants should entail initial serologic screening followed by vaccination of susceptible individuals or preemptive vaccination of all persons lacking immunization records. understanding the epidemiology of measles immunity in immigrant populations could help guide such decisions. . methods: we identified adults, years of age or older, who were screened for serologtc immunity to measles as part of a recently developed screening protocol at a downtown toronto community health centre. we subsequently determined if these individuals had any immunization records from their native country or from within canada. we then examined the relationship between several demographic factors and immunity to measles. results: % of immigrants had no prior immunization records. overall, % of the immigrants rested for immunity to measles were found to be immune; % of those under the age of , % of those between and years of age, % of those between and years of age, and % of those years of age or older. gender, education status, household income, and immigration status were nor ~ssoc ated wirh immunity to measles. immunity to measles was lowest among immigrants from eastern europe ( ~%), whil~ immigrants from other regions of the globe had greater than % immunity. c~lusrons: immigrants and refugees appear to have reasonably high levels of immunity to mea· sics, possibly related to natural infection wirh the measles virus. immigrants from eastern europe appear to have slightly. lower l~vel~ of immunity to the measles virus. universal screening for immunity to meales or preemptive vac:cmauon may both be inefficient public health strategies, however further research is needed to corroborate these findings. nancy r~ss, stephane tremblay, saeeda khan, daniel crouse, mark tremblay, and jean-marie berrhelor o~ve: the speed of the rise in obesity in places like canada suggests that rather than a shift in the gcncnc_ com~sirion of the population, the root of the obesity pandemic is an environment that suprrs ~besity. this paper examines the influence of neighbourhood and metropolitan characteristics. bour~lts:. while accounting. for individual socio-demographics and behaviours, residents of neighs with a large proportmn of poorly educated individuals had higher bmis than those living in poster sessions v neighbourhoods with more highly educated individuals (p <. ). residing in a neighbourhood with a high proportion of recent immigrants was associated with lower bmi for men (p<. ), but not women. neighbourhood dwelling density, a proxy for walkability, was not associated with bm! for either sex. metropolitan sprawl was associated with higher male bmi (p=. ) but the effect was negligible for women (p=. ). bmi was significantly lower for women (p<. ) living in a city in the province of quebec, even after accounting for the influence of individual and neighbourhood covariates. conclusions: bm! was strongly patterned by individual-level social position in urban canada. the incremental influence on bmi of neighbourhood related to the neighbourhood's social conditions and not to their physical form. metropolitan sprawl was associated with higher bm! for men, a group with longer car-dependent commutes than women. the findings suggest that both individuals and their environments (both social and physical) influence the distribution of bmi in urban populations. introduction: urban environments have been linked to a range of human health issues. in singapore, prevalence of end stage renal disease (esrd) is predicted to rise ( in to in , kidney international, vol. , . the clinical and economic burden of esrd has promoted development of strategies aimed at preventing the development and progression of chronic kidney disease. these include population based screening programs such as the national kidney foundation, sin-gapore\'s (nkfs) "partnership for prevention."the program, aims to reduce incidence of esrd through comprehensive intervention and screening for early detection of urinary abnormalities, blood pressure (bp), and random blood glucose (rbg). objective of this study is to examine gender, race and age wise prevalence of elevated bp, rbg and proteinuria. methodology: this current analysis includes , subjects, age to years, who underwent screening during september and december . participants were asked to give demographic information and the history of diseases. tests were given to get clinical information such as proteinuria, blood glucose, sbp, and dbp. blood pressure abnormalities were defined according to ]nc vi criteria. proteinuria was defined as the presence of plus or greater protein (equivalent to> mg/di) on dipstick analysis. results: there were , ( . %) males. racial distribution was chinese ( . % ), malay ( . % ), indians ( . %) and others ( . % ).among participants, who were apparently "healthy" (asymptomatic and without history of dm, ht, or kd), gender and race wise % prevalence of elevated (bp> / ), rbg (> mg/di) and positive urine dipstick for protein was as follows male: ( . ; . ; . ) female:( . ; . ; . ) chinese:( . ; . ; ) malay: ( . ; . ; . ) indian:( . ; . ; . ) others: ( . ; . ; . ) total:(l . , . , . ). percentage of participants with more than one abnormality were as follows. those with bp> / mmhg, % also had rbg> mg/dl and . % had proteinuria> i. those with rbg> mgldl, % also had proteinuria> and % had bp> / mmhg. those with proteinuria> , % also had rbg> mg/dl, and % had bp> / mmhg. conclusion: we conclude that sub clinical abnormalities in urinalysis, bp and rbg readings are prevalent across all genders and racial groups in the adult population. the overlap of abnormalities, point towards the high risk for esrd as well as cardiovascular disease. this indicates the urgent need for population based programs aimed at creating awareness, and initiatives to control and retard progression of disease. introduction: various theories have been proposed that link differential psychological vulnerability to health outcomes, including developmental theories about attachment, separation, and the formation of psychopathology. research in the area of psychosomatic medicine suggests an association between attachment style and physical illness, with stress as a mediator. there are two main hypotheses explored in the present study: ( t) that individuals living with hiv who were upsychologically vulne~able" at study entry would be more likely to experience symptoms of depression, anxiety and phys ca! illness over. the course of the -month study period; and ( ) life stressors and social support would mediate the relat nship between psychological vulnerability and the psychological ~nd physical outcomes. . (rsles), state-trait anxiety inventory (stai), beck depr~ssi~n lnvento~ (bdi), and~ _ -item pbys~i symptoms inventory. we characterized participants as havmg psychological vulnerability and low resilience" as scoring above on the raas (insecure attachment) or above on the das (negative expectations about oneself). . . . . . " . . ,, . results: at baseline, % of parnc pants were classified as havmg low resilience. focusmg on anxiety, the average cumulative stai score of the low-resilience group was significandy hi~e~ than that of the high-resilience group ( . sd= . versus . sd= . ; f(l, )= . , p <. ). similar results were obtained for bdi and physical symptoms (f( , )= . , p<. and f( , )= . , p<. , respec· tively). after controlling for resilience, the effects of variance in life stres".°rs averaged over time wa~ a_sig· nificant predictor of depressive and physical symptoms, but not of anxiety. ho~e_ver, these assooan~s became non-significant when four participants with high values were removed. s id larly, after controlling for resilience, the effects of variance in social support averaged over time became insignificant. conclusion: not only did "low resilience" predict poor psychological and physical outcomes, it was also predictive of life events and social support; that is, individuals who were low in resilience were more likely to experience more life events and poorer social support than individuals who were resilient. for individuals with vulnerability to physical, psychological, and social outcomes, there is need to develop and test interventions to improve health outcomes in this group. rajat kapoor, ruby gupta, and jugal kishore introduction: young people in india represent almost one-fourth of the total population. they face significant risks related to sexual and reproductive health. many lack the information and skills neces· sary to make informed sexual and reproductive health choices. objective: to study the level of awareness about contraceptives among youth residing in urban and rural areas of delhi. method: a sample of youths was selected from barwala (rural; n= ) and balmiki basti (urban slums; n= ) the field practice areas of the department of community medicine, maulana azad medical college, in delhi. a pre-tested questionnaire was used to collect the information. when/(calen· dar time), by , fisher exact and t were appliedxwhom (authors?). statistical tests such as as appropriate. result: nearly out of ( . %) youth had heard of at least one type of contraceptive and majority ( . %) had heard about condoms. however, awareness regarding usage of contraceptives was as low as . % for terminal methods to . % for condom. condom was the best technique before and after marriage and also after childbirth. the difference in rural and urban groups was statistically signif· icant (p=. , give confidence interval too, if you provide the exact p value). youth knew that contra· ceptives were easily available ( %), mainly at dispensary ( . %) and chemist shops ( . %). only . % knew about emergency contraception. only advantage of contraceptives cited was population con· trol ( . %); however, . % believed that they could also control hiv transmission. awareness of side effects was poor among both the groups but the differences were statistically significant for pills (p= . ). media was the main source of information ( %). majority of youth was willing to discuss a~ut contraceptive with their spouse ( . %), but not with others. . % youth believed that people in their age group use contraceptives. % of youth accepted that they had used contraceptives at least once. % felt children in family is appropriate, but only . % believed in year spacing. . conclusion: awareness about contraceptives is vital for youth to protect their sexual and reproduc· tive health .. knowledge about terminal methods, emergency contraception, and side effects of various contraceptives need to be strengthened in mass media and contraceptive awareness campaigns. mdbot:ls: elderly aged + were interviewed in poor communities in beirut the capital of f:ebanon, ~e of which is a palestinia~. refugee camp. depression was assessed using the i -item geriat· nc depressi~n score (~l?s- ). specific q~estions relating to the aspects of religiosity were asked as well as questions perta rung to demographic, psychosocial and health-related variables. results: depression was prevalent in % of the interviewed elderly with the highest proportion being in the palestinian refugee camp ( %). mosque attendance significantly reduced the odds of being depressed only for the palestinian respondents. depression was further associated, in particular communities, with low satisfaction with income, functional disability, and illness during last year. condiuion: religious practice, which was only related to depression among the refugee population, is discussed as more of an indicator of social cohesion, solidarity than an aspect of religiosity. furthermore, it has been suggested that minority groups rely on religious stratagems to cope with their pain more than other groups. implications of findings are discussed with particular relevance to the populations studied. nearly thirty percent of india's population lives in urban areas. the outcome of urbanization has resulted in rapid growth of urban slums. in a mega-city chennai, the slum populations ( . percent) face greater health hazards due to overcrowding, poor sanitation, lack of access to safe drinking water and environmental pollution. amongst the slum population the health of women and children are most neglected, resulting in burden of both communicable and non-communicable diseases. the focus of the paper is to present the epidemiology profile of children (below years) in slums of chennai, their health status, hygiene and nutritional factors, the social response to health, the trends in child health and urbanization over a decade, the health accessibility factors, the role of gender in health care and assessment impact of health education to children. the available data prove that child health in slums is worse than rural areas. though the slum population is decreasing there is a need to explore the program intervention and carry out surveys for collecting data on some specific health implications of the slum children. objective: during the summer of there was a heat wave in central europe, producing an excess number of deaths in many countries including spain. the city of barcelona was one of the places in spain where temperatures often surpassed the excess heat threshold related with an increase in mortality. the objective of the study was to determine whether the excess of mortality which occurred in barcelona was dependent on age, gender or educational level, important but often neglected dimensions of heat wave-related studies. methods: barcelona, the second largest city in spain ( , , inhabitants in ) , is located on the north eastern coast. we included all deaths of residents of barcelona older than years that occurred in the city during the months of june, july and august of and also during the same months during the preceding years. all the analyses were performed for each sex separately. the daily number of deaths in the year was compared with the mean daily number of deaths for the period - for each educational level. poisson regression models were fitted to obtain the rr of death in with respect to the period - for each educational level and age group. results: the excess of mortality during that summer was more important for women than for men and among older ages. although the increase was observed in all educational groups, in some age-groups the increase was larger for people with less than primary education. for example, for women in the group aged - , the rr of dying for compared to - for women with no education was . ( %ci: . - - ) and for women with primary education or higher was . ( %ci: . - . ). when we consider the number of excess deaths, for total mortality (>= years) the excess numbers were higher for those with no education ( . for women and . for men) and those with less than primary education ( . for women and - for men) than those with more than primary edm:ation ( . for women and - . for men). conclusion: age, gender and educational level were important in the barcelona heat wave. it is necessary to implement response plans to reduce heat morbidity and mortality. policies should he addressed to all population but also focusing particularly to the oldest population of low educational level. introduction: recently there has been much public discourse on homelessness and its imp~ct on health. measures have intensified to get people off the street into permanent housing. for maximum v poster sessions success it is important to first determine the needs of those to be housed. their views on housing and support requirements have to be considered, as th~y ar~ the ones affected. as few res.earch studies mclude the perspectives of homeless people themselves, httle is known on ho~ they e~penence the mpacrs on their health and what kinds of supports they believe they need to obtain housing and stay housed. the purpose of this study was to add the perspectives of homeless people to the discourse, based in the assumption that they are the experts on their own situations and needs. housing is seen as a major deter· minant of health. the research questions were: what are the effects of homelessness on health? what kind of supports are needed for homeless people to get off the street? both questions sought the views of homeless individuals on these issues. methods: this study is qualitative, descriptive, exploratory. semi-structured interviews were conducted with homeless persons on street corners, in parks and drop-ins. subsequently a thematic analysis was carried out on the data. results: the findings show that individuals' experiences of homelessness deeply affect their health. apart from physical impacts all talked about how their emotional health and self-esteem are affected. the system itself, rather than being useful, was often perceived as disabling and dehumanizing, resulting in hopelessness and resignation to life on the street. neither welfare nor minimum wage jobs are sufficient to live and pay rent. educational upgrading and job training, rather than enforced idleness, are desired by most initially. in general, the longer persons were homeless, the more they fell into patterned cycles of shelter /street life, temporary employment /unemployment, sometimes addictions and often unsuccessful housing episodes. conclusions: participants believe that resources should be put into training and education for acquisition of job skills and confidence to avoid homelessness or minimize its duration. to afford housing low-income people and welfare recipients need subsidies. early interventions, 'housing first', more humane and efficient processes for negotiating the welfare system, respectful treatment by service providers and some extra financial support in crisis initially, were suggested as helpful for avoiding homelessness altogether or helping most homeless people to leave the street. this study is a national homelessness initiative funded analysis examining the experiences and perceptions of street youth vis-a-vis their health/wellness status. through in-depth interviews with street youth in halifax, montreal, toronto, calgary, ottawa and vancouver, this paper explores healthy and not-so healthy practices of young people living on the street. qualitative interviews with health/ social service providers complement the analysis. more specifically, the investigation uncovers how street youth understand health and wellness; how they define good and bad health; and their experiences in accessing diverse health services. findings suggest that living on the street impacts physical, emotional and spiritual well·being, leading to cycles of despair, anger and helplessness. the majority of street youth services act as "brokers" for young people who desire health care services yet refuse to approach formal heal~h care organizational structures. as such, this study also provides case examples of promising youth services across canada who are emerging as critical spaces for street youth to heal from the ravages of ~treet cultur~. as young people increasingly make up a substantial proportion of the homeless population in canada, it becomes urgent to explore the multiple ways in which we can support them to regain a sense of wellbeing and "citizenship." p - (c) health and livelihood implications of marginalization of slum dwellers in provision of water and sanitation services in nairobi city elizabeth kimani, eliya zulu, and chi-chi undie . ~ntrodfldion: un-habitat estimates that % of urban residents in kenya live in slums; yet due to their illegal status, they are not provided with basic services such as water sanitation and health care. ~nseque~tly, the services are provided by vendors who typically provide' poor services at exorbitant prices .. this paper investigates how the inequality in provision of basic services affects health and livelihood circumstances of the poor residents of nairobi slums . . methods: this study uses qualitative and quantitative data collected through the ongoing longitudmal .health and demographic study conducted by the african population and health research center m slum communities in n ·rob" w d · · · · ai . e use escnpnve analytical and qualitative techmques to assess h~w concerns relating to water supply and environmental sanitation services rank among the c~mmumty's general and health needs/concerns, and how this context affect their health and livelihood circumstances. results: water ( %) and sanitation ( %) were the most commonly reported health needs and also key among general needs (after unemployment) among slum dwellers. water and sanitation services are mainly provided by exploitative vendors who operate without any regulatory mechanism and charge exorbitantly for their poor services. for instance slum residents pay about times more for water than non-slum households. water supply is irregular and residents often go for a week without water; prices are hiked and hygiene is compromised during such shortages. most houses do not have toilets and residents have to use commercial toilets or adopt unorthodox means such as disposing of their excreta in the nearby bushes or plastic bags that they throw in the open. as a direct result of the poor environmental conditions and inaccessible health services, slum residents are not only sicker, they are also less likely to utilise health services and consequently, more likely to die than non-slum residents. for instance, the prevalence of diarrhoea among children in the slums was % compared to % in nairobi as a whole and % in rural areas, while under-five mortality rates were / , / and / respectively. the results demonstrate the need for change in governments' policies that deprive the rapidly expanding urban poor population of basic services and regulatory mechanisms that would protect them from exploitation. the poor environmental sanitation and lack of basic services compound slum residents' poverty since they pay much more for the relatively poor services than their non-slum counterparts, and also increase their vulnerability to infectious diseases and mortality. since iepas've been working in harm reduction becoming the pioneer in latin america that brought this methodology for brazil. nowadays the main goal is to expand this strategy in the region and strive to change the drug policy in brazil. in this way harm reduction: health and citizenship program work in two areas to promote the citizenship of !du and for people living with hiv/aids offering law assistance for this population and outreach work for needle exchange to reduce damages and dissemination of hiv/aids/hepatit is. the methodology used in outreach work is peer education, needle exchange, condoms and folders distribution to reduce damages and the dissemination of diseases like hiv/aids/hepatitis besides counseling to search for basic health and rights are activities in this program. law attendance for the target population at iepas headquarters every week in order to provide law assistance that includes only supply people with correct law information or file a lawsuit. presentations in harm reduction and drug policy to expand these subjects for police chiefs and governmental in the last year attended !du and nidu reached and . needles and syringes exchanged. in law assistance ( people living with aids, drug users, inject drug users, were not in profile) people attended. lawsuits filed lawsuits in current activity. broadcasting of the harm reduction strategies by the press helps to move the public opinion, gather supporters and diminish controversies regarding such actions. a majority number of police officer doesn't know the existence of this policy. it's still polemic discuss this subject in this part of population. women remain one of the most under seviced segments of the nigerian populationand a focus on their health and other needs is of special importance.the singular focus of the nigerian family welfare program is mostly on demographic targets by seeking to increase contraceptive prevalence.this has meant the neglect of many areas of of women's reproductive health. reproductive health is affected by a variety of socio-cultural and biological factors on on e hand and the quality of the service delivery system and its responsiveness on the other.a woman's based approach is one which responds to the needs of the adult woman and adolescent girls in a culturally sensitive manner.women's unequal access to resources including health care is well known in nigeria in which stark gender disparities are a reality .maternal health activities are unbalanced,focusi ng on immunisation and provision of iron and folic acid,rather than on sustained care of women or on the detection and referral of high risk cases. a cross-sectional study of a municipal government -owned hospitalfrom each of the geo-political regions in igeria was carried out (atotal of ce~ters) .. as _part ~f t~e re.search, the h~spital records were uesd as a background in addition to a -week mtens ve mvesuganon m the obstemc and gynecology departments. . . . : little is known for example of the extent of gynecological morbtdtty among women; the little known suggest that teh majority suffer from one or more reproductive tr~ct infect~ons. although abortion is widespread, it continues to be performed under ilegal and unsafe condmons. with the growing v poster sessions hiv pandemic, while high riskgroups such ascomn;iercial sex workers and their clients have been studied, little has been accomplished in the large populat ns, and particularly among women, regardmgstd an hiv education. . . conclusions: programs of various governmentalor non-governmental agen,c es to mvolve strategies to broaden the narrow focus of services, and more importan~, to put wo~en s reproducnve health services and information needs in the forefront are urgently required. there is a n~d to reonent commuication and education activities to incorprate a wider interpretation of reproducnve health, to focus on the varying information needs of women, men, and youth and to the media most suitable to convey information to these diverse groups on reproductive health. introduction: it is estimated that there are - youths living on the streets, on their own with the assistance of social services or in poverty with a parent in ottawa. this population is under-serviced in many areas including health care. many of these adolescents are uncomfortable or unable to access the health care system through conventional methods and have been treated in walk-in clinics and emergency rooms without ongoing follow up. in march , the ontario government provided the ct lamont institute with a grant to open an interdisciplinary and teaching medical/dental clinic for street youth in a drop-in center in downtown ottawa. bringing community organizations together to provide primary medical care and dental hygiene to the streetyouths of ottawa ages - , it is staffed by a family physician, family medicine residents, a nurse practitioner, public health nurses, a dental hygienist, dental hygiene students and a chiropodist who link to social services already provided at the centre including housing, life skills programs and counselling. project objectives: . to improve the health of high risk youth by providing accessible, coordinated, comprehensive health and dental care to vulnerable adolescents. . to model and teach interdisciplinary adolescent care to undergraduate medical students, family medicine residents and dental hygiene students. methods: non-randomized, mixed method design involving a process and impact evaluation. data collection-qualitative:a) semi-structured interviews b) focus groups with youth quantitative:a) electronic medical records for months b) records (budget, photos, project information). results: in progress-results from first months available in august . early results suggest that locating the clinic in a safe and familiar environment is a key factor in attracting the over youths the clinic has seen to date. other findings include the prevalence of preventative interventions including vaccinations, std testing and prenatal care. the poster presentation will present these and other impacts that the clinic has had on the health of the youth in the first year of the study. conclusions: ) the clinic has improved the health of ottawa streetyouth and will continue beyond the initial pilot project phase. ) this project demonstrates that with strong community partnerships, it is possible meet make healthcare more accessible for urban youth. right to health care campaign by s.j.chander, community health cell, bangalore, india. introduction: the people's health movement in india launched a campaign known as 'right to health care' during the silver jubilee year of the alma ata declaration of 'health for all' by ad in collahoration with the national human rights commission (nhrc). the aim of the campaign was to establish the 'right to health care' as a basic human right and to address structural deficiencies in the pubic health care system and unregulated private sector . . methods: as part of the campaign a public hearing was organized in a slum in bangalore. former chairman of the nhrc chaired the hearing panel, consisting of a senior health official and other eminent people in the city. detailed documentation of individual case studies on 'denial of access to health care' in different parts of the city was carried out using a specific format. the focus was on cases where denial of health services has led to loss of life, physical damage or severe financial losses to the patient. results: _fourte_en people, except one who had accessed a private clinic, presented their testimonies of their experiences m accessing the public health care services in government health centres. all the people, e_xcept_ one person who spontaneously shared her testimony, were identified by the organizations worki_ng with the slum dwellers. corruption and ill treatment were the main issues of concern to the people. five of the fourteen testimonies presented resulted in death due to negligence. the public health cen· n:s not only demand money for the supposedly free services but also ill-treats them with verbal abuse. five of these fourteen case studies were presented before the national human right commission. the poster sessions v nhrc has asked the government health officials to look into the cases that were presented and to rectify the anomalies in the system. as a result of the public hearing held in the slum, the nhrc identified urban health as one of key areas for focus during the national public hearing. cond#sion: a campaign is necessary to check the corrupted public health care system and a covetous private health care system. it helps people to understand the structure and functioning of public health care system and to assert their right to assess heath care. the public hearings or people's tribunals held during the campaign are an instrument in making the public health system accountable. ps- (a) violence among women who inject drugs nadia fairbairn, jo-anne stoltz, evan wood, kathy li, julio montaner, and thomas kerr background/object ives: violence is a major cause of morbidity and mortality among women living in urban settings. though it is widely recognized that violence is endemic to inner-city illicit drug markets, little is known about violence experienced by women injection drug users (!du). therefore, the present analyses were conducted to evaluate the prevalence of, and characteristics associated with, experiencing violence among a cohort of female idu in vancouver. methods: we evaluated factors associated with violence among female participants enrolled in the vancouver injection drug user study (vidus) using univariate analyses. we also examined self-reported relationships with the perpetrator of the attack and the nature of the violent attack. results: of the active iou followed between december , and may , , ( . %) had experienced violence during the last six months. variables positively associated with experiencing violence included: homelessness (or= . , % ci: . - . , p < . ), public injecting (or= . , % ci: . - . , p < . ), frequent crack use (or= . , % ci: . - . , p < . ), recent incarceration (or = . , % cl: . - . , p < . ), receiving help injecting (or = . , % cl: . - . , p < . ), shooting gallery attendance (or = . , % ci: . - . , p < . ), sex trade work (or = . , % cl: . - . , p < . ), frequent heroin injection (or= . , % cl: . - . , p < . ), and residence in the downtown eastside (odds ratio [or] = . , % ci: . - . , p < . ). variables negatively associated with experiencing violence included: being married or common-law (or = . . % ci: . - . , p < . ) and being in methadone treatment (or = . , % ci: . - . , p < . ). the most common perpetrators of the attack were acquaintances ( . %), strangers ( . %), police ( . %), or dealers ( . %). attacks were most frequently in the form of beatings ( . %), robberies ( . %), and assault with a weapon ( . %). conclusion: violence was a common experience among women !du in this cohort. being the victim of violence was associated with various factors, including homelessness and public injecting. these findings indicate the need for targeted prevention and support services, such as supportive housing programs and safer injection facilities, for women iou. introduction: although research on determinants of tobacco use among arab youth has been carried out at several ecologic levels, such research has included conceptual models and has compared the two different types of tobacco that are most commonly used among the lebanese youth, namely cigarette and argileh. this study uses the ecological model to investigate differences between the genders as related to the determinants of both cigarette and argileh use among youth. methodology: quantitative data was collected from youth in economically disadvantaged urban communities in beirut, the capital of lebanon. results: the results indicated that there are differences by gender at a variety of ecological levels of influence on smoking behavior. for cigarettes, gender differences were found in knowledge, peer, family, and community influences. for argileh, gender differences were found at the peer, family, and community l.evels. the differential prevalence of cigarette and argileh smoking between boys and girls s therefore understandable and partially explained by the variation in the interpersonal and community envi.ronment which surrounds them. interventions therefore need to be tailored to the specific needs of boys and girls. introduction: the objective of this study was to assess the relationship between parents' employment status and children' health among professional immigrant families in vancouver. our target communmes v poster sessions included immigrants from five ethnicity groups: south korean, indian, chine~e, ~ussian, and irani~ with professional degrees (i.e., mds, lawyers, engineers, ma?~ger~, and uru~ers ty professors) w h no relevant job to their professions and those who had been hvmg m the studied area at least for months. methodology: the participants were recruited by collaboration from three local community agencies and were interviewed individually during the fall of . ra#lts: totally, complete interviews were analyzed: from south-east asia, from south asia, from russia and other eastern europe. overall, . % were employed, . % were underemployed, % indicated they were unemployed. overall, . % were not satisfied with their current job. russians and other eastern europeans were most likely satisfied with their current job, while south-east asians were most satisfied from their life in canada. about % indicated that their spouses were not satisfied with their life in canada, while % believed that their children are very satisfied from their life in canada. in addition, around % said they were not satisfied from their family relationship in canada. while most of the responders ranked their own and their spouses' health status as either poor or very poor, jut % indicated that their first child's health was very poor. in most cases they ranked their children's health as excellent or very good. the results of this pilot study show that there is a need to create culturally specific child health and behavioral scales when conducting research in immigrant communities. for instance, in many asian cultures, it is customary for a parent either to praise their children profusely, or to condemn them. this cultural practice, called "saving face," can affect research results, as it might have affected the present study. necessary steps, therefore, are needed to revise the current standard health and behavioral scales for further studies by developing a new scale that is more relevant and culturally sensitive to the targeted immigrant families. metboda: database: national health survey (ministry of health www.msc.es). two thousand interviews were performed among madrid population ( . % of the whole); corresponded to older adults ( . % of the . million aged years and over). study sample constitutes . % ( out of ) of those older adults, who live in urban areas. demographic structure (by age and gender) of this population in relation to health services use (medical consultations, dentist visits, emergence services, hospitalisation) was studied using general linear model univariate procedure. a p . ), while age was associated with emergence services use ( % of the population: %, % and % of each age group) and hos~italisation ( % .oft~~ population: %, % and %, of each age ~oup) (p . ) was fou~d with respect to dennst v s ts ( % vs %), medical consultations ( % vs %), and emergence services use ( % vs %), while an association (p= . ) was found according to hospitalisation ( % vs %). age. an~ g~der interaction effect on health services use was not found (p> . ), but a trend towards bosp tal sanon (p= . ) could be considered. concl.uions: demographic structure of urban older adults is associated with two of the four health se~ices use studi~. a relation.ship ber_ween age. and hospital services use (emergence units and hospitalisanon), but not with ~ut-hosp tal sei:vices (medical and dentist consultations), was found. in addition ro age, gender also contnbutes to explam hospitalisation. . sexua experiences. we exammed the prevalence expenences relation to ethnic origin and other sociodemographic variables as wc i as y j die relation between unwanted sexual experiences, depression and agreuion. we did so for boys and prts separately. mdhods: data on unwanted sexual expcric:nces, depressive symptoms (ce.s-d), aggrc:uion (bohi-di and sociodemographic facron were collected by self-report quescionnairc:s administettd to students in the: nd grade (aged - ) of secondary schools in amsterdam, the netherlands. data on the nature ol unwanted sexual experiences were collected during penonal interviews by trained schoolnursn. ltaijtj: overall prevalences of unwanted sexual experiences for boys and girls were . % and . % respectively. unwanted sexual experiences were more often ttported by turkish ( . %), moroc· an ( . %) and surinamese/anrillian boys ( . %) than by dutch boys ( . %). moroccan and turkish girls, however, reported fewer unwanted sexual experiences (respectively . and . %) than durch girls did ( . %). depressive symptoms(or= . , cl= . - . ) covert agression ( r• . , cl• . - . ) and cmrt aggression (or= . , cl• . - . ) were more common in girls with an unwanted sexual experi· met. boys with an unwanted sexual experience reported more depressive symptoms (or= . ; cl• i . .l· . ) and oven agression (or= . , cl= . - . ) . of the reported unwanted sexual experiences rnpec· timy . % and . % were confirmed by male and female adolescents during a personal interview. cond sion: we ..:an conclude that the prevalence of unwanted sexual experiences among turkish and moroccan boys is disturbing. it is possible that unwanted sexual experiences are more reported hy boys who belong to a religion or culture where the virginity of girls is a maner of family honour and talking about sexuality is taboo. more boys than girls did not confirm their initial disdosurc of an lllwalltc:d sexual experience. the low rates of disclosure among boys suggcsu a necd to educ.:atc hcahh care providen and others who work with migrant boys in the recognition and repomng of exu.il ... iction. viramin a aupplc:tmntation i at .h'yo, till far from tafl'eted %. feedinit pracn~:n panku· lerty for new born earn demand lot of educatton ernpha a• cxdu ve hrealt fecdtnit for dnared rcnoj of months was observtd in only .s% of childrrn thoulh colckturm w. givm n rn% of mwly horn ct.ildrm. the proportion of children hclow- waz (malnounshrdl .con" a• h!jh •• . % anj "rt'i· acimy tc.. compared to data. mother's ~alth: from all is womm in ttprod~uvr •ill' poup, % were married and among marned w~ .\ % only w\"rt' u mic wmr cnntr.-:cruve mt h· odl % were married bdorc thc •ar of yean and % had thnr ftnc prcicnancy hcftitt dlt' •icr nf yean. the lt'f'vicn are not uutfactory or they arc adequate but nae unh ed opumally. of thote' l'h mothen who had deliverrd in last one year, % had nailed ntmaral eum nat on ira" oncc, .~o-... bad matt rhan four ttmn and ma ortty had heir tetanus toxotd tnin,"t or"'" nlht "'"'"· ljn r ned rn· win ronductrd . % dchvcnn and % had home deh\'t'oc'i. ~md~: the tervtcn unbud or u led are !tu than dnarame. the wr· l'kft provided are inadequate and on dechm reprcwnttng a looun t ~p of h hnto good coytti\#' ol wr· ncn. l!.ckground chanpng pnoriry cannoc be ruled out u °"" of thc coatnbutory bc f. ps-ii ia) dcpn:wioa aad anuccy ia mip'mu ia awccr._ many de wn, witco tui~bmjer. jack dekker, aart·jan lttkman, wim gonmc:n. and amoud verhoeff ~ a dutch commumry-bucd icudy thawed -moarh•·prc:yalm«i al . ' . kw anx · ay daorden and . % foi' dqrasion m anmttdam. nm .. p tficantly hlllhn than dwwhrft .. dw ~thew diffamca m pttyalcnca att probably rdarcd to tlk' largr populanoa of napaan ..\mturdam. <turkish %, moroccan %, and surinam % . lndttd. ic'wt'll ltudla hatt ~ ~ high prevalena rata among migrant poupi in rbe ncdwrlands. howc'ytt au ttlluchn iuffenod from wry low raporne rara, or med screnung talel thac lack a ~y yabdarcd ~ in order to study the prevalence of depression and anxiety, and the (barriers to) use of mental health care among the different ethnic groups the following study was recently conducted: . the study consisted of a two-step approach. the first step was mcl~ded m the ~ h ith survey of (ahs), and consisted of three screening scales for depression and aruaety (klo, g::q- and mhl- ). in this survey all respondents were asked_ permission for~ second app~ :' t consisted of a structured interview containing the cidi for aruaety and depression, and questtollllalres on health care seeking, amongst others. all respondents who gave permission for a second approachwere invited by jetter for a suuctured interview with multilingual interviewers at home at a preset date and time in the following week. . in total, dutch, turkish, moroccan and surinam respondents took part in the ahs and gave permission for a second approach. in the second step, fo~ ~ tur~h, m~roc can surinamese and dutch respondents, information from the extensive interview was available (res~nse rates between and % ). since the data collection was completed only recently (june ), prevalence estimates can be presented at the conference for the first time. we have shown that with this approach it is feasible to achieve an acceptable response rate in a study on mental health among migrants. therefore we expect that this study will provide reli· able estimates of depression and anxiety in the turkish, moroccan and surinam migrants in amstw! ~· for the first time. in addition, insight into mechanisms underlying the differences between and within ethnic groups and into barriers to mental health care will provide pretexts for the improvement of pre· vention and mental health care for migrant groups. this study aimed to determine spatial patterns of mortality and morbidity of five major health problems in an urban environment: homicides, pregnancy among adolescents ((< years old), asthma hospitalization among young children(< years old) and two mosquito-borne diseasesdengue and visceral leishmaniasis, during - . all events were obtained through the city health database and, subsequently, geoproccsscd using the address of residence and the geographical and administrative division of the municipality, composed by unit of planning (up), which in tum were formed, each one, by census tract units. two research questions were investigated: are there spatial patterns to the events dis· tribution, and moreover, are these patterns overlapping across space? we use thematic maps, index of comparative mortality/morbidity by up and the overlapped rank of the th worse up rates for each event. a spatial pattern of high rates of homicides, proportion of young mothers and hospitalization of asthma were overlapping in areas social and economically disadvantaged. for mosquito-borne diseases, high rates with great dispersion were found in unprivileged areas in contrast with very low rares among privileged ones. these results pointed toward a coexistence of heavier burden of diseases for those living in areas of the city where misery, poverty, lack of political public health may be modulating social health problems. a possible environmental intervention in one mosquito•bome disease might be playing a role in the occurrence of other. although with limitations, this study may provide useful information for a joint urban planning under the public perspective, articulated for use in health impact assessment. jalil safaei bdrod#aion: the association of socioeconomic status (ses), usually measured by income, and health status is an established result in bcalth studies. the poor and low income individuals have lower health sta· tus then_ those with higher incomes. in general. such finding has been usually obtained from sample surveys on speafic populations. a problem with many sample survey$ is that their results are not comparable aaoss ~ndaries as they may use different sampling methods, ask different questions, categorize the answers differently, or define groups differently. moreover, the sample data need to be standardized using the demographic: katurea of a ~ population. this study, however, uses the national population health survey (nphs) cycle public use mictodata files which is based on a common survey template ·~~three~ area in canada, namely montreal, toronto, and vancouver. it also utili .es the built-m stanclatdizaaon of the nphs data which accounts for its complex survey design. . ~:the stu~ usc:s two well-known measures of health inequalitythe relative index of meqaality and die concentranon indexto capture the extent of income related health inequality among poster sessions v urban female and male populations in each of the three metropolitan areas. personal income is classified into ten groups by the nphs with "no income" as the first group and "more than $ , " as the last. health status is measured by three variables -having a chronic condition (chc), self assessed health (sah), and health utility index (hui) -using appropriate indices. alternative formulations are used to calculate the standard deviations of the estimated or calculated measures. the findings of the study suggest that the measured health inequality depends on the health measure used. for chc and hui the measured inequality indices do indicate poorer health for lower income individulas, however, they are not statistically insignificant. health inequalities are more pronounced when health is measured by sah. the results do not support any systematic ranking of the three metropolitan areas in terms of health inequalities. they do not reveal any systematic pattern of inequality between men and women, either. conclusions: despite the use of highly aggregated nphs data, income related health disparities are observed in the three metropolitan areas in canada. this is more the case with self perceived (sah) health. such disparities are preventable and call for broader health policies that address poverty and low income among other social determinants of health. introduction: the analysis of health indicators under the spatial perspective is configured as an important instrument in the detection of intra-urban differentials. this study aimed to examine the spatial distribution of the births occurred in belo horizonte, in , analyzing the presence of spatial clusters of health indicators for newborns (rn) and their mothers, using data from the information system on live birth database (sinasc). method: for each covered area of the basic units of health (ubs), we calculated the proportion of: adolescent mothers, mothers with less than years of schooling, first pregnancy, mothers with four or more pregnancies, dead babies born on previous pregnancies, stillbirths, cesarean section, less than four prenatal care attendance, moderate and severe hypoxemia in the st and th minutes of life, low or very low birth weight. we used empiric bayesian methods for smoothing the estimates. for spatial analysis, the indicators obtained from the global moran (i) index and local indicators of spatial association (lisa) were used. maps were built to allow the visualization of the spatial clusters. in all analysis, significance statistics was considered p~ . . results: a total of , births of residents in belo horizonte were registered in i. the estimated bayesian proportions for the entire municipality was close to the one observed for all variables. analysis using lisa showed the presence of relevant spatial clusters for adolescent and low educated mothers, dead babies form previous pregnancies, cesarean section, low attendance to the prenatal care especially in area with low socio-demographic characteristics. three areas presented consistent clusters, with important spatial auto-correlation for almost all studied indicators. conclusion: the used methodology was configured as a great instrument of detection risk areas where clustering occurs. it can easily be incorporated in any surveillance system as a mechanism for controlling events related to births in the municipality. moreover, it can be applied to discriminate target areas for prompt public health interventions, such as improving health services access and the consolidation of better obstetric practices. introduction: gentrification, the displacement of low income and non-majority people out of longtime neighborhoods and residences is a global phenomenon. it has been identified as occurring in both developed and less developed countries and as inequality persists or increases, many communities are vulnerable to disruption and loss. while there may be some benefits to gentrification, these benefits are less likely to impact those who have been forced to move out of a gentrifying community or those who remain but economically stressed. . . . . this paper lays out a theoretical framework for dent fymg and ~ddressm~. the_ health consequences of gentrification on residents living in a community prior .to o.r durmg gent~ ~ cat. n. by drawing on the literature of housing, sociology, health and urban plannmg, t places genmf catt~n and neighborhood change into the context of other forces affecting th~ .hea.lth of vulnerable populations. it then proposes solutions to prevent or mitigate the impacts of genmf cat on. results: four main categories of consequences potentiallr re~ult from ~entr~fica~~n: !'°°r housing· related issues, spatial effects, mental health impacts and contr bunons to racial ~spanttes m heal~. the housing issues include increased susceptibility to asthma, lead exposure, allergiesl~topy an~. acetdents/ injuries. spatial effects include reduced access to health ~are, reduce~ access to obslttadinonal food sources, decreased physical activity, and increased obesity. the __ pnmary mental health effects_ :ire increased stress increased risk of depression and disruption of trad t onal support networks. in addinon to the above he~lth issues, gentrification has the potential to increase racial disparities in health by reduc· ing access to long term and multi-culturally experienced health care provide~s. conclusions: public health practice provides a framework for addressmg the health consequences of gentrification. in this context primary prevention would involve preventing gentrification in the first place along with a renewed commitment to helping distressed communities a~~ im_proving the quality ~f life for long term residents. the next layer of meeting the challenges of gentrification would be to assjst long rime residents to stay in a community and thus potentially allowing them to participate in the bene~ts of gentrification (such as better public services). only if all these efforts fail -and these other prevennon strategies must be a priority, public policy should then work to help people and instirutions move to other communities through grants and the provision of alternative safe affordable housing and neighborhoods. sarah romans, marsha cohen, and tonia forte lnh'odlletion: there has been sustained interest in urban rural (ur) differences in mental health over the last years of epidemiological research, with most studies reporting higher urban rates of mor· bidity, particularly when psychotic disorders have been studied. most recently, in britain, urban rates of non-psychotic disorder were greater than rural and semi-rural rates, both before and after the more adverse circumstances of urban dwellers were considered (paykel et al ) . surprisingly, there were no ur differences in help seeking. in canada, wang ( ) found greater urban rates for major depression only after he controlled for the confounding effects of race, immigration, employment and marital status, a result reminiscent of work from the us (blazer et ) . rural participants were less likely to have sought help for their mental health problems. in this study, we sought to examine urban/rural differences in rates of depression and help seeking in canada. method; data came from the canadian community health survey . , a community survey conducted by statistics canada of people aged and older, with the total sample size of , respon· dents, % response. analyses used weighted data; differences were assessed by chi-squared. ra.its: bivariate cross-tabulations showed a modest increase in month depression rates for urban ( . %) over rural ( . %, p= . ) dwellers; there were no ur differences when the sample was examined separately by gender and age group ( - , - , - ) . in general, more urban ( . %) than rural people ( . %, p= . ) had sought mental health treatment in the past year. there was no ur difference in helping seeking amongst those with depression (u . %, r . % ns). amongst the whole population, helping seeking was gendered with more urban men accessing help ( . %) than rural men ( . %, p= . ); this did not apply for women ( . % vs . % p= . ). ~ons: the urban-rural demographic continues to generate intriguing findings, even recently when internal migration is common and people can seek out the environment most conducive to their health, ~th physical and mental. people with depression are a disadvantaged, frequently stigmatized group, with ~r quality of life a_nd often impaired function. unlike many other factors associated wi~h urban or rural hfe per se, depression can be treated. the low help seeking rates is a cause for concern, m both the ur~n and_ rural populations. it behooves researchers, policy makers and service planners to ensutt effective services are available for both humane and economic reasons. methods: using united states census income data, we assigned the manhattan community districts to two major socioeconomic groups, manhattan i and ii. manhattan i is composed of community districts with average household incomes above the median for new york city; manhattan ii is those below. with public new york city department of health death records and us census data, we calculated a "standard" new york city population and estimated mortality rate distributions for manhattan i and ii. we then compared these age-adjusted actual mortality distributions with a standard t-test. results: we explored premature deaths using several cut-off points (before the ages of , , and ), and with subcomparisons for males and females. every comparison showed the wealthier area, manhattan i, to have significantly lower premature mortality rates than the lower income manhattan ii. further, we compared age-adjusted mortality rates among the city's five boroughs, and found no significant differences based on local geography alone. conclusions: these findings suggest that in manhattan, characterized by its extremes of wealth and poverty, health status, as measured by premature mortality, does vary significantly with the local income level. in manhattan, the relative average income by community district varies as much as : . this ratio is greater than that found in the other cities we have studied: for example, the range among tokyo's kus is half that in manhattan, or about : . paris has shown the longest life expectancy and changing premature mortality rates. from our preliminary work, we expect to find less variation in premature mortality rates in comparable cities. this study will continue to explore the relationship of premature mortality rates and life expectancy to income levels and different health systems among wcp cities with a view to measuring health policy options. introduction: according to the world health organization (who), smoking-related illness is currently the world's second major cause of death, currently responsible for one out of ten adult deaths worldwide. the who's framework convention on tobacco control (fctc) aims to reduce tobaccorelated disease and deaths by changing national public policies. mexico, which, according to the who, had smoking prevalences of % among adults in and % among health care providers (hcps) in , ratified the fctc in . objective: to examine knowledge of and attitudes towards cigarette smoking and smoking cessation among hcps, and clinical practices regarding smoking cessation. methods: in june , a convenience sample of hcps from one public clinic in urban oaxaca, mexico, part of mexico's national network of public health care clinics, were interviewed in spanish using a verbally administered questionnaire that was standard among all participants. during primary care outpatient visits, hcps were observed treating patients to assess the relative importance of smoking cessation as a health care priority. results: of the hcps interviewed, including ten physicians, three nurses, and five medical students, % reported smoking regularly. all hcps reported assessing patients' history of smoking, knowledge of the health risks associated with smoking, and feeling qualified to discuss these risks with patients. all hcps reported counseling patients who currently smoked to quit. all hcps reported recommending nicotine replacement therapy (eg., patch and/or gum) and/or behavioral therapy (eg., psychologist, support groups) to patients who smoked. all hcps reported that there was no government funding for smoking cessation, and that all costs associated with smoking cessation were patients' out-of-pocket expenses. observation of hcp interaction with patients revealed that hcps always inquired about smoking history with new patients and rarely inquired about smoking history with returning patients. hcps were not observed counseling patients who reported current smoking on smoking cessation methods and its benefits. observation of the clinical environment suggested a focus on preventative child health (eg., immunization, water-borne illnesses), family planning, and chronic diseases (eg., diabetes, hypertension). conclusions: while the mexican government has made smoking cessation a public health priority and hcps report addressing smoking cessation, observation of hcps suggests: ) smoking status is assessed only in new patients; and ) smoking cessation methods are not addresse~. observ_atio~ of hcps and the clinical environment in a public clinic in oaxaca suggests that smoking cessation s of lower priority than other heath care issues. p - (a) urban agriculture and food and nutrition security in kampala, uganda fiona yeudall, renee sebastian, abdelrahman lubowa, selahadin ibrahim, and donald cole introduction: urban agriculture is an important livelihood strategy contributing to household food security by increasing access and availability to food in urban settings (koc et al., ) . the purpose of poster sessions v rhis study was to examine relationships between child nutritional securiry outcomes, household food security, and urban agriculture activiries in kampala, uga~da. . . questionnaires assessing socio-demographic, farmmg and household food secunry (hfsi characreristics were administered to households. food diversiry was ~lculate~ from ~e number of foods consumed over hours for one child ( - years) per household. heigh~ weight,. nud-upper·ann· circumference (muac) and tricep skinfolds (tsf) were measured for the mdex child. z-sc.ores for height-for·age (haz), weighr-for-age (waz) and body mass index (zbmi) were ~~ulated usmg cen· rres for disease control and prevenrion reference data. z-scores for body composition measures were calculated using nhanes i and ii data for african americans. the lms method was used to c~.t for skewed z·score indices. all dara was checked for normaliry and univariable and backward mulnvanablc linear regression analysis conducted. ruwlts: household food securiry was significantly associated with wealth (b= . , p< 'a acre were more dependenr on assets for hfs. although sex of head of household was ~ot related to j-:ifs, it modi· fied relationships in rhar female headed households had greater food securtry when fai:mmg less than , acre compared ro male headed households, and vice versa. hfs was significantly associated with food diversiry (s= . , p). urbanization, especially in developing countries, has substantially increased the vulnerability of rhe mass of low-income urban dwellers. the livelihoods and quality of life for many of the poor espe· cially in larin america, asia, and africa, have deteriorated significantly over the years. urban areas are increasingly unable to provide for their populations, resulting in poverry, massive unemploymenr, job cuts, poor housing, lack of or poor public services, and a compromised health status. botswana, a country rhat lies in the sourhern parr of africa, has had its share of urban problems such as rhe mush· rooming of squarters and low-income urban sertlements. despite efforts to address the substandard living conditions in low-income urban areas, these problems have continued to grow. these living con· diuons are porenrially stressful to rhe residenrs and likely affects their health. the primary aim of the udy wa to examine the complex relationship between communiry-level stressors and interveners and health-related quality of life among residents of low-income neighborhoods in francistown, botswana. u i"" a croa -icctional quantitative design (both descriptive and explanatory) and using primarily cloae-mded interview• with a random sample of residents, this study examined the role of chrome life trnson and environmental quality on overall health status qualiry of life) and the physical, psy· chological and level of independence domains of health. the major hypothesis of the study was that community-levrl stre sor would influence health-related quality of life and that social capital would moderate these relationships. findings indicate that neighborhood quality is a powerful predictor of healrh tatu rhan socioeconomic status and individual life stressors. social capital was also found to he a ificant positive predictor of healrh and also moderator of structural factors. social capital moderated the effects of low environmental quality on level of indrpendence and on physical health outcomn, but nor on psychological and global health outcomes. these findings suggest that as the environment get betttr. stresson are reduced, hence promoting berter health outcomes. the study ends with implication• for social justice, public health and social work practice, and research, focusing mostly on the ~ole of social capital and the environmental quality in predicting health outcomes. spt· cafically • anenhon should be focused on political and civic society's commitment for social justice and poveny alleviation, ~uction of the threat of insecuriry and violence; cultivating social capital and good governance; and improving the health and social environments, especially housing and environ· mental aiutanon to name a few. urban and other uprisings by non-elites that lead to transitions, can disrupt sexual and injection "risk" networks that transmit infectious diseases by changing mixing patterns. they can also weaken urban social networks, their associated protective norms and their informal social control mechanisms which can lead to increased sexual and drug risk behaviors and violence (fullilove ; wallace & wallace , aral , friedman & reid hankins et al ) . for example, the revolution and transition to theocratic rule, and subsequent urban and national conflicts, have been followed by many urban youth in iran engaging in clandestine high-risk sexual and drug behaviors. in palestine, conflicts and restrictions on movement have led to increased fatalities from chronic diseases due to limited access to hospitals and modern medical facilities (union of palestinian medical relief committees); and heroin use and violence-related blood exposure have also increased. social movements "from below" that are rooted both in urban social network dynamics and in underlying patterns of injustice can have both protective and risky effects. for example, the social movements that led to the collapse of the ussr and its dependent governments in other countries-with subsequent increases in sex trade, alcoholism, drug use, tuberculosis, hiv, stis, and mortality in many localities-were based originally on such city-based movements in eastern europe. their impacts on health were mediated by urban social dynamics and structures. some urban social movements have improved health by prevent· ing the spread of hiv, hepatitis and other diseases. examples include movements of (a) gays and lesbians and (b) drug users. these have been rooted in social networks that overlap with risk networks. theories of urban health should include social conflict as a core concept. mechanisms that generate conflicts and the pathways by which conflicts affect health should be a major part of urban health research agendas. p - (c) demographic characteristics of people seen with tuberculosis in lagos state university teaching hospital (lasuth) chest clinic john bako, adewale akeredolu, and wale alabi tuberculosis has become a resurgent public health problem in recent times in the world. because resources are limited, control programmes frequently must target population at greatest risk. the purpose of this study was to study the demographic characteristics of people seen with tuberculosis in lagos state university teaching hospital. a total of patients who have been both radiologically and bacteriologically confirmed tuberculosis patients were used for this study between january and march. ( %) were males, while ( %) were females. notable risk factors among patients with tuberculosis were overcrowding ( . % ), homelessness ( . %) cigarette smoking ( . % ), alcoholism ( . %), non vaccination ( %), secondary contact ( . %) and poor knowledge ( . l 'x,). man· agement history patterns among the patients were herbs ( . 'yo), orthodox medicine ( .h . .l'x.). intervention targeting early-identified groups may be an effective way to reduce the incidence of tuber· culosis. such intervention should focus on health education, modification of life style and improvement of standard of living. p - (c) profiles in urban health in cities of the americas in the countries of the americas, there is an increasing migration of national and international populations to urban centers. this presentation will focus on some of the issues created by this influx of populations, the ways that cities in countries are dealing with them, and the efforts to promote local participation and solutions in management and decision-making. the methodology used to collect this information has been to draw upon and analyze information produced by the mayor's and ministry of health and development offices in each of the cities under consideration. an analysis of the impact of urbanization on health and health determinants will be presented. the information covers issues such as health status by geographic areas within the cities, highlighting issues such as marginality, barriers and physical, economic and cultural constructs and inequities in the delivery of and access to essential services (such as health, education, water, and basic sanitation). issues of governance and citizen participation will be highlighted to provide insight in~o the balance of power and mechanisms for decision-making at the local level. part of the analysis will show the relationship between democratic processes and social participation. public ~olicies will be reviewed to indicate those that are most beneficial in promoting health and overcoming barriers to it, as well as ways of capitalizing on local assets and resources. final~y, evidence of effectiveness of various strategies will be indicated. the presentation will conclude wuh suggesuons for future strategic directions to improve the quality of life and the promotion of health in large urban centers of the americas. introduction: much of the illicit drug in mexico is concentrated in northern border areas. the mile border between the u.s. and mexico is also characterized by migration; the border crossing between tijuana, baja california, mexico and san diego, california, u.s.a. is rep~rt~dl~ the busiest land border crossing in the world. we attempt to describe the migration scene among m ect on drug users (idus) m tijuana and investigate service needs. methods: migration trends were investigated in a cross-sectional study conducted from february to june among idus in tijuana. enrollment criteria included informed consent, being years or older, and having injected drugs within the prior month. subjects were recruited by respondent-dnven sampling and were administered a quantitative survey and serology for hiv, hcv, and syphilis. logistic regression was used to compare idus who had migrated to the u.s. versus those who had not. results: of idus enrolled, % were male and median age and age at first injection were and , respectively. drug combinations injected most frequently in the past months were heroin ( % and crystal methamphetamine mixed with heroin ( %). of those enrolled, responded to quesnons on migration and drug treatment and were included in this analysis. although % had resided in tijuana for at least years, % of users were born outside of baja california. working outside of mexico was common, with % working abroad in the last years ( % in u.s.), and % in the past year. in the last months, % of idus had crossed the border to the u.s., with % crossing at least once per month. those working outside of mexico in the past year were less likely to have ever received substance abuse treatment, [ % vs. %, or . , ] and were marginally less likely to have received drug treatment in the past months [ % vs. %, or . , % ci ( . - . )]. drug use patterns, age and gender did not differ between migrants and non-migrants, although migrants were more likely to report being in need of substance abuse treatment ( % vs. %, respectively). conclusions: migration is common among idus in tijuana. maintaining drug treatment regimens and determining how to best target education and services to a highly mobile population pose challenges to officials on both sides of the border. these data underscore the need to develop coordinated binational prevention and treatment efforts. introduction: despite the expanding literature on the important role public policy plays in influencing the broader determinants of the public\'s health, profound differences exist among jurisdictions in rhe attention placed upon such activities. we take an international perspective on health by examining rhe d?minant public _health paradigms of canada, usa, uk, and sweden and exploring how these paradigms shape public health practice. _method: we carefully analyze governmental and public health agencies documents to discern ~he dommant para~igms driving public health approaches and practices. we also consider the unique paht · cal and economic contexts within each nation and consider how these contexts drive public health pahcy and approaches. . . ~u~: the canadian and usa public health communities -with some exceptions --focus upon m~ividuahzed approaches to risk management. in contrast, the uk and swedish public health scenes are oriented toward broader approaches to health determinants. we find that the extent to which govern· ments, public health agencies and public health workers concern themselves with public policy approaches £<_> ~ddress ~ro.ad~r .determinants of health depends upon the particular health parad'.~ adhered. ~o withm each urisd ctton. and whether a paradigm is adopted depends upon the ideologi~a and pol~ncal context of each nation. nations such as sweden that have a long tradition of public policies promonng social jus~ce an~ equity are naturally receptive to evolving population health concepts. '[he usa represen~ a ~bey en~ro~~t where such is~ues are clear!~ subordinate. ., our findings mdicate that there s a strong political component that influences pubh ~ealth a~proaches and practi~ within the jurisdictions examined. the implications are that those seek· m~ to raise the broader detennmants of the public's health should work in coalition to raise these issues with non-health organizations and age · ca d d th · - badrgrollnd: in developed countries, social inequalities in health have endured or even worsened comparatively throughout different social groups since the s. in france, a country where access to medical and surgical care is theoretically affordable for everyone, health inequalities are among the high· est in western europe. in developing countries, health and access to care have remained critical issues. in madagascar, poverty has even increased in recent years, since the country wenr through political crisis and structural adjustment policies. objectives. we aimed to estimate and compare the impact of socio· economic status but also psychosocial characteristics (social integration, health beliefs, expectations and representation, and psychological characteristics) on the risk of having forgone healthcare in these dif· fercnt contexts. methods: population surveys conducted among random samples of households in some under· served paris neighbourhoods (n= ) and in the whole antananarivo city (n= ) in , using a common individual questionnaire in french and malagasy. reslllts: as expected, the impact of socioeconomic status is stronger in antananarivo than in paris. but, after making adjustments for numerous individual socio-economic and health characteristics, we observed in both cities a higher (and statically significant) occurrence of reponed forgone healthcare among people who have experienced childhood and/or adulthood difficulties (with relative risks up to and .s respectively in paris and antananarivo) and who complained about unhealthy living conditions. in paris, it is also correlated with a lack of trust in health services. coneluions: aside from purely financial hurdles, other individual factors play a role in the non-use of healthcare services. health insurance or free healthcare seems to be necessary hut not sufficienr to achieve an equitable access to care. therefore, health policies must not only focus on the reduction of the financial barriers to healthcare, but also must be supplemented by programmes (e.g. outreach care ser· vices, health education, health promotion programmes) and discretionary local policies tailored to the needs of those with poor health concern .. acknowledgments. this project was supported by the mal>io project and the national institute of statistics (instat) in madagascar, and hy the development research institute (ird) and the avenir programme of the national institute of health and medical research (inserm) in france. for the cities of developing countries, poverty is often described in terms of the living standard~ of slum populations, and there is good reason to believe that the health risks facing these populations are even greater, in some instances, than those facing rural villagers. yet much remains to be learned ahour the connections between urban poverty and health. it is not known what percentage of all urban poor live in slums, that is, in communities of concentrated poverty; neither is it known what proportion of slum residents are, in fact, poor. funhermore, no quantitative accounting is yet available that would sep· arare the health risks of slum life into those due to a househoid•s own poverty and those stemminic from poveny in the surrounding neighborhood. if urban health interventions are to be effectively targeted in developing countries, substantial progress must be made in addressing these cenrral issues. this paper examines poverty and children's health and survival using two large surveys, one a demographic and health survey fielded in urban egypt (with an oversampling of slums) and the other a survey of the slums of allahabad, india. using multivariate statistical methods. we find, in both settings: ( substan· rial evidence of living standards heterogeneity within the slums; ( strong evidence indicating that household-level poverty is an imponant influence on health; and ( ) staristically significant (though less strong) evidence that with household living standards held constant, neighborhood levels of poverty adversely affect health. the paper doses with a discussion of the implications of these findings for the targeting of health and poverty program interventions. p - (a) urban environment and the changing epidemiological surfacr. the cardiovascular ~ &om dorin, nigeria the emergence of cardiovascular diseases had been explained through the concomitants o_f the demographic transition wherein the prevalent causes of morbidity and monality ~hangr pr~mmant infectious diseases to diseases of lifestyle or chronic disease (see deck, ) . a ma or frustration m the v poster sessions case of cvd is its multifactural nature. it is acknowledged that the environment, however defined is the d · f · t' b tween agents and hosts such that chronic disease pathogenesis also reqmre a me an o mterac ion e . spatio-temporal coincidence of these two parties. what is not clear is which among ~ever~( potennal fac· · h b pace exacerbate cvd risk more· and to what extent does the ep dem olog cal trans · tors m t e ur an s ' . . . . tion h othesis relevant in the explanation of urban disease outlook even the developmg cities like nigeri~: thesis paper explorer these within a traditional city in nigeria. . . . the data for the study were obtained from two tertiary level hospitals m the metropolis for years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the data contain reported cases of cvd in the two facilities for the period. adopting a series of parametric and non-parametric statistics, we draw inferences between the observed cases of cvds and various demographic and locational variables of the patients. findings: about % of rhe cases occurred in years ( ) ( ) ( ) coinciding with the last year of military rule with great instability. . % occurred among male. . % also occurred among people aged - years. these are groups who are also likely to engage in most stressful life patterns. ~e study also shows that % of all cases occurred in the frontier wards with minor city areas also havmg their •fair' share. our result conformed with many empirical observation on the elusive nature of causation of cvd. this multifactoral nature had precluded the production of a map of hypertension that would be consistent with ideas of spatial prediction. cvd -cardiovascular diseases. mumbai is the commercial capital of india. as the hub of a rapidly transiting economy, mumbai provides an interesting case study into the health of urban populations in a developing country. with high-rise multimillion-dollar construction projects and crowded slums next to each other, mumbai presents a con· trast in development. there are a host of hi-tech hospitals which provide high quality care to the many who can afford it (including many westerners eager to jump the queue in their healthcare systems-'medical tour· ism'), at the same time there is a overcrowded and strained public healthcare system for those who cannot afford to pay. voluntary organizations are engaged in service provision as well as advocacy. the paper will outline role of the voluntary sector in the context of the development of the healthcare system in mumbai. mumbai has distinct upper, middle and lower economic classes, and the health needs and problems of all three have similarities and differences. these will be showcased, and the response of the healthcare system to these will be documented. a rising hiv prevalence rate, among the highest in india, is a challenge to the mumbai public healthcare system. the role of the voluntary sector in service provision, advocacy, and empowerment of local populations with regards to urban health has been paramount. the emergence of the voluntary sector as a major player in the puzzle of urban mumbai health, and it being visualized as voices of civil society or communiry representatives has advantages as well as pitfalls. this paper will be a unique attempt at examining urban health in india as a complex web of players. the influence of everyday socio·polirical-cultural and economic reality of the urban mumbai population will be a cross cutting theme in the analysis. the paper will thus help in filling a critical void in this context. the paper will thus map out issues of social justice, gender, equiry, effect of environment, through the lens of the role of the voluntary sector to construct a quilt of the realiry of healthcare in mumbai. the successes and failures of a long tradi· tion of the active advocacy and participation of the voluntary sector in trying to achieve social justice in the urban mumbai community will be analyzed. this will help in a better understanding of global urban health, and m how the voluntary sector/ngos fir into the larger picture. ba~und: o~er. half _of n~irobi's . million inhabitants live in illegal informal settlements that compose yo of the city s res dent al land area. the majority of slum residents lack access to proper san· iranon and a clean and adequate water supply. this research was designed to gain a clearer understand· mg of what kappr · · · h f . . opnate samtanon means or the urban poor, to determine the linkages between gender, hvehhoods, and access to water and sanitation, and to assess the ability of community sanitation blocks to meet water and sanitation needs in urban areas. m~tbojs_: _a household survey, gender specific focus groups and key informant interviews were conducted m maih saba, a peri-urban informal settlement. qualitative and quantitative research tools were u~ to asses~ the impact and effectiveness of community sanitation blocks in two informal settlements. results ropna e samtarmn me u es not only safe and clean latrines, but also provision ° adequate drainage and access to water supply for cleaning of clothes and homes. safety and cleanliness poster sessions v were priorities for women in latrines. levels of poverty within the informal settlements were identified and access to water and sanitation services improved with increased income. environmental health problems related to inadequate water and sanitation remain a problem for all residents. community sanitation blocks have improved the overall local environment and usage is far greater than envisioned in the design phase. women and children use the blocks less than men. this is a result of financial, social, and safety constraints. the results highlight the importance a need to expand participatory approaches for the design of water and sanitation interventions for the urban poor. plans need to recognize "appropriate sanitation" goes beyond provision of latrines and gender and socioeconomic differences must be taken into account. lessons and resources from pilot projects must be learned from, shared and leveraged so that solutions can be scaled up. underlying all the challenges facing improving water and sanitation for the urban poor are issues of land tenure. p - (c) integrating tqm (total quality management), good governance and social mobilization principles in health promotion leadership training programmes for new urban settings in countries/ areas: the prolead experience susan mercado, faren abdelaziz, and dorjursen bayarsaikhan introduction: globalization and urbanization have resulted in "new urban settings" characterized by a radical process of change with positive and negative effects, increased inequities, greater environmental impacts, expanding metropolitan areas and fast-growing slums and vulnerable populations. the key role of municipal health governance in mitigating and modulating these processes cannot be overemphasized. new and more effective ways of working with a wide variety of stakeholders is an underpinning theme for good governance in new urban settings. in relation to this, organizing and sustaining infrastructure and financing to promote health in cities through better governance is of paramount importance. there is a wealth of information on how health promotion can be enhanced in cities. despite this, appropriate capacity building programmes to enable municipal players to effectively respond to the challenges and impacts on health of globalization, urbanization and increasing inequity in new urban settings are deficient. the who kobe centre, (funded by the kobe group( and in collaboration with regional offices (emro, searo, wpro) with initial support from the japan voluntary contribution, developed a health promotion leadership training programme called "prolead" that focuses on new and autonomous structures and sustainable financing for health promotion in the context of new urban settings. methodology: country and/or city-level teams from areas, (china, fiji, india, japan, lebanon, malaysia, mongolia, oman, philippines, republic of korea, tonga and viet nam) worked on projects to advance health promotion infrastructure and financing in their areas over a month period. tools were provided to integrate principles of total quality management, good governance and social mobili .ation. results: six countries/areas have commenced projects on earmarking of tobacco and alcohol taxes for health, moblization of sports and arts organizations, integration of health promotion and social health insurance, organizational reforms, training in advocacy and lobbying, private sector and corporate mobilization and community mobilization. results from the other six areas will be reported in ..;obcr. conclusions: total quality management, good governance and social mobilization principles and skills are useful and relevant for helping municipal teams focus on strategic interventions to address complex and overwhelming determinants of health at the municipal level. the prolead training programmes hopes to inform other processes for building health promotion leadership capacity for new urban settings. the impact of city living and urbanization on the health of citizens in developing countries has received increasing attention in recent years. urban areas contribute largely to national economies. however, rapid and unplanned urban growth is often associated with poverty, environmental degradation and population demands that outstrip service capacity which conditions place human health at risk. local and national governments as well as multi national organizations are all grappling with the challenges of urbanization. with limited data and information available, urban health characteristics, including the types, quantities, locations and sources in kampala, are largely unknown. moreover, there is n? basis for assessing the impact of the resultant initiatives to improve health ~onditions amo~g ~o": ": um ties settled in unplanned areas. since urban areas are more than the aggregation ?f ~?pie w~th md_ v dual risk factors and health care needs, this paper argues that factors beyond the md v dual, mcludmg the poster sessions v · i d h · i · ment and systems of health and social services are determinants of the health soc a an p ys ca environ . of urban populations. however, as part of an ongoing study? ~s pape~ .addresses the basic concerns of urban health in kampala city. while applying the "urban hvmg conditions and the urban heal~ pen· alty" frameworks, this paper use aggregated urban health d~ta t~ explore the role of place an~ st tu· tions in shaping health and well-being of the population m kampala by understanding how characteristics of the urban environment and specific features of the city are causally related to health of invisible and forgotten urban poor population: results i~dica~e that a .range o~ urb~n he~l~h hazards m the city of kampala include substandard housing, crowdmg, mdoor air poll.ut on, msuff c ent a~d con· taminated water, inadequate sanitation and solid waste management services, vector borne .diseases, industrial waste increased motor vehicle traffic among others. the impact of these on the envtronment and community.health are mutually reinforcing. arising out of the withdra"'.al of city pl~nning systems and service delivery systems or just planning failure, thousands of people part cularl~ low-mc~me groups have been pushed to the most undesirable sections of the city where they are faced with ~ va_r ety ~f envj· ronmental insults. the number of initiatives to improve urban health is, however, growing mvolvjng the interaction of many sectors (health, environment, housing, energy, transportation and urban planning) and stakeholders (local government, non governmental organizations, aid donors and local community groups). key words: urban health governance, health risks, kampala. introduction: the viability of urban communities is dependent upon reliable and affordable mass transit. in particular, subway systems play an especially important role in the mass transit network, since they provide service to vast numbers of ridersseven of the subway systems worldwide report over one billion passenger rides each year. surprisingly, given the large number of people potentially affected, very little is known about the health and safety hazards that could affect both passengers and transit workers; these include physical (e.g., noise, vibration, accidents, electrified sources, temperature extremes), biological (e.g., transmission of infectious diseases, either through person-to-person spread or vector-borne, for example, through rodents), chemical (e.g., exposure to toxic and irritant chemicals and metals, gas emissions, fumes), electro-magnetic radiation, and psychosocial (e.g., violence, workstress). more recently, we need to consider the threat of terrorism, which could take the form of a mass casualty event (e.g., resulting from conventional incendiary devices), radiological attack (e.g., "dirty bomb"), chemical terrorist attack (e.g., sarin gas), or bioterrorist attack (e.g., weapons grade anthrax). given the large number of riders and workers potentially at risk, the public health implications are considerable. methods: to assess the hazards associated with subways, a structured review of the (english) litera· ture was conducted. ruults: based on our review, non-violent crime, followed by accidents, and violent crimes are most prevalent. compared to all other forms of mass transit, subways present greater health and safety risks. however, the rate of subway associated fatalities is much lower than the fatality rate associated with automobile travel ( . vs. . per million passenger miles), and cities with high subway ridership rates have a % lower per capita rate of transportation related fatalities than low ridership cities ( . versus . annual deaths per , residents). available data also suggest that subway noise levels and levels of air pollutants may exceed recommended levels. . ~: there is a paucity of published research examining the health and safety hazards associated with subways. most of the available data came from government agencies, who rely on passively reported data. research is warranted on this topic for a number of reasons, not only to address important knowled~ gaps, but also because the population at potential risk is large. importantly, from an urban perspecnve, the benefits of mass transit are optimized by high ridership ratesand these could be adversely affu:ted by unsafe conditions and health and safety concerns. veena joshi, jeremy lim. and benjamin chua ~ ~rban health issues have moved beyond infectious diseases and now centre largely on chrome diseases. diabetes is one of the most prevalent non-communicable diseases globally. % of adult ¥ benefit in providing splash pads in more parks. given the high temperature and humidity of london summers, this is an important aspect and asset of parks. interviewed parents claimed to visit city parks anywhere between to days per week. corrduion: given that the vast majority of canadian children are insufficiently active to gain health benefits, identifying effective qualities of local parks, that may support and foster physical activity is essential. strategies to promote activity within children's environments are an important health initiative. the results from this study have implications for city planners and policy makers; parents' opinions of, and use of city parks provides feedback as to the state current local parks, and modifications that should be made for new ones being developed. this study may also provide important feedback for health promoters trying to advocate for physical activity among children. introdt clion: a rapidly increasing proportion of urban dwellers in africa live below the poverty line in overcrowded slums characterized by uncollected garbage, unsafe water, and deficient sanitation and overflowing sewers. this growth of urban poverty challenges the commonly held assumption that urban populations enjoy better health than their rural counterparts. the objectives of this study are (i) to compare the vaccination status, and morbidity and mortality outcomes among children in the slums of nairobi with rural kenya, and (ii) to examine the factors associated with poor child health in the slums. we use data from demographic and health survey representative of all slum settlements in nairobi city carried out in by the african population & health research center. a total of , women aged - from , households were interviewed. our sample consists of , children aged - months. the comparison data are from the kenya demographic and health survey. the outcomes of interest include child vaccination status, morbidity (diarrhea, fever and cough) and mortality, all dichotomized. socioeconomic, environmental, demographic, and behavioral factors, as well as child and mother characteristics, are included in the multivariate analyses. multilevel logistic regression models are used. l'nlimin ry rest lts: about % of children in the slums had diarrhea in the two weeks prior to the survey, compared to % of rural children. these disparities between the urban poor anj the rural residents are also observed for fever ( % against %), cough ( % versus %), infant mortality ( / against / ), and complete vaccination ( % against %). preliminary multivariate results indicate that health service utilization and maternal education have the strongest predictive power on child morbidity and mortality in the slums, and that household wealth has only minor, statistically insignificant effects. conclruion: the superiority of health of urban children, compared with their rural counterparts, masks significant disparities within urban areas. compared to rural residents, children of slum dwellers in nairobi are sicker, are less likely to utilize health services when sick, and stand greater risk to die. our results suggest policies and programs contributing to the attainment of the millennium development goal on child health should pay particular attention to the urban poor. the insignificance of socioeconomic status suggests that poor health outcomes in these communities are compounded by poor environmental sanitation and behavioral factors that could partly be improved through female education and behavior change communication. introduction: historic trade city surat with its industrial and political peace has remained a center of attraction for people from all the comers of india resulting in to pop.ulatio~ explosio~ a~d stressed social and service infrastructure. the topography,dimate and demographic profile of the city s threat to the healthy environment. aim of this analysis is to review the impact of managemt'nt reform on health indicators. method: this paper is an analysis of the changing profile of population, sanitary infr~s~rucrure, local self government management and public health service reform, secondary health stat st cs data, health indicator and process monitoring of years. . . health of entire city and challenge to the management system. plague outbr~ak ( ) was the turning point in the history of civic service management including p~blic ~e~lth service management. ~ocal self government management system was revitalized by reg~lar_ field v s ts o~ al~ cadre~, _decentraltzanon of power and responsibility, equity, regular vigilant momtormg, commumcanon facility, ream_approach and people participation. reform in public health service management was throu_gh stan~~rd zed intervention protocol, innovative intervention, public private partnership, community part c panon, academic and service institute collaboration and research. sanitation service coverage have reached nearer to universal. area covered by safe water supply reached to %( ) from % ( ) and underground drainage to % ( ) from % ( ) the overhauling of the system have reflected on health indicators of vector and water born disease. malaria spr declined to . ( ) from . 'yo(! ) and diarrhea case report declined to ( ) from ( ). except dengue fever in no major disease outbreaks are reported after . city is recipient of international/national awards/ranking for these achievements. the health department have developed an evidence and experience based intervention and monitoring system and protocol for routine as well as disaster situation. the health service and management structure of surat city have emerged as an urban health model for the country. introduction: the center for healthy communities (chc) in the department of family and com· munity medicine at the medical college of wisconsin developed a pilot project to: ) assess the know· ledge, attitudes, and behaviors of female milwaukee public housing residents related to breast cancer; develop culturally and literacy appropriate education and screening modules; ) implement the developed modules; ) evaluate the modules; and ) provide follow-up services. using a community-based participatory research model the chc worked collaboratively with on-site nurse case management to meet these objectives. methods: a "breast health kick off event" was held at four separate milwaukee public housing sites for elderly and disabled adults. female residents were invited to complete a -item breast health survey, designed to accommodate various literacy levels. responses were anonymous and voluntary. the survey asked women about their previous physical exams for breast health, and then presented a series of state· ments about breast cancer to determine any existing myths. the final part gathered information about personal risk for breast cancer, the highest level of education completed, and whether the respondents h;td ever used hormone replacement therapy and/or consumed alcohol. responses were collected for descriptive analysis. results: a total of surveys (representing % of the total female population in the four sites) were completed and analyzed. % reported that they had a physical exam in the previous rwo years. % of respondents indicated they never had been diagnosed with breast cancer. % reported having had a mammogram and % having had a clinical breast exam. those that never had a mammogram reported a fear of what the provider would discover or there were not any current breast problems ro warrant an exam. % agreed that finding breast cancer early could lower the chance of dying of cancer. over % reported that mammograms were helpful in finding cancer. however, % believed that hav· ing a mammogram actually prevents breast cancer. % indicated that mammograms actually cause cancer and % reported that a woman should get a mammogram only if there is breast cancer in her family. conclusion: this survey indicates that current information about the importance of mammograms and clinical breast exams is reaching traditionally underserved women. yet there are still critical oppor· tunities to provide valuable education on breast health. this pilot study can serve as a tool for shaping future studies of health education messages for underserved populations. located in a yourh serv· ~ng agency m downtow~ ottawa, the clinic brings together community partners to provide primary medical care. and dent~i hygiene t? the street youths of ottawa aged - . the primary goal of the project is to provide accessible, coordinated, comprehensive health and dental care to vulnerable adolescents. these efforts respond to the pre-existing body of evidence suggesting that the principle barrier in accessing such care for these youths are feelings of intimidation and vulnerability in the face of a complex healthcare system. the bruyere fhn satellite clinic is located in the basement of a downtown drop-in and brings together a family medicine physician and her residents, a dental hygienist and her nd year students, a nurse practitioner, a chiropodist and public health nurses to provide primary care. the clinic has been extremely busy and well received by the youth. this workshop will demonstrate how five community organizations have come together to meet the needs of high risk youths in ottawa. this presentation will showcase the development of the clinic from its inception through its first year including reaction of the youths, partnerships and lessons learned. it will also focus on its sustainability without continued funding. we hope to have developed a model of service delivery that could be reproduced and sustained in other large cities with faculties of medicine. methods: non-randomized, mixed method design involving a process and impact evaluation. data collection-qualitative-a) semi structured interviews with providers & partners b)focus groups with youth quantitative a)electronic medical records for months records (budget, photos, project information). results: ) successfully built and opened a medicaudental clinic which will celebrate its year anniversary in august. ) over youths have been seen, and we have had over visits. conclusion: ) the clinic will continue to operate beyond the month project funding. ) the health of high risk youth in ottawa will continue to improve due to increased access to medical services. p - (a) health services -for the citizens of bangalore -past, present and future savita sathyagala, girish rao, thandavamurthy shetty, and subhash chandra bangalore city, the capital of karnataka with . million is the th most populous city in india; supporting % of the urban population of karnataka, it is considered as one of the fastest growing cities in india. known as the 'silicon valley of india', bangalore is nearly years old. bangalore city corporation (bmp), is a local self government and has the statutory commitment to provide to the citizens of bangalore: good roads, sanitation, street lighting, safe drinking water apart from other social obligations, cultural development and poverty alleviation activities. providing preventive and promotive heahh services is also a specific component. the objective of this study was to review the planning process with respect to health care services in the period since india independence; the specific research questions being what has been the strategies adopted by the city planners to address to the growing needs of the population amidst the background of the different strategies adopted by the country as a whole. three broad rime ranges have been considered for analysis: the s, s and the s. the salient results are: major area of focus has been on the maternal and child care with activities ranging from day-care to in-patient-care; though the number of institutions have grown from to the current day , their distribution has been far from satisfactory; obtaining support from the india population projects and major upgradarions have been undertaken in terms of infrastructure; over the years, in addition to the dispensaries of modern system of medicine, local traditional systems have also been initiated; the city has partnered with the healthy cities campaign with mixed success; disease surveillance, addressing the problems related to the emerging non-communicable diseases including mental health and road traffic injuries are still in its infancy. isolated attempts have been made to address the risks groups of elderly care and adolescent care. what stands out remarkably amongst the cities achievements is its ability to elicit participation from ngos, cbos and neighbourhood groups. however, the harnessing of this ability into the health sector cannot be said totally successful. the moot question in all the above observed development are: has the city rationally addressed it planning needs? the progress made so far can be considered as stuttered. the analysis and its presentation would identify the key posirive elements in the growth of banglore city and spell a framework for the new public health. introduction: anaemia associated with pregnancy is a major public health problem all over the world. different studies in different parts of india shown prevalence of anaemia between - %. anaemia remains a serious health problem in pregnancy despite of strong action taken by the government of india through national programmes. in the present study we identified th~ social beha~iors, responsible for low compliance of if a tablets consumption in pregnancy at community level and intervention was given with new modified behaviors on trial bases. . in vadodara urban. anganwadies out of were selected from the list by random sampling for tips (trials of improved practices) study. . . participants: pregnant women ( , intervention group+ , control. group) registered m the above anganwadies. study was conducted in to three phases: phase: . formative research and baseline survey (frbs). data was collected from all pregnant women to identify behaviors that are responsible for low compliance of ifa tablets. both qualitative and quantitative data were collected. haemoglobin was estimated of all pregnant women by haemo-cue. phase: . phase of tips. behaviors were identified both social & clinical for low compliance of ifa tablets consumption in pregnancy from frbs and against those, modified behaviors were proposed to pregnant women in the intervention group on trial bases by health education. trial period of weeks was given for trial of new behaviors to pregnant women in the interven· tion group. phase: . in this phase, feedbacks on behaviors tried or not tried were taken from pregnant women in intervention group. haemoglobin estimation was carried out again in all pregnant women. at the end of the study, messages were formulated on the bases of feedbacks from the pregnant women. results: all pregnant women in the intervention group had given positive feedback on new modified behaviors after intervention. mean haemoglobin concentration was higher in intervention group ( . ± . gm%) than control group ( . ± . gm%). ifa tablets compliance was improved in intervention group ( . %) than control group ( . %). conclusion: all pregnant women got benefits after trial of new modified behaviors in the intervention group. messages were formulated from the new modified behaviors, which can be used for longterm strategies for anaemia control in the community. introduction: in order to develop a comprehensive mch handbook for pregnant women and to assess its effect among them, a pilot study was carried out at the maternal and child health training institute (mchti), in dhaka, bangladesh. methods: from mchti a sample of pregnant women was selected and all subjects were women who were attending the first visit of their current pregnancy by using a random sampling method. of the subjects, women were given the mch handbook as case and women were not given the handbook as control. data on pre and post intervention of the handbook from the cases and controls were taken from data recording forms between the st of november and st of october, and data was analysed by using a multilevel analysis approach. this was a hospital-based action (case-control) research, and was applied in order to measure the outcome of pre and post intervention following the introduction of the handbook. data was used to assess the effects of utilisation of the handbook on women's knowledge, practice and utilisation of mch services. results: this study showed that the change of knowledge about antenatal care visits was . % among case mothers. knowledge of danger signs improved . %, breast feeding results . %, vaccination . % and family planning results improved . % among case. results showed some positive changes in women's attitudes among case mothers and study showed the change of practice in antenatal care visits was .u. % in the case. other notable changes were: change of practice in case mother's tetanus toxoid (ti), . %; and family planning . %. in addition, handbook assessment study indicated that most women brought the handbook on subsequent visits ( . %), the handbook was highly utilised (i.e. it was read by . %, filled-in by . %, and was used as a health education tool by . %). most women kept the handbook ( . %) and found it highly useful ( . %) with a high client satisfaction rate of . %. conclusion: pregnant women in the case group had higher knowledge, better practices, and higher utilisation of mch services than mothers in the control groups who used alternative health cards. if the handbook is developed with a focus on utilising a problem-oriented approach and involving the recomendations .of end~users, it is anticipated that the mch handbook will contribute significantly to ensuring the quahry of hfe of women and their children in bangladesh. after several meetmgs to identify the needs of the community, a faso clinic was opened at ncfs. health care professionals from smh joined with developmental and social service workers from ncfs to implement the faso diagnostic process and to provide culturally appropriate after-care. the clinic is unique in that its focus is the high risk urban aboriginal population of toronto. it accepts referrals of not only children and youth, but also of adults. lessons learned: response to the faso clinic at native child and family services has been overwhelming. aboriginal children with f asd are receiving timely diagnosis and interventions. aboriginal youth and adults who have been struggling with poveny, substance abuse, and homelessness are more willing to enter the ncfs centre for diagnosis and treatment. aboriginal infants prenatally exposed to alcohol born at st. michael's hospital or referred by other centres have access to the developmental programs located in both of the partnering agencies. the presentation will describe the clinic's development, and will detail the outcomes described, including interventions unique to the aboriginal culture. p - (c) seeds, soil, and stories: an exploration of community gardening in southeast toronto carolin taran, sarah wakefield, jennifer reynolds, and fiona yeudall introduction: community gardens are increasingly seen as a mechanism for improving nutrition and increasing food security in urban neighbourhoods, but the evidence available to support these claims is limited. in order to begin to address this gap in a way that is respectful of community knowledge and needs, the urban gardening research opportunities workgroup (ugrow) project explored the benefits and potential risks of community gardening in southeast toronto. the project used a community-based research (cbr) model to assess community gardens as a means of improving local health. the research process included interviews, focus groups, and participant observation (documented in field notes). we also directly engaged the community in the research process, through co-learning activities and community events which allowed participants to express their views and comment on emerging results. most of the research was conducted by a community-based research associate, herself a community gardener. key results were derived from these various sources through line-by-line coding of interview transcripts and field note review, an interactive and iterative process which involved both academic and community partners. results: these various data sources all suggest that enhanced health and access to fresh produce are important components of the gardening experience. they also highlight the central importance of empowering and community-building aspects of gardening to gardeners. community gardens were thought to play a role in developing friendships and social support, sharing food and other resources, appreciating cultural diversity, learning together, enhancing local place attachment and stewardship, and mobilizing to solve local problems (both inside and outside the garden). potential challenges to community gardens as a mechanism for communiry development include bureaucratic resistance to gardens, insecure land tenure and access, concerns about soil contamination, and a lack of awareness and under· standing by community members and decision-makers of all kinds. conclusion: the results highlight many health and broader social benefits experienced by commu· nity gardeners. they also point to the need for greater support for community gardening programs, par· ticularly ongoing the ongoing provision of resources and education programs to support gardens in their many roles. this research project is supported by the wellesley central health corporation and the centre for urban health initiatives, a cihr funded centre for research development hased at the univer· sity of toronto. p - (c) developing resiliency in children living in disadvantaged neighbourhoods sarah farrell, lorna weigand, and wayne hammond the traditional idea of targeting risk reduction by focusing on the development of eff~ctive coping strategies and educational programs has merit in light of the research reportmg_ that_ ~ lupl.e forms of problem behaviour consistently appear to be predicted by increasing exposure to den_uf able risk factors. as a result, many of the disadvantaged child and youth studies have focused on trymg to better _unde.r· stand the multiple risk factors that increase the likelihood of the development of at nsk behaviour m ch ldren/youth and the potential implications for prevention. this in turn has led t_o. the conclus on that community and health programs need to focus on risk reduction by helpm~ md v duals develop more effective coping strategies and a better understanding of the limitations of cenam pathologies, problematic v poster sessions coping behaviours and risk factors potentially inheren~ in high needs co~unities. ~owever, another ai:ea of research has proposed that preventative interventions should cons de~ .~rotecnve fa~ors alo~~ with reducing risk factors. as opposed to just emphasizing problems, vulnerab ht es, and deficits, a res liencybased perspective holds the belief that children, youth and their families. have strengths, reso~ce.s and the ability to cope with significant adversity in ways that are not only effective, but tend to result m mcreased ability to constructively respond to future adversity. with this in mind, a participatory research project sponsored by the united way of greater toronto was initiated to evaluate and determine the resiliency profiles of children - years (n = ) of recent immigrant families living in significantly disadvantaged communities in the toronto area. the presentation will provide an overview of the identified protective factors (both intrinsic and extrinsic) and resiliency profiles in an aggregated format as well as a summary of how the children and their parents interpreted and explained these strength-based results. as part of the focus groups, current community programs and services were examined by the participants as to what might be best practices for supporting the development and maintaining of resiliency in children, families and communities. it was proposed that the community model of assessing resiliency and protective factors as well as proposed best strength-based practice could serve as a guide for all in the community sector who provide services and programs to those in disadvantaged neighbourhoods. p - (c) naloxone by prescription in san francisco, ca and new york, ny emalie huriaux the harm reduction coalition's overdose project works to reduce the number of fatal overdoses to zero. located in new york, ny and san francisco, ca, the overdose project provides overdose education for social service providers, single-room occupancy hotel (sro) residents, and syringe exchange participants. the project also conducts an innovative naloxone prescription program, providing naloxone, an opiate antagonist traditionally administered by paramedics to temporarily reverse the effects of opiate overdose, to injection drug users (idus). we will describe how naloxone distribution became a reality in new york and san francisco, how the project works, and our results. the naloxone prescription program utilizes multiple models to reach idus, including sro-and street-based trainings, and office-based trainings at syringe exchange sites. trainings include information on overdose prevention, recognition, and response. a clinician conducts a medical intake with participants and provides them with pre-filled units of naloxone. in new york, funding was initially provided by tides foundation. new york city council provides current funding. new york department of mental health and hygiene provides program oversight. while the new york project was initiated in june , over half the trainings have been since march . in san francisco, california endowment, tides foundation, and san francisco department of public health (sfdph) provide funding. in addition, sfdph purchases naloxone and provides clinicians who conduct medical intakes with participants. trainings have been conducted since november . to date, nearly individuals have been trained and provided with naloxone. approximately of them have returned for refills and reported that they used naloxone to reverse an opiate-related overdose. limited episodes of adverse effects have been reported, including vomiting, seizure, and "loss of friendship." in new york, individuals have been trained and provided with naloxone. over overdose reversals have been reported. over half of the participants in new york have been trained in the south bronx, the area of new york with the highest rate of overdose fatalities. in san francisco, individuals have been trained and provided with naloxone. over overdose reversals have been reported. the majority of the participants in san francisco have been trained in the tenderloin, th street corridor, and mission, areas with the highest rates of overdose fatalities. the experience of the overdose project in both cities indicates that providing idus low-threshold access to naloxone and overdose information is a cost-effective, efficient, and safe intervention to prevent accidental death in this population. p - (c) successful strategies to regulate nuisance liquor stores using community mobilization, law enforcement, city council, merchants and researchers tahra goraya presenta~ion _will discuss ~uccessful environmental and public policy strategies employed in one southen: cahf?rmna commumty to remedy problems associated with nuisance liquor stores. participants ~ be given tools to understand the importance of utilizing various substance abuse prevention str~tegi~ to change local policies and the importance of involving various sectors in the community to a~_ st with and advocate for community-wide policy changes. recent policy successes from the commultles of pa~ad~na and altad~na will highlight the collaborative process by which the community mobilized resulnng m several ordmances, how local law enforcement was given more authority to monitor poster sessions v nonconforming liquor stores, how collaborative efforts with liquor store owners helped to remove high alcohol content alcohol products from their establishments and how a community-based organiz,uion worked with local legislators to introduce statewide legislation regarding the regulation of nuisance liquor outlets. p - (c) "dialogue on sex and life": a reliable health promotion tool among street-involved youth beth hayhoe and tracey methven introduction: street involved youth are a marginalized population that participate in extremely risky behaviours and have multiple health issues. unfortunately, because of previous abuses and negative experiences, they also have an extreme distrust of the adults who could help them. in , toronto public health granted funding to a non governmental, nor for profit drop-in centre for street youth aged - , to educate them about how to decrease rhe risk of acquiring hiv. since then the funding has been renewed yearly and the program has evolved as needed in order to target the maximum number of youth and provide them with vital information in a candid and enjoyable atmosphere. methods: using a retrospective analysis of the six years of data gathered from the "dialogue on sex and life" program, the researchers examined the number of youth involved, the kinds of things discussed, and the number of youth trained as peer leaders. also reviewed, was written feedback from the weekly logs, and anecdotal outcomes noted by the facilitators and other staff in the organization. results: over the five year period of this program, many of youth have participated in one hour sessions of candid discussion regarding a wide range of topics including sexual health, drug use, harm reduction, relationship issues, parenting, street culture, safety and life skills. many were new youth who had not participated in the program before and were often new to the street. some of the youth were given specific training regarding facilitation skills, sexual anatomy and physiology, birth control, sexually transmitted infections, hiv, substance use/abuse, harm reduction, relationships and discussion of their next steps/future plans following completion of the training. feedback has been overwhelmingly positive and stories of life changing decisions have been reported. conclusion: clearly, this program is a successful tool to reach street involved youth who may otherwise be wary of adults and their beliefs. based on data from the evaluation, recommendations have been made to public health to expand the funding and the training for peer leaders in order ro target between - new youth per year, increase the total numbers of youth reached and to increase the level of knowledge among the peer leaders. p - (c) access to identification and services jane kali replacing identification has become increasingly more complex as rhe government identification issuing offices introduce new requirements rhar create significant barriers for homeless people to replace their id. new forms of identification have also been introduced that art' not accessible to homekss peoplt-(e.g. the permanent resident card). ar rhe same time, many service providers continue to require identifi· cation ro access supports such as income, housing, food, health care, employment and employmt·nt training programs. street health, as well as a number of other agencies and community health centres, h, , been assisting with identification replacement for homeless peoplt· for a number of years. the rnrrt·nr challenges inherent within new replacement requirements, as well as the introduction of new forn ' of identification, have resulted in further barriers homeless people encounter when rrring to access t:ssential services. street health has been highlighting these issues to government identification issuing offices, as well as policy makers, in an effort to ensure rhar people who are homeless and marginalized have ac'ess to needed essential services. bandar is a somali word for •·a safe place." the bandar research project is the product of the regent park community health centre. the research looks ar the increasing number of somali and afri· can men in the homeless and precariously house population in the inner city core of down~own toronto. in the first phase of the pilot project, a needs assessment was conducted to dennfy barners and issues faced by rhe somali and other african men who are homeless and have add cr ns issues. th_e second phase of rhe research project was to identify long rerm resources and service delivery mechamsms that v poster sessions would enhance the abiity of this population to better access detox, treatment, and post treatment ser· vices. the final phase of the project was to facilitate the development of a conceptual model of seamless continual services and supports from the streets to detox to treatment to long term rehabilitation to housing. "between the pestle and mortar" -safe place. p - (c) successful methods for studying transient populations while improving public health beth hayhoe, ruth ewert, eileen mcmahon, and dan jang introduction: street youth are a group that do not regularly access healthcare because of their mis· trust of adults. when they do access health care, it is usually for issues severe enough for hospitalization or for episodic care in community clinics. health promotion and illness prevention is rarely a part of their thinking. thus, standard public health measures implemented in a more stable population do not work in this group. for example, pap tests, which have dearly been shown to decrease prevalence of cer· vical cancer, are rarely done and when they are, rarely followed up. methods to meet the health care needs and increase the health of this population are frequently being sought. methods: a drop-in centre for street youth in canada has participated in several studies investigating sexual health in both men and women. we required the sponsoring agencies to pay the youth for their rime, even though the testing they were undergoing was necessary according to public health stan· dards. we surmised that this would increase both initial participation and return. results: many results requiring intervention have been detected. given the transient nature of this population, return rates have been encouraging so far. conclusion: it seems evident that even a small incentive for this population increases participation in needed health examinations and studies. it is possible that matching the initial and follow-up incentives would increase the return rate even further. the fact that the youth were recruited on site, and not from any external advertising, indicates that studies done where youth trust the staff, are more likely to be successful. the presentation will share the results of the "empowering stroke prevention project" which incor· porated self-help mutual aids strategies as a health promotion methodology. the presentation will include project's theoretical basis, methodology, outcomes and evaluation results. self-help methodology has proven successful in consumer involvement and behaviour modification in "at risk," "marginalized" settings. self-help is a process of learning with and from each other which provides participants oppor· tunities for support in dealing with a problem, issue, condition or need. self-help groups are mechanisms for the participants to investigate existing solutions and discover alternatives, empowering themselves in this process. learning dynamic in self-help groups is similar to that of cooperative learning and peertraining, has proven successful, effective and efficient (haller et al, ) . the mutual support provided by participation in these groups is documented as contributory factor in the improved health of those involved. cognizant of the above theoretical basis, in the self-help resource centre initiated the "empowering stroke prevention project." the project was implemented after the input from health organizations, a scan of more than resources and an in-depth analysis of risk-factor-specific stroke prevention materials indicated the need for such a program. the project objectives were:• to develop a holistic and empowering health promotion model for stroke prevention that incorporates selfhelp and peer support strategies. • to develop educational materials that place modifiable risk factors and lifestyle information in a relevant context that validates project participants' life experiences and perspectives.• to educate members of at-risk communities about the modifiable risk factors associated with stroke, and promote healthy living. to achieve the above, a diverse group of community members were engaged as "co-editors" in the development of stroke prevention education materials which reflected and validated their life experiences. these community members received training to become lay health promoters (trained volunteer peer facilitators). in collaboration with local health organizations, these trained lay health promoters were then supported in organizing their own community-based stroke prevention activities. in addition, an educational booklet written in plain language, entitled healthy ways to prevent stroke: a guide for you, and a companion guide called healthy ways to pre· vent stroke: a facilitator's guide were produced. the presentation will include the results of a tw<>tiered evaluation of the program methodology, educational materials and the use of the materials beyond the life of the project. this poster presentation will focus on the development and structure of an innovative street outreach service that assists individuals who struggle mental illness/addictions and are experiencing homelessness. the mental health/outreach team at public health and community services (phcs) of hamilton, ontario assists individuals in reconnecting with health and social services. each worker brings to the ream his or her own skills-set, rendering it extremely effective at addressing the multidimensional and complex needs of clients. using a capacity building framework, each ream member is employed under a service contract between public health and community services and a local grassroots agency. there are public health nurses (phn), two of whom run a street health centre and one of canada's oldest and most successful needle exchange programs, mental health workers, housing specialists, a harm reduction worker, youth workers, and a united church minister, to name a few. a community advisory board, composed of consumers and professionals, advises the program quarterly. the program is featured on raising the roors 'shared learnings on homelessness' website at www.sharedlearnings.ca. through our poster presentation participants will learn how to create effective partnerships between government and grassroots agencies using a capacity building model that builds on existing programs. this study aims to assess the effects of broadcasting a series of documentary and drama videos, intended to provide information about the bc healthguide program in farsi, on the awareness about and the patterns of the service usage among farsi-speaking communities in the greater vancouver area. the major goals of the present study were twofold; ( ) to compare two methods of communications (direct vs. indirect messages) on the attitudes and perceptions of the viewers regarding the credibility of messengers and the relevance of the information provided in the videos, and ( ) to compare and contrast the impact of providing health information (i.e., the produced videos) via local tvs with the same materials when presented in group sessions (using vcr) on participants' attitudes and perceptions cowards the bc healrhguide services. results: through a telephone survey, farsi-speaking adults were interviewed in november and december . the preliminary findings show that % of the participants had seen the aired videos, from which, % watched at least one of the 'drama' clips, % watched only 'documentary' clip, and % watched both types of video. in addition, % of the respondents claimed that they were aware about the program before watching the aired videos, while % said they leaned about the services only after watching the videos. from this group, % said they called the bchg for their own or their "hildren's health problems in the past month. % also indicated that they would use the services in the future whenever it would be needed. % considered the videos as "very good" and thought they rnuld deliver relevant messages and % expressed their wish to increase the variety of subjects (produ\:e more videos) and increase the frequency of video dips. conclusion: the results of this study will assist public health specialists in bc who want to choose the best medium for disseminating information and apply communication interventions in multi\:ultural communities. introduction: many theorists and practitioners in community-based research (cbr) and knowledge transfer (kt) strongly advocate for involvement of potential users of research in the development of research projects, yet few examples of such involvement exist for urban workplace health interventions. we describe the process of developing a collaborative research program. methods: four different sets of stakeholders were identified as potential contributors to and users of the research: workplace health policy makers, employers, trade unions, and health and safety associations. representatives of these stakeholders formed an advisory committee which met quarterly. over the month research development period, an additional meetings were held between resc:ar~h~rs and stakeholders. in keeping with participant observation approaches, field notes of group and md v ~ ual meetings were kept by the two co-authors. emails and telephone calls were also documented. qu~h tative approaches to textual analysis were used, with particular attention paid to collaborattve v poster sessions relationships established (as per cbr), indicators of stakeholders' knowledge utilization (as per kt), and transformations of the proposed research (as per cbr). results: despite initial strong differences of opinion both among stakeho~ders .an~ between stakeholders and researchers, goodwill was noted among all involved. acts of rec~proc ty included mu.rual sharing of assessment tools, guidance on data utilization to stakeho~der orga~ zat ns, and suggestions on workplace recruitment to researchers. stakeholders demonstrated mcreases m concep~ual. un~erstand ing of workplace health e.g. they more commonly discussed more complex,. psychosocial md cators of organizational health. stakeholders made instrumental use of shared materials based on research e.g. adapting their consulting model to more sophisticated dat~ analysis. sta~ehol?~rs recogni_zed the strategic use of their alliance with researchers e.g., transformational leadership trainmg as a~ inducement to improve health and safety among small service franchises. stakeholders helped re-define the research questions, dramatically changed the method of recruitment from researcher cold call to stakeholderbased recruitment, and strongly influenced pilot research designs. owing a great deal to the elaborate joint development process, the four collaboratively developed pilot project submissions which were all successfully funded. conclusion: the intensive process of collaborative development of a research program among stakeholders and researchers was not a smooth process and was time consuming. nevertheless, the result of the collaborative process was a set of projects that were more responsive to stakeholder needs, more feasible for implementation, and more broadly applicable to relevant workplace health problems. introduction: environmental groups, municipal public health authorities and, increasingly, the general public are advocating for reductions in pesticide use in urban areas, primarily because of concern around potential adverse health impacts in vulnerable populations. however, limited evidence of the relative merits of different intervention strategies in different contexts exists. in a pilot research project, we sought to explore the options for evaluating pesticide reduction interventions across ontario municipalities. methods: the project team and a multi-stakeholder project advisory committee (pac), generated a list of potential key informants (kl) and an open ended interview guide. thirteen ki from municipal government, industry, health care, and environmental organizations completed face to face or telephone interviews lasting - minutes. in a parallel process, a workshop involving similar representatives and health researchers was held to discuss the role of pesticide exposure monitoring. minutes from pac meetings, field notes taken during ki interviews, and workshop proceedings were synthesized to generate potential evaluation methods and indicators. results: current evaluation activities were limited but all kls supported greater evaluation effons beginning with fuller indicator monitoring. indicators of education and outreach services were imponant for industry representatives changing applicator practices as well as most public health units and environmental organizations. lndictors based on bylaw enforcement were only applicable in the two cities with bylaws, though changing attitudes toward legal approaches were being assessed in many communities. the public health rapid risk factor surveillance system could use historical baseline data to assess changes in community behaviour through reported pesticide uses and practices, though it had limited penetration in immigrant communities not comfortable in english. pesticide sales (economic) data were only available in regional aggregates not useful for city specific change documentation. testing for watercourse or environmental contamination might be helpful, but it is sporadic and expensive. human exposure monitoring was fraught with ethical issues, floor effects from low levels of exposure, and prohibitive costs. clinical episodes of pesticide exposure reported to the regional poison centre (all ages) or the mother risk program (pregnant or breastfeeding women) are likely substantial underestimates that would be need to be supplemented with sentinel practice surveillance. focus on special clinical populations e.g., multiple chemical sensitivity would require additional data collection efforts . . conc~ons: broad support for evaluation and multiple indicators were proposed, though con-s~raints associate~ with access, coverage, sensitivity and feasibility were all raised, demonstrating the difficulty of evaluating such urban primary prevention initiatives. interventionists. an important aim of the youth monitor is to learn more about the health development of children and adolescents and the factors that can influence this development. special attention is paid to emo· tional and behavioural problems. the youth monitor identifies high-risk groups and factors that are associated with health problems. at various stages, the youth monitor chancrs the course of life of a child. the sources of informa· tion and methods of research are different for each age group. the results arc used to generate various kinds of repons: for children and young persons, parents, schools, neighbourhoods, boroughs and the municipality of rotterdam and its environs. any problems can be spotted early, at borough and neigh· bourhood level, based on the type of school or among the young persons and children themselves. together with schools, parents, youngsters and various organisations in the area, the municipal health service aims to really address these problems. on request, an overview is offered of potentially suitable interventions. the authors will present the philosophy, working method, preliminary effects and future developments of this instrument, which serves as the backbone for the rotterdam local youth policy. social workers to be leaders in response to aging urban populations: the practicum partnership program sarah sisco, alissa yarkony, and patricia volland "'" tliu:tion: across the us, . % of those over live in urban areas. these aging urban popu· lations, including the baby boomers, have already begun encounter a range of heahh and mental hcahh conditions. to compound these effects, health and social service delivery fluciuates in cities, whit:h arc increasingly diverse both in their recipients and their systems. common to other disciplines (medicine, nursing, psychology, etc.) the social work profession faces a shortage of workers who are well-equipped to navigate the many systems, services, and requisite care that this vast population requires. in the next two decades, it is projected that nearly , social workers will be required to provide suppon to our older urban populations. social workers must be prepared to be aging-savvy leaders in their field, whether they specialize in gerontology or work across the life span. mllhotu: in , a study conducted at the new york academy of medicine d<> :umcntcd the need for improved synchroniciry in two aspects of social work education, classroom instruction and the field experience. with suppon from the john a. hanford foundation, our team created a pilot proj~"t entitled the practicum pannership program (ppp) in master's level schools of social work, to improvt" aginr exposure in field and classroom content through use of the following: i) community-university partnrr· ships, ) increased, diverse student field rotations, ll infusion of competcn ."}'·drivm coursework, enhancement of field instructors' roles, and ) concentrated student recruitment. we conductt"d a prr· and post-test survey into students' knowledge, skills. and satisfaction. icarlja: surveys of over graduates and field inltnk."tors rcflected increased numlk-n of . rrm:y· univmity panncrships, as well as in students placed in aging agencin for field placements. there wa marked increase in student commitments to an aging specialization. onr year por.t·gradu:nion rcvealrd that % of those surveyed were gainfully employed, with % employed in the field of aginic. by com· bining curricular enhancement with real-world experiences the ppp instilled a broad exposurr for llu· dents who worked with aging populations in multiple urban settings. coltdtuion: increased exposure to a range of levels of practicr, including clinical, policy/ajvocaq, and community-based can potentially improve service delivery for older adulh who live in elfin, and potentially improve national policy. the hanford foundation has now elected to uppon cxpantion of the ppp to schools nationwide (urban and rural) to complement other domntic initiatives to cnhalk"c" holistic services for older adults across the aging spectrum. bodrgnn.ntl: we arc a team of rcscarcbcn and community panncn working tcj c(her to develop an in"itepth understanding of the mental health needs of homeless youth ~ages to ) (using qualiutivc and quantitative methods ' panicipatory rncarch methods). it is readily apparmt that '-neless youth cxpcricnce a range of mental health problems. for youth living on the street, menul illnew may be either a major risk factor for homelessnal or may frequently emcsge in response to coping with rhe multitudinous stressors associated with homclcslllcsi including exposure to violence, prasutt to pamaplte in v poster sessions survival sex and/or drug use. the most frequent psychiatric diagnoses amongst the homeless gencrally include: depression, anxiety and psychosis. . . . the ultimate ob ective of the pr~am of rei:e~ is to ~evelop a plan for intervention to meet the mental health needs of street youth. prior t_o pl~nnmg mtervenbons, .it is necessary to undertake a comprehensive assessment ~f mental health needs m this ~lnerable populanon. thus, the immediate objective of this research study is to undertake a comprehensive assessment of men· tal health needs. . . melbotlology: a mixed methodology triangulating qualitative, participatory acnon and quantitative methods will capture the data related to mental health needs of homeless youth. a purposive sample of approximately - subjecrs. ages to , is currently being ~ted ~participate from the commu.nity agencies covenant house, evergreen centre fo~ srrc;et youth, turning p? ?t and street ~ serv~. youth living on the street or in short -term residennal programs for a mmimum of month pnor to their participation; ages to and able to give infonned consent will be invited to participate in the study. o..tcomes: the expected outcome of this initial survey will be an increased understanding of mental health needs of street youth that will be used to develop effective interventions. it is anticipated that results from this study will contribute to the development of mental health policy, as well as future programs that are relevant to the mental health needs of street youth. note: it is anticipated that preliminary quantitative data ( subjects) and qualitative data will be available for the conference. the authors intend to present the identification of the research focus, the formation of our community-based team, relevance for policy, as well as preliminary results. p - (a) the need for developing a firm health policy for urban informal worken: the case of despite their critical role in producing food for urban in kenya, urban farmers have largely been ignored by government planners and policymakers. their activity is at best dismissed as peripheral eveo, inappropriate retention of peasant culture in cities and at worst illegal and often some-times criminal· ized. urban agriculture is also condemned for its presumed negative health impact. a myth that contin· ues despite proof to the contrary is that malarial mosquitoes breed in maize grown in east african towns. however, potential health risks are insignificant compared with the benefits of urban food production. recent studies too rightly do point to the commercial value of food produced in the urban area while underscoring the importance of urban farming as a survival strategy among the urban poor, especially women-headed households. since the millennium declaration, health has emerged as one of the most serious casualties consequent on the poverty, social exclusion, marginalisation and lack of sustain· able development in africa. hiv/aids epidemic poses an unprecedented challenge, while malaria, tuber· culosis, communicable diseases of childhood all add to the untenable burden. malnutrition underpins much ill-health and is linked to more than per cent of all childhood deaths. kenya's urban poor people ~ace ~ h~ge burde~ of preventable and treatable health problems, measured by any social and bi~ medical md cator, which not only cause unnecessary death and suffering, but also undermine econonuc development and damage the country's social fabric. the burden is in spite of the availability of suitable tools and re:c=hnology for prevention and treatment and is largely rooted in poverty and in weak healah •rstems. this pa~ therefore challenges development planners who perceive a dichotomy instead of con· tmuum between informal and formal urban wage earners in so far as access to health services is con· cemed. it i~ this gap that calls for a need to developing and building sustainable health systems among the urban mformal ~wellers. we recommend a focus on an urban health policy that can build and strengthen the capacity of urban dwellers to access health services that is cost-effective and sustainable. such ~ health poli<=>: must strive for equity for the urban poor, displaced or marginalized; mobilise and effect ~ely use sufficient sustainable resources in order to build secure health systems and services. special anenti_on. should ~ afforded hiv/aids in view of the unprecedented challenge that this epidemic poses to africa s economic and social development and to health services on the continent. methods: a review of the literature led us to construct three simple models and a composite model of exposure to traffic. the data were collected with the help of a daily diary of travel activities using a sample of cyclists who went to or come back from work or study. to calculate the distance, the length of journey, and the number of intersections crossed by a cyclist different geographic information systems (gis) were operated. statistical analysis was used to determine the significance between a measure of exposure on the one hand, and the sociodemographic characteristics of the panicipants or their geographic location on the other hand. restlltj: our results indicate that cyclists were significantly exposed to road accidents, no matter of where they live or what are their sociodemographic characteristics. we also stress the point that the fact of having been involved in a road accident was significantly related to the helmet use, but did not reduce the propensity of the cyclists to expose themselves to the road hazards. condlllion: the efforts of the various authorities as regards road safety should not be directed towards the reduction of the exposure of the vulnerable users, but rather towards the reduction of the dangers to which they could face. keywords: cyclist, daily diary of activities, measures of exposure to traffic, island of montreal. p - (a) intra urban disparities and environmental health: some salient features of nigerian residential neighbourhoods olumuyiwa akinbamijo intra urban disparities and environmental health: some salient features of nigerian residential neighbourhoods abstract urbanization panicularly in nigerian cities, ponends unprecedented crises of grave dimensions. from physical and demographic viewpoints, city growth rates are staggering coupled with gross inabilities to cope with the consequences. environmental and social ills associated with unguarded rapid urbanization characterize nigerian cities and threaten urban existence. this paper repons the findings of a recent study of the relationship between environmental health across inrraurban residential communities of akure, south west nigeria. it discuses the typical urbanization process of nigerian cities and its dynamic spatial-temporal characteristics. physical and socio-demographic attributes as well as the levels and effectiveness of urban infrastructural services are examined across the core residential districts and the elite residential layouts in the town. the incidence rate of cenain environmentally induced tropical diseases across residential neighborhoods and communes is examined. salient environmental variables that are germane to health procurement in the residential districts, incidence of diseases and diseases parasitology, diseases prevention and control were studied. field data were subjected to analysis ranging from the univariate and bivariate analysis. inferential statistics using the chi-square test were done to establish the truthfulness of the guiding hypothesis. given the above, the study affirms that there is strong independence in the studied communities, between the environment and incidence of diseases hence health of residents of the town. this assertion, tested statistically at the district levels revealed that residents of the core districts have very strong independence between the environment and incidences of diseases. the strength of this relationship however thins out towards the city peripheral districts. the study therefore concludes that since most of the city dwellers live in urban deprivation, urban health sensitive policies must be evolved. this is to cater for the urban dwellers who occupy fringe peripheral sites where the extension of facilities often times are illegally done. urban infrastructural facilities and services need be provided as a matter of public good for which there is no exclusive consumption or access even for the poorest of the urban poor. many suffer from low-self esteem, shame and guilt about their drug use. in addition, they often lack suppon or encounter opposition from their panners, family and friends in seeking treatment. these personal barriers are compounded by fragmented addiction, prenatal and social care services, inflexible intake systems and poor communication among sectors. the experience of accessing adequate care between services can be overwhelming and too demanding. the toronto centre for substance use in pregnancy (t-cup) is a unique program developed to minimize barriers by providing kone-stop" comprehensive healthcare. t-cup is a primary care based program located in the department of family medicine at st. joseph\'s health centre, a community teaching hospital in toronto. the interdisciplinary staff provides prenatal and addiction services, case management, as well as care of newborns affected by substance use. regular care plan meetings are held between t-cup, labour and delivery nurses and social workers in the y poster sessions maternity and child care program. t-cup also connects "'.omen with. inpatient treatment programs and community agencies such as breaking the cycle, an on-site counselmg group for pregnant substance users. · f · d d h ith method: retrospective chart review, qualitative patient ~ans action stu ~· an ea care provider surveys are used to determine outcomes. primary outcomes mclude changes m maternal su~tance use, psychosocial status and obstetrical complications (e.g. pre-rupture of membrane, pre-eclampsia, placen· ral abruption and hemorrhage). neonatal measures ~~nsisted of .bir~h pa_rame~ers, length of h~spital st.ay and complications (e.g. feral distress, meconium stammg, resuscitation, aund ce, hypoglycemia, seventy of withdrawal and treatment length). chart review consisted of all t-cup patients who met clinical cri· reria for alcohol or drug dependence and received prenatal and intra-partum care at st. joseph's from october to june . participants in the qualitative study included former and current t-cup patients. provider surveys were distributed on-site and to a local community hospital. raulb: preliminary evaluation has demonstrated positive results. treatment retention and satisfaction rates were high, maternal substance use was markedly reduced and neonatal outcomes have shown to be above those reported in literature. conclusion: this comprehensive, primary care model has shown to be optimal in the management of substance use in pregnancy and for improving neonatal outcomes. future research will focus on how this inexpensive program can be replicated in other health care settings. t-cup may prove to be the optimal model for providing care to pregnant substance users in canada. lntrod ction: cigarette smoking is one of the most serious health problems in taiwan. the prevalence of smoking in is . % in males . % in females aged years and older. although the government of taiwan passed a tobacco hazards control act in , it has not been strongly enforced in many places. therefore, community residents have often reported exposure of second hand smoke. the purpose of the study was to establish a device to build up more smoke-free environments in the city of tainan. methods: unique from traditional intervention studies, the study used a healthy city approach to help build up smoke-free environments. the major concept of the approach is to build up a healthy city platform, including organizing a steering committee, setting up policies and indicators, creating intersectoral collaboration, and increasing community participation. first, more than enthusiastic researchers, experts, governmental officers, city counselors and community leaders in tainan were invited in the healthy city committee. second, smoke-free policies, indicators for smoke-free environments, and mechanisms for inter-departmen· tal inspections were set up. third, community volunteers were recruited and trained for persuading related stakeholders. lastly, both penalties and rewards were used for help build up the environments. raults: aher two-year ( aher two-year ( - execution of the project, the results qualitatively showed that smoke-free environments in tainan were widely accepted and established, including smoke-free schools, smoke-free workpla~es, smoke-free households, smoke-free internet shops, and smoke-free restaurants. smoke~s were. effectively educated not to smoke in public places. community residents including adults and children m the smoke-free communities clearly understand the adverse effects of environmental tobacco smoke and actively participated anti-smoking activities. conclruions: healthy city platform is effective to conquer the barrier of limited anti-smoking rc:sources. nor. only can it enlar:ge community actions for anti-smoking campaigns, but also it can provide par_merships for collaboratjon. by establishing related policies and indicators the effects of smoke· free environments can be susta ·ned a d th · · · ' · n e progression can be monitored m a commuruty. these issues are used ~· oi::c it~ goals, weuha identifies issues that put people's health at risk. presently, team com~u:c: ran ee~tion !earns. (iats) that design integrative solutions ~tesj'°~ g om six to fifteen members. methods in order to establish wo-poster sessions v projects for weuha, the following approach was undertaken: i. a project-polling template was created and sent to all members of the alliance for their input. each member was asked to identify thdr top two population groups, and to suggest a project on which to focus over a - month period for each identified population. . there was a % response to the poll and the top three population groups were identified. data from the toronto community health profile database were utilized to contextualize the information supplied for these populations. a presentation was made to the steering committee and three population-based projects were selected, leaders identified and iats formed. three population-based projects: the population-based projects and health care issues identified are: newcomer prenatal uninsured women; this project will address the challenges faced by providers to a growing number of non-insured prenatal women seeking care. a service model where the barrier of "catchments" is removed to allow enhanced access and improved and co-ordinated service delivery will be pilot-tested. children/obesity/diab etes: using a health promotion model this team will focus on screening, intervention, and promoting healthy lifestyles (physical activity and nutrition) for families as well as for overweight and obese children. seniors health promotion and circle of discharge: this team will develop an early intervention model to assist seniors/family unit/caregivers in accessing information and receiving treatment/care in the community. the circle of discharge initiative will address ways of utilizing community supports to keep seniors in the community and minimize readmissions to acute care facilities. results/expected outcomes: coordinated and enhanced service delivery to identified populations, leading to improved access, improved quality of life, and health care for these targeted populations. introduction: basic human rights are often denied to high-risk populations and people living with hiv/aids. their rights to work and social security, health, privacy, non discrimination, liberty and freedom of movement, marriage and having a family have been compromised due to their sero-positive status and risk of being positive. the spread of hiv/aids has been accelerating due to the lack of general human rights among vulnerable groups. to formulate and implement effective responses needs dialogue and to prevent the epidemic to go underground barriers like stigma need to be overcome. objective: how to reduce the situation of stigma, discrimination and human rights violations experienced by people living with hiv/aids and those who are vulnerable to hiv/aids. methodology and findings: consultation meetings were strm.-rured around presentations, field visits, community meetings and group work to formulate recommendations on how govt and ngos/cbos should move forward based on objective. pakistan being a low prevalence country, the whole sense of compl;u:enc.:y that individuals are not subject to situations of vulnerable to hiv is the major threat to an explosion in th•· epidemic, therefore urgent measures are needed to integrate human rights issues from the very start of the response. the protection and promotion of human rights in an integral component of ;tll responses to the hiv/aids epidemic. it has been recognized that the response to hiv/aios must he multi sectoral and multi faceted, with each group contributing its particular expertise. for this to occur along with other knowlcdg<" more information is required in human rights abuses related to hiv/ aids in a particular scenario. the ~·on sultarion meetings on hiv/aids and human rights were an exemplary effort to achieve the same ohj<..:tivc. recommendations: the need for a comprehensive, integrated and a multi-sectoral appro;u.:h in addressing the issue of hiv/aids was highlighted. the need social, cultural and religious asp•·ct' to he: prominently addressed were identified. it was thought imperative measures even in low prevalence countries. education has a key role to play, there is a need for a code of ethics for media people and h<"alth care providers and violations should be closely monitored and follow up action taken. p - (c) how can community-based funding programs contribute to building community capacity and how can we measure this elusive goal? mary frances maclellan-wright, brenda cantin, mary jane buchanan, and tammy simpson community capacity building is recognized by the public health agency of canada (phac) as an important strategy for improving the overall health of communities by enabling communities to addre~s priority issues such as social and economic determinants of health. in / phac.:, alberta/nwf region's population health fund (phf) supported community-based projects to build community capacity on or across the determinants of health. specifically, this included creating accessible and sup· portive social and physical environments as well as creating tools and processes necessary for healthy policy development and implementation. the objective of this presentation is to highlight how the community capacity building tool, developed by phac ab/nwf region, can demonstrate gains in v poster sessions · · the course of a pror· ect and be used as a reflective tool for project planning and community capacity over . . . . i · a art of their reporting requirements, pro ect sites completed the community caparny eva uanon. s p . . th t i ii i'd d . building tool at the beginning and end of their ~ne-year prorect. e oo ~o ects va an reliable data in the context of community-based health prorects. developed through a vigorous ~nd collabora ve research process, the tool uses plain languag~ to expl~re nine key f~atures o~ commuruty cap~city with 't ch with a section for contextual information, of which also mdude a four-pomt raong ems, ea f fu d · scale. results show an increase in community capacity over the course o the nde prorects. pre and post aggregate data from the one-year projects measure~ statistic.ally si~n~ficant changes for of the scaled items. projects identified key areas of commumty capacity bmldmg that needed strengthemng, such as increasing participation, particularly among people with low incomes; engaging community members in identifying root causes; and linking with community groups. in completing the tool, projects examined root causes of the social and economic determinants of health, thereby exploring social justice issues related to the health of their community. results of the tool also served as a reflec· cion on the process of community capacity building; that is, how the project outcomes were achieved. projects also reported that the tool helped identify gaps and future directions, and was useful as a project planning, needs assessment and evaluation tool. community capacity building is a strategy that can be measured. the community capacity building tool provides a practical means to demonstrate gains in community capacity building. strengthening the elements of community capacity building through community-based funding can serve as building blocks for addressing other community issues. needs of marginalized crack users lorraine barnaby, victoria okazawa, barb panter, alan simpson, and bo yee thom background: the safer crack use coalition of toronto (scuc) was formed in in response to the growing concern for the health and well-being of marginalized crack users. a central concern was the alarm· ing hepatitis c rate ( %) amongst crack smokers and the lack of connection to prevention and health ser· vices. scuc is an innovative grassroots coalition comprised of front-line workers, crack users, researcher! and advocates. despite opposition and without funding, scuc has grown into the largest crack specific harm reduction coalition in canada and developed a nationally recognized sarer crack kit distribution program (involving community-based agencies that provide outreach to users). the success of our coalition derives from our dedication to the issue and from the involvement of those directly affected by crack use. setting: scuc's primary service region is greater toronto, a diverse, large urban centre. much ofour work is done in areas where homeless people, sex trade workers and drug users tend to congregate. recently, scuc has reached out to regional and national stakeholders to provide leadership and education. mandate: our mandate is to advocate for marginalized crack users and support the devdopmentof a com.p.rehensive harm reduction model that addresses the health and social needs facing crack users; and to fac htare the exchange of information between crack users, service providers, researchers, and policy developers across canada. owrview: the proposed workshop will provide participants with an overview of the devdopment of scuc, our current projects (including research, education, direct intervention and consultation), our challenge~ and s~ccesses and the role of community development and advocacy within the coalition. pre-senter~ will consist of community members who have personal crack use experience and front-line work· ers-, sc.uc conducted a community-based research project (toronto crack users perspectives, ) , in w~ich s focus groups with marginalized crack users across toronto were conducted. participants iden· t f ed health and social issues affecti h b · · · d " red . . ng t em, arrsers to needed services, personal strategies, an oue recommendations for improved services. presenters will share the methodology, results and recommen· datmns resulting from the research project. conc/usio": research, field observations and consultations with stakeholders have shown that cradck shmoke~s are at an. increased risk for sexually transmitted infections hiv/aids hepatitis c, tb an ot er serious health issues health · ff, · ' ' · · . · issues a ectmg crack users are due to high risk behavmurs, socio· economic factors, such as homeless d. · · · · d · . . ness, scrsmmat on, unemployment, violence incarceraoons, an soc a so at on, and a lack of comprehe · h i h · ' ns ve ea t and social services targeting crack users. · · sinct · s, owever arge remains a gross underesurnaoon. poster sessions v these are hospital-based reports and many known cases go unreported. however teh case, young age at first intercourse, inconsistent condom use and multiple partnersplace adolescents at high risks for a diverse array of stls, including hiv. about % of female nigerian secondary school students report initiating sexual intercourse before age years. % of nigerian female secondary school students report not using a condom the last time they had sexual intercourse. more than % of urban nigerian teens report inconsistent condom use. methods: adolescents were studied, ages to , from benin city in edo state. the models used were mother-daughter( ), mother -son( ), father -son ( ), and father-daughter( ). the effect of parent-child sexual communicationat baseline on child\'s report of sexual behavior, to months later were studied. greater amounts of sexual risk communication were asociated with markedly fewer episodes of unprotected sexual intercourse, reduced number of sexual partners and fewer episodes of unprotected sexual intercourse. results: this study proved that parents can exert more influence on the sexual knowledge attitudes and practise of their adolescent children through desired practises or rolemodeling, reiterating their values and appropriate monitoring of the adolescents\' behavior. they also stand to provide information about sexuality and various sexual topics. parental-child sexual communication has been found to be particularly influential and has been associated with later onset of sexual initiation among adolescents, less sexual activity, more responsible sexual attitudes including greater condom use, self efficacy and lower self -reported incidence of stis. conclusions: parents need to be trained to relate more effectively with their children/wards about issues related to sex and sexuality. family -based programs to reduce sexual risk-taking need to be developed. there is also the need to carry out cross-ethnicaland cross-cultural studies to identify how parent-child influences on adolescent sexual risk behavior may vary in different regions or countries, especially inthis era of the hiv pandemic. introduction: public health interventions to identify and eliminate health disparities require evidence-based policy and adequate model specification, which includes individuals within a socioecological context, and requires the integration of biosociomedical information. multiple public and private data sources need to be linked to apportion variation in health disparities ro individual risk factors, the health delivery system, and the geosocial environment. multilevel mapping of health disparities furthers the development of evidence-based interventions through the growth of the public health information network (phin-cdc) by linking clinical and population health data. clinical encounter data, administrative hospital data, population socioenvironmental data, and local health policy were examined in a three-level geocoded multilevel model to establish a tracking system for health disparities. nj has a long established political tradition of "home rule" based in elected municipal governments, which are responsible for the well-being of their populations. municipalities are contained within counties as defined by the us census, and health data are linked mostly at the municipality level. marika schwandt community organizers from the ontario coaliti~n again~t pove~, .along ":ith ~edical practitioners who have endorsed the campaign and have been mvolved m prescnbmg special diet needs for ow and odsp recipients, will discuss the raise the rates campaign. the organizati~n has used a special diet needs supplement as a political tool, meeting the urgent needs o.f .poor ~ople m toront~ while raising the issues of poverty as a primary determinant of health and nutrtnous diet as a preventative health mea· sure. health professionals carry the responsibility to ensure that they use all means available to them to improve the health of the individuals that they serve, and to prevent future disease and health conditions. most health practitioners know that those on social assistance are not able to afford nutritious foods or even sufficient amounts of food, but many are not aware of the extra dietary funds that are available aher consideration by a health practitioner. responsible nurse practitioners and physicians cannot, in good conscience, ignore the special needs diet supplement that is available to all recipients of welfare and disabiliry (ow and odsp). a number of toronto physicians have taken the position that all clients can justifiably benefit from vitamins, organic foods and high fiber diets as a preventative health measure. we know that income is one of the greatest predictors of poor health. the special needs diet is a health promotion intervention which will prevent numerous future health conditions, including chronic conditions such as cardiovascular disease, cancer, diabetes and osteoporosis. many communiry health centres and other providers have chosen to hold clinics to allow many patients to get signed up for the supplement at one time. initiated by the ontario coalition against poverty, these clinics have brought together commu· niry organizers, community health centers, health practitioners, and individuals, who believe that poverty is the primary determinant of poor health. we believe that rates must be increased to address the health problems of all people on social assistance, kids, elders, people with hiv/aids -everyone. even in the context of understaffing, it could be considered a priority activity that has potentially important health promotion benefits. many clients can be processed in a two hour clinic. most providers find it a very interesting, rewarding undertaking. in the ontario coalition for social justice found that a toronto family with two adults and two kids receives $ , . this is $ , below the poverty line. p - (c) the health of street youth compared to similar aged youth beth hayhoe and ruth ewert . lntrod~on: street youth are at an age normally associated with good health, but due to their risky ~hav ours and th~ conditions in which they live, they experience health conditions unlike their peer~ an more stable env r~nments. in addition, the majority of street youth have experienced significant physical, sexual ~nd em.ot onal abuse as younger children, directly impacting many of the choices they make around their physical and emotional health. we examined how different their health really is. . , methodl: using a retrospective analysis of the years of data gathered from yonge street mis· ~ • evergreen health centre, the top conditions of youth were examined and compared with national tren~s for similar aged youth. based on knowledge of the risk factors present in the group, rea· sons for the difference were examined. d' ~its: street youth experience more illness than other youth their age and their illnesses can bt . irect t ·~kc~ to the. conditions in which they live. long-term impacts of abus~ contribute to such signif· ~~nt t e t d~slpl air that youth may voluntarily engage in behaviours or lack of self care in the hope at t cir ve~ w perhaps come to a quicker end. concl non: although it has ion b k h th' dy clearly shows d'fi . h g ee~ no~n t at poverty negatively affects health, ~siu be used to make ; erence m t .e health of this particular marginalized population. the infonnanon can relates to th . ecommendatio.ns around public policy that affects children and youth, especially as it e r access to appropriate health care and follow up. p - (cl why do urban children · b gt . tarek hussain an adesh die: how to save our children? the traditional belief that urban child alid. a recent study (dhs d fr r~n are better off than rural children might be no longer v urban migrants are highata th om h c~untn~s i demonstrates that the child survival prospects of rural· er an t ose m their r j · · ·grants. in bangladesh, currently million ~r~ ~ gm and lower than those of urban non-idi million. health of the urban ~ p~e are hvmg m urban area and by the year , it would be so the popu at on s a key a eals that urban poor have the worse h h . concern. recent study on the urban poor rev ea t situation than the nation as a whole. this study shows that infant poster sessions v mortality among the urban poor as per thousand, which are above the rural and national level estimates. the mortality levels of the dhaka poor are well above those of the rest of the city's population but much of the difference in death rates is explained by the experience of children, especially infants. analyzing demographic surveillance data from a large zone of the city containing all sectors of the population, research showed that the one-fifth of the households with the least possessions exhibited u child mortality almost three times as high as that recorded by the rest of the population. why children die in bangladesh? because their parents are too poor to provide them with enough food, clean water and other basic needs to help them avoid infection and recover from illness. researchers believed that girls are more at risk than boys, as mothers regularly feed boys first. this reflects the different value placed on girls and boys, as well as resources which may not stretch far enough to provide for everyone. many studies show that housing conditions such as household construction materials and access to safe drinking water and hygienic toilet facilities are the most critical determinants of child survival in urban areas of developing countries. the present situation stressed on the need for renewed emphasis on maternal and child healthcare and child nutrition programs. mapping path for progress to save our children would need be done strategically. we have the policies on hand, we have the means, to change the world so that every child will survive and has the opportunity to develop himself fully as a healthy human being. we need the political will--courage and determination to make that a reality. p - (c) sherbourne health centre: innovation in healthcare for the transgendered community james read introduction: sherbourne health centre (shc), a primary health care centre located in downtown toronto, was established to address health service gaps in the local community. its mission is to reduce barriers to health by working with the people of its diverse urban communities to promote wellness and provide innovative primary health services. in addition to the local communities there are three populations of focus: the lesbian, gay, bisexual, transgendered and transexual communities (lgbtt); people who are homeless or underhoused; and newcomers to canada. shc is dedicated to providing health services in an interdisciplinary manner and its health providers include nurses, a nurse practitioner, mental health counsellors, health promoters, client-resource workers, and physicians. in january shc began offering medical care. among the challenges faced was how to provide responsive, respectful services to the trans community. providers had considerable expertise in the area of counselling and community work, but little in the area of hormone therapy -a key health service for those who want to transition from one gender to another. method: in preparing to offer community-based health care to the trans community it was clear that shc was being welcomed but also being watched with a critical eye. trans people have traditionally experienced significant barriers in accessing medical care. to respond to this challenge a working group of members of the trans community and health providers was created to develop an overall approach to care and specific protocols for hormone therapy. the group met over a one year period and their work culminated in the development of medical protocols for the provision of hormone therapy to trans individuals. results: shc is currently providing health care to registered clients who identify as trans individuals (march ) through primary care and mental health programs. in an audit of shc medical charts (january to september ) female-to-male (ftm) and male-to-female (mtf) clients were identified. less than half of the ftm group and just over two-thirds of the mtf group presented specifically for the provision of hormones. based on this chart audit and ongoing experience shc continues to update and refine these protocols to ensure delivery of quality care. conclusion: this program is an example of innovative community-based health delivery to a population who have traditionally faced barriers. shc services also include counselling, health promotion, outreach and education. p - (c) healthy cities for canadian women: a national consultation sandra kerr, kimberly walker, and gail lush on march , the national network on environment and women's health held a pan-canadian consultation to identify opportunities for health research, policy change, and action. this consultation also worked to facilitate information sharing and networking between canadian women working as urban planners, policy makers, researchers, and service workers on issues pertaining to the health of women living in canadian cities. methods: for this research project, participants included front-line service workers, policy workers, researchers, and advocates from coast to coast, including francophone women, women with disabilities, racialized women, and other marginalized groups. the following key areas were selected as topics for du.bnes i alto kading .:auk of end·sugr ieaal clileue ia singapore, accounting for more than so% of new can singapore (nkfs) to embark on a prevention program (pp) empo~r d ahc j u f dieir condition bttter, emphasizing education and disease sdf·managemen lkilla a. essennal camponenn of good glycaemic control. we sought explore the effects of a pecialijed edu.:a on pro· pun od glycacmic conuol, as indicated by, serum hba ic values budine serum hba ic values were determined before un<k-rgmng the education progr ;am, which couisted of comprehensive dietary advice, ideal weight goals, and improving lipid profiln. serum hbaic values were obtained ar , , months later to determine impact of the program. analy • wu done uling paired !·tests significant reduction in hba le levels from ro month• was observed in females, chinese race, older age group(> so yean). ohew-ibmi ~ .nwm , wai hip ratio> l),up to primary and above secondary level education and those having om urine iclt showed that increasing hbalc levels ( ) had increasing urmary protein ( .± ; . ±i ih so± ) and crearinine (s .s ± s ± ; ioi± s) levels fbg rnults showed that the management nf d abetn m the nkfs preven· tion programme is effec;rive. results also indicated har hba le leve have a linnr trend wnh unnary protein and creatinine which are imponant determinants of renal diseate tal family-focused cinical palbway promoce politivc outcollln for ua inner city canu allicy ipmai jerrnjm care llctivirits in preparation for an infanr'' dilchargr honlr, and art m endnl lo improve effi.:k'fl.:tn of c.are. lere i paucity of tttran:h, and inconsi trncy of rnulta on ht-•m!*- of f m ly·fc"-'uw d nm a: to determinr whrthrr implrmentation of family.focuted c:pt n ntnn.tt.tl unit w"n mg an inner city ;ommunity drcl't'aki leftarh of lf•y (i.osi and rromclll'i family uo•fkllon and rt. j nest for dikhargr. md odt: family-focuk"d cpi data wm coll«ted for all infant• horn btrwttn and wft"k• t"lal mi atr who wrtt . dm ed to the ntonatal unit lmgdl of -.y . n. . day'o p c o.osi ind pma . d•mr., ho.nr . t . n. . ± i. i wb, p < o.os) wett n« fiamly f.lfrt n the pre.(]' poup. ~ .fxtmon icofn for famihn wrre high. and families noctd thc:y wnr mott prepued to ah thrar t..lby "'-· thett was .a cosi uving of s , (cdn) per patient d teharpd home n the pmi-cp poap c.-pated the p"''lfoup· cortclaion· lmplrmrnr.rion of family·foanrd c:p. in a nrona . i umt tc"fyidi an nnn an com· muniry decre.ned length of'"'" mft with a high dcgrft of family uujamon, and wrre coll~nt at least % percent of the kathmandu population lives in slum like conditions with poor access to basic health services. in these disadvantaged areas, a large proportion of children do not receive treatment due to inaccessibility to medical services. in these areas, diarrhea, pneumonia, and measles, are the key determinants of infant mortality. protein energy malnutrition and vitamin a deficiency persists and communicable diseases are compounded by the emergence of diseases like hiv/aids. while the health challenges for disadvantaged populations in kathmandu are substantial, the city has also experienced various forms of innovative and effective community development health programs. for example, there are community primary health centers established by the kathmandu municipality to deliver essential health services to targeted communities. these centers not only provide equal access to health services to the people through an effective management system but also educate them hy organizing health related awareness programs. this program is considered one of the most effective urban health programs. the paper/presentation this paper will review large, innovative, and effective urhan health programs that are operating in kathmandu. most of these programs are currently run by international and national ngos a) early detection of emerging diseases in urban settings through syndromic surveillance: data pilot study kate bassil of community resources, and without adequate follow-up. in november shelter pr.oviders ~et with hospital social workers and ccac to strike a working group to address some of th~ issues by mcre.asing knowledge among hospital staff of issues surrounding homelessness, and to build a stro?g workmg relationship between both systems in hamilton. to date the hswg has conducted four w~lkmg to~ of downtown shelters for hospital staff and local politicians. recently the hswg launched its ·~ool.k t for staff working with patients who are homeless', which contains community resources and gu dehnes to help with effective discharge plans. a scpi proposal has been submitted to incre~se the capacity of the hswg to address education gaps and opportunities with both shelters and hospitals around homelessness and healthcare. the purpose of this poster presentation is to share hamilton's experience and learnings with communities who are experiencing similar issues. it will provide for intera~tion around shared experiences and a chance to network with practitioners across canada re: best practices. introduction and objectives: canadians view health as the biggest priority for the federal government, where health policies are often based on models that rely on abstract definitions of health that provide little assistance in the policy and analytical arena. the main objectives of this paper are to provide a functional definition of health, to create a didactic model for devising policies and determining forms of intervention, to aid health professionals and analysts to strategize and prioritize policy objectives via cost benefit analysis, and to prompt readers to view health in terms of capacity measures as opposed to status measures. this paper provides a different perspective on health, which can be applied to various applications of health such as strategies of aid and poverty reduction, and measuring the health of an individual/ community/country. this paper aims to discuss theoretical, conceptual, methodological, and applied implications associated with different health policies and strategies, which can be extended to urban communities. essentially, our paper touches on the following two main themes of this conference: •health status of disadvantaged populations; and •interventions to improve the health of urban communities.methodology: we initially surveyed other models on this topic, and extrapolated key aspects into our conceptual framework. we then devised a theoretical framework that parallels simple theories of physkal energy, where health is viewed in terms of personal/societal health capacities and effort components.after establishing a theoretical model, we constructed a graphical representation of our model using selfrated health status and life expectancy measures. ultimately, we formulated a new definition of health, and a rudimentary method of conducting cost benefit analysis on policy initiatives. we end the paper with an application example discussing the issues surrounding the introduction of a seniors program.results: this paper provides both a conceptual and theoretical model that outlines how one can go about conducting a cost-benefit analysis when implementing a program. it also devises a new definition and model for health barred on our concept of individual and societal capacities. by devising a definition for health that links with a conceptual and theoretical framework, strategies can be more logically constructed where the repercussions on the general population are minimized. equally important, our model also sets itself up nicely for future microsimulation modeling and analysis.implications: this research enhances one's ability to conduct community-based cost-benefit analysis, and acts as a pedagogical tool when identifying which strategies provide the best outcome. p - (a) good playgrounds are hard to find: parents' perceptions of neighbourhood parks patricia tucker, martin holmes, jennifer irwin, and jason gilliland introduction: neighbourhood opportunities, including public parks and physical activity or sports fields hav~ been. iden.tified as correlates to physical activity among youth. increasingly, physical activity among children s bemg acknowledged as a vital component of children's lives as it is a modifiable determinant of childh~d obesity. children's use of parks is mainly under the influence of parents; therefore, the purpose of this study was to assess parents' perspectives of city parks, using london ontario as a case study.m~~: this qualitative study targeted a heterogeneous sample of parents of children using local parks w thm london. parents with children using the parks were asked for minutes of their time and if willing, a s.hort interview was conducted. the interview guide asked parents for their opinion 'of city parks, particularly the one they were currently using. a sample size of parents is expected by the end of the summer.results: preliminary findings are identifying parents concern with the current jack of shade in local parks. most parents have identified this as a limitation of existing parks, and when asked what would make the parks better, parents agree that shade is vital. additionally, some parents are recognizing the v poster sessions focused discussions during the consultation: . women in _poverty . women with disability . immi· grant and racialized women . the built and _physica_l environment. . . . . r its· participants voiced the need for integration of the following issues withm the research and policy :::na; t) the intersectional nature of urban women's health i~sues wh~ch reflects the reality of women's complex lives ) the multisectional aspect of urban wo_m~n s health, ss~es, which reflects the diversity within women's lives ) the interse~roral _dynamics within _womens hves and urban health issues. these concepts span multiple sectors -mdudmg health, educat n, and economics -when leveraging community, research, and policy support, and engaging all levels of government.policy jmplicatiom: jn order to work towards health equity for women, plans for gender equity must be incorporated nationally and internationally within urban development initiatives: • reintroduce "women" and "gender" as distinct sectors for research, analysis, advocacy, and action. •integrate the multisectional, intersectional, and intersecroral aspects of women's lives within the framework of research and policy development, as well as in the development of action strategies. • develop a strategic framework to house the consultation priorities for future health research and policy development (for example, advocacy, relationship building, evidence-based policy-relevant research, priority initiatives}.note: research conducted by nnewh has been made possible through a financial contribution from health canada. the views expressed herein do not necessarily represent the views of health canada.p - (c) drugs, culture and disadvantaged populations leticia folgar and cecilia rado lntroducci n: a partir de un proyecto de reducci n de daiios en una comunidad urbana en situ· aci n de extrema vulnerahilidad surge la reflexion sobre el lugar prioritario de los elementos sociocuhurales en el acceso a los servicios de salud de diferentes colectivos urbanos. las "formas de hacer, pensar y sentir" orientan las acciones y delimitan las posibilidades que tienen los individuos de definir que algo es o no problema, asf como tambien los mecanismos de pedido de ayuda. el analisis permanenre del campo de "las culturas cotidianas" de los llamados "usuarios de drogas" aporta a la comprension de la complejidad del tema en sus escenarios reales, y colabora en los diseiios contextualizados de politicas y propuestas socio-sanitarias de intervenci n, tornandolas mas efectivas.mitodos: esta experiencia de investigaci n-acci n que utiliza el merodo emografico identifica elementos socio estructurales, patrones de consumo y profundiza en los elementos socio-simb icos que estructuran los discursos de los usuarios, caracterizandolos y diferenciandolos en tanto constitutivos de identidades socia les que condicionan la implementaci n del programas de reduccion de daiios.resultados: los resultados que presentaremos dan cuenta de las caracteristicas diferenciadas v relaciones particulares ~ntre los consumidores de drogas en este contexto espedfico. a partir de este e~tudio de caso se mtentara co ? enzar a responder preguntas que entendemos significativas a la hora de pensar intcrvcnciones a la med da de poblaciones que comparten ciertas caracteristicas socio-culturales. (cuales serian las .motivaciones para el cambio en estas comunidades?, cque elementos comunitarios nos ayudan a i:nnstnur dema~~a? • cque tenemos para aprender de las "soluciones" que ellos mismos encuenrran a los usos problemat cos? methods: our study was conducted by a team of two researchers at three different sites. the mapping consisted of filling in a chart of observable neighbourhood features such as graffiti, litter, and boarded housing, and the presence or absence of each feature was noted for each city block. qualitative observations were also recorded throughout the process. researchers analyzed the compiled quantitative and qualitative neighbourhood data and then analyzed the process of data collection itself.results: this study reveals the need for further research into the effects of physical environments on individual health and sense of well-being, and perception of investment in neighbourhoods. the process reveals that perceptions of health and safety are not easily quantified. we make specific recommendations about the mapping methodology including the importance of considering how factors such as researcher social location may impact the experience of neighbourhoods and how similar neighbourhood characteristics are experienced differently in various spaces. further, we discuss some of the practical considerations around the mapping exercise such as recording of findings, time of day, temperature, and researcher safety.conclusion: this study revealed the importance of exploring conceptions of health and well-being beyond basic physical wellness. it suggests the importance of considering one's environment and one's own perception of health, safety, and well-being in determining health. this conclusion suggests that attention needs to be paid to the connection between the workplace and the external environment it is situated in. the individual's workday experience does not start and stop at the front door of their workplace, but rather extends into the neighbourhood and environment around them. our procedural observations and recommendations will allow other researchers interested in the effect of urban environments on health to consider using this innovative methodology. introduction: responding ro protests against poor medical attention for sexually assaulted women and deplorable conviction rates for sex offenders, in the late s, the ontario government established what would become over hospital-based sexual assault care and treatment centres (sactcs) across the province. these centres, staffed around the clock with specially trained heath care providers, have become the centralized locations for the simultaneous health care treatment of and forensic evidence collection from sexually assaulted women for the purpose of facilitating positive social and legal outcomes. since the introduction of these centres, very little evaluative research has been conducted to determine the impact of this intervention. the purpose of our study was to investigate it from the perspectives of sexually assaulted women who have undergone forensic medical examinations at these centres.method: women were referred to our study by sactc coordinators across ontario. we developed an interview schedule composed of both closed and open-ended questions. twenty-two women were interviewed, face-to-face. these interviews were approximately one-to-two hours in length, and were transcribed verbatim. to date, have been analyzed for key themes.results: preliminary findings indicate that most women interviewed were canadian born ( 'yo), and ranged in age from to years. a substantial proportion self-identified as a visible minority ( 'x.). approximately half were single or never married ( %) and living with a spouse or family of origin ( %). most were either students or not employed ( %). two-thirds ( %) had completed high school and onethird ( %) was from a lower socio-economic stratum. almost two-fifths ( %) of women perceived the medical forensic examination as revictimizing citing, for example, the internal examination and having blood drawn. the other two-thirds ( %) indicated that it was an empowering experience, as it gave them a sense of control at a time when they described feeling otherwise powerless. most ( %) women stated that they had presented to a centre due to health care concerns and were very satisfied ( % ) with their experiences and interactions with staff. almost all ( %) women felt supported and understood.conclusions: this research has important implications for clinical practice and for appropriately addressing the needs of sexually assaulted women. what is apparent is that continued high-quality medical attention administered in the milieu of specialized hospital-based services is essential. at the same time, we would suggest that some forensic evidence collection procedures warrant reevaluation. the study will take an experiential, approach by chroruclmg the impa~ of the transition f m the streets to stabilization in a managed alcohol program through the techruque of narrative i~:uiry. in keeping with the shift in thinking in the mental health fie!~ ~his stu~y is based on a paradigm of recovery rather than one of pathology. the "inner views of part c pants hves as they portray their worlds, experiences and observations" will be presented (charm~z, , ~· ~)-"i?e p~ of the study is to: identify barriers to recovery. it will explore the exj?cnence of ~n~t zanon pnor to entry into the program; and following entry will: explore the meanmg ~nd defirutto~s of r~overy ~~d the impact of the new environment and highlight what supports were instrumental m movmg pan apants along the recovery paradigm.p -st (a) treating the "untreatable": the politics of public health in vancouver's inner city introdudion: this paper explores the everyday practices of therapeutic programs in the treadnent of hiv in vancouver's inner city. as anthropologists have shown elsewhere, therapeutic programs do not siinply treat physical ailments but they shape, regulate and manage social lives. in vancouver's inner city, there are few therapeutic options available for the treatment of -ilv. public health initiatives in the inner city have instead largely focused on prevention and harm reduction strategies such as needle exchange programs, safe injection sites, and safer-sex education. epidemiological reports suggest that less than a quarter of those living with hiv in the downtown eastside (dtes) are taking antiretroviral therapies raising critical questions regarding the therapeutic economy of antiretrovirals and rights to health care for the urban poor.methods: this paper is drawn from ethnographic fieldwork in vancouver's otes neighborhood focusing on therapeutic programs for hiv treatment among "hard-to-reach" populations. the research includes participant-observation at inner city health clinics specializing in the treatment of hiv; semi· structured interviews with hiv positive participants, health care professionals providing hiv treatment, and administraton working in the field of inner city public health; and, lastly, observation at public meetings and conferences surrounding hiv treatment.r.awlts: hiv prevention and treatment is a central concern in the lives of many residents living in the inner city -although it is just one of many health priorities afflicting the community. concerns about drug resistance, cost of antiretrovirals, and illicit drug use means that hiv therapy for most is characterized by the daily observation of their medicine ingestion at health clinics or pharmacies. daily observed treatment (dot) is increasingly being adopted as a strategy in the therapeutic management of "untreatable" populations. dot programs demand a particular type of subject -one who is "compliant" to the rules and regimes of public health. over emphasis on "risky practices," "chaotic lives," and "~dh~rence" preve~ts the public health system from meaningful engagement with the health of the marginalized who continue to suffer from multiple and serious health conditions and who continue to experience considerable disparities in health.~ the ~ffec~s of hiv in the inner city are compounded by poverty, laclc of safe and affordable houamg, vanous llegal underground economies increased rates of violence and outbreaks of ~~~·~ly tr~nsmitted infections, hepatitis, and tuberculosi: but this research suggests 'that public health uunauves aimed at reducing health disparities may be failing the most vulnerable and marginal of citiztl s. margaret malone ~ vi~lence that occurs in families and in intimate relationships is a significant urban, ~unity, and pu~hc health problem. it has major consequences and far-reaching effects for women, ~~--renho, you~ sen on, and families. violence also has significant effects for those who provide and ukllc w receive health care violence · · i · · . all lasses, · is a soc a act mvolvmg a senous abuse of power. it crosses : ' : ' ~ s;nden, ag~ ~ti~, cultures, sexualities, abilities, and religions. societal responseshali ra y oc:used on identificatton, crisis intervention and services for families and individuajs.promoten are only "-"--:-g to add h · ' · i in intimate relationshi with"-~"'.". ress t e issues of violence against women and vjoence lenga to consider i~ m families. in thi_s p~per, i analyze issues, propose strategies, and note c~· cannot be full -...l'-~ whork towards erad canng violence, while arguing that social justice and equity y -. ucvcu w en thett are people wh mnhod: critical social theory, an analysis that addresses culturally and ethnically diverse communities, together with a population health promotion perspective frame this analysis. social determinants of health are used to highlight the extent of the problem of violence and the social and health care costs.the ottawa charter is integrated to focus on strategies for developing personal skills, strengthening community action, creating supportive environments, devdoping healthy public policies, and re-orientating health and social services. attention is directed to approaches for working with individuals, families, groups, communities, populations, and society.ratdts: this analysis demonstrates that a comprehensive interdisciplinary, multisectoral, and multifaceted approach within an overall health promoting perspective helps to focus on the relevant issues, aitical analysis, and strategies required for action. it also illuminates a number of interacting, intersecting, and interconnecting factors related to violence. attention, which is often focused on individuals who are blamed for the problem of violence, is redirected to the expertise of non-health professionals and to community-based solutions. the challenge for health promoters working in the area of violence in families and in intimate relationships is to work to empower ourselves and the communities with whom we work to create health-promoting urban environments. social justice, equiry, and emancipatory possibilities are positioned in relation to recommendations for future community-based participatory research, pedagogical practices for health care practitioners, and policy development in relation to violence and urban health. the mid-main community health center, located in vancouver british columbia (bc), has a diverse patient base reflecting various cultures, languages, abilities, and socio-economic statuses. due to these differences, some mid-main patients experience greater digital divide barriers in accessing computers and reputable, government produced consumer health information (chi) websites, such as the bc healthguide and canadian health network. inequitable access is problematic because patient empowerment is the basis of many government produced chi websites. an internet terminal was introduced at mid-main in the summer of , as part of an action research project to attempt to bridge the digital divide and make government produced chi resources useful to a broad array of patients. multi-level interventions in co-operation with patients, with the clinic and eventually government ministries were envisioned to meet this goal. the idea of implementing multi-level interventions was adopted to counter the tendency in interactive design to implement a universal solution for the 'ideal' end-user [ ), which discounts diversity. to design and execute the interventions, various action-oriented and ethnographic methods were employed before and during the implementation of the internet terminal. upon the introduction of the internet terminal, participant observation and interviews were conducted using a motion capture software program to record a digital video and audio track of patients' internet sessions. this research provided insight into the spectrum of patients' capacities to use technology to fulfil their health information needs and become empowered. at the mid-main clinic it is noteworthy that the most significant intervention to enhance the usefulness of chi websites for patients appeared to be a human rather than a technological presence. as demonstrated in other ethnographic research of community internet access, technical support and capacity building is a significant component of empowerment ( ). the mid-main wired waiting room project indicates that medical practitioners, medical administrators, and human intermediaries remain integral to making chi websites useful to patients and their potential empowerment. ( ) over the past years the environmental yo~th alliance has been of~ering a.youth as~t. mappin~ program which trains young people in community research and evaluation. wh ~st the positive expenenc~ and relationships that have developed over this time attest to the success of this program, no evaluations has yet been undertaken to find out what works for t.he youth, what ~ould be changed, and what long term outcomes this approach offers for the youth, their local community, and urban governance. these topics will be shared and discussed to help other community disorganizing and uncials governments build better, youth-driven structures in the places they live.p - (a) the world trade center health registry: a unique resource for urban health researchers deborah walker, lorna thorpe, mark farfel, erin gregg, and robert brackbill introduction: the world trade center health registry (wfchr) was developed as a public health response to document and evaluate the long-term physical and mental health effects of the / disaster on a large, diverse population. over , people completed a wfchr enrollment baseline survey, creating the largest u.s. health registry. while studies have begun to characterize / bealth impacts, questions on long-term impacts remain that require additional studies involving carefully selected populations, long-term follow-up and appropriate physical exams and laboratory tests. wtchr provides an exposed population directory valuable for such studies with features that make ita unique resource: (a) a large diverse population of residents, school children/staff, people in lower man· hattan on / including occupants of damaged/destroyed buildings, and rescue/recovery/cleanup work· ers; (b) consent by % of enrollees to receive information about / -related health studies; (c) represenration of many groups not well-studied by other researchers; (c) email addresses of % of enrollees; (d) % of enrollees recruited from lists with denominator estimates; and (e) available com· parison data for nyc residents. wfchr strives to maintain up-to-date contact information for all enrollees, an interested pool of potential study participants. follow-up surveys are planned.methods: to promote the wtchr as a public health resource, guidelines for external researcher.; were developed and posted on (www.wtcregistry.org) which include a short application form, a twopage proposal and documentation of irb approval. proposals are limited to medical, public health, or other scientific research. researchers can request de-identified baseline data or have dohmh send information about their studies to selected wfchr enrollees via mail or email. applications are scored by the wtchr review committee, comprised of representatives from dohmh, the agency for toxic subst~nces and disease registry, and wtchr's scientific, community and labor advisory committees. a data file users manual will be available in early fall .~suits: three external applications have been approved in , including one &om a non-u.s. ~esearcher, all requesting information to be sent to selected wtchr enrollees. the one completed mail· mg~~ wtchr enrollee~ (o , wfc tower evacuees) generated a positive survey response rate. three additional researchers mtend to submit applications in . wfchr encourages collaborations between researchers and labor and community leaders.conclusion: studies involving wtchr enrollees will provide vital information about the long· term health consequences of / . wtchr-related research can inform communities, researcher.;, policy makers, health care providers and public health officials examining and reacting to and other disasters. t .,. dp'"f'osed: thi is presentation will discuss the findings of attitudes toward the repeat male client iden· ie as su e a and substance us'n p · · · · i · 'd . . - g. articipants will learn about some identified effective strategies or service prov ers to assist this group of i · f men are oft · d bl men. n emergency care settings, studies show that this group en viewe as pro emaric patient d i r for mental health p bl h h an are more ikely to be discharged without an assessmen !) ea rofr ems t. an or er, more cooperative patients (forster and wu · hickey er al., · r y resu ts om this study suggest th · · ' ' l · d tel' mining how best to h . d at negative amtudes towards patients, difficu nes e · as well pathways l_e_ p patientsblan ~ck of conrinuity of care influence pathways to mental health care. • uc\:ome pro emat c when p ti k · che system. m a ems present repeatedly and become "get stuc id methods: semi-structured intervie d . · (n= ), ed nurses (n= ) other ed ;s were con ucted with male ed patients (n= ), ed phys oans ' sta (n= ) and family physicians (n= ). patients also completed a poster sessions v diagnostic interview. interviews were tape-recorded, transcribed verbatim and managed using n . transcripts were coded using an iterative process and memos prepared capture emergent themes. ethics approval was obtained and all participants signed a detailed informed consent form.introduction: urban settings are particularly susceptible to the emergence and rapid spread of nt•w or rare diseases. the emergence of infectious diseases such as sars and increasing concerns over the next influenza pandemic has heightened interest in developing and using a surveillance systt·m which detects emerging public health problems early. syndromic surveillance systems, which use data b, scd on symptoms rather than disease, offer substantial potential for this by providing near-real-rime data which are linked to an automated warning system. in toronto, we are piloting syndromic data from the · emergency medical services (ems) database to examine how this information can be used on an ongoing basis for the early detection of syndromes including heat-related illness (hri), and influenza-like-illness (ill). this presentation will provide an outline of the planned desi_gn of this system and proposed evaluation. for one year, call codes which reflect heat-related illness or influenza-like-illness will be selected and searched for daily using software with a multifactorial algorithm. calls will he stratified by call code, extracted from the -ems database and transferred electronically to toronto public health. the data will be analyzed for clusters and aberrations from the expected with the realtime outbreak and disease surveillance (rods) system, a computer-based public health tool for the early detection of disease outbreaks. this -ems surveillance system will be assessed in terms of its specificity and sensitivity through comparisons with the well-established tracking systems already in place for hr! and ill. others sources of data including paramedic ambulance call reports of signs and . this study will introduce complementary data sources t~ the ed ch e~ complamt an~ o~~rthe-counter pharmacy sales syndromic surveillance data currently bemg evaluated m ~ther ontar~o cltles. . syndromic surveillance is a unique approach to proactive(~ dete~tmg early c.hangesm the health status of urban communities. the proposed study aims to provide evidence of differential effectiveness through investigating the use of -ems call data as a source of syndromic surveillance information for hr! and ili in toronto. introduction: there is strong evidence that primary care interventions, including screening, brief advi<:e, treatment referral and pharmacotherapy are effective in reducing morbidity and mortality caused by substance abuse. yet physicians are poor at intervening with substance users, in part because of lack of time, training and support. this study examines the hypothesis that shared care in addictions will result in decreased substance use and improved health status of patients, as well as increased use of primary care interventions by primary care practitioners (pcps). methods: the addiction medicine service (ams) at st. joseph's health centre's family medicine department is in the process of being transformed from its current structure as a traditional consult service into a shared care model called addiction shared care (asc). the program will have three components: education, office systems and clinical shared care. as opposed to a traditional consult service, the patient will be booked with both a primary care liaison worker (pcl) and addictions physician. patients referred from community physicians, the emergency department and inpatient medical and psychiatric wards will be recruited for the study as well as pcps from the surrounding community. the target sample size is - physicians and a similar number of patients. after initial consult, patient will be recruited into the study with their consent. the shared-case model underlines the interaction and collaboration with the patient's main pcp. asc will provide them with telephone consults, advice, support and re-assessment for their patients, as well as educational sessions and materials such as newsletters and informational kits.results: the impact of this transition on our patient care and on pcp's satisfaction with the asc model is currently being evaluated through a grant provided by the ministry of health & long term care. a retrospective chart review will be conducted using information on the patient's substance use, er/clinic visits, and their health/mood status. pcp satisfaction with the program will be measured through surveys and focus groups. our cost-effectiveness analysis will calculate the overall cost of the program per patient..conclusion: this low-cost service holds promise to serve as an optimal model and strategy to improve outcomes and reduce health care utilization in addict patients. the inner city public health project introduction the inner city public health project (icphp) was desi.gned to explore new an~ innovative ways to reach marginalized inner city populations that par-t c pate m high health-nsk beha~ ors. much of this population struggles with poverty, addictions, mental illness and homelessness, creatmg barriers to accessing health services and receiving follow-up. this pro ect was de~igned to evaluat~ .~e success of offering clinics in the community for testing and followup of communicable diseases uuhzmg an aboriginal outreach worker to build relationships with individuals and agencies. v n(demographics~ history ~f testi~g ~nd immunization and participation in various health-risk behaviors), records of tesnng and mmumzat ons, and mterviews with partner agency and project staff after one year.. results: t~e chr ~as i~strumental in building relationships with individuals and partner agencies ' .° the c~mmun_ ~ re_sultmg m req~ests for on-site outreach clinics from many of the agencies. the increase m parnc pat n, the chr mvolvement in the community, and the positive feedback from the agen? staff de~onstrated that.the project was successfully creating partnerships and becoming increasingly integrated m the community. data collected from clients at the initial visit indicated that the project was reaching its target populations and highlighted the unique health needs of clients, the large unmet need for health services and the barriers that exist to accessing those services. ~usion: the outreach clinics were successful at providing services to target populations of high health-nsk groups and had great support from the community agencies. the role of the chr was critical to the success of the project and proved the value of this category of health care worker in an urban aboriginal population. the unmet health needs of this disadvantaged population support the need for more dedicated resources with an emphasis on reducing access barriers. building a caring community old strathcona's whyte avenue, a district in edmonton, brought concern about increases in the population of panhandlers, street people and homeless persons to the attention of all levels of government. the issue was not only the problems of homelessness and related issues, but feelings of insecurity and disempowerment by the neighbourhood residents and businesses. their concerns were acknowledged, and civic support was offered, but it was up to the community itself to solve the problem. within a year of those meetings, an adult outreach worker program was created. the outreach worker, meets people in their own environments, including river valley camps. she provides wrap-around services rooted in harm reduction and health promotion principles. her relationship-based practice establishes the trust for helping clients with appropriate housing, physical and/or mental health issues, who have little or no income and family support to transition from homelessness. the program is an excellent example of collaboration that has been established with the businesses, community residents, community associations, churches, municiple services, and inner-city agencies such as boyle street community services. statistics are tracked using the canadian outcomes research institute homes database, and feedback from participants, including people who are street involved. this includes an annual general meeting for community and people who are homeless. the program's holistic approach to serving the homeless population has been integral, both in creating community awareness and equipping residents and businesses to effectively interact with people who are homeless. through this community development work, the outreach worker engages old strathcona in meeting the financial and material needs of the marginalized community. the success of this program has been surprising -the fact is that homeless people's lives are being changed; one person at a time and the community has been changed in how they view and treat those without homes. over two years, the program has successfully connected with approximately seventy-five individuals who call old strathcona home, but are homeless. thirty-six individuals are now in homes, while numerous others have been assisted in obtaining a healthier and safer lifestyles by becoming connected with other social/health agencies. the program highlights the roots of homelessness, barriers to change and requirements for success. it has been a thriving program and a model that works by showing how a caring community has rallied together to achieve prosperous outcomes. the spn has created models of tb service delivery to be used m part~ers~ p with phannaceunca compa-. · · -. t' ns cooperatives and health maintenance orgamzanons (hmos). for example, the mes, c v c orgamza , . · b tb d' · spn has established a system with pharmaceutical companies that help patients to uy me cmes at a special discounted rate. this scheme also allows patients to get a free one-_month's worth of~ dru_g supply if they purchase the first months of their regimen. the sy_s~e~s were ~es gned to be cm~pattble with existing policies for recording and documentation of the ph hppme national tuberculosis program (ntp). aside from that, stakeholders were also encouraged to be dots-enabled through the use of m~nual~ and on-line training courses. the spn initiative offers an alternative in easing the burden of tb sc:rv ce delivery from rhe public sector through the harnessing of existing private-sector (dsos). the learnmgs from the spn experience would benefit groups from other locales that _work no~ only on ~ but other health concerns as well. the spn experience showcases how well-coordinated private sector involvements help promote social justice in health delivery in urban communities.p - (c) young people in control; doing it safe. the safe sex comedy juan walter and pepijn v. empelen introduction: high prevalence of chlamydia and gonorrhoea have been reported among migrants youth in amsterdam, originating from the dutch antilles, suriname and sub-sahara africa. in addition, these groups also have high rates of teenage-pregnancy (stuart, ) and abortions (rademakers ), indicating unsafe sexual behaviour of these young people. young people (aged - ) from the so· called urban scene (young trendsetters in r&b/hip hop music and lifestyle) in amsterdam have been approached by the municipal health service (mhs) to collaborate on a safe sex project. their input was to use comedy as vehicle to get the message a cross. for the mhs this collaboration was a valuable opportunity to reach a hard-to-reach group.mdhods: first we conducted a need assessment by means of a online survey to assess basic knowledge and to similtaneously examine issues of interest concerning sex, sexuality, safer sex and the opposite sex. second, a small literature study was conducted about elements and essential conditions for succesful entertainment & education (e&e) (bouman ), with as most important condition to ensure that the message is realistic (buckingham & bragg, ) . third a program plan was developed aiming at enhancing the stl/hiv and sexuality knowledge of the young people and addressing communication and educational skills, by means of drama. subsequently a safe sex comedy show was developed, with as main topics: being in love, sexuality, empowerment, stigma, sti, hivand safer sex. the messages where carried by a mix of video presentation, stand up comedy, spoken word, rap and dance.results: there have been two safe sex comedy shows. the attendance was good; the group was divers' with an age range between and year, with the majority being younger than year. more women than men attended the show. the story lines were considered realistic and most of the audients recognised the situations displayed. eighty percent of the audients found the show entertaining and % found it edm:arional. from this %, one third considers the information as new. almost all respondents pointed our that they would promote this show to their friends.con.clusion: the s.h<_>w reached the hard-to-reach group of young people out of the urban scene and was cons d_ered entert~mmg, educational and realistic. in addition, the program was able in addressing important issues, and impacted on the percieved personal risk of acquiring an sti when not using condoms, as well as on basic knowledge about stl's. introduction: modernity has contributed mightily to the marginality of adults who live with mental illnesses and the subsequent denial of opportunities to them. limited access to social, vocational, educational, and residential opportunities exacerbates their disenfranchisement, strengthening the stigma that has been associated with mental illness in western society, and resulting in the denial of their basic human rights and their exclusion from active participation in civil society. the clubhouse approach tn recovery has led to the reduction of both marginality and stigma in every locale in which it has been implemented judiciously. its elucidation via the prism of social justice principles will lead to a deeper appreciation of its efficacy and relevance to an array of settings. methods: a review of the literature on social justice and mental health was conducted to determine core principles and relationships between the concepts. in particular, fondacaro and weinberg's ( ) conceptualization of social justice in community psychology suggests the desirability of the clubhouse approach in community mental health practice. a review of clubhouse philosophy and practice has led to the inescapable conclusion that there is a strong connection between clubhouse philosophy-which represents a unique approach co recovery--and social justice principles. placing this highly effective model of community mental health practice within the context of these principles is long overdue. via textual analysis, we will glean the principles of social justice inherent in the rich trove of clubhouse literature, particularly the international standards of clubhouse development.results: fondacarao and weinberg highlight three primary social justice themes within their community psychology framework: prevention and health promotion; empowerment, and a critical pnsp<"<·tive. utilizing the prescriptive principles that inform every detail of clubhouse development and th<" movement toward recovery for individuals at a fully-realized clubhouse, this presentation asserts that both clubhouse philosophy and practice embody these social justice themes, promote human rights, and empower clubhouse members, individuals who live with mental illnesses, to achieve a level of wdl-heing and productivity previously unimagined.conclusion: a social justice framework is critical to and enhances an understanding of the clubhouse model. this model creates inclusive communities that lead to opportunities for full partic pil!ion civil society of a previously marginalized group. the implication is that clubhouses that an· based on the international standards for clubhouse programs offer an effective intervention strategy to guarantee the human rights of a sizable, worthy, and earnest group of citizens. to a drastic increase in school enrollment from . million in to . million in .s. however, while gross enrollment rates increased to °/., in the whole country after the introduction of fpe, it remained conspicuously low at % in the capital city, nairobi. nairobi city's enrollment rate is lower .than thatof all regions in the country except the nomadic north-eastern province. !h.e.d sadvantage of children bas_ed in the capital city was also noted in uganda after the introduction of fpe m the late s_-many_ education experts in kenya attribute the city's poor performance to the high propornon of children hvmg m slums, which are grossly underserved as far as social services are concerned. this paper ~xammes the impact of fpe and explores reasons for poor enrollment in informal settlements m na rob city. methods: the study utilizes quantitative and qualitative schooling data from the longitudinal health and demographic study being implemented by the african population and health research center in two informal settlements in nairobi. descriptive statistics are used to depict trends in enrollment rates for children aged - years in slum settlements for the period - . results: the results show that school enrollment has surprisingly steadily declined for children aged - while it increased marginally for those aged - . the number of new enrollments (among those aged years) did not change much between and while it declined consistently among those aged - since . these results show that the underlying reasons for poor school attendance in poverty-stricken populations go far beyond the lack of school fees. indeed, the results show that lack of finances (for uniform, transportation, and scholastic materials) has continued to be a key barrier to schooling for many children in slums. furthermore, slum children have not benefited from fpe because they mostly attend informal schools since they do not have access to government schools where the policy is being implemented.conclusion: the results show the need for equity considerations in the design and implementation of the fpe program in kenya. without paying particular attention to the schooling needs of the urban poor children, the millennium development goal aimed at achieving universal primary education will remain but a pipe dream for the rapidly increasing number of children living in poor urban neighborhoods.ps- (c) programing for hiv/aids in the urban workplace: issues and insights joseph kamoga hiv/aids has had a major effect on the workforce. according to !lo million persons who are engaged in some form of production are affectefd by hiv/aids. the working class mises out on programs that take place in communities, yet in a number of jobs, there are high risks to hiv infection. working persons sopend much of their active life time in workplaces and that is where they start getting involved in risky behaviour putting entire families at risk. and when they are infected with hiv, working people face high levels of seclusion, stigmatisation and some miss out on benefits especially in countries where there are no strong workplace programs. adressing hiv/aids in the workplace is key for sucessfull responses. this paper presents a case for workplace programing; the needs, issues and recommendations especially for urban places in developing countries where the private sector workers face major challenges. key: cord- -t v zw authors: knox, tamsin a.; jerger, logan; tang, alice m. title: alcohol, hiv/aids, and liver disease date: - - journal: alcohol, nutrition, and health consequences doi: . / - - - - _ sha: doc_id: cord_uid: t v zw globally, there are over million persons living with hiv/aids resulting in . million deaths annually. while the rate of hiv transmission is slowing, it is estimated that . million new infections occur yearly [ ]. in the united states, there are approximately . million living with hiv/aids, with , new hiv infections and , deaths from the disease annually [ ]. for those who can obtain effective antiretroviral therapy (art), hiv/aids has become a chronic disease with life expectancies over years [ ]. research in the last years has revealed the importance of alcohol in the hiv/aids epidemic. alcohol use, in moderate or hazardous amounts, has been associated with increased acquisition of hiv infection, progression of hiv infection, deleterious effects on hiv treatment, and acceleration in the comorbidities of hiv infection [ – ]. yet alcohol remains the “forgotten drug” of the hiv/aids epidemic [ ]. globally, there are over million persons living with hiv/aids resulting in . million deaths annually. while the rate of hiv transmission is slowing, it is estimated that . million new infections occur yearly [ ] . in the united states, there are approximately . million living with hiv/aids, with , new hiv infections and , deaths from the disease annually [ ] . for those who can obtain effective antiretroviral therapy (art), hiv/aids has become a chronic disease with life expectancies over years [ ] . research in the last years has revealed the importance of alcohol in the hiv/ aids epidemic. alcohol use, in moderate or hazardous amounts, has been associated with increased acquisition of hiv infection, progression of hiv infection, deleterious effects on hiv treatment, and acceleration in the comorbidities of hiv infection [ ] [ ] [ ] [ ] [ ] [ ] . yet alcohol remains the "forgotten drug" of the hiv/aids epidemic [ ] . alcohol has a complex relationship with hiv acquisition. risky sexual behaviors, among heterosexuals or among men who have sex with men (msm), that promote hiv transmission are increased in the setting of alcohol these include increased frequency of sexual encounters with new or anonymous partners and reduced condom use [ , ] . attention to the locations and clientele where alcohol is served [ ] has led to the development of an "ecological epidemiology" of the interplay of multiple risk factors around hiv transmission [ ] . once infected with hiv, alcohol use is associated with progression of hiv infection from asymptomatic infection, to symptomatic aids with declining immune function measured by low cd t-cell counts (< cells/mm [ ] ) in the blood, to death from wasting or an opportunistic infection. again, the relationship between alcohol use and progression of hiv infection is multifaceted. hazardous drinking has been associated with delayed testing and treatment for hiv infection [ , , ] , poor adherence to art therapy [ , ] , and increased hiv viral replication and shedding [ ] [ ] [ ] . simian immunode fi ciency virus (siv) infection in monkey models has con fi rmed fi ndings that regular intake of alcohol leads to more rapid progression of disease, weight loss, and death [ ] [ ] [ ] [ ] . alcohol use also complicates the care of persons with hiv infection. not only is adherence to art decreased, but drug interactions between alcohol and speci fi c art medications may increase the toxicity of therapy [ ] . hiv infection has numerous comorbidities including coexisting infections such as chronic viral hepatitis or tuberculosis as well as progressive organ dysfunction involving the liver, cardiovascular system, neurological dysfunction, or pulmonary disease. concurrent alcohol use may have a deleterious effect on any of these conditions [ ] [ ] [ ] [ ] [ ] . thus, the management of alcohol misuse is central to control and treatment of hiv/aids. this chapter summarizes recent research on the effects of alcohol on hiv infection. epidemiologic studies of alcohol use in hiv infection inconsistently de fi ne alcohol intake and problem drinking. many studies categorize alcohol intake as "none," "moderate" drinking (ranging from any alcohol intake to daily intake over the period studied), and "hazardous" drinking (including regular daily intake or binge drinking and may or may not include a diagnosed alcohol disorder). in addition, the studies screening for alcohol disorders use different criteria including the cage questions, audit questionnaire, self-reported drinking, or a physician's report of an alcohol disorder [ ] . thus, varying methodology and study population selection will greatly in fl uence the results from studies of alcohol use in hiv. prevalence of alcohol use among populations with hiv. there are wide apparent differences in rates of alcohol use and hazardous alcohol use due to the populations surveyed, the de fi nitions of "problem" alcohol use even in the same cohort, and the methods used to determine alcohol intake. in general, the prevalence of alcohol use disorders is several fold higher among populations with hiv infection compared to the general us population. some of the highest prevalence rates from problem drinking are among us veterans and homeless veterans [ , ] . among the veterans administration (va) population, hazardous drinking patterns are found more frequently in african-americans ( %) than in whites ( %, p < . ) [ ] . cook et al. determined that the prevalence of moderate and hazardous drinking among women with hiv infection was also higher than in the general us population [ , , ] . other characteristics were associated with hazardous drinking patterns such as lower education, unemployment, nonwhite race, depression, and drug use. in both this cohort and in a va cohort, hazardous alcohol use was associated with hepatitis c virus (hcv) infection [ , ] . among veterans with hcv infection, % were hazardous drinkers compared with % hazardous drinkers among matched controls without hcv infection [ ] . the increased alcohol use among idu and the high correlation of idu and hcv infection likely explain this fi nding [ , ] . alcohol intake appears to decline over time in persons with hiv infection as it does in noninfected persons with medical illness [ ] . lefevre et al. examined alcohol intake in a group of hivpositive patients of a university hospital clinic, mostly msm. in surveys repeated every months for a mean follow-up of months, the frequency of drinking decreased from . to . drinks/week ( p < . ) [ ] . in the swiss hiv cohort study, lower alcohol use was found in those who had been on art for longer periods of time [ ] . cook analyzed data from the women's interagency hiv study (wihs) on , hiv-positive women followed for years [ ] . there was a slight, approximately %, decrease in hazardous drinking over time but no change in the overall amount of drinking, possibly as some switched categories from hazardous to nonhazardous drinking. however, there was a signi fi cant decrease in alcohol consumption among women who were coinfected with hepatitis c and hiv from % with hazardous drinking patterns in to % in . alcohol has been implicated in accelerating the progression of hiv disease through a number of mechanisms. persons drinking alcohol heavily delay testing for hiv and have less connection with and retention in the health-care system [ , , ] , delaying the initiation of art. thus, heavy alcohol use predisposes persons to late presentation in the course of infection, with high hiv viral loads, low cd counts, and opportunistic infections, and promotes continued spread of hiv [ , ] . one of the central ways alcohol intake adversely affects hiv disease is by decreasing adherence to art. adherence to art is key to suppression of hiv replication, prevention of developing drug resistance, and long-term survival [ ] . this has been well documented among all subgroups with hiv infection [ , , , [ ] [ ] [ ] [ ] [ ] . while there are few studies of adherence in developing countries, one study from india con fi rms the association of alcohol use and risk of nonadherence or discontinuation of art medications [ ] . convincingly, there is a dose-response relationship between alcohol intake and adherence, with higher amounts of alcohol or more hazardous drinking being associated with poorer measures of adherence. samet et al. found that the amount of alcohol consumption was the strongest predictor of adherence with highest levels of adherence being found in those abstinent from alcohol compared to moderate use or at-risk use [ ] . chander et al., studying nearly , hivinfected persons receiving care at johns hopkins hospital in baltimore, maryland, found that adherence was % lower in moderate alcohol users and % lower in hazardous alcohol users compared to no alcohol use. adherence was further decreased by % with concurrent drug use [ ] . there may be several reasons for lower adherence in persons who use alcohol. drinking pattern affects the likelihood of noncompliance. braithwaite et al., studying , members of the veterans administration aging cohort study (vacs), found that abstainers missed art on % of days. nonbinge drinkers missed medication on % of drinking days and post-drinking days but only on % of nondrinking days. binge drinkers, in contrast, missed art on % of drinking days, . % of postdrinking days, and % on nondrinking days [ ] . therefore, while medication adherence was lower on drinking days for binge and non-binge drinkers, missing medications was increased twofold among binge drinkers on days they were either not drinking or post-drinking. this suggests that nonadherence was also due to factors not directly related to alcohol but related to characteristics common among binge drinkers [ ] . sankar et al. studied beliefs about alcohol and art medication interactions in a group of african-american patients treated for hiv [ ] . over three quarters of those surveyed felt that "alcohol and art do not mix"; one-third attributed this to alcohol making art ineffective and another third felt that alcohol made art more toxic. in this study, participants reported purposely skipping art doses when they drank, with light drinkers skipping % of the times when they drank and moderate drinkers % of the times. however, heavy drinkers skipped art only % of the time when they drank and reported that they felt no ill effects from drinking and taking art [ ] . thus, medication adherence is determined by amount of alcohol intake, drinking pattern (binge or non-binge drinking), and beliefs about the safety of alcohol combined with art. issues of medication adherence and alcohol are further discussed in chap. and in a meta-analysis by hendershot [ ] . alcoholics have increased susceptibility to bacterial infections including tuberculosis, pneumonia, and sepsis [ ] . in vitro studies have shown that alcohol impacts several areas of immune function, acting largely as an immunosuppressant. alcohol decreases t-cell proliferation reducing cd , cd , and natural killer (nk) cell numbers [ ] and reduces cd cell responses to bacteria [ ] . cell-mediated immune responses are decreased [ ] , and myeloid dendritic cells, which are involved in antigen presentation to the immune system, are decreased in number and function with chronic alcohol ingestion [ , ] . alcohol increases expression of pro-in fl ammatory cytokines such as tnf-alpha [ ] which may enhance immune dysfunction. experiments by bagasra et al. on human peripheral blood mononuclear cells (pbmc) have shown that cells from healthy persons who are infected in vitro with hiv- have higher levels of hiv replication when harvested after alcohol consumption [ ] . enhanced hiv replication was associated with a concurrent inhibition of cd cells by alcohol [ ] . siv infection, a macaque model for hiv, has produced evidence of the effect of alcohol on immune function and hiv replication. in rhesus macaques inoculated with siv infection, siv replication was -to -fold higher in monkeys with chronic alcohol ingestion compared to controls [ ] . siv replication persisted in the central nervous system of alcohol-fed monkeys but was undetectable in control monkeys. poonia et al. proposed that the mechanism of alcohol's effect on siv replication is through its effect on intestinal lymphocytes since the small intestine is one of the most lymphocyterich organs. alcohol-fed monkeys had lower numbers of cd cells (before and after siv infection) and higher numbers of cd cells in the small intestine after siv infection. they suggested that the - log increase in siv replication in alcohol-fed monkeys occurs because of the increase in number of cd cells susceptible to siv infection in the small intestine and reduction in cd cells which may control siv replication [ ] . chronic alcohol ingestion also altered the course of hiv infection with alcohol-fed monkeys having lower cd cell counts, lower caloric intake, higher tnf-alpha expression, and a more rapid progression to end-stage siv disease (mean days compared to days in controls) [ , ] . alcohol use has been shown to affect hiv progression and survival. in the pre-haart era, alcohol use was not associated with progression to aids [ ] [ ] [ ] . however, two well-controlled, longitudinal studies since the introduction of combination art have shown that alcohol is associated with hiv disease progression. samet et al. studied alcohol use in participants in the macs cohort over years [ ] . heavy alcohol use was associated with a lower mean cd cell count (by ~ cells/ml) but not a decline in cd percentage or hiv viral load when adjusted for adherence. baum et al. studied hiv-positive persons followed for . years [ ] . frequent alcohol users of ³ drinks/day were almost times more likely to develop a cd count £ cells/ml, which is an aids-de fi ning event. this effect was particularly marked in alcohol users not on art whose risk of developing a cd count £ cells/ml was nearly times nondrinkers. in this study, alcohol use was associated with higher hiv viral load in those on art but not in those without art. these results suggest that the effect of alcohol on hiv viral load is mediated through adherence. however, the effect of alcohol in lowering absolute cd count rather than percentage could be in fl uenced by the splenomegaly and secondary lymphopenia seen with alcoholism and chronic viral hepatitis [ ] . moderate to heavy alcohol use has also been associated with increased hiv viral shedding in the female genital tract after controlling for plasma viral load [ ] suggesting that alcohol may affect hiv transmission by physiological as well as behavioral risk factors. the vacs study has provided models for estimating the effect of alcohol on survival in hiv infection. using data on art adherence in the vacs cohort, braithwaite et al. developed a model simulating survival based on levels of alcohol consumption (nondrinkers, hazardous drinkers consuming ³ drinks on drinking days, and nonhazardous drinkers) [ ] . the model predicted decreased survival by > year in nonhazardous drinkers drinking at least once a week, . years in nonhazardous drinkers drinking daily, and up to . years in hazardous drinkers drinking daily. however, the vacs index, subsequently developed to predict decreases in life expectancy based on hiv and non-hiv characteristics, does not include a separate variable for alcohol or drug abuse beyond adjusting for severity of liver disease and coexisting hcv infection [ ] . in addition, a longitudinal study of changes in physical function with age in the same cohort did not show an effect of alcohol [ ] . further longitudinal studies in this cohort and others should de fi ne the impact of alcohol use on survival in hiv. persons with hiv infection are particularly vulnerable to the effects of alcohol. the detrimental effects of alcohol on the immune system have been covered above, and the effects of alcohol on general health and nutrition are covered in other chapters in this book. persons with hiv infection are at risk of poor nutritional status, and even a % weight loss has been associated with increased mortality [ ] [ ] [ ] [ ] . thus, further changes in nutritional status due to alcohol use, particularly lower body weight or micronutrient de fi ciencies, would exacerbate the nutritional effects of hiv [ , ] . approximately one-third of persons with hiv infection are coinfected with hcv, and approximately % have evidence of chronic hepatitis b virus (hbv) infection [ ] . the prevalence of hcv coinfection increases to almost % in those who acquired hiv from idu. persons with coinfection with chronic hepatitis have accelerated liver fi brosis leading to cirrhosis [ , ] . in a study of liver histology of idu who had acquired hcv infection, those with concurrent hiv infection developed cirrhosis in a mean of . years after infection compared to . years among hcv mono-infected persons ( p < . ) [ ] . persons with coinfection also have an increased risk of death from end-stage liver disease [ ] [ ] [ ] [ ] . they are also at higher risk for drug-induced hepatotoxicity from art [ , ] which may be related to altered cytochrome metabolism with progressive liver disease [ ] . other metabolic abnormalities are more common in coinfected persons including hyperglycemia, diabetes, and bacterial translocation from the small intestine to the portal system, predisposing coinfected chronic in fl ammation and progressive liver disease [ ] [ ] [ ] . hazardous alcohol use is increased in some populations with coinfection, particularly idus [ , ] . alcohol use further exacerbates the effect of coinfection on liver disease. alcohol use of > g/ day is associated with increased hcv replication [ , ] and progressive liver fi brosis assessed by serum markers [ ] , transient elastometry [ ] or by liver biopsy [ , [ ] [ ] [ ] . death from endstage liver disease is also more common in coinfected persons who use alcohol [ , , , ] . the incidence of, as well as deaths related to, hepatocellular carcinoma is also increased in those with coinfection who drink alcohol [ , ] . only one study did not fi nd an association of alcohol use and an hcv-related severe event (including decompensated cirrhosis, hepatocellular carcinoma, or death) [ ] , but in this cohort, only % consumed > g of alcohol daily. alcohol use also contributes to metabolic abnormalities in coinfected persons. it is associated with higher rates of liver steatosis [ ] and drug-induced liver disease [ , ] . the association of alcohol use with hepatocellular carcinoma is also discussed in chap. . the adverse effects of alcohol in coinfection argue strongly for intervention. hazardous alcohol use is a common reason for coinfected persons not receiving treatment for hcv infection, where treatment rates may be as low as % [ , [ ] [ ] [ ] [ ] . fortunately, alcohol use seems to decrease with interventions after hcv diagnosis in some populations [ , ] . treatment of chronic viral hepatitis whether due to hcv or hbv infection slows the progression of liver fi brosis [ , ] and reduces the incidence of drug-induced liver disease [ ] . treatment outcomes with pegylated interferon and ribavirin [ , ] and with the new protease inhibitors for hcv infection should continue to improve as more coinfected persons are being enrolled in treatment [ ] . persons with hiv infection have an increased risk of cardiovascular disease, particularly accelerated atherosclerosis and myocardial infarction [ ] [ ] [ ] . cardiovascular disease is likely due to a combination of additional risk factors found in hiv infection [ ] including ( ) chronic in fl ammation from hiv viral replication and subsequent immunode fi ciency [ ] , ( ) the effect of chronic in fl ammation on serum lipid levels [ ] , ( ) the metabolic effects of certain classes of antiretroviral medications [ , ] , ( ) increased prevalence of insulin resistance [ ] , and ( ) increased translocation of bacteria across the small intestine into the bloodstream as a result of immunode fi ciency [ ] . persons with hiv infection have been shown to have more rapid progression of atherosclerosis measured by intermediate markers such as carotid intima-media thickness, and this has correlated with mortality [ , , ] . alcohol use further increases the risk of cardiovascular disease in hiv infection. freiberg et al., studying the vacs cohort, found that the risk of cardiovascular disease was increased (or . , % ci . - . ) in hiv-infected men with alcohol abuse or dependence, when controlled for cardiac risk factors, art use, and cd count [ ] . furthermore, hcv infection may have an independent effect in increasing the risk of cardiovascular disease (or . , % ci . - . ) although alcohol use does not seem to affect this relationship [ ] . chapters and explore further the relationship of alcohol and cardiovascular disease. alcohol and hiv infection are both risk factors for pulmonary diseases. alcoholics have increased prevalence of oropharyngeal colonization by pathogenic bacteria and an increased risk of aspiration [ ] . in addition, they have impaired pulmonary immune function leading to a higher incidence of pneumonia [ , ] . studies have shown that alcohol use is a risk factor for the development of pneumonia in the absence of hiv, as well as more severe, multilobar pneumonia and more virulent pathogens including candida , gram-negative bacteria, and staphylococcus aureus infections. this, in turn, leads to longer hospitalizations and increased mortality related to alcohol use [ ] . the risk for adult respiratory distress syndrome (ards), which has a mortality of - % [ ] , is increased three-to fourfold in those with heavy alcohol intake [ , ] . similarly, persons with hiv infection are at an increased risk of community-acquired pneumonias, including unusual pathogens such as pseudomonas aeruginosa [ ] . hiv infection is also associated with pulmonary opportunistic infections, such as pneumocystis [ ] . while both alcohol use and hiv infection have an increased risk of pneumonia and tuberculosis, there are no studies to date that demonstrate the interaction of these risk factors for acute pulmonary disease [ ] . there is suggestive literature that depletions in zinc levels or pulmonary glutathione stores may mediate impaired host defense [ ] . chronic lung disease in alcoholics is largely related to associated tobacco use [ ] . however, persons with hiv infection have an increased risk of emphysema, lung cancer, and pulmonary hypertension, independent of smoking, and this is particularly evident in those with poorly controlled hiv infection [ ] . the adverse effects of alcohol use on hiv are evident, and interventions to mitigate alcohol use among hiv-infected individuals are needed. to date, clinical studies and a few randomized controlled trials (rcts) assessing the effectiveness of interventions have shown mixed results. in this section, we will brie fl y review the types of interventions that have been evaluated and discuss results from a few published trials. interested readers can refer to recent review articles for more complete reviews of the literature [ , , ] . many types of alcohol interventions have been tested among hazardous alcohol users with and without hiv infection. these include brief interventions as well as more intensive behavioral, social network, and medication interventions. brief interventions, also referred to as brief motivational interviews, are typically a single session discussing the patients' alcohol use. studies employing this type of intervention often involve exploration of the pros and cons of a patient's alcohol use, self-assessment of the patient's alcohol consumption severity, and a more formal assessment of the patient's alcohol consumption as compared to the general population [ ] . more extensive behavioral interventions have also been investigated, including cognitive-behavioral therapy, motivation enhancement, or -step programs. each of these behavioral interventions is directly aimed at investigating personal motivation behind alcohol consumption and developing personal behavior modi fi cation strategies [ ] . these interventions typically require multiple sessions. in addition to individualized plans and programs for those with increased alcohol consumption, social network and structural interventions which target larger populations and communities have also been evaluated. social network interventions have most commonly focused on employing in fl uential community leaders to change speci fi c behaviors or promote health-conscious decisions. these studies, often referred to as popular opinion leader (pol) or peer-based model interventions, may be particularly effective in communities that are dif fi cult for outside researchers to impact [ ] . alternatively, structural interventions, which may include political and legal action, may also be effective in altering individuals' behavior and environment. lastly, medications, such as disul fi ram, naltrexone, and acamprosate, have been shown to decrease alcohol consumption via physiologic effects, including decreasing cravings or causing adverse reactions when alcohol is consumed [ ] . in addition to the type of alcohol intervention, there are several other factors to consider when evaluating results from clinical trials of alcohol interventions. the fi rst is the setting in which the interventions are conducted. interventions have been conducted in various settings including primary care clinics [ , ] , hospital inpatient settings [ ] , emergent care settings [ ] , and social settings or drinking venues (places where alcohol is served) [ ] . a second important factor to consider is the population being targeted, which may vary depending on severity of alcohol use (dependent vs. nondependent drinkers), geographic region, and cultural practices around drinking. a third factor to consider is the outcome that is being targeted. for example, previous trials have examined the effects of alcohol interventions on decreasing alcohol consumption, improving adherence to antiretroviral medication and/or reducing sexual risk behaviors. the combination of the type of intervention, the setting in which the intervention is implemented, the population that is being targeted, and the expected outcomes of the trial will all contribute to the success or failure of an intervention. the published literature on rcts of alcohol interventions among populations affected by hiv re fl ects the various combinations of factors described above. for example, one study targeting msm in the usa with alcohol use disorders combined two types of interventions (motivational interviewing and peer-group education/support strategies) and examined the effects on reducing at-risk drinking and sexual risk behaviors [ ] . in this study, individuals receiving the combined intervention reported signi fi cantly lower number of days of drinking and number of heavy drinking days per -day period compared to control participants. another study tested the effects of a brief theorybased behavioral hiv-alcohol risk-reduction intervention on sexual risk behaviors in men and women recruited from informal drinking establishments in a suburban township of capetown, south africa [ ] . the authors reported signi fi cant reductions in unprotected intercourse, increased use of condoms, and less use of alcohol before sex in the intervention group compared to controls, with the largest impacts among lighter drinkers. these two studies illustrate the success of individual counseling interventions for reducing risk behaviors around alcohol consumption among persons at risk for or living with hiv. other interventions among individuals with hiv who consume alcohol have targeted the outcome of antiretroviral medication adherence. in two speci fi c studies [ , ] , motivational interviews and cognitive-behavioral skills training were not effective in improving long-term medication adherence. given the importance of adherence to art to controlling hiv infection, more research is needed to develop novel interventions targeting this outcome. interventions directed at alcohol-serving establishments have had mixed results. studies have focused on popular opinion leader (pol) models, in which community-de fi ned opinion leaders are identi fi ed and trained to help shift social norms and behaviors toward safer sexual practices [ ] . this type of intervention in gay bars in several us cities signi fi cantly reduced episodes of risky sexual behavior compared to control bars [ , , ] ; however, when this intervention was adapted for testing in several international settings, the fi ndings were negative in that comparable reductions in risky sexual behaviors and incidence of sexually transmitted infections were seen in both intervention and control communities [ ] . another study testing the effects of a peer-based intervention on reducing episodes of unprotected sex with non-wife partners in beer halls in zimbabwe found no difference compared to controls [ ] . in summary, interventions involving varied counseling approaches directed at decreasing alcohol consumption and/or risky sexual behavior appear promising in speci fi c settings. other areas of investigation, such as interventions aimed at improving art adherence among alcohol users or use of medications for alcohol dependence (such as naltrexone) in hiv-infected populations, need further research. more intervention studies will help to generalize fi ndings across different contexts and help to improve health outcomes and minimize the effects of alcohol on persons living with hiv. in this chapter, we have examined the prevalence of hazardous alcohol use in hiv which is much higher than found in the general us population. alcohol use and frequenting venues where alcohol is consumed has been shown to be an important risk factor for the acquisition of hiv infection. understanding the complex interrelationships between individual characteristics and venues should improve our approach to prevention [ , ] . the effect of alcohol on adherence to art is well documented. there are also good laboratory models, particularly with siv infection in macaques, to show that chronic alcohol use accelerates the progression of disease. finally, alcohol use has deleterious effects on health, particularly related to progression of liver disease in persons with hiv/hcv coinfection. health-care providers may underestimate the extent of hazardous drinking among their hiv patients. a study in the va population showed that the sensitivity for health-care providers' ability to diagnose hazardous drinking was only % [ ] . thus far, trials of interventions to reduce hazardous drinking in populations affected by hiv have shown mixed results. the underdiagnosis of hazardous alcohol use and lack of proven, effective treatment strategies raise the question of whether there is any "safe" level of alcohol intake in hiv. justice et al. examined the relationship of medical illness related to alcohol use in veterans with hiv infection [ ] . for diseases associated with alcohol use (hcv infection, hypertension, diabetes, chronic obstructive lung disease, and certain infections), there was a linear relationship between alcohol intake category (none, moderate, hazardous) and the disease. this suggests that there may be no "safe" level of alcohol intake for hiv-infected persons [ ] . more aggressive screening and treatment of alcohol-related disorders is clearly warranted to prevent hiv transmission and to improve treatment and outcomes of persons with hiv infection [ ] . racial and sex disparities in life expectancy losses among hivinfected persons in the united states: impact of risk behavior, late initiation, and early discontinuation of antiretroviral therapy med care (alcohol in hiv infection: insights from the veterans aging cohort study and the veterans affairs national health information system) alcohol use accelerates hiv disease progression a temporal and dose-response association between alcohol consumption and medication adherence among veterans in care alcohol's role in hiv transmission and disease progression the association between alcohol consumption and prevalent cardiovascular diseases among hiv-infected and hiv-uninfected men incidence and predictors of severe liver fi brosis in human immunode fi ciency virus-infected patients with chronic hepatitis c: a european collaborative study alcohol: the forgotten drug in hiv/aids causal links between binge drinking patterns, unsafe sex and hiv in south africa: its time to intervene integrating hiv/aids and alcohol research social and structural hiv prevention in alcohol-serving establishments: review of international interventions across populations hiv risk and the alcohol environment: advancing an ecological epidemiology for hiv/aids alcohol and hiv disease progression: weighing the evidence health services utilization for people with hiv infection: comparison of a population targeted for outreach with the us population in care alcohol use and antiretroviral adherence: review and meta-analysis increased human immunode fi ciency virus type replication in human peripheral blood mononuclear cells induced by ethanol: potential immunopathogenic mechanisms alcohol intake increases human immunode fi ciency virus type replication in human peripheral blood mononuclear cells alcohol consumption and hiv- vaginal rna shedding among women increased viral replication in simian immunode fi ciency virus/ simian-hiv-infected macaques with self-administering model of chronic alcohol consumption chronic alcohol consumption results in higher simian immunode fi ciency virus replication in mucosally inoculated rhesus macaques chronic binge ethanol consumption accelerates progression of simian immunode fi ciency virus disease chronic alcohol accentuates nutritional, metabolic, and immune alterations during asymptomatic simian immunode fi ciency virus infection risk factors for severe hepatic injury after introduction of highly active antiretroviral therapy focus on the heart: alcohol consumption, hiv infection, and cardiovascular disease modeling hiv and alcohol's effects: focus on the lung focus on the brain: hiv infection and alcoholism prevalence factors associated with signi fi cant liver fi brosis assessed by transient elastometry in hiv/hepatitis c virus-coinfected, patients liver-related deaths in, h. i. v. infected patients between in the french, germivic joint study group network detecting alcohol problems in hiv-infected patients: use of the cage questionnaire the association between hiv infection and alcohol use: a systematic review and meta-analysis of african studies alcohol as a correlate of unprotected sexual behavior among people living with hiv/aids: review and meta-analysis early alcohol initiation and subsequent sexual and alcohol risk behaviors among urban youths alcohol use, partner type, and risky sexual behavior among college students: fi ndings from an event-level study hiv and sexually transmitted diseases: lethal synergy alcohol and sexual hiv risk behavior among problem drinking men who have sex with men: an event level analysis of timeline followback data alcohol use and risk of hiv infection among men who have sex with men alcohol use and sexual risk behavior among human immunode fi ciency virus-positive persons depressive symptoms, utilization of mental health care, substance use and sexual risk among young men who have sex with men in explore: implications for age-speci fi c interventions risk factors for hiv infection among men who have sex with men longitudinal trends in hazardous alcohol consumption among women with human immunode fi ciency virus infection alcohol consumption, art usage and high-risk sex among women infected with hiv hiv, alcohol, and noninjection drug use alcohol abuse and stage of hiv disease in intravenous drug abusers the impact of illicit drug use and harmful drinking on quality of life among injection drug users at high risk for hepatitis c infection alcohol use and sexual risks for hiv/aids in sub-saharan africa: systematic review of empirical fi ndings multiple recent sexual partnerships and alcohol use among sexually transmitted infection clinic patients socioeconomic status and risk of hiv infection in an urban population in kenya randomized trial of a community-based alcohol-related hiv riskreduction intervention for men and women in cape town south africa hiv rates and risk behaviors are low in the general population of men in southern india but high in alcohol venues: results from probability surveys male alcohol use and unprotected sex with non-regular partners: evidence from wine shops in chennai women and substance use in india and bangladesh the impact of hiv and high-risk behaviours on the wives of married men who have sex with men and injection drug users: implications for hiv prevention estimation of hiv- incidence among fi ve focal populations in dehong, yunnan: a hard hit area along a major drug traf fi cking route the -month prevalence and trends in dsm-iv alcohol abuse and dependence: united states binge drinking among us adults associations between alcohol use and homelessness with healthcare utilization among human immunode fi ciency virusiinfected veterans alcohol problems and health care services use in human immunode fi ciency virus (hiv)-infected and hiv-uninfected veterans co-morbid medical and psychiatric illness and substance abuse in hcv-infected and uninfected veterans high prevalence of alcohol use among hepatitis c virus antibody positive injection drug users in three us cities reduction in alcohol consumption and health status alcohol consumption among hiv-infected patients self-reported alcohol consumption and its association with adherence and outcome of antiretroviral therapy in the swiss hiv cohort study hazardous alcohol use: a risk factor for non-adherence and lack of suppression in hiv infection adherence to protease inhibitor therapy and outcomes in patients with hiv infection gender differences in factors associated with adherence to antiretroviral therapy problem drinking and medication adherence among persons with hiv infection alcohol use and incarceration adversely affect hiv- rna suppression among injection drug users starting antiretroviral therapy alcohol consumption and antiretroviral adherence among hiviinfected persons with alcohol problems sero-positive african americans' beliefs about alcohol and their impact on anti-retroviral adherence access, adherence, quality and impact of arv provision to current and ex-injecting drug users in manipur (india): an initial assessment alcohol abuse, alcoholism, and damage to the immune system-a review chronic ethanol induces inhibition of antigen-speci fi c cd + but not cd + immunodominant t cell responses following listeria monocytogenes inoculation consequences of alcohol consumption on host defence alcohol exposure impairs myeloid dendritic cell function in rhesus macaques alcohol suppresses the granulopoietic response to pulmonary streptococcus pneumoniae infection with enhancement of stat signaling regulation of macrophage activation in alcoholic liver disease no evidence for a role of alcohol or other psychoactive drugs in accelerating immunode fi ciency in hiv- -positive individuals. a report from the multicenter aids cohort study cofactors of progression to acquired immunode fi ciency syndrome in a cohort of male sexual contacts of men with human immunode fi ciency virus disease determinants of hiv disease progression among homosexual men registered in the tricontinental seroconverter study alcohol consumption and hiv disease progression the impact of cirrhosis on cd + t cell counts in hiv-seronegative patients estimating the impact of alcohol consumption on survival for hiv + individuals towards a combined prognostic index for survival in hiv infection: the role of 'non-hiv' biomarkers association of age and comorbidity with physical function in hivinfected and uninfected patients: results from the veterans aging cohort study malnutrition in a population of hiv-positive and hiv-negative drug users living in chennai, south india. drug alcohol depend weight loss and survival in hivpositive patients in the era of highly active antiretroviral therapy increasing risk of % or greater unintentional weight loss in a cohort of hiv-infected patients weight loss and body-composition changes in men and women infected with hiv in fl uence of chronic alcohol abuse on body weight and energy metabolism: is excess ethanol consumption a risk factor for obesity or malnutrition? inadequate dietary intake and altered nutrition status in early hiv- infection hepatitis c virus infection as an opportunistic disease in persons infected with human immunode fi ciency virus in fl uence of human immunode fi ciency virus infection on the course of hepatitis c virus infection: a meta-analysis human immunode fi ciency virus infection modi fi es the natural history of chronic parenterally-acquired hepatitis c with an unusually rapid progression to cirrhosis increasing mortality due to end-stage liver disease in patients with human immunode fi ciency virus infection rates and risk factors of liver fi brosis progression in patients with chronic hepatitis c natural history of liver fi brosis progression in patients with chronic hepatitis c. the obsvirc, metavir, clinivir, and dosvirc groups little evidence that hepatitis, c. virus leads to a higher risk of mortality in the absence of cirrhosis excess alcohol intake: the swiss hepatitis c cohort, study. j viral hepatitis hepatotoxicity associated with antiretroviral therapy in adults infected with human immunode fi ciency virus and the role of hepatitis c or b virus infection highly active antiretroviral therapy-induced liver injury ritonavir greatly impairs cyp a activity in hiv infection with chronic viral hepatitis hepatitis c virus antibody-positive patients with hiv infection have a high risk of insulin resistance: a cross-sectional study the effect of haart and hcv infection on the development of hyperglycemia among hiv-infected persons human immunode fi ciency virus-related microbial translocation and progression of hepatitis c relative prevalence of comorbidities and treatment contraindications in hiv-mono-infected and hiv/hcv-co-infected veterans effect of alcohol use and highly active antiretroviral therapy on plasma levels of hepatitis c virus (hcv) in patients coinfected with hiv and hcv an overview of hiv and chronic viral hepatitis co-infection hazardous drinking is associated with an elevated aspartate aminotransferase to platelet ratio index in an urban hiv-infected clinical cohort risk factors for advanced liver fi brosis in hiv-infected individuals: role of antiretroviral drugs and insulin resistance liver fi brosis progression in human immunode fi ciency virus and hepatitis c virus coinfected patients. the multivirc group factors affecting liver fi brosis in human immunode fi ciency virusand hepatitis c virus-coinfected patients: impact of protease inhibitor therapy a comparison of fi brosis progression in chronic liver diseases the in fl uence of human immunode fi ciency virus coinfection on chronic hepatitis c in injection drug users: a long-term retrospective cohort study mortality related to chronic hepatitis b and chronic hepatitis c in france: evidence for the role of hiv coinfection and alcohol consumption hepatocellular carcinoma and nonhodgkin's lymphoma: the roles of hiv, hepatitis c infection, and alcohol abuse the french national prospective cohort of patients co-infected with hiv and hcv antiretroviral drugs and liver injury rates and predictors of hepatitis c virus treatment in hcv-hiv-coinfected subjects rates of hcv treatment eligibility among hcv-monoinfected and hcv/ hiv-coinfected patients in tertiary care referral centers barriers to treatment of hepatitis c in hiv/hcv coinfected adults in brazil barriers to treatment of hepatitis c in hiv/hcvcoinfected adults with alcohol problems medical care and alcohol use after testing hepatitis c antibody positive at std clinic and hiv test site screening programs awareness of hepatitis c diagnosis is associated with less alcohol use among persons co-infected with hiv liver fi brosis changes in hiv-hbv-coinfected patients: clinical, biochemical and histological effect of long-term tenofovir disoproxil fumarate use slower fi brosis progression in hiv/hcv-coinfected patients with successful hiv suppression using antiretroviral therapy managing symptomatic drug-induced liver injury in hiv-hepatitis c virus-coinfected patients: a role for interferon peginterferon alfa- a plus ribavirin versus interferon alfa- a plus ribavirin for chronic hepatitis c in hiv-coinfected persons peginterferon alfa- a plus ribavirin for chronic hepatitis c virus infection in hiv-infected patients care of hepatitis c virus infection in human immunode fi ciency virusinfected patients: modi fi cations in three consecutive large surveys between trends in rates of myocardial infarction among patients with hiv epidemiological evidence for cardiovascular disease in hiv-infected patients and relationship to highly active antiretroviral therapy cardiovascular disease risk factors in hiv patients-association with antiretroviral therapy. results from the dad study markers of atherosclerosis and in fl ammation and mortality in patients with hiv infection combination antiretroviral therapy and the risk of myocardial infarction microbial translocation is a cause of systemic immune activation in chronic hiv infection framingham risk score and early markers of atherosclerosis in a cohort of adults infected with hiv progression of atherosclerosis as assessed by carotid intima-media thickness in patients with hiv infection the association between hepatitis c infection and prevalent cardiovascular disease among hiv-infected individuals alcohol, immunosuppression, and the lung high alcohol intake as a risk and prognostic factor for community-acquired pneumonia incidence and outcomes of acute lung injury chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock the alcoholic lung: epidemiology, pathophysiology, and potential therapies bacterial pneumonia in hospitalized patients with hiv infection: the pulmonary complications, icu support, and prognostic factors of hospitalized patients with hiv (pip) study hiv-associated opportunistic pneumonias hiv infection and risk for incident pulmonary diseases in the combination antiretroviral therapy era effectiveness of hiv prevention for youth in sub-saharan africa: systematic review and meta-analysis of randomized and nonrandomized trials interventions targeting hiv-infected risky drinkers: drops in the bottle brief alcohol intervention and alcohol assessment do not in fl uence alcohol use in injured patients treated in the emergency department: a randomized controlled clinical trial motivational interviewing and cognitive-behavioral intervention to improve hiv medication adherence among hazardous drinkers: a randomized controlled trial randomised, controlled, community-level hiv-prevention intervention for sexual-risk behaviour among homosexual men in us cities screening in brief intervention trials targeting excessive drinkers in general practice: systematic review and meta-analysis effectiveness of brief alcohol interventions in primary care populations effectiveness of opportunistic brief interventions for problem drinking in a general hospital setting: systematic review preventive care in the emergency department: screening and brief intervention for alcohol problems in the emergency department: a systematic review reducing sexual risk behaviors and alcohol use among hiv-positive men who have sex with men: a randomized clinical trial a randomized controlled trial to enhance antiretroviral therapy adherence in patients with a history of alcohol problems community aids/hiv risk reduction: the effects of endorsements by popular people in three cities hiv prevention with male prostitutes and patrons of hustler bars: replication of an hiv preventive intervention results of the nimh collaborative hiv/sexually transmitted disease prevention trial of a community popular opinion leader intervention evaluation of a peer network-based sexual risk reduction intervention for men in beer halls in zimbabwe: results from a randomized controlled trial veterans aging cohort -site s. how harmful is hazardous alcohol use and abuse in hiv infection: do health care providers know who is at risk? med care (alcohol in hiv infection: insights from the veterans aging cohort study and the veterans affairs national health information system) role of alcohol in determining human immunode fi ciency virus (hiv)-relevant outcomes: a conceptual model to guide the implementation of evidence-based interventions into practice. med care (alcohol in hiv infection: insights from the veterans aging cohort study and the veterans affairs national health information system) the prevalence of alcohol consumption and heavy drinking among people with hiv in the united states: results from the hiv cost and services utilization study longitudinal assessment of the effects of drug and alcohol abuse on hiv- treatment outcomes in an urban clinic determinants of heterogeneous adherence to hiv-antiretroviral therapies in the multicenter aids cohort study key: cord- - z dd authors: valdiserri, ronald o.; holtgrave, david r. title: responding to pandemics: what we’ve learned from hiv/aids date: - - journal: aids behav doi: . /s - - - sha: doc_id: cord_uid: z dd nan to state the obvious, we are in the midst of a global pandemic. like sars and mers before it, a new coronavirus (sars-cov- ) that was previously confined to an animal species, has made its way into the human population with devastating results [ ] . given the scope of the problem and because at the time of this writing there is no vaccine to prevent infection or proven therapy to treat it, attention is understandably riveted on mitigating the immediate health and economic consequences of covid- . elected officials, community leaders, health care providers, and scientists are scrambling to respond to the expanding spread of disease in the united states and elsewhere around the world. at a time when society's efforts are necessarily focused on our acute response to this pandemic, it may seem wrongheaded to think about longer-term strategies in response to sars-cov- . but arguably there is benefit in planning beyond immediate needs and circumstances. said consideration derives from the fact that even after the current wave of this pandemic subsides, we will not have eradicated sars-cov- . nor will we be spared from future pandemics of other viruses, whether they be respiratory, enteric or bloodborne. what can history teach us about successful responses to past infectious disease pandemics? given the widespread implementation of social distancing (also known by the more accurate designation of "physical distancing") in response to covid- disease, public health leaders are deeply interested in the outcomes of these same so-called "nonpharmaceutical interventions" when they were deployed in response to another deadly pandemic of a respiratory virus, the influenza epidemic of - [ ] . contemporary analyses support the fact that these interventions, when implemented early and in a sustained manner, were successful in mitigating the consequences of pandemic influenza in the last century [ ] . that valuable information is being put to good use during the current wave of sars-cov- . but what can we say about the public health responses that were undertaken in the years following the - influenza pandemic, after the immediate threat had passed? certainly, there was increased research interest into the causative agent of influenza, leading to the eventual isolation of influenza a from human tissue samples in [ ] . and historians have noted that the lack of a national disease reporting system in the u.s.-which hindered a coordinated response to the influenza outbreak of / -was rectified several years later; by all u.s. states were participating in a national system to report disease [ ] . but given the periodicity of influenza, it's come-and-go nature, some experts have opined that our national response to pandemics typically follows a cycle of "panic-neglect-panic-neglect" [ ] . sadly, this supposition is supported by patterns of public health funding in the u.s. typically, after a national disease outbreak or other disaster there is an infusion of one-time supplemental funding which generally recedes after the emergency wanes and the attention of legislators turns to other, more immediate issues [ ] . when faced with a pandemic of a novel infectious disease, it's understandable that we quickly focus on the necessary biomedical tools required to prevent, diagnose, and treat the offending pathogen. do we have a test that can accurately diagnose infection? how long will it take for scientists to develop an effective vaccine that can prevent disease acquisition? are any drugs available that can cure or safely treat persons once they've become infected? to be sure, each one of these elements-accurate diagnostic test, effective vaccine, successful treatment-is critical but by themselves they do not constitute an adequate pandemic response. why? because, simply stated, a pandemic's impact is not just experienced at the level of the infected individual. by their very nature, pandemics adversely affect large segments of the population, thereby generating negative consequences that spread across social systems and structures. it follows, then, that successful responses to pandemics must include the implementation of societal-level responses and system-wide interventions. to wit, during a pandemic the goal of public health is to protect the health of the entire population, not just to prevent or treat disease among specific individuals. consider the following scenarios. the most accurate diagnostic test will be of little value without a stable system to deliver it in a timely manner to everyone in need-or a sufficiently scaled workforce that's been trained to properly collect and analyze the large influx of specimens. without strong community partnerships to amplify health communication messages coming from public health leaders, panic and misinformation can scuttle the uptake of strategies meant to keep communities safe. for example, a handful of anecdotal reports about negative reactions to a new vaccine could impede community uptake, resulting in substantial missed opportunities for immunization. and even curative treatments will be of little value if large segments of the population in need of them are uninsured or underinsured and unable to afford the therapy [ ] . each of these scenarios point out that effective biomedical tools, by themselves, cannot end epidemics. in addition to effective tools and interventions we need surveillance systems to assess and target their need; viable community partnerships across all segments of the public health system to assure that interventions are delivered in a timely, equitable and culturally competent manner; policies, processes and information systems that can continuously monitor the interventions' impact; and a standing public health workforce of sufficient size that is properly equipped and capable of providing these services, in collaboration with other community partners. if one needs proof of the importance of developing and sustaining system-level interventions to meet the ongoing threat of global pandemics, our nation's response to hiv/ aids provides such evidence. to be clear, this comparison is made in reference to our nation's eventual response to hiv-not to its initial response, which was typified largely by denial. early on, most legislators and policy makers ignored the emerging aids epidemic, characterizing it as the consequence of unhealthy behaviors practiced by homosexual men and persons who inject illicit drugs [ ] . but a cadre of fearless community activists and farsighted public health leaders were eventually able to push forward a comprehensive agenda that resulted in long term funding for surveillance systems to monitor the spread of disease [ ] , community-based systems to test for and prevent hiv infection among the vulnerable [ ] and a national system to provide comprehensive medical care, essential support services and needed medications for uninsured and underinsured persons living with hiv-the ryan white hiv/aids program [ ] . nor should we overlook america's substantial contribution to fighting the global spread of hiv. in the united states government implemented pepfar, the largest global health program devoted to a single disease, credited with saving millions of lives globally [ ] . true, we have not vanquished hiv from our world, but we have made substantial progress in preventing its spread and improving health outcomes for those who are living with the virus-even in the absence of a vaccine or curative treatment. our national progress has been such that the united states has now set a goal to reduce new hiv infections by % come [ ] . without denying the importance of prophylaxis that can prevent the acquisition of hiv [ ] or the impact of effective treatments that can reduce viral load such that the risk of sexual transmission is essentially nil [ ] , we would not be able to realistically visualize the end of aids in the united states without the continued public investment in systems that are necessary to prevent infection, improve health outcomes for those living with hiv and monitor changes in disease spread and outcome. which brings us back to the point of this commentary. we must not allow ourselves to fall into a cycle of "neglect" by ignoring the threat of future pandemics once this initial wave of sars-cov- has passed. our national response to hiv/aids has shown us that in addition to funding the biomedical enterprise so that it can deliver effective treatments (including an eventual vaccine), we must also invest in a strong, stable public health system that is ready to respond when calamities like covid- hit [ ] . addressing chronic underfunding in state and local health departments is key to that effort [ , ] . nor should we ignore the vital role that non-governmental organizations-especially community-based organizations-can play when they work in partnership with public health agencies. in the united states and across the world, ngos have been a critical component in successful efforts to prevent and treat hiv [ ] . and adequately funded hiv surveillance systems in the u.s.-a rarity among other infectious diseases like hepatitis c virus (hcv)-have provided increasingly detailed information that enable us to quickly identify emerging outbreaks and accurately target prevention and care services to underserved areas. we readily admit that the epidemiology, transmission dynamics and pathogenesis of these two viruses-hiv and sars-cov- -are vastly different. nor do we mean to infer that the interventions successful in preventing hiv can be directly applied to covid- disease. but the principles that we've learned from decades of grappling with the hiv pandemic-in the u.s. and abroad-are relevant in regard to developing successful, long-term responses to protect against other infectious disease pandemics. while maintaining an adequate public health infrastructure may "top the list" of necessities when it comes to protecting population health, other fundamental principles, listed below, are equally important. sustained investment in public health infrastructure is necessary in order to develop, implement and evalu-ate effective system-level interventions in response to emerging and ongoing health threats. approaches to assuring and preserving health must not be limited to the biomedical sciences; we must also actively address the psychosocial influences that affect well-being. affected communities must be actively engaged in identifying and implementing strategies in response to threats to their health and well-being. stigma and fear are constant companions of infectious disease pandemics; proactive steps must be taken to minimize their negative consequences. to reduce health disparities, proactively identify groups and communities at disproportionate risk of developing disease or poor health outcomes and design interventions to reduce these disparities and to promote health equity. in recognition of the interconnected nature of our world, there must be a global component in our response to infectious disease pandemics and this component must be based on the best available information and science. let's be sure to put the hard-won knowledge that we've acquired from our decades-long interaction with the hiv/ aids pandemic into practice as we prepare for the future of covid- and other pandemics that have yet to emerge. to paraphrase santayana, failure to learn from our past can only ensure repeated failure in our future. coronavirus has become a pandemic, w.h.o. says. new york times. the influenza epidemic in new york city: a review of the public health response nonpharmaceutical interventions implemented by us cities during the - influenza pandemic changing perceptions of pandemic influenza and public health responses how the flu pandemic revolutionized public health. smithsonian magazine better prepare than reach: reordering public health priorities years after the spanish flu epidemic ready or not: protecting the public's health from diseases, disasters, and bioterrorism. trust for america's health simple, effective but out of reach? public health implications of hcv drugs dawning answers: how the hiv/aids epidemic has helped to strengthen public health dawning answers: how the hiv/aids epidemic has helped to strengthen public health twenty-five years of hiv/ aids-united states health resources and services administration president's emergency plan for aids relief (pepfar) ending the hiv epidemic: a plan for the united states preexposure chemoprophylaxis for hiv prevention in men who have sex with men sexual activity without condoms and risk of hiv transmission in serodifferent couples when the hiv-positive partner is using suppressive antiretroviral therapy developing a financing system to support public health infrastructure america's public health infrastructure needs consistent funding. roll call the impact of chronic underfunding on america's public health system: trends, risks, and recommendations ending hiv in america: not without the power of community key: cord- -dvbua pf authors: nepal, binod title: aids denial in asia: dimensions and roots date: - - journal: health policy doi: . /j.healthpol. . . sha: doc_id: cord_uid: dvbua pf abstract aids denial has long been viewed as the obstacle to forging effective response in many asian countries. this article examines the dimensions and roots of this phenomenon. it identifies seven types of views, attitudes, or tendencies that can be described as denial, dissent, disagreements, or doubts. three major factors underlying the aids denial are discussed. these are ( ) historical impressions that stds are western diseases, ( ) desire of some asian leaders to forge eastern points of view, and ( ) long-held negative image towards the peoples or groups who happened to be at the front-line of the population groups exposed to the epidemic. the third factor is the most important source of denial. aids denial is not a new and isolated phenomenon but the one shaped by the global and historical institutions. asian aids denial reflects the authoritarian and moralist grievances arising from the perceived deterioration of traditional moral order. since the late s, well within a decade of the identification of the disease, asia has been warned to be heading towards a devastating aids epidemic. the epidemic has been described as the 'gathering storm' [ ] which could create a 'next wave' [ ] of infections and deaths in asia pushing the 'continent in peril' [ ] and putting the 'economic and social progress in jeopardy' [ ] . though the prevalence of the disease in asian regions such as south and southeast asia ( . %) and east asia ( . %) is much lower than that in sub-saharan africa ( . %), almost all the countries have detected the virus in their nationals [ ] . yet people who take drugs intravenously and those who sell sex are at the front-line of the population groups hit by the 'storm'. the virus has been detected in the majority of injecting drug users in one or more sites of china, india, indonesia, myanmar, nepal, thailand, and vietnam, and among one-tenth or more sex workers in some sites of cambodia, india, myanmar, nepal, thailand, and vietnam [ , ] . the incidence of hiv is rising among low-risk female populations in many countries [ ] . however, responses to this ongoing crisis have often remained scanty even in the countries which have been speculated to be at the risk of larger epidemics. dwyer et al. observed that although information about devastating impacts of hiv/aids in africa was widely circulated in the region, most countries in asia took no initiative to adopt the measures proven to be effective in controlling the epidemic [ ] . there are notable disagreements about the extent, prospect, and prevention of the disease. at the first hand, the control of aids epidemics looks simple, as thailand has shown that the disease can be contained provided that the leaders are committed and focused interventions are put in place [ ] . but many other countries have done little to reach the people who are the first to face the 'storm'. a review showed that only a small fraction of at-risk populations such as injecting drug users, sex workers, and migrants had been reached with the basic prevention services [ ] . not much was changed by [ ] . even thailand was no exception given that only a few drug injectors and homosexuals were receiving some outreach services [ ] . so, why are the responses to the prospective 'storm' low, slow, and fragmented? why is there little appre-ciation among the leaders that the disease might take a heavy toll if left unchecked? the phenomenon of low, slow, and fragmented responses has been described as the outcome of aids denial. time and again, aids denial has been mentioned as the serious obstacle to controlling aids in asia. the generic label, however, obscures many important dimensions of this challenge. the paper attempts to explore the dimension and roots of the aids denial in asia. the analysis is guided by the social constructionist approach which assumes that the diseases are biological phenomena but they carry socially constructed meaning. widespread stigma and discrimination against people with hiv/aids arise partly from the existing negative public attitude towards these people [ ] . the negative public image of hiv/aids and people carrying the virus is not only associated with the nature of the disease but also with the socially constructed meaning or understanding about the risk factors. the extent of stigma varies according to modes of transmission or behaviours perceived to be responsible for the infection and the pre-existing characteristics of the at-risk groups. many different social institutions contribute to the construction of specific public images of the target populations. the people and places at risk of contracting a disease are identified by the epidemiological studies but they do not necessarily become comprehensible to the masses. the public, the media, and the policy-makers begin to develop certain images about the disease and the at-risk people. according to schneider and ingram [ ] , 'officials develop maps of target populations based on both the stereotypes they themselves hold and those they believe to prevail among the segments of the public likely to become important to them.' formulation and shifts in policy for a particular group, subpopulation, or community depend on how they are viewed by policy-makers. gauri and liberman contend that where social institutions divide the population groups deeply, elites and common people perceive aids to be a disease of other people outside their community and who are unlikely to mingle with them [ ] . when responsible authorities take 'us' and 'they' approach by prejudicially linking the disease with specific sections of the populations, aids policies remain misguided and fragmented. to illustrate, despite very similar socio-demographic setups, response to aids were very different in brazil and south africa; unlike brazil where aids was considered a general threat for the entire population, aids was linked in south africa with the racial issues and aids policy was marred with racial divisions [ ] . like aids, the aids denialism is a global phenomenon. this has even tied the hands of the united nations (un) agencies which are looked for leading the global efforts to fight this pandemic. the political declaration adopted on june by the un general assembly mentioned the term 'vulnerable groups' five times but nowhere specified what they include [ ] . this was aimed at avoiding the acknowledgment of the existence of vulnerable groups such as injecting drug users and sex workers. yet much of the international comments on aids denial refer to south africa where the president thabo mbeki questioned the prevailing mainstream views on hiv/aids, and set up the presidential aids advisory panel [ ] [ ] [ ] . inclusion of the so-called dissident scientists in the panel was the most controversial aspect of his initiative and the major cause for severe criticism against him. refuting the established biomedical explanations, mbeki raised doubts about the role of sexual behaviours in driving the epidemic, attributed poverty as a cause for widespread aids deaths in africa, and expressed skepticism to the relevance of antiretroviral therapy. he was, therefore, branded as a 'denialist' and was even considered responsible for 'genocide' for the deaths due to aids in his country [ ] . no leader in asia has done anything as controversial as it was done by mbeki. yet asia is not free from denial if the term is understood as encompassing the range of dissenting voices and disagreements. schneider and fassin [ ] refer to denial as the 'individual or collective inability to face an intolerable reality by pretending that it does not exist'. there is, however, little clarity as to what the aids denial means in the asian contexts. mention of this term in one or the other context or to accuse governments [cf. , ] is not helpful to understand the full picture of the denial in this region. aids denial is a complex phenomenon manifested in various forms, ways, and contexts. seven major dimensions of denials, doubts, or disagreements about hiv/aids in asian societies are briefly discussed below. for sim-plicity, the term denial has been used here to represent the range of disagreements, controversies, doubts, or dissents. first, a small group of scientists and other professionals have doubted or even denied whether hiv has really been identified or whether it really causes aids. they are mostly from the us or europe but includes a few from asia. a group of the dissidents -leading among them is peter duesberg -argued that hiv is a harmless virus, and that aids is caused by drug abuse, anti-aids drugs, or malnutrition [ , ] . the other group of dissidents, primarily the perth group, questioned whether hiv was actually identified as a unique retrovirus [ ] . in , more than scientists and professionals signed a statement known as 'the durban declaration' dismissing those dissenting arguments [ ] . some of the signatories were from asia. nevertheless, the voices of aids dissidents appear to have no significant influence upon aids policies, as no countries have publicly subscribed to these views. second, aids has long been seen as foreigners' disease. a widely held view in asia in the pastand to a little extent so far -is that aids is a westerner's disease. initial cases of aids identified in some countries of asia belonged to the tourists or citizens returning from the west or the patients receiving the blood imported from the west. the first aids case in indonesia was found in a dutch tourist in bali, a tourist island, in . in china, the first aids case was identified in an argentina-born us citizen and the first four chinese identified with hiv were the haemophiliac patients who received blood imported from the united states (us) [ ] . the first aids patient documented in thailand was a thai male returned from the us [ ] . these incidents created an illusion about the source and prospect of the disease. third, many asian leaders were apparently confident about the persistence of moral order in their countries. many of them believed that deviant behaviours were absent or rare, and therefore the disease was unlikely to spread to the masses. moralistic and ideological roots of aids denialism in asia will be discussed in next section. to illustrate the illusion of moral order, it is sufficient to quote the then indian health minister: 'ours is a moral society. while tackling aids you [cannot] say you lead licentious lives because [you can use] condoms. i don't think that should be the message. ' [ ] fourth, aids has been considered a disease of deviants or isolated groups. when the disease began to appear among the local populations of asia, the virus was initially identified among people who were traditionally considered deviants or immoral. in india, a female sex worker from chennai was the first local person identified with hiv. initial outbreaks of hiv in this country occurred among injecting drug users in manipur, a northeastern state bordering on myanmar [ ] and female sex workers in mumbai [ ] . likewise, in indonesia, initial cases of hiv infections were found in costal areas frequented by thai fishermen [ ] . the first major outbreaks of hiv in china were limited to the injecting drug users mostly from the ethnic minorities in yunnan province [ , ] . this might have created a false hope that the mainstreams of the society would be insulated from the epidemic. fifth, denial of services to the people exposed to the disease was an inevitable outcome of the perception that individuals contracted the disease owing to their own sinful, deviant, or immoral behaviours. statistics reported by the government agencies showed that until recently only a small fraction of vulnerable groups such as injecting drug users, sex workers, and men who have sex with men were reached with outreach services [ ] . even in thailand which has one of a few model programs successful to control the epidemic at the national scale, the interventions have not covered all identified at-risk groups [ ] . some critical groups such as injecting drug users, prisoners, men who have sex with men (msm), and immigrants have been deprived of basic prevention and treatment services. therefore, despite growing evidence about the effectiveness, such programs as harm reductions and condom use remain controversial in the region [ ] . sixth, statistics on hiv/aids or at-risk groups are considered sensitive items deserving to be hidden. thailand, which developed a model condompromotion program later on, initially suppressed the results of hiv testing among sex workers for the fear that the news of hiv outbreaks would harm the tourism industry. though the country soon took bold steps to publicise the statistics and to insti-tute the much-admired condom-promotion campaign [ ] , many other countries in the region continued to show high sensitivity towards the statistics on hiv/aids and the most-at-risk groups. this is one of the reasons behind limited availability and quality of the statistics on the at-risk groups such as injecting drug users, sex workers and their clients, and men who have sex with men in the region [ ] [ ] [ ] . attitude of authorities in several countries of this region is probably reflected in the un theme group's observation about the local governments in china: many local governments do not want to know, or let others know about hiv/aids in their area for fear that it will reflect poorly on the locality and its officials. local governments sometimes suppress information and sometimes even actively oppose research on hiv/aids. [ ] finally, sensitivity about the disease is translated into denial of, or disagreement over, the scale of the epidemics. on several occasions, internal and external agencies have seriously doubted one another's estimates. generally, india and china kept questioning the validity of the hiv/aids estimates and relevance of the prevention programs prescribed by the international institutions and western health experts. in , indian officials disagreed with the un estimate of million people living with hiv/aids in the country, and the media even suspected that the 'figures were being inflated by the west to pressure india into accepting vaccine trial and other research on hiv infected people' [ ] . a doctor familiar with the aids situation in india, however, warned that 'denial, complacency, and blaming others for the epidemic are the main reasons why hiv has spread so successfully' in the country [ ] . similar disagreements erupted in when richard feachman, the executive director of the global fund to fight aids, tuberculosis, and malaria warned that india had the largest number of people living with hiv/aids in the world, surpassing south africa. he remarked, 'i don't believe in official statistics. india is already in [the] first place' [ ] . his arguments were refuted by several senior government officials of india citing that these two countries were not comparable and the gap in hiv prevalence levels were large [ ] . likewise, on september , the lancet published a news report entitled 'human rights organization blasts china over hiv/aids cover-up.' human rights watch accused chinese government of being 'in denial' over scale of hiv/aids epidemic. in this report, asian division director of human rights watch, a new york based organization, was quoted as commenting: 'the chinese government has been in denial about the problem for many years', and 'beijing's failure to act decisively in the aids epidemic continues to cost lives and cause incalculable suffering to those living with the virus' [ ] . though the aids denial is not so unique to asia, there are certain features specifically conducive for this phenomenon. this section discusses three salient factors: ( ) historical impressions that some sexually transmitted diseases (stds) are western diseases, ( ) desire of some asian leaders to forge eastern points of view, and ( ) long-held negative image towards the peoples or groups who happened to be at the highest risk of contracting the disease. these three factors are, however, interrelated. historically, the well known stds such as syphilis were understood by asians as the westerners' disease. european colonizers were seen as the sources of syphilis into asia. mukherji and chakravarti [ ] observed that syphilis, which is believed to have brought to europe by columbian voyagers, was unknown in ancient india until the arrival of portuguese, although gonorrhoea and soft chancre existed since ancient time. they maintained that the absence of any comment about syphilis in sanskrit works would illustrate the absence of this disease in this region. they noted: 'the disease is first mentioned in bhabaprakasa under the name of feringhi roga (portuguese disease) and mercurial preparations are recommended its treatment' [ ] . the term feringhi was used in many countries of asia not only to refer to portuguese but any european. in nepal, for example, local name of syphilis is viringi and it seems probable that the name was coined to identify the disease with the feringhi. medical history also indicates that incidence of venereal diseases was probably higher among europeans than asians. according to the annual report of the public health commissioner with the government of india, rates of hospital admissions for treatment of venereal diseases of british troops ( . per ) was four times higher than that of indian troops ( . per ) [ ] . an important ideological background to the aids denial stems from the desire of asian leaders to forge an independent view reflecting on the culture, traditions, and philosophies of the east. the thought exaggerates morality, hierarchical relations among the member of the society, community cohesiveness, and extended family systems as unique characteristics of the asian societies. this pattern of thought is sometimes referred, particularly in the east or southeast asia, as the asian values. though the concept of asian values has been criticised as having no factual base [ ] , it cannot be denied as having served the authoritarian officials to interpret the aids as a disease of deviants or bad people. this idea imagines asia as unique and denies or denounces behaviours that are considered to be inspired by the western thoughts and promotes oppressive or eliminative approach towards the people who are engaged in those behaviours. the concept of asian value -or exaggeration of morality in particular -is not the only background for aids denial. on several issues, asians have developed opinions different from that of the western scholars, governments, and institutions. the aids denial, which is considered the single most threat to effective aids policy in asia, parallels, to a limited extent, the previous debates on emerging issues of global concern. a relevant example is the great population debate -evolved in the s -about the role of aggressive family planning programs versus role of development for population control in the developing countries [ , ] . in the s, developing countries questioned the western policy of the uni-focal family planning programs to control population in the third world countries. on some occasions, development was argued as the best contraceptive. for aids, moral order has been seen as the best protection. this paves way for painting negative image of the people who rather need support. the construction of public impression about aids and the at-risk groups began with its initial epidemiological mystery. the disease remained mysterious for some years and societies developed various metaphors reflecting fear, stigma and moralistic misapprehensions [ ] . various perceptions about aids and at-risk groups evolved in the west permeated asia well before the disease arrived. in the us, aids was initially found among gays and hence characterized as a 'gay plague' [ ] . this prompted the asian policy-makers to dismiss the potential challenge of this epidemic assuming that homosexuality was absent in asia. in the s, aids cases detected in asia were mostly among foreigners, overseas returnees, and female sex workers. until the early s, aids in asia was generally interpreted as the foreigner's disease, particularly westerner's disease, associated with homosexuality and prostitution. for example, in , a journalist observed that the 'indian government's perception that "foreigners" are the principal carriers of hiv does not seem to have changed in recent years' [ ] . he added, 'most laws proposed to check the spread of aids are aimed at non-nationals' [ ] . similar was the situation in thailand where aids was initially perceived as 'a foreign disease, carried by foreigners and brought from foreign lands', and later as 'a disease of homosexuals' and then as 'a disease of intravenous drug users' [ ] . in the philippines, aids was mainly identified with the prostitutes and lower class gays who had contact with foreigners. even the upper class gays were arguing that 'low class gay people should be rounded up for aids testing since they're the only ones now who go around with the foreigners' [ ] . in some instances, people from high prevalence neighbouring regions were also blamed and cautioned. for example, when taiwan started to recruit foreign labourers in to make up its labour shortage, the labourers from south and southeast asia were characterized as the highest risk category who would pass hiv to innocent locals [ ] . it has been taking a long time to overcome the misinterpretation that aids is simply a disease of bad people. the groups identified as the high-risk are powerless, unorganized, often from disadvantaged backgrounds, and negatively viewed. so, these groups have been blamed for spreading the disease and considered to be personally accountable for the infections. major messages directed to the negatively viewed powerless groups are that 'they are bad people whose behaviour constitute a problem for others,' and that 'they can expect to be punished unless they change their behaviour or avoid contact with the government' [ ] . the negatively viewed powerless at-risk groups mostly included injecting drug users, female sex workers, men who have sex with men, and immigrants. in japan, as the official medical care system excludes undocumented foreign nationals, the immigrants are reluctant to take hiv test and to seek medical care for the fear of deportation [ ] . burmese migrants in thailand, especially those who lack work permit, also avoid visiting health facilities because of the fear of deportation [ ] . on may , a thai daily, the nation, reported that hiv prevalence among migrants was twice the prevalence in pregnant women, and hence the local public health experts were pointing out migrants as emerging vectors of hiv. marginal population groups such as idus, sex workers, and msms who are the most vulnerable to aids were stigmatized even without aids; the disease has added another burden upon them creating the phenomenon of double stigma [ , ] . in yunnan, china, for example, drug users carry stigma and are denied participation in the community activities and state sponsored services irrespective of their hiv status [ ] . a study from six asian countries identified that the tendency to blame, stigmatize, and discriminate the people vulnerable to, or living with, hiv is realised more clearly in interpersonal contexts such as health facilities but this is grounded in cultural, religious, institutional, and structural frameworks [ ] . in some instances, governments use strong negative terms such as social evils to described these people and emphasize punishment rather than support and care [ , ] . comparatively, aids carries more stigma than do other killer diseases such as severe acute respiratory syndrome and tuberculosis because aids is still seen as the consequence of one's own carelessness [ ] . aids denial has many dimensions but the most important one arise from the long-held negative attitude towards the vulnerable populations. there are some variations in the images of aids and at-risk groups across the regions but they are not merely local products; rather they have been shaped by the global and historical institutions as well. the echo has been felt up to the un general assemblies at the international level and down to the individuals at the micro-level. interestingly, no one in asia has taken views as extreme as the south african president mbeki, but there are many instances of disagreements, doubts, and denials that have been affecting the people directly exposed to the pandemic. while indifference, doubts, and blame underpin inaction or slow action in some instances, they have led to adopt negative policies in the other instances. overcoming denials is an important step towards instituting positive and comprehensive responses to aids. strategies can vary among the nations depending on their socio-cultural context and economic and technical ability. a general approach is to tackle pre-existing background stigma towards these vulnerable groups by promoting solidarity and intensifying advocacy. this helps reduce the long-held tendency to see aids as a disease of some careless people. the efforts of local and international networks of people with hiv have been showing some impacts but these institutions should have more than ceremonial recognition. further work is required to improve surveillance, research, and analysis and to better understand the extent and prospect of the epidemics and to show the implications to the society of the continued inactions. such work should be supplemented by conceptual debate on how broader social contexts, not only individual desires, underpin the risk behaviours. in sum, asian aids denial is a reflection of lamentation about the perceived deterioration of traditional moral orders and weakening hold on new generations, rather than the aids per se. when the authorities realise that they need to adapt their views and policies to suit the rapidly changing societies, the phenomenon of aids denial begins to fade. concerted advocacy spearheaded by organized members of the most vulnerable groups can speed up this process. aids in asia: the gathering storm the next wave of hiv/ aids: nigeria aids in asia: a continent in peril economic and social progress in jeopardy: hiv/aids in the asian and pacific region: integrating economic and social concerns, especially hiv/aids, in meeting the needs of the region report on the global aids epidemic hiv/aids surveillance database. us census bureau monitoring the aids pandemic network (map network) report on the global hiv/aids epidemic: th global report challenge and response: hiv in asia and the pacific breaking the silence: setting realistic priorities for aids control in less-developed countries unaids, world health organization (who), centers for disease control and prevention (cdc), policy project. coverage of selected services for hiv/aids prevention, care and support in low and middle-income countries in interventions to reduce hiv/aids stigma: what have we learned? social construction of target populations: implications for politics and policy boundary institutions and hiv/aids policy in brazil and south africa political declaration on hiv/aids denial defiance: a socio-political analysis of aids in south africa a synthesis report of the deliberations by the panel of experts invited by the president of the republic of south africa, the honourable mr the embodiment of inequality: aids as a social condition and the historical experience in south africa the aids scare in india could be aid-induced. editorial comments human rights organisation blasts china over hiv/aids cover-up: human rights watch accuses chinese government of being "in denial" over scale of hiv/aids epidemic hiv does not cause aids the aids dilemma: drug diseases blamed on a passenger virus a critique of the montagnier evidence for the hiv/aids hypothesis the durban declaration hiv infection and aids in china through acquired immune deficiency syndrome in thailand. a report of two cases india minister vows to beat aids rapid spread of hiv among injecting drug users in north-eastern states of india the current situation of the hiv/aids epidemic in indonesia current status of hiv infection in yunnan province of china hiv infection and aids in china thailand's response to aids: building on success, confronting the future aids and public policy: the lessons and challenges of 'success' in thailand estimates of the number of female sex workers in different regions of the world estimating the number of men who have sex with men in low and middle income countries estimates of injecting drug users at the national and local level in developing and transitional countries, and gender and age distribution un theme group on hiv/aids in china. hiv/aids: china's titanic peril the aids scare in india could be aid-induced india surpasses south africa in aids cases india's response to the hiv epidemic prostitution in india. calcutta: das gupta and company development as freedom famplan: the great debate abates. international family planning perspectives the politics of family planning: issues for the future aids and its metaphors understanding aids: historical interpretations and the limits of biomedical individualism india: less complacency now thailand: the 'foreign' disease philippines: focusing on the hospitality women sexual cultures in east asia: the social construction of sexuality and sexual risk in a time of aids japanese foundation for aids prevention. hiv/aids update sexuality, reproductive health and violence: experiences of migrants from burma in the third phase of hiv pandemic: social consequences of hiv/aids stigma and descrimination and future needs using case vignettes to measure hiv-related stigma among health professionals in china drug abuse, hiv/aids and stigmatisation in a daicommnity in yunnan hiv discrimination: integrating the results from a six-country situational analysis in the asia pacific sex in the city: sexual behaviour, societal change, and stds in saigon uncharted waters: the impact of u.s. policies in vietnam comparative stigma of hiv/aids, sars, and tuberculosis in hong kong this article draws on the research conducted by the author as a phd scholar at the demography and sociology program, the australian national university. the author would like to thank prof. terry hull and dr. zhongwei zhao for their insightful comments on an earlier version of this article. key: cord- -ue azoyf authors: hardon, anita; desclaux, alice; egrot, marc; simon, emmanuelle; micollier, evelyne; kyakuwa, margaret title: alternative medicines for aids in resource-poor settings: insights from exploratory anthropological studies in asia and africa date: - - journal: j ethnobiol ethnomed doi: . / - - - sha: doc_id: cord_uid: ue azoyf the emergence of alternative medicines for aids in asia and africa was discussed at a satellite symposium and the parallel session on alternative and traditional treatments of the aidsimpact meeting, held in marseille, in july . these medicines are heterogeneous, both in their presentation and in their geographic and cultural origin. the sessions focused on the role of these medications in selected resource poor settings in africa and asia now that access to anti-retroviral therapy is increasing. the aims of the sessions were to ( ) identify the actors involved in the diffusion of these alternative medicines for hiv/aids, ( ) explore uses and forms, and the way these medicines are given legitimacy, ( ) reflect on underlying processes of globalisation and cultural differentiation, and ( ) define priority questions for future research in this area. this article presents the insights generated at the meeting, illustrated with some findings from the case studies (uganda, senegal, benin, burkina faso, china and indonesia) that were presented. these case studies reveal the wide range of actors who are involved in the marketing and supply of alternative medicines. regulatory mechanisms are weak. the efficacy claims of alternative medicines often reinforce a biomedical paradigm for hiv/aids, and fit with a healthy living ideology promoted by aids care programs and support groups. the aidsimpact session concluded that more interdisciplinary research is needed on the experience of people living with hiv/aids with these alternative medicines, and on the ways in which these products interact (or not) with anti-retroviral therapy at pharmacological as well as psychosocial levels. a large number of new treatments offered to people living with hiv/aids (plwa) have appeared over the last fifteen years in the therapeutic domain of aids. these med-icines are particularly heterogeneous, both in their presentation and in their geographic and cultural origin. they constitute a group of products with a therapeutic aim that occupies a space between the customary traditional, popular and biomedical sectors of health care [ ] . these products often mix reference to biomedicine and science with notions of traditional health culture and nature in a syncretic way. they consist mainly of herbs and nutritional substances and are packaged as 'modern' pharmaceuticals: capsules, tablets, and solutions. the names of these alternative treatments reflect their reference to biomedicine: immunocomplex, viralgic, virjint, etc. their accompanying leaflets provide detailed information on substance, as well as dosage, indications, and biomedical efficacy claims. their diffusion follows contemporary paths in the global economy and makes use of new information technologies. in this paper, we will use the term "alternative" to consider a generic category including medicines that recently appeared for aids which have not been authorised by drug regulatory authorities, nor recommended by who. other terms, such as neo-traditional or neo-phytotherapeutic, may be discussed for the characterization of some of these treatments, related to their local meanings or their social status. the emergence of alternative medicines for aids in asia and africa was discussed at a satellite symposium and the parallel session on alternative and traditional treatments of the aidsimpact meeting, held in marseille, in july . we were especially interested in the role of these medications since the introduction and rapid scale-up of highly active anti-retroviral therapy (haart) in resource poor settings. twenty anthropologists and health researchers attended the satellite session and presented exploratory findings from asia and africa (uganda, senegal, benin, burkina faso, china and indonesia). the aims of the satellite, the results of which were presented at the parallel session [ ] , were to ( ) identify the actors involved in the diffusion of these alternative medicines for hiv/aids, ( ) explore uses and forms of these medicines, and the way they are given legitimacy, ( ) reflect on underlying processes of globalisation and cultural differentiation, and ( ) define priority questions for future research in this area. we present here the insights generated at the meeting, illustrated with some findings from the studies that were discussed. there has been an increased professionalisation and commercialisation of traditional medicine in response to the development of biomedicine. this trend is not specific to aids and not necessarily a recent development. social scientists first noted this trend in the late s: charles leslie [ ] for example has shown how, in india, in response to an increased authority of biomedicine and the globalisation of health markets, unani and ayurvedic medicine production changed; and afdhal and welsch [ ] described the rise of 'modern' jamu in indonesia. jamu is the traditional term for indonesian indigenous medicines usually prepared from herbal medicines such as leaves, bark, roots and flowers. nowadays a multimillion dollar industry is involved in the production of ayurvedic and unani medicines in india, and of jamu in indonesia. a rapidly expanding assortment of powders, creams, pills, capsules and cosmetics has been manufactured both in small cottage industries as in large factories with increasingly sophisticated technologies [ , ] . the modernization of the manufacturing of these drugs has been accompanied with more modern biomedical modes of presenting their efficacy [ ] . under globalization, similar trends occurred in other regions and these products diffused more rapidly. at the seminars in marseille, we discussed the ways in which such alternative remedies operate in the therapeutic domain of aids care. in the first decade of the aids epidemic there was no effective treatment for hiv/aids and patients were faced with nearly certain premature death. at that time, there were regular hypes offering hope for life. but with the introduction of art, alternative treatments are now marketed for many additional purposes too: to prevent aids, to kill viruses, to delay the need for art, to restore and enhance health while on art, to treat opportunistic infections, and to alleviate adverse side effects of other treatments. biomedical practitioners generally discourage the use of alternative medicines, fearing interactions with art and also through the concern that patients may stop using art. at the aidsimpact sessions egrot and colleagues [ ] presented findings on the supply of what they label "neo-traditional medicines" to refer to the boundary-crossing nature of these treatments in west africa. the "designers" of the inventoried products are extremely heterogeneous. in some cases these people are nationals of african countries who present themselves as healers. some say they have undertaken "research" on the basis of therapeutic products that were already known locally. others refer to a dream revelation (classic in the universe of healers in africa) of a plant composition that is "efficacious" against aids, while yet others speak of a divine revelation. physicians, scientists and academics are solicitated, brought into involvement or spontaneously engage themselves in the exploitation of neo-traditional products. the case studies in west africa show that other treatments, such as immunicomplex or aloe vera, originate in europe and the usa. alternative medicines from europe and the usa occupy the same shelves in ordinary pharmacies as those originating from africa and china, often along with a few 'immune-boosting' food products (honey, olive oil). specialized "bio", "natural health" and "health food" shops make these products available to the more affluent. the distributors and marketing men of these products also target health workers and clinics directly. the west africa case studies noted that health workers also have started to prescribe alternative products such as immuboost (nhi t) or viralgic (pharma concept) (see figure ) . a case study from uganda showed how health workers operating an anti-retroviral treatment program adopted a locally available traditional ointment as an alternative medication for skins problems of people living with hiv and aids. the skin problems result from adverse effects of art or symptoms of opportunistic infections. the health workers obtained the recipe from local traditional healers (patients had told them that the cream works well), and the patients help collect the ingredients. they 'repackage' this traditional remedy into what is now called 'mobile cream' (to make clear it is produced by the so called 'mobile' art program). one of the nurses reports: "the mobile cream, which we ourselves prepare either at our chief nurse's home or here at the office depending on how busy we are at the office, is very efficacious for many kinds of skin related conditions. we are quick to prescribe it to the patients because we know it works and it is popular among patients too because it works for them [ ] ." content analysis of drug information leaflets, advertisements, product catalogues, and brochures distributed by medical representatives in the west africa case studies [ , ] casts light on the range of effects that are attributed to these drugs. most commonly cited (biomedical) properties are immune-stimulation and antioxidant. some manufacturers suggest that the products have antiviral properties as well. the antiviral dimension refers either to the opportunistic infections such as herpes (mentioned for example in the product information for immuboost) or eventually to the immunodeficiency syndrome itself. indeed, some products boldly claim anti-hiv activity as well, and are marketed as natural art (see figure ). however, such efficacy claims are not static. the producer of virusinest (nesto-pharma) recently withdrew the antiviral claim, stating in its information leaflet: "the analyses carried out among patients do not allow the anti-hiv assertion to be upheld". there may be also inconsistencies between various information sources. the brochure for viralgic (pharma concept) says that this is a product which renders the virus undetectable, but the website of the manufacturer presents the drug as immunostimulant (result of trials published on the web site), and present the product as treatment for opportunistic infections: "antiherpes...for healthy persons". a case study on indonesia [ ] dealt with the demand for alternative medicines among plwa. as afdhal and welsch noted two decades ago, indonesia has a thriving market for jamu. jamu are sold for a wide range of indications: common colds, influenza, headaches, aches and pains, high blood pressure, beauty, improvements in sexual performance, and recently to treat and prevent hivrelated health problems. aids prevalence is below % (i.e. this is a low prevalence area), but the disease is stigmatised, because of its association with intravenous drug use and prostitution. hardon and her colleagues conducted interviews with women and men who live with hiv and use anti-retroviral therapy, mainly intravenous drug users and their partners. all of them had better health since taking these modern drugs. nonetheless, all of them see the need to take jamu as well. they do so in tobacoak's, west africa part out of their intention to live positively (i.e. eating and sleeping well, and keeping a positive outlook on life), as promoted by many of the support groups in which plwa participate. the respondents do not make distinctions between modern medicines and jamu in these health maintenance and restoring practices. rather they distinguish the drugs by their effects. they use popular jamu to treat side effects of haart, such as itchiness. these jamus are not specifically promoted for hiv and aids in indonesia, perhaps partly because the disease is so stigmatised. however one neo-traditional preparation stood out in the narratives of our respondents as a product which can treat hiv/aids: virgin coconut oil. ceri, for example, started using coconut oil shortly after she found out she was hivpositive. she says: actually, the effect is not only for your immune system. so, i feel better, don't feel tired, and have more energy. i think what influences most is self-suggestion. it's self-suggestion that matters... mia (a year old woman from jakarta) was given virgin coconut oil by a friend from yogjakarta: i got boxes. a box contains capsules. it took it every day until i felt sick, but there was no effect. my cd level did not increase. three months, three months made me look like a coconut you just needed to squeeze (laughing). i became very oily. the good effect when you take vco is that your skin is silk smooth, your face is fairer and if you take a shower, you don't need any lotion, because your skin is naturally oily. that is the positive effect. your hair is also stronger. but buli, a -year-old ex-drug user from karawang, one of the most active members of the support group in karawang says: in indonesia, the drug sellers were not very willing to discuss the effects of vco. they would acknowledge that indeed these drugs are used by plwa, or they would deny knowing anything about the drugs. but their pharmacies are full of advertisements for the products and they have prominent positions on their shelves (see figure ). content analysis of the package information for vco in indonesia revealed that they are marketed as real 'curealls', i.e. to kill viruses and bacteria and/or strengthen the immune system, efficacy claims that we also found in west africa. for example the package leaflet for vicofit (manufactured by sumber dinamis in bogor) states that the drug has "a high content of lauric acid which has antivirus, anti-bacterials and anti-protozoa properties." and that it is "believed to help improve the health condition of those with cholesterol, diabetes, coronary heart disease, hepatitis c, hiv positive, cancer, prostate, uric acid, osteoporosis, influenza and weight problems". the package for virjint (produced by pt vermindo international) states that the medicine is safe for daily use and without side effects. it lists two dosages: one for prevention ( × capsules per day) and another for treatment ( × capsules per day). the leaflet stipulates that the indications are: -"to increase energy and body stamina -to increase body resistance (meningkatkan daya tahan tubuh) against bacterial, viral and fungal pathogens -to reduce weight -anti-oxidant, anticancer, and anti-hiv -to overcome uric acid, hypertension, stroke, heart disease, atherosclerosis, osteoporosis, influenza, hepatitis, chickenpox, herpes, tb, diabetes, epilepsy, eczema, liver, haemorrhoids, kidney, peradangan (burning sensation), infection, degenerative disease." the packages cite clinical research conducted elsewhere (philippines, usa) to give legitimacy to the products. for example the leaflet of holistic virgin coconut oil states: "based on research conducted in the philippines, holistic virgin coconut oil is very effective to fight against sars and aids". one of the key characteristics of alternative medicines in asia and africa is that they move from one cultural and geographic space to another, apparently without being constrained by trade-barriers, or regulatory mechanisms. some governments promote the production and diffusion of neo-traditional medicines. they do so for economic reasons: alternative medicines are big business, but they also do so for ideological reasons: neo-traditional medicines reflect an attractive hybrid of modernity and national heritage, providing a sense of national identity in the globalized health economy [ ] . the governments of india, china, indonesia, and some african countries support research programs to further advance these neo-traditional products, and facilitate market diffusion. while registered pharmaceuticals are regulated heavily upon market entry (proof of efficacy is assessed by national drug regulatory authorities), this is not the case for alternative medicines. art programs, which are sponsored by the same governments, usually discourage the use of alternative medicines, fearing the toxicity of the drugs, or that these medicines will interact with anti-retroviral medication and lead to discontinuation of art therapy [ ] . governmental agencies may have contradictory attitudes towards the use of alternative medicines for aids, discouraging it within art programs and supporting it within divisions of traditional medicine. an exception is the chinese government, which officially supports a complementary medicine program for aids care and research [ ] . mass-produced alternative medicines meet an increasing demand for health products, a trend which has been labelled the "commodification of health" [ , ] : from the slums of djakarta to rural settings in burkina faso, people believe more and more that they need pharmaceutical 'things' to protect their health and to treat illness symptoms. people living with hiv and aids are particularly uncertain about their health and their future: art may be accessible and improve health now, but they wonder if this will be the case in the future. this uncertainty makes them an attractive market for the 'best of both worlds', alternative medicines, which come with assertions of 'natural' safety and 'biomedical' efficacy [ ] . however the case studies presented in marseille suggest that people especially want to use alternative medicines to delay onset of art, treat opportunistic infections, restore health and alleviate adverse effects once on art. immuneboosters are popular, though our case studies suggest that plwa are often ambivalent about alternative medicines that claim anti-hiv efficacy. the case studies make clear that the market of alternative medicines for hiv/aids is dynamic. it adapts to progress in biomedicine, which has produced potent anti-retrovi-ral medications. in some cases, the efficacy claims for alternative medicines reinforce a biomedical paradigm for hiv/aids, and fit with a healthy living ideology promoted by aids care programs and support groups. more interdisciplinary research is needed on the experience of people living with hiv/aids with these alternative medicines, the ways in which the products and their representations move from one cultural setting to another, and on the ways in which these products interact (or not) with anti-retroviral therapy at pharmacological as well as psychosocial levels. more research is also needed to assess the economic impact of these therapies, since people seem to be spending much on these 'other' medicines while art is provided for free. a blanket denial of the relevance of these products for the quality of life of plwa does not make sense for patients, who need precise information that make clear which products are likely to have negative interactions with art, and which ones could be beneficial. unfortunately research on the interactions between alternative medicine and antiretroviral drugs is sparse [ ] . to be able to inform patients better, more clinical research is needed on the benefits and risks of those alternative medicines that are perceived to be beneficial by people living with hiv and aids. patients and healers in the context of culture: an exploration of the borderland between anthropology, medicine and psychiatry berkeley alternative and traditional treatments for aids in the time of art in resource-poor settings: a comparative analysis of recent anthropological studies abstracts aids impact th international conference indigenous pharmaceuticals, the capitalist world system, and civilization the rise of the modern jamu industry in indonesia: a preliminary overview ayurvedic and unani health and beauty products: reworking india's medical traditions an overview on neotraditional medicines for hiv/ aids in west africa. naarps workshop alternative and traditional treatments for hiv/aids staying healthy while on haart: the experiences of providers and patients on haart in uganda's resource limited settings. naarps workshop alternative and traditional treatments for hiv/aids non-conventional hiv/aids treatments in west-africa: based on the case of benin. proceedings naarps workshop alternative and traditional treatments for hiv/aids on coconut oil, buah merah and other treatments used by people living with aids in west-java neo-traditional treatments for aids in china: national aids treatment policy and local/global use of tcm (traditional chinese medicine use of traditional herbal medicine by aids patients in kabarole district, western uganda facettes de la recherche médicale et de la gestion du vih-sida dans le système de santé chinois: un autre exemple d'adaptation locale de la biomédecine' (an outline of aids medical research and management of hiv and aids in the chinese public health system: another example of biomedicine localisation) the anthropology of pharmaceuticals: a biographical approach. annual review of anthropology agenda for an anthropology of pharmaceutical practice use of traditional medicine by hiv-infected individuals in south africa in the era of antiretroviral theraphy the authors thank john kinsman for his editorial suggestions and rosalijn both for her assistance in preparing the manuscript. the authors prepared papers for a joint seminar held in aix-en-provence, see reference list for the titles of the contributing papers. a summary of the insights from the papers was subsequently presented at the marseille impact meeting, based on which a draft of this manuscript was written by ah and ad. all authors have contributed to the final manuscript. key: cord- -i n mu b authors: callaghan, chris title: pseudoscience in medicine: cautionary recommendations date: - - journal: afr health sci doi: . /ahs.v i . sha: doc_id: cord_uid: i n mu b introduction: certain real life applications of scientific and social science ideas that knowingly reject accumulated empirical biomedical evidence have been termed ‘pseudoscience,’ or empirical rejectionism. an uncritical acceptance of empiricism, or even of evidence-based medicine, however, can also be problematic. objectives: with reference to a specific type of medical denialism associated with moral failure, justified by dissident aids and anti-vaccine scientific publications, this paper seeks to make the argument that this type of denialism meets certain longstanding definitions for classification as pseudoscience. methods: this paper uses a conceptual framework to make certain arguments and to juxtapose arguments for evidence-based approaches to medicine against literature that highlights certain limitations of an unquestioning approach to empiricism. results: discussions of certain real life examples are used to derive the important insight that, under certain conditions, moral failure can result in the violation both type i and type ii scientific error types, with catastrophic consequences. conclusion: it is argued that the validity of all theory should not be assumed before sufficient empirical evidence has accumulated to support its validity across contexts. however, caution is required, to avoid the consequences of an unquestioning approach to empiricism. certain emergent problems with potentially catastrophic consequences require medical responses in a matter of hours, or days. examples of these include outbreaks of zika , ebola , lassa , middle east respiratory syndrome (mers-cov) , swine flu/h n , or rapidly increasing global antibiotic resistance . to meet these challenges, healthcare professionals require up to date scientific knowledge. it is not enough that this knowledge is up to date. it also needs to be scientifically rigorous. a reliance on empirical evidence and rigor, however, should not be confounded with a dogmatic faith in empiricism itself, which can also be problematic [ ] [ ] [ ] . in light of this tension, between a need for a pragmatic approach to evidence-based medicine (ebm), and the dangers of an uncritical acceptance of ebm, amidst uncertainties asso-ciated with its shortcomings, this paper seeks to provide a discussion of these issues, and to derive cautionary recommendations for those exposed to these same issues. in doing so,dissident examples of aids , and vaccine denialism [ ] [ ] [ ] [ ] [ ] [ ] [ ] are employed as an interpretive schema, or lens, through which to view events that link dissident perspectives in scientific publication to harmful outcomes. such an approach offers a useful heuristic in order to highlight a certain type of harmful use of science, which, according to established literature , has previously been categorised as 'pseudoscience.' these examples are taken to represent pseudoscience in medicine, which is defined here as scientific denialism associated with moral failure, justifying itself in terms of dissident scientific publication in order to advance agendas with the potential to do medical harm to human populations. according to kuhn , [with the exception of extraordinary problems] the "three classes of problems-determination of significant fact, matching of facts with theory, and articulation of theory-exhaust, i think, the literature of normal science, both empirical and theoretical (p. ) ." medical pseudoscience, as discussed here, falls outside of kuhn's classes of problem. this definition of medical pseudoscience is derived here,specifically, from two examples. the first relates to the moral failure on the part of a government, associated with aids denialism, which justified its medically harmfulactions at the time on the basis of certain dissident scientific publications . the policy stance in this case persisted, for years, after the emergence of evidence of the large scale loss of human life caused by these actions. the second example relates to the emergence of the anti-vaccination movement, based on the publication of two scientific papers in particular , , which mooted a causal relationship between measles-mumps-rubella (mmr) vaccination and autism. this movement has also been linked to an increase in fatalities due to non-vaccination . through the use of a heuristic, in the form of the interpretive schema offered by these two examples, a textured discussion of the dangers of medical pseudoscience is provided here. the problems of dogmatic empiricism are also, however, highlighted, to demonstrate the pervasiveness of medical pseudoscience as a problem that cannot be simplistically argued away with reference to notions of scientific evidence. in light of the problem of medical pseudoscience, the objective of this paper is to inform those potentially affected by the phenomena discussed here, and to provide cautionary insights on the basis of a considered engagement with the literature. given recent literature that highlights the vulnerability of the scientific publication process to political and ideological agendas , it is important to note, up front, that science itself is also subject to agendas of power , , , and that an empirical approach to solving these problems of medical denialism cannot also be considered to be value free or more just than other, non-empirical approaches. indeed, although some have argued that political conservatives in the us have been prone to deny scientific evidence related to climate change, recent evidence finds that scientific denialism may characterise those both on the left and the right of the political spectrum . if no political denomination at this time has a monopoly on dissident, or anti-science, discourse, the arguments made in this paper are perhaps timely, and serve to provide cautionary insights, particularly for those at the nexus of ideological and political forces, where scientific work, and particularly empirical findings, might be vulnerable to immoral misrepresentation. it is argued here that the use of the term pseudoscience, albeit uncomfortable, might therefore be useful (or even necessary), in that such uncomfortable debates may be to the benefit of those most vulnerable and powerless in the face of medical need. the paper proceeds as follows. the need for a cautionary perspective on empiricism is first introduced. to further contextualise the discussions, the topic of medical nihilism is then also introduced. certain challenges associated with the notion of consensus are then considered, and discrepancies between published recommendations and clinical practice are then discussed. finally, consideration of the topics of medical denialism and academic pseudoscience round off the paper, and the conclusion section summarises its objective and its key arguments. unwarranted faith in empiricism can amount to little more than dogma. it must be acknowledged that here is little in the way of evidence to date that demonstrates that an empirical approach can eliminate the dangers inherent in human interpretation and subjectivity. the pervasiveness of medical denialism [ ] [ ] [ ] [ ] [ ] , and well-known historical cases, such as the rejection of semmelweiss's empirical evidence of how to reduce infections in sur-gicalprocedures , seem to highlight this problem. the discussions of medical pseudoscience undertaken here therefore need to be grounded in an acknowledgement of the limitations of empiricism itself. the problem of medical nihilism, according to poland , highlights seemingly insoluble problems associated withhuman choices to believe or disbelieve medical evidence. an important debatein the literature relates to discussions of medical nihilism. the mckeown thesis derives from mckeown's argument that in certain contexts the fall in the crude mortality rate over time was largely "due not to life-saving advancements in the field of medicine or public health, but instead to improvements in overall standards of living (p. )," and especially those related to advances in nutrition that resulted from improved economic conditions . debates about mckeown's thesis have persisted in light of the question, are "public health ends better served by targeted interventions or by broadbased efforts to redistribute the social, political, and economic resources that determine the health of populations? (p. )" . the mckeown thesis has, however, led to what some have termed medical health nihilism , whereby some (perhaps "an entire generation of social scientists, historians, and policymakers") have considered the contributions of economics and nutrition to overshadow the role of public health interventions (p. ) . while some, for example, have questioned the provision of treatment for multi-drug resistant tuberculosis,in certain contexts, in that it may not be cost effective, farmer and nardell stress that it is important to avoid the trap of medical health nihilism, in that even though poverty and inequality persist, it is necessary to, nevertheless, "move forward with focused interventions and insist on universal access to high-quality tb care (p )." consensus about medical phenomena, can, however, be problematic under certain conditions. according to social empiricism, consensus is typically epistemologically undesirable (solomon, ) . dissent is valuable, even when there is no discussion (because deliberation can sometimes "make things worse rather than better"), as it does not require discussion to make it valuable, as originally argued by the likes of mill, popper and longino (p. ) . an over-reliance on the dogma of empiricism might therefore open scientific endeavour up to the shortcomings of problematic forms of consensus. ebm, based on the work of clinical epidemiologists in the s and s, emerged as a "new paradigm" at the start of the s, associated with methods such as randomised controlled trials, systematic reviews, and meta-analyses, which produced "an extensive and powerful body of research (p. )" . relying heavily on statistics, probability theory and utility theory provide ebm with its conceptual underpinnings. with its hierarchy of evidence, ebm takes its epistemic techniques as superior to traditional methods such as expert opinion, clinical experience, and physiological reasoning. this stance has not gone unchallenged, however. indeed, solomon stresses that ebm has been described as a kuhnian paradigm, and that it has been criticised in terms of its procedural aspects , , in terms of its fallibility, or its lack of replicability , and its incompleteness as a philosophy of science. in terms of the latter, there has been a persistent criticism of ebm that it ignores the basic sciences that inform research and clinical practice, whereby it is "scientifically superficial: it measures correlations," failing to "theorize about the complete organism, still less the complete organism in its social and environmental context (p. )" . further, according to solomon , literature suggests that "publication bias, time to publication bias and pharmaceutical funding bias (which subtly affects trial design and evaluation) are responsible for the worse-than-expected track record" of random controlled trials, systematic reviews, and meta-analyses (p. ). considering these criticisms, solomon suggests an instrumental, or pragmatic approach, whereby evidence should be ranked with reference to actual (and not theoretically expected) reliability of results. according to solomon , with the "recent emphasis on translational medicine, we are seeing a restoration of the recognition that clinical research requires an engagement with basic theory (e.g. physiological, genetic, biochemical) and a range of empirical techniques," in that ebm "works best when used in this context (p. )." translational medicine seeks to develop interdisciplinary synergies between researchers, and to create interactive linkages between basic science research and research in clinical medicine. translational medicine might ultimately hold the key to reducing problems associated with discrepancies between published recommendations and clinical practices. much work in other fields draws on precedent in medical research, in order to follow a systematic process, so as to develop evidence-informed knowledge . thus medical science is acknowledged to lead the way in evidence-based research, notwithstanding the problems associated with dogmatic approaches to empiricism. research on medical practice patterns has revealed a discrepancy between "published recommendations and clinical practices" . according to bryg and johns : the emotional appeal of interventional therapy is often so strong that rational thought is denied…physicians and patients often feel better trying "something" rather than waiting; interventional procedures are powerful and seductive for those seeking action….many different factors can be given to explain differences between clinical practices and recommendations based on controlled trials. the current efforts to address the medicolegal system and remuneration may not be enough. to change the "art' of medicine through the "science' of randomized trials, attention to all of these issues is needed to change practice patterns and help us "practice what we preach (p. )." seminal theory also points to how discrepancies between published recommendations and clinical practices. the seminal work of kuhn predicts that paradigmatic change can occur in scientific research, but that researchers typically reject novel facts that do not conform to the assumptions and values associated with a particular paradigm. in light of the potential consequences of pseudoscience, this paper seeks to explore the central tenet of kuhn's work, that advances in science are subject to changes in human values systems and not only to the objective advances of science itself, in relation to examples of how evidence can be ignored, at great human cost. by making these relationships explicit, we might be less likely to repeat the mistakes of the past. kuhn's theory suggests that advances in science are essentially a function of how the values and beliefs of scientists in fields change, whereby in 'normal science' fields will typically resist paradigmatic change in the face of contrary evidence, until eventually a tipping point is reached, and sets of values and beliefs then change to accommodate the new paradigm. kuhn's theory can be used to draw useful inferences, particularly when applied to the phenomenon of 'pseudoscience' and its potentially harmful influence. as discussed, a powerful example of kuhn's theory in the medical context is the work of semmelweiss. the case of semmelweiss illustrates how professionals can reject innovative ideas even in the face of evidence of the catastrophic human costs associated with this rejection. semmelweiss, a doctor in the s, demonstrated dramatically lower surgical mortality rates due to handwashing using a chloride of lime solution. even after providing evidence of this life saving process, his ideas were rejected. it was only two decades later that his work was revisited by the medical profession , and the 'new paradigm' of sterile hand washing was embraced. other seminal work, for example by lakatos also stresses the subjectivity of the research process, as fields like newtonian physics were shown to have rejected novel facts that challenged the 'hard core,' or fundamental tenets of the field. this work can also be taken to support kuhn's arguments that it cannot always be assumed that objective evidence will be the basis for how scientific decisions are made. there are other examples of kuhn's theory at work in the social sciences. events such as the sokal affair, orsokal hoax have highlighted the vulnerability of the academy to empirical rejectionism, or rejection of evidence-based approaches in academic or scientific research, or pseudoscience. still and dryden suggest two types of pseudoscience, one related to academic fields entailing deep engagement with some kind of academic process, termed 'big' pseudoscience, and one related to 'erroneous' public beliefs, with less of a deep engagement in academia, but often with a tenacious grip on the beliefs of many within populations. a core argument presented in this paper is that, as predicted by kuhn's theory, professional medical work, including policymaking, requires constant vigilance on the part of medical professionals so as to avoid the influence of pseudoscience. the examples of aids and vaccine denialism might be a useful interpretive schema, or lens, through which to view events that link dissident perspectives in scientific publication to harmful outcomes. as stressed previously, science is also an agenda of power , , , and an empirical approach to solving these problems of medical denialism therefore cannot also be considered to be value free or more just than other, non-empirical approaches. nattrass summarises certain catastrophic events at the nexus of pseudoscience, political power, and moral failure on a national scale: aids policy in post-apartheid south africa has been shaped by persistent antipathy towards antiretroviral drugs (arvs). this hostility was framed initially by [the president's] questioning of aids science and subsequently by direct resistance to implementing prevention and treatment programmes using arvs. once that battle was lost in the courts and in the political arena, the health minister [at the time] continued to portray arvs as 'poison' and to support alternative untested therapies. demographic modelling suggests that if the national government had used arvs for prevention and treatment at the same rate as the western cape (which defined national policy on arvs), then about , hiv infections and , deaths could have been prevented between and . two key scientific bodies, the medicines control council (mcc) and the medical research council (mrc) fall under the ambit of the national department of health. although notionally independent, both have experienced political interference as a consequence of their scientific approach towards aids (p. ). this example is illustrative, offering useful insights into a paradoxical situation of power misuse that led to the deaths of many who were the most vulnerable and powerless. this paradox seems to mirror the anti-science discourse driven by politicians in current political discourse, whether relating to the denial of climate change, or the selective use of science in support of political agendas (for a useful summary of these current issues, see washburn and skitka ). given the hundreds of thousands that may have died due to the amoral implementation of political ideology in the case of south africa, describing this using the term 'medical pseudoscience' is perhaps necessary (uncomfortable as the term may be to the academic ear), so as to not do disservice to those that have perished due to the application of this particular type of scientific denialism. indeed, it would seem that such events pass out of consideration relatively quickly, both by the public and by academic discussions. those involved in this perpetration live on, with little in the way of accountability. this example seems to illustrate a unique form of pseudoscience, which bears classification as such, and the development of its own stream of literature.exploring this paradox is useful, as it can offer insights into tensions between science and agendas of power. further exploration of this example offers more detailed insights into the harm that pseudoscience can cause. the use of this particular example might also serve to highlight the differences between pseudoscience and discourse that highlights legitimate criticisms of evidence-based approaches to medicine. this particular form of pseudoscience is taken here to relate to the power relationships of political actors and the prioritisation of ideology, in such a way as to actively engage in empirical rejectionism, at the expense of the most vulnerable and powerless in a society. an important lesson can be learned from these events. this large scale loss of human life was found to be due to scientific denialism on the part of certain respected academics. according to nattrass the cause can be traced back to the publication of scientific research, as accomplished (highly respected at the time) academics argued that azt itself caused aids rather than treating or preventing it. an example of the link between these events and scientific publication is duesberg's . denialist members of the presidential aids advisory panel (half orthodox scientists, half aids denialists) asserted that "aids would disappear instantaneously if all hiv testing was outlawed and the use of antiretroviral drugs was ter-minated (p. ) . another example of this type of pseudoscience, in the form of medical denialism, or empirical rejectionism, is the spread of the anti-vaccine movement. the link between dissident academic publication and the rise of the pseudoscientific anti-vaccine movement is also seen in the emergence of the populist anti-vaccine movement, which advocated halting mmr immunisation . this example of vaccine nihilism, according to poland , highlights the problem that "there are no magical solutions to the deep divide between those who accept the scientific method and evidence and those who do not and simply choose to disbelieve the evidence (p. )." this movement emerged on account of scientific publications that put forth the thesis that mmr vaccine was linked with the development of autism , . this example also serves to highlight the dangers of denialism, and its potential human costs [ ] [ ] [ ] . policy applications of pseudoscientific ideas and ideologies, including economic ideas, and the human costs of these are beyond the scope of this work, but further study of examples like this by further research might be instructive. this example clearly highlights kuhn's predictions, challenging assumptions that empirical rejectionist behaviour is necessarily benign. resistance to scientific thought itself has a long history. contestations between empirical rejectionist belief systems and science, and the catastrophic costs in human life caused by belief-system resistance to science throughout history is well documented . following kuhn , a condition for scientific advancement seems to be its coincidental alignment or convenient instrumental value for powerful agendas. in contrast to south african aids denialism in the context of a developing nation, the anti-vaccine movement serves as a cautionary tale about the pervasiveness of pseudoscientific beliefs in developed nations. academic literature on pseudoscience may offer further insights into these discussions. seeking to define prevalence of pseudoscience in the psychology discipline, lilienfeld suggests that academics follow bunge's seven 'indicators of pseudoscience' for guidance. these include: (i) overuse of ad hoc hypotheses to avoid refutation, (ii) emphasising confirmation, above refutation, (iii) lack of self-correction, (iv) reversed burden of proof, (v) excessive reliance on testimonial and anecdotal evidence, (vi) use of obscurantist language, and ( ) lack of connectivity with other disciplines. the use of science to justify the objectives of the aids denialist state, and the objectives of the anti-vaccine movement are considered to warrant the term 'pseudoscience' as they seem to meet these criteria. more than this, these examples offer examples of moral failure that seem to require differentiation from other instances of conflict with empiricism. thus, it is arguably useful to differentiate these examples by using the term pseudoscience, so as not to confound their discussion with broader debates on empiricism itself. it is therefore important to provide an informed discussion that embraces these broader debates, and which locates these two examples of a specific form of pseudoscience in relation to debates on empiricism, and the weaknesses of dogmatic empiricism as a potential remedy for the problem of denialist pseudoscience. to understand the real threats of pseudoscience it is perhaps necessary to return to first principles. an example of this kind of 'first principle' can perhaps be found in the doctrine 'do no harm.' with reference to the field of psychology, which has no equivalent of the food and drug administration's (fda's) oversight function, lilienfeld stresses the importance of the medical and mental health professions' credo primum non nocere, or 'first, do no harm.' the harm associated with pseudoscience is well illustrated in light of the examples considered above. the tensions between unlimited thought in academic contexts (which are good) and opportunistic use of ideas for political or ideological reasons that are largely inseparable from issues of power use and abuse, which can lead to loss of human life (which are bad) are not independent of real life contexts informed by medical science. a conceptual framework is needed in order to better understand these tensions. according to solomon , from "the work of historians of science, sociologists of science, anthropologists of science, feminist critics, social psychologists and decision analysts, we now know much more about the variety and pervasiveness of bias," whereby no one "has designed a group (or individual) scientific practice in which bias is eliminated, or even reduced to insignificant levels (p. )." solomon's work has sought to offer scientists a heuristic based on decision vectors, or the decisions that are made to accept one theory over another, particularly when both offer overlapping predictions about phenomena, or where both seem to fit the available data. these decision vectors can be based on empirical data or conceptual rationales. arguably, the wellspring for most pseudoscientific ideas has been academia. as well it is expected to be, given academic freedom and the role of the academy in generating all types of ideas, without limit. how do we then differentiate theory from recommendations for healthcare practice? figure offers a model, with the hope that it might be a useful heuristic for understanding the tensions between the two scientific error states, namely between making a type error of rejecting a true novel finding, versus making a type ii error of failing to reject false novel findings. these representations acknowledge the criticisms of empiricism highlighted in previous sections, and relate only to discussions of the tensions between theorising and empirically testing theory. in health sciences research, the centre line (in bold) shown in figure represents the optimal state, where the types of errors are balanced. this, in many studies, is put at the % confidence threshold, where statistical testing is at the five percent level of significance. as we know, however, this value is arbitrary, as increasing the size of a sample can increase the chances of obtaining a significant effect. a health science practitioner or researcher, however, needs to navigate between modes in different roles. as a theorist, one might need to be open to all ideas, and to consider all potentialities. to theorise innovatively, one would need to sacrifice validity temporarily, to develop models that can then be tested for validity. dissident theory that predicted that hiv was caused by arvs, for example, is an example falling into the low validity portion of the continuum shown in figure . however, so should all health theory that has not been empirically tested, in some way. this example is useful as a special case, however, in that it represents the extreme of type error, whereby these scientists rejected accumulated evidence that clearly supported the use of arvs. a type ii error, however, is also evident, in that there was a failure to reject theory that was patently at odds with the accumulated evidence to date. the model shown in figure is only useful in that it identifies problems related to validity versus problems related to conservatism and lack of innovation, but it does not show that at the extremes, both the violation of type and type ii errors can converge. the example of aids denialism illustrates that it is important for a healthcare practitioner to understand that there is not simply one continuum of error that can be made, but that both kinds of errors can mirror each other at the extreme. whereas many have discussed the example of semmelweiss , this instance of a type i error has seemingly not to date been considered in relation to an example of the coincidence of type and ii. this is however evident in a government's refusal to allow treatment of hiv victims with arvs on the basis of theory developed by respected academics. similarly, while seminal theory bylakatos ( ) also stresses how core tenets of fields can reject new knowledge, this theory also relates primarily to type errors, as does kuhn's seminal work. the sokal hoax highlights the potential for theory to be published by respected journals, but which was specifically formulated on the basis of confounding logics. further research should differentiate between extreme forms of type i and type ii error violation. the two forms of pseudoscience discussed here might be taken to exhibit characteristics of these extremes, and that such a characterisation might be useful in differentiating them from other forms of medical denialism. a contribution of this paperis arguably in the way it identifies and highlights dangers associated with the way that both type i and type ii errors can actually be committed under certain circumstances. at these extremes, a phenomenon is identified, termed medical pseudoscience, a relatively unique form of pseudoscience that takes the form of extreme denialism, but which is vulnerable to those with political agendas or other motives associated with moral failure. knowledge of this categorisation is arguably important, particularly when healthcare providers and policy makers can be lulled into a false sense of security in deriving policy or practice from dogmatic perspectives of empiricism that do not acknowledge the shortcomings of empiricism, or ebm itself. certain conclusions and recommendations that derive from this analysis are now presented. the objective of this paper was to provide a discussion of the dangers of medical pseudoscience, which might be particularly relevant in a global context wherein anti-science, or dissident and denialist discourse, seems to alsobe driven by political forces, making such discourse vulnerable to agendas associated with moral failure. it is concluded that taking recourse to unquestioning approaches of empiricism may however also be wrongheaded. instead, the approach of solomon - is recommended, one of cautious pragmatism. more specifically, evidence should be ranked with reference to actual (and not theo-retically expected) reliability of results . thus, threats associated with medical nihilism might be mitigated, pragmatically, to reduce harm. in extending debates about dissident and denialist medical discourse, this work sought to build on other, related, work. such work includes research that highlighting the dangers of inflexible and slow responses to epidemics , a lack of an adequate bioethical response to novel discoveries , constraints posed by human values to scientific progress itself , and changes to the scientific discovery process on account of emergent technologies , . this work also sought to extend discussions of empiricism to embrace issues associated with medical pseudoscience. it is also concluded that these examples of medical pseudoscience might benefit from further research that conceptualises them as extreme forms of the violation of type and type ii errors, whereby at the extremes, such phenomena share epistemic similarities. in conclusion, much hope rests on the promise of translational medicine , and its potential to address certain of the shortcomings of empiricism through a more interdisciplinary and pluralistic approach to both the methodological and theory-development processes of medical science. going forward, however, epistemic caution may be an important watchword in a world in which political forces may increasingly have the power to harnessscientific and medical denialism in pursuit of ideological agendas. world health organization "global alert and response. disease outbreak news world health organization "lassa fever middle east respiratory syndrome coronavirus (mers-cov): announcement of the coronavirus study group critical care services and h n influenza in australia and new zealand centres of disease control and prevention social empiricism groupthink versus the wisdom of crowds: the social epistemology of deliberation and dissent just a paradigm: evidence-based medicine in epistemological context hiv is not the cause of aids aids and the scientific governance of medicine in post-apartheid south africa ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children mmr vaccination and autism how irrational thinking hinders scientific progress, harms the planet, and threatens our lives how the case against the mmr vaccine was fixed secrets of the mmr scare: the lancet's two days to bury bad news mmr vaccine and autism: vaccine nihilism and postmodern science science, pseudoscience, and the frontline practitioner: the vaccination/autism debate pseudoscience in contemporary clinical psychology: what it is and what we can do about it the structure of scientific revolutions. similarly motivated to deny attitude-inconsistent science the subject and power critical perspectives on international pharmaceutical innovation: malthus, foucault and resistance ignaz semmelweis and the birth of infection control the mckeown thesis: a historical controversy and its enduring influence public health nihilism vs pragmatism: history, politics, and the control of tuberculosis editorials and topics for our times why there's no cause to randomize the philosophy of evidence-based medicine contradicted and initially stronger effects in highly cited clinical research towards a methodology for developing evidence-informed management knowledge by means of systematic review falsification and the methodology of scientific research programmes a physicist experiments with cultural studies the social psychology of 'pseudoscience': a brief history disaster management, crowdsourced r&d and probabilistic innovation theory: toward real time disaster response capability ethics preparedness for public health emergencies: recommendations from the presidential bioethics commission citizen science and biomedical research: implications for bioethics theory and practice values infections and the epidemiology of values: implications for management reinventing discovery surviving a technological future: technological proliferation and modes of discovery anonymous inputs and insights resulting from the review process are gratefully acknowledged. key: cord- -sdz d r authors: karnik, ankur a.; karnik, ashok m. title: pneumothorax and barotrauma date: - - journal: critical care medicine doi: . /b - - . - sha: doc_id: cord_uid: sdz d r nan weissberg and refaely reported on patients with pneumothorax. of male and female patients, . % of the pneumothoraces were spontaneous, . % were traumatic, and . % were iatrogenic. chen and col-leagues, in their university-based teaching hospital icu, found that of patients who developed pneumothorax while in the icu, % were related to procedures, most commonly thoracentesis. the reported recurrence rates of pneumothorax vary widely, depending on the type of pneumothorax and the duration of follow-up. a compilation of studies showed that the recurrence rate in "primary" spontaneous pneumothorax (psp) ranged from % to % with a mean recurrence rate of % in those without defi nitive preventive treatment. table - categorizes episodes of pneumothorax seen at nassau university medical center, a -bed hospital and trauma center in the suburbs of new york city. conventionally, psp has been defi ned as a pneumothorax that occurs spontaneously in a patient who has no underlying lung disease. however, a condition is unlikely to remain "primary" or "idiopathic" as we gain understanding about this disease process. diagnoses labeled as "primary" then shift into the category of "secondary." understanding the development of ptx in a patient who has known blebs and bullae is easy. however, computed tomography (ct) can detect abnormalities predisposing to psp in patients with normal chest radiograph. ct has demonstrated emphysema-like changes (elcs) in patients with psp. bense and others reported on nonsmoking cases of spontaneous pneumothorax (sp) who were not defi cient in alpha- antitrypsin. in cases ( %), ct showed elcs. these changes were found mainly in the upper and peripheral regions. no elcs were detected in the control group. other investigators , have also reported similar fi ndings on ct in their cases of psp. described a patient with recurrent psp in whom inhalation of aerosolized fl uorescein followed by autofl uorescence thoracoscopy allowed in vivo localization of various areas of extensive subpleural fl uorescein accumulation, which were not visible with normal white thoracoscopy. this has led to the concept of "porous" pleura. in a study on swedish patients, bense and colleagues found that smoking increased the risk of developing psp -fold in women and -fold in men. although cessation of smoking appears to reduce the risk of recurrence, continued smoking increases the risk of recurrence. cottin and colleagues found that in smokers who underwent surgery for recurrence or persistence of psp, ( . %) had evidence of respiratory bronchiolitis. smit and colleagues performed spirometrically controlled high-resolution ct density measurements in patients with sp and found that the mean lung density was lower in patients with pneumothorax. they hypothesized that peripheral airway infl ammation leads to airway obstruction with a check valve phenomenon, causing air trapping and development of pneumothorax. no correlation was found between air trapping and smoking habit or elcs. although rare, familial inheritance of pneumothorax has been reported. , the analyses suggest two possible models of inheritance: an autosomal dominant gene with incomplete penetrance and an x-linked recessive gene. the occurrence of recurrent sp in a finnish brother and his sisters also raises the possibility of autosomal recessive inheritance. as in sp, patients with marfan syndrome are tall, and pneumothorax is a common pulmonary complication. marfan syndrome is caused by the mutation in the fbn gene on chromosome . this gene is responsible for the formation of -to -nm microfi brils in the extracellular matrix of connective tissue. cardy and colleagues hypothesized that familial sp is caused by a connective tissue disorder that exhibits mendelian inheritance and postulated fbn as the causative gene. another interesting syndrome in which patients develop sp has been described. brit-hogg-dube (bhd) is an autosomal dominant cancer syndrome characterized by benign skin and renal tumors, pleuropulmonary blebs and cysts, and sp. the gene has been mapped to chromosome p . and recently identifi ed, expressing a novel protein called folliculin. , as a result of a breach in the visceral or parietal pleura, air enters the pleural space. when the amount of air is large and the increase in intrapleural pressure great, the mediastinum shifts to the opposite side and the diaphragm is depressed (fig. - ) . a decrease in vital capacity, functional residual capacity, total lung capacity, and oxygen transfer occurs. in a large pneumothorax, the arterial oxygen pressure (pao ) falls and the alveolar-arterial oxygen pressure difference [p(a-a)o ] increases. the factors that lead to hypoxemia during a large pneumothorax are anatomic shunt, hypoventilation, and relative overperfusion of partially collapsed, underventilated lungs. anthonisen reported that in patients with pneumothorax, airway closure occurs at low lung volumes and suggested that this was the main cause of ventilation maldistribution in such patients. animal studies suggest that the progressive hypoxemia with increasing pneumothorax is primarily the result of increasing degrees of pulmonary vascular shunting associated with increasing parenchymal collapse. the classifi cation given in box - combines the circumstances of occurrence of pneumothorax, the etiologic factors, and the state of the underlying lung. when pneumothorax occurs without trauma and is not iatrogenically induced, it is called sp. sp occurring in an otherwise healthy person is called psp, as mentioned earlier. secondary sp (ssp) occurs in patients with a variety of underlying lung diseases. other interesting categories of sp are catamenial pneumothorax, pneumothorax in drug addicts and acquired immunodefi ciency syndrome (aids) patients, and familial sp. investigators have found subpleural blebs or bullae at apices on chest radiographs and at thoracotomy in patients with sp. the pathogenesis of these blebs and the factors that lead to their rupture remain controversial. psp is classically seen in previously healthy young men with an asthenic body habitus. melton and colleagues found that the incidence of psp rose with increasing height among adults of both sexes, more so in males. it reached a fi gure of more than per , personyears for those inches or taller. it has been suggested that the greater prevalence of sp in tall, thin males is the result of a combination of circumstances. in an extremely long and narrow chest, the apical alveoli are underperfused; such alveoli are more readily torn by gravitational stress. inherited weakness of connective tissue might also contribute to the pathogenesis, as suggested by the numerous reports of sp in families and concurrent occurrence of sp in twins. morrison and colleagues have reported a family exhibiting spontaneous pneumothorax in a father and three offspring and suggested that isolated autosomal dominant pneumothorax may be a distinct entity. most patients with sp are heavy smokers. in one series, % of all patients were smokers. an increase in cigarette consumption during a particular year was followed within to years by an increased incidence of sp; the reverse occurred with decreased cigarette consumption. smoking increases the relative risk of developing sp about -fold in women and -fold among men, and there is a statistically signifi cant dose-response relationship between smoking and sp. pneumothorax secondary to underlying lung disease in adults, sp has been reported to occur as a result of a large variety of diseases including asthma, staphylococcal septicemia, pulmonary infarction, sarcoidosis, idiopathic pulmonary hemorrhage, pulmonary alveolar proteinosis, familial fi brocystic pulmonary dysplasia, tuberous sclerosis, cryptogenic fi brosing alveolitis, eosinophilic granuloma, coccidioidomycosis, echinococcal disease, chronic obstructive pulmonary disease (copd), shaver's disease (bauxite pneumoconiosis), lymphangioleiomyomatosis, von recklinghausen's disease, gastropleural and colopleural fi stulas through the diaphragm into the left pleural cavity, radiation therapy to the thorax, wegener's granulomatosis, cystic fi brosis, acute bacterial pneumonia, and as a complication of the chemotherapy used in the treatment of malignancy and pulmonary metastases from a variety of malignancies. the most common cause of secondary sp, however, is copd. sp in copd patients is a serious complication with excessive morbidity and mortality. , the clinical presentation of pneumothorax in copd patients is often atypical-pain may be absent, anxiety and breathlessness may predominate and be out of proportion to the collapsed lung, and the classic sign of hyperresonance may not be helpful because of the underlying emphysema. the air leak in these patients is usually large, and the tissues slow to heal, so it is weeks before the tubes can be taken out. when the peripheral veins of chronic abusers of drugs become obliterated because of a sclerotic or infectious process, the individual may attempt to use larger veins in the groin or neck. attempted subclavicular or supraclavicular injection ("pocket shoot") of drugs in the street setting has led to unilateral or bilateral pneumothoraces. [ ] [ ] [ ] [ ] [ ] douglas and levison found that the incidence of pneumothoraces is equal in both sexes and that it is less of a problem in teenagers (because they are unwilling to invade the clearly dangerous territory of neck veins or because they have not yet exhausted the peripheral veins) and in addicts older than years of age (probably because either conservation alters their behavior or they do not survive to their fi fth decade). it was also noted that although most drug users describe using small ( -or -gauge) needles, a large, complete, or tension pneumothorax usually develops. quite often the pneumothorax is bilateral. , pneumothorax in acquired immune defi ciency syndrome patients since the fi rst report of spontaneous pneumothorax in patients with aids in by wollschlager and colleagues, numerous other authors [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] have reported on the occurrence of pneumothorax in these patients. sp is an uncommon event ( . %) in the general population and occurs rarely in association with infectious pneumonia. spontaneous pneumothorax in patients with aids has become the leading cause of nontraumatic pneumothorax in this population. with the diagnosis of aids, a patient's risk of sustaining a nontraumatic pneumothorax increases to times that of general population. a high incidence ( % to %) has been reported in patients with aids and pneumocystis carinii pneumonia (pcp). , , pneumocystis carinii, which was thought to be a protozoan, has been renamed as pneumocystis jerovici and is now classifi ed as an archiascomycetous fungus. mechanical ventilation and bronchoscopy are quite often required in aids patients, and these two factors further increase the chance of pneumothorax occurring in these patients. , in patients with aids, the pneumothorax is frequently bilateral, recurrent, and not responsive to conservative therapy. , most often it is related to the infection with p. jerovici, but other infections like mycobacterium tuberculosis, m. avium intracellulare, pulmonary cytomegalovirus, pneumococcus organisms, or pulmonary toxoplasmosis may be associated. in a study of patients of aids with pcp, the overall mortality was reported to be . %; pneumothorax was found to be one of the seven factors that predicted -day mortality. the exact pathogenesis of the pneumothorax in these patients is not clear. in aids patients who have or have had active pcp, large confl uent areas of thin-walled blebs, distributed randomly on the surface of each lobe, have been reported. it has been postulated that the cystic changes may result from a check-valve mechanism caused by airway infl ammation and resultant partial airway obstruction or may be the result of disordered parenchymal architecture secondary to chronic infection and infl ammation. , various investigators , , have pointed out that the incidence of spontaneous pneumothorax is especially high in those patients who receive aerosolized pentamidine for pcp prophylaxis. this has been attributed to poor distribution of the aerosolized pentamidine at the periphery of the lung, which allows the development of a peripheral necrotizing pneumonitis, producing a bronchopleural fi stula with resultant pneumothorax. alternately, an ongoing acute infection in inadequately treated areas may eventually result in cystic dilation of distal airway. martinez and colleagues have suggested that the sulfi te in the isethionate component of the aerosol may cause an irritant cough, resulting in a rupture of the cysts. it has been found that low diffusing capacity of lung for carbon monoxide before pentamidine therapy for secondary prophylaxis is associated with an increased risk of bilateral pneumothoraces and increased mortality in these patients. a "catamenial pneumothorax" is defi ned as a spontaneous or recurrent pneumothorax occurring within hours from the onset of menstruation. alifano and colleagues described women with spontaneous pneumothorax who had been referred for surgical treatment. in eight cases ( %), the catamenial character of the pneumothorax was recognized by clinical history. in all eight cases, the pneumothorax was recurrent (one to four previous episodes) and right sided. a diaphragmatic abnormality was found in all eight cases. two mechanisms have been described for pneumothorax related to endometriosis. the most common is the movement of endometrial implants to the diaphragm, preferentially to the right side because of the recognized peritoneal circulation up from the pelvis to the right side. these implants then create channels or "holes" through the diaphragm that allow the implants or air to move into the chest. the second and much less frequent cause of endometrial implants in the chest is through the venous implants that lodge in the lung itself. clinical manifestations of thoracic endometriosis include chest pain, dyspnea, and hemoptysis. bilateral pneumothoraces and concurrent hemothorax, hemoptysis, chest pain, and pneumothorax have been described. traumatic pneumothorax most often occurs as a result of penetrating injury but may also occur with closed chest trauma consequent to alveolar rupture from thoracic compression, fracture of a bronchus, esophageal rupture, or rib fractures that lacerate the pleura. , traumatic pneu-mothorax can be subclassifi ed into open, closed, tension, or hemopneumothorax. a tension pneumothorax needs to be managed immediately by letting the air out with a large-bore needle. open pneumothorax should have a moist sterile gauze pack placed over the open wound, followed by a chest tube. hemopneumothorax requires insertion of a chest tube. increasing use of computed tomography (ct) scan to evaluate blunt abdominal trauma has revealed a new diagnostic entity that has been called occult pneumothorax. [ ] [ ] [ ] [ ] [ ] [ ] in the series of trauma patients reported by hill and colleagues, there were patients ( pneumothoraces) who were seen to have a pneumothorax on ct that was not seen on admission chest radiograph. the management of these pneumothoraces is controversial. wolfman and colleagues, reporting on occult pneumothoraces, suggested that most small (minuscule) occult pneumothoraces can be managed by close observation. moderatesized pneumothoraces can also be managed by observation if the patient is not on a ventilator, but most of the anterolateral pneumothoraces need chest tube placement. the leading causes of iatrogenic pneumothorax are transthoracic needle aspiration ( % to %), subclavian venipuncture ( % to %), and thoracentesis ( % to %). positive pressure ventilation has been reported to be the causative factor in only % of all iatrogenic pneumothoraces. most patients require treatment for to days, and hospitalization is prolonged in only a small number of patients because of this complication. , an important complication of mechanical ventilation is barotrauma. in one of the series, of patients receiving ventilatory support for longer than hours developed pneumothorax. more recently, lassence and colleagues reported that iatrogenic pneumothorax occurred in % of intensive care unit patients. risk factors were aids, acute respiratory distress syndrome (ards), or cardiogenic pulmonary edema at admission, body weight less than kg, central vein or pulmonary artery catheter insertion, and use of inotropic agents during the fi rst hours. when the lungs are exposed to high volumes, tissue disruption may occur. air passes along bronchovascular bundles to the lung hilum and then to other interstitial spaces and may enter pleural or pericardial cavities. in a ventilated patient, a rise in peak and plateau pressures should alert the clinician to the possible complication of pneumothorax. petersen and baier reported a % incidence of barotrauma in patients who required a peak airway pressure above cm h o. an early radiologic feature and a harbinger of life-threatening barotrauma is the presence of pulmonary interstitial emphysema. pulmonary interstitial emphysema manifests radiologically as small parenchymal cysts, circular cuffs around larger pulmonary vessels projected end-on (perivascular halos), small dots representing small peripheral vessels surrounded by areas of radiolucency, linear streaks of air radiating toward the hilum, and large cystic collections of air and subpleural air. , the air, having entered the interstitium, then dissects proximally along bronchovascular sheaths toward the lung hilum and mediastinum. once in the mediastinum, the accumulated air takes the path of least resistance and may produce subcutaneous emphysema, pneumopericardium, pneumoperitoneum, or retroperitoneum ( fig. - ). if the mediastinal pressure rises abruptly or if decompression via these routes is not suffi cient, the mediastinal parietal pleura may rupture, resulting in pneumothorax. entry of gas into the pulmonary circulation may produce systemic air embolism. even pneumoscrotum has been described as an unusual complication of barotrauma. pneumomediastinum can produce several interesting radiographic signs such as pneumopericardium, continuous diaphragm sign, continuous left hemidiaphragm sign, naclerio's sign, v sign at confl uence of brachiocephalic veins, thymic spinnaker-sail sign, ring-round-the-artery sign, and extrapleural sign. previous studies had shown that the factors that predispose to barotrauma are high peak and mean airway pressures, positive end-expiratory pressure (peep), use of volume-cycled ventilators, intubation of the right bronchus, chronic airways obstruction, and aspiration pneumonia. [ ] [ ] [ ] [ ] however, some studies , have shown that the incidence of barotrauma is independent of airway pressure. experts now accept that pulmonary edema and lung injury during mechanical ventilation are the consequence of "volutrauma" rather than "barotrauma." the best treatment for barotrauma is early recognition, and prevention-delayed treatment has a mortality of %. the recommended preventive measures are to decrease peak airway pressure by decreasing tidal volume, peak fl ow, and ventilatory rate; to use the best peep; and to employ assist-control mode, independent lung ventilation, and high-frequency positive pressure ventilation. in a study published by the acute respiratory distress syndrome network, it was found that treatment with a ventilator strategy designed to protect the lungs from excessive stretch resulted in decreased mortality and increased the number of days without ventilator use in patients with acute lung injury and acute respiratory distress syndrome. after a literature review of more than procedures of fi beroptic bronchoscopy (fob) with transbronchial biopsy, milam and colleagues found that the rate of pneumothorax was . %. after analyzing their series of patients who had undergone fob with transbronchial biopsy, milam and colleagues, frazier and colleagues, and blasco and colleagues concluded that an immediate postbronchoscopic chest radiograph rarely provides clinically useful information and that in fob without transbronchial biopsy, an immediate postbronchoscopy radiograph is not necessary. in a study published in june , izbicki and colleagues also concluded that in asymptomatic patients, routine radiograph after transbronchial biopsy is not necessary. when biopsies are performed, the following groups of patients should be considered for postbronchoscopy radiograph: comatose or mentally retarded patients, patients receiving positivepressure ventilation, patients with severe respiratory compromise as a result of disease or surgery, patients with bullous disease, patients who complain of chest pain, and outpatients. pneumothorax after bronchoalveolar lavage without biopsy is extremely rare. similarly, the complication of pneumothorax after transbronchial needle aspiration is also low ( of patients). the incidence of pneumothorax after percutaneous needle biopsy [ ] [ ] [ ] [ ] is much higher and ranges from % to %. although some authors have found that a more central location of the lesion, copd, and lung hyperinfl ation increase the risk of pneumothorax, [ ] [ ] others found no correlation between development of pneumothorax and spirometric parameters or the presence of obstructive airways disease. , however, kazerooni and others found that in patients with emphysema, there is a high incidence of pneumothorax after transthoracic needle aspiration; there is rapid development of pneumothorax in these cases, requiring chest tube placement. delayed pneumothorax after percutaneous fi ne needle aspiration, although extremely unusual, has been reported in two cases and patients should be warned of this possible complication. more recently, choi and colleagues reported on their series of patients who had undergone transthoracic needle biopsy (ttnb). a follow-up chest radiograph was obtained immediately and hours, hours, and hours after the biopsy procedure. a pneumothorax that developed after hours was defi ned as delayed pneumothorax. pneumothorax developed in of the patients ( . %), and delayed pneumothorax developed in patients ( . %). female gender and absence of emphysematous changes correlated with an increased rate of delayed pneumothorax. the reported incidence of pneumothorax after thoracentesis ranges from . % to . %. [ ] [ ] [ ] [ ] [ ] various mechanisms may explain the pneumothoraces that occur after thoracentesis: the lung may be punctured at the time of needle entry or after the fl uid has been withdrawn or a small amount of air may be drawn into the chest during aspiration or along the needle track if high negative intrapleural pressures develop. raptopoulos and colleagues found that ultrasonographically guided thoracentesis, use of the smallest possible needle, and aspiration of the smallest possible amount of fl uid are complicated by pneumothorax signifi cantly less often than thoracentesis done with conventional techniques. age, sex, underlying lung condition, overall clinical condition, size of the effusion, and type of tap (diagnostic or therapeutic) had no signifi cant effect on the occurrence of pneumothorax after thoracentesis. in a recent review article, feller-kopman concluded that the use of ultrasound for thoracentesis has been associated with improved yield and reduced complication rate and is quickly becoming the standard of care for procedural guidance. colt and colleagues, reporting on thoracenteses performed in adult patients, found that hospitalization status, critical illness, effusion size or type, presence of loculations, operator, needle type, amount of fl uid withdrawn, occurrence of dry tap, and type of thoracentesis were not associated with increased frequency of pneumothorax. the only predictor showing signifi cant correlation was repeated thoracentesis. after an analysis of thoracenteses in patients, aleman and colleagues concluded that, in asymptomatic patients, the risk of developing pneumothorax was so low that the practice of obtaining a routine chest radiograph may not be justifi ed. chakrabarti and colleagues reported the use of blind percutaneous pleural biopsy by abrams needle in patients; pneumothorax was seen in eight patients ( %), with only two patients requiring specifi c intervention. in james fi rst reported pneumothorax as a complication of passing a narrow-bore nasogastric tube. since that time numerous authors [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] have reported this complication. narrow-bore feeding tubes are particularly likely to give rise to pneumothorax because of the tube's small diameter ( . mm), self-lubricating properties, and wire stylet-all of which permit their undetected entry into the tracheobronchial tree, perforation of pulmonary tissue, and lodging in the pleural cavity. other factors associated with increased risk of a misplaced feeding tube include the presence of an endotracheal or tracheostomy tube (these may increase pulmonary passage of the tube by preventing glottis closure and perhaps by inhibiting swallowing), altered mental status, denervation of airways, esophageal stricture, enlargement of the heart, and neuromuscular weakness. the clinical signs commonly used to ascertain correct placement of the feeding tube may be misleading. normally, to confi rm the correct placement of a feeding tube in the stomach, a small amount of air is injected. this produces a characteristic gurgle in the left upper quadrant of the abdomen, but a "pseudoconfi rmatory gurgle" with a feeding tube in the chest has been reported. aspiration of large amounts of fl uid through the tube is also taken to be a test of correct placement into the stomach, but delayed aspiration of a large quantity of undigested enteral feeding solution from the pleural space, mistaken for gastric contents, has been reported. percutaneous tracheostomy was fi rst described in . in , ciaglia and colleagues described percutaneous dilational tracheostomy (pdt). fikkers and colleagues described cases of subcutaneous emphysema and pneumothorax after percutaneous tracheostomy in a series of cases. they described of their own cases which had developed complications to include subcutaneous emphysema, mediastinal emphysema, and pneumothorax. their review of literature showed that the incidence of subcutaneous emphysema was . % and that of pneumothorax . %. findings associated with ptx included diffi cult pdt and the use of a fenestrated cannula. development of air in the pleural space after partial resolution of total bronchial obstruction, as a complication of lobar collapse, and after therapeutic thoracentesis for malignant effusions has been described. acute lobar collapse results in a sudden increase in negative pleural pressure surrounding the collapsed lobe. although the parietal and visceral pleural surfaces remain intact, the gas originating from the ambient tissues and blood is drawn into the pleural space, producing a pneumothorax called pneumothorax ex vacuo. recognition of this type of pneumothorax is crucial because managing it requires relieving the bronchial obstruction rather than inserting a chest tube. the diagnosis of trapped lung requires documentation of chronicity and absence of pleural infl ammation, pleural malignancy, or endobronchial lesion. the pathognomonic radiographic sign of a trapped lung is the pneumothorax ex vacuo, characterized as a small to moderate-sized air collection after evacuation of effusion. experts have recognized that sports-related air leaks and pneumothorax occur more frequently than the literature suggests. levy and colleagues and patridge and colleagues each described three cases of pneumothorax or pneumomediastinum caused by blunt trauma sustained during a contact sport. kizer and colleagues identifi ed patients who had sustained a spontaneous or traumatic air leak while engaged in an outdoor sport. although traditionally the term barotrauma has been used to describe development of extra alveolar air in a patient on mechanical ventilation, there are other situations in which, because of increased intraalveolar pressure, air leaks out of alveoli. pulmonary barotrauma (pbt) of ascent is a well-known complication of compressed air diving. tetzlaff and colleagues found that preexisting small lung cysts or end-expiratory fl ow limitation may increase the risk of pbt, although neuman and colleagues contested these conclusions. some experts have suggested that even minor forms of pbt should be considered a contraindication to further diving because the divers are prone to recurrences that can occur even at shallow depths. clinically signifi cant pbt has been reported from self-infl ating bag-valve devices, after infl ation of party balloons, as a result of blast injury, , during submarine escape training, after automobile air bag deployment, and in a normal healthy volunteer after repeated measurements of maximal respiratory pressure. the clinical features of pneumothorax depend on its size, the underlying lung condition, and whether the pneumothorax is tension in type. psp usually develops in tall, thin males while the patients are at rest. most often the onset of symptoms is not related to physical exertion. surprisingly, many patients do not seek medical attention immediately after developing symptoms. in one series, % of patients waited for more than week after developing symptoms. chest pain and dyspnea are the two main symptoms associated with the development of pneumothorax. in one series of patients, all patients had one of the two symptoms and of patients ( %) had both. the chest pain is sudden in onset; pleuritic in nature initially; and then becomes a persistent dull ache, localized to the affected site. the degree of dyspnea depends on the size of the pneumothorax and the condition of the underlying lung. cough, malaise, orthopnea, or hemoptysis may be the presenting symptoms. small pneumothoraces (< %) may not be detectable clinically, especially in a patient with emphysema. larger pneumothorax may produce tachycardia and tachypnea. decreased motion, vocal resonance, and breath sounds on the side of pneumothorax; hyperinfl ation; and hyperresonance usually exist. pleural friction rub may be present. in a large pneumothorax, the trachea and apex beat may be shifted to the opposite side and liver dullness may be masked. the presentation in tension pneumothorax is more dramatic. because of a ball-valve mechanism, air enters the pleural cavity but cannot escape, thereby building up positive pressure. as the tension continues to increase, the diaphragm is fl attened, the mediastinum is shifted to the opposite side, and ultimately cardiopulmonary collapse results. in left-sided pneumothorax and in pneumomediastinum, systolic clicks, crunching, and whooping sounds have been described. [ ] [ ] [ ] various unusual presentations and physical signs of pneumothorax have been described. horner's syndrome may occur and is attributed to traction on sympathetic ganglion, secondary to mediastinal shift in tension pneumothorax. , unilateral periorbital emphysema resembling ptosis was reported by widder in two obtunded, cachectic patients. the presence of undue resonance obtained by digital percussion on the medial zone of the clavicle with the patient in the orthostatic position has been described as an early and sole sign of pneumothorax. the clinical features of pneumothorax in certain situations may not be typical, and the diagnosis is made by having a high index of suspicion. during a transbronchial biopsy a patient may complain of pleuritic pain, followed by progressive dyspnea. after subclavian vein catheterization, progressive dyspnea or alteration in the vital signs should alert the clinician to this complication. in a mechanically ventilated patient, development of pneumothorax can be suspected by new-onset respiratory distress, hypotension, agitation, unilateral decrease in breath sounds, worsening oxygenation, and a decrease in static and dynamic compliance. , , in sports-related pneumothorax, the presentation may be atypical, and pneumothorax may be diffi cult to recognize because an athlete's physical fi tness may mask the serious injury and athletes may be more inclined to downplay their symptoms. simultaneous bilateral pneumothoraces is a rare and interesting condition. in humans, the right and left pleural spaces are completely separated. theoretically, any patient who has undergone a median sternotomy, mediastinal surgery, heart or heart-lung transplant surgery is at risk for having a persistent pleuro-pleural channel. most pleural rents probably heal but rarely a pleuro-pleural channel persists. schorlemmer and colleagues have referred to this condition as "iatrogenic buffalo chest" because the north american buffalo is one of few mammals that have communicating pleural spaces. a unilateral thoracic procedure in this situation has been described to cause bilateral pneumothoraces , and "shifting pneumothorax." johri and colleagues reported a patient who had undergone a thymoma resection in the remote past and developed bilateral pneumothoraces after undergoing transthoracic needle biopsy of a right lung nodule. sayar and colleagues described patients who presented with simultaneous bilateral spontaneous pneumothorax (sbsp). they represented % of all patients with pneumothorax. of the patients, ( %) had no underlying lung disease. in seven patients, sbsp was secondary to pulmonary metastases, histiocytosis, undefi ned interstitial pulmonary disease, tuberculosis, pneumonia, and chronic obstructive pulmonary disease. the presence of pneumothorax may produce electrocardiographic changes suggesting myocardial ischemia or infarction. poor r wave progression in the anterior precordial leads with a decrease in r-wave from v to v , rightward shift of frontal axis, diminution of precordial r voltage, decrease in qrs amplitude, and precordial twave inversion have all been described. [ ] [ ] [ ] the absence of st-segment elevation and a signifi cant q-wave and reversal of electrocardiographic changes in the sitting position suggest pneumothorax. most of these changes have been described in left-sided pneumothorax. alikhan and biddison have described a new ecg sign of right-sided pneumothorax: loss of s-wave in lead v and prominent r-wave voltage, which may mimic posterior wall myocardial infarction. strizik and forman found pr-segment elevation in inferior leads and reciprocal prsegment depression in an avr lead in a case of left tension pneumothorax and attributed these to atrial ischemia or injury. the chest radiograph confi rms the presence of pneumothorax in most cases. the air in the pleural space rises to the apex of the hemithorax and causes relaxation atelectasis of the upper portion of the lung. classically, the clinician fi nds a visceral pleural line with absence of lung markings peripheral to this line. when the fi lm cartridge used for the portable chest fi lm is placed under the patient, the skin on the back can fold over on itself to produce a line that runs down the hemithorax, which can easily be mistaken for pneumothorax ( fig. - ). this line, pro- duced by the redundant skinfold, can be differentiated from the line of pneumothorax by the following three features: ( ) the lung markings are present peripheral to the skinfold; ( ) the skinfold has a wavy appearance; and ( ) in the skinfold, there is a gradual increase in radiodensity as the line is approached from the hilum. however, in the presence of a consolidated lung, a pneumothorax presents as an edge instead of a line. when pneumothorax is strongly suspected clinically but a pleural line is not clearly seen, possibly because of an overlying rib, gas in the pleural space can be detected by either of two procedures: ( ) radiography in the erect posture (potentially more diagnostic with full expiration) or ( ) radiography in the lateral decubitus position with a horizontal x-ray beam. some authors, - however, have suggested that the expiratory fi lm does not increase diagnostic capability. the diagnosis of pneumothorax in the critically ill patient is more diffi cult to establish. the following four variables occur statistically more often in patients with initial failure to diagnose pneumothorax: mechanical ventilation, atypical radiographic location of pneumothorax, altered mental status, and development of pneumothorax after peak physician staffi ng hours. in the icu setting, radiographs are typically obtained in the supine position, making pneumothorax diagnosis more diffi cult. in the supine position the gas within the pleural space rises to the highest point in the hemithorax, which, in this position, is the anterior costophrenic sulcus. various authors have described the depression and clear visualization of the diaphragm anteriorly, creating a "double" appearance to the diaphragm, a deep lateral costophrenic angle on the involved side ("the deep sulcus sign") ( fig. - ) , an unusually distinct cardiac apex and pericardial fat tags, and increased hyperlucency of the upper abdominal quadrants. [ ] [ ] [ ] [ ] [ ] a sharp line outlining the descending aorta may be produced by air trapped behind the inferior pulmonary ligament. any of these fi ndings should lead to a prompt cross-table lateral or decubitus study or a ct scan to establish the diagnosis of pneumothorax. although not done commonly for the diagnosis of pneumothorax, ct of the chest may detect an unsuspected pneumothorax in a critically ill patient (fig. - ) . in view of the diffi culty of clinically diagnosing pneumothorax in critically ill patients, hall and colleagues have recommended daily chest radiographs for this group of patients. in those patients who are treated with peep, interstitial gas may be seen as an early sign of barotrauma: more than % of these go on to develop features of barotrauma. the interstitial gas is manifested radiographically by cystic changes, linear streaks along the bronchi and vessels, halos of gas around vessels, and subpleural gas. ct scan may also be useful to detect pneumothorax in complex cystic lung diseases. ultrasound examination is not used in the routine diagnosis of pneumothorax but may be of diagnostic utility. during the ultrasound examination, a kind of back-andforth movement of lung ("lung sliding"), synchronized with respiration, is normally seen. lichtenstein and menu found that absence of lung sliding was suggestive of pneumothorax. in a normal subject, in vertical orientation, the ultrasound screen shows artifacts rising from the pleural line and spreading to the edge of the screen ("comet-tail" artifacts). lichtenstein and colleagues, in a more recent report, concluded that ultrasound detection of "comet-tail" artifact at the anterior wall allows complete pneumothorax to be excluded. the goals of management of pneumothorax are ( ) to rid the pleural space of air and allow re-expansion of the lung with the least possible morbidity and ( ) to decrease the likelihood of recurrence. approaches for the management of the initial episode include observation, supplemental oxygen, simple aspiration of the pneumothorax, or tube thoracostomy. the choice of therapy in a given patient depends on various factors such as the size of pneumothorax, whether the pneumothorax is primary or secondary, the condition of the lungs, the clinical stability of the patient, the occupation of the patient, and whether the pneumothorax has occurred in a special setting. for prevention of recurrence, chest tube placement with pleurodesis or various surgical interventions including thoracotomy or video-assisted thoracic surgery (vats) may be necessary. however, as a postal survey of american college of chest physicians (accp) members showed, there exists marked practice variation in the clinicians' approaches to the management of spontaneous pneumothorax and bronchopleural fi stula. this was partially explained by differences between pulmonologists and thoracic surgeons. many new recommendations that suggest a shift from the previous practices have been made and are discussed later. a number of methods have been described to measure the size of pneumothorax. [ ] [ ] [ ] engdahl and colleagues found that the size of pneumothorax measured from a chest radiograph did not correlate with ct, whereas the size of pneumothorax as estimated by ct correlated well with the amount of air aspirated in of patients treated with drainage. they suggested that the decision to treat should be based on clinical status and, if it is considered important to determine the size, ct should be used. various approaches to the management of pneumothorax are discussed in subsequent sections. an estimated . % of the volume of pneumothorax is absorbed each hours. therefore if a patient has a % pneumothorax, it will take days for the air to be absorbed spontaneously. different authors have used different sizes of pneumothorax in recommending expectant management: less than %, less than %, , or an apical collapse of less than cm and lateral collapse of less than cm. the absorption of gas from the pleural space depends, besides other factors, on the gradient between the partial pressure in the capillaries and in the pleural space. on room air, the net gradient is only mm hg, whereas it exceeds mm hg when the patient is on % oxygen. studies , have shown that administering % oxygen increases absorption of air fourfold to sixfold. hospitalized patients with any type of pneumothorax, who are not subjected to aspiration of air or tube thoracostomy, should be treated with supplemental oxygen at high concentrations. in those patients whose pneumothorax is large (more than % to %), progressive, or tension type; who are symptomatic; have an underlying chronic lung disease; are on a ventilator; or who have a recurrent pneumothorax, the pleural space air needs to be removed by various therapeutic means rather than be allowed to be absorbed spontaneously. the following methods have been used for the removal of air. inserting an intercostal tube is a traumatic, painful procedure associated with a risk of hemorrhage. if connected to an underwater seal, the tube confi nes the patient to bed, thereby increasing the risk of thromboembolism and prolonging the duration of hospitalization. in view of these disadvantages, some investigators have treated pneumothorax by simple aspiration. [ ] [ ] [ ] [ ] simple aspiration is usually performed in the second intercostal space in the midclavicular line. the catheter is connected to a three-way tap with the exit tube placed under water to ensure correct direction of airfl ow. resistance is felt as the reexpanded lung impinges on the cannula. a confi rmatory chest radiograph is performed. a large tension pneumothorax needs to be evacuated immediately. thoracocentesis using a catheter (e.g., seldinger technique) that is advanced into the pleural cavity by means of a metal needle, a butterfl y needle, or a regular disposable needle is fraught with danger because the lung may be punctured. wung and colleagues have described the use of a spring-loaded veress needle (american cystoscope makers, inc., stamford, conn.) for emergency thoracentesis. this needle consists of a slender spring-loaded inner tube, which is blunt tipped and has a side aperture, enclosed in a -gauge sharp needle. the spring action allows the inner needle to retract while the outer needle is puncturing the chest wall but lets it spring out as soon as the pleural cavity is punctured. simple aspiration is a technique with low morbidity that is well tolerated and allows the patient to be mobile and return to work rapidly. it may be used as the initial procedure in the absence of signs of tension. unfortunately, simple aspiration leaves the patient with a % to % chance of recurrence. , [ ] [ ] [ ] however, in a recent randomized, prospective, multicenter pilot study involving patients with the fi rst episode of psp, noppen and colleagues reported that manual aspiration seemed equally effective as chest tube drainage and was safe, well tolerated, and feasible as an outpatient procedure in the majority of patients. devanand and colleagues, after a meta-analysis of three randomized controlled trials (rcts) with a combined total of patients, concluded that simple aspiration is advantageous in the initial management of psp because of shorter hospitalization. no significant difference in recurrence was reported at year using either modality, but the effi cacy data were inconclusive. modern chest tubes are made of clear plastic with varying internal diameters, multiple holes and distance markers, and radiopaque stripes that outline the proximal drainage hole. they are pliable but not supple enough to kink. the second intercostal space in the midclavicular line is generally chosen for insertion of the tube because the area is wide and avascular. the tube is inserted using the trocar or blunt dissection method. most institutions now prefer the latter. after insertion the tube is directed anteroapically and secured to prevent accidental removal. the tube is then connected to a water-seal drainage or a drainage system. to avoid the risk of reexpansion pulmonary edema, it is recommended that negative suction not be applied in the absence of a bronchopleural fi stula. bell and colleagues, in chest tube removals in trauma patients, found that the post-chest tube removal pneumothoraces rates did not differ whether the chest tube was removed at end-expiration or end-inspiration. in the absence of trauma and with good aseptic technique, prophylactic antibiotics are not recommended. the complications associated with thoracostomy that have been reported in the literature include laceration of the lung, spleen, liver, and stomach; intercostal artery bleeding; infarction of a peripheral segment of the lung aspirated into the drainage part of the chest tube; and delayed pulmonary perforation and subcutaneous emphysema. , a blocked tube may result in a residual pleural space with the development of empyema. a number of authors , have described the use of small lumen catheters for treating a simple pneumothorax. in view of the ease of insertion, good response, and low incidence of complications, it has been suggested that a small lumen catheter may be a useful alternative to tube thoracotomy. although catheter failure included kinking, malposition, inadvertent removal by the patient, occlusion of the tube or valve by pleural fl uid, and large air leak, no complication attributable to tube placement occurred. liu and colleagues reported their experience with the use of pigtail catheters in patients versus traditional chest tube in patients and found that the pigtail drainage was no less effective than the traditional chest tube. the questions pertaining to chest tubes such as smallbore tube versus large-bore tube, whether to apply suction or not, and whether the tube should be taken out at the end of inspiration or expiration have been discussed nicely by baumann should be in a review article in . these points are summarized in the management algorithms given later. samelson and colleagues and martin and colleagues have described their experiences with the thoracic vent (one-way valve feature) in managing simple pneumothorax. the thoracic vent is inserted in the second intercostal space in the midclavicular line. the authors point out that this device has the advantage of a urethane tube that does not kink, a self-contained one-way valve, and a unique signal diaphragm that refl ects pleural pressure; however, the device is not suitable for use in patients who are expected to have large-volume or protracted air leaks. as mentioned earlier, the initial episode of spontaneous pneumothorax may be managed by simple observation or drainage. once the initial episode of pneumothorax has resolved, the decision as to the need for measures to prevent recurrence must be made. in the following groups of patients, further management needs to be planned after the resolution of pneumothorax: recurrent pneumothorax, patients with chronic air leak, patients with demonstrable large bullae, and patients who live in remote areas or pursue an occupation in which a recurrence could be a hazard (e.g., airline personnel or divers). different recurrence rates have been reported by various authors and range from % to %. , , , the following are established risk factors for recurrence: more than one previous episode, copd, air leak for more than hours during the fi rst episode, and large cysts seen on radiograph. the following are possible risk factors for recurrence: nonoperative management of fi rst episode (versus tube drainage) and tube drainage for only hours during fi rst episode (versus to days). further management in these high-risk groups is aimed at preventing recurrence. the following approaches have been used. chemical pleurodesis via chest tube, at thoracotomy, or vats can be used to institute preventive measures. pleurodesis (adhesion of visceral and parietal pleura) can be done by introducing the sclerotic agent via a chest tube, or it can be done in the operating room with open thoracotomy or thorascopy. however, there is no consensus about the timing or method of pleurodesis. a practical approach is outlined later in the management algorithm. because sterile tetracycline is no longer available, intrapleural instillation of doxycycline has been used as an alternative for pleurodesis. talc, fi nely powdered magnesium silicate, is another effective pleural irritant, producing fi brosis and adhesions. numerous complications and side effects such as fever, pain, infection, and respiratory failure have been reported with its use, but lange and colleagues found that although talc may result in mild restrictive respiratory impairment in long-term follow-up, it was not clinically signifi cant and there were no recorded cases of mesothelioma. in the past, patients with failed pleurodesis underwent surgical intervention. thoracic surgery in such patients is complicated by partial pleural symphysis. also, previous chemical pleurodesis makes lung transplantation more diffi cult technically. in view of these concerns, kirby and ginsberg recommend that chemical pleurodesis be used only in selected patients who are too ill for surgery. the objectives of surgical treatment are to obtain full reexpansion of the affected lung, control complications, tackle the underlying lung problem, and prevent recurrence through pleural sclerosis by mechanical abrasion or pleurectomy. surgical management during the fi rst episode of sp is indicated under the following circumstances: % to % of patients have a persistent leak resulting from a large fi stula that needs to be closed surgically; about % of patients have frank hemothorax, and surgical intervention is required in these patients to control the bleeding; a trapped lung may fail to reexpand, and decortication is required in such cases. if the patient is a diver, airline pilot, or lives in a remote area, surgery should be considered after the fi rst episode to prevent a recurrence. apical bullous disease can be surgically approached by a transaxillary approach , or through the auscultation triangle. in a young female, a cosmetically acceptable scar is produced by a submammary anterolateral incision. in an older individual with diffi cult pneumothorax complicated by other problems, a formal posterolateral thoracotomy is recommended. , , if bilateral pleurectomy is required, a midline sternotomy is preferred. this permits access to both pleural cavities with minimum interference with respiratory function and causes minimal postoperative pain. sites of air leaks and obvious bullae are oversewn. with modern stapling instruments, blebs and bullae can be excised easily with an airtight seal, without sacrifi cing a great amount of normal underlying lung tissue. if one large cyst is fed by a major bronchial branch, then control of the feeding bronchus and marsupialization or plication of the bulla is performed. segmentectomy and lobectomy to deal with underlying pathology are rarely necessary. obliteration of pleural space can be achieved by abrasion of the pleura with a dry gauze sponge, apical pleurectomy, or an extensive pleurectomy. when bilateral pleurectomy is advisable, it should be done in stages, to days apart. in most of the cases, blebectomy and pleural abrasion are suffi cient. in their study, murray and colleagues suggested an entirely different approach to the problem of recurrent pneumothorax. they used a limited axillary thoracotomy as primary treatment for recurrent pneumothorax, without a preoperative chest tube. modern thoracoscopy allows minimally invasive access to the chest cavity. it allows full visualization of the lung and pleura and, when combined with resection of blebs and pleurodesis or pleurectomy, results in a low recurrence rate, minimal patient discomfort, and rapid recovery. identifi ed bullae can be treated with a variety of modalities. [ ] [ ] [ ] chemical or mechanical pleurodesis can be performed during vats. [ ] [ ] [ ] thoracoscopic identifi cation and treatment of bronchopleural fi stulas are also possible in patients with prolonged air leaks despite chest tube drainage. bilateral vats has been found to be a safe and effi cacious procedure for patients with bilateral bullous disease and patients presenting with simultaneous or nonsimultaneous bilateral sp. , pneumocystis jerovici pneumonia-related pneumothorax is complicated by a virulent form of necrotizing subpleural lesions, which result in diffuse air leaks that are refractory to the standard treatment. , asymptomatic patients can be observed. an aggressive stepped-care management with large-bore intercostal tube drainage, chemical pleurodesis, and early video-assisted thoracic talc poudrage has been recommended for symptomatic patients. in patients with an air leak persisting for more than days, thoracotomy with stapling of blebs and mechanical pleurodesis has been recommended. when chemical pleurodesis is unsuccessful and open surgical pleurectomy is not desirable because of the patient's underlying disease, morbidity, and poor prognosis, thoracoscopic pleural ablation offers a therapeutic alternative. pleurodesis as an initial step in the management of pneumothorax in cystic fi brosis is considered contraindicated because it results in extensive pleural adhesions that jeopardize subsequent lung transplantation. therefore noyes and orenstein have recommended a stepwise management of pneumothorax in cystic fi brosis. if initial tube thoracostomy does not bring resolution of air leak within days, blebectomy should be performed. if blebectomy proves unsuccessful, with either continuing air leak or recurrence, a defi nitive pleural ablative procedure should be undertaken. the initial episode of catamenial pneumothorax is managed in the usual manner. recurrences, which occur hours before or after menstrual fl ow, are managed by pleurodesis or hormonal treatment. therapeutic options include oral contraceptive pills, danazol, progestational agents, and gonadotropin-releasing hormone (gnrh) analogues. thoracotomy should be considered if the patient is unable to take ovulation-suppressing drugs, has a recurrent pneumothorax while on drugs, or wants to become pregnant. at thoracotomy, any diaphragmatic defects should be closed, any subpleural blebs should be oversewn, and pleural abrasion should be performed to effect a pleurodesis. , a patient who has a previous or current catamenial pneumothorax is at increased risk for barotrauma with positive pressure ventilation and represents a unique challenge to the anesthetist. postoperative hormonal therapy is often required to prevent recurrences. hysterectomy or tubal ligation may benefi t selected patients. pneumothorax complicating pregnancy is managed in the usual way, but in view of the high rate of recurrence of pneumothorax during parturition, thoracotomy with resection of apical blebs (if present) should be considered. air or gas trapped in body cavities expands in direct proportion to the decrease in atmospheric pressure. at an altitude of , feet, a pneumothorax will increase . times in size. if a patient with pneumothorax, especially secondary to copd, has to be transported, the following precautions should be taken: (a) the ability of the patient to take supplemental oxygen without causing alveolar hypoventilation must be established before the fl ight and supplemental oxygen administered during the fl ight; (b) a chest tube with a heimlich fl utter valve should be in place; and (c) the patient should travel with a medically knowledgeable companion. the epidemic of the severe acute respiratory syndrome (sars) brought several ethical issues associated with new, severe epidemic diseases into sharp focus. of the six cases described by sihoe, pneumothoraces were bilateral in three patients, mechanical ventilation was indicated in three patients, and two patients died. air leaks or recurrences occurred in all four patients who accepted chest tubes. these air leaks took to days to resolve. peripheral leukocytes and serum lactate dehydrogenase were higher in sars patients with pneumothorax. these complications refl ected severe pathologic changes in lung tissues and the strong pulmonary and systemic infl ammatory responses that accompany sars. during the sars epidemic, health care providers were at risk, with substantial risk for those who performed bronchoscopy. by the end of the epidemic, approximately % of reported cases were in health care workers and some died. felice concluded that if multiple management options are available and they can be expected to result in equivalent, optimal patient outcomes, options that pose lesser risks to health care providers should be selected. lymphangioleiomyomatosis (lam) is a rare and frequently fatal disease that exclusively affects women of childbearing age. thin-walled cyst formation occurs in the pulmonary parenchyma, and lung function declines progressively. the lam pleural disease consensus group reviewed the responses to a questionnaire by patients. of these, patients (incidence, %) reported at least one spontaneous pneumothorax during their lifetime and out of ( %) indicated that they had subsequent pneumothoraces. because of the morbidity and cost associated with multiple recurrences, the authors recommended early, defi nitive intervention, preferably at the time of the initial pneumothorax. although pleurodesis may be associated with an increased risk of perioperative bleeding with lung transplantation, their data suggested that the complications are manageable and do not preclude successful transplantation. a persistent pulmonary air leak, which may occur as a result of pneumothorax or after pulmonary resection, is a diffi cult and frustrating problem to manage. convention-ally, the air leak persisting for more than days is called bronchopleural fi stula and it is not an uncommon problem. in the series reported by chee and colleagues, the overall incidence of bronchopleural fi stula was . %. in pulmonary resection cases, cerfolio and colleagues, on univariate analysis, found that the increased age and the following fi ndings on pulmonary function testing predicted air leak on postoperative day one: low forced expiratory volume in second/forced vital capacity ratio (fev /fvc), increased residual volume/total lung capacity ratio (rv/tlc), increased rv, and increased functional residual capacity (frc). in the patients with air leaks who are managed by tube thoracostomy, cerfolio and colleagues found that conversion from suction to a water seal is an effective way of sealing an expiratory air leak. if the leak persists beyond days, tube thoracostomy is deemed to have failed and a more defi nitive treatment is planned. such cases are usually managed surgically, but patients who are unfi t or unwilling for surgery pose a management dilemma. chemical pleurodesis may be tried but does not succeed if the lung has failed to expand. in such a situation, autologous "blood patch" pleurodesis has been found useful. , kinoshita and colleagues have described a technique for such cases. they used a large amount of diluted fi brin glue for pleurodesis in patients with intractable pneumothorax or intrapleural dead space and found it useful. if pleurodesis also fails, the leak is localized during fi ber-optic bronchoscopy and the fi stula is sealed by using a sealant. pectoral myoplasty, in which the right pectoralis major muscle was transferred into the thorax and draped over the area of lung with multiple leaks, has been used when other interventions fail. murata and colleagues have described a closure with intravenous administration of a coagulation factor xiii concentrate. ferguson and colleagues reported closure of a persistent distal bronchopleural fi stula using a one-way endobronchial valve designed for the treatment of emphysema. ziskind and colleagues, in , described a case of pneumothorax in which accidental application of high, negative intrapleural pressure led to acute pulmonary edema. since that time, unilateral expansion pulmonary edema has been recognized as a complication that can occur during the management of pneumothorax (fig. - ). re-expansion pulmonary edema tends to occur with greater frequency in patients to years of age, when there is complete collapse of the lung, when the pneumothorax has remained untreated for more than hours, and when rapid re-expansion occurs secondary to the application of negative pressure; age-related changes in the older patients seem to afford some protection. , the exact pathogenesis of re-expansion pulmonary edema is not known, but various factors such as bronchial obstruction, decrease in surfactant, and increased capillary permeability , have been implicated. the development of bilateral re-expansion pulmonary edema after unilateral pleurodesis in a young male without heart disease might suggest that forces leading to ipsilateral reexpansion pulmonary edema also affect the contralateral lung. pavlin and colleagues have described three cases of re-expansion hypotension that followed rapid evacuation of persistent unilateral pneumothorax. besides the presence of pulmonary collapse for more than days, the other risk factors were signifi cant arterial hypoxemia during pneumothorax, an elevated or rising hemoglobin and hematocrit level, and development of respiratory distress after insertion of a pleural drain. the mechanism of hypotension and shock after pulmonary re-expansion is not clear, but volume depletion and myocardial depression possibly play a role. slow expansion by intermittent clamping of the chest tube, especially in high-risk patients, may prevent both reexpansion edema and reexpansion hypotension. , paradoxically, vigorous fl uid therapy may be advantageous in preserving circulation dynamics despite coexisting pulmonary edema. myocardial stimulants may be useful if myocardial depression is suspected. diuretics have been used to manage re-expansion pulmonary edema but may prove dangerous in the presence of hypovolemia and shock. it has been recommended that a more logical approach in patients with shock and hypoxemia may be to use mechanical ventilation with peep, which would reduce further fl uid shift into the re-expanded lung. plasma expanders, fl uid replacement, and vasopressor therapy can be used as needed. , development of tension pneumothorax has been reported after inadvertent, improper attachment of a heimlich valve. , a more aggressive approach to managing pneumothorax has been advocated recently. guidelines for managing pneumothorax have been published. , pneumothorax size: american college of chest physician (accp) guidelines defi ne a small pneumothorax as less than cm in apex-to-cupola distance; british thoracic society (bts) guidelines defi ne a small pneumothorax as a visible rim of less than cm between the lung margin and chest wall. stable patient: the accp defi nes a stable patient as one who has all of the following: respiratory rate less than breaths per minute; heart rate greater than beats per minute or less than beats per minute; normal blood pressure; room air saturation of greater than %; and ability to speak in whole sentences. may need to be replaced by a larger tube if leaking persists and creates management diffi culty. the clinician fi nds it most practical to use a "roadmap" in different clinical scenarios. the difference between didactic medicine and bedside medicine is that the former is taught in a classroom and begins with a "diagnosis"; the latter starts at the bedside with a clinical scenario as the starting point. figure - represents an algorithmic approach to management that is based on the accp and bts guidelines and practical experience. it can be applied to most patients with pneumothoraces. ■ psp occurs primarily in tall, thin, previously healthy young men, most of whom are smokers. chest radiograph often shows apical subpleural blebs or bullae. rupture of these bullae is not related to physical activity but may be related to changes in atmospheric pressure. copd is the most common cause of secondary pneumothorax. presentation of pneumothorax in copd is often atypical and causes excessive morbidity and mortality. ■ a high incidence of pneumothorax occurs in aids patients, related to pcp and the mechanical ventilation and bronchoscopy that are commonly required in these patients. in this group of patients, pneumothorax is frequently bilateral, recurrent, and unresponsive to conservative therapy. ■ traumatic pneumothorax, which occurs as a result of a penetrating injury, may occur with closed chest trauma. ■ ptx is a common complication of mechanical ventilation. interstitial emphysema is a harbinger of this complication. high peak and mean airway pressures, peep, use of volume-cycled ventilators, intubation of right mainstem bronchus, chronic airways obstruction, and aspiration pneumonia increase the incidence. ■ pneumothorax ex vacuo, sports-related pneumothorax, and barotrauma unrelated to mechanical ventilation are interesting conditions that are not common, but they are important to be aware of. ■ simultaneous bilateral pneumothoraces and "shifting pneumothoraces" are rare but interesting conditions and may develop because of persistent pleuro-pleural communication called iatrogenic buffalo chest. ■ an immediate postbronchoscopy chest radiograph is rarely useful but should be done in certain groups of patients (e.g., comatose, mentally retarded, ventilated, or with respiratory compromise). ■ ptx induced by a misplaced small-bore feeding tube is not uncommon. clinical signs may be misleading. ■ a visceral pleural line with absence of lung markings peripherally is the classic radiographic sign of ptx. when the chest radiograph is obtained in the supine position, the signs are very different. ■ the approach to management of a ptx is dictated by the clinical condition rather than merely the size of the ptx, which is best estimated by ct scan of the chest. expectant therapy is recommended for a small psp in a stable patient. reabsorption of air is hastened by % oxygen. ■ air can be removed by simple aspiration, a small lumen catheter, or tube thoracostomy. unstable patients with large secondary ptxs must be managed with tube thoracostomy. ■ a staged approach is recommended for chest tube removal. in psp cases, the tube can be removed to hours after evidence of air leak was last seen; this waiting period is to hours in secondary ptx. ■ defi nitive management of recurrent pneumothorax or persistent leak can be done by open thoracotomy or video-assisted thoracoscopy associated with pleurodesis, pleural abrasion, parietal pleurectomy, or bullectomy. in patients unsuitable or unwilling for surgery, chemical pleurodesis via a chest tube may be done. ■ ptx tends to recur in patients with cystic fi brosis. blebectomy, without stripping the pleura, is recommended in these patients so that they may remain transplant candidates. pleurodesis should not be done in these cases because adhesion development jeopardizes subsequent lung transplantation. ■ ptx in pregnancy is managed in the usual manner initially. in view of the high recurrence rates during parturition, thoracotomy with resection of blebs should be considered. ■ re-expansion pulmonary edema is an important complication and can be prevented by slow expansion in high-risk patients. spontaneous pneumothorax cited by ransdell ht, mcpherson: management of spontaneous pneumothorax spontaneous pneumothorax ) : . cited by kirby tj, ginsberg rj: management of the pneumothorax and barotrauma thoracentesis: the plan of continuous aspiration experience with , patients pneumothorax in the icu. patient outcomes and prognostic factors current aspects of spontaneous pneumothorax nonsmoking, non-alpha -antitrypsin defi ciency-induced emphysema in nonsmokers with healed spontaneous pneumothorax identifi ed by computed tomography of the lungs computed tomography in the etiologic assessment of idiopathic spontaneous pneumothorax value of computed tomography in the detection of bullae and blebs in patients with primary spontaneous pneumothorax do bullae indicate a predisposition to recurrent pneumothorax? management of primary spontaneous pneumothorax fluorescein-enhanced autofl uorescence thoracoscopy in primary spontaneous pneumothorax management of spontaneous pneumothorax smoking and the increased risk of contracting spontaneous pneumothorax recurrence of pneumothorax the impact of spontaneous pneumothorax, and its treatment, on the smoking behavior of young adult smokers respiratory bronchiolitis in smokers with spontaneous pneumothorax lung density measurements in spontaneous pneumothorax demonstrate air trapping familial primary spontaneous pneumothorax consistent with true autosomal dominant inheritance familial primary spontaneous pneumothorax consistent with true autosomal dominant inheritance primary spontaneous pneumothorax in two siblings suggests autosomal recessive inheritance familial spontaneous pneumothorax and fbn mutations clinical and genetic studies of brit-hogg-dube syndrome pleuropulmonary pathology of birt-hogg-dube syndrome fishman's pulmonary diseases and disorders respiratory gas exchange in patients with spontaneous pneumothorax spontaneous pneumothorax in emphysema regional pulmonary function during experimental unilateral pneumothorax in the awake state regional lung function in spontaneous pneumothorax the pathophysiology of progressive tension pneumothorax pathogenesis of spontaneous pneumothorax with special reference to the ultrastructure of emphysematous bullae infl uence of height on the risk of spontaneous pneumothorax familial spontaneous pneumothorax familial primary spontaneous pneumothorax consistent with true autosomal dominant inheritance spontaneous pneumothorax in norfolk time relation between sale of cigarettes and the incidence of spontaneous pneumothorax smoking and the increased risk of contracting spontaneous pneumothorax fraser and paré's diagnosis of diseases of the chest spontaneous pneumothorax in chronic obstructive pulmonary disease: complications, treatment and recurrences diseases of the pleural space complications of attempted central venous injection performed by drug abusers man's worst enemy-himself spontaneous bilateral pneumothorax in drug addicts alternate therapy for traumatic pneumothorax in "pocketshooters pneumothorax in drug abusers: an urban epidemic? pulmonary manifestations of acquired immunodefi ciency syndrome (aids) pneumocystis carinii pneumonia with spontaneous pneumothorax: a report of three cases spontaneous pneumothorax with pneumocystis carinii infection: occurrence in patients with acquired immuno-defi ciency syndrome spontaneous pneumothoraces in aids patients receiving aerosolized pentamidine (letter) pneumocystis carinii pneumonia complicated by lymphadenopathy and pneumothorax pneumothorax in patients with immunodefi ciency syndrome cystic parenchymal changes associated with spontaneous pneumothorax in an hiv-positive patient spontaneous pneumothorax in patients with acquired immunodefi ciency syndrome treated with prophylactic aerosolized pentamidine pneumothorax with pneumocystis carinii pneumonia in aids: incidence and clinical characteristics spontaneous pneumothorax in aids patients with recurrent pneumocystis carinii pneumonia despite aerosolized pentamidine prophylaxis pneumothorax in aids safi rstein bh: spontaneous pneumothorax in pneumocystis carinii pneumonia: common or uncommon? bilateral pneumothoraces hasten mortality in aids patients receiving secondary prophylaxis with aerosolized pentamidine: association with a lower dco prior to receiving aerosolized pentamidine spontaneous pneumothorax complicating pneumonia spontaneous pneumothorax in the aids population treatment of pneumothorax in the patients with aids surgical management of spontaneous pneumothorax in patients with acquired immunodefi ciency syndrome pneumocystis carinii: an update value of bronchoalveolar lavage in the diagnosis of pulmonary infection in acquired immunedefi ciency syndrome pneumothorax in aids: case reviews and proposed clinical management simultaneous bilateral pneumothorax in an hiv-infected patient pneumothorax during pulmonary toxoplasmosis in an aids patient (letter) aids-related pneumocystis carinii pneumonia in the era of adjunctive steroids catamenial pneumothorax. a prospective study secondary spontaneous pneumothorax. catamenial pneumothorax catamenial pneumothorax and other thoracic manifestations of endometriosis major airway injury in closed chest trauma injuries to the tracheobronchial tree in closed trauma management of the pneumothorax and barotrauma an objective method to measure and manage occult pneumothorax occult traumatic pneumothorax: immediate tube thoracostomy versus expectant management occult pneumothorax in patients with abnormal trauma: ct studies ct detection of occult pneumothorax in multiple trauma patients tube thoracostomy for occult pneumothorax: a prospective randomized study of its use failure of chest x-rays to diagnose pneumothoraces after blunt trauma the occult pneumothorax: an increasing diagnostic entity in trauma validity of ct classifi cation on management of occult pneumothorax: a prospective study iatrogenic pneumothorax: etiology and morbidity. results of a department of veterans affairs cooperative study signifi cance of iatrogenic pneumothoraces management of subcutaneous emphysema, pneumomediastinum, and pneumothorax during respirator therapy pneumothorax in the intensive care unit: incidence, risk factors and outcome barotrauma in human research (editorial) the icu book incidence of pulmonary barotrauma in a medical icu pulmonary interstitial gas: first sign of barotrauma due to peep therapy pulmonary interstitial emphysema in the adult respiratory distress syndrome pneumothorax and barotrauma another complication of barotrauma (letter) pneumomediastinum: old signs and new signs pneumothorax complicating continuous ventilatory support pulmonary barotrauma complicating positive end expiratory pressure (abstract) incidence of pneumothorax and pneumomediastinum in patients with aspiration pneumonia requiring ventilatory support barotrauma: pathophysiology, risk factors and prevention the relation of pneumothorax and other air leaks to mortality in the acute respiratory distress syndrome evaluation of a ventilator strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome the acute respiratory distress syndrome network: ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome immediate chest roentgenography following fi beroptic bronchoscopy pneumothorax following transbronchial biopsy: low diagnostic yield with routine chest roentgenograms safety of the transbronchial biopsy in outpatients is routine chest radiography after transbronchial biopsy necessary? a prospective study of cases the value of transbronchial needle aspiration in the diagnosis of peripheral pulmonary lesions predicting risk of pneumothorax in needle biopsy of the lung pneumothorax with fi ne-needle aspiration of thoracic lesions. is spirometry a predictor? transthoracic needle aspiration in the study of pulmonary infections in patients with hiv percutaneous transthoracic needle aspiration biopsy: a comprehensive review of its current role in the diagnosis and treatment of lung tumors prediction of pneumothorax rate in percutaneous aspiration of the lung postbiopsy pneumothorax: estimating the risk by chest radiography and pulmonary function tests risk of pneumothorax not increased by obstructive lung disease in percutaneous needle biopsy traill zc, gleeson fv: delayed pneumothorax after ct-guided percutaneous fi ne needle aspiration lung biopsy incidence and risk factors of delayed pneumothorax after transthoracic needle biopsy of the lung thoracentesis: a safer needle thoracentesis: complications, patient experience and diagnostic value value of chest ultrasonography versus decubitus roentgenography for thoracentesis complications associated with thoracentesis complications associated with thoracentesis: a prospective, randomized study comparing three different methods pneumothorax after thoracentesis (letter) factors affecting the development of pneumothorax associated with thoracentesis ultrasound-guided thoracentesis evaluation of patient-related and procedure-related factors contributing to pneumothorax following thoracentesis the value of chest roentgenography in the diagnosis of pneumothorax after thoracentesis the role of abrams percutaneous pleural biopsy in the investigation of exudative pleural effusion an unusual complication of passing a narrow bore nasogastric tube pneumothorax attributable to nasogastric tube fatal hydrothorax and empyema complicating a malpositioned nasogastric tube inadvertent transbronchial insertion of narrow-bore feeding tubes into the pleural space pneumothorax from nasogastric feeding tube insertion: a report of fi ve cases pneumothorax complicating smallbore feeding tube placement incorrect positioning of nasogastric feeding tubes and the development of pneumothorax entrifl ex feeding tube: need for care in using it patient safety: effect of institutional protocols on adverse events related to feeding tube placement in the critically ill elective percutaneous dilational tracheostomy: a new simple bedside procedure; preliminary report emphysema and pneumothorax after percutaneous tracheostomy. case reports and an anatomic study spontaneous pneumothorax following partial resolution of total bronchial obstruction pneumothorax ex vacuo asymptomatic hydropneumothorax after therapeutic thoracentesis for malignant pleural effusion pleural fi brosis pulmonary barotrauma: diagnosis in american football players. three cases in three years sports-related pneumothorax pulmonary air leaks resulting from outdoor sports. a clinical series and literature review risk factors for pulmonary barotrauma in divers recommend caution in defi ning risk factors for barotrauma in divers (letter) pulmonary barotrauma and related events in divers sudden severe barotrauma from self-infl ating bag-valve devices clinically signifi cant pulmonary barotrauma after infl ation of party balloons tension pneumoperitoneum after blast injury: dramatic improvement in ventilatory and hemodynamic parameters after surgical decompression blast lung injury from an explosion on a civilian bus pulmonary barotrauma in submarine escape training bilateral pneumothorax following airbag deployment pneumomediastinum, pneumothorax and subcutaneous emphysema following the measurement of maximal expiratory pressure in a normal subject the management of spontaneous pneumothorax spontaneous pneumothorax systolic clicks due to left sided pneumothorax clicks and sounds (whoops) in left sided pneumothorax: clinical and phonocardiographic study clicks secondary to pneumothorax confounding the diagnosis of mitral valve prolapse horner's syndrome occurring with spontaneous pneumothorax horner's syndrome occurring with spontaneous pneumothorax ptosis associated with iatrogenic pneumothorax: a false lateralizing sign orriols r: a new physical sign in pneumothorax cardiovascular-pulmonary monitoring in the intensive care unit worsening oxygenation in the mechanically ventilated patient: causes, mechanisms, and early detection bilateral pneumothoraces secondary to iatrogenic buffalo chest; an unusual complication of median sternotomy and subclavian catheterization frequency and management of pneumothoraces in heart-lung transplant recipients communication between the two pleural cavities after major cardiothoracic surgery: relevance to percutaneous intervention shifting pneumothorax after heartlung transplantation bilateral pneumothoraces after unilateral transthoracic needle biopsy of a lung nodule simultaneous bilateral spontaneous pneumothorax report of cases and review of literature electrocardiogram changes suggestive of coronary artery disease in pneumothorax: their reversibility with upright posture the electrocardiographic manifestations of spontaneous left pneumothorax left tension pneumothorax mimicking myocardial ischemia after percutaneous central venous cannulation electrocardiographic changes with right-sided pneumothorax new ecg changes associated with a tension pneumothorax the radiology of abnormal intrathoracic air the value of routine expiratory chest fi lms in the diagnosis of pneumothorax comparison of upright inspiratory and expiratory chest radiographs for detecting pneumothoraces expiratory chest radiographs do not improve visibility of small apical pneumothoraces by enhanced contrast risk factors for the misdiagnosis of pneumothorax in the intensive care unit basilar pneumothorax in the supine adult the deep sulcus sign supine subpulmonary pneumothorax radiographic recognition of pneumothorax in the intensive care unit radiology in the intensive care unit thoracic computed tomography in the critically ill patient effi cacy of daily routine chest radiographs in intubated, mechanically ventilated patients role of ct in management of pneumothorax in patients with complex cystic lung disease a bedside ultrasound sign ruling out pneumothorax in the critically ill a comet-tail artefact: an ultrasound sign ruling out pneumothorax the clinician's perspective on pneumothorax management spontaneous pneumothorax management guidelines previewed determining the size of pneumothorax in the upright patient textbook of respiratory medicine pneumothorax size: correlation of supine anteroposterior with erect posteroanterior chest radiographs chest radiograph-a poor method for determining the size of a pneumothorax pneumothorax: a therapeutic update spontaneous alveolar rupture at birth northfi eld tc: oxygen therapy for spontaneous pneumothorax treatment of pneumothorax by simple aspiration a place for aspiration in the treatment of spontaneous pneumothorax results of simple aspiration of pneumothoraces spontaneous pneumothorax (sp): comparison of simple aspiration and tube thoracostomy a spring-loaded needle for emergency evacuation of pneumothorax the diffi cult pneumothorax manual aspiration versus chest tube drainage in fi rst episodes of primary spontaneous pneumothorax. a multicenter, prospective, randomized pilot study simple aspiration versus chest-tube insertion in the management of primary spontaneous pneumothorax: a systematic review chest tubes: indications, techniques, management and complications recurrent re-expansion pulmonary edema chest tube removal: end-inspiration or end-expiration? delayed pulmonary perforation: a rare complication of the tube thoracostomy complications of percutaneous dart therapy in management of pneumothorax treatment of pneumothoraces utilizing small caliber chest tubes role of small caliber chest tube drainage for iatrogenic pneumothorax pigtail tube drainage in the treatment of spontaneous pneumothorax the thoracic vent: clinical experience with a new device for treating simple pneumothorax use of a pleural catheter for the management of simple pneumothorax spontaneous pneumothorax spontaneous pneumothorax in norfolk management of secondary spontaneous pneumothorax. there is confusion in the air tetracycline pleurodesis: adios, farewell, adieu talc pleurodesis for the treatment of pneumothorax and pleural effusion lung function - years after treatment of idiopathic spontaneous pneumothorax with talc poudrage or simple drainage surgical experience in the management of spontaneous pneumothorax pleurectomy through the triangle of auscultation pleurectomy for recurrent pneumothorax (letter) a limited axillary thoracotomy as primary treatment for recurrent spontaneous pneumothorax thoracoscopic ablation of blebs in the treatment of recurrent or persistent spontaneous pneumothorax nd:yag laser pleurodesis through thoracoscopy: new curative therapy in spontaneous pneumothorax videothoracoscopic ligation of bulla and pleurectomy for spontaneous pneumothorax talc pleurodesis during videothoracoscopy for pneumocystis carinii pneumonia-related pneumothorax. a new technique treatment of complicated spontaneous pneumothorax by simple talc pleurodesis under thoracoscopy and local anesthesia pleural abrasion: a new method of pleurodesis colt hg: thoracoscopy: new frontiers bilateral video-assisted thoracoscopic surgery for bilateral spontaneous pneumothorax bilateral videoassisted thoracoscopic surgery in the supine position for primary spontaneous pneumothorax treatment of aids-related spontaneous pneumothorax. a decade of experience heart-lung transplantation: lessons learned and future hopes treatment of pneumothorax in cystic fi brosis in the era of lung transplantation (editorial) recurring catamenial pneumothorax treated with a gn-rh analogue catamenial pneumothorax catamenial pneumothorax spontaneous pneumothorax complicating pregnancy-case report and review of the literature ama commission on emergency medical services: medical aspects of transportation board commercial aircraft commercial air transportation of a patient recovering from pneumothorax severe acute respiratory distress syndrome complicated by spontaneous pneumothorax sars, pneumothorax and our response to epidemics lymphangioleiomyomatosis. management of pneumothorax in lymphangioleiomyomatosis. effects on recurrence and lung transplantation complications persistent air leak in spontaneous pneumothorax-clinical course and outcome a prospective algorithm for the management of air leaks after pulmonary resection autologous "blood patch" pleurodesis for persistent pulmonary air leak autologous blood patch pleurodesis for secondary spontaneous pneumothorax with persistent air leak intrapleural administration of a large amount of diluted fi brin glue for intractable pneumothorax medical management and therapy of bronchopleural fi stulas in the mechanically ventilated patient pectoral myoplasty for recurrent pneumothorax: an extrathoracic solution to an intrathoracic problem the treatment of refractory pneumothorax in diffuse panbronchiolitis by intravenous administration of coagulation factor xiii concentrate closure of a bronchopleural fi stula using bronchoscopic placement of an endobronchial valve designed for the treatment of emphysema acute pulmonary edema following treatment of spontaneous pneumothorax with excessive negative intrapleural pressure clinical analysis of reexpansion pulmonary edema unilateral pulmonary edema resulting from treatment of spontaneous pneumothorax experimental pulmonary edema following re-expansion of pneumothorax evidence for increased permeability in reexpansion pulmonary edema changes in pulmonary microvascular permeability accompanying re-expansion oedema: evidence from dual isotope scintigraphy bilateral reexpansion pulmonary edema following unilateral pleurocentesis reexpansion hypotension: a complication of rapid evacuation of prolonged pneumothorax re-expansion pulmonary edema: a potentially serious complication of delayed diagnosis of pneumothorax peep ventilation-the treatment for life-threatening re-expansion pulmonary edema tension pneumothorax complicating smallcaliber chest tube insertion baumann mh, strange c: treatment of spontaneous pneumothorax. a more aggressive approach? management of spontaneous pneumothorax on behalf of the bts pleural disease group, a subgroup of the bts standards of care committee: bts guidelines for the management of spontaneous pneumothorax the authors thank faroque khan, mb, macp, for valuable advice and for contributing most of the radiographs; dvorah balsam, md, for fig. - ; and leonard octavius barrett, md, facs, chief of thoracic surgery at numc, for his comments regarding the surgical therapy. key: cord- -uu rbtem authors: andiman, warren a. title: where have all the “aids babies” gone? a historical memoir of the pediatric aids epidemic in new haven and its eventual eradication date: - - journal: yale j biol med doi: nan sha: doc_id: cord_uid: uu rbtem s.l. was one of our first hiv-positive babies. he was born at yale-new haven hospital (ynhh) in . his mother was a sex worker who also injected drugs. he died at ½ years following multiple episodes of opportunistic infection and metastatic lymphoma. in the years between and , hiv-positive mothers gave birth at ynhh. the mother-to-child transmission (mtct) rate was percent. women represented percent of all hiv cases in the us compared with percent in new haven. we had a six times greater proportion of children living with hiv. the mean number of hiv-exposed babies rose annually from ( - ) to ( - ). our first team of caregivers comprised a nurse practitioner, a social worker, and me. we were, in time, joined by a growing number of colleagues. enlightened and generous hospital administrators provided us with outpatient space and the promise of continued funding to support additional staff and in , an independent pediatric aids care program. we implemented the proven mtct prevention guidelines articulated in the pediatric aids clinical trials group (pactg) protocol and by , the mtct rate at ynhh fell to percent. since , the mtct rate at ynhh has been zero percent. combination antiretroviral therapy, cart, made its debut in the mid- s; five classes of drugs with multiple agents in each were licensed between and . we designed individual treatment plans for each child and gradually entered an era when our clinic was populated with healthier long-term survivors. our program flourished, based on a multidisciplinary approach which honored interprofessional collaboration. on the morning of january , , a jolting banner headline appeared on the front page of the journal-courier (new haven, conn., - : "candida lawler dies; autopsy due." the newspaper's publishers understood that their readers were already familiar with ms. lawler's story; articles revealing her identity had been published in the new haven register as early as february [ ] . her story received national attention when the cbs television news magazine, minutes, revealed grave concerns about ms. lawler, a -year-old woman living with hiv, and whether she and others who were similarly afflicted, should be quarantined. city officials believed that their isolation would stanch the spread of the deadly infection during high risk sexual liaisons with sex workers and sharing syringes during illicit drug use. shawn, ms. lawler's son, was one of our first three "aids babies" and the earliest to whom that label could be applied with certainty. he was born in september , and spent the first months of his life withdrawing from heroin and methadone-drugs that had traversed the placenta. ms. lawler had what are now known as significant risk factors for people living with hiv/aids, including drug use and engagement in sex work. rehabilitation efforts had failed. at the time of her premature death from aids-related pneumonia, the journal-courier mourned the "once vivacious and beautiful woman with long black coal hair…who now appeared aged and emaciated." she might well have been designated new haven's "patient zero," the first publicly-named and shamed aids patient in the elm city. however, a search of the medical records at yale-new haven hospital (ynhh) would have revealed names of at least a dozen additional patients living with hiv. lawler was one among many women living with hiv, but mother-to-child transmission was not yet widely recognized as a possible outcome of maternal infection. at age ½ months, shawn recovered uneventfully from a bout of bronchiolitis, but was re-admitted months later, lethargic, malnourished, and covered with a disfiguring purplish rash. he had hepatosplenomegaly and marked lymphadenopathy. his discharge diagnoses included disseminated meningococcemia and failureto-thrive. months later, he developed intractable oral thrush and candida diaper dermatitis. he had suffered hair loss, seborrhea, and eczema. he was thinner. these striking clinical signs, particularly his multiple infections and skin diseases, ultimately suggested an immunologic deficit. a comprehensive diagnostic work-up was undertaken. abnormal numbers of "atypical lymphocytes" were found in his blood and he failed to respond to skin test antigens. lymphocyte subset enumeration revealed far too few cd +t cells, an aberration shared with his mother. we had recently learned that these abnormalities were characteristic of a new disease, referred to by some as "grid," or "gay-related immunodeficiency disorder," "the gay plague." in the early s, the disease spread among men who had sex with men and intravenous drug users, including women. we wondered whether shawn, a toddler, was similarly affected. did ms. lawler pass hiv to her baby during pregnancy, at the time of birth, or perhaps, post-partum through breastfeeding. ms. lawler's blood was send to max essex's lab in boston. he had developed a test for human t-cell leukemia virus iii, htlviii, the name of the virus thought to be the cause of the world's newest immunodeficiency disease. ms. lawler carried antibodies to htlviii. (hiv was the name later assigned by an international congress.) shawn's blood carried the same antibodies. initially, we were unable to determine whether his antibodies were acquired from his mother in utero or were raised actively in response to his own infection. shawn followed an insidious downhill course, common in the early years of the epidemic. there were no antiretrovirals and few drugs to treat some of his multiple infections. at months of age, shawn was admitted to the hospital in respiratory distress. his chest x-ray revealed many large nodules and impressive mediastinal lymphadenopathy. cultures for the usual suspects were negative, but a lung biopsy showed evidence of lymphoid interstitial pneumonitis (lip), an entity only rarely reported in adults and almost never in children. lip was, for the first years of the epidemic, the most common aids-related illness in the pediatric population, an ominous predictor of advanced hiv disease. nevertheless, it responded temporarily to steroids and during his second year of life, shawn gained some weight, was less breathless and more playful. shawn presented with weakness of his left hand and face at age months. a ct scan of his head revealed a mass lesion deep in the midbrain. normal bone marrow was replaced by a b cell lymphoma. several courses of chemo-and radiotherapy stabilized his condition for almost a year, during which time he lived in a crib in an isolation room with other infants infected with hiv. the final event was an unrelenting metastatic infection with mycobacterium avium intracellulare (mac), resulting in grotesque enlargement of his regional lymph nodes, liver, and spleen. standard anti-infective agents and two experimental drugs donated by the cdc, ansamycin and clofazimine (neither of which is currently used), did nothing to change the course of the infection. shawn died at ½ years of age. hiv-infected babies began to appear regularly in the emergency room and various clinics. the obstetricians were caring for ever-increasing numbers of women testing positive for hiv. in new haven, the mean number of hiv-exposed babies rose annually from to ( - ) . in fact, percent of all babies born to mothers testing positive for hiv were also testing positive and in immediate need of complex and prolonged interdisciplinary care. we had moved into crisis mode. simultaneous with our need to devise an effective intervention, i had my first triennial leave, a mini-sabbatical during which i could devote myself exclusively to learning more about hiv and aids. previously, i had been involved in research studying the ways in which the epstein-barr virus displayed its pathology in both healthy and immunodeficient children. but now we were witness to the debut of a novel disease caused by a puzzling new virus, one that snared mothers and infants, in addition to men. new diseases weren't being seen that often-a rule that seems to have been broken with some frequency of late (viz. zika, west nile, mers, sars, covid- ). i reasoned that this was my chance to enter a challenging clinical arena on the ground floor, to make this growing plague the center of my academic focus moving forward. descriptions of pediatric aids came to us from the earliest epicenters as graphic retrospective reports. four of the "hot spots" were cities with large indigent populations, people who used drugs, men who had sex with men, and some of their female sex partners: new york city, newark, san francisco, and miami. the majority of babies were infected intrapartum with infectious blood and genital secretions, less so in utero. at the start of my explorations, i sought allies who could show me the ropes, introduce me to a few patients, and teach me some of the relevant clinical science. none of my usual teachers in the pediatrics department could help because they knew no more than i did, having read a few articles and listened to ominous stories on the news. so i made inquiries of colleagues in the department of internal medicine who had been caring for most of the patients. they all came up with the same name, leetha fraulino, aprn. i was surprised to learn that fraulino was a nurse practitioner who had come to ynhh from her previous position as a clinician with the greater new haven visiting nurses association. among her clients in the community were a handful of adult aids patients, some of whom had already spent some time in the hospital and some who were safely managed at home. she recognized the need for a place where the growing number of patients living with hiv could be followed in specialized settings, where they could receive both medical and much-needed psychosocial support. she imagined a place where preventive and supportive care, that included access to good nutrition and decent housing, would forestall the need for visits to the emergency department that frequently ended in moves to the icu. hospital administrators, alarmed by the increasing numbers of uninsured, critically ill patients and the uncompensated costs incurred in their care, agreed to give fraulino access to a few examining rooms in one of the ambulatory clinics for one afternoon a week. she was acquainted with many of her former clients and agreed to have me join her on her daily rounds. we reviewed x-rays, checked the results of laboratory tests, and shared insights we had gathered from the patients with the residents and nurses, including details of each one's social situation, and relationships with significant others and family. having anticipated a surge of hiv-positive babies, fraulino welcomed the chance to have a pediatrician as her ally. we were among the first troops on the front lines, joined in battle against a powerful new foe. i was hooked and my professional life was forever changed. the histories shared by most hiv-positive mothers and their female kinfolk indicated that their babies had been born into "at risk families." about half the mothers had used intravenous drugs which they often shared. some were sex workers and still others reported that they did not consume illicit drugs but had had sexual relationships with men who had. babies born addicted to drugs were immediately transferred to hospital units that were specially equipped to care for these irritable, tremulous, jittery newborns who sometimes spent weeks or months in isolettes at a distance from bright lights and disturbing sounds. they were swaddled and received round-theclock feedings on demand. among a series of impediments, we faced one insurmountable problem: we were not able to discharge hiv-exposed babies to the care of mothers still battling addiction; and experienced foster parents refused to take "aids babies" into their homes for fear of infection. there was only one alternative-the nurses, doctors, and social workers became their de facto guardians. the babies stayed in the hospital for months, sometimes for more than a year. in the early s, we cared for an average of hiv-exposed infants, born each year to hiv-positive mothers. we were obliged to track down a group of persons connected to each index mother, e.g. current and former sex partners, people who injected drugs, and older children. we invited them to meet with us to learn of their infection status. these meetings were long and excruciating. most of the contacts never imagined they might be carrying hiv, complicated by the fact that they might have already spread the virus to unknowing partners. they all needed to be directed to healthcare centers-destinations other than emergency rooms or the community, clinic, or hospital. physician specialists volunteered to help us in the clinics. they knew that aids was a growing epidemic, that they would soon be called upon. they wanted to be well-prepared, knowing they would become the teachers, transmitting their knowledge to the junior troops who were gathering close behind. well-concealed beneath the armor of denial and girded by their selfless efforts, there was sometimes a gnawing worry about the possibility of getting infected with hiv by accidental needlestick, a saliva or vomit-laden splash, perhaps by a urine, fecal, or blood-soaked bed, or maybe a bite or scratch by an agitated patient. (other than by sex or needle-sharing, the risk posed by other behaviors or body fluids was still unknown.) ynhh, the academic epicenter of medical care in southern connecticut, was committed to serving the entire population of new haven and the surrounding towns. its promise of excellent care for all who presented themselves was being challenged by the financial burdens incurred in caring for those who required costly emergency and prolonged intensive care. our team was called upon to educate an already receptive hospital administration. we were invited to present the facts of the epidemic, in all its alarming detail, to the hospital board of trustees. we reminded them that the uncontrolled demand for expensive care could be mitigated by creating a program devoted to longitudinal outpatient care for both adults and children, similar to those for patients with other chronic diseases. the caregivers would forge trusting relationships with their patients in a way that would ensure adherence to care and stimulate the creation of individualized care plans. we would introduce new treatments as soon as they became available. the social workers would focus their efforts on the financial, nutritional, and housing needs of the patients. timely arrangements could be made for in-home nursing care. we would strengthen the education of parents, spouses, friends, and neighbors. our first formidable ally was dr. john fenn, a surgeon and the hospital's chief of staff. he had heard of our work and already learned a bit about the clinical aspects of aids. he knew that the hospital was carrying a heavy burden and that babies and toddlers were beginning to fill isolettes in the nurseries and cribs on the wards. dr. fenn invited himself to make rounds with us a few times a week. he was deeply affected by what he saw and heard. after scrubbing, gowning, and masking, he would sometimes sit on the bed listening to patients' stories. he thanked fraulino and me and commended us for keeping abreast of every patient's status and carried these stories and descriptions of our daily routines to the hospital president, the chairmen of internal medicine, pediatrics, obstetrics and gynecology, and the vice president for nursing. in the wake of these meetings, fraulino and i "walk-in" clinics. those with substance abuse disorders were transferred to drug rehabilitation programs. women were given appointments with gynecologists who would provide access to birth control, cancer screenings, and treatment for sexually transmitted infections. we helped the homeless mothers, rejected by their families, to find housing and food stamps. by the mid- s, we had access to reliable antibody assays and both antigen and nucleic acid-based tests that allowed us to measure accurately the present status and arc of the epidemic in children and women of childbearing age. we compared the demographic features of hiv infection in new haven with the state of connecticut and the entire country. we learned that new haven was different! cumulative data through december , revealed that women represented percent of aids cases in the us compared with percent in new haven. similarly, children represented percent of all national cases compared with percent of our local cases. new haven had more than double the proportion of infected drug users compared with the rest of the country. in , the connecticut department of public health reported that one in every african american women giving birth in new haven was hiv-positive, a proportion twice that of all women giving birth in the state, regardless of ethnicity. national statistics revealed that connecticut ranked fourth per capita in the incidence of aids in women and first per capita in the nation in the incidence of aids in children. intravenous drug use by the mother or her partner was the risk behavior that precipitated infection in percent of the babies. in the us, the majority of patients were white ( % white, % black and hispanic) whereas in new haven, hiv infection was far more common in people of color ( % black, % hispanic, % white and other). we lived and worked in a small american city (population estimated , ) with a disproportionate onslaught of aids. we were crippled by a dearth of antiretrovirals and effective anti-infectives for many of the opportunistic infections. we needed more clinicians and financial aid to support our efforts. slowly, providers with a multiplicity of skills emerged from their quotidian workplaces and asked fraulino and myself if they could help. june holmes, msw, was one of the first to volunteer. she already knew some of the patients through her work in other parts of the hospital. like fraulino and me, she believed she would be most effective if she could serve our patients even before they were hospitalized and, again, at time of discharge. continuity of care was paramount, starting with the trust built during the first encounter, whether in interviewed on multiple occasions for articles in the new haven register, the new haven advocate, channel , the local tv station, and a few radio shows. i remember a few occasions when we chided reporters for having portrayed our patients in a light that may have stoked fear and derision among news consumers. it took some time to sensitize the media and other people of influence. in time, the hospital's board of trustees gave the go-ahead for the "official" creation of the "aids care program." soon the city of new haven and local charitable organizations joined us in common cause. fraulino, now the aids program coordinator and clinical supervisor and b. joyce simpson, rn, mph, once described in great detail the institutional response to the aids epidemic, using ynhh as the paradigm. they reminded us that public teaching institutions are responsible for making subspecialty expertise and stateof-the-art technology accessible to the public and local community needs and providing treatment with new antiretrovirals and anti-infectives. fraulino continued to see all the adults and children with aids-related diagnoses and introduced me to them as the medical director. she assessed their needs and assisted patients and their families to gain access to necessary support services. she participated in discharge planning in conjunction with the nursing and medical staff and developed a long-term plan for each patient. she organized the outpatient clinics and acted as the primary liaison between the inpatient and outpatient settings. in response to a growing patient population, the hospital mounted a second phase of planning. over the course of a year, we were introduced to additional subspecialists, with either adult or pediatric credentials. simpson became our pediatric research nurse and pediatric aids program coordinator. she collected, organized, and analyzed data that fulfilled the specific aims of our various grants. we also welcomed an educator with a graduate degree in public health who oversaw hiv testing and counseling services and two hiv counselors with backgrounds in nursing. the social workers guided families through the onerous process of applying for entitlements, including supplemental security income (ssi) and medicaid. finally, we developed cordial relationships with allies from pediatric and adult psychiatry, neurology, surgery, the chaplain's office, the child life program (evaluates developmental milestones and provides play therapy), nutritional services, respiratory therapy, and pharmacy. the team recognized the importance of establishing collaborative relationships with community-based agencies and organizations. we were living in the midst of a public health crisis and we saw ourselves as the catalysts for change. either individually or in pairs we educated leaders in the visiting nurses association, the methadone maintenance programs, the department of children and met with the same leaders to provide first-hand accounts in all their startling details. we made clear our need for funding and asked for official promises by the hospital and medical school to establish an aids care program, in perpetuity, dedicated to the ongoing outpatient and inpatient care of hiv-infected patients of all ages. we believed that health professionals on the front lines could be effective only with generous private and public support and the backing of two superlative academic institutions-ynhh and yale medical school. at the insistence of two successive chairs of pediatrics, doctors howard pearson and joseph warshaw, the hospital agreed to support half my salary. the pediatrics department would contribute much of the remainder to support my teaching efforts and a small percentage of my ongoing research projects. in a letter written in january , dr. fenn agreed to relieve me of some of my responsibilities in the adult aids effort, by funding two new half-time physician slots. both these physicians would serve the rapidly expanding adult population and i would be allowed to spend more time with the children who were hiv-positive and their families. the hospital also assigned us pediatric clinic space for one, and then two afternoons a week. full time rn and social service positions were added to the mix. dr. fenn penned an official note to dr. warshaw that fully acknowledged the work that fraulino and i had already done. he wrote the following: "the goal in the recent expansion of the program was to allow warren andiman and leetha fraulino some relief from their extraordinary burden and to make sure that the hospital was supplying resources commensurate with the magnitude of the epidemic facing us. i am comfortable that we are doing our part and that we have now provided dr. andiman with the help he most certainly needed and the opportunity to engage in other academic activities." ynhh serves the entire city of new haven, and with the university they are the city's largest employers. as such, the hospital and medical school are obliged to foster cordial relations with the city's leaders and provide them a voice in its stated missions. to keep these leaders apprised of the magnitude and severity of the "aids problem," g. harold welch, the president of the hospital, invited me to meet three city aldermen. after the dinner meeting, he wrote: "the three aldermen who attended are all members of the ynhh board of trustees." the meeting was designed to foster "helpful communication between the city's leaders, their constituents and the hospital. the hope was that the city would take appropriate action in the future." it did, in fact, "take a village" to support our program and keep its accomplishments in the public eye. the media started to take increasing interest in our work and in the changing state of the epidemic. fraulino and i were its attention on the rapid identification and treatment of aids-defining conditions, primarily opportunistic infections, but also certain malignancies, e.g. lymphoma and sarcoma, central nervous system afflictions, including aids encephalopathy, and chronic skin conditions. in the late s, treatments were limited, and cures were unattainable. the relentless pace of disability and disease continued. fifty percent of our hiv-infected children died before the age of years. most of our hiv-positive children had challenging home lives, including difficulties accessing food, transportation, and decent living conditions. their lives were chaotic, lonely, and stressful. some had already lost family members to aids and others faced the possibility of a parent's incarceration or hospitalization. following years of reluctance on the part of "professional" foster parents to bring babies living with hiv into their homes, we joined with the connecticut state department of social services and rolled-out intensive educational programs that featured infection control guidelines. the state increased payments to cover the costs of fostering a fragile, chronically ill child. these inducements encouraged some foster families to care for "aids babies." for the most part, these placements proved to have positive outcomes. there were impressive gains in growth and development and increased adherence to clinic visits and prescription refills. the number of hospital "boarder babies" slowly decreased and by , fell to zero. sometimes the child remained in foster care temporarily, until the mother was released from prison or committed to a drug treatment program. adequate housing was required for family reunification. remarkably, some foster families adopted the children they had nurtured so successfully. the minority of hiv-infected children who reached school age, were consigned to a space in the basement of a municipal building and were "taught" by someone with little or no requisite educational background or training. no classroom in new haven's public schools found space for a child living with hiv. the task of righting this discriminatory practice fell to the pediatric aids care program. our nurses, social workers, and i became community educators whose principal goal was to share the evidence that hiv is not spread by casual contact and that minor incidents of bleeding, spitting, urinating, and even biting, could be managed by the simple application of standard precautions: gloves, soap and water, and the prudent use of diluted household bleach, as needed. at some point, as the abysmally inadequate education of our patients was deemed untenable, i was asked to serve as families (dcf; formerly dcys, department of child and youth services), community aids support groups, like aids project new haven, churches sympathetic to our philosophy of care, connecticut hospice, and other long-term aids residency facilities. the collaborations resulted in improved care and a modest reduction in costs that would otherwise have been borne by the hospital. the pediatric aids epidemic in new haven grew at an alarming rate. along with the hiv-positive babies, who constituted percent of our patient population, we decided early on to continue to follow, temporarily, the percent of babies who had been exposed to the virus but were uninfected (some infants by ). we had to guarantee their safe release either to their biological mothers or to foster parents, often close relatives. we found placements for those "new" mothers who required drug treatment and safe housing. the early development of the now independent pediatric program mirrored in many ways the genesis of the adult program. therefore, we were not surprised when a willing group of talented, motivated, and energetic health professionals with diverse skills asked if they could help. we found assignments along the entire spectrum of their training-attendings, residents, post-docs, rns, aprns, social workers, nursing, and medical students. at the beginning, few of these assignments were designated as "official" and none was accompanied by bonuses or special treatment. these were professionals who incorporated their work with hiv-positive children into elective slots or a variety of required outpatient rotations. by , the hospital recognized the need to split the aids care program in two: an adult medicine arm and a pediatric arm. it was obvious that the number of patients needing urgent care was growing too rapidly to remain under the aegis of one medical director who had other clinical, research, and teaching obligations. also, my training as a general pediatrician with expertise in infectious diseases was no longer a good match for the enormous challenge posed by a population of seriously ill adults with life-threatening diseases and chronic conditions. the hospital set out to hire two experienced, academically-trained internists who had already served on the front lines of a city-wide aids epidemic similar to ours. the two saviors, gerald friedland and peter selwyn, by now leaders in the field, and both from montefiore hospital in the bronx, ny, joined the effort in to lead the adult program. in the absence of an effective antiretroviral agent, the pediatric aids care program initially focused much of . the regimen was comprised of antepartum zdv, given orally times daily, starting at to weeks post-conception and continuing through the remainder of the pregnancy. zdv was also administered to the mother intravenously during labor and delivery. the newborn received oral zdv syrup, beginning at hours postpartum and continuing every hours for the first weeks of life. periodic hiv cultures were done to distinguish between infants infected in utero and those infected intrapartum or postpartum. based on data derived from the mother-infant pairs who completed the study, zdv treatment was associated with a percent reduction in mtct ( % in the treatment group vs % in the placebo group). the drug regimen was well-tolerated. when the study results were published, the cdc recommended that the protocol be applied universally to all hiv-positive pregnant mothers. as per the cdc recommendations, we implemented the protocol and by , the mtct rate at ynhh dropped to percent, half the rate we witnessed previously. simpson, our pediatric research nurse made herself available, even at night, to attend the delivery of every hiv-positive mother. she guided the nurses and mothers through the steps of the pactg protocol. she met with each mother and learned about her social support system and living situation. she discovered whether there was money to buy formula, diapers, and clothing. the mother received her first -week appointment to the pediatric hiv clinic and a prescription for her child's zdv syrup. before hospital discharge, the nursing staff judged whether the mother could provide a safe home for her baby. the side effects associated with zdv were easily managed, but the inevitable appearance of resistance convinced us that additional antiretrovirals were needed to use in combination with zdv. combination treatment met its earlier success with regimens for tuberculosis and subsequently, for other complex infections and cancer chemotherapy, diseases in which drug resistance had been a significant obstacle to cure. we participated in large multicenter clinical trials assessing the utility of combining non-nucleoside reverse transcription inhibitors (nnrtis), e.g. nevirapine, with a growing number of newer nucleoside reverse transcriptase inhibitors (nrtis) e.g. lamivudine. in time, the protease inhibitors, entry/ fusion inhibitors, and integrase inhibitors were licensed sequentially in the decade between and . drug side-effects and resistance demanded that we follow the children closely and prepare to intervene with either temporary or permanent alterations in individual drug regimens. in good time, we witnessed varying declines in an expert witness in a complaint brought by the american civil liberties union against the city of new haven. based on the preponderance of the scientific evidence and the recognition that the children were being discriminated against on the basis of physical disability, a clear violation of the american disabilities act, the presiding judge found in favor of the right of hiv-positive schoolchildren to an education equal to their same age peers. as a result, our children gained admission to the city's classrooms with the promise that only the child's teacher, the school nurse, and the principal would be informed of the student's hiv status, an important concession that became operative in instances of accident or emergency. the most basic principle of public health, prevention, had not been fulfilled. we were treating disease but not preventing it. the fda approved the use of zidovudine (zdv, azt) to treat advanced hiv disease in adults. but we learned that zdv, the first in a new class of drugs, reverse transcription inhibitors, provided only short-term survival advantage and its benefits lasted only a few months. despite these disappointments, we convinced some of our pediatric pharmacists to create a syrupy concoction of zdv powder that could be fed by mouth to infants and toddlers. (once a drug is licensed, it can be used off-label if prescribers believe that the benefits outweigh the risks.) we knew of only two adverse reactions, mild anemia and liver dysfunction and monitored both by doing periodic blood tests that led to a change in dose or discontinuation of the drug, if necessary. as in adults, zdv treatment resulted in only temporary clinical improvement-weight gain, greater alertness and activity level, and fewer life-threatening infections. within a few years, the fda approved the use of zdv for children. we were buying time in the hope that more effective antiretroviral agents would arrive. clinical relief is not prevention. fifteen to percent of hiv-positive mothers were still transmitting hiv to their offspring and with some exceptions, the infected babies died before the age of years. nevertheless, we witnessed a veritable miracle in , when the results of the nih-funded study, pactg protocol was published. until that time, strategies for reducing the risk of vertical transmission of hiv were limited to the avoidance of pregnancy altogether or refraining from breastfeeding, which was the most common cause of postnatally-acquired hiv. the double-blind placebo-controlled study, pactg , investigating the effects of antiretroviral therapy during pregnancy, was initiated in the parties expressing vehement objections argued that administering hiv tests by way of blood draw to newborns, absent informed consent and expressly against the will of the parents involved, constitutes an illegal search, forbidden under the fourth amendment to the us constitution. the cha filed a motion for a temporary restraining order enjoining the execution and enforcement of the law a mere "scant hours" before the law was scheduled to go into effect. because the judge presiding over the us district court concluded that the plaintiff had not proved the likelihood of success in demonstrating that the statute at issue was unconstitutional, the motion for a temporary restraining order was denied and the law went into effect. despite the law, by there was only limited evidence that providing antiretroviral therapy to the newborn would lessen the severity of infection, even if there was no prior treatment of the mother during the latter part of pregnancy, labor, and delivery. we now know that early postnatal treatment does lower the viral load in the infant and limits damage to the immature immune system. we also know that the discovery and treatment of hiv infection in a previously untested mother may be lifesaving and nearly always prevents vertical infection in all subsequent births, if the mother continues her treatment. connecticut public act no. - was the powerful tool we were waiting for. we went into the community and educated physicians who cared for pregnant women. we urged them to become familiar with the new statute and to call us with questions. our nurses constructed detailed protocols for the labor and delivery floors. the mothers were given postpartum appointments to the high risk obstetrics clinic and their infants made visits to the pediatric hiv clinic at weeks of age, while still receiving oral zdv. we had foreknowledge of the impressive preliminary results of the pactg prevention study and had been following its guidelines, even before the study was published. this head start and our intensive educational efforts in the hospital and community resulted in a steady decline in the number of newborns testing hiv-positive. the last infant that tested hiv-positive was born at ynhh in . for each of the past years, we have screened and treated about twenty hiv-positive pregnant women, a significant decrease from earlier decades. none of the babies born to hiv-positive mothers between and late were infected. nevertheless, we still care for a few hiv-positive children who have come to us from other parts of the world, mainly africa, and for a handful of adolescent men who have had sex with older hiv-positive men. viral loads and rises in cd + t-cell numbers to more normal levels. many of the children felt better and returned to their regular activities, including school attendance. as with adults, combination therapy with an ever-increasing number of agents, altered forever the natural history of pediatric hiv infection, changing it from a rapidly fatal to a chronic, manageable disease, including for some who had survived beyond early childhood. despite these gains, our pre-eminent wish remained unshaken, i.e. to eradicate mtct of hiv, a goal that would prevent the life-long morbidities and suffering that accompany pediatric hiv infection and its attendant limitations and stigma. the pactg protocol, when practiced consistently, proved to be a lifesaver. for all mothers at risk who sought prenatal care and were not already being treated with antiretrovirals, hiv testing was offered. if the test results were positive, simple drug regimens were prescribed along with intensive counseling and admonitions to adhere closely to the instructions for drug compliance. hiv care and obstetric care were linked. when close to term, the mothers were given explicit instructions to appear early in labor, so that zdv could be administered intravenously before their baby's birth. but routine hiv screening was not yet part of obstetric care and it soon became obvious that we were missing some women at risk: those who failed to receive prenatal care and those who did receive care but whose hiv infection status was unknown or not recorded. we posed an audacious question: shouldn't hiv testing be a mandatory part of obstetric care? in the early years, hiv testing was permitted only after a counseling session and signed consent. times change. connecticut public act no. - became law on october , after much contentious opposition mounted by the connecticut civil liberties union foundation, the connecticut hospital association (cha), and by editorials and harsh opinion pieces in local newspapers. the first part of the law read as follows: [ ] ." ( . %) had been mildly symptomatic or asymptomatic; c). ( %) were seroreverters, i.e. they permanently lost all passively-acquired maternal antibody and were uninfected; d). % were deceased and . % were lost to follow-up. once we had optimal practices in place for preventing mtct of hiv and managing the care of children who survived without the burden of lifelong infection, we formally joined the pactg. the pactg (now impaact) is a consortium of academic pediatric institutions charged with testing the efficacy of new antiretrovirals and anti-infectives. we also tested live virus vaccines for their safety in hiv-positive children whose immune function had been restored by antiretrovirals. lastly, we participated in a detailed collaborative natural history study of hiv-infected and hiv-uninfected peers who were exposed to hiv perinatally, i.e. affected but not infected. ultimately, between the years and , we enrolled scores of children in one or more clinical trials each. the results of these studies meant healthier and more productive lives for thousands of infected and affected hiv-affected children worldwide. among hiv-positive children born prior to , about half, our longer-term survivors, were healthy enough to attend school free of the bane of aids-related conditions. many children were lucky to have found loving foster families who later adopted the children they had raised. the number of "active" patients in in our care fell by percent in the decade ending in . the survivors met with our caregivers every to months. eighty percent ranged in age from to years; percent were older than , and percent were younger than years. fifteen children died in the years between and , half in the hospital and half at home or in hospice. there were only three deaths between and . among our long-term survivors (lts), adverse medical and social issues are common. their outcomes have ranged from excellent to poor. over percent have maintained undetectable viral loads and cd + t-cell counts in the normal range. the number of emergency visits and hospitalizations has fallen precipitously. however, non-adherence to medical regimens, unprotected sexual intercourse, stigmatization, unchecked family discord, depression, and school drop-outs have stymied the realization of the fully successful social and physical outcomes we had hoped for. many families failed to disclose the hiv diagnosis to their children for fear of precipitating untoward psychological repercussions, including long-term stigma. some hiv-positive young after a half dozen years of familiarizing myself with the protean manifestations of pediatric aids, i began participating in research studies that would answer pressing clinical questions. i re-examined the statistics extracted from older studies conducted without benefit of appropriate study design and methodologies. intending to correct these deficiencies, i set myself the task of embarking upon a prospective, longitudinal cohort study to determine the true risk of mtct of hiv, the relationship between the degree of immunodeficiency and the incidence of aids-defining illnesses and survival, and the connection between specific gestational variables and transmission risk. between and , i was awarded an uninterrupted series of grants and contracts, the first few of which were designed to answer definitively the questions i had enunciated. the earliest of my grants coincided with the inauguration of two private foundations created to support basic and clinical research on hiv and aids: amfar (the american foundation for aids research) and egpaf (the elisabeth glaser pediatric aids foundation). we joined an international alliance of american and european academic centers and our collective data ultimately became the basis for what we now know about the epidemiology, pathogenesis, and natural history of pediatric aids. among the most important of our local and international collaborative findings were the following: i). among babies born to hiv-positive mothers and followed since birth at ynhh between the years and , the overall risk of transmission of hiv was percent (range - %); ii). the risk of mtct was percent for mothers who received no antiretrovirals during labor and delivery versus percent for mothers who received antenatal and intrapartum antiretrovirals and whose newborns received zdv for the first weeks of life (as per pactg protocol ); iii). among ynhh mothers who received antiretroviral therapy during pregnancy, the risk of mtct was percent for those whose cd +t-cell counts were < cells/ul versus percent for those mothers with median cd + t-cell counts > / ul; iv). a meta-analysis of more than a dozen prospective cohort studies (including ours) by the international perinatal hiv group demonstrated that elective c-section before onset of labor and before rupture of membranes, resulted in a decline in the risk of vertical transmission from percent to percent. when c-section was combined with antiretroviral therapy during the third trimester, the risk of mtct of hiv fell further, to percent; v). among hiv-exposed children enrolled in our prospective study (including those enrolled in collaborative studies during which they had received varying lengths and combinations of antiretrovirals), we recorded the range of clinical outcomes in : a). ( . % had been severely or moderately symptomatic; b). women and men became parents unintentionally, but all their offspring are uninfected (all the pregnant young women complied with their prenatal clinic appointments and took their medications). a minority of our lts have completed high school, college, or job-training and a few have been successfully employed. a handful have been incarcerated on drug charges or acts of violence. one patient, lost to follow-up, died by gunshot. those of us working in resource-rich countries encountered the "coming of age" of the first and largest cohort of hiv-positive children-those born between the early s and the late s. we confronted their need for a major health care transition. data collected by the cdc in , revealed that approximately , american youth, ages - years, were living with hiv/aids. this was a percent increase from , attributed to high-risk adolescent sexual behavior and increasing survival of children infected perinatally. developmentally appropriate youth ought to receive care in adult healthcare practices sometime in their early s. but there are numerous everyday tasks that represent major hurdles for many teens, in particular adherence to their medical regimens. ultimately, with diligent guidance, most of them progress to a point where they can be safely transitioned. during the years - , under the guidance of sostena romano aprn, mba, our longest-serving nurse practitioner, and anne murphy, msw, we transitioned patients, ages to years of age, to adult practices: to yale's adult nathan smith clinic, nine to other hospital-based clinics in connecticut, and eight to private practices close to the patients' homes. we have continued this practice as our patients enter late adolescence and young adulthood. the eradication of mtct of hiv in new haven was made possible by the confluence of six nourishing streams: ). the creation of effective antiretrovirals, anti-infectives, and sensitive diagnostic tests; ). the flood of grants and contracts from federal, state, local, and private funding agencies; ). wise and generous support from yale-new haven hospital and the department of pediatrics; ). the passage in of connecticut public act no. - ; ). the creation of an effective multidisciplinary approach to care which honors respectful interprofessional collaboration; ). the spontaneous and enthusiastic union in common cause of doctors, nurses, social workers, students, administrators, and volunteers to serve patients in need, their families and friends, in new haven county and beyond. rethinking complicity in the surveillance of sex workers: policing and prostitution in america's model city special session reduction of maternal-infant transmission of hiv- with zidovudine treatment european collaborative study: children born to women with hiv- infection: natural history, and rate of transmission a prospective cohort study of children born to hiv-infected mothers. trend in the risk of vertical transmission, mortality, and aids-indicator diseases public act no. - duration of ruptured membranes and vertical transmission of hiv- : a meta-analysis from prospective cohort studies update on successes and challenges regarding mother-to-child transmission of hiv- transition from pediatric to adult healthcare services for young adults with chronic illnesses: special case of human immunodeficiency virus infection this term was widely used in medical circles and the media in the s to refer to hiv-exposed infants who faced lengthy hospitalizations to ease them through withdrawal from opioids and/or cocaine as they awaited foster home assignments. the term has disappeared now that the rates of vertical transmission of hiv have fallen to negligible numbers. names of patients have been changed to protect their identity. all babies born to hiv-infected mothers are "hiv-positive" until to months of age because they all acquire hiv antibodies transplacentally. but only a fraction are "hiv-infected." eighty percent are "exposed" to hiv and are temporarily hiv-positive, but remain "uninfected." unfortunately, in late , an hiv-positive baby was born at ynhh after a gap of years. the teenage mother received prenatal care at a clinic unaffiliated with ynhh. she was non-compliant with the antiretroviral regimen that was prescribed for her. she was surprised to learn that her newborn baby was infected. the baby received antiretrovirals soon after birth, the mother's regimen was re-started, and the baby's biological father appeared for testing and treatment. all three have been adherent to their various regimens and, as of last report, all are doing well. since the start of we have followed nine hiv-exposed babies, but no mother-to-child transmissions of hiv have occurred. key: cord- -d xe oh authors: halepas, steven; ferneini, elie m. title: a pinch of prevention is worth a pound of cure: proactive dentistry in the wake of covid- . date: - - journal: j oral maxillofac surg doi: . /j.joms. . . sha: doc_id: cord_uid: d xe oh nan a pinch of prevention is worth a pound of cure: proactive dentistry in the wake of covid- . we live in an increasingly globalized and transnational world. with modern advances in travel, humans move around today more than in any previous generation. while this has tremendous benefits in cultural and societal advancements, it also creates great liability in epidemiology as modern outbreaks have no borders and cross all levels of society, regardless of race, ethnicity or socio-economic status. the coronavirus pandemic (covid- ) has ushered in unprecedented times. as the average infected person spreads the disease to two or three others, its spread is exponential. a large number of healthcare workers who died in china in the early days of this disease were ents and ophthalmologists. this is possibly due to the high viral shed from the nasal cavity. in wuhan, people became infected after an endoscopic pituitary surgery on a single covid- patient. sars-cov- has been demonstrated to remain aerosolized for hours after contamination and on plastics and stainless steel for up to hours. this makes the dental community a relatively high-risk population. pandemics inflict devastating consequences on communities and cause long-term rippling effects in the economy and the health care system. aids was first described as gay related immunodeficiency syndrome (grids) in . young gay men began falling ill and dying of opportunistic infection and fear of the "gay plague" spread rapidly along with the social stigma. two years later, the cdc documented heterosexual transmission of aids . what was originally referred as a "gay virus" transformed into one of the greatest ongoing pandemics and scientific challenges of modern medicine. the aids pandemic resulted in acceptance of "universal precautions" that revolutionized the standard of care throughout medicine. prior to hiv/aids, dentists did not commonly wear masks or eye protection. in the late s and early s, in an attempt to protect health care workers, osha and the cdc proposed guidelines to reduce exposure to bloodborne pathogens such as hiv and hepatitis b. dentistry resisted this change at every step. dentists argued that 'children would be frightened of the masks.' the ada led a fight against osha's universal precautions rule, arguing that no dentists had contracted these pathogens. in an op-ed published in the new york times on november , , dr. avrum goldstein, a periodontist from new haven, ct, expressed his opposition this way: "...these regulations will bring about changes in the dentist-patient relationship and make it more difficult to practice dentistry. by its nature, dentistry is an intimate occupation. the dentist works within an inch of a patient's head, probing sensitive, often tender areas of the patient's body. the mouth embodies our ability to smile, kiss, talk and eat-all very emotional qualities. patients' needs a warm and trusting relationship with their dentist to help overcome fears and make necessary dentistry possible. it will be more difficult to establish this relationship when the dentist is gowned, shielded, and masked. [these barriers] will have a profound effect on the relationship between the dentist and patient." in , the ada challenged the rule in the us court of appeals for the seventh circuit and lost. in , the ada's resistance to masks and eye protection seems preposterous, particularly given the information we have about bloodborne pathogens today. as a species, we are reluctant to change. this is evident not only by dentistry's resistance to adopt universal precautions, but also throughout history. the technology needed to eradicate smallpox was first described in , but took nearly years to execute. this strand of coronavirus may be new, but we have seen the same societal reaction to outbreaks countless times. with fear and panic brings blame and bigotry. on march , , the president of the united states referred to the coronavirus as the "chinese virus." global threats require unified efforts, which is why terms such as the "chinese virus" are so detrimental. "anti-chinese hostility has been a recurrent problem, whether with plague in san francisco in , sars in , or covid- today." aids was not contained in the s because it was considered a gay disease. syphilis was not eradicated with the invention of penicillin because it was said to limit promiscuity. if we learn anything from history, it is that we must come together as a species to fight as one, or perish as individuals. after the sars outbreak in and , the united nations adopted the international health regulations in an effort to prevent and contain future outbreaks. few countries have met their commitments. this is likely due to the cost associated with adopting these advances, as well as society's opposition to change. the cost of an economic bailout will far succeed the cost to prevent a global outbreak. the world needs a coordinated effort by a global institution with enough authority and funding to be efficient . this is of particular interest to doctors as epidemics too often claim the lives of healthcare providers. on march , the ada said, it "is deeply concerned for the health and well-being of the public and the dental team. in order for dentistry to do its part to mitigate the spread of covid- , the ada recommends dentists nationwide postpone elective procedures for the next three weeks. concentrating on emergency dental care will allow us to care for our emergency patients and alleviate the burden that dental emergencies would place on hospital emergency departments." are dental offices prepared to treat these potentially infected patients? if a patient is suspected to have covid- and emergency dental care is indicated, it is recommended to perform the dental treatment in a negative pressure room or airborne infection isolation room. what will come of this pandemic? the aids pandemic resulted in masks, gowns, and eye protection. samaranayake et al. published a retrospective review in after the peak of the sars outbreak. it found that the sars outbreak had a large impact on providers with some countries reporting that - % of those infected were health care workers. the study recommended preprocedural rinsing whenever possible to reduce the number of antimicrobial releases into the environment. the utilization of rubber dams can also reduce microbial aerosolization by up to %. hand hygiene is still the singlemost effective method of reducing transmission. following the sars outbreak, n masks are used throughout hong kong for routine dentistry. protecting the healthcare workers and patients is of upmost importance and we must focus on preventing future outbreaks. as a profession, we should explore methods of reducing transmission of all infectious agents. external mouth suctions, which work like the scavenger systems in our nitrous oxide devices, are being tested for effectiveness in korea. commercial air purifiers and air exchange devices are also being explored for the dental setting. creating negative pressure operatories may seem a drastic and expensive approach now, but in years dentists may think we were ludicrous for working without them, just as we judge those before us who did not use gloves. this pandemic will impact the delivery of care, the question is when and how. will dentistry accept the advances or continue our history of fighting change? a history of aids: looking back to see ahead history in a crisis-lessons from covid- the next epidemic -lessons from ebola coronavirus disease : implications for clinical dental care severe acute respiratory syndrome and dentistry: a retrospective view key: cord- - j mmoht authors: des jarlais, don c.; stuber, jennifer; tracy, melissa; tross, susan; galea, sandro title: social factors associated with aids and sars date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: j mmoht we conducted a survey of new york city area residents to assess knowledge and worry about aids and sars. specific sociodemographic groups of persons were more likely to be less informed and more worried about contracting the diseases. we conducted a survey of new york city area residents to assess knowledge and worry about aids and sars. specific sociodemographic groups of persons were more likely to be less informed and more worried about contracting the diseases. p ublic reaction to emerging infectious diseases is a critical factor in controlling the diseases. informed behavior change may be needed to control disease transmission. negative public reactions, such as stigmatizing persons at risk for the disease, may greatly hamper prevention and treatment efforts ( , ) . the current public health strategy to control emerging infectious diseases includes timely and complete public reporting ( ) . providing timely and complete information, however, cannot determine public reaction to the information. in this study, we examined contrasting relationships between sociodemographic characteristics and knowledge and worry about aids and severe acute respiratory syndrome (sars). aids may be considered the prototype of an emerging infectious disease. while aids has received considerable public attention since the early s, the strong emotions associated with it create the possibility of nonrational information processing. the stigmatization of persons with or at risk for aids has persisted despite public information about the disease ( ). in contrast, sars emerged quite abruptly in - and received intense public media attention, but the disease was declared contained by the world health organization in ( ); little public media attention has been paid to sars since then. data for this study came from a cohort of adults (> years of age) who lived in metropolitan new york city (nyc). the cohort was recruited through a random digit dial telephone survey conducted from march to june , . additional details on the sampling are provided elsewhere ( , ) . the response rate was %. this rate is typical for well-conducted telephone surveys ( ) . a total of , respondents was interviewed from september , , to february , , for this study. we first asked if respondents had heard about sars and aids; persons who had heard about the diseases were asked if they had heard "a great deal," "some," or "not much" about the diseases. we also asked respondents if they were "not at all worried," "somewhat worried," or "very worried" about contracting the diseases. the analyses were weighted to correct potential selection bias related to the number of household telephones, persons in the household, and oversampling. the analyses were also weighted to make the sample demographically similar to the nyc metropolitan area population according to us census . the institutional review board of the new york academy of medicine approved the study. table presents the sociodemographic characteristics of respondents and their relationships to self-reported knowledge of aids and sars. in this analysis, we compared characteristics of respondents who reported knowing "nothing" or "not much" and "some" or "a lot" about the diseases. we considered respondents who reported knowing "nothing" or "not much" to be poorly informed. five percent of the respondents reported being poorly informed about aids, and % reported being poorly informed about sars. table presents the sociodemographic characteristics of the respondents and shows their relationship to worry about contracting aids or sars. in this analysis, we examined characteristics of respondents who reported that they were "very worried" about contracting aids or sars. there were no meaningful difference in the percentage of subjects who reported being "very informed" about each disease or "very worried" about contracting each disease. the factors associated with being poorly informed and worried about contracting aids and sars varied; respondents in the lower socioeconomic group were likely less informed and more worried about both of the diseases. particularly, racial/ethnic minority status, lower formal education, and lower income were associated with being poorly informed and worried. being poorly informed about aids and being poorly informed about sars were strongly related. of respondents who reported being poorly informed about aids, % reported also being poorly informed about sars; % of the respondents who reported not being poorly informed about aids reported being poorly informed about sars (p< . ). a strong relationship existed between being very worried about both diseases. of the respondents who reported being very worried about aids, % reported also being very worried about sars; % of the respondents who were not very worried about aids were very worried about sars (p = . ). finally, we examined the relationships between being informed and worried about contracting aids/sars. these analyses were confined to respondents who reported having some information about aids/sars; respondents who reported that they had not heard about the diseases were not asked the follow-up questions. in these respondents, no relationship between having heard and being worried about getting the diseases was shown. given the widespread disparities in health among racial/ethnic and socioeconomic groups in the united states ( ) , that these factors were associated with being less informed and more worried about contracting aids or sars was not surprising. the data presented here, however, are likely not related to access to healthcare services (particularly for sars) and suggest more fundamental issues in obtaining information and developing realistic concerns about diseases. the high percentage of spanishspeaking respondents who were poorly informed about aids and sars and very worried about getting sars suggests possible language and cultural issues in acquiring and processing information. the data from this study were collected in a major city of an industrialized country and should not be generalized to developing and transitional countries. nevertheless, if obtaining and evaluating information is adversely affected by factors such as low education level, low income, and ethnic minority status, then properly informing the public may be particularly difficult in developing and transitional countries. the epidemiology of aids and sars has been very different in nyc (> , aids cases [ ] , sars cases). despite this difference, strong parallels existed in the relationships of socioeconomic factors to knowledge and worry about both diseases. the limitations of this study included using single items to measure knowledge and worry about aids and sars and the standard limitations of telephone surveys, e.g., inability to contact households without telephones, moderate refusal rates. however, this study strongly suggests that adequate public knowledge and emotional assessment may be critical to control these diseases. our data suggest that socioeconomic class and race/ethnicity factors may help shape public understanding of emerging infectious diseases. targeted communication to different population subgroups may be required to achieve public understanding of an emerging infectious disease. traditional beliefs about the cause of aids and aids-related stigma in south africa hiv testing from a community perspective communicating in a crisis: risk communication guidelines for public officials. washington: the department hiv-related stigma and knowledge in the united states: prevalence and trends - united nations aids/world health organization. aids epidemic update. geneva: the programme stigmatization of newly emerging infectious diseases: aids and sars hispanic ethnicity and post-traumatic stress disorder after a disaster: evidence from a general populations survey after health disparities based on socioeconomic inequities: implications for urban health care new york city department of health and mental hygiene. hiv epidemiology program st quarter report key: cord- -ubf eux authors: carvalho, john j. title: our common enemy: combatting the world's deadliest viruses to ensure equity health care in developing nations date: - - journal: zygon doi: . /j. - . . .x sha: doc_id: cord_uid: ubf eux in a previous issue of zygon (carvalho ), i explored the role of scientists—especially those engaging the science‐religion dialogue—within the arena of global equity health, world poverty, and human rights. i contended that experimental biologists, who might have reduced agency because of their professional workload or lack of individual resources, can still unite into collective forces with other scientists as well as human rights organizations, medical doctors, and political and civic leaders to foster progressive change in our world. in this article, i present some recent findings from research on three emerging viruses—hiv, dengue, and rotavirus—to explore the factors that lead to the geographical expansion of these viruses and the increase in frequency of the infectious diseases they cause. i show how these viruses are generating problems for geopolitical stability, human rights, and equity health care for developing nations that are already experiencing a growing poverty crisis. i suggest some avenues of future research for the scientific community for the movement toward resolution of these problems and indicate where the science‐religion field can be of additional aid. the beginning of the twenty-first century has witnessed economic instability in war-torn areas such as the middle east, the advent of more advanced terrorist activity, and global warming. within this new era, the emergence of viruses and the infectious diseases they cause is becoming a worldwide threat of the utmost importance. indeed, unlike the migration of peoples, which can be curbed by national and continental boundaries, viruses have no boundaries that constrict their spread. they are free to expand their geographical habitats irrespective of governmental restrictions, economic factors, or other forces that normally affect the movements of populations. as a result, many developing countries are experiencing larger outbreaks of viral diseases, including diseases such as polio thought to be eradicable by vaccine programs. and not only the developing nations are suffering from emerging viruses. even in developed countries such as the united states, certain viruses have expanded their geographical range and become more frequent in first-world hospitals. of the emerging viruses, five have particular importance for what scientists and world leaders can learn concerning their impact on geopolitical stability, human rights, and equity health care for the underprivileged in both developed and developing nations. they are ( ) human immunodeficiency virus (hiv), the causative agent of acquired immune deficiency syndrome (aids), ( ) dengue virus, the causative agent of dengue fever and dengue shock syndrome, ( ) rotavirus, the causative agent of viralinduced gastroenteritis, ( ) influenza virus, and, surprisingly, ( ) the coronavirus that causes severe acute respiratory syndrome (sars). this last one is included not because of the number of illnesses it has caused but rather because of the economic impact and societal panic it has been responsible for recently (gostin, bayer, and fairchild ; zhong and zeng ) -manifestations that can tell us much about what could transpire if more deadly viruses or deadlier versions of the sars coronavirus surfaced. for the sake of this synopsis, i focus on hiv, dengue, and rotavirus. by far, the greatest emerging threat internationally is hiv because developing nations, especially those in africa, are experiencing the enormous influence of this virus. since its discovery in , hiv has confounded scientists with its enigmatic biology and, consequently, has caused a worldwide pandemic. globally, estimates of hiv infections range from to million, with . million infections in sub-saharan africa alone (white and fenner ; flint et al. ; fauci ; kuritzkes and walker ) . to make matters worse, the distress caused by hiv/aids is somewhat of an underestimate, because persons presently infected will eventually die if a cure is not discovered-creating further instability at the geopolitical, economic, and social levels and reversing progress in many societies for decades while simultaneously contributing to the geographical expansion of the virus (see below). some estimates suggest that the workforce in fifteen countries will be million fewer by and that some nations, including south africa, will experience a percent lower gdp by the beginning of the next decade because of the impact of hiv (piot et al. ) . many scholarly journals consider the effect of geopolitical stability on public health, but rarely do they consider the effects of public health on geopolitical stability. consequently, the contribution of hiv/aids to such stability is underappreciated. increase in hiv/aids cases is linked to the breakdown of country boundaries, a rise in the number of ill refugees migrating across borders and to different areas within their host countries, an increase in military personnel or world peacekeepers becoming infected with the virus, and the deterioration of national infrastructures. unaids estimates that hiv rates among armed forces in some developing nations is higher than that of the general population and that hiv is responsible for causing a percent mortality in some militaries, to say nothing of the financial burden these militaries must face to combat the virus (feldbaum, lee, and patel ) . furthermore, the impact of the virus on some civilian populations such as in sub-saharan africa raises the alarming possibility of a "state meltdown" (feldbaum, lee, and patel ) . that hiv is causing problems in certain strategically important nations such as russia, china, and india is of much concern given that estimates suggest these regions could witness - million hiv cases by (eberstadt ) . the effect of hiv on the geopolitical order of these strategic nations, as well as developing nations that require robust militaries or the presence of peacekeeping forces in order to maintain national stability, has great importance for world peace (feldbaum, lee, and patel ) . furthermore, in many of these hardest hit nations hiv/aids is disproportionately affecting younger people, so that the coming decades may reveal a population inversion, with individuals in their s and s outnumbering those in their s and s (piot et al. ) . the expansion of hiv/aids is not just an economic and geopolitical crisis; it is also a human-rights problem. in a previous article in zygon i mentioned that the united nations' universal declaration on human rights affirms that all persons should have the right to adequate medical care and social services in order for the war on global poverty to be successful (carvalho , ) . unfortunately, as the hiv/aids pandemic spreads, it is largely the "poorest of the poor" who suffer from inadequate health care and lack of equity social services (reviewed extensively in farmer ) . indeed, hiv/aids exacerbates and prolongs poverty in every respect. it has a devastating impact on the stability of households in developing nations. in africa, . million children have been orphaned because of aids, and this phenomenon is causing serious strain on national health infrastructures and human relief agencies (piot et al. ) . similarly, education-a primary means of breaking the poverty cycle-in many nations is being detrimentally affected because sick teachers are dying, children are dropping out of schools because of personal illness or the illness of parents or guardians, and families cannot pay for school supplies because of the economic burden of hiv/aids on household incomes (piot et al. ) . hiv/aids also contributes to problems in the agricultural industries of these nations as manpower dwindles because people become sick with the virus and livestock need to be sold off to handle family funeral expenses (piot et al. ) . the impact on food supply further exacerbates the poverty-and therefore human rights-crisis already exhibited in these regions. furthermore, the progression from infection to full-blown aids appears to occur faster in patients living in lower-income countries because of malnutrition and the lack of equity health care (pinching ; piot et al. ; farmer ; sanchez and swaminathan ; wanke ; cohen ) . in summary, the hiv/aids pandemic has emerged into an economic, geopolitical, and human-rights crisis that feeds off poverty and the lack of equity health care in developing nations while further intensifying poverty and the lack of equity health care. these factors lead to the inability to control hiv and thus promote the geographical expansion of the virus. arguably, hiv/aids is a model case by which to measure how viruses can expand their presence in the world by collaborating with and strengthening the factors that allow them to perpetuate in the human population. although hiv/aids is considered the most pressing worldwide concern for scientists, dengue virus is also alarming. dengue is a member of the flaviviridae family of viruses, which includes yellow fever, japanese encephalitis, and west nile viruses, among others (reviewed in gubler, kuno, and markoff ; lindenbach, thiel, and rice ) . it is the causative agent of two major diseases, dengue hemorrhagic fever and dengue shock syndrome (deen et al. ) . early epidemics of dengue were documented in jakarta, cairo, and philadelphia in the late s (mairuhu et al. ). since that time, epidemics have occurred on all continents every ten to thirty years, but the disease was relatively benign, showing just fever and severe bone and back pain in patients (mairuhu et al. ) . after the disease became more fatal, displaying signs of hemorrhage in subjects from the philippines in and shock in those from southeast asia (mairuhu et al. ) . during the s dengue spread into india, pakistan, china, sri lanka, and the maldives. it has since become a significant health problem in south and central america and the caribbean, where a recent outbreak was documented in puerto rico (mairuhu et al. ; torres and castro ; morens and fauci ; usa today ; msnbc ) . the disease is presently confined to tropical and subtropical regions and is transmitted to humans by the bite of infected female mosquitoes of the genus aedes (aedes aegypti, aedes albopticus, and aedes polynesiensis) (gubler, kuno, and markoff ) . according to the world health organization, nearly half the world's population is now living in dengue endemic areas, and it is estimated that annually there are - million dengue fever cases, , of them the dengue hemorrhagic fever variety (deen et al. ; gubler, kuno, and markoff , ) . given the possibility for severe disease in infected individuals and the ease by which dengue is transmitted by mosquitoes, the spread of dengue virus could be considered one of the most dangerous emerging threats facing the world. a number of factors of human origin contribute to the geographical expansion of dengue virus and increased incidence of severe disease. these factors exacerbate one other to amplify both the spread of the virus and the negative impact of each factor on suffering human populations. for example, the failure to control the spread of aedes mosquito populations is critical because these mosquitoes are the vectors that carry the virus. mosquito programs have met with repeated failure in certain countries and have been linked to a resurgence of the virus in the americas in the s (gubler ) . much of this failure came from insecticide resistance and reduction in program support in poorer nations (mairuhu et al. ). in addition, as resolutions to control global warming were neglected by governments over the past few decades, climate changes have resulted in large areas of standing water following major monsoons that have acted as ideal breeding grounds for mosquitoes (torres and castro ) . concurrently, haphazard deforestation has compounded the emergence of vector-borne diseases like dengue (torres and castro ) . the above factors are coupled with unprecedented population growth and uncontrolled urbanization, both of which have greatly expanded the geographical range of the mosquitoes and the viruses they harbor-in essence providing hyperendemic areas where multiple serotypes of dengue virus can circulate in human and aedes populations simultaneously. for example, in latin america, population growth and uncontrolled migration from the countryside to the cities have resulted in poor housing conditions, inappropriate disposal of waste, and lack of adequate food, clean water and health care-all of which are concurrent with an increase in infected mosquitoes carrying different versions of dengue virus (torres and castro ) . the biology of the virus itself compounds the problem, with new, more pathogenic dengue serotypes emerging that cause the more severe hemorrhagic and shock forms of the disease, such as in cuba in when , infections were reported (mairuhu et al. ; guzman ) . the multiple circulating serotypes can contribute to more severe forms of disease upon secondary infections (mairuhu et al. ). one immunological theory postulates that some dengue-specific antibodies from prior infections can cross-react with viruses from secondary infections without neutralizing the virus but acting as a mediator for increased uptake of the virus into target immune cells (such as monocytes and macrophages) where the virus can replicate and then be secreted from these cells (clyde, kyle, and harris ) . as indicated, these factors feed off each other. by far, social inequalities that stem from poverty are the biggest concern. educational scarcity on dengue virus and the diseases it causes, poor sanitation, lack of quality public health surveillance, and delayed clinical diagnosis are dominantly seen in more underprivileged areas (morse ; ligon ; torres and castro ; khun and manderson ; ) . spread of the virus in these areas further aggravates the lack of equity health care-a human rights issue-to the most disadvantaged. much of this is a result of the economic impact of dengue on poor nations. estimates of total costs from epidemics in puerto rico, cuba, and nicaragua are as high as $ . million, $ million, and $ . million, respectively (torres and castro ) . endemic dengue contributes even more to the economic burden (torres and castro ) . because most families in endemic areas such as latin america and the caribbean earn us $ , /y ear, the economic load of dengue is harshest for the poorest families in society, where even a brief hospital stay takes a significant toll on household income. in turn, the missing workdays by sick patients results in reduced revenue for the already cash-strapped governments these citizens belong to. essentially, lack of financial resources contributes to the deterioration of the established public health infrastructure, a breakdown that in turn jeopardizes the maintaining of mosquitocontrol, entomological-surveillance, and prevention programs and reduces the likelihood of rapid diagnoses in hospitals and clinics because of poorly trained staff or lack of medical resources including available doctors. as with the hiv pandemic, it is the poorest of the poor who suffer from the inadequate health care in dengue endemic regions, such as latin america and cambodia (torres and castro ; khun and manderson ; ) . and when poor families do not have access to health care, there is the further possibility of infected individuals not seeking treatment, which in turn leads to underreporting of disease cases, which further hampers governmental effort on resource allocation to combat the disease (torres and castro ; khun and manderson ; ) . the lack of equity health care in endemic areas becomes a human rights issue rather than just a medical one-an issue that has great importance for the medical community's attempts to stop the geographical expansion of dengue virus. rotavirus, a member of the reoviridae family of viruses, is the major causative agent of viral-induced gastroenteritis (reviewed in estes and kapikian ) . there are approximately . million rotavirus infections and , rotavirus-induced deaths per year, affecting mostly children in developing nations, with percent of deaths occurring in south asia and sub-saharan africa (bresee et al. ; parashar et al. ; estes and kapikian ) . rotavirus is spread by fecal-oral contamination and via airborne viruses or contaminated respiratory droplets (estes and kapikian ) . new rotavirus strains can emerge from nucleic acid "reassortment," whereby simultaneous or asynchronous infection of organisms with human and animal rotaviruses leads to new, more pathogenic viruses being produced with mixed genetic material from both humans and animals (cook et al. ) . the geographical expansion of rotavirus, like hiv and dengue, is caused by a variety of factors: the ability of the virus to infect many different types of organisms, contaminated water supplies, poor hygiene and inadequate sanitation, lack of education, lack of prevention/treatment strategies and the supplies needed to carry out prevention/treatment, and the cycle of poverty in rotavirus endemic regions (levine et al. ; cook et al. ; estes and kapikian ) . as with hiv and dengue, poverty and rotavirus infections feed off each other. viral infections add to the economic burden on suffering nations. sick children and adults may be absent from school or work, impeding gdp (gray et al. ) . rotavirus outbreaks may deter travelers willing to visit exotic countries, which leads to loss of the tourism dollars that may be the foundation of the economies for such countries (diemert ) . medical costs for treatment of infected individuals can be enormous. studies of eight latin american and caribbean countries (argentina, brazil, chile, dominican republic, honduras, mexico, panama, and venezuela) reveal that for every , children born in , us $ , was expended in direct medical costs during their first five years of life (rheingans et al. ). indirect costs likely increase these numbers, further indicating that rotavirus gastroenteritis results in substantial economic burden for poorer families in these nations. in poland, each nosocomial infection can cost as much as us $ , for treatment, with yearly impact amounting to us $ . million (chandran et al. ) . overall, the cost of treatment in the united states is around $ billion, due partly to increased hospital visits from rotavirus infections (estes and kapikian ) . the economic burden of rotavirus exacerbates difficulties in providing equity health care, with poorer populations suffering the most during epidemics. the data in the literature on the effects of rotavirus on geopolitical instability are underappreciated. nevertheless, if the hiv pandemic teaches us anything, it is that it is highly likely that the lack of proper health care and economic difficulty in the poorest rotavirus endemic regions contribute to problems in geopolitical stability and that the continued geographical expansion of rotavirus will likely intensify these problems in the future. to make matters more worrisome, the zoonotic potential of rotavirus can have a detrimental impact on agricultural safety, with poorer nations lacking adequate protections. global warming has been a cause of increased monsoons, with greater potential for contaminated cattle excreta to run off into fresh water supplies such as rivers and lakes (cook et al. ) . contaminated water supplies can further contaminate crops. already, outbreaks of rotavirus infections from contaminated food have been seen around the world (cook et al. ) . the zoonotic potential of rotavirus becomes further important because more dangerous viruses could emerge and because rotavirus can be repeatedly introduced into the human population from a variety of sources (cook et al. ). scholars have written on the link between human rights, world poverty, and the epidemiology of disease (sen ; farmer ) . i myself have suggested how the theoretical discussions in the science-religion dialogue could contribute to concerns for equity health care in the developing world (carvalho ) and how such discussions can expand the science-religion audience (carvalho ) . i and others also have suggested that scientists and science-religion scholars-who understand the impact of technology, philosophy, religion, and culture on societies-should engage the wider political and social realm to tackle present, practical problems (carvalho ; ; deane-drummond ; polkinghorne ; wildman ) . continuing with these themes, it is clear that the geographical expansion of three viruses (hiv, dengue, and rotavirus), the increase in frequency of the infectious diseases they cause, and the relationship between these viruses and geopolitical stability, human rights, and equity health care for developing nations are problems of great concern promoted not only by biological and technological factors but also by social, religious, and cultural ones. consequently, the issues must be tackled from many different angles: clinical intervention, biomedical research, philosophical analysis of social/cultural/religious issues, and public policy. in my view, scholars in the biomedical research and public policy arenas have a number of avenues to pursue to combat the geographical expansion of hiv, dengue, and rotavirus and the increase in the infectious diseases they cause. for example, unlike with hiv, most of the data on the economic and societal impact for dengue and rotavirus are derived from epidemic as opposed to endemic cases. this lack of sufficient data is relevant for how governments will allocate resources for research, prevention, and more aggressive control activities. this is an area for immediate attention by the scholarly community. similarly, better epidemiological and entomological surveillance must be established, and the sources of the vectors for the viruses-such as water reservoirs that act as breeding grounds for dengue-infected mosquitoes-must be reduced, partly through curbing global warming. there should be additional research on the control of the zoonotic potential of rotaviruses given the large number of animals able to be infected with these viruses and the recurrent infection of the human population. better and more rapid clinical diagnosis of patients, especially underprivileged individuals, is a must. delays in diagnosis in poorer communities continue to contribute to the geographical expansion of hiv, dengue, and rotavirus. in order to achieve this end, the health funding structures in developing nations need to be evaluated. indeed, the creation of appropriate funding mechanisms (such as the availability of equity health insurance) is crucial to ensure access to health care for poorer families. otherwise sick individuals who do not have insurance and who cannot present cash for clinical care will not seek treatment, which invariably leads to delayed diagnosis and inappropriate surveillance and, additionally, detrimentally influences how funds are allocated to combat the viruses. at the public policy level, there needs to be enforcement of international human rights standards to protect the most underprivileged, such as refugees who may be infected with hiv (see unhcr ) . in terms of the science-religion dialogue, i would argue that public policies should contain insights from science-religion scholars or biologists who maintain a human rights perspective, because human rights and equity health care are inherently linked to the epidemiology of hiv, dengue, and rotavirus. science-religion scholars could act as resources for education on the moral dimension of viral infections. hiv, for example, has become a major epidemic in certain developing nations-such as those in latin america and the caribbean-because people in these regions possess an erroneous theological view that hiv infection is a "moral curse" that is a "punishment" for unethical behavior. (we have even seen this position in the united states.) societies in these areas therefore impose a great stigma on hiv-infected patients that leads to widespread discrimination in all forms, including unwillingness from physicians to even treat the disease (ramirez ) . such discrimination promotes the lack of equity health care for the neediest individuals and can be witnessed in dengue and rotavirus cases as well. given that science-religion scholars are likely to promote more correct theological insights into morality while simultaneously possessing a quality understanding of science, they could be powerful proponents in educating societies that viral diseases result largely from causes that are not based on incorrect presuppositions about morality or social taboos. educational campaigns dealing with hiv/aids could have benefited greatly in the earlier years of the epidemics if erroneous theology had been corrected by insights from the science-religion field. this can be seen especially with the early epidemics in the united states and mexico (cohen ) . such insights could prevent future mistakes in handling disease epidemics. it cannot go unnoticed that activism from religious organizations that accept advice from science-religion scholars or the human rights field could be pivotal in curbing the geographical expansion of viruses in certain underprivileged communities. cases in point are mexico and honduras (cohen ) . additionally, the burden caused by these viruses to underprivileged families-financial, psychological, social, religious, and cultural-needs to be better defined, as does how this burden relates to human rights and equity health care. science-religion scholars are more likely to understand the complicated dimensions of many societies, so once again they would be helpful in educating the scholarly community on the religious and cultural parameters of viral epidemics. for example, during the hiv/aids epidemic in africa some ritual practices involving blood may have resulted in hiv infections. similarly, male circumcision has been suggested to reduce hiv infections (morris ) , but circumcision practices that reuse unsterilized objects in certain communities could be problematical (see unaids ) . cultural insights from science-religion scholars on the religious traditions in these communities could have resulted in an educational campaign to modify cultural and religious ceremonies to make them safer. to illustrate with another case, it greatly surprised the medical community when polio vaccine distribution in the muslim world met fierce resistance due to mistrust of western medicine (roberts ) . knowing this is important for vaccine distribution for other viruses like rotavirus. again, an educational campaign with religious and cultural insights from science-religion experts on islam could be helpful in future public policy and procedures for vaccine distribution in muslim communities. apart from these concerns, the issue of equity needs to be further explored and the problems resolved. lack of equity health care is not the only crisis exacerbated by viruses; equity in education (such as access to educational materials and scientific data in developing nations) is also a problem. for example, a proper theological perspective on the dignity and rights of the human person could have thwarted epidemics within certain communities, such as the mayan community in guatemala, where individuals are treated as second-class citizens and are not afforded access to health care or even educational materials on hiv (cohen ) . scholars within the science-religion field have suggested that addressing the health crisis in poorer areas of the world could help eliminate superstitious beliefs (budenholzer , - ) . i would claim that some of these beliefs clearly have a negative impact on equity. i have argued that biologists should address global health in numerous ways (carvalho ) . i also have articulated that professional societies should devote sections of their journals to philosophical analysis and public policy suggestions that attempt to resolve world health issues (carvalho ) . interdisciplinary collaboration has been successful in other cases, and it is my expectation that continued interdisciplinary collaboration should keep biomedical research focused and relevant. science-religion scholars could provide a "moral compass," encouraging the biomedical community to focus not only on discovering drugs helpful to already developed nations (and therefore profitable to drug companies) but also on research into antiviral medications that would have a greater impact on developing countries and therefore be more likely to slow the geographical expansion of viruses from their niches into first-world communities. in addition, science-religion scholars with expertise in bioethics and/or human rights could be helpful as interdisciplinary collaborators for public policy initiatives such as the implementation of new medicines or vaccines. research on vaccines is always ongoing in the biomedical community, but it is important to determine proper cost/benefit information whenever a new vaccine is made, and such cost/benefit information needs to take into account the wider impact of vaccine distribution. for example, the removal of one rotavirus vaccine from the international market in because of a side effect that occurred in very few cases and that could have been resolved by a simple medical procedure may have thwarted an additional million rotavirus-induced deaths in the developing world (strauss and strauss , - ) . cost/benefit analysis is based on financial feasibility and the goal of causing no harm in any patient. much of this analysis presently is based on the effects that could occur to already developed nations. science-religion scholars could have provided additional bioethical insights into cost/benefit analysis for such vaccine distribution in developing nations. by educating public health agencies and governments on the burdens (financial, social, cultural) of rotavirus epidemics in these poorer countries, science-religion scholars could have presented a better case for how the vaccine would have slowed the geographical expansion of rotavirus in the hardest hit endemic areas and how it would have aided poorer communities at many levels beyond just the medical. it is doubtful that previous cost/benefit analysis took into consideration how the additional rotavirus deaths would have also impacted family structure and family relationships to the wider community, or the added economic burdens and burdens on national health infrastructure resulting from the new deaths because of lack of an adequate vaccine. in conclusion, the battle against infectious diseases must involve a multifaceted approach that takes into account the social, religious, and cultural dimensions of disease epidemics. the interdisciplinary background of scholars within the science-religion dialogue could be extremely valuable in identifying what these dimensions are and how they can be approached for resolution. rotavirus in asia: the value of surveillance for informing decisions about the introduction of new vaccines sars and superstition the scientist as statesman: biologists and third world health a biologist's perspective on the future of the science-religion dialogue in the twenty-first century nosocomial rotavirus infections: a systematic review recent advances in deciphering viral and host determinants of dengue virus replication and pathogenesis hiv/aids in latin america and caribbean experiencing wonder and seeking wisdom the who dengue classification and case definitions: a time for a reassessment prevention and treatment of traveler's diarrhea the future of aids rotaviruses pathologies of power: health, human rights, and the new war on the poor. berkeley: univ years of hiv/aids science: reaching the poor with research advances the national security implications of hiv/aids principles of virology: molecular biology, pathogenesis, and control ethical and legal challenges posed by severe acute respiratory syndrome rotavirus aedes agypti and aedes agypti-borne disease control in the s: top down or bottom up flaviviruses deciphering dengue: the cuban experience health seeking and access to care for children with suspected dengue in cambodia: an ethnographic study poverty, user fees and ability to pay for health care for children with suspected dengue in rural cambodia hiv- : pathogenesis, clinical manifestations, and treatment pediatric diarrhea: the challenge of prevention emerging and re-emerging infectious diseases: review of general contributing factors and of west nile virus flaviviridae: the viruses and their replication dengue: an arthropod-borne disease of global importance dengue and hemorrhagic fever: a potential threat to public health in the united states why circumcision is a biomedical imperative for the st century factors in the emergence of infectious diseases dengue fever surging in puerto rico rotavirus and severe childhood diarrhea factors affecting the natural history of human immunodeficiency virus infection the global impact of hiv/aids science and religion: bottom-up style, interfaith context hiv/aids in latin america economic and health burden of rotavirus gastroenteritis for the birth cohort in eight latin american and caribbean countries polio: the final assault? cutting world hunger in half development as freedom viruses and human disease the health and economic impact of dengue in latin america male circumcision and hiv note on hiv/aids and the protection of refugees, idps and other persons of concern puerto rico warns of dengue fever outbreak nutrition and hiv in the international setting retroviridae from grand dreaming to problem solving what we have learnt from the sars epidemics in china key: cord- -ep ezoko authors: gamble, lena j; matthews, qiana l title: current progress in the development of a prophylactic vaccine for hiv- date: - - journal: drug des devel ther doi: . /dddt.s sha: doc_id: cord_uid: ep ezoko since its discovery and characterization in the early s as a virus that attacks the immune system, there has been some success for the treatment of human immunodeficiency virus- (hiv- ) infection. however, due to the overwhelming public health impact of this virus, a vaccine is needed urgently. despite the tireless efforts of scientist and clinicians, there is still no safe and effective vaccine that provides sterilizing immunity. a vaccine that provides sterilizing immunity against hiv infection remains elusive in part due to the following reasons: ) degree of diversity of the virus, ) ability of the virus to evade the hosts’ immunity, and ) lack of appropriate animal models in which to test vaccine candidates. there have been several attempts to stimulate the immune system to provide protection against hiv-infection. here, we will discuss attempts that have been made to induce sterilizing immunity, including traditional vaccination attempts, induction of broadly neutralizing antibody production, dna vaccines, and use of viral vectors. some of these attempts show promise pending continued research efforts. since its discovery and characterization in the early s as a virus that attacks the immune system, leaving patients unable to fight off opportunistic infections, there has been an ebb and flow of effective treatments and hope as scientists continue to search for ways to eradicate human immunodeficiency virus- (hiv- ) from the human population similar to what has been accomplished in the case of smallpox. the majority of the effort and nearly all of the success has come in the area of patient treatment rather than inhibition of contraction or spread of the virus. a class of treatments, antiretroviral therapies (arts) and later highly active antiretroviral therapies (haarts), has been the mainstay of disease control during the last years. notwithstanding the increased life span of patients, increased time to full-blown aids, and decreased contraction of opportunistic infections and aids-related diseases (ie, non-hodgkin's lymphoma, kaposi's sarcoma, etc) by patients treated with haart, there are several reasons why development of an hiv- vaccine is still warranted. five of these reasons are as follows: ) nearly two-thirds of the patients who contract hiv- live in underdeveloped countries and cannot afford the expensive haart regimen, ) both the art and haart regimen are complex and are disruptive to patients' lives and diets, making long-term compliance an issue, ) the potential side effects of art/haart treatments negatively affect the long-term health of patients and include diabetes, cardiovascular disease, fractures, etc, - ) development of haart drug resistance, and ) the presence of latent hiv- reservoirs harboring viral strains that were produced through mutation throughout the duration of the infection of the host also play a role in the failure of haart. these reasons, as well as many others, underscore the need for a prophylactic hiv- vaccine. possibly, the strongest argument for development of a prophylactic vaccine may be the need for control of the virus spread worldwide. every day, patients worldwide are infected with hiv- . production of a vaccine that could inhibit infection, reduce spread, or both would aid in the reduction of the burden of aids and aids-related diseases. the expenses incurred by the aids epidemic can hardly be calculated. they range from tens of thousands of dollars per patient for the haart regimen, to millions of dollars required for building of orphanages by governments for children whose parents have succumbed to the disease, to the unknown cost of educational materials and condoms in the effort to prevent further spread of the disease. this public health challenge has not gone unnoticed and has been addressed by scientists' ongoing efforts to develop a safe and effective hiv- vaccine. a prophylactic hiv- vaccine would offer sterilizing immunity to patients, preventing infection upon presentation of the virus. a prophylactic vaccine must also be effective at all possible portals of hiv- entry, especially the mucosa. for this to occur, the vaccine must offer broad and durable immunity. several consortia have worked diligently to produce a vaccine that will induce broadly reactive neutralizing antibodies (nabs). these consortia include major international efforts as well as efforts of individual countries, regions, and institutions including, but not limited to: the international aids vaccine initiative neutralizing antibody consortium, the center for hiv-aids vaccine immunology, the hiv vaccine trials network, us military hiv research program, the collaboration for aids vaccine discovery, and the vaccine research center at the national institutes of allergy and infectious diseases of the national institutes of health. to date, however, no hiv- candidate vaccine has induced broadly reactive nabs. in the absence of a vaccine that can prevent infection of hiv- , there are still many benefits to be realized from production of a therapeutic vaccine. a therapeutic vaccine would be supremely valuable if it were able to increase the titer of virus necessary for infection, increase the time to clinical manifestation of virus, control viral load after infection, and reduce secondary transmission. [ ] [ ] [ ] [ ] [ ] a vaccine that could induce this type of response would invariably decrease contagiousness, decrease the need for costly and potentially dangerous art/haart, and decrease the number of opportunistic infections of patients. while the effect of controlling the normal hiv- pathology with therapeutic vaccines will be favorable for the individual patient as well as society, the effect of preventing hiv- infections in humans with a prophylactic vaccine is also broadly appealing. this potential for eradicating the hiv- virus from human hosts drives scientists to continue to find ways to circumvent the challenges presented by this unique virus in order to induce production of the nabs that are critical for sterilizing immunity. this review, therefore, will focus on the specific challenges presented by hiv- and strides that have been made toward creating a prophylactic vaccine, including past efforts that have failed and lessons that have been learned from those failures. we will also discuss novel vaccine options and some of the promising trials that are currently underway. while several problems face scientists who are attempting to create an hiv- vaccine, three problems in particular have posed extremely daunting challenges. these three problems are ) degree of diversity of the virus, ) ability of the virus to evade the hosts' immunity, and ) lack of appropriate animal models in which to test vaccine candidates. these three major problems will be discussed in more detail below. traditionally, prophylactic vaccines have been made by exposing some part of a pathogen's structure as an antigen to the host's immune system, and eliciting an immune response, resulting in the production of long-term memory lymphocytes that are capable of mounting a strong immune response upon later infection with the pathogen. the premise upon which this manipulation of the immune system is based is the ability of the immune system to make long-lasting antibodies to conserved structures on exposed proteins that are native to the pathogen. ideally, both humoral and cell-mediated immunity would be induced creating long-lasting immunity. traditional attempts to recreate this process using live attenuated simian immunodeficiency virus- (siv- ) viruses in an effort to vaccinate macaques against siv- have been proven safe and effective in macaques that were subsequently challenged with siv- . , however, an incidental study of the effect of liveattenuated hiv- (containing deletions of the nef gene and the long terminal repeat) was proven pathogenic in humans when three out of six treated patients developed late-onset immunosuppression. [ ] [ ] [ ] killed viruses have also been tested as a potential vaccine approach, but safety concerns have halted their use. these safety concerns include incomplete inactivation of the virus leading to potential residual infectivity during the vaccine preparation. due to the ineffectiveness of traditional vaccine approaches to date, scientists have attempted to use recombinant hiv- proteins to stimulate the production of nabs. these attempts failed due to their inability to induce a lasting, broad range of nabs that would inhibit infection in humans. [ ] [ ] [ ] [ ] perhaps these failures are a result of the inherent diversity of hiv- . this diversity has presented a major roadblock to development of a prophylactic vaccine. there are three main groups of hiv- (m, o, and n) as well as a recently discovered group, p. each group consists of several subtypes, clades. the various clades display biological differences with respect to transmission, replication, and disease progression. , these differences result in an inability to produce a generalizable vaccine that would induce the breadth of nabs necessary to counter an infection by a wide range of hiv- clades that may be encountered in a natural setting. the degree of diversity seen in hiv- is greater than that of any other virus observed. , this problem is being addressed by development of multiclade (multiple env and/ or subtype b gag, pol, nef) , and mosaic vaccines which incorporate sets of immunogenic proteins from different clades or bivalent proteins from clades b and c. [ ] [ ] [ ] there are proof of principle studies that illustrate immunological protection against hiv- in nonhuman primates that were passively treated with broadly reactive nabs. [ ] [ ] [ ] these studies show that protection against infection with hiv- can be conferred by the presence of broadly reactive nabs. the next step toward production of a prophylactic vaccine would involve induction of production of these or similar broadly reactive nabs by the host's immune system. the rate at which the hiv- virus mutates, due to the nature of the reverse transcriptase enzyme responsible for transcribing its rna, ensures that nearly every daughter virion will have a different genome than its parent. when these changes occur in the hiv- env protein that is needed for antibody recognition, they inhibit the immune system's ability to mount a sufficient response. one attempt to circumvent this problem has been to induce the production of nabs to the conserved regions of hiv- proteins. a major problem with this approach is that the conserved regions of hiv- proteins are often shielded from exposure to nabs within the hiv- envelope. the native structure of the envelope protein, reportedly the only hiv- protein susceptible to nabs, shields it from the immune system as a glycosylated trimer of heterodimers. the glycosylation of the envelope protein allows for the carbohydrates to masquerade as 'self' thereby forming an immunologically silent face and protects neighboring epitopes via an 'evolving glycan shield'. [ ] [ ] [ ] additionally, the gp coreceptor binding site, another conserved site, is not presented until primary binding to cd + has occurred. an attempt to create antibodies to the cd -binding region of the gp protein was made in rhesus macaques in and results indicated that vaccinated hosts were able to withstand challenge with shiv. other attempts to create an hiv- vaccine have focused on overcoming the ability of hiv- to escape immune surveillance through use of antibodies that are able to neutralize diverse isolates of hiv- . these antibodies include pg , pg , f , g , e , b , [ ] [ ] [ ] [ ] and most recently scd - b and others. identification of these antibodies gives hope that their induction or the induction of other such broadly reactive nabs may provide the basis for a prophylactic vaccine in the future. the use of animal models for development of therapeutics offers the benefit of thorough testing and validation prior to introduction of a vaccine in humans. in the past, vaccines were made by observing and then mimicking the immune response mounted by individuals who had recovered from a particular disease. to date, however, there are no known cases of individuals who have recovered from hiv- infection. however, data can be gathered from long-term nonprogressors -patients who have been infected with hiv- for at least years and do not display any hiv- -related symptoms. , another option that may be critical to the development of a prophylactic vaccine is the use of relevant animal models. such models will allow for analysis of the effect of a potential vaccine on an intact host prior to use in humans. one particular challenge with the use of animal models for development of a prophylactic hiv- vaccine is that there are very few naturally occurring disease models of hiv- . only a few nonhuman primates are susceptible to infection with hiv- and infected animals do not progress to aids. therefore, it is important to use other disease models that mimic the hiv-aids pathologic progression. one such potential model is feline immunodeficiency virus (fiv). fiv was discovered in and is known to cause an aids-like disease in domestic cats and mimics hiv-related dementia in humans. a vaccine for fiv was approved by the fda in . while the fiv model is potentially informative, its use is not sufficient as a basis for development of a prophylactic hiv- vaccine. an ideal animal model would display a pathological response to infection with hiv- that is very similar to the one that occurs in humans. unfortunately, hiv- does not cause pathology leading to the development of aids in any host other than humans. [ ] [ ] [ ] [ ] however, animal models have been developed and used that allow partial understanding of the pathology of hiv- , the natural immunological response to infection, and the response of the host to novel therapeutics. one of these models involves the simian immunodeficiency virus mac (siv mac ) that replicates and causes an aids-like disease in baboons, cynomolgus, and pigtailed macaques. while the similarities of siv mac to hiv- have allowed for insight into pathology, transmission, and immunological response of the infected host to the virus, the differences between siv mac and hiv- are still too great to be able to draw conclusions regarding potential human responses to an hiv- prophylactic vaccine. therefore, to broaden the scope of animal model usage, a chimeric shiv virus was engineered to incorporate both siv and hiv- proteins or genes. while macaques infected with shiv do go on to develop aids, the time to progression is much different from the time to progression to aids of hiv- -infected humans. infection of macaques with siv mac strain mimics hiv- infection in humans by leading to chronic, slow disease progression. route and dose required for infection, viral tropism, replicative capacity of the viruses, and pathology of siv/shiv-infected monkeys are all very different than these parameters in humans. , this distinction has been well characterized by the recent phase iib step trial, which involved healthy, uninfected volunteers. the result of this trial was termination at its first scheduled efficacy assessment due to its failure to suppress viral load in subsequently infected individuals and then-suspected increased hiv- infection due to interaction of the immune system with vaccine components. the vaccine, a recombinant adenovirus serotype (ad ) virus incorporating the gag, pol, and nef genes from hiv- , had been previously tested in an shiv model in macaques and the results of that experiment were not suggestive of the results of the human trial. this disparity underscores the need for animal models that more closely reflect the pathology seen in human infection with hiv- as well as identification of immunological correlates of protection that reflect control of hiv- viral load in human subjects. therefore, the search for an appropriate animal model or the appropriate use of current animal models in the search for a prophylactic hiv- vaccine continues. until a model can be derived that will allow for observation of each stage of infection, progression of disease, and response of the immune system in a way that is comparable to this process in humans, we will not be able to logically predict which vaccine candidates should be moved forward to clinical trials. several attempts to stimulate the immune system to provide protection against hiv infection have been attempted so far (table ) . hope for creating a prophylactic vaccine lies in the ability of the scientific community to identify and induce a broad neutralizing antibody response that would offer sterilizing immunity to vaccinated patients. to this end, several novel approaches are being studied. as mentioned in the previous section, there are several daunting problems facing scientists who are attempting to create an hiv- vaccine. in hopes of creating a vaccine which elicits sterilizing immunity to hiv- , researchers have focused their efforts on ( ) the use of plasmid dna vaccines, ( ) live recombinant vectors for vaccine development (expressing or presenting hiv antigens), and ( ) mucosal immunity. these critical topics will be discussed in more detail below. vaccines should elicit a robust immune response that is long lasting and is able to provide protection against various strains of a pathogen. plasmid dna vaccinations can induce a strong humoral and t-cell response. dna-based vaccination has been used as a powerful tool to fight against parasitic, fungal, bacterial, and viral infections. [ ] [ ] [ ] [ ] [ ] there are multiple advantages for using plasmid dna for vaccination: they are generally safe, nontoxic, and through the delivery of a gene encoding important immunogenic epitopes, the dnabased vaccine exploits biosynthetic machinery of the host cell. one such example was in , whereby wolff and colleagues illustrated protein expression after intramuscular (im) injection of plasmid dna into myocytes. despite these promising results, there had been speculation regarding dna vaccination strategies. for example, it was shown that protein production in response to dna plasmids that contained hiv inserts elicited substantial cellular response in mice and nonhuman primates. however, these products were poorly immunogenic in humans. one strategy to improve immune response of the plasmid dna vaccine strategy is by coadministration of dna plasmids coding for cytokines (eg, inf-g, il- , il- , il- , and il- ). [ ] [ ] [ ] [ ] a second strategy which has been utilized to improve plasmid dna vaccination has been the administration of plasmid dna with adjuvants (eg, cpg oligodeoxynucleotides), or the use of dna-delivery systems (eg, microparticles, cochleates, and linear polyenimines). [ ] [ ] [ ] [ ] a third strategy to improve vaccine efficacy involves the coadministration of plasmid dna in combination with viral vectors. for instance, research performed by harari and colleagues in demonstrated that vaccination by means of an hiv- clade c dna prime in combination with a pox vector (nyvac) boost induces a reliable polyfunctional and longlasting anti-hiv t-cell response in human participants. along these same lines, work recently published by jaoko and group demonstrated safety and immunogenicity of a multiclade hiv- ad-based vaccine alone or in combination with a multiclade hiv- dna vaccine in africa. these results also demonstrated that dna priming increased the frequency and magnitude of cellular and humoral responses; however, there was no effect of recombinant ad dosage on immunogenicity endpoints. the previously mentioned dna-delivery strategies have been used in combination with viral vectors or alone by means of a variety of immunization routes (eg, im, intravenous [iv], intradermal [id], intranasal [in] , oral, rectal, or vaginal). in the majority of reported studies, dna vaccines have been administered by the im and/or id routes. however, as it relates to hiv vaccination, mucosal immunity could potentially be an important factor to consider, with mucosal immunity being achieved optimally by in or oral routes of administration. the topic of mucosal immunity will be discussed in more detail in a later section within this review. after immunization, it is assumed that the dna vaccination immunogen is produced in the skeletal muscles, dendritic cells, and macrophages at the site of immunization. however, in adults, the skeletal muscles are not involved in a high level of protein synthesis as compared to the liver. therefore, the delivery of dna to cells, which are capable of high protein synthesis, such as hepatocytes, epithelia cells of the intestines, or salivary pancreas, may result in high levels of protein expression. the hepatocytes express enzymes involved in the formation of intrachain and interchain disulfide bonds required for proper folding and assembly of proteins. in addition, the liver expresses glycosyltranferases, which are essential for synthesis of both n-and o-linked glycan side chains; this may not be the case for other cell types, , the significance of this point being the fact that broadly crossclade nabs such as g recognize glycan moieties on the heavily glycosylated hiv- envelope antigens. , , another advantage of protein expression within the liver is that significantly lower amounts of dna are needed for protein expression of a particular antigen in the hepatocytes vs another cell type. for the immunization of humans, milligram quantities of dna are necessary to achieve adequate levels of immune response. any method whereby there would be a reduction in dna quantity needed to vaccinate humans would provide significant economic advantages. based on the previously mentioned reasons, it is not a surprise that the liver has been exploited extensively as a site for gene delivery due to its ability to produce proteins and glycoproteins. [ ] [ ] [ ] [ ] hydrodynamic delivery is the application of controlled hydrodynamic pressure in capillaries to enhance endothelial and parenchymal cell permeability; this methodology had its inception in the late s with investigations into intravascular injection of plasmid dna solution for gene delivery in whole animals. [ ] [ ] [ ] [ ] hydrodynamic plasmid dna delivery is well tolerated in mice. in , raska and colleagues demonstrated in mice that iv hydrodynamic vaccination with hiv- envelope dna injections resulted in high levels of expression of hiv antigen in the liver. in mice, immunological data illustrated that hydrodynamic administration of hiv- plasmid dna was superior to vaccination with dna by in, id, im, and intrasplenic routes. further results illustrated that after boosting, hydrodynamic vaccination yielded levels of hiv- -specific antibodies that were -fold higher than those elicited by other routes tested. however, this delivery scheme is not feasible in large animals and humans. as an alternative, receptor-mediated dna binding to hepatocytes could be a viable approach. molecules with terminal galactose residues covalently linked to dna are recognized by the hepatocyte-expressed galactosespecific asialoglycoprotein receptor for internalization. this alternative would avoid delivery through the hepatic system and the need for expansion of the blood volume. in addition, galactose-linked dna packaged in delivery vehicles such as liposomes, choleates, or microspheres can be given by oral administration, which would be absorbed by the intestine and ultimately delivered to the hepatic vein. as an additional alternative to hydrodynamic delivery in humans, it might be possible to express hiv antigens in the liver by means of plasmid dna delivery via viral vectors such as the ad. ads have been shown to transduce the liver efficiently in vivo by means of the hexon proteins. , in this regard, production of translation of hiv- proteins primarily in the liver might allow for the production of heavily glycosylated hiv- envelope antigens and thus the production of nabs. prophylactic vaccine for hiv- live recombinant vectors for vaccine development viral vectors are potent inducers of cellular and humoral response. viral vectors can express proteins from bacteria or viral pathogens to vaccinate against infectious diseases. there are several viral vaccine vectors that have been used successfully in models for vaccination. these vectors include alphaviruses, human rhinoviruses (hrvs), ads, picornaviruses, poxviruses, measles viruses, influenza, and vaccinia viruses. , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] each of these vectors has its respective disadvantages and advantages with respect to vaccine development. some advantages of a few of these vectors include their ability to naturally infect a wide variety of cell types and tissues of interest. [ ] [ ] [ ] [ ] [ ] [ ] each respective vector has its own set of disadvantages. for instance, one disadvantage of using the poliovirus or the hrv as a vaccine vector is the insert size limit restriction of these vectors as compared to the large insert size (∼ kb) accommodation of ad vectors. the most common disadvantage of the majority of viral vaccine vectors is reduced vaccine efficacy due to vector preexisting immunity (pei). [ ] [ ] [ ] [ ] [ ] various strategies have been employed to circumvent the problems associated with vector pei. specifically, as it relates to ad vectors, pei is a tremendous problem. of the identified serotypes of ad vectors, human serotypes (ad ) and (ad ) have been the most extensively used for gene therapy protocols. ad has been used for hiv- vaccination protocols, most recently in the step study. as it relates to ad and ad , pei to these vectors may be found in up to % of the american population and up to % of the population of other countries. this ad pei can limit the effectiveness of ad-based vaccinations. [ ] [ ] [ ] to circumvent ad or ad pei, researchers have employed the use of vector chimeras, , use of alternative serotypes, [ ] [ ] [ ] [ ] [ ] [ ] [ ] and the use of nonhuman ads, such as chimpanzee ad. the chimpanzee ad virus was demonstrated to not be significantly neutralized by human sera, which gives chimpanzee ad an advantage for human vaccine development. [ ] [ ] [ ] other strategies have been used to reduce the immune response against ad vectors such as the use of helperdependent ad (hd-ads) vectors, - the use of ad delivery in combination with biochemical modifications such as pegylation, [ ] [ ] [ ] [ ] [ ] [ ] [ ] and the use of vector delivery by means of cell vehicles. , with respect to the hd-ads, these vectors were produced to further increase the safety and cloning capacity of first-generation ad vectors. hd-ads lack ad genes and contain only the packaging signals and end terminal repeats. these vectors were designed to avoid cellular immunity and diminish liver toxicity, thus promoting long-term transgene expression. [ ] [ ] [ ] [ ] the reduced immune response against hd-ads has allowed for transgene expression in mice and baboons for years. , , , this long-term transgene expression could be helpful for antigen production for an hiv vaccine, thus producing an opportunity to have increased protection against hiv, with reduced frequency of vaccinations. although nabs to ad may reduce the immunogenicity of ad -based vectors in animal model systems, their effect on the immunity in subjects with previous ad exposure is still largely unknown. as previously mentioned, the step trial, which tested a merck recombinant ad (rad ) vaccine (encoding hiv- gag, pol, and ne genes), failed to yield protection, either by lowering viral load or by decreasing acquisition of infection. analysis of data from this study aroused speculation that subjects with pre-existing nabs from wild-type ad infection had an increased risk of hiv infection after vaccination. one recent study has shown that there was no causative role for ad -specific cd + t cells in increasing hiv- susceptibility in the merck trial. in this regard, there are multiple studies ongoing to elucidate a concrete finding with respect to the role of ad pei and increased activation of cd + t cells in the mucosal milieu. , recently, there was a report by cheng and colleagues that attempted to characterize the specificity of rad nabs in ad immune subjects and determine the impact of ad exposure on immune responses elicited by ad -based vaccinations. cheng and colleagues reported that rad nabs were directed toward different components of the ad virion, depending on whether the ad infection was natural or from ad-based hiv vaccine trials. for example, ad nabs generated by natural infection are directed primarily to fiber components, while vector exposure elicits responses primarily to capsid proteins other than fiber. nabs elicited by natural infection significantly reduced the cd + and cd + cell responses to hiv gag after dna/rad vaccination. this report concluded that ad nabs differ based on the route of exposure and that previous ad exposure compromises ad vaccine-induced immunity to weak immunogens, such as hiv- gag. these results have a tremendous impact on hiv- vaccine trials and the design of next generation viral vaccine vectors. viral vectors such as ad, influenza, and polio have been used as vaccine vectors for many reasons. one important advantage of these vectors, which makes them attractive, is that they can provide mucosal immunity because they can easily infect the mucosal surfaces as well as act to induce cytokine and chemokine production at the mucosal entry sites. ad, influenza, and polio also have the advantage of being able to be delivered orally, without the use of needles. this is an important fact in developing countries where needle cost is prohibitive to vaccine administration. as it relates to hiv vaccine development, mucosal immunity is a debatable factor to consider. when deciding upon a vaccine agent, the importance of considering if the ultimate goal is to induce systemic immunity, mucosal immunity, or both is worth careful consideration. [ ] [ ] [ ] it is believed that % of hiv- i nfection will occur from heterosexual viral transmission and most of the rest will occur from homosexual or perinatal transmission. although the biology of sexual transmission is poorly understood, it is clear that the essential first step in the infection pathway is the transfer of infectious virus or hiv-infected cells through the mucosal surfaces. after hiv has entered a new host, the hiv or hiv-infected cells will soon encounter susceptible host target cells at the mucosal point of entry where the virus replicates and then invades local lymphatic tissues, initiating systemic hiv infection. on this basis, strong immunity is required to provide a protective immunological barrier at the most common point of entry, the mucosal surfaces of the reproductive tract. due to the compartmentalization of the secretory and systemic immune systems, parenterally administered antigens do not consistently stimulate mucosal immunity. therefore, it is important to consider a vaccine regime that induces mucosal immunity. since cd + ccr + memory t cells are the primary target of hiv infection in the gut and mucosa and rapid depletion of this subset occurs early after infection, , several studies have investigated the role of hiv mucosal immunity. previous studies have demonstrated the importance of a mucosal siv/hiv vaccine producing both strong mucosal antibody and cd + response capable of blocking the escape of virus from the intestinal mucosa into systemic lymphoid organs. , [ ] [ ] [ ] [ ] [ ] however, in other instances, the necessity of exclusive mucosal hiv immunity will be further debated based on the promising results found in a heterologous prime/boost regimen using dna/ . -expressing siv and hiv- transcripts , and modified vaccinia virus ankara (mva/ . )-expressing siv and hiv- transcripts under the control of vaccinia virus early/late promoter. in this case, either id or im dna/mva vaccination was able to provide protection against a intrarectal shiv- . challenge. along these same lines, recently, promising results were found by hessell and colleagues in . hessell and colleagues demonstrated that after an iv administration of monoclonal antibodies f or e to six monkeys followed by a shiv ba-l challenge, five out of six monkeys from either group showed complete protection and sterilizing immunity. a low level of viral replication could not be ruled out for the six monkeys in either group. replicative ad yields a robust immune response at the mucosal sites partly because ad is known to infect and replicate in epithelial cells. [ ] [ ] [ ] [ ] various strategies have been used to achieve mucosal immunity via the oral route. one such strategy embodies the development of replication-defective recombinant ad serotype (ad ) vector. serotype vectors are being currently used because ad has a natural tropism for the gut and causes no pathological disease outside of the gastrointestinal tract. ad vectors are likely to have a preferential tropism for the gut because ad appears to have a resistance to acidic ph and the capsid configuration of long and short fibers allows the ad virus to preferentially infect the gut. , live recombinant vectors for vaccine development engineered to express/present hiv- antigens as previously mentioned, viral vectors are potent inducers of cellular and humoral responses. of note, viral vectors have been practically used for human applications and have progressed treating a variety of disease contexts such as cancer and infectious diseases. [ ] [ ] [ ] [ ] traditional viral vector immunization embodies the concept that the vector uses the host cell machinery to express antigens, which are encoded as transgenes within the viral vector. cellular and humoral immune responses are generated against these antigens. over the last years, several viral vectors have been derived to express hiv- antigens for vaccine purposes. some researchers have taken an alternative approach to conventional transgene expression of antigens by means of viral vectors; this alternative approach embodies the capsid incorporation of antigens. this innovative paradigm is based upon the vector presenting the antigen as a component of the capsid rather than an encoded transgene. incorporation of immunogenic peptides into the vector capsid offers potential advantages. in this regard, the processing of the capsidincorporated antigen via the exogenous pathway should result in a strong humoral response similar to the response provoked by native ad capsid proteins. in this arrangement, potentially, hiv peptide antigens accrue the potent immunostimulatory effects of the native ad vector capsid proteins, which effectively perform an adjuvant function. on this basis, the immune response directed against vector capsid proteins with repetitive vector administration should achieve a booster effect against the incorporated antigen. most importantly, as it relates to hiv infection, this strategy yields the potential of generating antibodies to hiv proteins. recent crystallographic, cryo-electron tomography, and molecular modeling studies have provided valuable insight to molecular surfaces recognized by antibodies as well as assisted in rationale vaccine design of immunogens. [ ] [ ] [ ] [ ] [ ] these structural technologies can also potentially improve the abilities of scientists to advance the antigen capsidincorporation strategy. if the antigen capsid incorporation is effective, it can provide a way forward with respect to inducing sterilizing immunity. , , the antigen capsid-incorporation strategy has been used for ad-based vaccines in the context of many diseases. , [ ] [ ] [ ] [ ] [ ] one of the first examples where the antigen capsid-incorporation strategy was used was with research performed by crompton in . crompton and colleagues inserted an eight-amino acid sequence of the vp capsid protein of poliovirus type into two regions of the ad serotype hexon. one of the chimeric vectors produced grew well in tissue culture. in addition, antiserum raised against the ad with the polio insert specifically recognized the vp capsid of polio type . as it relates to ad serotype, wu and group demonstrated that his epitopes could be incorporated into ad hexon hypervariable regions (hvrs) - (now reclassified as - ) without perturbing viral viability and any major biological characteristics such as replication, thermostability, or native infectivity. this study by wu and colleagues demonstrated that his appeared to be surface exposed at these regions. with respect to peptide incorporation within ad hexon, hvr and hvr appear to be the most promising locales for peptide/antigen incorporation based on x-ray and peptide analyses along with molecular studies. our laboratory and others have focused on incorporations at hvr or single-site incorporations (such as fiber and pix). , - -, , , however, we recognized that the ability to place antigen within multiple sites of the ad capsid protein would hold important potential for presenting multiple epitopes/ antigens or several copies of the same epitope within a single ad vector-based vaccine. in an effort to create multivalent hiv vaccine vectors, our study explored the use of ad hvr and hvr in hopes of creating vectors which contained hiv antigenic epitopes at both locales. to compare the flexibility and capacities of ad hvr and hvr , we genetically incorporated identical epitopes of incrementally increasing size within hvr or hvr of ad hexon. we incorporated identical epitopes ranging from to amino acids within the ad hexon hvr or hvr region. viable viruses were produced with incorporations of amino acids plus a -amino acid linker at hvr or hvr . in addition, viable viruses were produced with incorporations of up to amino acids plus a -amino acid linker at hvr . with respect to identical antigen incorporations at ad hvr or hvr , hvr was more permissive allowing an epitope incorporation of amino acids in total. these model antigens were surface exposed via elisa analysis. in vivo immunization with these vectors illustrated an antigen-specific immune response. along these same lines, abe and colleagues evaluated the ability of ad -based vectors expressing an hiv transgene to induce antigen-specific immune responses under ad preimmune conditions. to overcome limitations that are generally experienced as a result of pei to ad , they constructed vectors that have a modification in the hvr . their study characterized various immunological parameters generated by these vectors such as vector neutralization, acquisition of adaptive immune response, and comparison of protective immunity. first, in order to evaluate the utility of the modified ad vector, they measured the neutralizing activity of sera by a modified ad vector. they administered ad-luc (luciferase protein expressed as a transgene in the ad e region), ad-hisluc (his epitope presented in hvr region and luciferase protein expressed as a transgene), or ad-end/ aaaluc vector (containing three amino acid mutations in hvr and expressing luciferase protein) to mice im. after administration of these vectors, neutralizing activity against ad was observed for - weeks. the hexon-modified vector (ad-hisluc) generated the lowest ad -specific neutralizing activity, which was significantly lower than what was generated by ad-luc at weeks and , and by ad-end/aaaluc vector at week . the individual neutralizing activity of ad-hisluc immunization was significantly lower than that of ad-luc immunization. additional studies performed by abe and colleagues support the concept that modified hexon thwarts ad nabs and promotes cellular immune responses. studies performed by this research group indicate that a change in the immunogenic epitope is necessary to avoid neutralization by pre-existing nabs. our recently published work exploits the antigen capsidincorporation strategy for hiv vaccination. our novel vectors were constructed in hopes of moving toward the goal of creating vectors that will provide cellular and humoral hiv immunity. our study is the first of its kind to genetically incorporate an hiv antigen within the ad hexon hvr alone or in combination with genomic incorporation of a gag transgene (ad /hvr -mper-l (gag)). in this study, we successfully incorporated a -amino acid epitope of hiv- within hvr . the hiv- region selected for hvr incorporation was the membrane proximal ectodomain region (mper) derived from hiv- glycoprotein (gp ). our rationale for choosing a portion of the mper (eknekel-leldkwaslwnwfditn) derived from gp was based on the fact that the gp envelope protein ectodomain is a target of three broadly neutralizing anti-hiv- antibodies. when the mper was incorporated into hvr in combination with transgene expression, we observed growth kinetics and thermostability changes similar to those of other capsid-incorporated vectors generated in other studies, , indicating that incorporation of the mper epitope within hvr was not dramatically detrimental to virological characteristics. , in addition, we demonstrated that the mper epitope is surface exposed within hvr . most importantly, we observed a humoral anti-hiv response in mice vaccinated with the hexon-modified vector. the mper-modified vector allows boosting compared to adcmvgag, possibly because the ad /hvr -mper-l (gag) ad elicits less anti-ad immune response. it is possible that the mper epitope reduced the immunogenicity of the ad vector. this finding is noteworthy because hvr has not been fully explored for antigen capsid-incorporation strategies. these vectors are currently being analyzed by cryo-electron microscopic analysis to determine the critical correlates related to antigen placement/configuration and immune response. in addition, with respect to hiv- vaccination, the antigen capsid-incorporation strategy has been evaluated within the context of hrv. research groups have constructed human rhinovirus:hiv- chimeras in an effort to stimulate immunity against hiv- . , in an effort to develop hiv- vaccines, researchers within this same group generated combinatorial libraries of hrv capsid-incorporated hiv- gp epitope. their results indicated that they were successful in eliciting antibodies whose activity can mimic the nab effect. commercial and clinical ad development of hiv- vaccines have progressed preferentially more than vector systems such as hrv because the flexibility of ad generally exceeds current rhinovirus systems. for example, because hrv is a relatively small rna virus, the hrv platform can display an array limited to copies of a single hiv- epitope. , in contrast, the ad vector platform allows incorporation of the hiv- mper epitope into three structurally distinct locales, including hvr , hvr , and protein ix (our unpublished data). in comparison, the ad mper antigen capsid-incorporation display platform could present an array of hiv- epitope copies within ad hexon and hiv- epitope copies within pix. if a multivalent ad vector is generated with hiv- epitopes within the hexon and the pix locales, this would represent hiv epitopes within one ad vector. another significant difference between the ad and hrv platforms is in the number of locales that have been successfully used for heterologous epitope insertion. finally, in contrast to the rhinovirus that lacks this capacity, the ad platform has sufficient coding capacity allowing for hiv- transgene expression in combination with presenting the same or a different antigen on the viral capsid surface. this latter finding is important because it provides the basis for constructing vectors that will provide cellular and humoral hiv- immunity. vectors which provide both cellular and humoral immunity may be the way forward with respect to prophylactic hiv vaccine development. recently, there have been encouraging developments regarding hiv vaccination. in the s, in thailand, there was a substantial increase in the prevalence of infection with hiv- . [ ] [ ] [ ] by first observation, these groups consisted of intravenous-drug users and commercial sex workers; this infected group then expanded to the general population. by the mid s, the overall seroprevalence of hiv- reached a peak of . % among members of the royal thai army and of . % among people from northern thailand. , the thai ministry of public health acted by starting an effective hiv-prevention campaign. with this effort, the number of new hiv- infections per year decreased from an estimated , in to , in . , [ ] [ ] [ ] although this decrease was promising, there was still a desire to do more to prevent hiv infection. to achieve this goal, an hiv phase iii study was begun. the thai phase iii hiv vaccine study, also known as rv , opened in the fall of . the placebo-controlled trial tested the safety and effectiveness of a prime-boost regimen of two vaccines: alvac-hiv vaccine (the prime), a modified canarypox vaccine, and aidsvax b/e vaccine (booster), a gp vaccine. the vaccines were based on the subtype e and b hiv- strains that commonly circulate in thailand. the subtype b hiv- strain is the most commonly found strain in the united states. the trial, conducted in the chonburi and rayong provinces of thailand, enrolled , women and men aged - years at various levels of risk for hiv infection. study participants received the placebo or alvac hiv vaccine at enrollment and again after , , prophylactic vaccine for hiv- and months. the placebo or aidsvax b/e vaccine was given to participants at and months. participants were tested for hiv- infection every months for years. during each clinic visit, study participants were counseled on how to prevent hiv- infection. the results showed that of placebo recipients became infected with hiv- compared with of participants who received the vaccine. this level of effectiveness in preventing hiv- infection was found to be statistically significant. the vaccine strategy had no effect, however, on the amount of virus in the blood of volunteers who acquired hiv- infection during the study. based on the final analysis of the study, the surgeon general of the us army, the trial sponsor, announced that the prime-boost investigational vaccine regimen was safe and % effective in preventing hiv- infection. with respect to an hiv- vaccine that can provide sterilizing hiv immunity, this is the best result in humans to date. however, the modest protection effect appeared limited to low-risk individuals, and there were data which suggest that this effect was confined to the first year following administration of the vaccine. efforts must continue to focus on evaluating the immune response induced by the vaccine to establish potential correlates of protection. over the last three decades, the world has been faced with the emergence and subsequent epidemic of hiv/aids. there has been much progress with respect to diagnosis and prevention. on the treatment front, there have been several significant advances with respect to drug development (ie, art/haart). however, there is a desperate need for an effective and safe vaccine. there has been tremendous difficulty with regard to developing a vaccine that provides sterilizing immunity. this has been the case due to some of the factors mentioned in this review such as hiv diversity, immune evasion, and lack of appropriate animal models. due to these obstacles, many researchers assumed that the control of hiv- viremia by vaccination would be a more realistic goal than the development of sterilizing immunity. the road to a safe and effective hiv- vaccine received a serious setback in the fall of with the premature termination of the merck-hiv- vaccine step trial due to the lack of efficacy and early speculation that the vaccine might have increased the risk of hiv infection in some populations of vaccinees. in late , promising results came in from thailand in response to their efforts to create a safe and effective vaccine against hiv- . a community-based, randomized, multicenter, double-blinded, placebo-controlled efficacy trial using a prime-boost combination showed % effectiveness in preventing hiv- infection. these results lend promise to the hope of producing an hiv- vaccine vector that yields sterilizing hiv- immunity. in the future, research scientists must work together to increase hiv- vaccine effectiveness beyond %. realization of this goal may be accomplished by some of the techniques mentioned in this review, such as acquisition of hiv mucosal immunity, development of effective prime-boost strategies, development of better animal models, better molecular antigen modeling and presentation, avoidance of pei (by the means of using novel vector serotypes in combination with pegylation), and/or induction of nabs (by means of capsid incorporation of hiv antigens within viral vectors). these are just a few considerations that scientists and clinicians must consider with respect to the development of an effective and safe hiv- vaccine. scientists and clinicians must also consider that one vector or scheme may not be sufficient with respect to providing effective hiv- immunity and some combination of the above-mentioned potential strategies may offer the most promising method of producing an effective hiv- prophylactic vaccine. submit your manuscript | www.dovepress.com dovepress dovepress report on the global aids epidemic adherence to antiretroviral therapy: a survey of factors associated with medication usage lipodystrophy, metabolic disorders, and human immunodeficiency virus infection: aquitaine cohort, france, . groupe d'epidemiologie clinique du syndrome d'immunodeficience acquise en aquitaine a syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with hiv nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virus-infected individuals the latent hiv- reservoir in patients undergoing haart: an archive of pre-haart drug resistance mucosal immunity to hiv: a review of recent literature hiv vaccine design and the neutralizing antibody problem aids/hiv. developing an aids vaccine: need, uncertainty, hope hiv- vaccine development: progress and prospects t cell vaccines for microbial infections the failed hiv merck vaccine study: a step back or a launching point for future vaccine development? protection by attenuated simian immunodeficiency virus in macaques against challenge with virus-infected cells rapid development of vaccine protection in macaques by live-attenuated simian immunodeficiency virus long-term symptomless hiv- infection in recipients of blood products from a single donor genetic instability of live, attenuated human immunodeficiency virus type vaccine strains update on long-term symptomless hiv type infection in recipients of blood products from a single donor hiv vaccines: new frontiers in vaccine development placebo-controlled phase trial of a recombinant glycoprotein vaccine to prevent hiv- infection correlation between immunologic responses to a recombinant glycoprotein vaccine and incidence of hiv- infection in a phase hiv- preventive vaccine trial lessons from failure -preparing for future hiv- vaccine efficacy trials randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein hiv- vaccine among injection drug users in global and regional distribution of hiv- genetic subtypes and recombinants in a new human immunodeficiency virus derived from gorillas preferential in-utero transmission of hiv- subtype c as compared to hiv- subtype a or d cell reservoirs in lymph nodes infected with hiv- subtype e differ from subtype b: identification by combined in situ polymerase chain reaction and immunohistochemistry different rates of disease progression of hiv type infection in tanzania based on infecting subtype relation between chemokine receptor use, disease stage, and hiv- subtypes a and d: results from a rural ugandan cohort escape artist par excellence genetic subtypes, humoral immunity, and human immunodeficiency virus type vaccine development viral sequence diversity: challenges for aids vaccine designs standardized assessment of nab responses elicited in rhesus monkeys immunized with single-or multi-clade hiv- envelope immunogens a phase / study of a multiclade hiv- dna plasmid prime and recombinant adenovirus serotype boost vaccine in hiv-uninfected east africans (rv ) mosaic vaccines elicit cd (+) t lymphocyte responses that confer enhanced immune coverage of diverse hiv strains in monkeys hiv vaccines: mosaic approach to virus diversity mosaic hiv- vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys antibody protects macaques against vaginal challenge with a pathogenic r simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro human neutralizing monoclonal antibodies of the igg subtype protect against mucosal simian-human immunodeficiency virus infection protection of macaques against vaginal transmission of a pathogenic hiv- /siv chimeric virus by passive infusion of neutralizing antibodies evolutionary and immunological implications of contemporary hiv- variation the antigenic structure of the hiv gp envelope glycoprotein structure of an hiv gp envelope glycoprotein in complex with the cd receptor and a neutralizing human antibody antibody neutralization and escape by hiv- cell entry by enveloped viruses: redox considerations for hiv and sars-coronavirus antibodies to cd -induced sites in hiv gp correlate with the control of shiv challenge in macaques vaccinated with subunit immunogens broad and potent neutralizing antibodies from an african donor reveal a new hiv- vaccine target efficient neutralization of primary isolates of hiv- by a recombinant human monoclonal antibody. science a conserved neutralizing epitope on gp of human immunodeficiency virus type a potent cross-clade neutralizing human monoclonal antibody against a novel epitope on gp of human immunodeficiency virus type cross-clade neutralization of primary isolates of human immunodeficiency virus type by human monoclonal antibodies and tetrameric cd -igg scd - b bifunctional protein: extremely broad and potent neutralization of hiv- env pseudotyped viruses from genetically diverse primary isolates analysis of memory b cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from hiv- -infected individuals long-term nonprogression in hiv infection: methodological issues and scientific priorities the immunology of hiv-infected long-term nonprogressors-a current view long-term observations of human immunodeficiency virus-infected chimpanzees simian and feline immunodeficiency viruses: animal lentivirus models for evaluation of aids vaccines and antiviral agents the feline model of neuroaids: understanding the progression towards aids dementia feline immunodeficiency virus model for designing hiv/aids vaccines human immunodeficiency virus infection of human-pbl-scid mice suppression of hiv infection in azt-treated scid-hu mice disseminated and sustained hiv infection in cd + cord blood cell-transplanted rag -/-gamma c-/-mice animal models of aids infection of cynomolgus monkeys with a chimeric hiv- /sivmac virus that expresses the hiv- envelope glycoproteins a chimeric simian/human immunodeficiency virus expressing a primary patient human immunodeficiency virus type isolate env causes an aids-like disease after in vivo passage in rhesus monkeys highly pathogenic shivs and sivs target different cd + t cell subsets in rhesus monkeys, explaining their divergent clinical courses efficacy assessment of a cell-mediated immunity hiv- vaccine (the step study): a doubleblind, randomised, placebo-controlled, test-of-concept trial replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity importance of the nef gene for maintenance of high virus loads and for development of aids protective effects of a live attenuated siv vaccine with a deletion in the nef gene molecular and biological characterization of simian immunodeficiency virus macaque strain h proviral clones containing nef size variants macaques infected with live attenuated sivmac are protected against superinfection via the rectal mucosa immunization with a live, attenuated simian immunodeficiency virus (siv) prevents early disease but not infection in rhesus macaques challenged with pathogenic siv live, attenuated simian immunodeficiency virus sivmac-m , with point mutations in the env transmembrane protein intracytoplasmic domain, provides partial protection from mucosal challenge with pathogenic sivmac protection of macaques against simian immunodeficiency virus infection with inactivated vaccines: comparison of adjuvants, doses and challenge viruses. the european concerted action on 'macaque models for aids research' whole inactivated siv vaccine grown on human cells fails to protect against homologous siv grown on simian cells protection of monkeys by a split vaccine against sivmac depends upon biological properties of the challenge virus dual-subtype vaccine (fel-o-vax fiv) protects cats against contact challenge with heterologous subtype b fiv infected cats dual-subtype fiv vaccine protects cats against in vivo swarms of both homologous and heterologous subtype fiv isolates effect of dual-subtype vaccine against feline immunodeficiency virus infection dual-subtype fiv vaccine (fel-o-vax fiv) protection against a heterologous subtype b fiv isolate efficacy testing of recombinant human immunodeficiency virus (hiv) gp as a therapeutic vaccine in early-stage hiv- -infected volunteers. rgp hase ii vaccine investigators randomised trial of mnrgp hiv- vaccine in symptomless hiv- infection phase ii controlled trial of post-exposure immunization with recombinant gp versus antiretroviral therapy in asymptomatic hiv- -infected adults. vaxsyn protocol team repeated immunization with recombinant gp human immunodeficiency virus (hiv) envelope protein in early hiv- infection: evaluation of the t cell proliferative response a phase i evaluation of the safety and immunogenicity of vaccination with recombinant gp in patients with early human immunodeficiency virus infection. military medical consortium for applied retroviral research two double-blinded, randomized, comparative trials of human immunodeficiency virus type (hiv- ) envelope vaccines in hiv- -infected individuals across a spectrum of disease severity: aids clinical trials groups a nd a randomized, placebocontrolled study of the immunogenicity of human immunodeficiency virus (hiv) rgp vaccine in hiv-infected subjects with . or = / mm cd t lymphocytes improved cell-mediated immune responses in hiv- -infected asymptomatic individuals after immunization with envelope glycoprotein gp immunization with envelope mn rgp vaccine in human immunodeficiency virus-infected pregnant women immunogenicity of the yeast recombinant p /p :ty virus-like particles (p -vlp) in healthy volunteers immunization with recombinant p /p :ty virus-like particles in human immunodeficiency virus-infected persons safety and immunogenicity of a candidate therapeutic vaccine, p virus-like particle, combined with zidovudine, in asymptomatic subjects therapeutic vaccination with p -vlp and zidovudine augments hiv-specific cytotoxic t lymphocyte activity in asymptomatic hiv-infected individuals induction of potent humoral and cell-mediated immune responses following direct injection of dna encoding the hiv type env and rev gene products retroviral vectors for vaccine development: induction of hiv- -specific humoral and cellular immune responses in rhesus macaques using a novel mlv(hiv- ) pseudotype vector a single administration of lentiviral vectors expressing either full-length human immunodeficiency virus (hiv- )(hxb ) rev/env or codon-optimized hiv- (jr-fl) gp generates durable immune responses in mice rabies virus-based vaccines elicit neutralizing antibodies, poly-functional cd + t cell, and protect rhesus macaques from aids-like disease after siv(mac ) challenge highly attenuated rabies virus-based vaccine vectors expressing simian-human immunodeficiency virus . p env and simian immunodeficiency virusmac gag are safe in rhesus macaques and protect from an aids-like disease protection of rhesus monkeys against infection with minimally pathogenic simian-human immunodeficiency virus: correlations with neutralizing antibodies and cytotoxic t cells vaccination with alvac and aidsvax to prevent hiv- infection in thailand vector-mediated gene transfer engenders long-lived neutralizing activity and protection against siv infection in monkeys enhancement of humoral immunity to sivenv following simultaneous inoculation of mice by three recombinant adenoviruses encoding sivenv/poliovirus chimeras, tat and rev replication-defective adenovirus serotype vectors elicit durable cellular and humoral immune responses in nonhuman primates adenovirus vectored vaccines replication-deficient recombinant adenoviruses expressing the human immunodeficiency virus env antigen can induce both humoral and ctl immune responses in mice multi-envelope hiv- vaccine devoid of siv components controls disease in macaques challenged with heterologous pathogenic shiv cytotoxic t lymphocyte and antibody responses generated in rhesus monkeys immunized with retroviral vector-transduced fibroblasts expressing human immunodeficiency virus type- iiib env/rev proteins evaluation of a self-inactivating lentiviral vector expressing simian immunodeficiency virus gag for induction of specific immune responses in vitro and in vivo chimaeric hiv- subtype c gag molecules with large in-frame c-terminal polypeptide fusions form virus-like particles optimization of chimeric hiv- virus-like particle production in a baculovirus-insect cell expression system increased incorporation of chimeric human immunodeficiency virus type gp proteins into pr gag virus-like particles by an epstein-barr virus gp / -derived transmembrane domain recombinant human immunodeficiency pr gag virus-like particles presenting chimeric envelope glycoproteins induce cytotoxic t-cells and neutralizing antibodies development of hiv/aids vaccine using chimeric gag-env virus-like particles dna vaccines induction of gp -specific protective immune responses by genetic vaccination with linear polyethylenimine-plasmid complex dna vaccines: a review comparison of protective effect of protein and dna vaccines hsp in murine model of systemic candidiasis dna vaccines against human immunodeficiency virus type in the past decade direct gene transfer into mouse muscle in vivo enhancement of human immunodeficiency virus type -dna vaccine potency through incorporation of t-helper molecular adjuvants modulation of cellular and humoral immune responses to a multiepitopic hiv- dna vaccine by interleukin- dna immunization/ viral protein boost evaluation in macaques of hiv- dna vaccines containing primate cpg motifs and fowlpoxvirus vaccines co-expressing ifngamma or il- augmentation and suppression of immune responses to an hiv- dna vaccine by plasmid cytokine/ig administration cell-specific delivery of genes with glycosylated carriers organspecific gene expression in the rhesus monkey eye following intravenous non-viral gene transfer systemic linear polyethylenimine (l-pei)-mediated gene delivery in the mouse targeted gene delivery to cancer cells: directed assembly of nanometric dna particles coated with folic acid an hiv- clade c dna prime, nyvac boost vaccine regimen induces reliable, polyfunctional, and long-lasting t cell responses safety and immunogenicity study of multiclade hiv- adenoviral vector vaccine alone or as boost following a multiclade hiv- dna vaccine in africa differential effect of lentil feeding on proteosynthesis rates in the large intestine, liver and muscle of rats delivery of dna hiv- vaccine to the liver induces high and long-lasting humoral immune responses immunopathogenesis and immunotherapy in aids virus infections a role for carbohydrates in immune evasion in aids electrically mediated plasmid dna delivery to hepatocellular carcinomas in vivo tail-vein injection of mannan-binding lectin dna leads to high expression levels of multimeric protein in liver mechanism of plasmid delivery by hydrodynamic tail vein injection. ii. morphological studies mechanism of plasmid delivery by hydrodynamic tail vein injection. i. hepatocyte uptake of various molecules the efficient expression of intravascularly delivered dna in rat muscle hydrodynamics-based transfection in animals by systemic administration of plasmid dna high levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid dna hydrodynamic gene delivery: its principles and applications the asialoglycoprotein receptor: relationships between structure, function, and expression synthesis of antisense oligonucleotides conjugated to a multivalent carbohydrate cluster for cellular targeting adenovirus serotype hexon mediates liver gene transfer adenovirus serotype hexon is critical for virus infection of hepatocytes in vivo viral vectors for malaria vaccine development human rhinovirus type :human immunodeficiency virus type (hiv- ) v loop chimeras from a combinatorial library induce potent neutralizing antibody responses against hiv- broad neutralization of human immunodeficiency virus type (hiv- ) elicited from human rhinoviruses that display the hiv- gp eldkwa epitope use of adenovirus in vaccines for hiv development of nonhuman adenoviruses as vaccine vectors poliovirus vaccine strains as mucosal vaccine vectors and their potential use to develop an aids vaccine control of a mucosal challenge and prevention of aids by a multiprotein dna/mva vaccine recombinant poxviruses as mucosal vaccine vectors induction of neutralizing antibody responses to anthrax protective antigen by using influenza virus vectors: implications for disparate immune system priming pathways subcutaneous administration of a recombinant vaccinia virus vaccine expressing multiple envelopes of hiv- an adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism targeted adenoviral vectors viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics live attenuated measles vaccine as a potential multivalent pediatric vaccination vector infection of monocytes during measles vaccinology, immunology, and comparative pathogenesis of measles in the quest for a preventative against aids preexisting immunity to poliovirus does not impair the efficacy of recombinant poliovirus vaccine vectors strategies to overcome host immunity to adenovirus vectors in vaccine development neutralizing antibodies to adenovirus serotype vaccine vectors are directed primarily against the adenovirus hexon protein construction and characterization of adenovirus serotype packaged by serotype hexon hexon-chimaeric adenovirus serotype vectors circumvent pre-existing anti-vector immunity immune responses to adenovirus and adeno-associated virus in humans the impact of developmental stage, route of administration and the immune system on adenovirus-mediated gene transfer circumventing the immune response to adenovirus-mediated gene therapy hexon gene switch strategy for the generation of chimeric recombinant adenovirus sero-switch' adenovirusmediated in vivo gene transfer: circumvention of anti-adenovirus humoral immune defenses against repeat adenovirus vector administration by changing the adenovirus serotype circumvention of vectorspecific neutralizing antibody response by alternating use of human and non-human adenoviruses: implications in gene therapy generation of a novel replication-incompetent adenoviral vector derived from human adenovirus type : manufacture on per.c cells, tropism and immunogenicity dependence of adenovirus infectivity on length of the fiber shaft domain adenovirus type virions contain two distinct fibers human adenovirus type contains two fibers structure-based identification of a major neutralizing site in an adenovirus hexon characterization of a family of chimpanzee adenoviruses and development of molecular clones for gene transfer vectors replication-defective vector based on a chimpanzee adenovirus chimpanzee adenovirus vaccine protects against zaire ebola virus efficient flpe recombinase enables scalable production of helper-dependent adenoviral vectors with negligible helper-virus contamination high-capacity, helperdependent, 'gutless' adenoviral vectors for gene transfer into brain regulatable gutless adenovirus vectors sustain inducible transgene expression in the brain in the presence of an immune response against adenoviruses immunization against the transgene but not the teton switch reduces expression from gutless adenoviral vectors in the brain comparison of replicationcompetent, first generation, and helper-dependent adenoviral vaccines protection against mucosal shiv challenge by peptide and helper-dependent adenovirus vaccines effects of shielding adenoviral vectors with polyethylene glycol (peg) on vector-specific and vaccine-mediated immune responses pegylated adenovirus for targeted gene therapy development of pegylated adenovirus vector with targeting ligand neutralizing antibody evasion ability of adenovirus vector induced by the bioconjugation of methoxypolyethylene glycol succinimidyl propionate (mpeg-spa) pegylated adenovirus vectors containing rgd peptides on the tip of peg show high transduction efficiency and antibody evasion ability evaluation of polyethylene glycol modification of first-generation and helper-dependent adenoviral vectors to reduce innate immune responses pegylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile vaccination against hepatitis c virus with dendritic cells transduced with an adenovirus encoding ns protein cell vehicle targeting strategies current strategies and future directions for eluding adenoviral vector immunity factors influencing therapeutic efficacy and the host immune response to helper-dependent adenoviral gene therapy in hemophilia a mice elimination of innate immune responses and liver inflammation by pegylation of adenoviral vectors and methylprednisolone administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons baseline ad serostatus does not predict ad hiv vaccine-induced expansion of adenovirusspecific cd + t cells translational mini-review series on vaccines for hiv: t lymphocyte trafficking and vaccine-elicited mucosal immunity route of adenovirus-based hiv- vaccine delivery impacts the phenotype and trafficking of vaccine-elicited cd + t lymphocytes differential specificity and immunogenicity of adenovirus type neutralizing antibodies elicited by natural infection or immunization distribution of poliovirus antibody in serum, nasopharynx and alimentary tract following segmental immunization of lower alimentary tract with poliovaccine local antibody response to experimental poliovirus infection in the central nervous system of rhesus monkeys strategies for optimizing targeting and delivery of mucosal hiv vaccines primary hiv- infection is associated with preferential depletion of cd + t lymphocytes from effector sites in the gastrointestinal tract cd + t cell depletion during all stages of hiv disease occurs predominantly in the gastrointestinal tract mucosal aids vaccine reduces disease and viral load in gut reservoir and blood after mucosal infection of macaques impact of vaccineinduced mucosal high-avidity cd + ctls in delay of aids viral dissemination from mucosa a novel functional ctl avidity/activity compartmentalization to the site of mucosal immunization contributes to protection of macaques against simian/human immunodeficiency viral depletion of mucosal cd + t cells intranasal immunization is superior to vaginal, gastric, or rectal immunization for the induction of systemic and mucosal anti-hiv antibody responses prophylactic vaccine for hiv- comparison of the oral, rectal, and vaginal immunization routes for induction of antibodies in rectal and genital tract secretions of women nucleocapsid protein zinc-finger mutants of simian immunodeficiency virus strain mne produce virions that are replication defective in vitro and in vivo an internalization signal in the simian immunodeficiency virus transmembrane protein cytoplasmic domain modulates expression of envelope glycoproteins on the cell surface broadly neutralizing monoclonal antibodies f and e directed against the human immunodeficiency virus type gp membrane-proximal external region protect against mucosal challenge by simian-human immunodeficiency virus shivba-l immunogenicity of recombinant human adenovirus-human immunodeficiency virus vaccines in chimpanzees long-term protection of chimpanzees against high-dose hiv- challenge induced by immunization protection against mucosal simian immunodeficiency virus siv(mac ) challenge by using replicating adenovirus-siv multigene vaccine priming and subunit boosting evaluation of combination dna/replication-competent ad-siv recombinant immunization regimens in rhesus macaques novel adenovirus vaccine vectors based on the enteric-tropic serotype human viral gastroenteritis unique physicochemical properties of human enteric ad responsible for its survival and replication in the gastrointestinal tract human enteric adenovirus type (tak) contains a second fiber protein gene adenovirus-based primeboost immunization for rapid vaccination against anthrax development of a preventive vaccine for ebola virus infection in primates adenoviral expression of a truncated s subunit of sars-cov spike protein results in specific humoral immune responses against sars-cov in rats adenoviruses as vectors for hiv vaccines characterization of a permissive epitope insertion site in adenovirus hexon challenges for structure-based hiv vaccine design designing immunogens to elicit broadly neutralizing antibodies to the hiv- envelope glycoprotein rational antibody-based hiv- vaccine design: current approaches and future directions molecular architecture of native hiv- gp trimers structural definition of a conserved neutralization epitope on hiv- gp one step forwards, one step back prospects for vaccine protection against hiv- infection and aids modification to the capsid of the adenovirus vector that enhances dendritic cell infection and transgene-specific cellular immune responses protection against p. aeruginosa with an adenovirus vector containing an oprf epitope in the capsid optimization of capsid-incorporated antigens for a novel adenovirus vaccine approach epitopes expressed in different adenovirus capsid proteins induce different levels of epitope-specific immunity expression of a foreign epitope on the surface of the adenovirus hexon identification of sites in adenovirus hexon for foreign peptide incorporation structural and phylogenetic analysis of adenovirus hexons by use of high-resolution x-ray crystallographic, molecular modeling, and sequence-based methods protective immunity to pseudomonas aeruginosa induced with a capsid-modified adenovirus expressing p. aeruginosa oprf rgd inclusion in the hexon monomer provides adenovirus type -based vectors with a fiber knob-independent pathway for infection adenovirus type with modified hexons induces robust transgene-specific immune responses in mice with pre-existing immunity against adenovirus type structure and mechanistic analysis of the anti-human immunodeficiency virus type antibody f in complex with its gp epitope genetic incorporation of a herpes simplex virus type thymidine kinase and firefly luciferase fusion into the adenovirus protein ix for functional display on the virion derivation of a triple mosaic adenovirus based on modification of the minor capsid protein ix genetic incorporation of hsv- thymidine kinase into the adenovirus protein ix for functional display on the virion hiv antigen incorporation within adenovirus hexon hypervariable for a novel hiv vaccine approach use of random systematic mutagenesis to generate viable human rhinovirus chimeras displaying human immunodeficiency virus type v loop sequences drug design, development and therapy the asian epidemic model: a process model for exploring hiv policy and programme alternatives in asia hiv/aids prevention in thailand: success and challenges the epidemiology of hiv infection and aids in thailand preventive hiv vaccine development in thailand impact of thailand's hiv-control programme as indicated by the decline of sexually transmitted diseases risk factors for hiv infection among young adult men in northern thailand hiv/aids preventive vaccine 'prime-boost' phase iii trial: foundations and initial lessons learned from thailand grant support was provided by national institutes of health grants r ai - , p ai - a , and p ca - s . we thank erin e thacker for her thoughtful insight. the authors report no conflicts of interest in this work. submit your manuscript here: http://www.dovepress.com/drug-design-development-and-therapy-journal drug design, development and therapy is an international, peerreviewed open-access journal that spans the spectrum of drug design and development through to clinical applications. clinical outcomes, patient safety, and programs for the development and effective, safe, and sustained use of medicines are a feature of the journal, which has also been accepted for indexing on pubmed central. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. key: cord- -t eccng authors: frimpong, shadrack; paintsil, elijah title: a case for girl-child education to prevent and curb the impact of emerging infectious diseases epidemics date: - - journal: yale j biol med doi: nan sha: doc_id: cord_uid: t eccng not only do epidemics such as hiv/aids, ebola virus disease (evd), and the current coronavirus disease (covid- ) cause the loss of millions of lives, but they also cost the global economy billions of dollars. consequently, there is an urgent need to formulate interventions that will help control their spread and impact when they emerge. the education of young girls and women is one such historical approach. they are usually the vulnerable targets of disease outbreaks – they are most likely to be vehicles for the spread of epidemics due to their assigned traditional roles in resource-limited countries. based on our work and the work of others on educational interventions, we propose six critical components of a cost-effective and sustainable response to promote girl-child education in resource-limited settings. "study after study has taught us that there is no tool for development more effective than the education of girls. no other policy is as likely to raise economic productivity, lower infant and maternal mortality, or improve nutrition and promote health -including the prevention of hiv/aids." kofi a. annan, former secretary-general, united nations [ ] . as it has been the case of hiv/aids and, most recently, the ebola virus disease (evd), the ongoing coro-navirus disease (covid- ) is a stark reminder of a painful reality: epidemics will continue to be the bane of human existence. consequently, there is an urgent need to critically assess the literature of approaches that have previously mitigated outbreaks and design robust interventions to fight these emerging outbreaks. one such method is the education of young people, especially girls and women. the fact that education is an essential social determinant of health has been well documented [ ] . early childhood education provides access to higher-income earning potentials, reducing one's likelihood of getting infected by disease during an epidemic [ ] . the benefits of education in improving health outcomes are high in children and young people, who often depend on their parents and guardians for their livelihoods, including financial resources to access education [ , ] . for instance, a study in ghana found that the higher the level of education a mother has, the better the child's chances of survival [ ] . also, according to unicef, young boys and girls who have higher education levels usually have more knowledge about infectious diseases, are less likely to get infected, and tend to adopt behaviors and attitudes that prevent them from being infected [ ] . these health-related benefits of education become even more critical in epidemics such as hiv/aids and evd. indeed, several studies from around the world have confirmed that hiv infection rates are at least twice as high among adolescents who drop out of primary school than those who stay in school [ ] . the west african evd outbreak killed over , people, left many children orphaned, and exposed to malnutrition, hunger, and preventable deaths [ ] . deeply affected by the negative repercussions of the lack of quality education, young girls and women in low-and middle-income countries (lmics) usually must contend with power dynamics, traditional roles, and social inequities in communities [ ] . while the global community has made significant headway over the years to leverage access to education as a tool to enhance health outcomes for young girls and women, there still exist gaps in addressing health challenges for this vulnerable population in many lmics across the globe [ ] . prior educational interventions have often failed to adequately engage the communities in which they operate or are not financially sustainable without long-term donor support [ ] . consequently, they crumble during epidemics when donor funding becomes limited, schools close, and teachers and administrators die or become sick. financially sustainable and community-driven educational interventions for young girls can help to address these challenges and improve health outcomes in lmics and help curb epidemics. given the limited resources available for tackling the myriads of global health challenges, we must assess prospective educational interventions in the light of rigorous evidence before implementing them. consequently, we ask: how exactly have global education efforts to improve health performed so far? evidence from published literature sheds some light. in a study of eight sub-saharan african countries, gupta et al. found that females who had eight or more years of schooling were % more likely to avoid sex before age compared to their peers with less education [ ] . also, in zimbabwe, studies have con-firmed that among - -year-old adolescent girls, those who drop out of school are about five times more likely to have hiv than their colleagues who stay in school [ ]. evidence from surveys in malawi, haiti, uganda, and zambia further corroborates these findings by showing a secure link between higher education and fewer sexual partners [ ] . the general observation here is that these outcomes are not limited to one country. indeed, kirby et al. also found that, in countries, women with some form of schooling were about five times more likely to have used condoms during sexual encounters than uneducated women in similar backgrounds and settings [ ] . these findings underscored global commitments such as the millennium development goals (mdgs) related to hiv/aids, education and girls; the dakar framework for action related to girls' education; and the current sustainable development goals (sdg # ) to promote inclusive and equitable quality education for all [ ] . based on these initiatives, many lmics have made commitments to improving girl-child education. in ghana, the early s was the era of media campaigns dubbed "send your girl child to school" [ ] . similarly, many other african governments, with the help of international partners, joined these laudable efforts by providing hundreds of millions of dollars to establish schools for girls and to embark on public education programs in rural communities [ ] . a natural follow-up question would be; how have these educational commitments and interventions affected health outcomes so far? in a recent systematic review, psaki et al. concluded that, even though investments in schooling may yield positive ripple outcomes for sexual and reproductive health, these effects may not be as pronounced as expected [ ] . in a similar light, mensch et al. also concluded in their review that, while improvements in women's educational outcomes such as grade attainment have helped to improve health in several places, the effect may be overestimated [ ] . regardless, these two studies highlight the critical roles that educational quality and an intervention's implementation level (community versus national) might play in the synthesis of these outcomes and the conclusions they reported. although there is a wealth of evidence that education is essential for preventive health in the population, the global community failed to meet the mdg # of equal access to education for girls by . why then are educational efforts still failing to address the health challenges of young girls and women, as we have observed in the hiv/aids epidemic and, most recently, the evd crisis [ ] ? the answer to this question may stem from the challenges of financial sustainability and community engagement that these epidemics expose. this answer corroborates the caveats that mensch et al. ( ) and psaki et al. ( ) highlighted. for instance, during the hiv/aids and recent evd outbreaks, many young girls had to drop out of school to provide and care for their families who were sick and dying, consequently increasing their risk of exposure to these lethal viruses [ ] . in these situations, when parents or guardians died, these girls dropped out of school due to default in payment of school fees. in , there were as many as million aids orphans [ ], and the west african evd outbreak left tens of thousands of orphans in its wake [ ] . faced with a compounded challenge of affording their nutritional and accommodation needs, they engaged in risky transactional sex as a means of survival [ ] . in some cases, these were non-consensual sexual encounters. evidence from the children's ebola recovery assessment of girls in sierra leone found that many young girls who had dropped out of school ended up in ebola-quarantined households where they became subjects of rape and other forms of sexual assault [ ] . moreover, the united nations population fund (unfpa) reported that many young girls in the democratic republic of congo encountered rape and sexual attacks from members of armed groups in communities such as north kivu and ituri [ ] . beyond issues of gender-based violence and school drop-outs, epidemics also weaken the capacity and quality of educational systems. in many countries that are hard-hit by hiv/aids and evd, many teachers died, and the few that survived also had to suspend their teaching roles to cater for their sick and dying family members [ ]. in , at the peak of the hiv/aids crisis, about of primary school teachers ( % of trained teachers) in zambia died from the disease, and close to % of the teachers in the central african republic also died [ , ]. these teacher shortages are prevalent in rural areas where schools lose staff. teachers who are affected by disease outbreaks migrate to urban areas for better healthcare for themselves or concerned family members in their care [ ] . in malawi, the student-teacher ratio in many schools jumped to about to due to aids-related illnesses [ ] . worldwide, out of the countries where over % of school-aged girls are out of school, are in sub-saharan africa [ ] . yet, this same population of girls remains the most vulnerable during pandemics when schools are closed. in a recent comprehensive report, the malala fund forecasted that there is a high likelihood that more than million secondary school-aged girls in lmics may not return to school after the covid- pandemic [ ] . there is a need for educational interventions for young girls that can withstand the financial shortfalls and the capacity-weakening effects on educational systems that pandemics cause. an organization that implements such interventions is cocoa , a nonprofit in rural western ghana which transforms communities by using revenues from existing community resources such as cocoa, to finance educational and health outcomes (figure ). the details concerning cocoa 's model the following are essential ingredients for successful community engagement: ( ) community "knocking" -this is the first step in entering a community. use this period to share your concept and vision about the project with community elders, usually, the chief, for their acceptance and input; ( ) shared leadership -the community should be involved in the governance of the project right from the start. cocoa collaborated with their partner communities to establish a local decision-making body called the village committee (vc) [ ] . this group comprises some of the community's respected citizens from diverse religious, ethnic, and occupational backgrounds. the vc serves as a link between cocoa and the broader community and ensures that cocoa 's operations, including those at its tarkwa breman girls school and tarkwa breman community clinic, reflect the needs and cultural standards of the community and its members [ ] . this alignment is especially important because many such rural communities still do not prioritize girl-child education due to persisting cultural beliefs; ( ) community education -the community should be reminded continually of the components, their role in the project's successes, and challenges. such educational efforts will deepen buy-in and ensure the continued success of the program; ( ) shared successes -the project's progress should be celebrated with the community in such a way that they know and feel that their contributions matter; and ( ) sustainability plan -the community should be involved in formulating strategies that will ensure project longevity. zero tuition costs: efforts to eliminate tuition costs and make education compulsory in many countries have helped increase educational access for young girls, significantly reduced their vulnerability to child marriages, and many sexually transmitted diseases such as hiv/aids. and its impact have already been discussed in a separate publication [ ] . herein, we draw on published evidence and our own experiences with cocoa to propose six general components (figure ) that should be considered in insulating educational models from epidemics: active community engagement: in a review of interventions that improve girls' education and gender equality, unterhalter et al. highlight the effectiveness of programs that focused on shifting gender norms and encouraging inclusion through community involvement [ ] . this finding matches our experience and shared belief that the currency for successful interventions in sub-saharan africa is a strong community engagement. working together with community leaders and members enables external project partners to appreciate cultural nuances and local contexts that need to be considered before, during, and after the implementation process. in many rural communities, community leaders and members coordinate mutual support such as construction labor, contribute resources such as land, and are willing to engage in initiatives that will help financially sustain the intended interventions over the long term. for an education model to be sustainable, it would similarly need to include the inputs and perspectives of the residents and their leaders right from the planning phase, throughout the implementation phase, and post-implementation evaluation efforts as well. cocoa , a nonprofit organization in rural western ghana, provides an example of how to solicit and successfully engage a community. as a community-based organization, cocoa transforms rural communities by using revenues from existing community resources such as cocoa to finance educational and health outcomes [ ] . from our experience with community engagement, ysis and systematic reviews has suggested approaches such as conditional cash transfers and bonuses as effective incentives for increasing girls' school enrollment in developing countries [ , ] . while successful, these approaches rely on external funding to meet non-tuition expenses, which may not always be available. on the other hand, interventions like cocoa 's "farm-for-impact" model seek to consistently keep communities at the forefront of decision making and revenue-generation. consequently, they provide a much better independent pathway to self-support the education of their daughters when donor funding becomes limited or ceases [ ] . the process of community-led revenue generation and decision making further imbues a strong sense of communal ownership, which can translate into educational outcomes. for instance, preliminary findings from cocoa show that the school attendance rate is %, compared to the national rural attendance rate of about % for similar schools under the ghana government's free compulsory universal basic education (fcube) program [ ] . school-based food and nutrition initiatives: epidemics such as hiv/aids and evd cause many young girls to drop out of school when their parents and guardians are affected or die. consequently, they end up resorting to transactional sex to obtain support for food and accommodation [ ]. even for families that remain intact without any deaths during outbreaks, school-based food programs may ease the burden of feeding. this challenge occurs because many families are generally in great need of food during epidemics, as many farmers fall sick and agricultural productivity and output may suffer as a result. indeed, the world food program (wfp) found that in some places, when families were incentivized with food rations for sending their daughters to school, enrollment of girls in school tripled [ ] . health-centric and school-based curriculum: the instruction of health habits, hygiene, and sanitary conditions and local cultural contexts and their impact on health behaviors should not just be a footnote in educational programs. instead, they should receive the same attention as math and reading. right from an early age, schools should provide students with age-appropriate health education that will arm them with the knowledge, skills, and tools to take care of their health and be aware of risky health behaviors. in south africa, such health-centric and life skills-based curricula have helped to improve young people's odds of using condoms during sex [ ] . synthesis of established evidence also shows that school-based sexual health education has the potential to improve condom use among young people in sub-saharan africa and to reduce the prevalence of sexually transmitted infections such as chlamydia [ ] . such comprehensive approaches to education can be achieved by ensuring that for instance, eliminating tuition fees has been found to reduce child marriages in eight countries in sub-saharan africa, including ghana, ethiopia, and rwanda, despite the challenges encountered in the implementation of this policy [ ] . additionally, the government of ghana's free compulsory universal basic education (fcube), which aimed to provide tuition-free education for all students in public primary schools, has led to a marked increase in enrollment rates [ ] . in countries such as kenya, uganda, and tanzania, eliminating tuition fees has helped to improve school enrollment and student attendance rates, particularly for young girls [ ] . in uganda, the government's efforts at easing the burden of tuition led to a % increase in girls' enrollment in school with an almost double effect for the poorest economic fifth of girls [ ] . in a systematic review of studies from reports, baird et al. also substantiated such findings of the impact of financial incentives on educational outcomes [ ] . they found that both conditional and unconditional cash transfer programs improved the likelihood of school attendance and enrollment compared to programs without cash transfers [ ] . with that said, it is essential to note that zero tuition costs come at a cost to a nation. in response, several governments have devised ways of domestically financing such interventions via taxation and innovative funding models [ ] . public-private partnerships models for funding primary and secondary education should be encouraged. zero non-tuition expenses through community-led revenue generation: as koski et al. have shown, removing the cost of tuition alone would not be enough to reduce child marriage since other barriers to school enrollment may persist [ ] . in ghana, despite the fcube, there are still gender disparities in educational access. many young girls are not benefitting from the scheme, and these probably may be due to financial difficulties related to the cost of textbooks, school uniforms, and transportation, which disproportionately plague marginalized households in rural communities [ ] . stack et al. found in a study in rural western ghana that in the face of financial challenges, . % of heads of households, typically males, opted for the male child against . % who chose the female child. of these, . % stated that it would depend on the specific circumstances, while . % refused to answer [ ] . thus, the contribution of non-tuition expenses towards school attendance is not trivial. community and private initiatives could take this burden off parents and heads of households. a thriving community initiative like this is the cocoa 's "farm-for-impact" model. community members assist with work on a community-run cocoa farm in exchange for tuition-free education and subsidized healthcare. the revenues from the farm are applied to finance educational and healthcare services in rural communities in ghana [ ] . evidence from meta-anal-they are theory-driven, address social determinants like social norms, improve cognitive-behavioral skills, train facilitators like teachers, and include schools, families, and communities [ ] . safe and protected learning spaces: while schools serve as nurturing grounds for student learning, they can also expose young girls to gender-based violence (gbv) and negatively impact the attainment of educational objectives [ ] . several studies have reported a high prevalence of gbv, such as sexual harassment, unsolicited advances, touching, groping, and sexual assaults [ , ] . for instance, a human rights watch (hrw) study in south african schools revealed that teachers raped young girls in empty classrooms, lavatories, and dormitories [ ] . in dodowa, ghana, similar findings of sexual assault of young girls in schools have also been documented [ ] . such instances of school-based gbv make schools less attractive places for young girls, who consequently struggle to concentrate on their academics and may, therefore, drop out [ ] . for other deterred girls, they may not enroll at all. schools pursuing sustainable educational models should strive to make their learning environments safe for young girls by working with community leaders, teachers, students, and related government stakeholders to implement preventive and punitive measures for perpetrators. evidence from systematic reviews highlights the role of interventions such as life skills training programs and positive peer relationship training approaches to promote self-esteem and to reduce bullying and rape [ ] . activities such as drama and arts can also help young people evaluate their gender roles and the steps they can take to ensure that their study spaces are safe and conducive to learning [ ]. successfully achieving this goal would require seeing boys as crucial partners to the solution, rather than external opponents. education has proven to be an effective intervention for improving health outcomes and reducing the spread and impact of epidemics. while the global community has made significant progress in leveraging quality girlchild education as a tool to enhance health in lmics, challenges such as financial bottlenecks continue to impede such efforts, especially during outbreaks. sustainable educational models that prioritize active community engagement, abolish tuition and non-tuition expenses, incorporate school-based food programs, infuse health-centric and skill-based curriculum, and promote safe learning spaces are much needed. successful implementation of such efforts would significantly improve educational access and health outcomes for young girls and, consequently, provide long-lasting approaches to fight the spread and impact of epidemics when they emerge. social determinants of health inequalities. the lancet unaids. educate girls, fight aids social factors influencing child health in ghana what was the effect of the west african ebola outbreak on health programme performance, and did programmes recover? public health action sexual initiation among adolescent girls and boys: trends and differentials in sub-saharan africa [internet]. archives of sexual behavior hiv infection and reproductive health in teenage women orphaned and made vulnerable by aids in zimbabwe school-based programs to reduce sexual risk behaviors: a review of effectiveness barriers to school attendance and gender inequality: empirical evidence from a sample of ghanaian schoolchildren. research in comparative and international education causal effects of education on sexual and reproductive health in low and middle-income countries: a systematic review and meta-analysis. ssm popul health evidence for causal links between education and maternal and child health: systematic review ebola crisis: the unequal impact on women and children's health. the lancet global health perception of students on the impact of ebola virus disease conditional cash transfers for education: a comparative analysis between the funder and country. international development, community, and environment (idce) the effects of an ngo development project on the rural community of tarkwa bremen in western ghana impacts of conditional cash transfer programs on educational outcomes in developing countries a meta-analysis. rand labor and population bringing hope to a generation, food aid to help orphans and other vulnerable children. rome: world food programme programming for hiv prevention in south african schools school-based sexual health education interventions to prevent sti/hiv in sub-saharan africa: a systematic review and meta-analysis effective elements of school health promotion across behavioral domains: a systematic review of reviews literature review on the intersection of safe learning environments and educational achievement. u.s. agency for international development scared at school: sexual violence against girls in south african schools a global review of current issues and approaches in policy, programming, and implementation responses to school-related gender-based violence (srgbv) for the education sector school-based interventions to promote adolescent health: a systematic review in low-and middle-income countries of who western pacific region /ijabr_v ( ) - .pdf . the impact of ebola on education in sierra leone teenage pregnancies in ebola-affected sierra leone [internet]. world vision new ebola outbreak hits women and girls hardest in the democratic republic of the congo education for all -the quality imperative united states agency for international development bureau for africa, office of sustainable development african states' varying progress toward gender equality in education brookings education and covid- . malala fund re-imagining community development: the cocoa model interventions to enhance girls' education and gender equality. education rigorous literature review. department for international development the impact of eliminating primary school tuition fees on child marriage in sub-saharan africa: a quasi-experimental evaluation of policy changes in countries taking education for all goals in sub-saharan africa to the task conditional, unconditional and everything in between a systematic review of the effects of cash transfer programs on schooling outcomes we are grateful to priya bhirgoo for her assistance with helpful comments and edits. key: cord- -c qdmkw authors: weiss, robin a title: hiv and aids: looking ahead date: journal: nat med doi: . /nm - sha: doc_id: cord_uid: c qdmkw although the future of hiv science is uncertain, we need to reappraise hiv diversity, pathogenesis and immunity. the aids pandemic threatens the success of existing vaccine programs and may accelerate the emergence of new infectious diseases. a pollo conferred on cassandra the gift of clairvoyance but later added the caveat that no-one would listen to her prophesy; thus, her warnings of the fall of troy and the house of agamemnon went unheeded. doctors and scientists are less farsighted, and making predictions exposes us to ridicule in hindsight. not long after the us surgeon general declared that it was "time to close the book on infectious diseases", hiv began to 'cruise' the san francisco bath houses while severe acute respiratory syndrome (sars) lay further in the future. in margaret heckler, then us secretary for health and human services, declared on behalf of the national institutes of health that "we hope to have a [aids] vaccine ready for testing in about years." how foolhardy it was to accept an invitation from nature medicine to comment on the next years of hiv science! if we could foresee the future of research, then we would surely be doing it now. the other contributors to this issue have made the sensible prognostications, whereas anything i put forward here must be regarded as unsure prediction, idle speculation or even wild conjecture . the pace of hiv science, like all science, is driven by technology with unexpected breakthroughs. without pcr, we would not have accurate measurements of hiv viral load and turnover; without rapid dna sequencing and bioinformatics, we would not have such an exquisite database on hiv genetic variation; and if plant virologists had not been curious to investigate gene silencing, we would not have rna-mediated interference (rnai) as a medical research tool. thus, my message for future progress on hiv is that we ignore non-hiv research at our peril. no doubt this prophesy will fall on deaf ears at the funding agencies, especially those in the charitable sector: the late bernie fields' exhortation to "get back to basics" in hiv science is not part of their mission. our colleagues at the institut pasteur must have felt as frustrated as cassandra when so few heeded their first report in may on a previously unknown retrovirus that was possibly associated with aids. at that time, 'lymphadenopathy virus' (lav) was just one more candidate agent alongside other animal and human viruses, and alongside an idea that a fungal infection secretes a cyclosporin-like immunosuppressant. but none of us present at the cold spring harbor laboratory meeting on human retroviruses in the fall of should have failed to be impressed by how the french scientists hardened their evidence. by early , they had detected the virus in individuals with aids, including gay men, two brothers with hemophilia and a heterosexual couple from africa and their child, and had pointed out the similarity of lav to animal lentiviruses on account of its cytopathic effects and morphology . they were accurate in almost every finding, including the only correct interpretation of the open reading frames when the viral genome was cloned and sequenced . hard on the heels of the second french report came news of other hiv isolates from the united states , . apart from the overoptimistic claims of a vaccine, early hiv research was extraordinarily fruitful (see accompanying reviews in this issue [ ] [ ] [ ] . propagating hiv in t-cell lines provided ample antigen for diagnostic tests of infection that by had been translated into kits suitable for the mass screening of blood donors. cd was identified as the cellular binding receptor for hiv in . the importance of the regulatory and auxiliary genes began to be elucidated in . azidothymidine (zidovudine) became the first antiretroviral drug to enter clinical trials in . meanwhile, we began to grasp the scale of the aids pandemic unfolding before our eyes: 'slim' disease in africa was indeed aids . figure illustrates both the success of hiv science and the formidable challenges before us; it contrasts the control of mortality from aids in the united states with its exponential rise in sub-saharan africa. but fig. a belies the heterogeneity of the african epidemic. as the 'four-city' studies have shown , we still do not know why hiv spread explosively in some places and not in others. fifteen years ago, aids in south africa was seen in a handful of gay white men who had traveled to the united states, but now more than four million south african black men, women and children are infected with hiv. by contrast, it was estimated years ago that about % of adults in kinshasa were infected, but this proportion remained stable until recently, despite the imploding infrastructure and human conflict that the democratic republic of congo has suffered. predicting the future of the hiv epidemic will be no easier than interpreting the recent past. epidemiological evidence for the transmission of hiv by sexual and parenteral routes was clear before hiv was identified, and mother-to-child transmission soon after. the modes of transmission remain the same today and seem unlikely to change tomorrow. i previously questioned whether biting insects with large mouthparts might act as 'dirty needles' to transfer hiv passively, given that another lentivirusequine infectious anemia virusis transmitted in this way. but there is no evidence of transmission by insects, and if it were occurring then we would expect to see more children seroconverting before puberty. it was recently postulated that in africa, contaminated syringes and needles are responsible for more hiv transmission than is sexual contact. although the number of infections by unsterile injections may have been underestimated during the pandemic phase of hiv, as well as during the mid-twentieth century , sexual spread is driving the african pandemic , . if injection were the main route of hiv infection in africa, as it has been in eastern europe and china, then again we would expect to see more children of hiv-negative parents developing aids. as valdiserri et al. argue in this issue, much has been accomplished in reducing the transmission of hiv and, given politi-cal will, persuasive 'risk' education and sufficient resources, "the science exists to turn the pandemic around." certainly, the continuing spread of disease could be slowed significantly, as has been seen in senegal, thailand and uganda, but whether without an efficacious vaccine we can reduce r to less than onethat is, reduce the mean rate of transmission from one infected person to less than one other personremains speculative. india is currently estimated to have million people infected with hiv (second only to south africa), and this number could rise to million in the next years. perhaps we should not be too pessimistic. people do change their outlook and lifestyle in the face of devastating disease. for example, male circumcision has been identified as a factor that lessens the risk of female-to-male hiv infection in africa . who would have thought a few years ago that men imbued with their traditional social customs would readily come forward to take part in randomized controlled trials of adult circumcision? whereas the 'sexual synapse' is a frequent route of hiv transmission from one person to anotherone that may be blocked specifically by a condom and hopefully one day by vaginal viricidesthe 'immunologi-cal synapse' is a pathway for virus transmission from cell to cell (see accompanying review in this issue) and has been elegantly shown for human t-cell lymphotropic virus type i. we are only just beginning to understand the impact of the multiple delivery of virions from dendritic or other antigen-presenting cells to cd + t-helper-cells. i propose that the immunological synapse may account for the recent observation that although only a small proportion of cd + t-cells in a lymphoid organ are infected by hiv, these cells contain several proviruses . this type of 'multihit' infection at the cellular level may overcome the saturatable restriction factors of the host cell , . packaged rna genomes transcribed from more than one provirus in the same infected cell will assemble into heterozygous virions, which in turn will accelerate genetic recombination and the evolution of drug resistance and immune escape. in the future, we should pay more attention to the comparative pathology of lentiviruses, including hiv- (ref. ) . in this issue, stevenson points to the lessons to be learned from primates that are naturally infected with a high viral load but do not develop disease. he contrasts oncoviruses to hiv and the primate lentiviruses that can infect nondividing macrophages and dendritic cells. i argue further that all lentiviruses are macrophage-tropic, but only some infect lymphocytes (primate and feline immunodeficiency viruses). for example, let us consider maedi-visna virus, which is solely macrophage-tropic. maedi-visna in sheep is the prototypic disease from which lentiviruses derive their name . infected sheep develop a wasting disease and neurodegeneration similar to that seen in humans with aids, but they do not show t-helper-cell immune deficiency. as maedi-visna is remorselessly progressive, with a high rate of mortality, i have argued previously that the infection, activation and apoptosis of t-cells in hiv are epiphenomena alongside the underlying progression of macrophage disease. like the prophecies of cassandra, this view remains unheeded perhaps because it would necessitate a complete reappraisal of both hiv pathogenesis and the inability of the immune system to ultimately control lentivirus infection. such a question has been posed for the katie ris variation observed in rna viruses in general ; for hiv, the answer is probably a lot of each. hiv generates variants at a far greater rate than do other rna viruses such as measles, polio and even influenza (fig. ) . the rapid radiation of hiv- group m into the subtypes or clades that comprise today's pandemic strains and all of their variants could have arisen from a conjunction of two features of hiv: the extraordinarily high level of sustained replication and turnover in vivo , and the functional tolerance of amino acid substitutions. it is estimated that humans were first infected with hiv- group m about years ago and with hiv- about years ago , with the viruses crossing from chimpanzees and sooty mangabeys, respectively . in the early years, hiv- radiated out into the different clades that we know today, probably from small founder populations of virus. the regions in which hiv- has been present the longest have the most complex array of genotypes (fig. ) . in the next years the pattern will change, and an increasing number of circulating recombinant forms (crfs) of hiv- will become apparent. thus, the neat geographic delineation of subtypesb in the americas, e in thailand, a and d in east africa and c in southern africaare likely to be superseded by crf viruses. indeed, crfs between hiv- groups m and o have been described , even though the parental genomes derive from distinct zoonotic events . it is possible that natural recombinants could arise between hiv- and hiv- now that hiv- has spread across west africa, where hiv- was already endemic. although there are some constraints to the co-packaging of hiv- and hiv- rna , it is worth investigating the possibility of hybrids in dually infected persons. does hiv variation matter? although there is no evidence that hiv has evolved in terms of virulence or modes of transmission in the past years, evolution of drug resistance and of immune escape (see accompanying review in this issue and refs. , ) clearly occurs under selective pressure. thus, hiv mutation and recombination have a great impact on therapy and vaccine design. i remain to be convinced, however, that the emphasis of vaccine design on the basis of clades is hiv science. efficacious, broadly based vaccines require immunogens representing those regions of the virus that change the least. when these have been identified, clades can be addressed. for humoral immunity, the challenge is not only the immunogen itself but also the access of antibodies to the neutralization targets. given the effect of the n-linked sugars of gp on immune escape from hiv , the glycobiology of hiv is back in fashion. will the drop in aids mortality owing to antiretroviral therapy (fig. ) be maintained so that people on treatment can expect a normal life span? this will depend on the ability of the virus to develop multidrug resistance while remaining fit for transmission. we shall need new drug targets , but a big practical challenge in the future will be to marry good drug therapy to easy adherence, particularly in resourcepoor settings. this means that drug formulation must be designed to optimize appropriate use. even then, if drugs administered to one infected individual are shared among their family or community such that several persons are simultaneously taking suboptimal doses, this could be a recipe for the rapid evolution and spread of multidrug-resistant hiv strains. in the future, i expect that host genetic variation will also have a larger role in hiv science. in addition to identifying individual host factors , [ ] [ ] [ ] , whole-genome scanning for pharmacogenomics and for what i call 'infectogenomics' (host genes that affect the virulence of infection) will provide information on how to better manage hiv infection. hiv may have a severe impact on several of the immunization programs for children and adults. inactivated or subunit vaccines may simply be ineffective in people infected with hiv: this has been shown for the pneumococcal polysaccharide vaccine , although antiretroviral therapy may restore responsiveness . with viruses, hiv-positive individuals have the potential to become long-term shedders of what would otherwise be acute, short-lived infections, changing the dynamics of immunization and eradication. thus, the large numbers of children with aids in africa may impede campaigns to eradicate measles and polio and to protect against yellow fever. a recent detailed review on the safety, immunogenicity and effectiveness of vaccines in children with hiv concludes that the benefits currently far outweigh the risks. nevertheless, epidemiological modeling will be needed to see whether one can minimize the untoward effects of hiv on other infectious diseases. another concern is that an 'attenuated' vaccine may itself act as a virulent pathogen in the immunocompromized individual. case reports of severe complications of bacillus calmette-guérin (bcg), measles and polio have been reported, and world health organization (who) guidelines recommend withholding bcg and yellow fever vaccines from symptomatic children infected with hiv . hiv hiv yea yea % % c c j g d figure the scale of hiv variation. sequence divergence of envelope glycoproteins of hiv (gp , v -c ) compared with that of influenza a h (ha ). the length of the spokes indicates the degree of divergence with the scale indicated. hiv variation in a single person years after infection ( genomes analyzed) is similar to that of worldwide influenza a ( genomes analyzed) in a single year. the greatest degree of variation is in the democratic republic of congo, where hiv first developed and has diversified into subtypes a-k (except for subtype b, prevalent in the west, and subtype e, prevalent in thailand). adapted with permission from ref. . gulliver's travels in hivland aids: time to turn to basic science isolation of a t-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (aids) isolation of new lymphotropic retrovirus from two siblings with haemophilia b, one with aids isolation of human t-lymphotropic retrovirus (lav) from zairian married couple, one with aids, one with prodromes a new type of retrovirus isolated from patients presenting with lymphadenopathy and acquired immune deficiency syndrome: structural and antigenic relatedness with equine infectious anaemia virus nucleotide sequence of the aids virus frequent detection and isolation of cytopathic retroviruses (htlv-iii) from patients with aids and at risk for aids isolation of lymphocytopathic retroviruses from san francisco patients with aids hiv and aids: years of science hiv- pathogenesis years of therapy for hiv- infection slim disease: a new disease in uganda and its association with htlv-iii infection multicentre study on factors determining differences in rate of spread of hiv in sub-saharan africa: methods and prevalence of hiv infection let it be sexual: how health care transmission of aids in africa was ignored the injection century: massive unsterile injections and the emergence of human pathogens expert group stresses that unsafe sex is primary mode of hiv transmission in epidemiology: sexual transmission of hiv in africa accomplishments in hiv prevention science: implications for stemming the epidemic male circumcision and risk of hiv infection in sub-saharan africa: a systematic review and meta-analysis male circumcision: current epidemiological and field evidence hiv- transmission, acute infection, and the quest for strategies to prevent infection spread of htlv-i between lymphocytes by virus-induced polarization of the cytoskeleton multiply infected spleen cells in hiv patients cellular inhibitors with fv -like activity restrict human and simian immunodeficiency virus tropism restriction of multiple divergent retroviruses by lv and ref human immunodeficiency virus type cultivation of visna virus in tissue culture lentivirus tropism and pathogenesis are rna viruses adapting or merely changing? evolutionary and immunological implications of contemporary hiv- variation modelling viral and immune system dynamics timing the ancestor of the hiv- pandemic strains tracing the origin and history of the hiv- epidemic aids as a zoonosis: scientific and public health implications human immunodeficiency virus type intergroup (m/o) recombination in cameroon nonreciprocal packaging of human immunodeficiency virus type and type rna: a possible role for the p domain of gag in rna encapsidation antibody neutralization and escape by hiv- rapid evolution of the neutralizing antibody response to hiv type infection isolation of a human gene that inhibits hiv- infection and is suppressed by the viral vif protein the effect of genetic variation in chemokines and their receptors on hiv transmission and progression to aids global survey of genetic variation in ccr , rantes, and mip- α: impact on the epidemiology of the hiv- pandemic -valent pneumococcal polysaccharide vaccine in hiv- -infected ugandan adults: double-blind, randomised and placebo controlled trial smallpox vaccination and patients with human immunodeficiency virus infection or acquired immunodeficiency syndrome disseminated vaccinia in a military recruit with human immunodeficiency virus (hiv) disease aids-related malignancies risk of human immunodeficiency virus infection in herpes simplex virus type -seropositive persons: a meta-analysis interactions between herpes simplex virus type and human immunodeficiency virus type infection in african women: opportunities for intervention infection with gb virus c and reduced mortality among hiv-infected patients effect of coinfection with gb virus c on survival among patients with hiv infection hiv- suppression during acute scrub-typhus infection decrease in human immunodeficiency virus type load during acute dengue fever catastrophic ape decline in western equatorial africa vaccine for aids and ebola virus infection hiv and aids in relation to other pandemics there is much concern over the risk of reintroducing smallpox vaccination to people infected with hiv because disseminated vaccinosis may ensue, as has been reported in an hiv-positive military recruit . aids is characterized by opportunistic infections and by what we may call opportunistic neoplasms . some opportunistic infections in turn exacerbate hiv in a vicious cycle. thus, genital herpes simplex infection is a risk factor for hiv transmission , while hiv increases and prolongs herpes shedding . other concurrent infections may ameliorate the risk or severity of hiv infection, as has been reported for gb virus c , , scrub-typhus and dengue . elucidating the mechanisms of cross-protection may give us clues to controlling hiv.many opportunistic infections are either zoonoses or come from nonparasitic, freeliving microbes. although they are typically not transmitted between humans, this pattern might change in the future if the opportunistic infections were to hop from one immunocompromised host to another. high-density immunodeficient populations are arguably unique in the annals of host-parasite evolution .thus, viruses, bacteria, fungi and protozoa now have million hiv-infected people in whom to adapt to human parasitism. zoonoses occur naturally, but the prevalence of hiv infection could greatly increase the chances of an infection of animal origin, such as sars, influenza, ebola or nipah viruses, to adapt more rapidly to human transmission. individuals with aids would be the 'superspreaders', as they are for tuberculosis. it is perhaps reassuring that such a horrific situation has not yet occurred, but predictive modeling is required to determine whether it could occur in the future. the aids pandemic compounds the threat from the deliberate or accidental release of new infectious agents. like cassandra, i shall end with a true prophesy that is at the same time optimistic and grim: years from now, the risk of further lentivirus transfer from apes to humans will approach zero because feral chimpanzees will be extinct, thanks to the bushmeat trade and the ebola epidemic , unless the apes are protected by immunization. who would have predicted years ago that we would have a vaccine for ebola before one for hiv key: cord- -ji jbct authors: morens, david m.; folkers, gregory k.; fauci, anthony s. title: the challenge of emerging and re-emerging infectious diseases date: - - journal: nature doi: . /nature sha: doc_id: cord_uid: ji jbct infectious diseases have for centuries ranked with wars and famine as major challenges to human progress and survival. they remain among the leading causes of death and disability worldwide. against a constant background of established infections, epidemics of new and old infectious diseases periodically emerge, greatly magnifying the global burden of infections. studies of these emerging infections reveal the evolutionary properties of pathogenic microorganisms and the dynamic relationships between microorganisms, their hosts and the environment. merging infections (eis) can be defined as "infections that have newly appeared in a population or have existed previously but are rapidly increasing in incidence or geographic range" . eis have shaped the course of human history and have caused incalculable misery and death. in , a new disease -acquired immune deficiency syndrome (aids) -was first recognized. as a global killer, aids now threatens to surpass the black death of the fourteenth century and the - influenza pandemic, each of which killed at least million people , . of the 'newly emerging' and 're-emerging/resurging' diseases that have followed the appearance of aids (fig. ) , some have been minor curiosities, such as the cases of monkeypox imported into the united states , whereas others, such as severe acute respiratory syndrome (sars), which emerged in the same year , have had a worldwide impact. the anthrax bioterrorist attack in the united states falls into a third category: 'deliberately emerging' diseases. eis can be expected to remain a considerable challenge for the foreseeable future. here we examine the nature and scope of emerging and reemerging microbial threats, and consider methods for their control. we emphasize that emergence results from dynamic interactions between rapidly evolving infectious agents and changes in the environment and in host behaviour that provide such agents with favourable new ecological niches. about million (> %) of million annual deaths worldwide are estimated to be related directly to infectious diseases; this figure does not include the additional millions of deaths that occur as a consequence of past infections (for example, streptococcal rheumatic heart disease), or because of complications associated with chronic infections, such as liver failure and hepatocellular carcinoma in people infected with hepatitis b or c viruses (fig. ) . the burden of morbidity (ill health) and mortality associated with infectious diseases falls most heavily on people in developing countries , and particularly on infants and children (about three million children die each year from malaria and diarrhoeal diseases alone ). in developed nations, infectious disease mortality disproportionately affects indigenous and disadvantaged minorities . eis have been familiar threats since ancient times. they were once identified by terms such as ȕșȓȖș ȝ (loimos) , and later as 'pestilences' , 'pestes' , 'pests' and 'plagues' . many examples can be cited in addition to the black death and the influenza pandemic, such as certain biblical pharaonic plagues and the unidentified plague of athens, which heralded the end of greece's golden age . the age of discovery, starting in the fifteenth century, was a particularly disastrous period with regard to the spread of infectious diseases. importation of smallpox into mexico caused - million deaths in - , effectively ending aztec civilization , . other amerindian and pacific civilizations were destroyed by imported smallpox and measles [ ] [ ] [ ] [ ] [ ] . historians have referred to these events as apocalypses and even as genocide . for centuries, mankind seemed helpless against these sudden epidemics. but the establishment of the germ theory and the identification of specific microbes as the causative agents of a wide variety of infectious diseases [ ] [ ] [ ] led to enormous progress, notably the development of vaccines and ultimately of antimicrobials . in fact, the era of the identification of microbes had barely begun when optimists at the end of the nineteenth century predicted the eradication of infectious diseases . by the s, which witnessed the widespread use of penicillin, the development of polio vaccines and the discovery of drugs for tuberculosis, complacency had set in , and in , the us surgeon general stated that "the war against infectious diseases has been won" . some experts remained sceptical, aware of recurrent lessons from history. they were less persuaded by successes than alarmed by failures such as the lack of progress against infections in the developing world and the global spread of antimicrobial resistance. richard krause, then the director of the us national institute of allergy and infectious diseases, warned in (ref. ) that microbial diversity and evolutionary vigour were still dynamic forces threatening mankind. as krause was completing his book the restless tide , aids -one of history's most devastating pandemics -was already insidiously emerging. the emergence of aids led to renewed appreciation of the inevitability and consequences of the emergence of infectious diseases [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in the past years, some of the factors that resulted in aids have also led to re-emergences of historically important diseases such as cholera, diphtheria, trench fever and plague. many re-emergences have been catalysed by wars, loss of social cohesion, and natural disasters such as earthquakes and floods, indicating the importance not only of microbial and viral factors, but also of social and environmental determinants [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the challenge of emerging and re-emerging infectious diseases the classification of eis as 'newly emerging' , 're-emerging/resurging' or 'deliberately emerging' is useful because the underlying causes of emergence and the optimal prevention or control responses frequently differ between the groups. newly emerging infections are those that have not previously been recognized in man. many diverse factors contribute to their emergences (see box ); these include microbial genetic mutation and viral genetic recombination or reassortment, changes in populations of reservoir hosts or intermediate insect vectors, microbial switching from animal to human hosts, human behavioural changes (notably human movement and urbanization), and environmental factors. these numerous microbial, host and environmental factors interact to create opportunities for infectious agents to evolve into new ecological niches, reach and adapt to new hosts, and spread more easily between them. any discussion of recent eis must begin with the human immunodeficiency virus (hiv) that causes aids. hiv has so far infected more than million people worldwide . before jumping to humans an estimated - years ago , perhaps as a consequence of the consumption of 'bush meat' from non-human primates, hiv- and hiv- had ample opportunity to evolve in hosts that were genetically similar to man (the chimpanzee, pan troglodytes, and the sooty mangabey, cercocebus atys). but hiv/aids might never have emerged had it not been for disruptions in the economic and social infrastructure in post-colonial sub-saharan africa. increased travel, the movement of rural populations to large cities, urban poverty and a weakening of family structure all promoted sexual practices, such as promiscuity and prostitution, that facilitate hiv transmission [ ] [ ] [ ] [ ] . such complex interactions between infectious agents, hosts and the environment are not unique to the epidemiology of hiv/aids. the examples cited below further illustrate how changes in population density, human movements and the environment interact to create ecological niches that facilitate microbial or viral adaptation. some infectious agents that have adapted to non-human hosts can jump to humans but, unlike hiv, are not generally transmitted from person to person, achieving only 'dead end' transmission. infections in animals that are transmitted to humans (zoonoses), and those transmitted from one vertebrate to another by an arthropod vector (vector-borne diseases), have repeatedly been identified as ranking among the most important eis , . examples include the arenavirus haemorrhagic fevers (argentine, bolivian, venezuelan and lassa haemorrhagic fevers) and hantavirus pulmonary syndrome (hps). viruses in these groups have co-evolved with specific rodent species whose contact with humans has increased as a result of modern environmental and human behavioural factors. farming, keeping domestic pets, hunting and camping, deforestation and other types of habitat destruction all create new opportunities for such infectious agents to invade human hosts [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the first epidemic of hps, detected in the southwestern region of the united states in (ref. ) , resulted from population booms of the deer mouse peromyscus maniculatis, in turn caused by climate-related and recurrent proliferation of rodent food sources. increased rodent populations and eventual shortages of food drove expanded deer mouse populations into homes, exposing people to virus-containing droppings. the - malaysian nipah virus epidemic further illustrates the influence of human behaviours and environmental perturbations on newly emerging human infections. pigs crammed together in pens located in or near orchards attracted fruit bats whose normal habitats had been destroyed by deforestation and whose droppings contained the then-unknown paramyxovirus. virus aerosolization caused infection of pigs, with overcrowding leading to explosive transmission rates and ultimately to infections in pig handlers. variant creutzfeldt-jakob disease (vcjd) is another example of a zoonotic disease emerging in humans. vcjd is caused by the humanadapted form of the prion associated with the emerging epizootic (large-scale animal outbreak) of bovine spongiform encephalopathy (bse) figure global examples of emerging and re-emerging infectious diseases, some of which are discussed in the main text. red represents newly emerging diseases; blue, re-emerging/resurging diseases; black, a 'deliberately emerging' disease. adapted, with permission, from ref. . epizootic/vcjd epidemic, primarily affecting great britain, probably resulted from the now-abandoned practice of supplementing cattle feed with the pulverized meat and bones of previously slaughtered cattle. bse itself is suspected to have emerged because of even earlier use of cattle feed containing the agent of sheep scrapie, a prion disease recognized by farmers more than years ago . alarmingly, the new bse prion has become uncharacteristically promiscuous: unlike most known prions, it readily infects multiple species in addition to humans. this suggests the possibility of further emerging diseases associated with prions with currently unknown transmissibility to humans . the recent reports of variant strains of the bse prion suggest that the bse agent could be a more serious threat than other animal prions. infectious agents indirectly transmitted to or between humans by way of human-modified environments account for other emerging zoonoses, as well as certain non-zoonotic diseases, which are discussed below. for example, legionnaires' disease, first identified in , is caused by legionella pneumophila, whose emergence as a human pathogen might not have occurred were it not for the environmental niche provided by air-conditioning systems . campylobacter jejuni and shiga-toxin-producing escherichia coli (e. coli o :h and other agents of haemolytic-uraemic syndrome) infect agricultural animals, gaining access to humans through food, milk, water or direct animal contact. other enteric pathogens, such as the vibrios causing classical cholera (re-emerging; see below) and serogroup o cholera, and the zoonotic protozoa cryptosporidium parvum and cyclospora cayetanensis , seem to have come from environmental or animal organisms that have adapted to human-to-human 'faecal-oral' transmission through water. some eis come from microorganisms that once caused familiar diseases, but which now cause new or previously uncommon diseases. streptococcus pyogenes caused a fatal pandemic of scarlet and puerperal fevers between and (ref. ) . scarlet fever, then the leading cause of death in children, is now rare, but has been largely supplemented by other streptococcal complications such as streptococcal toxic shock syndrome, necrotizing fasciitis and re-emergent rheumatic fever . when new microbes are discovered, their emergences as disease-causing pathogens may be delayed. for example, in , robert koch was unable to show that the newly discovered koch-weeks bacillus caused serious disease. more than a century later, a fatal ei dubbed brazilian purpuric fever was linked to virulent clonal variants of haemophilus influenzae biogroup aegyptius (the koch-weeks bacillus) . although the bases of emergences of new and more severe diseases caused by s. pyogenes and h. influenzae biogroup aegyptius are not fully known, in both cases complex microbial genetic events are suspected. the distinctive clonal variants associated with severe h. influenzae biogroup aegyptius disease have been shown by pcr (polymerase chain reaction)-based subtractive genome hybridization to contain not only a unique plasmid, but also unique chromosomal regions, some of which are encoded by bacteriophages . this research has narrowed the search for virulence determinants to unique proteins, some of which may have been acquired from other organisms by horizontal gene transfer. streptococcus pyogenes has been studied more extensively, but the basis of severe disease emergence seems to be more complex than for h. influenzae biogroup aegyptius. many factors associated with streptococcal virulence have been identified in strains bearing the m surface protein as well as in other m protein strains, among them bacteriophage-encoded superantigen toxins and a protein known as sic (streptococcal inhibitor of complement), which seems to be strongly selected by human host mucosal factors. several lines of evidence suggest that changes in streptococcal virulence reflect genetic changes associated with phage integration, large-scale chromosomal rearrangements and possibly the shuffling of virulence cassettes (clusters of genes responsible for pathogenicity), followed by rapid human spread and immune selection , . infectious agents that are associated with chronic diseases are one of the most challenging categories of newly emerging (or at least newly appreciated) infections. examples include the associations of hepatitis b and c with chronic liver damage and hepatocellular carcinoma, of certain genotypes of human papillomaviruses with cancer of the uterine cervix, of epstein-barr virus with burkitt's lymphoma (largely in africa) and nasopharyngeal carcinoma (in china), of human herpesvirus with kaposi sarcoma, and of helicobacter pylori with gastric ulcers and gastric cancer [ ] [ ] [ ] . some data even suggest infectious aetiologies for cardiovascular disease and diabetes mellitus , major causes of death and disability worldwide. other associations between infectious agents and idiopathic chronic diseases will inevitably be found. re-emerging and resurging infections are those that existed in the past but are now rapidly increasing either in incidence or in geographical or human host range. re-emergence is caused by some of the factors that cause newly emerging infectious diseases, such as microbial evolutionary vigour, zoonotic encounters and environmental encroachment. re-emergences or at least cyclical resurgences of some diseases may also be climate-related -for example, the el niño/southern oscillation (enso) phenomenon is associated with resurgences of cholera and malaria . the impact of both new and re-emerging infectious diseases on human populations is affected by the rate and degree to which they spread across geographical areas, depending on the movement of human hosts or of the vectors or reservoirs of infections. travel has an important role in bringing people into contact with infectious agents . an increase in travel-associated importations of diseases was anticipated as early as , when commercial air travel was still in its infancy . this has since been demonstrated dramatically by an international airline hub-to-hub pandemic spread of acute haemorrhagic conjunctivitis in (ref. ) , by epidemics of meningococcal meningitis associated with the hajj, and more recently by the exportation of epidemic sars (a newly emerging disease) from guangdong province, china, to hong kong, and from there to beijing, hanoi, singapore, toronto and elsewhere (fig. ) . the persistent spread of hiv along air, trucking, drug-trafficking and troop-deployment routes is a deadly variation on this theme [ ] [ ] [ ] . plasmodium falciparum malaria was neglected for several decades, but is now among the most important re-emerging diseases worldwide (fig. ) . years of effective use of dichlorodiphenyltrichloroethane (ddt) led to the abandonment of other mosquito-control programmes, but the insecticide fell into disuse because of mosquito resistance and concerns about the insecticide's potentially harmful effects on humans and wildlife. consequently, malaria has re-emerged, and the situation has been worsened by the development of drug resistance to chloroquine and mefloquine . research efforts focus on the development of vaccines and new drugs, and on re-establishing public health measures such as the use of bed nets. tuberculosis is one of the most deadly re-emerging diseases (fig. ) . the discovery of isoniazid and other drugs initially led to effective tuberculosis cures, empty sanitoria and the dismantling of public health control systems in developed nations. consequently, by the s, when tuberculosis had re-emerged in the era of hiv/aids, local and state health departments in the united states lacked field, laboratory and clinical staff and so had to reinvent tuberculosiscontrol programmes . the remarkable re-emergence of tuberculosis was fuelled by the immune deficiencies of people with aids, which greatly increases the risk of latent mycobacterium tuberculosis infections progressing to active disease, and being transmitted to others. inadequate courses of anti-tuberculosis therapy compound the problem, leading to the emergence and spread of drug-resistant and multidrug-resistant strains , and a need for more expensive treatment strategies such as directly observed therapy. it has been known for over a century that tuberculosis is a disease of poverty, associated with crowding and inadequate hygiene. the continuing expansion of global populations living in poverty makes tuberculosis more difficult to control. . immune deficiency associated with aids, and with chemotherapy for cancer, immune-mediated diseases and transplantation, has contributed to an enormous global increase in the numbers of immunosuppressed people over the past few decades (probably more than % of the world's population), setting the stage for the re-emergence of many opportunistic infections. hiv, which has infected more than million people globally , is the largest single cause of human immune deficiency and markedly increases vulnerability to a wide range of opportunistic pathogens, including pneumocystis carinii, various fungi, tuberculosis, protozoa and herpesviruses . breakthroughs in cancer therapy and in immunosuppressive therapies used to treat immune-mediated diseases and for transplantation , can also leave patients susceptible to opportunistic infections. human organ transplantation adds a further risk of infection with undetected pathogens in donor tissues, and transplantation of animal organs introduces the risk of transmission to humans of animal microbes . the emergence of zoonotic and vector-borne diseases can also be associated with human behaviours and environmental perturbation. although west nile virus is now a major epidemiological concern in the developed world, dengue remains the most significant and widespread flavivirus disease to have emerged globally . a - epidemic in hawaii -fortunately without fatalities -is a reminder that dengue has also re-emerged in locations once considered to be dengue-free. usually transmitted by aedes aegypti mosquitoes, dengue has recently been transmitted by aedes albopictus -a vector switch of potential significance with respect to dengue re-emergence . in the americas, including many us southern states, a. albopictus has been spreading into areas where a. aegypti mosquitoes are not found, and persisting for longer seasonal periods, putting tens of millions more people at risk of dengue infection. dengue re-emergence is further complicated by disturbing increases in a serious and formerly rare form of the disease, dengue haemorrhagic fever (dengue shock syndrome being its highly fatal form). these severe complications are thought to result from the evolution of dengue viruses to escape high insight review articles nature | vol | july | www.nature.com/nature population immunity, seen in increased viral virulence and human immunopathogenesis due to antibody-dependent enhancement of viral infection . cholera is also of interest, not only as an important cause of mortality, but also because of the complexity of factors that determine its re-emergence. both virulent and avirulent strains of these zoonotic bacteria are maintained in the environment and are rapidly evolving in association with phyto-and zooplankton, algae and crustaceans. such environmental strains seem to act as reservoirs for human virulence genes (for example, genes for the phage-encoded cholera toxin and the toxin-coregulated pilus (tcp) factor associated with attachment), and to undergo gene transfer events that lead to new strains containing further virulence gene combinations. these result in periodic cholera emergences that cause epidemics and pandemics . thus, although the disease we know as cholera has appeared to be clinically and epidemiologically stable at least since the third pandemic (in the s), modern evidence suggests that such apparent stability masks aggressive bacterial evolution in complex natural environments. influenza a viruses, which are endemic gastrointestinal viruses of wild waterfowl, have evolved elaborate mechanisms to jump species into domestic fowl, farm animals and humans. periodic gene segment reassortments between human and animal viruses produce important antigenic changes, referred to as 'shifts' . these can lead to deadly pandemics, as occurred in , , and (refs , ) . in intervening years, shifted viruses undergo continual but less dramatic antigenic changes called 'drifts' , which allow them partially to escape human immunity raised by previously circulating influenza viruses. influenza drift is an evolutionary success story for the virus. influenza a has a seemingly inexhaustible repertoire of mutational possibilities at several critical epitopes surrounding the viral haemagglutinin site that attaches to human cells. it remains something of a mystery how zoonotic influenza viruses mix with each other and with human strains to acquire the additional properties of human virulence and human-to-human transmissibility. before , mild cases of human disease associated with avian influenza viruses were occasionally reported . these events have become more frequent, sometimes resulting in severe cases of disease and death. avian influenza has recently made dead-end jumps to humans -for example, the hong kong outbreak of the newly emergent h n influenza, the h n epidemic in the netherlands, the - h n and h n epizootics in asia and elsewhere, and occasional cases of h n disease (fig. ) . meanwhile, back-switches of human h n viruses have emerged in pigs, from which both doubly mixed (pig-human) and triply mixed (pig-human-avian) viruses , have been isolated. such enzootic/zoonotic mixing is suspected to have occurred in the influenza pandemic of - , which was caused by an h n virus with an avian-like receptor-binding site . the predicted virulence genes of this virus are now being sought from -year-old pathology specimens and from frozen corpses . the implications of interspecies genetic mixing for future influenza pandemics are troubling. although much remains speculative about how influenza viruses emerge and spread, it seems clear that the process is driven by prolific and complex viral evolution (genetic reassortment and mutational 'drift'), interspecies mixing and adaptation, and ecological factors that bring humans into contact with animals and each other. by whatever means new influenza virus pandemic strains emerge, they eventually reach a critical threshold of human transmission beyond which epidemic and pandemic spread follows mathematically predictable patterns. the dynamics and determinants of such epidemic development have been studied since the nineteenth century for several infectious diseases. for influenza, both historical and prospective epidemics have been described or predicted using deterministic and stochastic mathematical models, often with surprising accuracy when compared with actual epidemic data. more complicated mathematical models that describe how diseases spread by means other than personto-person aerosol transmission have generally been less successful in describing and predicting epidemics, but have nonetheless been helpful in planning public health responses to epidemics caused by hiv , vcjd and other diseases. mathematical modelling is also used to determine the impact of emerging epidemics. for example, it has been difficult to estimate overall influenza mortality because fatal infections are often neither diagnosed nor accurately recorded in hospital records and death certificates, especially in the elderly. recent epidemiological attempts to obtain improved influenza mortality estimates from seasonal excess mortality data have indicated that influenza mortality may be insight review articles nature | vol | july | www.nature.com/nature greater than was previously suspected, because influenza deaths are frequently coded under seemingly unrelated categories such as cardiovascular diseases. the same approaches also show that other influenza-like deaths may actually be due to other agents, such as respiratory syncytial virus (rsv), a common childhood virus that in the past decade has emerged as a major cause of adult mortality . deliberately emerging microbes are those that have been developed by man, usually for nefarious use. the term 'deliberately emerging' refers to both naturally occurring microbial agents such as anthrax , and to bioengineered microorganisms such as those created by the insertion of genetic virulence factors that produce or exacerbate disease. deliberately emerging microbes include microorganisms or toxins produced in a form that would cause maximal harm because of ease of dissemination, enhanced infectivity or heightened pathogenicity . as concepts, bioterrorism and biowarfare are probably not new. the alleged catapulting of plague-ridden corpses over enemy walls in the siege of caffa (the modern crimean port of feodosia, ukraine) and the dispatch of smallpox-impregnated blankets to indians by british officers in the seven years war ( - ) have frequently been cited as examples of bioterrorism or biowarfare , . two modern attacks have been well documented. in , an oregon religious cult spiked restaurant salad bars with salmonellae in an attempt to sway a local election . a anthrax attack , in which a terrorist mailed anthrax-spore-filled letters to prominent figures, including two us senators, resulted in illness in at least people and the death of five of these individuals. public alarm was elevated by the knowledge that bacillus anthracis is a common and easily obtainable enzootic and soil organism found in laboratories worldwide, and that scientific technology had increased its lethality: the spores had been weaponized by being concentrated, finely milled and packed with a dispersal agent to increase their capacity to disseminate . the united states, the united kingdom, the soviet union and other nations once had sophisticated offensive bioweapons programmes that included the production of weaponized anthrax spores . soviet scientists continued to produce large quantities of organisms adapted for biowarfare and bioterror -among them the agents of smallpox, plague, tularaemia and marburg virus -for several years after their signing of the bioweapons and toxins treaty convention in , which forbade such activities . by , the soviet programme was annually producing , tonnes of weaponized anthrax spores, packing them into warheads and other delivery devices . before the anthrax attacks , the us scientific community had for several years been bolstering its biodefence research capacity. the anthrax attacks greatly accelerated this expansion as part of a national defence plan, which includes efforts to provide a knowledge base for the development of effective countermeasures against agents of bioterror, such as diagnostics, therapeutics and vaccines, and to translate this knowledge into the production and delivery of such measures . bioterror agents have been grouped into three categories of risk . the six category a agents (anthrax, smallpox, plague, tularaemia, viral haemorrhagic fevers and clostridial botulinum toxin) are given top priority because they are highly lethal and readily deployed as weapons. category b and c agents include food-borne and water-borne organisms that incapacitate but usually do not kill. infectious diseases will continue to emerge and re-emerge, leading to unpredictable epidemics and difficult challenges to public health and to microbiology and allied sciences. surveillance and response, the key elements in controlling eis, be they naturally occurring or deliberately engineered, depend on rapid clinical diagnosis and detection and containment in populations and , which along with state and local health departments and other agencies have been making significant strides in national surveillance-response capacity. the enormous influx of us government-funded research resources (largely through the national institutes of health) and public health resources (mainly through the cdc, and state and local public health agencies) in response to the increased threat of a bioterrorist attack will fortify the response capabilities related to all eis. however, it is clear that surveillance and other activities that traditionally fall within the domain of public health are not in themselves sufficient to adequately address the problem of eis. of critical importance are basic, translational and applied research efforts to develop advanced countermeasures such as surveillance tools, diagnostic tests, vaccines and therapeutics . genomics, proteomics and advances in nanotechnology are increasingly being exploited in diagnostic, therapeutic and microbial research applications, and in rational drug and vaccine design. direct and computational structural determination , prediction of protein-protein interactions between microorganisms and drugs, and sophisticated bioinformatics techniques support research in all of the above areas. these technologies have led to numerous advances in real-world utility against eis, most notably in the development of more than antiretroviral drugs that can effectively suppress hiv replication. where they are available and properly used in hiv-infected individuals, these medications have dramatically reduced hiv morbidity and mortality . gene-and protein-based microarrays can be used to detect pathogen signals, to monitor resistance to anti-infective agents, to characterize host gene responses to recent infections, and to facilitate the development of new drugs and vaccines . basic and applied research together have provided promising new vaccine platforms, such as recombinant proteins, immunogenic peptides, naked dna vaccines, viral vectors of extraneous genes encoding immunogenic proteins (including chimaeras), replicons and pseudovirions . many novel vaccine candidates are now being developed against eis such as hiv, ebola virus, west nile virus, dengue, the sars coronavirus, tuberculosis and malaria. of particular note are novel tuberculosis vaccines that recently entered clinical trials -the first time in more than years that new approaches to vaccination for tuberculosis have been assessed in humans . chimaeric flavivirus vaccines for west nile virus, dengue and japanese encephalitis virus are effective in animal models and are in various stages of clinical testing . our growing understanding of the human immune system is also helping to accelerate vaccine development. this is especially true in the case of innate immune responses, which are evolutionarily older, less specific and faster-acting than the adaptive responses that have been the traditional targets of vaccines . as we learn more about innate immunity and its relationship with the adaptive immune system, opportunities to create more effective vaccine adjuvants will emerge. for example, synthetic dna sequences that contain repeated cpg motifs mimic the stimulatory activity that bacterial dna fragments exert on the innate immune system. these sequences show promise as vaccine adjuvants that accelerate and augment immune responses . we can anticipate more progress of this kind as we continue to delineate the complex interactions between innate and adaptive immune responses. the sequencing of the human genome, the genomes of six other animals, including the mouse, and those of microbial vectors and microbes themselves (for example, p. falciparum and its mosquito vector, anopheles gambiae), have elevated microbiology to a wholegenome level. the ability to sequence microbial genomes in a few days or less, and to examine host-vector-microbe interactions at both the genome level and at the tertiary protein structural level, will help us to understand the molecular mechanisms that underlie the pathogenesis of infectious disease and host defences, including resistance and immune evasion. these advances will facilitate the development of new countermeasures. other fertile areas of research include the use of geographical information systems and satellite imaging to support field study and epidemic prevention (for example, predicting hps and rift valley fever epidemics in indigenous areas by satellite imagery of water and vegetation related to animal reservoir and vector prevalence). underlying disease emergence are evolutionary conflicts between rapidly evolving and adapting infectious agents and their slowly evolving hosts. these are fought out in the context of accelerating environmental and human behavioural alterations that provide new ecological niches into which evolving microbes can readily fit. it is essential that broadly based prevention strategies, as well as new and improved countermeasures (that is, surveillance tools, diagnostics, therapeutics and vaccines), be continually tested, refined and upgraded, requiring a strengthened relationship between public health and basic and clinical sciences. the challenge presented by the ongoing conflict between pathogenic microorganisms and man has been well summarized by a noted champion of the war on eis, joshua lederberg: "the future of microbes and mankind will probably unfold as episodes of a suspense thriller that could be entitled our wits versus their genes" . the global scientific and public health communities must confront this reality not only with wit, but also with vision and sustained commitment to meet a perpetual challenge. in figure of this review, the pie chart was drawn incorrectly, with the wedge sizes not in proportion to the total size. the correct figure is shown below. asthma and chronic obstructive pulmonary disease . million factors in the emergence of infectious diseases the wordsworth encyclopedia of plague and pestilence updating the accounts: global mortality of the - "spanish" influenza pandemic centers for disease control and prevention. multistate outbreak of monkeypox -illinois the severe acute respiratory syndrome investigation of bioterrorism-related anthrax, united states, : epidemiologic findings threats to global health and survival: the growing crises of tropical infectious diseases -an "unfinished" agenda emerging infectious diseases among indigenous peoples ǼșȓȖșȕșȍȓȊ -sive, pestis nuperae apud populum londinensem grassantis narratio historica epidemiology of the plague of athens the columbian exchange: biological and cultural consequences of princes and peasants. smallpox in history ch island populations of the pacific the gifts of civilization. germs and genocide in hawai'i agents of apocalypse: epidemic disease in the colonial philippines measles in fiji, : thoughts on the history of emerging infectious diseases die aetiologie der milzbrand-krankheit, begründet auf die entwicklungsgeschichte des bacillus anthracis. beiträge zur biologie der pflanzen spreading germs: diseases, theories, and medical practice in britain the greatest benefit to mankind: a medical history of humanity from antiquity to the present the extermination of infectious diseases the evolution and eradication of infectious diseases infectious diseases: considerations for the st century the restless tide: the persistent challenge of the microbial world (national foundation for infectious diseases committee on emerging microbial threats to health. emerging infections. microbial threats to health in the united states committee on emerging microbial threats to health in the st century. microbial threats to health in the united states: emergence, detection and response emerging and re-emerging infectious diseases: a multidisciplinary perspective emerging and re-emerging infectious diseases infectious history emerging infectious diseases in the st century emerging and re-emerging infectious diseases human frontiers, environments and disease the origins of acquired immune deficiency viruses: where and when? phil population migration and the spread of types and human immunodeficiency viruses the aids knowledge base slowing heterosexual hiv transmission a novel hantavirus associated with an outbreak of fatal respiratory disease in the southwestern united states: evolutionary relationships to known hantaviruses nipah virus: a recently emergent deadly paramyxovirus variant creutzfeldt-jakob disease and the acquired and transmissible spongiform encephalopathies nützliche und auf die erfahrung gegründete einleitung zu der landwirthschaft identification of a second bovine amyloidotic spongiform encephalopathy: molecular similarities with sporadic creutzfeldt-jakob disease scrapie and chronic wasting disease severe streptococcal infections in historical perspective emerging infections brazilian purpuric fever: evolutionary genetic relationships of the case clone of haemophilus influenzae biogroup aegyptius to encapsulated strains of haemophilus influenzae identification and characterization of genomic loci unique to the brazilian purpuric fever clonal group of h. influenzae biogroup aegyptius: functionality explored using meningococcal homology group a streptococcus: allelic variation, population genetics, and host-pathogen interactions genome sequence of a serotype m strain of group a streptococcus: phage-encoded toxins, the high-virulence phenotype, and clone emergence identification of herpesvirus-like dna sequences in aids-associated kaposi's sarcoma microbes and malignancy: infection as a cause of human cancers helicobacter pylori-associated diseases current clinical topics in infectious diseases vol el niño and health epidemiology in relation to air travel acute haemorrhagic conjunctivitis: dealing with a newly emerging disease two worlds of malaria research toward vaccines against malaria the global situation of mdr-tb staphylococcus aureus resistant to vancomycin -united states methicillin (oxacillin)-resistant staphylococcus aureus strains isolated from major food animals and their potential transmission to humans the crisis in antibiotic resistance surveillance for aids-defining opportunistic illnesses, - . mmwr (cdc surveillance summary no. ss- ) infections in patients with cancer undergoing chemotherapy: aetiology, prevention, and treatment impact of current transplantation practices on the changing epidemiology of infections in transplant recipients xenotransplantation: public health risks -patient vs. society in an emerging field the outbreak of west nile virus infection in the new york city area in outbreak of west nile infection west nile virus: epidemiology and ecology in north america dengue and dengue haemorrhagic fever antibody-dependent enhancement of infection and the pathogenesis of viral disease molecular ecology of toxigenic vibrio cholerae the next influenza pandemic: lessons from hong kong a molecular whodunit avian influenza viruses infecting humans structure of the uncleaved human h haemagglutinin from the extinct influenza virus the origin of the pandemic influenza virus: a continuing enigma potential impact of low-efficacy hiv- vaccines in populations with high rates of infection short-term projections for variant creutzfeldt-jakob disease onsets mortality associated with influenza and respiratory syncytial virus in the united states the chilling true story of the largest covert biological weapons program in the world -told from the inside by the man who ran it (random house document zur geschichte des schwarzen todes. mitgetheilt und eingeleitet smallpox and the indians in the american colonies a large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars biodefence on the research agenda: the world needs new and creative ways to counter bioterrorism threats in bioterrorism: i. cdc category a agents world health organization. consensus document on the epidemiology of severe acute respiratory syndrome (sars) preventing emerging infectious diseases: a strategy for the st century (department of health and human services protein structure prediction and structural genomics guidelines for using antiretroviral agents among hiv-infected adults and adolescents new technology platforms in the development of vaccines for the future the jordan report: th anniversary adjuvants of immunity: harnessing innate immunity to promote adaptive immunity recent advances in the discovery and delivery of vaccine adjuvants the value of complete microbial genome sequencing (you get what you pay for) the authors thank r. m. krause for helpful discussions, and j. weddle for graphic design. the authors declare that they have no competing financial interests.insight review articles key: cord- -cvvyf cb authors: kelley, patrick w. title: global health: governance and policy development date: - - journal: infectious disease clinics of north america doi: . /j.idc. . . sha: doc_id: cord_uid: cvvyf cb global health policy is now being influenced by an ever-increasing number of nonstate and non-intergovernmental actors to include influential foundations, multinational corporations, multi-sectoral partnerships, and civil society organizations. this article reviews how globalization is a key driver for the ongoing evolution of global health governance. it describes the massive increases in bilateral and multilateral investments in global health and it highlights the current global and us architecture for performing global health programs. the article closes describing some of the challenges and prospects that characterize global health governance today. recent inspection rates it would cost the fda $ . billion and take more than years to inspect the , foreign facilities involved with registered food production for export to the united states. governance structures for building consensus and for collectively managing public health actions are necessary because the world's inhabitants cannot create societies and economies that are largely self-contained and insulated from outside threats. the world's inhabitants increasingly share the same air, water, exposure to infectious diseases, foods, pharmaceuticals, and health workforce. through climate change, the impact of human activities in a few countries can affect harvests, the epidemiology of infectious diseases, and the potential for global natural disasters. even among countries with strong public health programs, harmonization of standards and processes is important for effective and efficient collective action. today's global health governance structures include a complex web of un agencies, public/private partnerships, donor and recipient governments, foundations, corporations, and civil society organizations. a recent report from the kaiser family foundation identified multilateral international health treaties, commitments, partnerships, and other agreements, of which are legally binding under international law. the united states is a party to of these of agreements, of which are legally binding. these agreements cover many topical areas, including specific diseases, environmental issues, trade and intellectual property, specific populations (eg, refugees or children), health security/preparedness, water, and food/nutrition. in the aftermath of the nineteenth-century international sanitary conferences that focused on threats to ports and trade, the early twentieth century saw international $ , global health governance reflected in new institutions, such as the international sanitary bureau (isb) based in washington, dc, and the office internationale d'hygié ne publique in paris. the isb subsequently became the pan american health organization, which since has been one of regional offices of the who. when the un system was conceived in , brazil and china proposed the who. the who constitution contains several key principles, including: health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity. the enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social condition. the health of all peoples is fundamental to the attainment of peace and security and is dependent upon the fullest co-operation of individuals and states. the broad mandate of the who has core functions: the provision of collective health leadership, the shaping of research as well as the generation and dissemination of knowledge, the setting of norms and standards and the promotion and monitoring of their implementation, the production of ethical and evidence-based policy options, the provision of technical support and capacity-building, and the monitoring of health situations and trends. the organization has a -point agenda: promote development; foster health security; strengthen health systems; harness research, information, and evidence; enhance partnerships; and improve performance. this agenda is shaped at annual meetings in geneva by the member countries that compose the world health assembly. an -person secretariat based in geneva and at the regional and country offices performs who programs. the breadth of the programs undertaken is vast, although not always deep. some of the topics addressed include hiv/aids; malaria; tuberculosis; chronic noncommunicable diseases; mental disorders; violence; traffic safety; visual impairment; maternal and child health; aging; disasters; health equity; environmental health; nutrition and food safety; drug access; research; health systems strengthening; and tobacco, alcohol, and drug abuse, and other unsafe behaviors. when the who was envisioned, the concept of its operations was quite vertical and focused primarily on relationships with member states. few other actors were engaged in global health. since its founding, the who has celebrated major accomplishments but has also suffered from an erosion of its influence. beyond the eradication of smallpox (an event that has likely saved more than million lives since ), who technical leadership has also played a role in the near eradication of polio; the containment of the deadly sars epidemic; the landmark who framework convention on tobacco control (the first treaty negotiated under the auspices of who); and the revision of the international health regulations (ihr). compared with the previous ihr that was focused on classical diseases of international importance, plague, yellow fever, and cholera, the revision is more powerful and practical in that it encompasses all acute public health risks of transnational significance. the new ihr defines broad reporting requirements and establishes the authority of the who to initiate disease-control actions, if necessary, through use of information sources other than country governments. the new ihr also requires countries to strengthen their existing surveillance capacities. many have hoped that the who would take a stronger role in the setting and enforcement of norms, given its extraordinary constitutional authorities and its quasi-legislative power to adopt binding regulations. the who has, however, leaned more toward providing technical advice than toward exerting bold, proactive leadership through binding norms and regulations. kelley given its mandate, the who is handicapped by a modest budget and by its dependent fiscal relationships. the proposed budget for to was $ . billion before currency adjustments. because only about . % of the who budget comes from the dues assessments of member countries, its flexibility in focusing its program based on the scientific priorities it determines is constrained. wealthier countries pay larger assessments and thus have more influence over the direction of who programming than poorer countries, which have the greater need for help. moreover, the remaining . % of the budget is projected as "voluntary contributions," which are largely earmarked by donors for specific purposes. this arrangement contributes to fragmented programming and perhaps to certain donor-influenced compromises. in this century, the who also faces growing challenges. although its members are sovereign governments, many other powerful actors (including nongovernmental entities, such as other un agencies, foundations, corporations, and civil society organizations) have entered the global-health arena. placating these competing interests is not a recipe for bold action. the who is the lead un agency for health. owing to the increasing recognition that health is fundamental to the broader un goals of fostering the international rule of law, global security, economic development, social progress, human rights, and world peace, health issues have now taken a more prominent place than they had in the united nation's first years. in , world leaders came together at the un headquarters to adopt the millennium development goals (mdgs), of which are focused on health. the leaders of un member states agreed to partner to achieve these goals by . the health-related goals have directly provided high-level, consensus global health policy direction (box ). another goal is related to hunger reduction. regrettably, the mdgs lack a target for chronic diseases, such as cardiovascular diseases and cancers, which now account for more than % of the global burden of disease. since , progress toward the mdg targets has been mixed. for example, between and , the number of individuals infected with hiv placed on antiretroviral drugs rose from , to million (ie, % of the . million people in target c: have halted and begun to reverse the incidence of malaria and other major diseases by need). in developing countries, % of births in still took place without a trained birth attendant present, and maternal mortality remains shockingly high. as a result of the hiv/aids pandemic and its immense scale and impact on human life, dignity, rights, social cohesion, and economic development, a un general assembly special session issued a formal declaration of commitment on hiv/aids in june . that declaration endorsed the establishment of the "global aids and health fund," which would pool contributions from countries and from the private sector to fund hiv prevention and treatment efforts. it also set out a policy approach to providing leadership; improving prevention, care, and treatment; preserving human rights; reducing the vulnerability of women and children at risk for or affected by hiv/aids; and mobilizing financial resources. a un special session on noncommunicable diseases and their prevention will convene in september . as illustrated in box , the un has spawned a wide array of specialized agencies and other entities with direct or indirect interests in health. to some degree, these compete with the who for legitimacy and resources, and some have a significant role in global health governance. in world trade organization treatment, especially among migrants, women and girls, peacekeepers, travelers, and orphans; it unites the relevant un agencies, civil society organizations, governments, and the private sector; it advocates for rights, resources, and accountability; it empowers actors with strategic information; and it supports country leadership. created by the general assembly in for post-war relief, unicef is now focused on providing on-the-ground, long-term humanitarian and developmental assistance to children and mothers in developing countries. funded by governments and the private sector, the unicef expenditures totaled $ . billion. based in rome, the food and agriculture organization of the united nations (fao) operates through regional offices and through more than country offices around the world. with a biennial budget in to of $ . million, the fao leads un efforts to enhance food security and to eliminate hunger, the number-one mdg. the fao provides a neutral forum in which all countries can negotiate agreements and debate policy. its experts disseminate technical information and assist countries with disease outbreaks and in developing sound agriculture policies. where issues of human health and animal health intersect (eg, avian influenza or food safety emergencies), the fao plays a role. although not actually a un agency, the world organization for animal health (previously known as the office international des epizooties and still known as the oie) is also an intergovernmental organization; it seeks to perform global disease control for the animal population. based in paris and having regional and subregional offices worldwide, the oie is an important partner of the who, the fao, and the world trade organization (wto). like the who, it operates under the collective control and authority of an assembly of member countries. oie relevance to global health governance stems from the often-underappreciated connection between human health and animal health. this connection, embodied in the one-health concept, is most evident in the context of emerging zoonotic diseases and food safety. in , an institute of medicine (iom) committee concluded that the oie rules lacked critical provisions found in the who ihr, provisions that would be valuable for an organization involved in protecting animals capable of transmitting infections to humans. the committee recommended that the oie create legally binding obligations for members to develop and maintain core surveillance-and-response capabilities, that the oie be authorized to publically disseminate the animal-disease information received from nongovernmental sources when the member state does not do so in a timely and accurate way, and that the oie director general be empowered to declare animalhealth emergencies and related recommendations as appropriate. the wto, a member of the un family since , is primarily concerned with the rules of trade between nations. with globalization, however, trade and health are increasingly connected. the wto has several agreements related to health and health policies, including the agreements on technical barriers to trade; the sanitary and phytosanitary measures; the trade-related intellectual property rights (trips); and the trade in services. although trade can be restrained for scientifically valid reasons related to health, relevant interpretations can be controversial. some health issues relevant to wto agreements include food safety and protection from zoonotic diseases; trips patent protection for pharmaceuticals (to balance incentives for drug development vs ensuring affordable access to drugs); tobacco control; biotechnology; and the transnational migrations of health workers, patients, and investment in health services. the world bank group, founded in , is a critical source of financial and technical help for developing countries. headquartered in washington, dc, it employs more than , people worldwide. the bank provides low-interest loans, interest-free credits, and grants to developing countries for health and other purposes. the world bank consists primarily of unique development institutions owned by member countries: the international bank for reconstruction and development (ibrd) and the international development association (ida). the ibrd serves middle-income and creditworthy poorer countries; whereas, the ida mission is to serve the world's poorest countries. ibrd lending is primarily financed through aaa-rated bonds sold on the world's financial markets; the ida funds come from donor countries and are replenished periodically. additional funds come from repayments of loan principal on longterm, no-interest loans. the ida accounts for more than % of world bank lending, and its loans are largely supervised and evaluated by the world bank country offices. ida loans have been used to improve sanitation and water supplies, support immunization programs, and combat the hiv/aids pandemic. in fiscal , the world bank health, nutrition, and population program lent $ . billion, a -fold increase from . since , the bank group provided $ billion in country-level project financing and $ million in private health and pharmaceutical investments. in fiscal , the bank disbursed $ million for existing hiv projects and committed nearly $ million to new hiv/aids efforts. it also committed funds in fiscal for pandemic preparedness. achieving the mdgs will require an estimated $ billion to $ billion annually. higher-income countries have made substantial policy commitments to support the lower-income countries that have insufficient resources to provide a basic package of essential health benefits (estimated at $ per capita per year). funding for action by wealthier countries has often been coordinated through governance mechanisms, including the annual group of eight (g ) summits. g progress toward these commitments is summarized in table . in , the un millennium project estimated that to meet the mdgs, the total overseas development assistance (oda) from high-income countries would need to rise to . % of gross national income (gni). in absolute terms, the us government has contributed great amounts to oda; however, as depicted in fig. , the relative amount contributed in was only . % of us gni, a figure less generous than the percentage contributed by most european countries, australia, and canada. the us government's global health program, compared with that of many other donor governments, cuts across many departments. it draws upon both the foreign-assistance structure but also the government's extensive public health capabilities. in addition to well-known actors, such as the us agency for international development and the us centers for disease control and prevention, executive branch agencies with a significant involvement in global health include the departments of state, defense, agriculture, homeland security, labor, and commerce, as well as the national institutes of health, the food and drug administration, the environmental protection agency, the peace corps, and the health resources and services administration. these agencies carry out programs in more than countries and are overseen by more than congressional committees. the us financial commitment to global health has dramatically increased over the last decade, especially with the implementation of the president's emergency plan for aids relief (pepfar) and the president's malaria initiative (fig. ) . originally authorized in at about $ billion, pepfar focused on countries, mostly in africa. over its first years, pepfar sought to support antiretroviral treatment for million people infected with hiv; prevent million hiv infections; and provide care, including care for orphans and vulnerable children, for million individuals. the program has been viewed as a major success for us global health policy. with wide bipartisan support, pepfar was reauthorized in for another years at $ billion, with substantial increases in the prevention, treatment, and care targets. the legislation also authorized $ billion for tuberculosis programming and $ billion for malaria efforts. although pepfar represents a landmark us achievement in global health, it also illustrates how policy can be skewed by nonscientific factors. fig. shows that among i r e l a n d f i n l a n d u n i t e d k i n g d o m s w i t z e r l a n d s p a i n f r a n c e g e r m a n y a u s t r i a c a n a d a a u s t r a l i a n e w z e a l a n d p o r t u g a l u n i t e d s t a t e s g r e e c e j a p a n i t a l y health called for a rebalancing of this portfolio to better support initiatives against noncommunicable diseases, malnutrition, and injuries. the signature global health program of the obama administration, the global health initiative (ghi), aims to provide $ billion in health assistance between and . although hiv/aids still dominates the ghi, increased investments are being made for neglected tropical diseases, malaria, maternal and child health, and family planning (box ). the aims of the ghi are to implement a woman-centered and girlcentered approach; increase impact and efficiency through strategic coordination and integration; strengthen and leverage key partnerships, multilateral organizations, and private contributions; encourage country ownership and investing in country-led plans; improve metrics, monitoring, and evaluation; and promote research and innovation. the us government's policy commitment to global health has been greatly lauded as a reflection of our vital health and economic self-interests, our humanitarian values, and "smart power." [ ] [ ] [ ] in many ways, it is an important form of diplomacy; however, some aspects of it may also hinder diplomatic prerogatives. some forms of oda can be used as leverage in diplomatic negotiations, but once a patient infected with hiv is taken into a pepfar-funded treatment program, it would be unethical for the us government to threaten the loss of those lifesaving drugs for diplomatic advantage. beyond un agencies and national governments, the global health enterprise is now a much more horizontal and networked endeavor than it was even years ago. although this makes it harder for the who to lead, it also brings a wider array of talent and resources to bear on problems. fig. illustrates an example of the partnership paradigm of global health governance today: the roll back malaria (rbm) partnership, a -member collaboration. even though the who was one of the founders of rbm and hosts the secretariat, it is not positioned as the dominant core of the effort. the rbm partnership not only works to facilitate policy coordination at the global level but also executes an operating framework with performance targets reflective of the mdg malaria goal; it articulates technical strategies and provides multidirectional accountability through its partners forum. a decision-making partnership board with members ( ex-officio) represents the broad rbm constituencies and meets periodically. there are voting members of the board representing foundations ( seat), malaria-endemic countries ( seats), multilateral institutions ( seats), ngos ( seats), organization for economic cooperation and development (oecd) donor countries ( seats), private sector ( seats), and research and academia ( seat). the stop tb partnership (http://www.stoptb.org/) also has many similarities to rbm. founded in , the global alliance for vaccines and immunizations (gavi) is another innovative partnership that links developing-world governments and donor governments; philanthropic foundations; the financial community; vaccine manufacturers from developed and developing countries; research and technical institutes; civil society organizations; and intergovernmental entities, such as who, unicef, and the world bank. immunizations funded by gavi have prevented an estimated . million deaths in developing countries. gavi also supports innovative financing box the goals and targets of the us government global health initiative hiv/aids: the us president's emergency plan for aids relief will: ( ) support the prevention of more than million new hiv infections; ( ) provide direct support for more than million people on treatment; and ( ) support care for more than million people, including million orphans and vulnerable children. malaria: the president's malaria initiative will reduce the burden of malaria by % for million people, representing % of the at-risk population in africa, and expand malaria efforts into nigeria and the democratic republic of the congo. tuberculosis (tb): save approximately . million lives by reducing tb prevalence by %, which will involve treating . million new tb cases and , multidrug-resistant cases of tb. maternal health: save approximately , women's lives by reducing maternal mortality by % across assisted countries. child health: save approximately million children's lives, including . million newborns, by reducing under- mortality rates by % across assisted countries. nutrition: reduce child undernutrition by % across assisted food-insecure countries, in conjunction with the president's feed the future initiative. family planning and reproductive health: prevent million unintended pregnancies by meeting unmet need for modern contraception. contraceptive prevalence is expected to rise to % across assisted countries, reflecting an average annual increase of percentage points. first births by women younger than years should decline to %. neglected tropical diseases: reduce the prevalence of neglected tropical diseases by % among % of the affected population, and eliminate onchocerciasis in latin america by , lymphatic filariasis globally by , and leprosy. data from available at: http://www.usaid.gov/ghi/factsheet.html. mechanisms, such as advanced market commitments to reduce the costs of immunizations needed by developing countries. the un declaration of commitment on hiv/aids called for the establishment of a global fund of pooled contributions to support hiv/aids needs. this global fund to fight aids, tuberculosis, and malaria (gfatm), unlike the previously mentioned partnerships, has as its sole focus mobilizing and distributing financial resources in a manner driven by technically sound national plans and priorities and principles of transparency and accountability. the gfatm is a partnership between governments, civil society, the private sector, and affected communities. more than countries have pledged funds to the gfatm; other major donors include the bill and melinda gates foundation, unitaid, and chevron. about $ billion has been pledged, of which more than $ billion has already been paid. with funding approved for more than programs in nearly countries, the gfatm is the source of onequarter of all international financing for aids globally as well as for two-thirds of that for tuberculosis and three-quarters of that for malaria. an innovative fiscal contribution to solving the crisis of antimalarial drug resistance and the dwindling number of effective drugs has been the creation of the affordable medicines facility for malaria (amfm). conceived by the iom committee on the economics of antimalarial drugs, the amfm was designed to re-engineer market forces to favor the effective treatment of resistant malaria through the appropriate use of artemisinin-containing combination antimalarial drugs (acts). in the committee recommended the commitment of $ to $ million per year to subsidize the entire global act market to create a steady supply of affordable and desirably priced acts in all malarious areas. several donors accepted this recommendation. the amfm was established by the gfatm and initially capitalized with more than $ million. although the greatest sources of funding, technical support, and leadership will continue to come from donor governments, recipient governments, and un agencies, contributions from the world of philanthropy have never been more significant. early in the twentieth century, rockefeller philanthropy supported efforts to eliminate hookworm, first domestically and then internationally. it has since taken on many other disease-control efforts directed toward conditions, including malaria, schistosomiasis, yellow fever, and vaccine-preventable childhood infections. in , it created the china medical board to develop modern medicine in that country but arguably its most significant contributions to advancing global health governance were investments to establish the johns hopkins school of hygiene and public health as well as schools of public health at harvard and the university of michigan. reflecting the emergence of the new era in global health governance, in the rockefeller foundation established an initiative to create innovative new public-private partnerships, including the medicines for malaria venture, the global alliance for tb drug development, and the international partnership on microbicides. over the years, many other foundations have made important contributions to facilitating global health action, including the ford foundation, atlantic philanthropies, the carnegie corporation, the bloomberg family foundation, the burroughs wellcome trust, the burroughs wellcome foundation, and the doris duke charitable foundation. the most noteworthy newcomer is the bill and melinda gates foundation. with assets of approximately $ billion, the gates foundation is the largest private philanthropy in the world. its current annual disbursements are approximately $ billion, much of which goes to global health. among foundations, its major commitments to gavi (at least $ . billion), the rotary international polio-eradication effort ($ million), and the gfatm ($ million) give it a uniquely powerful and sometimes controversial voice in global health governance. its investments in research, implementation, and advocacy encompass enteric and diarrheal diseases; hiv/aids; malaria, pneumonia, tuberculosis, and neglected and other infectious diseases; family planning; nutrition; maternal, neonatal and child health; tobacco control; and vaccine-preventable diseases. private funding now accounts for almost one-quarter of global health aid. unlike the foundations previously mentioned, the william j. clinton foundation is not a grant-making organization. for nearly a decade, however, it has been a unique contributor to advancing global health. by capitalizing on the influence of former president bill clinton, this foundation has catalyzed many initiatives. among these initiatives have been tremendous gains in access to hiv/aids treatment through negotiations with suppliers of drugs and diagnostic tests. through successive agreements, suppliers to low-income countries have reduced the prices of first-line treatments by %, pediatric medicines by %, and second-line hiv/aids medicines by a cumulative reduction of %. over the last decade, the corporate sector has also been making an increasing mark on global health. although corporate initiatives are too numerous to catalog in detail, their donations of drugs are especially noteworthy. since , for example, merck has donated ivermectin for the control of onchocerciasis (river blindness) worldwide. in , in partnership with glaxosmithkline, this commitment was expanded to include the elimination of lymphatic filariasis; ivermectin and glaxosmithkline's albendazole were coadministered in african countries and in yemen (countries where lymphatic filariasis and onchocerciasis are coendemic). over years, more than billion treatments for these infections have been provided though a large partnership. johnson and johnson donates enough mebendazole each year to treat million children for intestinal helminthes; boehringer ingelheim donates nevirapine to prevent mother-to-child transmission of hiv. pfizer has proved to be a valuable and innovative partner with its support for capacity-building activities, such as the pfizer global health fellows program. each year, this program deploys up to talented employees to work on high-impact, capacity-building projects in developing countries. similarly, bd strengthens capacity through a partnership with pepfar to improve laboratory systems in countries highly affected by hiv/aids and tb. the emerging corporate role in global health is not limited to companies focused on the business of health. companies as diverse as exxonmobil, warner brothers, and nike have engaged in important partnerships focused on controlling malaria, hiv/ aids, and violence against girls. american cyanamid has donated millions of dollars of the larvicide temephos to support guinea worm eradication efforts. formal business coalitions have developed to take on issues of malaria, tuberculosis, and hiv/aids. the role of civil society organizations in global health predates all of those entities previously named. the who lists ngos with which it has an official relationship. as the who notes: no longer the domain of medical specialists, health work now involves politicians, economists, lawyers, communicators, social scientists and ordinary people everywhere. the involvement of civil society has profoundly affected not only the concepts underpinning public health but the formulation and implementation of public health programs and policies as well. global health: governance and policy development civil society organizations span a wide array of secular and faith-based entities. they include groups with a disease-specific orientation; groups with a professionalspecialty focus; charities that work on the ground; and global professional service organizations, such as rotary international. (rotary international is a key global partner in the who campaign for polio eradication. ) perhaps the most exciting recent development in the united states has been the explosion in interest in global health education at universities. suffice it to say that if governance is the constellation of mechanisms a society uses to effect collective action toward common goals, then the catalyst of the many new us multidisciplinary university programs in global health education will initiate and energize an unprecedented level of collective action. despite the vast inflow of resources for global health, the remaining policy challenges are significant. perhaps today's most acute global health challenge is achieving the health-related mdgs. current trends indicate that none of these basic targets will be near achievement by . overall access to care is still lacking or suboptimal for billions of people. access to clean water and essential medicines is uneven. modern pharmaceuticals are often unaffordable or unavailable. globalization has brought some health benefits to the world's poorest, but it has also fostered the transnational spread of infectious diseases, the brain drain of skilled health care workers from developing countries, and the trade in poor-quality food and pharmaceuticals. surveillance for human and animal diseases is of variable quality and the enforcement of the relevant regulatory regimes needs improvement. despite the challenges that remain in coordinating the many diverse players now engaged in global health, the vast increase in the commitment of both private and public wealth over the last decade is to be celebrated. commitments have gone far beyond money and have brought forth legions of individuals who choose to commit themselves in the global context to the universal value of health. research is steadily discovering and developing new technological interventions. new mechanisms of cooperation have been developed, and there is a growing interest in implementation science and in program evaluation to increase accountability and effectiveness. improved global health governance to better catalyze and coordinate collective action remains an essential underpinning to meeting the diverse challenges to saving lives in all parts of the globe. global governance in health -do historical experiences of industrialized countries teach any lessons? the emergence of new virus diseases: an overview learning from sars: preparing for the next disease outbreak (workshop summary) the domestic and international impacts of the -h n influenza a pandemic: global challenges, global solutions (workshop summary) infectious disease movement in a borderless world (workshop summary) convention on the prohibition of the development, production and stockpiling of bacteriological (biological) and toxin weapons and on their destruction top u.s. agricultural import sources drug safety: preliminary findings suggest recent fda initiatives have potential, but do not fully address weaknesses in its foreign drug inspection program (testimony before the subcommittee on oversight and investigations, committee on energy and commerce, us house of representatives). washington, dc. the united states government accountability office global climate change and extreme weather events: understanding the contributions to infectious disease emergence (workshop summary) global health policy: u.s. participation in international health treaties, commitments, partnerships, and other agreements constitution of the world health organization the role of the who in public health global health governance report (commissioned paper). the u.s. commitment to global health: recommendations for the public and private sectors draft proposed programme budget united nations united nations general assembly special session on hiv the convention on the rights of the child. new york: unicef one health initiative task force: final report. one health -a new professional imperative sustaining global surveillance and response to emerging zoonotic diseases world trade organization/world health organization the world bank annual report -year in review. the international bank for reconstruction and development/the world bank millennium development goals for health: what will it take to accelerate progress? global health policy: the u.s. government's global health policy architecture: structure, programs, and funding committee for the evaluation of the president's emergency plan for aids relief (pepfar) implementation. pepfar implementation: progress and promise. institute of medicine public law - . united states global leadership against hiv/aids, tuberculosis, and malaria reauthorization act of the institute of medicine committee on the us commitment to global health. the u.s. commitment to global health: recommendations for the public and private sectors report of the csis commission on smart global health policy: a healthier, safer, and more prosperous world america's vital interest in global health: protecting our people, enhancing our economy, and advancing our international interests the institute of medicine committee on the u.s. commitment to global health. the u.s. commitment to global health: recommendations for the public and private sectors no good deed goes unpunished: the unintended consequences of washington's hiv/aids programs the global fund to fight aids, tuberculosis, and malaria -pledges about the global fund saving lives: buying time: economics of malaria drugs in an age of resistance rockefeller foundation-our history governing global health global health fellows: pfizer investments in health. available at: https:// globalhealthfellows.pfizer.com/login.asp?returnurl home.asp. accessed september bd's global health initiative global business coalition on hiv/aids, tuberculosis and malaria world health organization. list of ngos in official relations with who world health organization. civil society initiative (csi) rotary international/the rotary foundation the dramatic expansion of university engagement in global health: implications for us policy: a report of the csis global health policy center key: cord- - h si authors: sharpstone, d; gazzard, b title: gastrointestinal manifestations of hiv infection date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: h si the harrowing picture of emaciated terminally ill aids patients is a reminder of our lack of understanding of immunological mechanisms that normally control opportunistic infections. many gastrointestinal pathogens in patients with aids are resistant to treatment and lead inexorably to weight loss and death. although knowledge of the pathogenesis and clinical significance of weight loss has improved considerably, this has not yet led to a sustained effort to improve nutritional status during early stages of disease. most of the morbidity and mortality of late aids is associated with gastrointestinal disease. whilst oesophageal candidosis responds readily to treatment and cytomegalovirus enteritis may be cleared by antiviral agents, the two commonest protozoal pathogens-microsporidia and cryptosporidia-cannot be eradicated. these protozoa cause disruption of small-bowel villus architecture by unknown mechanisms and severe malabsorption, maldigestion, and diarrhoea. weight loss is a major contributor to death in most patients with aids and is commonly caused by protozoal gut infection. the host metabolic response to these infections is typical of starvation and patients are likely to respond to the provision of additional calories, ideally by the enteral route. by contrast, weight loss associated with other opportunistic infections-mycobacterium avium intracellulare and cytomegalovirus-is characterised by cachexia and is unlikely to respond to simple refeeding. the commonest cause of oesophageal symptoms is candidosis; odynophagia or dysphagia with oral candidosis is an aids-defining diagnosis and can be treated empirically with a systemic azole. the second most frequent cause is cytomegalovirus (cmv), which produces either diffuse oesophagitis or discrete ulceration. the aetiology of these lesions can be confirmed by biopsy of the centre of ulcerated areas. detection of cmv inclusion bodies is enhanced by immunoperoxidase staining. oesophagoscopy occasionally reveals vesicles typical of herpes simplex oesophagitis, diagnosed either by biopsy or smears from brushings showing typical giant cells. as many as % of oesophageal ulcers leading to dysphagia are idiopathic, possible causes being unknown opportunistic viruses or hiv itself. these ulcers may respond to thalidomide. pathogenesis hiv was initially believed to cause intestinal symptoms since hiv-seropositive individuals free from intestinal pathogens commonly have diarrhoea. however, the frequency of "pathogen-negative diarrhoea" depends on the extent of the diagnostic investigations and the definition of diarrhoea. in a prospective study of pathogen-negative diarrhoea, follow-up revealed an unsuspected pathogen in only a minority. most patients had low-volume diarrhoea that either resolved spontaneously or was controlled with antimotility agents, a response that accords with the features of irritable bowel syndrome. hiv-seropositive persons free from intestinal pathogens do have minor abnormalities of villus architecture, characteristically a mild villus atrophy associated with either crypt hypoplasia or hyperplasia. these minor abnormalities are unlikely to cause diarrhoea since they occur in symptom-free individuals and are associated either with no or with very mild malabsorption of carbohydrates. however, there is a consistent increase in small-bowel permeability in hiv-seropositive individuals; this functional abnormality and the minor structural abnormalities of the small bowel mucosa may be due to the immunological changes produced by hiv infection of lamina propria lymphocytes. activated t cells cause villus atrophy in fetal gut explants, and hiv causes activation of these cells. hiv can be identified in the lamina propria of both the large and small intestine but its detection or quantification is not related to diarrhoea. whether hiv also infects small-bowel mucosal cells, as was initially shown by in-situ hybridisation, is unknown. other possible mechanisms for villus damage include ingress of foreign antigens because of the increased permeability that sets in motion a vicious circle of release of cytokines and other inflammatory mediators. alternatively, bacterial overgrowth in the small intestine of hiv-seropositive patients, as reported in some small studies, might produce an inflammatory response and villus atrophy. bacterial overgrowth might occur because of the hypochlorhydria reported in aids patients. hypochlorhydria is common in those with starvation and systemic infection and may therefore occur in advanced aids without any hiv-induced defects in gastric secretion. neither hypochlorhydria nor bacterial overgrowth is a universal finding in patients with advanced hiv infection, so these mechanisms are unlikely to have an important role in villus atrophy. the harrowing picture of emaciated terminally ill aids patients is a reminder of our lack of understanding of immunological mechanisms that normally control opportunistic infections. many gastrointestinal pathogens in patients with aids are resistant to treatment and lead inexorably to weight loss and death. although knowledge of the pathogenesis and clinical significance of weight loss has improved considerably, this has not yet led to a sustained effort to improve nutritional status during early stages of disease. fluoresce with agents such as calcofluor, thereby providing an excellent screening test. results can be confirmed with giemsa staining. cryptosporidia in the stool is diagnosed by a modified ziehl-neelsen or auramine stain. enteric bacteria are usually detected by routine stool cultures but are occasionally found only in the blood. stool culture of mycobacterium avium intracellulare is tedious and of uncertain pathogenic significance since colonisation can occur without diarrhoea. the value of stool electron microscopy for enteroviruses is debatable since in some studies these organisms have a similar prevalence in individuals with solid stools and in those with diarrhoea. detection is of limited value because enteroviruses produce a self-limiting infection, even in most hiv-seropositive persons, and are untreatable. mucosal biopsy: although diagnosis by stool analysis alone has been suggested by johanson and sonnenberg, this study may have overestimated the value of symptomatic treatment and ignored the possibility that cytomegalovirus infection sometimes responds to therapy. gut biopsy is the only way to diagnose infection with cmv or adenovirus. infections are commonly found in the large intestine, and sigmoidoscopy with rectal biopsies is probably the best initial invasive gastroenterological investigation in patients with diarrhoea. - % of cases of cmv colitis affect only the right side of the colon or small intestine, so colonoscopy or small-intestinal biopsy may be indicated in individuals with persistent diarrhoea and negative rectal biopsy. starvation, and diarrhoea is often out of proportion to the mucosal abnormalities, so a secretory component is likely. a secretory response was shown in isolated segments of human jejunum exposed to faeces from calves infected with cryptosporidia but not in patients with moderately increased stool volumes due to cryptosporidiosis. decreased intestinal transit time may exacerbate diarrhoea in protozoal infection, but whether this is a primary motility defect or a consequence of malabsorption or enteric nerve damage is unclear. another possibility is that motility changes or nerve damage are mediated by nitric oxide release as a result of stimulation of nitric oxide synthase in macrophages infected by hiv or opportunistic organisms; this possibility remains unexplored. changes in the immunological responses in the gut mucosa allow the persistence of protozoal infection in hiv-seropositive individuals, and abnormal immune responses themselves may be important in the pathogenesis of diarrhoea. the cd lymphocyte population of the lamina propria in hiv-seropositive patients shows a disproportionate reduction compared with the circulating cd count. experiments in immunocompromised mice have shown that cd -positive cells are essential for the eradication of cryptosporidia. cd responses may be important in controlling infection in cd -count-depleted mice, and interferon-gamma released from macrophages may also have a role. altered cd or macrophage responses in hiv-seropositive individuals who are unable to mount a cd response to cryptosporidial infection may lead to aberrant cytokine release and consquent intestinal damage. increased concentrations of tumour necrosis factor-alpha have been reported in the faeces but not in the mucosa of patients with protozoal diarrhoea. studies of the complex balance between various cytokines and their tissue receptors are awaited. stool analysis is the initial investigation for hivseropositive subjects with diarrhoea and three samples will identify about % of pathogens. cryptosporidia may not always take up appropriate stains in the stool and some infections are diagnosed only by histological examination of small or large bowel biopsy specimens. histological examination of duodenal biopsy specimens may also reveal previously unsuspected microsporidia, giardia, m avium intracellulare; or isospora. ultrastructural examination of enteric biopsy specimens by electromicroscopy is not done routinely but enables speciation of organisms such as microsporidia and maybe a useful addition to light microscopy ( figure) . analysis of six stool samples and histological examination of small and large bowel biopsy speicmens detect more than % of infectious causes of diarrhoea in hiv-seropositive individuals. most individuals in whom no pathogens are found by these initial investigations have minor symptoms that usually resolve spontaneously. a few have continued large-volume diarrhoea, and in some of these widespread kaposi's sarcoma of the gut or lymphoma is subsequently diagnosed. after stool analysis, acutely ill individuals with diarrhoea should be treated with ciprofloxacin, to which most enteric bacteria in hiv-seropositive individuals are sensitive. in those with chronic diarrhoea, antimotility agents reduce symptoms. oral rehydration therapy may also be important to maintain electrolyte balance. the somatostatin analogues octreotide and vapreotide are used in hiv-seropositive individuals with diarrhoea because of a motility effect and possibly because hiv has aminoacid sequences similar to vasoactive intestinal peptide (vip) and may induce diarrhoea by upregulating vip receptors. increased concentrations of vip have been shown in some patients with pathogen-negative diarrhoea, in whom octreotide has likewise been successful. somatostatin analogues are most effective for pathogen-negative diarrhoea and less so in protozoal diarrhoea, with one placebo-controlled study showing no effect. these expensive agents are unlikely to have a wide role in the treatment of hiv-related diarrhoea. microsporidiosis: two genera of microsporidia are associated with diarrhoea. enterocytozoon bieneusi is found only in human beings. there is no known effective treatment, although uncontrolled studies suggest that some patients may respond to albendazole, thalidomide, or atovaquone. encephalitozoon spp are much less commonly associated with diarrhoea, but infection with these organisms can also cause disseminated disease; organisms are eradicated by albendazole, with resolution of symptoms. cryptosporidiosis: there are many anecdotal reports of treatment for cryptosporidiosis that are difficult to interpret in view of the variable natural history of this infection. in at least a third of patients, diarrhoea resolves spontaneously, especially in those with an initial cd count above /l. investigation of suitable therapeutic agents is hampered by inability to culture the organism in vitro and the major differences between animal models and human infection. although many agents have been used, the only one with proven efficacy is paromomycin, which reduces stool volumes by about %. quantitative stool analyses have shown some reduction in oocyst excretion with therapy but the organism is seldom eradicated. because therapy of this infection is so difficult, primary prophylaxis would be a highly desirable goal. human cryptosporidiosis is a waterborne infection. since the minimum infectious dose is low-between one and five oocysts in gnotobiotic animals and - oocysts in healthy human beings -standard screening tests of metropolitan water supplies may not be sensitive enough for detection. boiling water eliminates infective oocysts, so this strategy is sensible for hiv-seropositive patients with cd counts of less than /l. enteritis: the treatment of cytomegalovirus enteritis remains controversial. both ganciclovir and foscarnet reduce symptoms and improve macroscopic and microscopic appearances of the colon with weeks' therapy. however, relapse with a median time of weeks is very common. both initial treatment and the decision to give maintenance therapy will therefore depend on the initial severity of symptoms. since diagnosis of cytomegalovirus enteritis is improving, patients with milder symptoms are being detected and the quality of life with treatment-anti-cmv agents have to be given intravenously and have considerable toxicitymay not be enhanced compared with no therapy. whether such patients left untreated will develop complications of cmv enteritis such as toxic dilation and perforation, which were common in the early years of the epidemic, remains to be determined. oral ganciclovir in a high dose to overcome problems of bioavailability may have a limited role as primary prophylaxis in preventing the development of cmv disease. nevertheless, such therapy has major toxicity, only limited benefit, and is extremely expensive. widespread use of primary prophylaxis must await the development of more effective agents or of other markers that allow better prediction of patients who are most likely to develop cmv disease. mycobacterium avium-intracellulare (mai): about % of severely immunosuppressed hiv-seropositive patients have mai-induced diarrhoea. primary prophylaxis with rifabutin of clarithromycin may reduce the incidence of mai but established small-bowel infection necessitates treatment with conventional quadruple therapy. such treatment must include the most effective agentsclarithromycin or azithromycin. resistance to these drugs will probably be limited by the addition of rifabutin and their efficacy improved by ethambutol. weight loss is a common feature of late hiv infection. initially wasting was thought to be a feature of hiv infection per se. however, although there is a slight increase in resting energy expenditure (ree) in individuals at most levels of immunosuppression, weight and lean body mass are normal unless an opportunistic infection supervenes. the pattern of weight loss characteristic of starvation, with decreased ree and relative preservation of lean body mass, is seen with enteric protozoal infection. the starvation response is probably caused by a combination of voluntary reduction of intake to reduce diarrhoea and anorexia related to malabsorption. certain opportunistic infections, especially m avium intracellulare and cmv, produce a cachectic response in which the ree is further raised and there is a more pronounced loss of lean body mass, likely to be related to inappropriate cytokine release. although increase in fat mass may improve body image, repletion of lean body mass is probably required to improve locomotor function and many aspects of quality of life. hiv-seropositive individuals losing weight because of starvation are likely to respond to food supplements given orally, parenterally, or enterally via a nasogastric tube or percutaneously by gastroenterostomy tube. such patients may also benefit from appetite stimulants. however, refeeding is likely to be ineffective in those with cachexia, who may improve lean body mass in response to anabolic agents (eg, recombinant human growth hormone). abdominal pain cmv infection is associated with an arteritis and the consequent ischaemia may be associated with acalculous cholecystitis or appendicitis. cmv colitis commonly gives rise to abdominal pain with bloody diarrhoea and rebound tenderness. the other origin of abdominal pain unique to hiv-seropositive patients is an aids-related sclerosing cholangitis caused by various opportunists including microsporidia, cmv, and cryptosporidia. this condition is associated with sclerosis of both the intrinsic and the extrinsic hepatic system and with changes in the pancreatic duct. sclerosing cholangitis may also be common in those without pain, but it is usually the discomfort that leads to investigation. since the natural history of this pain is variable, how frequently sphincterotomy improves symptoms is unclear. background low adherence of patients to prescribed, selfadministered medical interventions is ubiquitous. low adherence limits the benefits of current medical care. efforts to assist patients to follow treatments might improve the efficiency of care and substantially enhance benefits. our objective was to summarise the results of randomised controlled trials (rcts) of interventions to help patients follow prescriptions for medications. methods a previous systematic review was updated through computerised searches in medline, international pharmaceutical abstracts, psychinfo, and hstar online databases; bibliographies in articles on patient adherence; articles in the reviewers' personal collections; and contact with authors. articles were judged of interest if they reported original data concerning an unconfounded rct of an intervention to improve adherence with prescribed medications, with one or more measure of medication adherence, one or more measure of treatment outcome, at least % follow-up of each group studied, and, for longterm treatments, at least months of follow-up for studies with positive initial findings. information on study design features, interventions and controls, and findings were ex tracted by one reviewer (rk) and checked by the other two reviewers. findings relevant citations and abstracts were screened, full text articles were reviewed in detail, and rcts met all criteria. the studies were too disparate in clinical problems, adherence interventions, measures and reporting of adherence, and the clinical outcomes studied to warrant meta-analysis. seven of interventions were associated with improvements in adherence and six interventions led to improvements in treatment outcomes. for short-term treatments, one study showed an effect on adherence and outcome of counselling and w ritten information. the interventions that were effective for longterm care were complex , including various combinations of more convenient care, information, counselling, reminders, self-monitoring, reinforcement, family therapy, and other forms of additional supervision or attention. even the most effective interventions did not lead to substantial improvements in adherence. interpretation although adherence and treatment outcomes can be improved by certain-usually complexinterventions, full benefits of medications cannot be realised at currently achievable levels of adherence. it is time that additional efforts be directed towards developing and testing innovative approaches to assist patients to follow treatment prescriptions. lancet ; : - introduction non-adherence with prescribed treatments is very common. typical adherence rates for prescribed medications are about % with a range from % to over %. to the extent that treatment response is related to dose, non-adherence reduces treatment benefits and can bias assessment of the efficacy of treatments. with increasing numbers of efficacious self-administered treatments, the need is apparent for better understanding and management of non-adherence. in previous reviews, we have examned the accuracy of clinical measures of non-adherence, interventions to improve attendance at appointments for medical services, and interventions to enhance medication adherence. in the last review some of the included trials were acute hiv infection presenting with painful swallowing and esophageal ulcers natural history and prognosis of diarrhoea of unknown cause in patients with acquired immunodeficiency syndrome (aids) effects of zidovudine treatment on the small intestinal mucosa in patients infected with the human immunodeficiency virus intestinal absorptive capacity, intestinal permeability and jejunal histology in hiv and their relation to diarrhoea t-cell activation can induce either mucosal destruction or adaptation in cultured human fetal small intestine intestinal mucosal inflammation associated with human immunodeficiency virus infection human immunodeficiency virus detected in bowel epithelium from patients with gastrointestinal symptoms duodenal mucosal t cell subpopulation and bacterial cultures in acquired immunodeficiency syndrome association of gastric hypoacidity with opportunistic enteric infections in patients with aids decreased gastric acid secretion and bacterial colonisation of the stomach in severely malnourished bangladeshi children prevalance of enteric pathogens in homosexual men with and without acquired immunodeficiency syndrome infectious diarrhea in patients with aids gastrointestinal symptoms in patients infected with human immunodeficiency virus: relevance of infective agents isolated from gastrointestinal tract prevalence of intestinal protozoans in french patients infected with aids prevalence of intestinal microsporidiosis in hiv-infected individuals referred for gastroenterological evaluation faecal tumour necrosis factor-alpha in hiv-related diarrhoea the diagnosis of aids-related chronic diarrhoea: a prospective study in patients light and electron microscopic appearances of pathological changes in hiv gut infection enterotoxic effect of stool supernatant of cryptosporidium-infected calves on human jejunum jejunal water and electrolyte transport in aids-related cryptosporidiosis small bowel transit in hivseropositive individuals autonomic denervation in jejunal mucosa of homosexual men infected with hiv loss of mucosal cd lymphocytes is an early feature of hiv infection mechanisms of innate and acquired resistance to cryptosporidium parvum infection in scid mice cryptosporidium infection in an adult mouse model: independent roles for ifn-␥ and cd + t lymphocytes in protective immunity faecal tumour necrosis factor-alpha and faecal alpha-one-antitrypsin in hiv infection diarrhoea in hiv-infected patients: no evidence of cytokine-mediated inflammation in jejunal mucosa an algorithm for the investigation of diarrhoea in hiv infection use of the fluorochrome calcofluor white in the screening of stool specimens for spores of microsporidia salmonella, campylobacter and shigella in hiv positive patients gastrointestinal viral infections in homosexual men who were symptomatic and seropositive for human immunodeficiency virus efficient management of diarrhea in the acquired immunodeficiency syndrome (aids): a medical decision analysis cytomegalovirus in aids: presentation in patients and a review of the literature spectral and sequence similarity between vasoactive intestinal peptide and the second conserved region of human immunodeficiency virus type envelope glycoprotein (gp ): possible consequences on prevention and therapy of aids elevated plasma levels of vasoactive intestinal peptide in aids patients with refractory idiopathic diarrhea: effects of treatment with octreotide octreotide therapy of large volume refractory aids-associated diarrhea: a randomized controlled trial treatment with albendazole for intestinal disease due to enterocytozoon bieneusi in patients with aids thalidomide for microsporidiosis atrovaquone is effective treatment for the symptoms of gastrointestinal microsporidiosis in hiv- infected patients paromomycin for cryptosporidiosis in aids: a health information research unit intestinal function and injury acquired immunodeficiency syndrome-related cryptosporidiosis infective dose size studies on cryptosporidium parvum using gnotobiotic lambs the infectivity of cryptosporidium parvum in healthy volunteers treatment of aids-associated gastrointestinal cytomegalovirus infection with foscarnet and ganciclovir: a randomized comparison the microbial causes of diarrhea in patients infected with the human immunodeficiency virus body composition studies in patients with the acquired immunodeficiency syndrome prospective analysis of patterns of weight change in stage iv human immunodeficiency virus infcction the metabolic sequelae of specific opportunistic infections in aids anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection natural history of aids related sclerosing cholangitis: a study of cases key: cord- -rxdw c authors: sawyer, alexandra; ayers, susan; field, andy p. title: posttraumatic growth and adjustment among individuals with cancer or hiv/aids: a meta-analysis date: - - journal: clin psychol rev doi: . /j.cpr. . . sha: doc_id: cord_uid: rxdw c there is increasing research on posttraumatic growth after life-threatening illnesses such as cancer and hiv/aids, although it is unclear whether growth confers any psychological or physical benefits in such samples. consequently, this meta-analysis explored the relationship between posttraumatic growth and psychological and physical wellbeing in adults diagnosed with cancer or hiv/aids and examined potential moderators of these relationships. analysis of studies (n = ) of posttraumatic growth after cancer or hiv/aids revealed that growth was related to increased positive mental health, reduced negative mental health and better subjective physical health. moderators of these relationships included time since the event, age, ethnicity, and type of negative mental health outcome. it is hoped that this synthesis will encourage further examination of the potentially complex relationship between posttraumatic growth and adjustment in individuals living with life-threatening medical conditions. parallel other traumatic stressors in many ways. the diagnosis may be sudden and unexpected, the disease and treatment may pose threats to one's life, and the experience may evoke intense emotional responses of fear and helplessness. at the same time living with a life-threatening illness is not an acute, singular stressful experience, but rather a series of unfolding threats and stressors (cordova, ) . cumulatively, these experiences can constitute a traumatic stressor for many individuals with cancer or hiv/aids. experiencing a lifethreatening illness was first recognised as an event that could precipitate posttraumatic stress disorder (ptsd) in the dsm-iv (american psychiatric association [apa], ) . rates of ptsd in cancer patients range from % to % (kangas, henry, & bryant, ) and in hiv/aids patients from % to % (botha, ; kelly et al., ; martinez, israelski, walker, & koopman, ) . over the past decade there has been an important shift in emphasis of research from a nearly exclusive focus on the negative aftermath of such events to consideration of possible positive outcomes (linley, ) . researchers have used a number of different terms to describe individuals' reports of benefits in the face of adversity, including posttraumatic growth, adversarial growth, benefit-finding, and thriving. throughout this paper tedeschi, park, and term posttraumatic growth (ptg) will be used to describe a positive change in one's previous level of functioning as a result of the struggle with highly challenging life circumstances. this term differs from resilience, optimism, hardiness, which describe individuals who have adjusted successfully despite adversity (o'leary & ickovics, ) , whereas individuals experiencing ptg are transformed by their struggle with adversity. a rapidly increasing literature now testifies to the prevalence of positive life changes and personal growth following cancer and hiv/ aids. equally high rates of positive changes have been reported across both illnesses. between % and % of people living with hiv/aids have been shown to report positive changes since diagnosis (milam, (milam, , a siegel & schrimshaw, ) . likewise, data suggest that between % and % of cancer survivors also report positive changes (collins, taylor, & skokan, ; fromm, andrykowski, & hunt, ; petrie, buick, weinman, & booth, ; rieker, edbril, & garnick, ) . within the general ptg literature three common categories of growth outcomes have been identified (joseph & linley, ; tedeschi et al., ) . first, individuals often report that their relationships are enhanced in some way. for example many individuals with cancer or hiv/aids require practical and emotional support, and positive interpersonal experiences may strengthen a person's appreciation of some relationships. second, people change their views of themselves in some way. for example patients may develop a greater sense of personal resilience and strength, an acceptance of their vulnerabilities and limitations, which are typified by a heightened awareness of their own mortality and the fragility of life. third, there are often reports of changes in life philosophy. for example people diagnosed with cancer or hiv/aids are faced with the concern that their disease might progress and shorten their life and these concerns may lead to a shift in priorities and values, and to a different appreciation and approach to day-to-day life. together these positive changes in psychological well-being can lead to a whole new way of living. finally certain changes have been identified specific to individuals facing a serious illness. a recent focus of the ptg research has been the relationship between ptg and health behaviours (milam, ; milam, ritt-olsen, & unger, ) . luszczynska, sarkar and knoll ( ) found that ptg significantly predicted adherence to antiretroviral therapy in individuals diagnosed with hiv. furthermore, women with breast cancer have described making positive changes in health related behaviours and engaging in more careful cancer surveillance as a result of their experience (sears, stanton, & danoff-burg, ) . studies that compare ptg in cancer and hiv/aids patients suggest that growth is experienced in the same multidimensional manner across both illnesses (lechner & weaver, ). therefore, alongside psychological, interpersonal, and life orientation changes, positive changes in health behaviours may also occur following a life-threatening illness diagnosis. several models have now been proposed regarding the occurrence of ptg. the three most detailed models to date include tedeschi and calhoun's ( calhoun's ( , ) functional descriptive model, organismic valuing theory and christopher's ( ) biopsychosocial-evolutionary theory. although with some variation, most models hypothesize that the experience of a highly stressful or traumatic event violates an individual's basic beliefs about the self and the world and that some type of meaning making or cognitive processing to rebuild these beliefs and goals occurs, resulting in perceptions that one has grown through the process (horowitz, ; janoff-bulman, ; tedeschi & calhoun, ) . although offering different levels of explanation at both the social cognitive and biological evolutionary levels, they are complimentary in that they are underpinned by the notion that people are intrinsically motivated towards growth (joseph & linley, ) . an important issue to be addressed in the literature is whether ptg following the diagnosis of a life-threatening illness is associated with psychological and physical benefits (zoellner & maercker, ) . however, the current literature is unclear. for example some studies report there is no significant relationship between ptg and distress (cordova, cunningham, carlson, & andryowski, ; schulz & mohamed, ) , and other studies suggest distress and ptg can co-exist (tomich & helgeson, ) . for example barakat, alderfer, and kazak ( ) found that ptg and posttraumatic stress symptoms were positively correlated in adolescent survivors of cancer. however, other studies have reported an inverse relationship between measures of ptg and psychological distress (linley & joseph, ; updegraff, taylor, kemeny, & wyatt, ; urcuyo, boyers, carver, & antoni, ) . therefore, it remains to be established whether the experience of ptg in relation to a life-threatening illness confers any benefit in terms of psychological or physical health. given the discrepant findings on this relationship a systematic integration of the literature is needed, and a meta-analysis is an ideal tool to do this. a previous meta-analysis conducted by helgeson, reynolds, and tomich ( ) investigated the association between ptg and adjustment after a wide range of events such as sexual assault, natural disaster, bereavement, childhood abuse and illness. they found that ptg was related to more positive affect and less depression, but also to more intrusive thoughts about the event. ptg was unrelated to anxiety, distress, quality of life and subjective physical health. as such the aim of the current paper is to present a meta-analysis of the existing literature that will aim to objectively summarize ptg and its relation to adjustment in individuals living with a life threatening illness (cancer or hiv/ aids) and to examine potential moderators of this relationship. one possible explanation for the inconsistency between ptg and adjustment is that the relationship is moderated by other variables. therefore five possible moderators will be examined that might attenuate or accentuate the growth-adjustment relationship. these were chosen because they are commonly assessed within the literature, and have prior empirical and theoretical foundations. the first variable that might moderate the relationship between ptg and adjustment is the length of time since the diagnosis. research and theory suggest that ptg is unlikely to occur shortly after the critical event, but rather takes time to occur and is more likely to be reported in hindsight tedeschi & calhoun, . therefore it is hypothesized that ptg is associated with positive adjustment when a longer time since the health event has elapsed. three characteristics of the sample will also be examined as moderators: age, gender, and ethnicity. past research has indicated that women (bellizzi, ; milam, ) , younger participants linley & joseph, ; milam, ; widows, jacobson, booth-jones, & fields, ) , and ethnic minorities are more likely to report ptg. however, it is not clear if and how these individual differences differentially relate to ptg and adjustment . therefore no specific predictions about directionality regarding how these variables might moderate the growth-adjustment relationship will be made. it is also possible that the quality of the study might moderate the relationship between growth and health. for example studies that use a valid measure of growth should reflect actual ptg, and distinguish from other processes such as self-enhancement, positive illusion, and "pseudogrowth" (lechner & antoni, ; park & lechner, ) . less validated measures may fail to capture ptg, and therefore account for some of the variation in the research. through examination of these moderators it is hoped that the meta-analysis will identify subgroups of adults whose experience of ptg is likely to be positively or negatively related to mental and physical health. in summary, the purpose of the present study is two-fold. primarily it is concerned with estimating the overall effect size of the relationship between ptg following a life threatening illness (cancer or hiv/aids) and various indicators of adjustment. secondly, this analysis hopes to identify the variability amongst studies and explore potential moderators of the growth and adjustment relationship. it is hoped that such a review of the extant literature will lead to an enhanced understanding of the impact of ptg on the adjustment process in individuals living with life-threatening illnesses. a systematic search was conducted to identify studies of ptg in individuals following cancer or hiv/aids. the primary search method for the selection of studies was a review of the psychological and medical literature using the following computerized databases up to october : medline, psycharticles, psychinfo, pubmed, and web of science. relevant key words were used to search for articles within these databases. search terms included key words related to ptg: posttraumatic growth, post-traumatic growth, benefit finding, stress related growth and adversarial growth. these terms were crossed with the following health-related key terms: health, illness, disease, life-threatening, chronic, medical, terminal, cancer, hiv, aids. additional studies were located through the inspection of the reference sections of obtained papers and reviews. relevant journals were also manually searched to locate papers that may not have been identified in the databases. these journals were: psycho-oncology, psychology and health, journal of traumatic stress, british journal of health psychology and journal of consulting and clinical psychology. in addition, active researchers in the field of psychological growth in health samples were contacted to ask for recent papers in the field and for unpublished research to reduce the effect of publication bias. a search of abstracts from relevant conferences was also conducted to locate additional unpublished work in the area. however, no unpublished studies were retrieved. this literature search yielded a preliminary database of published papers. these papers were examined to determine eligibility for inclusion in the meta-analysis. studies had to meet eight criteria for inclusion. first, studies were included only if the sample were adults aged or over. this decision was made because the current literature is unclear whether children or adolescents differentially experience ptg in comparison to adults (ickovics, meade, et al., ; ickovics, milan, et al., ; milam et al., ) , and also only a small number of studies have explored ptg in children and adolescents following illness (too few to include adult vs. child as a moderator variable). this resulted in the exclusion of nine studies. second, the studies had to use a quantitative measure of ptg, which was assessed in relation to a measure of positive psychological adjustment, negative psychological adjustment or physical health. studies that included a purely qualitative assessment of ptg, or papers that were reviews of the literature were excluded from the analysis. this resulted in the exclusion of studies. third, ptg must be measured in cancer or hiv/ aids patients. this criterion resulted in the exclusion of studies. fourth, intervention studies were excluded from the analysis unless they measured ptg at baseline prior to manipulation and effect sizes could be extracted. this resulted in the exclusion of studies. fifth, controlled comparison studies that did not report relevant data for the patient sample were excluded. this resulted in the exclusion of nine studies. longitudinal studies which measured ptg at different time points to adjustment measures were excluded. however, when longitudinal studies reported cross-sectional relationships these were included in the analysis. this resulted in the exclusion of seven studies. studies needed to include the relevant effect sizes (namely the correlation coefficient r) or sufficient statistical information that could be used to compute this statistic. authors of papers with unclear statistical information were contacted to enquire about further information and if this was unable to be provided these papers were excluded from the analysis. only two papers were excluded as a result of this criterion. finally, the authors of five non-english articles were contacted for copies of their papers but these were not provided. of the articles yielded by the literature search studies met all of the requirements for inclusion and were therefore used in the metaanalysis. studies included in the meta-analysis are identified with an asterisk in the reference section and a detailed list of the studies is provided in table . from these papers a number of variables were extracted for analysis: i) sample size, ii) sex composition, iii) ethnicity, iv) mean age, v) time since event, vi) health event vii) adjustment outcome, and viii) effect sizes for these relationships. the methodological quality of each study was also assessed based on a checklist developed by mirza and jenkins ( ) . the five criteria that were assessed were: ) clear study aims, ) sample representative of population, ) clear inclusion and exclusion criteria, ) validated measure of ptg, and ) appropriate statistical analysis. the studies were then given a total score of quality with the highest possible being eight ( = yes, = no). table displays the quality scores for each individual study. quality scores ranged from - ; however most studies were of good quality with over % of studies scoring or more. as expected, the concept of adjustment was operationally defined in a number of ways across individual studies. in our analysis measures were combined and a separate analysis was conducted for positive psychological adjustment, negative psychological adjustment and subjective physical health. psychological adjustment was defined in this paper as the psychological outcome, either positive or negative, following illness. specific adjustment measures associated with each adjustment outcome were also examined as moderators to explore how they might explain variability within the growth-adjustment relationship. these adjustment measures were coded as follows: a) positive psychological adjustment was coded either as psychological health (e.g. positive affect, mental health) or general well-being (e.g. life satisfaction), b) negative psychological adjustment was coded as specific symptoms (e.g. depression, anxiety, ptsd) or general distress, and c) subjective physical health was coded as either general physical health, physical symptoms, or functional ability. to examine the role of possible moderators in the growthadjustment relationship, the following information in each paper was coded and used in the analysis as follows: (i) time since diagnosis was examined as a continuous moderator by using the mean time in months, (ii) sample gender composition was examined as continuous variable coded as percentage of female participants, (iii) sample age was examined as a continuous moderator by using the mean time in years, (iv) it was decided to code ethnicity as a categorical variable, either as b % white or ≥ % white, as this strategy minimized data exclusion, and (v) the methodological quality of each study was examined as a continuous moderator. all analyses in this paper were carried out on spss (version ) using syntax specified in field and gillett (in press) . a separate metaanalysis was carried out for each adjustment outcome. in the present study the correlation coefficient (r) was chosen as the effect size estimate for a number of reasons. first, this was a common metric for which the greatest number of effect sizes could be reported or converted; second, it is easily computed from either chi-square, t, f, and d; and third it is readily interpretable (rosenthal & dimatteo, ) . a number of papers reported correlation coefficients only for the subscales of ptg. therefore to guarantee the independence assumption among effect sizes the coefficients were averaged to produce a single effect size associated with overall ptg. when a study did not report the effect size or probability value but stated only the relationship was nonsignificant an effect size of zero was assigned to that relationship. this is a conservative strategy because it generally underestimates the true magnitude of effect sizes (durlak & lipsey, ; rosenthal, ) . however, this approach is preferable to excluding nonsignificant results from the meta-analysis, because this would result in an overestimation of combined effect sizes (rosenthal, ) . the authors of these papers were contacted for further information and there was only one study where an effect size of zero assumed. in meta-analysis two common statistical procedures are used: fixedand random-effect models (hedges, ; hedges & vevea, ; hunter & schmidt, ) . real social science data have been shown to contain variability in effect sizes as the norm, which indicates variable population parameters (field, ; field, ; field & gillet, in press; hunter & schmidt, ) . for this reason, and so the results can be generalized beyond the studies included in the meta-analysis, a random effects model was carried out. hedges and vevea's ( ) method was applied using fisher-transformed correlation coefficients with results reported after the back transformation to the pearson product-moment correlation coefficient (see field, ; overton, ) . using this method, each effect size is weighted by a value reflecting both the within study variance ( /n − for correlation coefficients in which n is the sample size) and the between study variance (τ ). the exact weight function for each effect size is w * i = n i − +τ − (see field & gillet, in press for a guide to using hedges and vevea's method). moderator analyses were conducted also using a random-effects general linear model in which each z-transformed effect size can be predicted from the transformed moderator effect (represented by regression coefficient, β). the moderator effect, β, is estimated using generalised least squared (gls). in both the main analysis and moderator analyses, between study variance was estimated noniteratively (e.g. dersimonian & laird, ) . for a technical overview of the gls moderator analysis that we employed see overton ( ) or field and gillet (in press). in any meta-analysis publication bias is a concern. this bias refers to the tendency that the decision to publish a paper is determined by the results of the study (begg, ) . for example studies with nonsignificant findings are less likely to be published than those with significant outcomes, which could result in a positive bias within the literature. there are different approaches to estimating publication bias: rosenthal's ( ) fail-safe n, funnel plots and sensitivity analysis. the fail safe n estimates the number of unpublished, nonsignificant studies that would have to exist for the obtained probability value of the population effect size estimate to be rendered nonsignificant. this measure is problematic because its emphasis is on significance testing the population effect size rather than estimating the population effect size itself. therefore, we have chosen to report table stem and leaf plot of effect sizes for negative mental health (rs). . , , , . , , , , , , , , . , , , , , , , , , , , , , −. , , , , , , , −. , , , , , , , , , , , , −. , , , , , , , −. , , , −. , , measures that specifically address bias in the population effect size estimate. first, we produce funnel plots of the effect found in each study against the standard error (light & pillemer, ). an unbiased sample will show a cloud of data points that is symmetric around the population effect size and has the shape of a funnel (reflecting greater variability in effect sizes from studies with small sample sizes/less precision). second, we performed a sensitivity analysis, which is a method that uses weights to model the process through which the likelihood of a study being published varies (usually based on a criterion such as the significance of a study). we applied the methods proposed by vevea and woods ( ) because they can be applied to relatively small samples of studies such as we have. there were studies included in the meta-analysis; with a total of participants. sample sizes from individual studies ranged from to . . % of the studies focused on individuals with a cancer diagnosis and . % included individuals with a hiv/aids diagnosis. length of time since treatment/diagnosis varied and ranged from to months (m= . , sd= . ). mean age of the sample was . (sd= . ). of the studies that provided information on ethnicity, the majority (n= ) included samples predominantly composed of white participants. tables - graphically represent the effect sizes included in each adjustment meta-analysis by means of a stem and leaf plot. the stem identifies the first digit of an effect size and the leaf identifies the final digit of an effect size. for positive mental health (table ) , the bulk of effect sizes were in the range of to . , but the range was quite wide (−. to . ) suggesting the influence of moderator variables. for negative mental health (table ) , the distribution of effect sizes is relatively symmetrical and is centered around to −. . again, the range of effect sizes was quite large (−. to . ) suggesting that moderator variables might usefully explain some of this variability. finally, for physical health (table ) the effect size distribution looks skewed and is centered around to −. . three studies appeared to have relatively large positive effect sizes that were inconsistent with the bulk of studies. table shows the individual meta-analyses for each adjustment outcome. ptg was significantly related to higher levels of positive psychological adjustment (ptg explained . % of the variance), lower levels of negative psychological adjustment (ptg explained only . % of the variance), and higher reported levels of physical health (ptg explained . % of the variance). the results suggest considerable variation in effect sizes for the three adjustment outcomes, and it is therefore important to examine factors that moderate these relationships. the funnel plots shown in figs. - suggest publication bias might be present in the data, as indicated by the non-funnel like and asymmetric distribution of data points around the estimated mean, typical of biased data sets. in particular, for positive mental health ( fig. ) and physical health (fig. ) , the data cloud is relatively sparse for small studies (the bottom part of the figure). this pattern is indicative of one-tailed publication bias (vevea & woods, ) . for negative mental health (fig. ) the cloud is a little sparse around zero for small studies, which indicates two-tailed publication bias (vevea & woods, ) . we calculated several publication-bias corrected estimates based on our interpretation of the funnel plots of the overall population effect sizes on positive mental health, negative mental health and physical health. we used vevea and woods ' ( ) weight function model of publication bias to calculate population effect size estimates under different selection bias scenarios. based on the funnel plots, for positive mental health and physical health we assumed moderate (mot) or severe (sot) one-tailed selection bias, and for negative mental health we assumed moderate (mtt) and severe (stt) two-tailed selection bias. the values corrected for selection bias were as follows: for positive mental adjustment, the original population estimate of . was reduced to . (mot), −. (sot); for negative mental adjustment, the original estimate of −. became −. (mtt) and −. (stt); for physical health the original estimate of . became . (mot), −. (sot). as such, the estimate of population effect size for negative mental health was unaffected by publication bias. if we assume moderate publication bias, then estimates for positive mental health and physical health were slightly reduced, but if severe publication bias is assumed then the estimates change quite dramatically. as such, our conclusions come with the caveat that if severe publication bias was, in reality, present in the literature then our conclusions would be quite different for positive mental health and physical health outcomes. five moderators that might explain significant amounts of effect size variation for each adjustment outcome were examined. subcategories of each adjustment outcome were also initially explored as moderators. categories of positive psychological adjustment did not significantly moderate the relationship between ptg and positive mental health (p n . ). time emerged as a significant moderator of positive psychological adjustment (β = . , p b . ), implying the longer the time since the event, the stronger the relationship between ptg and positive mental health. the age of the sample emerged as a significant moderator (β = −. , p b . ), indicating that samples with younger participants, showed a stronger relationship between ptg and positive adjustment. ethnicity also moderated the relationship between ptg and positive mental health, χ ( ) = . , p b . , indicating that samples comprised of more than % non-white participants demonstrated a stronger relationship between ptg and positive psychological adjustment. gender (β = . , p n . ) and quality (β = . , p n . ) did not significantly moderate the relationship between ptg and positive psychological adjustment. categories of negative mental health moderated the relationship between ptg and negative psychological adjustment. dummy coding revealed that ptsd symptoms had a stronger negative relationship with ptg in comparison to depression (χ ( ) = . , p b . ), but not in comparison to anxiety (χ ( ) = . , p n . ) and general distress (χ ( ) = . , p n . ). time since the health event, measured in months, moderated negative mental health (β = −. , p b . ), indicating the shorter the time since the event, the stronger the relationship between ptg and negative adjustment. ethnicity was also a significant moderator, χ ( ) = . , p b . , indicating that samples with more than a % white composition demonstrated a stronger negative relationship between ptg and negative adjustment. age also appeared as a moderator (β = . , p b . ), indicating that samples with older participants demonstrated a stronger negative relationship between ptg and negative adjustment. quality of the study (β = . , p n . ) and participant's gender (β = . , p n . ) did not moderate the relationship between growth and negative mental health. categories of physical health did not significantly moderate the relationship between ptg and physical health (p n . ). ethnicity moderated the relationship between ptg and physical health (χ ( )= . , pb . ), indicating that samples comprised of more than % nonwhite participants demonstrated a stronger relationship between ptg and physical health. furthermore, time (β=. , pn . ), gender (β= −. , pn . ), age (β=. , pn . ), and study quality (β=−. , p=. ) did not significantly moderate the relationship between ptg and physical health. this meta-analytic review summarized the findings from studies examining the association between ptg following cancer or hiv/aids and positive psychological adjustment, negative psychological adjustment, and subjective physical health. despite variability in effect sizes this analysis demonstrated a small positive relationship between ptg and positive mental health. therefore, individuals who perceive ptg following cancer or hiv/aids also report enhanced psychological well-being. furthermore, a small negative relationship was found between ptg and negative mental health. individuals who perceive ptg following cancer or hiv/aids also report reduced symptoms of negative mental health. finally, ptg displayed a small positive relationship with measures of subjective physical health, implying that ptg may also confer some physical benefit. these findings suggest that ptg is associated with positive adaptive consequences, and is therefore an important construct to be studied in clinical and health research. an additional aim of the study was to examine factors that might moderate the relationship between ptg and adjustment, and therefore provide further insight by accounting for variability in effect sizes reported previously. study quality and gender were the only variables that did not moderate the relationship between ptg and outcomes. therefore the implications of these findings are that studies of differing quality do not account for differences in the growth-adjustment relationship and that there are no significant differences between men and women in the growth-outcome relationship. other moderators examined had varying effects on relationships between ptg and different outcomes; each of which will be discussed in turn. subcategories of positive mental health, and subjective physical health did not significantly moderate their relationship with ptg. however, subcategories of negative mental health did moderate the growth-negative mental health relationship. specifically, in comparison to depression, ptsd symptoms showed a stronger negative relationship with ptg. time since the illness emerged as a significant moderator for positive and negative mental health. in the short term, there was a stronger relationship between ptg and negative mental health, but over time there was an increased relationship between ptg and positive mental health. these results are consistent with the results from a previous meta-analysis looking at ptg following a range of traumas . together these findings suggest that in the short-term ptg is influential in reducing negative symptoms, but in the long-term ptg is more instrumental in enhancing positive well-being. this is consistent with tedeschi and calhoun's ( calhoun's ( , ) functional-descriptive model of ptg, which states that the management of emotional distress is essential in the initial stages post-trauma. on the other hand, ptg reported later might reflect more substantive life changes that have positive consequences for quality of life (tomich & helgeson, ) . time since the health event did not moderate the relationship between ptg and physical health. age appeared to differentially affect the relationship between ptg and adjustment. younger adults demonstrated a stronger positive relationship between ptg and positive mental health. in comparison older adults displayed a stronger negative relationship between ptg and negative mental health. one explanation is that core beliefs of young people may be more affected than those of older people. for example younger people tend to view the world as less just and less benevolent, and the older groups tend to view the world as luckier and more controllable (calhoun, cann, tedeschi, & mcmillan, ) . being diagnosed with cancer or hiv/aids when young might shatter more natural and social rules or beliefs which would generate a greater possibility of reconstructing these core beliefs and therefore promote ptg. another explanation might be that younger people may be more capable and adept at making changes to their lives, which results in enhanced well-being. whereas, older participants may be dealing with other significant life events and be less adaptable compared with younger samples, and therefore ptg may be more useful in reducing and managing distress. age did not act as a significant moderator between ptg and self-reported physical health. ethnicity was a significant moderator of the relationship ptg and all three adjustment measures. specifically, non-white samples displayed a larger effect size for the relationship between ptg and positive mental health and also subjective physical health, compared to samples composed primarily of white participants. in comparison samples composed of predominantly white participants showed a stronger relationship between ptg and negative mental health. this variability may be explained by differences in culture e.g. family, religion, spirituality, which has shown to be important or associated with ptg following stressful life events (milam, a; shaw, joseph, & linley, ; tedeschi & calhoun, ) . because of these differences, growth in ethnic minority samples may reflect more fundamental and existential changes resulting in enhanced wellbeing. in comparison, growth in predominantly white samples may be used more as a strategy to reduce distress. the results of this study should be interpreted with the following limitations in mind. though the present findings indicate that ptg and positive mental health, negative mental health, and subjective physical health are associated (albeit modestly), only cross-sectional data were included in the analysis, which constrains causal inference. for example it is not clear if ptg leads to better psychological and physical health, or if these factors result in an enhanced perception of ptg. furthermore, even though studies were included in the analysis only if they used a clear measure of ptg the final data set consisted of studies that used varying conceptions of ptg, which could be problematic. for example, past research has indicated that benefit finding and ptg are related but distinct constructs, and might therefore have unique predictors and outcomes (sears et al., ) . therefore, future research in the area should ascertain if such constructs are theoretically and empirically interchangeable. the present study did not examine type of illness as a moderator because there were not enough studies of hiv/aids to include cancer vs. hiv/aids as a moderator variable. although research suggests that people with hiv/aids report similar levels and areas of ptg compared to individuals with cancer, there are unique differences between the illnesses, particularly in social responses to individuals with hiv/aids compared to those with cancer (lechner & weaver, ) . for example hiv/aids is an infectious disease and people who are hiv positive may face more stigma because of fear, lack of knowledge concerning transmission, and greater perceived accountability (lechner & weaver, ). this may hinder opportunities for emotional processing and therefore may not facilitate ptg and positive adjustment as readily as cancer and other illnesses. furthermore, meta-analysis, like any other procedure, has its advantages and disadvantages, and this study is no exception. first, where authors of papers reported significant findings but did not include enough statistical information to calculate the effect size, these effect sizes were coded as zero. this is a conservative approach and therefore may have lowered the effect size estimate for each meta-analysis conducted. second, as with many meta-analytic studies, the current findings may over represent those studies that are published and have significant results, preventing the generalization of the current findings to unpublished reports (rosenthal, ) . for the overall effects, our publication bias analysis showed that the population effect size estimates were relatively unaffected when corrected for moderate selection bias. this finding gives us some confidence that the results are not idiosyncratic to our sample of studies. however, when correcting for severe publication bias the effect of growth on positive mental adjustment and physical health became strongly negative (the opposite direction to the population effects). although this is a correction for severe publication bias, the current findings should be viewed within the context of these results. despite these limitations, this study has significant implications for research and practice. a weakness in the literature is the lack of consensus between theorists as to whether ptg is best conceptualized as an adaptive coping strategy that people use following a challenging life event, or as an outcome of the struggle with a traumatic event (affleck & tennen, ; park & helgeson, ; tedeschi & calhoun, . the findings from this study suggest that shortly after the event ptg may be used as a coping strategy to manage and reduce emotional distress associated with the illness threat. however over time ptg grows and is more significant in enhancing positive well-being. this implies that adjustment to serious illness is an ongoing process that occurs over time tedechi & calhoun, ) . as recognized by butler ( ) a challenge of future work is to psychometrically separate these processes so they can be reliably investigated. the results suggest that ptg is associated with a reduction in negative mental health, which was particularly prominent when ptsd symptoms were the outcome. this supports joseph and linley's ( , conceptualization of how ptg and ptsd relate to each other. traumatic events are thought to shatter assumptions about the self and the world and lead to the symptoms of ptsd. these experiences of reexperiencing, avoidance and arousal are viewed as the cognitive emotional processing of the new trauma related information as individuals search for new meaning in life (joseph & linley, ) . as these new meanings are found, and the person's view of themselves and the world is reconstructed, ptg should occur and symptoms of distress should decrease. therefore ptg should be predictive of lower distress, because as people find new meaning they can overcome the cognitive disruption and confusion characterized by ptsd . support for this has been reported by frazier, conlon and glaser ( ) who found that among sexual assault survivors who reported ptg over months were the least distressed. however, joseph and linley ( ) note that this does not mean to imply that the alleviation of distress should automatically lead to the enhancement of growth. according to their organismic valuing theory of growth, ptg should only relate to reduced distress through accommodation (i.e., changing one's global meaning to incorporate the stressor) as opposed to assimilation (i.e., changing one's view of the stressor so that it is consistent with one's global meaning). as such they caution that therapeutic work may impede or disrupt the cognitive processes that are necessary for accommodation and therefore ptg. nonetheless these findings suggest ptg may be a useful target for therapeutic intervention in health care and clinical settings, where the aim is long-term emotional and physical adjustment. psychotherapy for traumatic events such as a serious illness has predominantly focused on the negative effects of trauma, and the goal of therapeutic intervention to promote growth as opposed to alleviate distress will be a major paradigm shift. it is therefore important to raise clinician's awareness of the possibility of positive change. for example, clinicians might recognize the patient's struggle to understand the impact of the illness not only as a posttraumatic response but also as a potential precursor to growth (zoellner & maercker, ) . the empirical study of ways to facilitate ptg is in its infancy and only a few intervention studies have included ptg as an endpoint (antoni et al., penedo et al., ) . nonetheless some interventions, which contain techniques aimed at promoting growth, have shown to successfully improve outcomes. for example antoni et al. ( ) found that a psychosocial intervention that taught participants broad cognitive behavioural stress management techniques, served to increase reports of perceived benefits from having had breast cancer, and simultaneously reduced levels of depression. this study demonstrates that ptg can be altered and can be incorporated easily within cognitive behavioural stress-management interventions. however, the findings from the metaanalysis suggest that clinicians should be sensitive to the timing of ptg discussions. for example the present analysis suggests that ptg might be a useful target in the short-term to reduce distress, but in order to enhance well-being ptg should be targeted later on in the adjustment process. however, in agreement with park and helgeson ( ) it is cautioned that large scale interventions to facilitate ptg in cancer and hiv/aids patients should be avoided until researchers understand more about the origins of ptg, the conditions under which ptg is verdical, the best methods to assess ptg, and its relations to psychological and physical health, are fully understood. care should also be taken to avoid imposing an expectation of ptg in the face of serious illness. patients with cancer or hiv/aids often report feeling burdened with the pressure to stay positive and encouraging the identification of positive changes from their illness may be potentially offensive to patients, serve to minimise their experience and lead them to suppress reports of distress (bellizzi & blank, ; cordova, ) . this meta-analysis of growth in cancer and hiv/aids patients illustrates the promising and exciting nature of this area of research. however, the review also indicates much remains to be learned and highlights areas of research where future work is needed. the present study indicates that in the short term, ptg is associated with a reduction in negative mental health, whereas over longer term, ptg is associated with an enhancement in positive well-being. therefore a clear point of focus is the use of longitudinal studies to further disentangle and clarify the temporal course of this relationship. experimental designs, such as the interventions described earlier, will also help to reveal the causal role of ptg in adjustment and to isolate mechanisms responsible for the effects (algoe & stanton, ). many of the conclusions reached in this paper regarding moderators of the growth-adjustment relationship are based on theoretical considerations rather than on direct empirical evidence and future studies should attempt to validate and test these hypotheses. moreover, to further explicate the growth-adjustment relationship studies should continue to identify additional mediators and moderators. a particularly relevant moderator to medical populations that should be investigated is the perception of the severity of an illness. a previous meta-analysis found that perceptions of the severity of a traumatic event are related to ptg . as such it might be expected that ptg may have a stronger relationship with psychological well-being and physical health for more subjectively severe illnesses and caution must therefore be taken when generalizing the current findings to less threatening illnesses characteristics and indeed wider trauma populations. the majority of the studies included in the present paper measured ptg so that only positive changes were assessed. this could be problematic because participants may develop a 'response bias' which may lead individuals to over-report ptg, and it may also restrict our characterisation of the life changes that health events may precipitate (tomich & helgeson, ) . furthermore, a recent prospective study of severe acute respiratory syndrome (cheng, wong, & tsang, ) found that positive associations between ptg and positive well-being are more likely to be found among individuals who perceive benefits from the event, as well as the costs. therefore, examining positive and negative change simultaneously should be considered as a focus of future research investigating ptg and adjustment in health samples. particularly pertinent for this population is the possibility that ptg can serve to improve physical health. although this paper only looked at subjective measures of physical health there is promising preliminary data which suggests that ptg may be related to better physiological functioning. for example cruess et al. ( ) found that among women with breast cancer, cognitive behavioural stress management reduced levels of cortisol through the enhancement of ptg. yet, no studies have addressed possible mechanisms for the relationship between ptg and physical health. a recent model proposed by bower, low, moskowitz, sepah, and epel ( ) suggests that factors often associated with growth such as coping, positive affect and improved relationships, can lead to a state of enhanced allostasis (maintaining stability, or homeostasis, through change, sterling & eyer, ) , which buffers against future stress responses. this is a promising model, which merits increased attention in future research. furthermore, the relationship between ptg and health behaviours such as exercise, medication adherence, requires a more detailed examination; particularly regarding how these behaviours might moderate the relationship between ptg and physical health. finally, it is acknowledged that the ways in which ptg is manifested might contain elements that are distinctive to specific cultural environments (calhoun & tedeschi, ) . this paper included only three studies conducted in non-western countries and therefore it is clear that there is a need to examine ptg in more diverse ethnic and cultural groups to fully understand the relationship between growth and adjustment. on the basis of this meta-analysis it can be concluded that ptg following cancer or hiv/aids is related to better positive mental health and self-reported physical health, and less negative mental health. this does not preclude that many individuals might experience distress, but rather that ptg is a worthy phenomenon to be studied in clinical and health research. it is hoped that this meta-analysis will encourage further examination of the caveats addressed in this research, so that in the future ptg can perhaps become a viable therapeutic aim in individuals living with a life-threatening illness. construing benefits from adversity: adaptational significance and dispositional underpinnings medical illness and positive life change: can crisis lead to personal life transformation? diagnostic and statistic manual of mental disorders cognitive-behavioural stress management intervention decreases the prevalence of depression and enhances benefit finding among women under treatment for early stage breast cancer posttraumatic growth in adolescent survivors of cancer and their mothers and fathers publication bias expressions of generativity and posttraumatic growth in adult cancer survivors predicting posttraumatic growth in breast cancer survivors positive and negative life changes experienced by survivors of non-hodgkins lymphona posttraumatic stress disorder and illness behaviour in hiv+ patients benefit finding and physical health: positive psychological changes and enhanced allostasis perceptions of positive meaning and vulnerability following breast cancer: predictors and outcomes among long-term breast cancer survivors growing pains: commentary of the field of posttraumatic growth and hobfoll and colleagues recent contribution to it traumatic events and generational differences in assumptions about a just world foundations of posttraumatic growth a path model of the effects of spirituality on depressive symptoms and -h urinary-free cortisol in hiv-positive persons perception of benefits and costs during sars outbreak: an month prospective study a broader view of trauma: a bio-psychosocial evolutionary view of the role of the traumatic stress response in the emergence of pathology and/or growth assessing spiritual growth and spiritual decline following a diagnosis of cancer: reliability and validity of the spiritual transformation scale a better world or a shattered vision? changes in life perspectives following victimization facilitating posttraumatic growth following cancer posttraumatic growth following breast cancer: a controlled comparison study breast cancer as trauma: posttraumatic stress and posttraumatic growth cognitive behavioural stress management reduces serum cortisol by enhancing benefit finding among women being treated for early stage breast cancer personal changes, dispositional optimism, and psychological adjustment to bone marrow transplantation meta-analysis in clinical-trials a practitioner's guide to meta-analysis the problem in using fixed-effects models of meta-analysis on realworld data is the meta-analysis of correlation coefficients accurate when population effect sizes vary? how to do a meta-analysis positive and negative life changes following sexual assault positive and negative psychosocial sequelae of bone marrow transplantation: implication for quality of life assessment positive consequences of head and neck cancer meta-analysis fixed-and random-effects models in meta-analysis a meta-analytic review of benefit finding and growth posttraumatic growth in chinese cancer survivors stress response syndromes fixed effects vs. random effects meta-analysis models: implications for cumulative research knowledge urban teens: trauma, posttraumatic growth, and emotional distress among female adolescents psychological resources preotect health: -year survival and immune function among hiv-infected women from four us cities psychometric properties of the dutch version of the posttraumatic growth inventory among cancer patients posttraumatic growth: three explanatory models. psychological inquiry, positive adjustment to threatening events: an organismic valuing theory of growth through adversity growth following adversity: theoretical perspectives and implications for clinical practice trauma, recovery, and growth: positive psychological perspectives on posttraumatic stress posttraumatic stress disorder following cancer: a conceptual and clinical review the psychosocial impact of cancer and lupus: a cross validation study that extends the generality of "benefit finding" in cancer patients with chronic disease posttraumatic stress disorder in response to hiv infection psychosocial and sociodemographic correlates of benefit-finding in men treated for localised prostate cancer still stable after all this…? temporal comparison in coping with severe and chronic disease posttraumatic growth and group-based interventions for persons dealing with cancer: what have we learned so far? medical illness and positive life change: can crisis lead to personal life transformation? summing up: the science of reviewing research positive adaptation to trauma: wisdom as both process and outcome positive change following trauma and adversity: a review the association of benefit finding to psychosocial and behaviour adaptation among hiv+ men and women received social support, self-efficacy, and finding benefits in disease as predictors of physical functioning and adherence to antiretroviral therapy posttraumatic stress disorder in women attending human immunodeficiency virus outpatient clinics post-traumatic growth in acquired brain injury: a preliminary small scale study posttraumatic growth among hiv/aids patients positive changes attributed to the challenge of hiv/aids posttraumatic growth and hiv disease progression posttraumatic growth among adolescents risk factors, prevalence, and treatment of anxiety and depressive disorders in pakistan: systematic review the psychosocial impact of multiple sclerosis: exploring the patient's perspective. health psychology wellbeing, posttraumatic growth and benefit finding in long-term breast cancer survivors the interaction of post-traumatic growth and post-traumatic stress symptoms in predicting depressive symptoms and quality of life traumatic distress and positive changes in advanced cancer patients personal growth and psychological distress in advanced breast cancer resilience and thriving in response to challenge: an opportunity for a paradigm shift in women's health a comparison of fixed-effects and mixed (random-effects) models for meta-analysis tests of moderator variable effects meaning making and psychological adjustment following cancer: the mediating roles of growth, life meaning and restored just-world beliefs introduction to the special section: growth following highly stressful life events -current status and future directions measurement issues in assessing growth following stressful life experiences a randomized controlled trial of group-based cognitive-behavioral stress management in localized prostate cancer: development of stress management skills improves quality of life and benefit finding positive effects of illness reported by myocardial infarction and breast cancer patients post-traumatic growth after head injury: a long-term follow-up curative testis cancer therapy: psychosocial sequelae the 'file drawer problem' and tolerance for null results writing meta-analytic reviews meta-analysis: recent developments in quantitative methods for literature reviews measuring the meaning of life for patients with incurable cancer: the life evaluation questionnaire (leq) posttraumatic growth and ptsd symptomatology among colorectal cancer survivors: a month longitudinal examination of cognitive processing the report of posttraumatic growth in malaysian cancer patients: relationships with psychological distress and coping strategies turning the tide: benefit finding after cancer surgery changes in finding benefit after cancer surgery and the prediction of well-being one year later the yellow brick road and the emerald city: benefit-finding, positive reappraisal coping, and posttraumatic growth in women with early-stage breast cancer religion, spirituality, and posttraumatic growth perceiving benefits in adversity: stress-related growth in women living with hiv/aids stress-related growth among women living with hiv/aids: examination of an exploratory model allostasis: a new paradigm to explain arousal pathology finding benefit from cancer trauma and transformation: growing in the aftermath of suffering posttraumatic growth: conceptual foundations and empirical evidence posttraumatic growth: positive changes in the aftermath of crisis posttraumatic growth in prostate cancer survivors and their partners is finding something good in the bad always good? benefit finding among women with breast cancer positive and negative effects of hiv-infection in women in low socioeconomic resources finding benefit in breast cancer: relations with personality, coping, and concurrent well-being publication bias in research synthesis: sensitivity analysis using a priori weight functions predictors of posttraumatic growth following bone marrow transplantation for cancer facets of spirituality as predictors of adjustment to cancer: relative contributions of having faith and finding meaning posttraumatic growth in clinical psychology -a critical review and introduction of a two component model key: cord- -hs cfdsu authors: gona, philimon n.; gona, clara m.; ballout, suha; rao, sowmya r.; kimokoti, ruth; mapoma, chabila c.; mokdad, ali h. title: burden and changes in hiv/aids morbidity and mortality in southern africa development community countries, – date: - - journal: bmc public health doi: . /s - - - sha: doc_id: cord_uid: hs cfdsu background: the southern africa development community (sadc) countries remain the epicentre of the hiv/aids epidemic with the largest number of people living with hiv/aids. anti-retroviral treatment (art) has improved survival and prevention of mother-to-child transmission (pmtct) of hiv, but the disease remains a serious cause of mortality. we conducted a descriptive epidemiological analysis of hiv/aids burden for the sadc countries using secondary data from the global burden of diseases, injuries and risk factor (gbd) study. methods: the gbd study is a systematic, scientific effort by the institute for health metrics and evaluation (ihme) to quantify the comparative magnitude of health loss due to diseases, injuries, and risk factors by age, sex, and geographies for specific points in time. we analyzed the following outcomes: mortality, years of life lost (ylls), years lived with disability (ylds), and disability-adjusted life-years (dalys) due to hiv/aids for sadc. input data for gbd was extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service utilisation, disease notifications, and other sources. country- and cause-specific hiv/aids-related death rates were calculated using the cause of death ensemble model (codem) and spatiotemporal gaussian process regression (st-gpr). deaths were multiplied by standard life expectancy at each age-group to calculate ylls. cause-specific mortality was estimated using a bayesian meta-regression modelling tool, dismod-mr. prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases to calculate ylds. crude and age-adjusted rates per , population and changes between and were determined for each country. results: in , hiv/aids caused , deaths overall in sadc countries, and more than million dalys. this corresponds to a -fold increase from , deaths ( , , dalys) in . the five leading countries with the proportion of deaths attributable to hiv/aids in were botswana at the top with . % ( % ui; . – . ), followed by south africa . % ( . – . ), lesotho, . % ( . – . ), eswatini . % ( . – . ), and mozambique . % ( . – . ). the five countries had relative attributable deaths that were at least times greater than the global burden of . % ( . – . ). similar patterns were observed with ylds, ylls, and dalys. comoros, seychelles and mauritius were on the lower end, with attributable proportions less than %, below the global proportion. conclusions: great progress in reducing hiv/aids burden has been achieved since the peak but more needs to be done. the post- decline is attributed to pmtct of hiv, resources provided through the us president’s emergency plan for aids relief (pepfar), and behavioural change. the five countries with the highest burden of hiv/aids as measured by proportion of death attributed to hiv/aids and age-standardized mortaility rate were botswana, south africa, lesotho, eswatini, and mozambique. sadc countries should cooperate, work with donors, and embrace the un fast-track approach, which calls for frontloading investment from domestic or other sources to prevent and treat hiv/aids. robust tracking, testing, and early treatment are required, as well as refinement of individual treatment strategies for transient individuals in the region. we sought to determine hiv/aids related morbidity and mortality trends from to . we assessed morbidity and mortality in the sadc countries using a descriptive epidemiological analysis of hiv/aids burden based on secondary data from gbd study in , , , and . we used secondary data from the gbd study. examining time trends of hiv/aids morbidity and hiv/aids mortality enable comparisons across the countries to understand the changing burden facing the sadc population to support policy and programmatic development in the region. the united nations (un) fast-track or " - - " approach to combatting the worldwide hiv/aids epidemic calls for % of people living with hiv knowing their status, % of people who know their status receiving treatment, and % of people on hiv/aids treatment having a suppressed viral load by [ , ] . the second phase of the approach calls for upgrading the framework to - - by [ ] . hiv/aids-related deaths more than halved since the peak in . in , approximately , people died from the disease worldwide, compared to . million in and . million in [ ] . in , approximately . million new hiv infections occurred, compared to . million in [ ] . a better understanding of the long-term trends in hiv/aids-related morbidity and mortality is needed to enable continued improvements on the impact of ongoing hiv/aids treatment programs [ , ] . sub-saharan africa (ssa), with more than billion people, is the epicenter of the hiv/aids pandemic. the southern african development community (sadc) countries comprise ground-zero of the pandemic, with prevalence in eight countries exceeding % in [ ] . while incidence has progressively declined since the mid- s, hiv/aids morbidity and mortality nonetheless continued to increase (see fig. right panel) , reaching a peak in [ , ] . between and incidence of hiv declined by % worldwide. there was an estimated % fewer hiv/aids-related deaths in ssa in versus [ ] . despite the gains sadc countries have the highest morbidity of hiv/aids, with approximately million people living with the disease in [ ] . of all people living with hiv/aids worldwide at the peak of the epidemic , % resided in ten sadc countries, making hiv/aids the leading cause of death [ ] . hiv/ aids-related mortality in southern ssa increased from being ranked th in to st in ; in eastern ssa countries the ranking increased from th to rd [ , ] . .while great progress has been achieved since to , with a decline in, the number of hiv/aids-related deaths globally by %, sadc countries accounted for nearly in of all people dying from hiv/aids-related causes in [ ] . hiv/aids, therefore, remains a massive public health threat in the region. timely and robust evidence on mortality and trends are essential to informing policy and goal setting, program evaluation, and decision-making. such assessment is an essential starting point for informed health policy debate to measure progress in achieving the united nations (un) health-related strategic development goals (sdgs) [ , , ] and un fast-track approaches " - - " and " - - ". the gbd is a systematic, scientific effort by the institute for health metrics and evaluation (ihme) to quantify the comparative magnitude of health loss due to diseases, injuries, and risk factors by age, sex, and geographies for specific points in time. the gbd study estimates country-specific incidence, prevalence, mortality, years of life lost (ylls), years lived with disability (ylds), and disability-adjusted life-years (dalys) due to diseases such as hiv/aids. input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service utilization, disease notifications, and other sources. cause-specific crude and age-standardized death rates per , population were obtained from the cause of death ensemble model (codem) and spatiotemporal gaussian process regression (st-gpr). deaths were multiplied by standard life expectancy at each -year age-group to calculate ylls. cause-specific mortality was estimated using a bayesian meta-regression modelling tool, dismod-mr. prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases to calculate ylds [ ]. ylls were calculated using the product of age-specific life expectancy from the reference life table used in the gbd study. ylds were calculated as a product of the prevalence of hiv/aids and the disability weights used to quantify health levels associated hiv/aids [ , ] . case definition for hiv/aids used in the gbd and comprehensive details for the methodology and modeling processes for hiv/aids are provided in supplementary appendix , page www.thelancet.com/ journals/lancet/article/piis - ( ) - /full-text#seccestitle [ , ] . all gbd estimates adhere to the guidelines on accurate and transparent health estimate reporting (gather). gather recommends making available statistical code, details on why some sources are used and others are not, and how primary data are adjusted. methodology underlying distinct differences in estimation among unaids, who and ihme are provided [ ] . .the hiv/aids-related outcomes were assessed for each country in sadc, a regional economic community whose aim is to increase regional socioeconomic integration to achieve greater economic growth and poverty alleviation. levels of development and poverty, social service delivery, and economic performance vary greatly. nine of the countries were classified in as either low or low-middle income. only mauritius seychelles and south africa were classified as high-middle income. the ability for each country to respond to the high burden of hiv/aids also varies considerably. sadc aims to strengthen economic cooperation and integration, providing for cross-border investment and trade, and free movement of goods and services across borders [ , ] . the gbd results tool was used to extract sex-pooled age-standardized morbidity and mortality rates per , population for years , , , and . (available at http://ghdx.healthdata.org/gbd-results-tool). to facilitate comparison of hiv/aids outcomes of morbidity and mortality across countries, time, age-groups, and sex, the institute for health metrics and evaluation (ihme) improved previously established metrics like prevalence and incidence. how long do people live with hiv/aids is assessed using hiv/aids-specific mortality rates and hiv/aids-specific years ylls. what causes people to get sick is assessed hiv/aids-specific ylds which reflect the amount of time in a year that people live with a condition accounting for the severity of that condition. adding together ylls and ylds yields dalys. to facilitate comparisons across sadc countries and eliminate potential confounding by age, outcomes are presented as age-standardized rates per , population i.e., the average of the age-specific hiv/aids rates weighted by country-specific proportions of a standard population in the corresponding age groups [ , , , ] . expected rates (e) were determined using a linear equation with the country's socio-demographic index (sdi) in used as a linear predictor [ ] . the sdi, which ranges from to is a summary measure of where a location is on the spectrum of socio-demographic development. the index is calculated from the geometric mean of three rescaled components: total fertility rate of women under years of age, lag-distributed income per capita, and average educational attainment in the population > years., we calculated the observed-to-expected (o/e) rate ratio. uncertainty for each outcome was quantified using uncertainty intervals (uis) based on bootstrap draws from the posterior distribution [ , ] . uis were determined by the th and th ordered values of the posterior distribution of the draws, and point estimates were computed from the mean of the draws. changes over time were considered statistically significant when the % ui of the percentage change did not cross zero [ ] . gbd uses the joint united nations program on hiv and aids (unaids) estimates as inputs in their modeling ensemble [ , ] . for example, pediatric hiv/aids mortality estimates in gbd were produced with the cd -countspecific mortality and progression parameters developed by unaids [ ] . each iteration of gbd re-analyses the entire time series by use of newly available data sources from across all estimation years and continually improved methods. new data and modelling approaches effectively improve model validity and decrease uncertainty from various sources with the consequence that estimates for a given cause, location, and year might differ between gbd iterations and unaids. statistical, analytical, processing, and estimation code used to generate the gbd results are available on their website: http://ghdx.healthdata.org hiv/aids morbidity and mortality remain major public health problems in sadc countries. nearly all new infections in worldwide occurred in just countries, four sadc countries, i.e., mozambique, zimbabwe, zambia, and tanzania. between and , hiv incidence worldwide declined by %, and hiv/aids mortality declined by %, but corresponding declines in sadc countries during the same period were and %, respectively. the five leading countries with the proportion deaths attributable to hiv/aids in were botswana at the top with the five leading countries with the greatest agestandardized mortality rate per , population in were lesotho . ( . - . ) at the top, followed by table ). these five countries had agestandardized mortality exceeding -fold the global mortality rate of . ( . - . ). while the % uis for eswatini, south africa, mozambique, botswana overlap, there is no substantial difference in the rates for these countries, but the rate for lesotho is substantially higher than that for the other four since the % uis do not overlap. seychelles, mauritius and comoros had mortality rate lower than the global rate per , . heterogeneity in rates between countries in was high, with rate ratio between comoros, the country with the lowest age-standardized mortality rate ( . ( . - . )), and lesotho, the country with the highest age-standardized mortality rate ( . (( . - . ) nearly -fold higher. looking back in time, in , , and , botswana and eswatini had consistently the highest age-standardized mortality rates. zimbabwe dropped out of the top in (table ) . (table ) . the map on fig. shows the annual percent changes in hiv-associated mortality for males and females from for each metric, the sdi, a measure of where the country is on the spectrum of development based on income, (table ) , ylds (table ) and dalys (table ) . to gain better perspective on the ylls percentage for sadc countries, the corresponding ylls percentages were . and . % in the member states of the organisation for economic co-operation and development (oecd) and the member states of the european union (eu) ( - % deficit), respectively. figure displays the ratio of ylls to ylds as proportions of dalys attributable to hiv/aids in sadc countries, worldwide, oecd, and eu . more dramatically from fig. , and highlighting the heterogeneity of the changes in the burden among rich and poor countries, the levels of ylls proportions of dalys due to hiv/ aids in sadc countries in were equal to the levels in oecd and eu countries, several years before the advent and widespread use of highly active antiretroviral treatment (haart). botswana, south africa, lesotho, eswatini, mozambique, and namibia all had increasing (worsening) burden, with aroc ranging from + . % in botswana to + . % in madagascar, suggesting that in these countries, the burden of hiv/aids has not abated, but has worsened compared to the levels in . (fig. ). we analyzed mortality and morbidity due to hiv/aids in sadc countries between and using estimates from the gbd study. the five leading countries with the proportion deaths attributable to hiv/aids in were botswana, south africa, lesotho, eswatini, and mozambique, also had the highest age-standardized mortality, yll, yld rates. botswana, eswatini, and lesotho were among the top five countries with highest mortality and morbidity in , , , and . comoros, seychelles, mauritius and madagascar had the lowest rates in . double-digit increasing slopes in aroc (%) observed in countries is worrisome. indicating significant risk that the progress made in slowing the hiv epidemic could be reversed without a continued robust investment in health. while the negative aroc (%) in four countries, drc, tanzania, zimbabwe, and zambia is encouraging, the aroc (%) observed in madagascar, south africa, and angola are concerning. while most sadc countries, except for comoros, seychelles, madagascar and mauritius had morbidity and mortality rates in greater than the global rate, there was substantial heterogeneity among the countries. the disparity in rates, measured using rate ratios, between the lowest rates observed in comoros, and highest rates observed in lesotho exceeded -fold in suggesting that sadc countries are on very diverse trajectories regarding the burden of hiv/aids. while art has extended life for most people living with hiv, it is sobering that two-thirds of hiv/aids-related deaths in lmics occurred in individuals not on art [ ] . loss to follow-up from care and defaulting, especially for first-line treatment, significantly affect survivability. ideally, when one defaults on the first line, the next step would be initiation into the second line, which because of cost, is out of reach for most rural communities in the sadc, thereby compromising survival of patients [ , ] . our most poignant finding is that the ratio of hiv/ aids-related ylls/dalys of . % for oecds in (fig. , first bar) is nearly equivalent but smaller, at . %, than the hiv/aids-related ratio of ylls/dalys in sadc countries nearly three decades later in (fig. , sadc bar) [ ]. it is astounding that the ratio for sadc was lower than the ratio experienced in oecd member states years prior, a period during which there was no widespread use of art or secondary prophylaxis against opportunistic infections? despite the advent of potent art, sadc still lags by almost years demonstrating the uneven progress that has been achieved in different regions. notably, unaids endorsed the concept of "undetectable" = "untransmittable" based on strong scientific evidence that hiv is not sexually transmitted from people living with hiv/aids to their hiv-negative partner if the partner hiv-positive continues to take effective art and is virally suppressed [ ] [ ] [ ] [ ] . having many infected people not on treatment increases the risks for infection to the general population. ensuring those who are infected are virally suppressed is a powerful tool to improve survival for those infected and prevent new infections. it has been argued that hiv/aids has remained a massive public health threat, but global financing has plateaued, domestic health spending has stayed low among high-burden countries, and the disease incidence has not declined as quickly in younger as in older populations [ ] . eswatini, botswana, and lesotho had among the highest mortality rates in the world before the downward shift of the world epidemic since , suggesting that the extremely high rates during the peak in continue to drive the epidemic decades later. the mortality rates in eswatini and lesotho remain among the highest in the world, exceeding more than a decade after the global decline. our study showed hiv/ aids caused more ylls than ylds at all times, underscoring that in sadc countries survival following hiv infection is very short. it is desirable to decrease the proportion of ylls contributing to dalys so that patients live longer. one likely explanation of the relatively small proportion of ylds to dalys in sadc is people with hiv/aids present late for care after the onset of opportunistic infections, underscoring the need for early and periodic testing for hiv while their health is still intact. strategies should be developed to ensure that more people who are unaware of their hiv status are tested and if necessary linked to care immediately. health systems in the sadc region need improvement to help lengthen the lives of individuals with the disease and convert the burden of hiv/aids into mostly ylds rather than ylls. premature mortality, measured using ylls, is indicative of failure of healthcare management of hiv/aids cases in the region to convert the burden of hiv/aids into mostly ylds, therefore extending the lives of the hiv/aids-affected individuals. countries with better healthcare access and quality index have the potential to reduce future burden [ ] . we detected huge disparities between the observed mortality compared to that expected based on the country's level of sdi. accordingly, sadc countries are relatively underperforming with respect to the expected reduction in disease burden compared to other countries of similar sdi. at current rates of decline in the burden of hiv/aids, sadc countries might not meet the sdgs target for the disease and are far from the unaids goal of ending aids by [ ] . our study suggests that sadc countries have made some progress, but hiv/aids mortality and morbidity rates are still unacceptably high. while the global mortality and morbidity rates in were approximately doubled compared to levels, sadc countries such as south africa had rate that was -times, angola -times, and mozambique -times the rate, increases pointing to a cascade of orders of magnitude. in the sadc region, most people with hiv/aids are reliant on medications provided by sources outside of the region. individuals between and years of age, the peak years of economic production, are the most affected by the epidemic [ ] . our findings, therefore, imply that sadc countries are economically and socially vulnerable. the number of people who do not know their hiv status is of concern. a pregnant woman with untreated hiv has up to a % chance of transmitting the virus to the baby. if the woman and their baby receive antiretroviral treatment, that risk drops to % [ , ] . for hiv infection to become a rare occurrence, sadc countries should coordinate efforts to reduce new hiv infections, increasing access to hiv/aids treatment and care, particularly to religious minorities that discourage contact of their members with the healthcare system [ ] [ ] [ ] . government health spending is a primary source of funding in the health sector across the world, but in ssa, only about a third of all health spending is sourced from the government [ ] . in southern africa, public funding for healthcare grew by only . % each year between and [ ] . keeping the coverage of aids-related services at levels would lead to an increase in the burden of hiv/aids in almost all sadc countries. art in sadc countries is available through "cost-free" programs funded by the global fund, pepfar, and corresponding governments [ , ] . the heavily donor-funded art programs have been a success story, but there is uncertainty about their long-term sustainability [ ] . pepfar was the largest donor, providing $ . billion in , followed by the global fund: with contributions from the uk ($ . million), france ($ . million), the netherlands ($ . million), and germany ($ . million). the us government recently proposed a % reduction in pepfar and global fund assistance [ , ] . any reduction in funding could have significant impact on hiv prevention and treatment, as most of the countries are dependent on these organizations for most of their hiv/aids programming budgets [ ] . sadc countries should try to ramp up their domestic financing programs in order to reduce dependency on these other organizations/countries and be able to sustain the programs. the un fast-track framework advocates for frontloading resources required for full implementation of basic programs by investing $ . billion in lmics in . by , the investment amount would drop to $ . billion, in the process averting nearly million new hiv infections and million aids-related deaths [ , , ] . for fast-track goals to be successful in marking a transition toward ending the hiv/aids epidemic, sustained and intensified regional commitment by sadc countries together with the un and the african union over the next decade will be required. our study is subject to a few previously described limitations regarding the estimation of hiv/aids burden [ , ] . firstly, our study estimated mortality with hiv/aids as the underlying cause of death without accounting for deaths from other non-communicable causes among people with hiv/aids. secondly, national-level estimates may obscure substantial heterogeneity at sub-national level. thirdly, we had no access to traditional risk factors that influence transmission of hiv/aids such as presence of other sexually transmitted infections, stage of infection, male circumcision, and use of art and pre-exposure prophylaxis (prep), therefore we could not explore the importance of these factors. fourthly, sdi was used as a linear predictor to estimate expected rates in , yet the sdi does not always exhibit a linear association with all causes of death including hiv/aids-related deaths. fifthly, time lags in available data, absence of data from specific regions, age groups, or time periods, or unreliability in the data that are available or for geographical areas with the highest hiv/aids-related mortality can affect the precision of estimations. sixth, because gbd results for hiv/aids are a combination of data and estimation, lags in data reporting mean that estimates for the most recent years rely more on the modelling process, as do estimates for locations with low levels of data completeness. despite these limitations, this study gives an insight on the disparities in morbidity and mortality within the sadc region. efforts are underway to collect data at local levels to further reveal the granularity of estimates to reveal nuances hidden by aggregated data. this higher resolution will aid governments in focusing their efforts in regions with higher burden. for better resolution and to illuminate geographic inequality in hiv/aids burden, future analyses should use spatially resolved data at a × -kilometer grid level. community-level estimates can help identify where interventions and health policies will have the greatest impact by targeting the most vulnerable individuals. in the absence of a preventive vaccine, at current rates of decline in the burden of hiv/aids, sadc countries will not meet the un's health-related sdgs by or achieve the unaids goal of ending aids by [ , ] . our study should help to inform decisions about policy and programs aiming to improve resource allocation and track accountability. sadc countries need to continue to ensure access and adherence to art and strengthen behavioral interventions to prevent new infections. early testing should be encouraged, perhaps rewarded, in order to link individuals testing positive to care early, when their immune systems are still strong, potentially increasing ylds while reducing ylls and preventing new infections. eliminating hiv/aids will take sustained coordination across multiple health and social sectors in the region, along with adequate funding and supportive public policies. governments in sadc countries should plan strategically as a block in efforts to eliminate the hiv/aids epidemic. the double-digit increasing slopes in aroc (%) observed in countries indicate significant risk that the progress made in slowing the hiv epidemic could be reversed without a continued robust investment in health. it is unacceptable for governments to outsource the huge financial undertaking to outside forces. governments should take responsibility for their people by making hiv/aids funding a priority. hiv/aids programming, including funding for art manufacture, procurement, and distribution across the region, should comprise a significant proportion of the national budgets. sadc should expand its mission to include increasing domestic funding, collaborative licensing, and procurement and manufacture of art. rather than importing hiv/aids medications from abroad, local manufacturing and distribution of art would guarantee seamless supply of the medications for all people in need. for this strategy to be effective, the sadc countries should gaurantee access to medications for people in transit and and make sure they receive care upon return. the coronavirus disease (covid- ) pandemic disrupted and put the world on edge forcing governments to implement, social distancing, and community containment, city lockdowns or traffic controls, measures which disrupted the continuum of hiv/aids care because of restricted hospital visits, sadc government and community partners should collaborate to sustain hiv service provision for people living with hiv/aids to avoid disruption of routine hiv services. strategies such as dispensing art in - -month doses to meet the needs of people living with hiv and reduce facility visits would reduce disruption [ ] . while our study looked at epidemiological data on the burden of hiv/aids in the sadc countries, gbd data does not address issues surrounding the economic impact of hiv, such as healthcare and occupational perspectives. healthcare costs of hiv/aids and the occupational situation of people living with hiv/aids need to be discussed. in high-income countries, the trends indicate that an increasing proportion of the intermediate-age hiv-positive population will age prematurely, experiencing high rates of cardiovascular disease events, cancers, and neurocognitive impairment [ ] and becoming frailer. regarding occupational perspectives, the decreased life expectancy of hivpositive persons may prompt this population to retire early from the labor market [ , ] . strategies should be developed to alleviate poverty, improve economic and financial opportunities for people with hiv/aids, and improve infrastructures to empower individuals with hiv/aids to continue with productive economic activity. gbd results are detailed and carefully researched using transparent methods but they are estimated and rely on many assumptions. to minimize the need for extrapolation, more primary data are needed from all countries where data accuracy and reliability can be poor. in nearly four decades the hiv/aids epidemic has changed dramatically as the virus has rapidly spread to all geographic regions. globally, significant progress has been made in improving diagnosis and access to treatment. however, if hiv/aids-related mortality continues at current level in sadc, none of the countries will reach the sdg target of ending the epidemic by . the downward trajectories observed elsewhere have been sluggish in the sadc regions. there is a need to strengthen existing strategies and create new ones to help end the disparity and help keep hiv/aids on a steeper downward trajectory. education about hiv transmission and prevention and testing and immediate treatment of individuals who test positive, should be implemented and maintained and funded. health ministries should increase efforts to ensure that accessible, affordable and stigma-free testing and treatment, including better access to viral load testing, is available to all people living with hiv/aids [ ]. additionally, pharmaceutical interventions like pre-and post-exposure prophylaxis which have changed prevention and treatment protocols for hiv/aids in other regions have not been fully implemented in sadc. sadc countries are facing challenges in meeting hiv/aids-related sdg targets; however, opportunity remains to take actions to accelerate progress by adopting regional multi-sectoral commitments and investments to help attain the sdgs for hiv by , or achieve the unaids goal of ending aids by [ , ] . regional coordination among sadc countries will further promote the attainment of sdgs. who validates elimination of mother-to-child transmission of hiv and syphilis in cuba implementing primary healthcare-based pmtct interventions: operational perspectives from muhima cohort analysis (rwanda) global, regional, and national incidence, prevalence, and years lived with disability for diseases and injuries for countries and territories, - : a systematic analysis for the global burden of disease study disease and injury incidence and prevalence collaborators. global, regional, and national incidence, prevalence, and years lived with disability for diseases and injuries for countries and territories, - : a systematic analysis for the global burden of disease study global, regional, and national disability-adjusted life-years (dalys) for diseases and injuries and healthy life expectancy (hale) for countries and territories, - : a systematic analysis for the global burden of disease study global, regional, and national incidence, prevalence, and mortality of hiv, - , and forecasts to , for countries and territories: a systematic analysis for the global burden of diseases, injuries, and risk factors study cause of death collaborators. global, regional, and national agesex-specific mortality for causes of death in countries and territories, - : a systematic analysis for the global burden of disease study institute for health metrics and evaluation (ihme) guidelines for accurate and transparent health estimates reporting: the gather statement metric partnerships: global burden of disease estimates within the world bank, the world health organization and the institute for health metrics and evaluation hiv development assistance and adult mortality in africa global burden of disease collaborative network. global burden of disease study (gbd ) disability weights. seattle: institute for health metrics and evaluation (ihme) disability weights for the global burden of disease study ): the international bank for reconstruction and development /the world bank mortality collaborators. global, regional, and national agesex-specific mortality and life expectancy, - : a systematic analysis for the global burden of disease study an integrative meta-regression framework for descriptive epidemiology unaids reference group on estimates modelling and projections. improved methods and assumptions for estimation of the hiv/aids epidemic and its impact: recommendations of the unaids reference group on estimates, modelling and projections producing hiv estimates: from global advocacy to country planning and impact measurement, global health action survival of people on antiretroviral treatment in zambia: a retrospective cohort analysis of hiv clients on art southern african development community. sadc hiv and aids strategic framework global, regional, and national incidence and mortality for hiv, tuberculosis, and malaria during - : a systematic analysis for the global burden of disease study institute for health metrics and evaluation (ihme) what is required to end the aids epidemic as a public health threat by ? the cost and impact of the fast-track approach pepfar funding and reduction in hiv infection rates in focus sub-saharan african countries: a quantitative analysis side effects' are 'central effects' that challenge retention in hiv treatment programs in six sub-saharan african countries: a multicountry qualitative study prevention of hiv- infection with early antiretroviral therapy sexual activity without condoms and risk of hiv transmission in sero-different couples when the hivpositive partner is using suppressive antiretroviral therapy hiv transmission in male serodiscordant couples in australia, thailand and brazil institute for health metrics and evaluation. financing global health : funding universal health coverage and the unfinished hiv/aids agenda. seattle: institute for health metrics and evaluation healthcare access and quality collaborators. health access and quality based o mortality from causes amenable to personal healthcare in countries and territories, - : a novel analysis from the global burden of disease study what will become of me if they take this away? unaids: fast-track: ending the aids epidemic by donor government funding for hiv in low-and middle-income countries in undetectable=untransmittable-public health and hiv viral load suppression tang w maintaining hiv care during the covid- pandemic lancet hiv published online a systematic review and meta-analysis of studies evaluating the performance and operational characteristics of dual point-of-care tests for hiv and syphilis trends and drivers of government health spending in sub-saharan africa economic impact of hiv in the highly active antiretroviral therapy era -reflections looking forward publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none of the other authors has competing financial interests. all authors report no conflicts.authors' contributions png conceptualized the study, had access to raw data, analyzed data, wrote the first draft of the manuscript, and interpreted the data. cmg, sb, ccm, and rk, contributed to the clinical, epidemiological, policy implications sections, and strengthened the intellectual content and recommendations of the study. srr co-wrote the first draft of the paper strengthened the intellectual content of the study. ahm supervised the development of the study, critiqued earlier drafts, and shaped the overall interpretation in relation to previous related studies. the authors read and approved the final manuscript. bill & melinda gates foundation. the funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. the corresponding author had full access to all the data in the study and had final responsibility for the decision to submit the manuscript. data that support the findings of this study are available at: table : http://ghdx.healthdata.org/gbd-results-tool?params=gbd-api- permalink/ c dc c b f c f tables , , , : http://ghdx.healthdata.org/gbd-results-tool?params=gbdapi- -permalink/ aea bf cff c deb a a b, or by request from the authors.ethics approval and consent to participate not applicable. not applicable. none.author details key: cord- -g dli a authors: chang, hernan r.; dulloo, abdul g.; bistrian, bruce r. title: role of cytokines in aids wasting date: - - journal: nutrition doi: . /s - ( ) - sha: doc_id: cord_uid: g dli a abstract there is now a large literature implicating cytokines in the development of wasting and cachexia commonly observed in a variety of pathophysiologic conditions. in the acquired immunodeficiency syndrome (aids), cytokines elicited by primary and secondary infections seem to exert subtle and sustained effects on behavioral, hormonal, and metabolic axes, and their combined effects on appetite and metabolism have been postulated to drive wasting. however, correlations of increased blood levels of a particular cytokine with wasting in aids have not been consistent observations, perhaps because cytokines act principally as paracrine and autocrine hormones, as well as indirectly by activating other systems. a better understanding of the mechanisms underlying the catabolic effects of cytokines is clearly needed if more efficacious strategies are to be developed for the prevention and treatment of wasting in aids. in this review we first examine the interacting factors contributing to the aids wasting syndrome. we then analyze the complex and overlapping role of cytokines in the pathophysiology of this condition, and put forward a number of hypotheses to explain some of the most important features of this syndrome. there are close interrelationships between malnutrition and infection. malnutrition enhances susceptibility to infections, exacerbates their harmful effects, and influences their outcome. infections also can produce malnutrition: the wasting syndrome and cachexia are common complications of infections, and they play an important role in the morbidity and mortality of the aids. indeed, although wasting is not universally observed in aids patients, the wasting syndrome in a human immunodeficiency virus (hiv)-seropositive individual is generally utilized to establish the diagnosis of aids and is defined by a decrease in body mass greater than % in the absence of concomitant opportunistic infections, malignancies, and other identifiable causes of weight loss. independent of the causes of wasting, aids patients who experience weight loss beyond a certain percentage of ideal body weight are at greater risk of death, thereby establishing a link between survival and the extent of body cell mass depletion. [ ] [ ] [ ] [ ] consequently, reversing wasting should improve the life expectancy and quality of life. however, this has proved to be difficult and the outcome of nutritional supplementation is poor, with the tendency for weight gain to be fat and water and not lean tissue. the causes of malnutrition leading to wasting in aids are believed to be a combination of several factors, which, as shown in table i , can be classified under three main categories: ) reduced nutrient intake, ) malabsorption, and ) metabolic disturbances. of the factors that may underlie the reduction in nutrient intake in hiv patients, anorexia is usually the most prominent. it is primarily the result of the cytokine responses to the infection per se, but it can also be caused or exacerbated (as an unwanted side effect) by certain medications employed in hiv patients receiving multidrug therapy for concomitant medical problems. a diminished ability to ingest nutrients can also be observed in hiv patients suffering from some central nervous system (cns) processes such as dementia or tumors. furthermore, the almost universal presence of inflammatory processes, infections, or both, involving the digestive tract of aids patients producing gingivitis, stomatitis, esophagitis, or enteritis, often impair the ability to ingest, in large part due to pain preventing intake or aggravated by food intake, as well as absorb nutrients. the net effect is that all these factors contribute to a deficit of energy and nutrient supply to meet the body's needs. in addition to reduced nutrient intake, intestinal malabsorption (due to intestinal dysfunction and inflammation) can also be an important contributory factor to malnutrition in aids cases. [ ] [ ] [ ] [ ] [ ] however, a causal link between abnormal malabsorption tests and wasting is not clear. in hiv-infected children, although postnatal gain in weight and lean body mass were found to be lower than in an hiv-negative comparison group, an earlier study by the same group found that lactose malabsorption was not associated with higher rates of diarrhea or growth failure. this underlies the fact that carbohydrate malabsorption in hiv-infected children is not the only factor responsible for growth failure. moreover, fat malabsorption is generally more clearly related to development of malnutrition. in fact, malabsorption, particularly of fat but also certain minerals and vitamins, is common in patients with protracted diarrhea, and patients with hiv infection are prone to develop a variety of enteric infectious processes that cause diarrhea. these include those due to protozoan, viral, bacterial, and fungal pathogens (see table ii ), as well as neoplasm (lymphoma, kaposi sarcoma) and disseminated infectious processes. the role of several additional enteric pathogens (including enteroaggregative escherichia coli) in the pathogenesis of diarrhea and malabsorption has not been adequately studied and certainly deserves more attention. , furthermore, the paucity of food in the intestine over long periods of time, in conjunction with protein-energy malnutrition, may provoke structural changes and functional intestinal atrophy. the resulting decline in digestive functions could further impair absorption of both macronutrients (fat, protein, and carbohydrates) and micronutrients (vitamins and minerals). thus, absorptive dysfunction compounds the problem of reduced nutrient intake and often aggravates anorexia through abdominal symptoms. in fact, in many if not most malabsorption syndromes, it is generally the reduction in oral intake induced by symptoms related to malabsorption (cramps, bloating, pain, and diarrhea) that is responsible for most of the energy gap between intake and total expenditure. like many pathophysiologic conditions such as sepsis and cancer, a hypermetabolic state, characterized by an increase in resting energy expenditure (ree) and disturbances in the metabolism of protein (muscle proteolysis) and fat (hypertriacyglycerolemia), has also been implicated in the aids wasting syndrome. in fact, an earlier notion that hypermetabolism is the major driving force behind wasting in aids has been particularly attractive because it provided an explanation for the excessive loss of muscle, and the difficulty of reversing the wasting syndrome (with nutritional therapy most often resulting in gain in body fat and water, with marginal or no gain in lean tissue). these metabolic abnormalities have been associated with futile cycling, such as that occurring when fatty acids are being mobilized at an accelerated rate from adipose tissue, and then reesterified into triacylglycerol for storage again in fat, as well as the wasteful use of substrates underlying the conversion of glucose into fatty acids, before being stored as fat (i.e., de novo lipogenesis). the contribution of these metabolic pathways to the hypermetabolic state is, however, unclear and hypertriacylglycerolemia in the hiv patients does not correlate with wasting. - moreover, although an increase in ree has been reported in all stages of hiv infection, - the notion that hypermetabolism is the primary factor underlying wasting in aids has been challenged by more recent studies in patients with hiv indicating that the increase in ree per se is not sufficient to cause wasting. first, ree is increased even in asymptomatic hiv-infected patients with normal cd cell counts, but such individuals can usually sustain their weight and lean body mass for prolonged periods. second, in patients who were actively losing weight or had stable weight, ree was about % higher than normal, but their total energy expenditure (tee) was found to be no greater than that predicted for healthy individuals. these apparent discrepancies between increased ree coexisting with normal or low tee have been reconciled with data indicating that the increased ree is largely compensated by energy saved as a result of reduced physical activity, and it is loss of appetite leading to decreased intake, coupled with malabsorption, that primarily drives wasting in aids. to what extent such reduction in physical activity is the result of lethargy and fatigue from the illness per se or that of a normal adaptive physiologic response to save energy is unknown. however, it is clear that the decrease in physical activity will alter the quality of life, which may further deteriorate because a drastic reduction in locomotor activities might lead not only to muscle atrophy and consequential functional impairments, but can also contribute to the failure to rebuild lean body mass during realimentation. furthermore, an increase in ree during active weight loss is by no means trivial, because this is counterproductive to the adaptive reduction in ree that is the normal response in order to buffer the energy deficit and hence contributes to exacerbate the negative energy balance even further. the most likely scenario in the development of the wasting in hiv-infected patients can be summarized as follows: • despite increased ree in response to hiv-infection, the patients can maintain their weight often for long periods of time, most probably through reductions in the amount of energy they expend on physical activity. this "compensation," however, may still be deleterious because it interferes with lifestyle and increases the susceptibility to muscle atrophy, and consequential functional impairment. • subsequent weight loss is primarily caused by poor appetite, malabsorption, or both, generally triggered by secondary infections. , furthermore, the persisting hypermetabolic state is counterproductive to the adaptive down-regulation of resting metabolism that normally occurs in uncomplicated starvation, thereby exacerbating the wasting process. • the rate of weight loss and the severity of wasting is likely to be dependent upon the type, severity, and outcome of the secondary infection. aids patients with malnutrition due principally to malabsorptive symptoms seem to restore body weight and lean body mass when recovering from secondary opportunistic infection or when receiving nutritional support, , similar to what has been observed in non-hiv individuals recuperating from starvation, anorexia nervosa, and other clinical conditions, although both body fat and lean tissue are being recovered, fat is being restored at a disproportionately faster rate relative to lean tissue repletion. - however, when protein energy malnutrition is largely a reflection of systemic illness and inflammation, the recovery of lean tissue seems to be even poorer or delayed, such that body weight repletion is more as fat than body protein, similar to patients with sepsis, presumably related to inefficient protein anabolism. it is against this background presentation of the interacting factors contributing to malnutrition and functional impairment in hivinfected patients-namely anorexia, malabsorption, hypermetabolism, lethargy, and impaired fat and protein metabolism-that the role of cytokines in the aids wasting syndrome is discussed in the following sections. in the s, beutler and cerami isolated a -kda protein while searching for a mediator to account for the metabolic changes (particularly hypertriacylglycerolemia) observed in animals infected with the protozoan parasite trypanosoma cruzi (chagas' disease agent). this protein was termed cachectin, as it was supposed to mediate the wasting and hypertriacylglycerolemia found in those experimental animals. cachectin was subsequently found to reduce the activity of lipoprotein lipase (lpl) (potentially accounting for lower triacylglycerol turnover in vivo) and to promote lipolysis in vitro. in addition, purified cachectin was able to produce anorexia, weight loss, and fever when injected into experimental animals. subsequently, when the cachectin dna sequence was isolated, it become apparent that its dna sequence was identical to that coding for tumor necrosis factor (tnf). tnf had been previously isolated from the serum of animals injected with bacterial endotoxins and was able to produce necrosis of transplanted tumors in animals. furthermore, administration of purified or recombinant tnf to experimental animals provokes very similar metabolic and hemodynamic changes to those observed during bacterial sepsis that could be blocked by the use of specific antisera or monoclonal antibodies. , administration of recombinant tnf to humans suggested that this cytokine could play an important role in the early activation of the hemostatic mechanism in septicemia. recent experimental studies with knockout mice (for the -kda tnf receptor) have confirmed the importance of tnf in the pathophysiology of endotoxic shock. , it is now well established that tnf and other cytokines (e.g., interleukins, interferons) are a group of hormonelike polypeptide mediators released by various cell types having pleiotropic actions on many cell types, and they play a regulatory role in normal and abnormal homeostasis and in host defense mechanisms (inflammatory and immune responses). cytokines share some general characteristics in their mode of action: different cytokines can have a similar effect on several target cells (redundancy); they can activate the secretion of other cytokines (producing a "cascade"); and they can also initiate their own secretion (autocrine), act in a paracrine fashion on neighboring cells, or act on distant cells as hormones. in addition to their pleiotropic actions on many body systems, they could potentially contribute to the wasting and cachexia of aids by their ability to induce anorexia, alter energy expenditure, increase muscle proteolysis and net protein breakdown, and initiate various abnormalities of lipid metabolism. a role for tnf in aids wasting syndrome was postulated in earlier studies indicating that tnf serum levels were elevated in patients with aids. however, subsequent studies failed to show high-serum tnf levels in most aids patients, and no correlation appeared to exist between serum tnf levels and the magnitude of weight loss in aids patients. - at least in some studies the choice of the methods to determine tnf activity (immunoassay versus bioassay) might account for the differences observed. pentoxifylline, a xanthine that inhibits the production of tnf by decreasing activity of the transcription factor nf-kb, has been used to highlight indirectly the possible importance of tnf in the hypertriacylglycerolemia observed in aids patients. administration of pentoxifylline was shown to reduce the triacylglycerol levels in aids patients, although this reduction was only marginally significant (p ϭ . ) and the study was open label (nonblinded). more importantly, pentoxifylline does not alter other aspects of aids wasting, emphasizing the fact that aids wasting is not entirely tnf dependent. interleukin- (il- ) shares many of the characteristics of tnf and can also produce anorexia, hypertriacylglycerolemia, and stimulate hepatic fatty acid synthesis. , in addition, il- reduces lpl activity and produces lipolysis. , moreover, both tnf and il- can promote hiv- replication in in vitro cellular systems, which has led to the suggestion that cytokines may be important for the progression of hiv infection to aids. thus, tnf production is linked to hiv infection and the potential role of tnf in this setting is a source of this enhanced production. , naturally occurring cytokine antagonists such as the soluble form of the p (type i) tnf receptor (tnfsrp ) and the il- ␤ receptor antagonist (il- ra) are produced in the body to counteract the potentially harmful effects of excessive tnf and il- production, respectively. , enhanced plasma levels of soluble tnf receptors have been reported to be correlated with rapid progression toward aids in hiv- infected patients. moreover, a study suggested that enhanced tnfsrp and tnfsrp (type ii) were predictive of worsening nutritional status in hiv patients. a more recent study showed that high serum levels of il- ␤, tnf, and il- together with an excess of the natural inhibitors il- ra and tnfsrp were seen in asymptomatic hiv- -positive african women but not in african women with aids or in hiv-negative controls. this study suggests that cytokine antagonists may play a role in modulating cytokineassociated symptoms in the early phases of hiv infection. alternatively, because most of the aids patients in that study were at the endstage of their disease and therefore likely to have significant protein-energy malnutrition, it might only reflect the inability or reduced ability to synthesize new proteins, including cytokines. on the other hand, another study has found no correlation between elevated soluble tnf receptor types i and ii levels and metabolic disturbances in hiv infections. other studies have shown increased serum/plasma levels of il- , tnf, il- , and interferon-␥ in some populations of hivinfected patients. , , , il- , an important mediator of the acute-phase response, reduces lpl activity in vitro and in vivo and promotes fatty acid synthesis. , in contrast to tnf and il- , il- serum levels are consistently raised in aids and il- has been implicated in the development of cachexia in inflammatory and neoplastic processes. , , , - serum levels of il- in hiv-infected patients are high when compared with non-infected normal subjects. the levels of il- appear to increase according to the stage of hiv disease and appear to be higher in terminal stages of the disease. , however, no data has been provided yet to link il- blood levels directly with the development of wasting and cachexia in aids patients. a major problem with studies regarding cytokines and circulating soluble receptors in the bloodstream of patients with hiv is that cytokines principally act in an autocrine and paracrine manner, thus making blood levels not necessarily relevant for a proper interpretation of their effects on tissues, organs, or body systems. moreover, cytokines are rapidly internalized by cells and they can activate the release of other substances. with respect to cytokine actions, it is therefore more adequate to think in terms of effects on tissues, organs, or systems rather than trying to simply correlate a complex clinical syndrome such as wasting with elevated circulating cytokine levels. for instance, il- has been more consistently found in the blood of hiv patients, and this is probably due to its longer half-life in serum as well as related to its major role in the acute-phase response as compared with il- and tnf, which are rapidly cleared from the bloodstream. the role of some cytokines such as tnf, il- , il- , il- , and interferon-␥ in controlling food intake, energy expenditure, or both, have been underscored by many experimental studies. [ ] [ ] [ ] [ ] [ ] [ ] [ ] these studies have demonstrated that exogenous administration of those cytokines may mimic the hypermetabolism and anorexia associated with infection. in addition, pretreatment with specific anticytokine antibodies blocked the anorectic and thermogenic effects to the exogenous administration of cytokines as well as those of cytokine-secreting tumors. furthermore, other studies utilizing techniques of intracerebroventricular microinjection have demonstrated the anorexigenic effects of several substances that can be induced by cytokines. those substances include plateletactivating factor, several chemokines/intercrines such as il- , platelet factor- , interferon-inducible protein- , monocyte chemotactic protein- /monocyte chemotactic and activating factor (mcp- /mcaf), regulated-upon-activation of normal t cell ex-pressed and presumably secreted (rantes), as well as ␤ microglobulin, a marker for immune activation. - these findings suggest an interaction (and perhaps redundancy or synergistic action) of several immunomodulators that are released during inflammatory and immune processes to induce anorexia. what are mechanisms (and mediators) by which anorexia and hypermetabolism are produced? several neurotransmitters, amino acids, peptides, and cytokines can potentially influence food intake during starvation and infectious processes. in addition, some neurotransmitters function during normal regulation of food behavior. prominent among them are corticotropin-releasing hormone (crh), neuropeptide y (npy), cholecystokinin (cck), norepinephrine, acetylcholine, serotonin, dopamine, glutamate, ␥-aminobutyric acid, and others. [ ] [ ] [ ] the paraventricular nuclei (pvn) and the hypothalamus appear to be important areas for the control of compensatory feeding behavior in response to changes in energy homeostasis. crh and npy appear to play a prominent role in the responses to starvation. increases of npy in the pvn area produce hunger together with activation of the hypothalamic-pituitary-adrenal (hpa) axis. increases of crh produce a reduction in messenger rna (mrna) for npy together with anorexia and activation of the hpa axis, as well as increased thermogenesis, lipolysis, hyperglycemia, and inhibition of expected insulin secretion. , , the paradoxical activation of the hpa axis (together with the secretion of glucocorticoids) during the secretion of both substances, crh and npy, which have opposite effects on feeding behavior, might be explained by the fact that when the hpa axis is activated, it is done so in the setting of different orchestrated responses. , several cytokines, such as tnf, il- , and il- , as well as other mediators of inflammation, which were initially and collectively called "tissue corticotropin-releasing factor," can activate the hpa axis during inflammatory states. , activation of the hpa axis by cytokines leads to the secretion of glucocorticoids, an action believed to participate in the negative feedback control of the immune response. , during inflammatory states tnf is secreted first and promotes the cellular secretion of il- ; and the release of both cytokines leads to the secretion of il- , which in turn acts in conjunction with glucocorticoids to elicit the production of many mediators of the acute-phase response by the liver. , , tnf, il- , and il- act in a synergistic manner, whereas glucocorticoids down-regulate the secretion of those cytokines , - and other inflammatory mediators including nitric oxide, platelet activating factor, and prostanoids. - tnf, il- , and il- also participate in the stimulation of the hpa axis during endotoxin administration. noteworthy, anti-il- antibodies can almost completely block the stimulation of the hpa axis by endotoxin. as these cytokines do not appear to cross the blood-brain barrier in significant amounts, how can these cytokines be acting at the cns level? one explanation is that tnf, il- , and il- , produced peripherally, can act on crh neurons through the activation of other cells such as astrocytes or microglial cells in the brain or cells in the area postrema, which are not protected by the blood-brain barrier, to secrete cytokines or other substances. alternatively, activated endothelial cells, phagocytic cells, or activated t cells migrating through the blood-brain barrier can initiate further cellular production of cytokines to act on crh-producing neurons. to gain an insight into these mechanisms we performed a study in which transgenic mice expressing high levels of soluble tnf-r fusion protein (and therefore having blunted circulating tnf levels) showed reduced thermogenesis and blunted mrna expression for tnf, il- , il- , and crh in the brain in response to a parenteral challenge (d. arsenijevic, i. garcia, h. r. chang, and a. g. dulloo, unpublished observations). these results support the hypothesis that local production of tnf, il- , and il- in the brain may mediate the increased brain production of crh to produce anorexia and hypermetabolism during endotoxin administration. furthermore, that study demonstrates that tnf is necessary for eliciting the increased production of crh and that tnf is indeed needed as an amplifier of the inflammation cascade through up-regulation of il- and il- production. this finding is in agreement with other data showing that cns administration of antibodies to neutralize il- ␤, il- , or tnf inhibits the thermogenic and anorectic responses to peripherally injected endotoxin in the rat. further systems such as the noradrenergic system may be activated during inflammatory stress. the overall effect should be the enhancement of crh production, which carries the previously mentioned effects including anorexia, lipolysis, and increased thermogenesis and therefore weight loss. systemic administration of il- also stimulates the expression of crh mrna in the pvn together with dose-dependent activation of the hpa axis and sustained suppression of food intake. , this effect of il- is partially reversed by crh antisera administration. il- receptors have been demonstrated in hypothalamic structures. , almost identical effects on crh release and food intake have been reported for tnf, il- , il- , and interferon-␥, suggesting that sustained and moderate increases in the levels of those cytokines (which act synergistically) can potentially increase crh, thereby blocking the normal compensatory hypothalamic response to weight loss (i.e., increased appetite and reduced thermogenesis). and indeed, elevated levels of several cytokines, including il- and il- , have been reported in the cerebrospinal fluid of aids patients. thus, local production of cytokines within the cns can contribute to the wasting syndrome and cachexia observed in hiv infection and aids through chronic release of crh. another potential mechanism by which sustained production of cytokines could enhance the secretion of crh is through reduction of the sensitivity of target tissues to the effects of glucocorticoids. for instance, a decreased affinity of glucocorticoid receptors for cortisol has been described in phagocytic cells from some aids patients. in those aids patients, there were elevated levels of cortisol and corticotropin associated with signs of glucocorticoid deficiency including hyponatremia and postural hypotension pointing to a glucocorticoid-resistant condition. by this mechanism, hpa axis activation would be resistant to the negative feedback mechanism provided by the secretion of glucocorticoids. interestingly, il- in combination with il- has been described to produce resistance of t cells to the action of glucocorticoids by reducing the affinity of the glucocorticoid receptor for its ligand. il- is involved in antiinflammatory mechanisms together with other cytokines, such as il- and il- , and they are able to augment the expression of il- ra. - both insulin and glucocorticoids play an important role in the peripheral response to fasting and starvation. they also appear to play a role in the cns regulation of energy balance by regulating npy synthesis and release. thus, insulin, as opposed to its peripheral anabolic effects, promotes a state of negative energy balance (through anorexia and increased energy expenditure) by reducing npy gene expression in the hypothalamus. fasting (which lowers insulin levels) increases hypothalamic npy gene expression. glucocorticoids have opposing effects to insulin, thus promoting a state of positive energy balance with an increase of caloric intake. , peripherally, glucocorticoids, as well as glucagon, catecholamines, and growth hormone, may induce insulin resistance when these hormones are present in enhanced levels and in the presence of stress or infections such as in sepsis. current data, however, suggest that glucagon and catecholamines are not highly elevated in aids, whereas elevated basal cortisol levels have been found frequently. , administration of tnf to humans has been found to produce a hyperglycemic state without alterations in insulin levels, suggesting an insulin resistance-like state. moreover, infusion of tnf into experimental animals produces marked insulin resistance. these findings may help to partly explain the hyperglycemia and the relative insulin resistance observed in several infectious processes. however, hiv infection is characterized by high rates of insulin clearance as well as an increased sensitivity of peripheral tissues to insulin. is there a role for leptin? the newly described molecule leptin and its putative receptor also appear to play a role in maintaining normal weight. leptin is the protein product of the ob gene and its circulating levels reflect energy stores in adipocytes, suggesting its role as an "adipostat." - the leptin receptor gene is highly expressed at the hypothalamic level. , increased leptin levels produce anorexia and increased energy expenditure, possibly by reducing the release of npy , at the hypothalamic level. thus, reduced leptin levels induce hunger and reduced thermogenesis, pointing to a role for reduced levels of leptin in the adaptive changes to fasting/starvation. on the other hand increased leptin levels may be related to resistance to obesity (anorexia and enhanced thermogenesis), and may be acting on melanocyte-stimulating hormone and the melanocortin- receptor, in other regions of the brain. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] glucocorticoids and insulin have been demonstrated to up-regulate the production of leptin. [ ] [ ] [ ] cytokines, such as tnf and il- , and endotoxin, are able to stimulate leptin production and anorexia is directly proportional to the increase of leptin pointing to a potential role of this molecule in the anorexia associated with infection. however, a first study measuring leptin levels in patients with aids found that leptin levels were not increased relative to body fat in patients who were anorexic, were losing weight, or had a history of weight loss. also, leptin levels were not elevated during secondary infection, suggesting a lack of a link between increased leptin levels and anorexia in aids. another study comparing the levels of leptin in hiv-infected men to age-and body-fatmatched uninfected individuals showed no differences in serum leptin levels and there was no correlation with lean body mass. there was, however, correlation between leptin concentrations and percent body fat and body fat content, extending the notion that circulating leptin levels directly reflect adipose tissue mass, even in hiv-infected men with low body-fat content. a significant loss of lean body mass mainly due to muscle proteolysis has long been appreciated to be characteristic of wasting and cachexia in trauma and sepsis (as well as in aids, cancer, fasting, and acidosis). well before the wealth of information that currently exists on cytokine pathophysiology, several investigators were searching for mediators, such as the so-called "muscle proteolysis factor," that could be responsible for the metabolic disturbances and wasting observed. theoretically the loss of lean body mass could be due to an increase in tissue protein degradation or a decrease in tissue protein synthesis or a combination of both. accelerated protein breakdown in muscle is necessary to meet the needs of the anabolic response in liver, hemotopoietic, and wound tissue during stress and infection. on the other hand, in starvation (and in the absence of infection) there is increased appetite on refeeding, reduced energy expenditure, and relative preservation of muscle mass, but also no requirement for enhanced anabolism in those select tissues. in the wasting of aids and in the presence of cytokines there might be maintenance or declines in basal metabolic rate together with anorexia and muscle catabolism. what, therefore, would be the cause for muscle wast-ing in aids? tnf and il- have been shown to produce skeletal muscle catabolism in addition to their anorectic and net nitrogen loss effects, , but by different mechanisms. moreover, administration of tnf and il- to experimental animals have been found to produce weight loss, net nitrogen loss, skeletal muscle catabolism, and increased liver weight. , the effects were observed independent from and additive to those resulting from semistarvation. , recent evidence strongly suggests that activation of the ubiquitin-proteasome pathway is responsible for muscle wasting in several catabolic states. the activation or the suppression of the pathway is related to the rate of ubiquitin conjugation to proteins. higher rates of ubiquitin conjugation result in enhanced muscle proteolysis. glucocorticoids promote muscle proteolysis, an action that opposes the anabolic effects of insulin, by increasing mrnas encoding ubiquitin and proteasomes subunits and therefore increasing ubiquitin-protein conjugates. in the fasting state, muscle proteolysis may take place in the presence of glucocorticoids and when insulin levels are low. glucocorticoids in combination with several cytokines such as tnf, il- , and il- participate in stimulation of the ubiquitinproteasome pathway producing muscle proteolysis. [ ] [ ] [ ] in aids, all the requisite conditions for muscle proteolysis are present: increased basal levels of cortisol, low circulating insulin levels, and subtle release of several cytokines that may be acting synergistically. interference with tnf production by anti-tnf antibodies or by administration of pentoxifylline produces blockade of muscle proteolysis in vivo. , pentoxifylline may be acting to block muscle proteolysis through inhibition of the proteasome-dependent activation of the transcription factor nf-kb, which is also needed for tnf production. blockade of il- action by administering soluble il- ra to experimental animals prevents muscle proteolysis in response to endotoxin. recently, a novel glycoprotein, able to produce muscle proteolysis in vitro, as opposed to tnf and il- , which are unable to do so and are only effective in vivo, has been described in rodents and in the urine of cachectic patients with certain cancers. whether this glycoprotein also is produced in aids patients with cachexia is unknown. because cytokines such as tnf and il- are not able to produce muscle proteolysis in vitro, their effects on muscle proteolysis may be indirect. , , several subtle endocrine alterations have been demonstrated in hiv patients that potentially may be related to cytokine production. thyroid hormone, adrenal, and gonadal homeostasis could be altered during hiv infection by cytokines. the euthyroid sick syndrome can be observed with severe caloric depletion and severe illnesses, and is characterized by impaired peripheral conversion of thyroxine to t , resulting in high normal or normal circulating levels of thyroxine and lower levels of t . in addition, enhanced rt levels are present due to reduced clearance, whereas thyrotropin (tsh) levels appear to be within normal limits. in aids patients with anorexia and weight loss, conversion of thyroxine to t is decreased (euthyroid sick syndrome) as well as the levels of insulin-like growth factor-i (igf-i), whereas in stable hiv patients t levels are normal. , the reduction in t in those patients might be the consequence of an adaptive response to caloric deprivation, as is also observed during fasting and malnourished states. maintenance of such low levels of t during nutritional rehabilitation may hamper the buildup of lean body mass. infusion of il- to patients with cancer and normal thyroid function has been shown to acutely decrease tsh and t and to enhance levels of rt , but after several weeks of il- administration only tsh was found to be elevated. similarly, infusion of tnf to normal persons produced acute de-creases of tsh and t and increased rt . the clinical significance of such changes in thyroid function upon cytokine administration are not completely understood but suggest that the changes observed in aids patients may be due to the effects of cytokines. in aids, increased basal levels of cortisol have been demonstrated, and this might reflect the activation of the stress response. as a result of such cortisol levels, the cortisol response to provocative testing may be abnormal. cytokines can directly stimulate the release of corticotropin (acth), crh, and cortisol, - , which might suggest their potential role for the mild cortisol elevations in hiv patients. the demonstration of glucocorticoid resistance in some hiv patients may provide an additional explanation for cortisol elevations in the serum of some aids patients. data on gonadal function in aids has been gathered mostly from male patients. there are substantial data to indicate that hiv infection is accompanied by hypogonadism. hypogonadism in aids can be primary (testicular) or central in etiology, and may be due to the release of cytokines. for instance, administration of tnf to healthy men produces a rise in luteinizing hormone (lh) followed by a decrease in testosterone levels. moreover, il- has been shown at high levels to block steroidogenesis by inhibiting the binding of lh to leydig cells. a particularly noteworthy relationship is that crh, which is induced by cytokines, is also produced by leydig cells of the testes and produces autocrine effects by inhibiting testosterone biosynthesis. decreases in testosterone levels may make difficult any attempt to increase muscular mass. indeed, administration to aids patients of megestrol acetate, which stimulates appetite, also lowers testosterone levels, and results in weight gain but mainly of fat mass. recent experimental data suggest that the appetite-stimulant effect of megestrol acetate involve stimulation of synthesis, transport, and release of neuropeptide y in the hypothalamus. the nutritional status of an individual can be one of the major determining factors in resistance to infection. hiv infection, on the other hand, often produces malnutrition leading to wasting and cachexia. wasting syndrome in aids is multifactorial: hiv infection of gastrointestinal tissue and lymphoid tissue particularly, anorexia, inadequate nutrient intake and malabsorption, and catabolic effects on intermediary metabolism play important roles along with similar effects of repeated secondary infections. currently available preventive/therapeutic approaches for wasting in aids include baseline nutritional assessment (table iii) , early diagnosis of malnutrition and maintenance of adequate nutritional intake, early diagnosis/prevention of opportunistic infections, and appetite stimulants as well as anabolic hormonal therapy. - adequate antiretroviral therapy might be considered during early stages of hiv infection as part of the wasting preventive measures, because successful treatment of the primary infection with hiv or secondary infections is the most potent of anabolic therapies. cytokines play a complex and overlapping role in the development of wasting and cachexia in aids. they can exert behavioral, hormonal, and endocrine effects that can persist for long periods of time to produce wasting and cachexia. multipronged therapeutic approaches are therefore required to counteract their effects on different body systems. attempts have been made to modulate the release of certain cytokines such as tnf by pharmacologic means in aids patients, with the aim of arresting or reversing the wasting process. for instance, pentoxifylline has been found in pilot studies to decrease tnf serum levels as well as serum triacylglycerols in aids patients. , however, viral load was not altered and there was no benefit in terms of weight gain. , other pilot studies have failed to show any benefits of pentoxifylline administration to aids patients in terms of weight gain or effect on serum tnf levels. similar observations have been made in cancer patients with cachexia, where pentoxifylline failed to improve anorexia or cachexia. thalidomide, a drug with sedative effects that has been used for many years for the therapy of some reactive forms of leprosy (erythema nodosum leprosum), has been found to down-regulate tnf production in vitro. thalidomide has shown in pilot studies to promote weight gain in hiv patients with wasting. , thalidomide administration produced a reduction in serum tnf levels in a pilot study of hiv patients with wasting and tuberculosis. however, in a recent trial in which thalidomide was effective for the therapy of aphthous ulceration of the mouth, there were increases in tnf and soluble tnf receptor type ii as well as viral load. thalidomide has potent antiinflammatory properties and has been successfully used for therapy of certain types of aphthous ulcerations in aids patients as well as for the treatment of graft-versus-host disease in allogeneic bone marrow transplantations. , an additional mechanism by which thalidomide might promote weight gain is by improving the absorption of nutrients through the gastrointestinal tract. to date, no firm evidence has been provided to indicate that pharmacologic blockade or manipulation of cytokine production is useful in the prevention or therapy of wasting and cachexia in aids. in fact, sustained blockade of cytokine production may produce harmful effects as they are needed for a proper functioning and tuning of the immune system and blockade of a particular cytokine may in turn produce blockade of other cytokines, which may have unpredictable results. for instance, administration of pentoxifylline produced an increase in mycobacterial load in macrophages from aids patients with disseminated mycobacteriumavium-intracellulare complex infection. an alternative way of counteracting the effects of cytokines may include use of a cytokine with inhibitory actions on other cytokines or a drug or drugs that enhance the release of inhibitors, although these agents would be subject to the same concerns. for instance, epinephrine has been shown to increase the release of the antiinflammatory cytokine il- , which has been previously found to inhibit tnf. , however, it is difficult to see how this could be clinically applied, although oral or b-agonist therapy would be theoretically possible. finally, the use of antiinflammatory cytokines might be possible. potentially new approaches for prevention/therapy of wasting and cachexia of aids may include drugs that selectively can modulate the release of mediators acting at the target tissues, organs, or systems. for example, selective inhibitors or antagonists of crh that can go across the blood-brain barrier or agents that can down-regulate hypothalamic release of crh may effectively combat anorexia. also, specific inhibitors of the ubiquitinproteasome pathway might be useful to arrest muscle catabolism. however, the most effective therapy for wasting induced by infectious agents is always the successful treatment of the infection rather than the body's cytokine response to infection. ultimately the ideal nutritional solution to aids wasting will be successful antiretroviral therapy. further work in this area is greatly needed and hopefully the results of those studies will enhance our knowledge and help us to explore new therapeutic avenues for wasting and cachexia of aids. revised classification system for hiv infection and expanded surveillance case definition for aids among adolescents and adults nutritional status, gastrointestinal dysfunction, and survival in patients with aids magnitude of body-cell-mass depletion and the timing of death from wasting in aids body weight as an essential data in the management of patients with human immunodeficiency virus infection and the acquired immunodeficiency syndrome body composition studies in patients with the acquired immunodeficiency syndrome quality of life in persons with human immunodeficiency virus infection. measurement by the medical outcomes study instrument d-xylose malabsorption: characteristic finding in patients with the aids wasting syndrome and chronic diarrhea enteropathy associated with the acquired immunodeficiency syndrome malabsorption and mucosal abnormalities of the small intestine in the acquired immunodeficiency syndrome small intestinal structure and function in patients infected with human immunodeficiency virus (hiv): evidence for hiv-induced enteropathy steatorrhea: a common manifestation in patients with hiv/aids growth and body composition in children infected with human immunodeficiency virus- malnutrition and carbohydrate malabsorption in children with vertically transmitted human immunodeficiency virus- infection gastrointestinal manifestations of hiv infection summary of the st united states-japan interleukin- : an overview cachexia and the acute-phase protein response in inflammation are regulated by interleukin- quantitative analysis of serum il- and its correlation with increased levels of serum il- r in hiv-induced diseases increased interleukin- production is associated with disease progression in hiv infection interferon-␥, more a cachectin than tumor necrosis factor cytokines, muscle proteolysis and the catabolic response to infection and inflammation the role of interleukin- in lipopolysaccharide-induced weight loss, hypoglycemia and fibrinogen production in vivo inhibition of central actions of cytokines on fever and thermogenesis by lipocortin- involves crf metabolic effects of cachectin/tumor necrosis factor are modified by site of production tumor necrosis factor and regulation of metabolism in infection role of systemic versus tissue levels tumor necrosis factor in the malnutrition (cachexia) of infection and cancer immunomodulators and feeding regulation: a humoral link between the immune and nervous systems chemokines/intercrines and central regulation of feeding modulation of feeding by ␤ -microglobulin, a marker of immune activation the lateral hypothalamus: a primary site mediating excitatory amino acid-elicited eating neuropeptide regulation of appetite and weight central effects of crf on metabolism and energy balance the hypothalamus, intrinsic connections and outflow pathways to the endocrine system in relation to the control of feeding and metabolism food deprivation and ingestion induce reciprocal changes in neuropeptide y concentrations in the paraventricular nucleus hypothalamic neuropeptide y messenger ribonucleic acid levels in pre-obese and genetically obese (fa/fa) rats: potential regulation thereof by corticotropin-releasing factor feast and famine: critical role of glucocorticoids with insulin in daily energy flow hypothalamic response to starvation: implications for the study of wasting disorders the hypothalamic-pituitary-adrenal axis and immunemediated inflammation neuroendocrine-immune system interactions. the immune-hypothalamo-pituitary-adrenal axis glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates glucocorticoids selectively inhibit the transcription of interleukin- ␤ gene and decrease the stability of interleukin- ␤ mrna glucocorticoid inhibition of interleukin- induced interleukin- production by human lung fibroblasts: evidence for transcriptional and post-transcriptional regulatory mechanisms the arginine-nitric oxide pathway glucocorticoids suppress group ii phospholipase a production by blocking mrna synthesis and post-transcriptional expression cdna cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase synergistic roles of interleukin- , interleukin- , and tumor necrosis factor in adrenocorticotropin response to bacterial lipopolysaccharide in vivo cytokines and thermogenesis the participation of the nervous system in the inflammatory reaction interleukin- stimulates corticotropin-releasing factor gene expression in rat hypothalamus interleukin- stimulates the secretion of of hypothalamic corticotropinreleasing factor anorexia induced by interleukin : involvement of corticotropin-releasing factor interleukin- immunoreactive inervation of the human hypothalamus immunoregulators in the nervous system human immunodeficiency virus type (hiv- ) infection of the central nervous system: an evaluation of cytokines in cerebrospinal fluid cortisol resistance in acquired immunodeficiency syndrome combination of il- with il- reduces glucocorticoid receptor-binding affinity and t cell response to glucocorticoids coordinated anti-inflammatory effects of interleukin- . interleukin- suppresses interleukin- production but up-regulates gene expression and synthesis of interleukin- receptor antagonist il- inhibits cytokine production by activated macrophages interleukin- is a new human lymphokine regulating inflammatory and immune responses biologic control of the tumor necrosis factor and interleukin- signaling cascade update on cytokines altered expression of hypothalamic neuropeptide mrnas in food-restricted and fooddeprived rats neuroendocrine control of the development of obesity: understanding gained from studies of experimental animal models insulin resistance-mechanisms, syndromes and implications evidence of endocrine involvement early in the course of human deficiency virus infection endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome tumor necrosis factor mimics the metabolic response to acute infection in healthy humans tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output positional cloning of the mouse obese gene and its human homologue leptin levels in human and rodent: measurement of plasma leptin and ob rna in obese and weight-reduced subjects recombinant mouse ob protein: evidence for a peripheral signal linking adiposity and central neural networks the hypothalamic leptin receptor in humans. identification of incidental sequence polymorphisms and absence of the ob/ob mouse and fa/fa rat mutations localization of leptin receptor mrna and the long form splice variant (ob-rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization activation of ␤ adrenergic receptors suppresses leptin expression and mediates a leptinindependent inhibition of food intake in mice the role of neuropeptide y in the antiobesity action of the obese gene product role of the melanocortinergic neurons in feeding and the agouti obesity syndrome the alphabet of weight control transient increase in obese gene expression after food intake or insulin administration induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake acute and chronic effect of insulin on leptin production in humans: studies in vivo and in vitro endotoxin and cytokines induces expression of leptin, the ob gene product, in hamsters: a role for leptin in the anorexia of infection serum leptin levels in the acquired immunodeficiency syndrome serum leptin concentrations in human immunodeficiency virus-infected men with low adiposity muscle proteolysis induced by a circulating peptide in patients with sepsis or trauma infusion of tumor necrosis factor/cachectin promotes muscle catabolism in the rat. a synergistic effect with interleukin- cachectic effects of recombinant human tumor necrosis factor in rats metabolic changes in rats during a continuous infusion of recombinant interleukin- mechanisms of host wasting induced by administration of cytokines in rats mechanisms of muscle wasting. the role of the ubiquitin-proteasome pathway evidence that tumor necrosis factor participates in the regulation of muscle proteolysis during sepsis effects of tumor necrosis factor or interleukin- on muscle amino acid uptake and the role of glucocorticoids interleukin- induces skeletal muscle protein breakdown in rats tumor necrosis factor-␣ mediates changes in tissue protein turnover in a rat cancer cachexia model pentoxifylline decreases body weight loss and muscle protein wasting characteristics of sepsis the ubiquitinproteasome pathway is required for processing of the nf-b precursor protein and the activation of nf-b reduced muscle protein breakdown in septic rats following treatment with interleukin- receptor antagonist characterization of a cancer cachectin factor the toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors tumor necrosis factor can induce fever in rats without activating protein breakdown in muscle or lipolysis in adipose tissue alterations of thyroid function in patients with systemic illnesses: the euthyroid sick syndrome thyroid hormone levels in the acquired immunodeficiency syndrome (aids) or aids-related complex elevation of serum thyroxine-binding globulin (but not of cortisol-binding globulin and sex hormone-binding globulin) associated with the progression of human immunodeficiency virus infection effects of acute and chronic interleukin- administration on thyroid metabolism in humans tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man role of endotoxin and interleukin- in modulating acth, lh, and sex steroid secretion effects of tumor necrosis factor on the hypothalamic-pituitary-testicular axis in healthy men interleukin- inhibits leydig cell steroidogenesis in primary culture effects of megestrol acetate therapy on body composition and circulating testosterone concentrations in patients with aids megestrol acetate stimulates food and water in the rat: effects on regional hypothalamic neuropeptide y concentrations nutrition support and the human immunodeficiency virus (hiv) nutrition and hiv infection nutritional aspects of hiv infection wasting syndrome in aids: pathophysiologic mechanisms and therapeutic approaches use of pentoxifylline therapy for patients with aids-related wasting: pilot studies pentoxifylline therapy in hiv seropositive subjects with elevated tnf pentoxifylline for treatment of cancer anorexia and cachexia? a randomized, doubleblind, placebo-controlled trail thalidomide exerts its inhibitory action on tumor necrosis factor-␣ by enhancing mrna degradation effects of thalidomide on wasting syndrome in patients with aids: a randomized, double blind, placebo controlled clinical trial (abstract b) the effect of thalidomide on the pathogenesis of human immunodeficiency virus type and m. tuberculosis infection thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection treatment of resistant aphthous ulceration with thalidomide in patients positive for hiv antibody thalidomide: rationale for renewed use in immunological disorders pentoxifylline aggravates impairment in tumor necrosis factor-␣ secretion and increases mycobacterial load in macrophages from aids patients with disseminated mycobacterium-avium intracellulare complex infection epinephrine inhibits tumor necrosis factor-␣ and potentiates interleukin- production during human endotoxemia controlling the production of interleukin- and tumor necrosis factor in disease for an additional perspective key: cord- - lakgpxp authors: yoon, sung‐won title: sovereign dignity, nationalism and the health of a nation: a study of china's response in combat of epidemics date: - - journal: stud ethn natl doi: . /j. - . . .x sha: doc_id: cord_uid: lakgpxp this paper seeks to understand the role of nationalism in china's policy towards the combat of emerging infectious diseases. by locating nationalism as a factor which facilitates or impedes global governance and international collaboration, this paper explores how nationalism influences china's political decision‐making. given her historical experience, china has in its national psyche an impulse never to become ‘the sick man of the east’ again. today, china's willingness to co‐operate with international bodies emanates out of reputational concerns rather than technical‐medical considerations. this was clearly manifested in her handling of two epidemics in recent years: the severe acute respiratory syndrome (sars) and hiv/aids episodes. this paper concludes that china's nationalism plays an inhibiting role in china's attempts to further incorporate herself into the architecture of global health governance in the long run. as well as a regulatory approach to a new disease outbreak. sars demonstrated that simple divisions between national and global health policy do not work in practice. during the outbreak, governments had to realise that a disease in any one part of the world is a threat to the rest of the world. however, ironically governments were in general reluctant to acknowledge the existence of the outbreak. most notably, the chinese government's response to sars was critical to the functioning of global governance in infectious disease control. it is a classic textbook example and a fundamental test case of how nationalism can impede or facilitate global governance and international collaboration. china had initially covered up the outbreak, but later reversed its stance to fully co-operate with the world health organization (who). scholars viewed china's initial response to sars within the context of china's poor public health infrastructure, ineffective and fragmented bureaucratic system, and political transition in leadership at the time of the outbreak. at the same time, china's remarkable u-turn towards international collaboration was demonstrated in the framework of the tremendous power of international organisation (i.e. who) in facilitating china's submission and the changing nature of international politics where sovereignty has been curtailed (eckholm : ) . some scholars have even gone further to argue that china's sars episode demonstrated the governance transition from westphalian to post-westphalian strategies (fidler ; ). yet, despite some scholars' claims based on china's initial reluctance and subsequent acquiescence to international forces, there is no evidence that china's sovereignty has been curtailed or that china has been integrated into global health governance. while the existing literature has focused on china's stunning reversal during the sars outbreak, less attention has been paid to the extent to which this turnaround has continued during the aftermath of sars. indeed, in light of the chinese leadership's attitude and commitment towards other infectious diseases such as hiv/aids and the recent cases of avian influenza, china's newfound openness did not seem to be genuine. this leads to the following questions: what were the factors that inhibited and then facilitated the collaboration during the outbreak? what eventually brought china back to 'business as usual' after the outbreak? what ultimately motivates the government's agenda and actions towards infectious diseases? this paper argues that nationalism in the form of national pride and security consciousness in china are enduring driving forces that have studies in ethnicity and nationalism: vol. , no. , shaped chinese policy towards emerging infectious diseases. by locating nationalism as a factor which facilitates or impedes international collaboration, this paper explores how the chinese leadership has exhibited ways in which nationalism affected much of their political decision-making in their quest to restore national pride and to secure china's developmental goals and national interests. it is argued that more often than not, nationalism hindered the formulation and implementation of health policy at both the provincial and national levels. maintaining a positive image of china in the international arena and securing the interests of the regime were key driving forces that affected policy-making. more specifically, this usually revolves around the ruling elites' competency in the handling of a national crisis and in its foreign policy. given the historical experiences of china, it has in its national psyche an impulse never to become the 'sick man of asia' again. the reaction of the chinese authorities at both the central and provincial levels towards unknown health threats is often to deny and cover up the disease's existence. this could be in part to avoid the stigma of being a 'sick' nation as well as to buy time in order to search for an indigenous solution to the problem. this sort of mentality belies a negotiated basis of existence behind the modern chinese nation -as if to say that there are no problems that modern china cannot handle or solve. yet it is also the same desire to appear 'healthy', 'confident' and a 'responsible' member of the international community that often swings chinese response to disclosure and collaboration. however, the latter only happens when the disease in question and china's handling of it is put under international scrutiny and often criticism. in short, china's compulsion to co-operate with international bodies emanates out of reputational concerns rather than medical considerations. nationalism can then be rapidly conjured up as a force which legitimises the draconian measures taken in the name of the nation to defend its sovereignty. one of the most immediate effects is that public health threats are often securitised and political-security solutions are sought rather than technical-medical ones. this means that any information pertaining to the outbreak is treated as classified, and is revealed on a 'need to know' basis, and collaboration is discouraged. it also means that the development of treatments is often seen as an opportunity to showcase the work of indigenous scientists who are 'able' to come up with a cure. an interrelated point pertains to the prospect of china's integration into global health governance. unless and until the chinese leadership examines the nationalistic element embedded in their approach towards growing disease sung-won yoon: sovereign dignity, nationalism and the health of a nation epidemics and globalising health challenges, china's ascendance to great power status will actually be harmed rather than helped. history is replete with examples of nationalist wars, where historical enemies and entire cities were wiped out, territories annexed and glory won, often at an exorbitant cost. history is equally manifested with examples where massive genocide has taken place in the name of the nation to realise some deranged nationalist blueprint, such as hitler's efforts to achieve a pure and superior aryan race or pol pot's infamous year zero project to restart civilisation in pursuit of a communist utopia. yet, such apocalyptic devastation is not always wrought by genocides or wars, but often through inaction, ineptness or impotence by national leaders who fail to defend the nation against aggression, man-made disasters, and pandemics. just as the great athenian statesman pericles learnt from the athenian plague in the fifth century bc and the roman emperor marcus aurelius from the outbreak of smallpox, epidemics could besiege large segments of any given population with quick and lethal consequences on a scale far greater than imperialistic wars or disastrous famines. the primitive state of medical science, limited understanding of hygiene, poor sanitary conditions, and widespread poverty often enable plagues and epidemics to thrive and spread with ease. the plague of justinian (sixth century ad), the black death (fourteenth and fifteenth centuries ad), and the bubonic plague ( - ) stand in testimony throughout the ages to remind the world of the imagery of the four horsemen of the apocalypse described in revelation : : 'and i looked, and behold, a pale horse; and his name that sat on him was death, and hell had followed him'. it was not until the advent of modern advances in science and technology that the verse was more associated with nuclear weapons than with epidemics. since the peloponnesian war in bc, when a plague that originated in ethiopia spread to the persian empire and to athens, the world has seen nation-states combat these epidemics at a localised and, at most, a national level (hays : ; porter ; watts ) . health policy on disease epidemics was a matter of sovereign discretion and exclusively dependent on the concerned nation's capabilities. when the black death (bubonic plague) in the fourteenth century spread through international travel and trading routes afflicted europe and north america, quarantine measures aimed exclusively at preventing disease threats from entering a nation from outside its borders were taken in major european nations. as in defence or foreign policy, health policy is most certainly an exclusive jurisdiction of the national government or ruling regime, and on numerous occasions, great rulers who have built their empires on military conquests have seen their legitimacy to rule crumble very quickly with the unbridled spread of pandemics in their nations. religion, as opposed to science, became the salvation from diseases and epidemics until the eighteenth century. nonetheless, the combat of plagues and epidemics has always invariably been seen and recognised as a national 'problem' for leaders, even though pathogens, bacteria and epidemics in general have no respect for political borders or sovereign rights over territory or people. however, as the rapid growth of populations and intensified human interactions in the sixteenth century and the process of industrialisation from the eighteenth century offered many communicable diseases opportunities to spread more widely, nations began to contemplate types of global response. one dimension of this response was a nascent form of international conferences. these early conferences were widely supported by the economic and political elites, as they believed that the spread of epidemic diseases would hamper the expansion of trade and the development of commerce. therefore, in retrospect, most nations' responses to epidemics were not born out of historically nationalistic gestures underpinned by a statist discourse to protect and defend against westphalian notions of sovereign dignity. instead, the nations' responses were traditionally based on more rationalistic and interest-based considerations. elites regard the protection of the nation's health to be of paramount importance, sometimes not so much to defend the citizen's right to life or liberty, but out of a less altruistic desire to ensure that the state's interests are maintained (e.g. keeping the economy vibrant, harvesting crops, maintaining troop levels, and rendering services and goods). as norman howard-jones observed, the very first international health conferences in the nineteenth century were not motivated by a wish for the general enhancement of the world's health, but by the desire to protect certain favoured (european) nations from contamination by their less favoured (eastern european) counterparts (howard-jones : - ) . therefore, earlier forms of collaborative action illuminated these politicians' concerns about the impact of outbreaks on their nationals and, in particular, the rationale that underpinned the sense of nationalism behind the ruling elite's orientation towards healthy policy. one of the fundamental pillars of understanding in the westphalian notion of sovereignty in the modern fraternity of nation-states is the very fact that sung-won yoon: sovereign dignity, nationalism and the health of a nation all nation-states are sovereign entities, with their own jurisdiction over territories and peoples. extrapolating from this, all nations are therefore born 'equal' in this fraternity of nations, as enshrined in article of the charter of the united nations that membership in the un is 'based on the principle of the sovereign equality'. the stark reality is that the members in this community of nations can hardly be equal. we hear of 'great powers' all the time, as much as we hear of the influence of the 'bi-polar' or the 'uni-polar' world. the logic that drives and motivates nations in this fraternity today is the quest to become 'great', and this desire for nationalism underpins most nationalist thinking and discourse within any given state. while there is no definite statistical evidence for this, it would not be an exaggeration to say that most nations wished that they could at least play in the finals of the world cup. for that matter, americans beam with pride as the us is consistently regarded as the only superpower left in the world, just as a significant number of russians look back nostalgically with pride to a glorious past. the french are convinced that they are the most superior civilisation and culture left in the world, and point to the vibrancy and the romance of their capital, paris, and the french dominance in luxury and designer goods industry. it is also quite clear that the chinese are extremely proud of their economic rise and perceive the hosting of the olympic games as a sign that it has made it in the world. in short, nations thrive on pride and sovereign dignity. most nations regard themselves as 'strong', founded on science, rationality, and progress. this vocabulary is found not only in discourse pertaining to health but also politics and economics. a healthy nation is strong, resilient, and able to withstand any political, economic, or health crisis. in , the french medical community thought that the disease creating havoc in the eastern mediterranean would never affect france, expecting that it be confined to weaker and less civilised populations experiencing a poor and unhealthy climate. the cholera killed , people in four days in paris (delaporte ) , thus confounding most of the elites. today when political leaders speak of a healthy nation, they more often use 'health' as an analogy to draw comparisons, alluding to their aspirations for the country to be strong in all dimensions. the 'health' of a nation is therefore founded on both symbolic and substantive terms, and they are often intertwined in reality. in symbolic terms, a 'sick' nation is one that is weak. tsar nicholas i described the crumbling ottoman empire as the 'sick man of europe', just as russia has been tagged with the same label in the last two decades after the demise of the soviet union. in asia, one saw the japanese labelling the decaying qing china the 'sick man of east asia'. qing china was not only weak economically, militarily, and politically, but was also plagued by internal stifle, unrest, and opium addiction. the most potent symbol of this 'sick man of east asia' was the imagery of chinese men hooked on opium, a drug introduced by the british to reduce its trade deficit as its demand for chinese tea, silk, and porcelain increased. this imagery has underpinned various versions of chinese nationalism ever since. william a. callahan ( ) eloquently discusses the role of shame in chinese nationalism. as callahan argues, nationalism in china very often commemorates its weaknesses rather than celebrating the glories of chinese civilisation ( : ) . the official narrative of modern china is generally a tragic tale of its fall from being the 'centre of the universe' beginning with the opium wars, to the incursion of western powers into imperial china, to the grand finale of the invasion of china by the japanese. this is intricately linked with the rise of the communist party of china (cpc) and the founding of the people's republic of china (prc), and provides the very basis of the legitimacy with which the cpc stakes its political right to reign. it is this deeply seeded shame that motivates the modern chinese state never to fall behind again -whether in economic or political terms -as modern china seeks to erase the 'shame and humiliation' today. this quest for greatness is a significant impetus for china's economic rise. in essence, 'achievement' is used as a remedy to get rid of the shame that china has written into much of its official discourse over the past developmental trajectory. one need not look far for evidence. china's national anthem written in (translated below), one year after the japanese invasion of china, poignantly documents the sense of shame behind the 'sick' nation: arise, ye who refuse to be slaves! with our very flesh and blood, let us build our new great wall! the peoples of china are in the most critical time, everybody must roar his defiance. arise! arise! arise! millions of hearts with one mind, brave the enemy's gunfire, march on! brave the enemy's gunfire, march on! march on! march on! sung-won yoon: sovereign dignity, nationalism and the health of a nation numerous scholars have documented how the obsession with 'humiliation' and the goal of turning 'grief' to 'strength' have significantly influenced china's foreign and security policy towards the united states and japan (dittmer and kim ; gries ; shambaugh : - ) . one of the most important dimensions is china's obsession with sovereignty or perceived infringements of her sovereignty or pride. this has made china hypersensitive to any sort of international criticism, it as an infringement of her sovereignty or meddling in her internal affairs. obviously one could argue that this is a political strategy of the cpc to deflect any sort of political challenge, but given the rise of nationalism within china over the last decade, one cannot help but realise that these sentiments might be more widespread than conceived. while china maintains a discourse of equality and camaraderie of friendship with other nations of the world, its actions and its policies often belie china's real intention of ascendance and greatness. as such, china is not only concerned with building capabilities associated with a great power, it is also extremely concerned with portraying an image that it is one. most interestingly, china's obsession with sovereign dignity and pride and its place in chinese nationalism is clearly manifested in its handling of two health-related issues: china's approach towards the handling of the aids epidemic and its response to the sars epidemic in - . the impulse for china's reticence on sars perhaps the most pertinent question discussed in this paper is why the chinese leadership tried to cover up the extent of sars and later took decisive action. answering this entails an understanding of a number of factors, but it is argued that nationalism and sovereign dignity played a part in china's response to sars. despite all the changes that the country has undergone, the traditional so-called 'face-saving' approach seemed to be as intact as ever and even deeply engrained in the mentality of the chinese leadership. therefore, when there is an event that could damage national pride, it is highly embarrassing for them to admit. the best way to resolve the troublesome event is to actively avoid or deny. thus the mode of dealing with national calamity is to identify a problem before the outside world discovers it, take measures to address it, and only afterwards report the improved situation. these mechanics have been generally at the heart of the chinese leadership's crisis management, particularly with regard to emerging infectious diseases. this was evident in china's response to sars. the crucial feature of the sars outbreak in china from early january through early february was that the provincial authorities kept the lid on the situation. the cpc has tended to suppress negative news such as diseases and disasters out of fear that such information would disrupt national stability. cover-ups are usually started by local officials who want to avoid embarrassment in front of their superiors due to their incapability to control the situation themselves. therefore, there is no incentive for local officials to pass the information up the chain of command. when early cases occurred in guangdong province, the local authority was at least aware of the situation. anxious to avoid criticism for their mishandling of earlier outbreaks and in an effort to maintain guangdong as a location of commercial dynamism and economic growth, the provincial leaders concealed the gravity of the disease. later, provincial party secretary zhang dejiang, the highest-ranking official in guangdong, stated: 'if we made a contrary decision, it would have been impossible to achieve a gdp growth rate of . per cent' (cctv interview, june ) . this denotes the fact that the guangdong leadership feared the impact of the disease's outbreak on national development. the potential 'loss of face' also contributed to provincial leaders' concealment, as the disastrous public health problem would eventually contribute to the negative effects on the cpc's legitimacy. sars was considered something that needed to be defeated before it became embarrassing. therefore, the suppression of information at the provincial level was not only motivated by development goals for the nation but was also prompted by the desire to save face and maintain reputation. once the virus spread internationally, the nature of the problem and the possibilities for resolution broadened significantly. when the chinese government failed to address the growing epidemic, the health problem in china became a political issue and an embarrassment for the central government. however, the central government's long-overdue response to growing infectious diseases was not reversed abruptly. beijing's initial reaction to the epidemic was silence and an unwillingness to co-operate. until early april , an international team of experts was not permitted to investigate hospitals in beijing. china's health minister zhang wenkang declared at a press conference that there were twelve sars cases in beijing but claimed that the disease had not spread to other parts of china (abraham : ) . the discourse that sars was under control was also backed by hong tao, the esteemed chinese microbiologist, who asserted that the cause of the disease was chlamydia and that the outbreak was dying down. due to sung-won yoon: sovereign dignity, nationalism and the health of a nation systematic problems in the chinese scientific community -a lack of coordination; stifling political influence; hesitation to challenge authorities; and isolation from the rest of the world -the chlamydia hypothesis was firmly established in china (enserink : ) . when the world-leading scientific labs confirmed that the causative agent was a coronavirus that had never before been seen in humans, china's persistent assertion had to be withdrawn. it was another national embarrassment that the emerging power was short of a scientific solution. there was a major turning point on april . faced with widespread international criticism of china's unresponsiveness, president hu jintao and premier wen jiabao finally declared a war against sars, calling for accurate and timely information about the disease to be provided and shared amongst units and international partners. this announcement was widely reported by chinese newspapers and television. shortly after the declaration, health minister zhang wenkang and beijing mayor meng xuenong were dismissed, ostensibly for their inadequate response to sars. premier wen went on to attend the asean-china leaders meeting in bangkok on april and stated that 'the chinese government is here in a spirit of candour, responsibility, trust and cooperation' (macan-markar ) . in hindsight, as the country's reputation suffered abroad, the leadership needed to re-establish itself as a responsible member of the international community in the eyes of its international counterparts. having exposed the emerging power's incapability of handling a disease crisis, the only way of restoring national pride was to show the world that the great china had the capacity to deal with the national threat efficiently and effectively in a short period of time. the chinese leadership made a lot of effort to inform the general public of the dangers of sars and to mobilise society in the name of the 'national' spirit. depicting the combat against sars as a 'baptism of fire' for the entire nation and urging the public to unite around the communist leadership to defeat the national crisis, the chinese government set up the 'sars control and prevention headquarters of the state council' headed by vice premier wu yi. the government created a fund for new building projects and the provision of more healthcare services (balasegaram and schnur, : ) . amazingly, the government was able to build a dedicated hospital for the treatment of sars within a week. apart from government initiatives, the propaganda department made an effort to 'nationalise' a regional outbreak into a national crisis and, in doing so, mobilised an entire nation into the battle against sars virus. the people's daily ( may ) used traditional maoist revolutionary rhetoric, such as calling for the people to 'build out a new great wall -on the great spirit of the fight against sars' (ren zhongping, ) . the propaganda department worked towards alerting the people about the disease and instilling in every individual a sense of patriotism and national duty to rally around the cpc. in guangxi province, minority groups sang songs about sars; in inner mongolia, murals were painted to depict the sars experience; and in beijing, banners spurred comrades on, harkening back to mao's campaigns during the cultural revolution (balasegaram and schnur : - ) . having decided to be transparent, the media sprung into full action with reports of 'whitecoated warriors' and 'angels in white coats', describing heroic stories of doctors and nurses working for love of their nation and its people. community leadership also re-introduced the traditional neighbourhood committee by revitalising the grassroots party structure. this committee, mainly consisting of elderly residents, barred outsiders and checked for sars symptoms in their neighbourhood. these committees created groups of ten households and appointed one volunteer. the volunteers were in turn grouped in tens and reported to a higher authority. this structure continued upwards until it meshed seamlessly with the communist party system that ruled the country (south china morning post ) . yet, what is important to note here is that this nationalism extends beyond making sars an immediate enemy of the nation. the image of a china being 'sick', the inability of chinese scientists and people to eradicate the virus independently, the ineptness of the chinese health system to effectively contain the outbreak were all smudges on the chinese image that the leadership wanted erased. by encouraging the national spirit and mobilising the energy of the entire population, the government was able to show the international community that china in fact had the capacity to deal with the national crisis, thereby restoring the national pride and dignity that was commensurate with china's international reputation and image as a rising great power. the success of this reversal did ameliorate the damage done to china's image by its previous bungling. china's handling of the sars crisis, unfortunately, does not represent its approach to epidemics in general. scrutinising the prc's approach to the hiv/aids epidemic in the country, china's reticent approach to international co-operation is clear. compared to the recent sars episode, the aids epidemic has been around for more than two decades. although its sung-won yoon: sovereign dignity, nationalism and the health of a nation effects are less 'visible' than the sars outbreak, in reality, the aids epidemic is probably more devastating and has had a much higher death toll than sars. aids, however, did not receive much attention from the central authorities until very recently. however, the actual number of aids carriers is believed to be much greater. the inaccuracy of the estimate is due to the fact that there is massive underreporting of the disease, especially the rural areas. there are many reasons for underreporting, but a shortage of adequate resources and a lack of openness in confronting the epidemic at many levels of government (provincial and local levels) are some of the major factors that contribute to china's slow response. exact figures are difficult to gauge because the government at the local level is very reticent to report on actual cases (human rights watch ). when aids was first reported in beijing in , the initial cases were treated with disdain and the disease was labelled as 'foreign'. the government warned that young women having sexual relations with foreigners could be in danger, and that 'foreigners' would facilitate aids becoming an epidemic in the prc. the government also tightened immigration controls and required all foreign students entering china to present a certificate from their country of origin testifying that they were not infected with aids. during the s, although aids began to spread from yunnan province to other parts of country, the chinese government officially denied that it had an hiv/aids problem. this was exposed as a lie by a few whistleblowers, at least one of whom was imprisoned for revealing 'state secrets' (watts : ) . therefore, the real extent of hiv/aids cases remains unknown as the government's long-standing position towards this epidemic has always been that aids is a 'foreign' disease requiring surveillance and border control, as well as action against social undesirables such as prostitutes, drug users, and blood brokers. the chinese government's response to aids was initially persistent silence and a refusal to acknowledge that the issue was serious. a major factor behind the government's recent change in its attitude towards the aids epidemic seemed to be the outbreak of sars in china in studies in ethnicity and nationalism: vol. , no. , , which exposed the dangers of not reacting to emerging infectious diseases. yet, it took almost two decades and a lot of pressure, internationally and domestically, before the chinese government decided to institute measures to 'contain' the aids epidemic. despite some candidness surrounding the discussion of aids in china, the scale of the problem is still being played down, mainly due to the government's tight control on media and infected aids patients not coming forward for fear of discrimination. thus the true extent of the problem remains unclear. yet, the chinese government was actually forced to address the aids epidemic for reasons very similar to those that led to the disclosure of the sars epidemic. it was sparked by the revelation of the very controversial case of an entire aids village in henan province, where thousands of poor farmers were infected by hiv while selling blood to the health authorities. initially the villagers were isolated and ostracised, and local authorities acted in the name of the national interest and the public good to cover up this outrageous negligence on the part of the health authorities. due to the mounting weight of evidence that china is in the grip of a major epidemic, the chinese government came under tremendous international criticism for their inaction over aids. the government seems to have increased efforts to fight aids by reversing some policies. despite enhanced intervention measures and infrastructure, stigmatisation, fear, and hidden infection constitute a vicious circle that fuels the aids epidemic in china. the prevalent societal attitude in china towards aids was and still is very prejudiced. aids is regarded as a 'foreign' disease and is associated with promiscuity, perversion, and homosexuality. hiv carriers are shunned by society as social outcasts and are seen as 'deserving' the disease because of their 'morally' decadent lifestyles. according to a survey conducted in china, seventy-five per cent of respondents said they would sung-won yoon: sovereign dignity, nationalism and the health of a nation avoid hiv/aids carriers and forty-five per cent responded that the disease was a consequence of moral degeneration (the un theme group on hiv/ aids in china ). the dominant narrative in china of these unknown diseases is characterised by a lack of understanding and education, and is 'nationalistic' in the sense that biological threats and diseases are still perceived by the majority of people to be 'foreign', even though germs do not respect political boundaries. it is very unlikely that health policy towards epidemics will be reconfigured overnight without a corresponding change in societal attitudes and government perceptions. there are other factors at work that have prevented the chinese state from addressing the aids issue openly and candidly. chinese nationalism has often compelled the chinese state to securitise any issue it perceives to be damaging to its national interests. the literature on aids has long highlighted that it is a significant security threat. significantly, other than the direct impact of aids on the constituent population, aids has grave consequences for the 'affected' nation. aids heightens the prospect of wars internally and externally and hollows out military and state capacities, weakening both to the point of failure as this is a disease that targets the most economically active and demographically most reproductive segment of any nation's populace (singer ) . moreover, aids will also have a tremendous and significant impact on the demographics of the population, as the disease has demonstrably killed off the most productive and strongest segment of the population first, rather than the infirm and weak segments. aids will dramatically increase health costs per capita within a relatively short period of time. it could possibly affect prospects for inward investment and long-term economic development. the chinese state realises that the aids epidemic might well have more disastrous and far-reaching consequences than previously thought. yet, at the same time, the chinese government realises that the inability to handle and contain any epidemics would have repercussions for their legitimacy to govern internally and china's reputation externally. given china's historical experiences, china has an obsession with sovereign dignity which has been rigidly built into her strategic and political culture. china therefore has a propensity to construe issues critical to china's interests as a zero-sum game, as the chinese outlook is very much influenced by neorealist thinking. this has rendered china hypersensitive to any threats and often to frame its responses to any challenges to its well-being by securitising these challenges. as such, china's initial reaction to the infectious diseases is most distinctly characterised by securitising the disease, as opposed to taking a biomedical and technical approach. china's incomplete turnabout on aids is in large part due to her reticence and inability to adjust her approach to perceive aids as something beyond a security issue. this is also significantly highlighted in the sars episode. right from the beginning of the sars outbreak, information about the disease was deemed to be a state secret. divulging data regarding infectious disease outbreaks could make one a defendant in a treason case (saich : ) . therefore, there was no reason to go public regarding a curious incident or with rumours of a new disease. despite recent changes, china is still characterised by its obsession with the notion of security and much information remains confidential, including information about infectious diseases. the scope of classified information is wide and can be flexibly applied to anything considered related to national security (human rights watch/asia and human rights in china : - ) . while a regulation had amended a regulation that classified high-level infectious diseases as highly secret with the secrecy extending from the first occurrence of the disease until the day it was announced, infectious diseases still remained national security matters. when a report on earlier cases of sars was produced in january in guangdong, the report was labelled neibu or 'top secret', which meant that information about the situation must be kept among only the highest national officials (human rights watch/asia and human rights in china : ). the classification of sars as a secret may have been motivated not only by the post-cold war legacy (i.e. their obsession with security), but also the leadership's desire to hide from other nations vulnerable issues which could be regarded as national threats. in order to deal with the national secret, the top officials needed to close the lid tight. an array of actions and policies demonstrated this. for example, the ministry of health explicitly ordered the heads of beijing hospitals to report sars only through channels upward on a confidential basis but not to any media. according to one ministry of health official, they had been told by higher levels that the outbreak was a closed matter: 'this came from quite high up in our ministry. . . . we did not have that information and once we were told that the outbreak was officially closed, we could not secure cooperation' (greenfeld : ) . hiv/aids has been securitised in much the same way as sars. aids activists in china have been either detained or arrested by the chinese officials for 'harming the state security' or 'revealing state secrets' sung-won yoon: sovereign dignity, nationalism and the health of a nation (benjamin kang lim ) . with regard to releasing official figures on aids patients, the government withheld information from the public while they checked political matters and prepared for immediate economic repercussions. national interests and security maintained precedence over transparency. this sort of 'secrecy' with regard to national security issues is typical of post-communist regimes and of most countries. it also characterises what might be a first response for any country that is sensitive to the judgement of international opinion. interviews with the chinese scientists involved in the aftermath of sars revealed that many of them felt that it was a great shame that the virus was not first identified by chinese scientists, since the virus outbreak occurred primarily in china and the majority of the victims were chinese (ensernik : - ) . in fact, many of the scientists were frustrated by the way information was 'partitioned' and the epidemic 'securitised'. yet, it is not only that securitisation of this epidemic that would pose a problem. a more important problem is how the prc elites could possibly believe that there could be a response other than a bio-medical solution to a health threat. this situation may be slowly changing as the chinese government becomes more amenable to outside co-operation as long as their regime and defined national interests are not compromised. there seems to be an inverse correlation between china's propensity to cooperate internationally and her desire to protect her core national interest and national aspiration i.e. reunification with taiwan. this aspiration is intricately linked to the regime's legitimacy and political survival and if threatened would lead the chinese government to become more hardline and nationalistic, and less willing to discuss any form of cross-border cooperation. the sars episode saw the regime's legitimacy challenged by the fact that the authorities appeared to be quite inept at handling the crisis, but more importantly the sars episode was also politicised as a reunification and a security issue. chinese nationalism complicated the handling of this medical crisis across the taiwan straits. preventing taiwanese independence has been a foremost chinese national priority. in that respect, china has consistently exerted tremendous political and diplomatic pressure to prevent taiwan from gaining membership in any international organisation. taiwan has made seven efforts to join the who. china insists that taiwan is an 'inalienable' part of china and should therefore not be recognised as an individual entity. when sars cases mounted in taiwan, the taiwanese government asked the who for assistance. in response to this, zhang wenkang, china's minister of health, stated: 'we hope that the leaders of taiwan authority no longer spread rumours with ulterior motives, or even use the disease as an excuse and in the name of human rights to try to enter the who, which is only opened to sovereign nations' (mirsky ) . this symbolised china's long-standing position towards taiwan, which denies taiwan's place in the international system. but it also reflected how chinese leaders regarded sovereignty issues over other impending issues such as the immediate crisis of the epidemic. for china's leadership, the health crisis was no longer a health issue but a political one. there is no guessing how the ruling elites would choose when deciding between political survival and enhancing international co-operation. the process of globalisation significantly impacts the socio-political context of health. emerging infectious diseases, in particular, have triggered the political aspect of public health because the threat of the trans-border spread of disease challenges the traditional state-centric approach to infectious disease policy. the pathogenic threats highlight the inability of states to act alone to prevent the spread of infectious diseases amid globalisation. as a consequence, emerging infectious diseases have forced a reconceptualisation of public health governance both nationally and globally, leading to an increase in the process of global collaboration. the concept of global health governance has therefore emerged in this context, characterised by the relative decline in the salience of states alone and the increased involvement of new ways of norm setting and compliance processes. the question that this article considers is whether nations and national dignity have been virtually impacted and eventually weakened by the new health governance mechanism which is able to set and control the rules of health at a global level. it is argued that global health governance may influence the nation's response to the threats posed by emerging infectious diseases such as sars or aids as a mode of building political compromises but does not considerably alter the nation's behaviour, at least for china. it is argued that in case of china, sovereign dignity and nationalism outweighed the global values in the response to infectious diseases. the chinese government's initial silence on sars and aids, and its lack of co-operation despite its awareness of the extent of the epidemic, demonstrated the nature of national pride inherent in china's response to national crisis. in pursuit of national prosperity through foreign investment and international trade, any discourse or narrrative on potential disasters such the sars or aids epidemics would naturally be suppressed at the first instance. in addition, the chinese leadership's obsession with issues of national security further allowed the sars virus to spread across the world. no one could disclose information about the epidemic unless they had security clearance, because sharing information pertaining to or even acknowledging the existence of any infectious disease is regarded as a crime by revealing 'state secrets'. if anything, the sars and aids episodes have shown that the existence of epidemics cannot be contained by censorship, regulation or legislation alone. however, once the information about the sars outbreak was divulged, the growing epidemic was beyond the national public health capacity, and to make matters worse, other nations began to criticise china's unresponsiveness, the chinese government had to institute 'damage control' measures by denying that it had any role in intentionally concealing the disease's existence. this would undoubtedly further damage china's national pride and dignity by announcing to the world that china was not able to deal with domestic public health problems. by the same token, the chinese government therefore had to show the international community that as an emerging power, it could still address the public health crisis, this time through mobilising the nation to participate in international efforts to stem the epidemic. with the help of international health expertise, china was able to successfully curb the sars epidemic in a very short period and with remarkable efficiency. its successful efforts somewhat ameliorated the embarrassment it caused itself by the bungled handling of the disease outbreak, and to a certain extent restored some of its lost national pride and international reputation. in the aftermath of the incident, china's successful story of controlling sars was a sign that china was incorporated into the global health governance where international health problems are resolved for the greater global public good. it seems, however, that china's leadership was only prepared for limited and selective openness. in light of china's response to recent cases of avian influenza, the need to preserve an infallible national image still takes precedence over public health concerns in the minds of china's leaders (cyranoski a: - ; cyranoski b cyranoski : . indeed, the incidents surrounding reporting of avian influenza in china clearly demonstrate how the chinese government has hindered progress towards halting the epidemic, denied the presence of an outbreak, prevented the exchange of information on the flu virus, and allegedly promoted widespread misuse of antiviral vaccination in chickens. scientists were often faced by less than cooperative local and central officials, whose primary concern was how health problems would negatively impact on national development goals. therefore, china's long tradition of avoiding sensitive questions and denying negative developments has yet to change. rather, it appears that national pride in a great china invariably contributes to the national response to emerging infectious diseases. in an era of rapid globalisation, it remains uncertain to what extent the chinese leadership's concern with nationalism and sovereign pride would modify itself to fit into the global governance if a more serious threat posed by a new transnational but more lethal disease than sars emerges. clearly, china's national pride and security would do little to further the achievement of china's incorporation into global health governance, not to mention the health of the population of an emerging world power. twenty-first century plague: the story of sars china: from denial to mass mobilization', in world health organization, western pacific region, sars: how a global epidemic was stopped china rejects internet claims of human cases national insecurities: humiliation, salvation, and chinese nationalism flu in wild birds sparks fears of mutating virus china's chicken farmers under first for antiviral abuse' disease and civilization: the cholera in paris, china's quest for national identity nationalism and the health of a nation eckholm, erik china's missed chance sars, governance and the globalization of disease from international sanitary conventions to global health security: the new international health regulations china syndrome: the true story of the st century's first great epidemic china's new nationalism: pride, politics and diplomacy the burdens of disease: epidemics and human response in western history the scientific background of the international sanitary conferences locked doors: the human rights of people living with hiv/aids in china sars strengthens china-asean ties joint united nations programme on hiv/aids, and world health organization containing sars: the scandal over taiwan', international herald tribune health, civilisation and the state: a history of public health from ancient to modern times building our new geat wall -on the great spirit of resisting and attacking sars', people's daily, may is sars china's chernobyl or much ado about nothing? beautiful imperialist: china perceives america neighbourhood watchers join sars battle hiv/aids: china's titanic peril aids in china: new legislation, old doubts epidemics and history: disease, power, and imperialism summary of probable sars cases with onset of illness from sung-won yoon is a phd candidate at the who collaborating centre on global change and health, london school of hygiene and tropical medicine (lshtm). prior to coming to lshtm, she completed her graduate studies at seoul national university and ewha womans university in korea. sung-won has worked as a policy researcher for various korean universities, think-tanks and the parliament of the republic of korea for several years, principally researching on social and health care issues. she was awarded a fully funded research fellowship by the korean government to undertake research work at london school of economics and political science before she embarked on her work at lshtm. key: cord- -fzq t x authors: kern, p.; müller, g.; schmitz, h.; rácz, p.; meigel, w.; riethmüller, g.; dietrich, m. title: detection of coronavirus-like particles in homosexual men with acquired immunodeficiency and related lymphadenopathy syndrome date: journal: klin wochenschr doi: . /bf sha: doc_id: cord_uid: fzq t x coronavirus-like particles were identified by electronmicroscopy in the feces of homosexual men. the particles banded at a density of . g/ml after cesium chloride density gradient centrifugation. to determine whether the presence of this virus might be related to clinical symptoms, several patient groups were studied prospectively. in of ( %) homosexual males with acquired immunodeficiency syndrome (aids) or unexplained lymphadenopathy syndrome (las), coronavirus particles were found. in contrast, such particles were found in none of heterosexual controls and in only of homosexual males without aids or las. thus, coronavirus excretion correlated significantly ( α< . ) with the clinical diagnosis of aids or with syndromes belonging to the aids-related complex. in addition, such particles identified in the serum of one patient with las and diarrhea suggest invasion and systemic spread of the agent and underline that this virus behaves differently from “common cold” human coronaviruses. the outbreak of kaposi sarcoma, its prodrome -las [ , ] , and opportunistic infections in homosexual men from the united states and europe [ ] and in patients from central africa [ ] has abbreviations: aids = acquired immune deficiency syndrome; las=unexplained, generalized lymphadenopathy syndrome; sp.=species; em=electronmicroscopy; rifn ~a=recombinant leukocyte c~a interferon; cvlp=coronavirus-like particles; csc = cesium chloride initiated intensive search for causative and opportunistic infectious agents. considerable evidence has recently been accumulated with regard to the etiologic role of human t-lymphotropic retroviruses lav/htlv-iii [ , , ] . however, high prevalences of antibody to lav/htlv-iii among homosexuals [ ] suggest that the exposure to the virus is much more common than aids itself. thus, host response to infection can be expected to range from subclinical to severe and may be influenced by concomitant infectious agents. multiple intestinal parasitic infestations and other microbial infections are often seen in homosexual men [ ] . in the search for viruses, we observed cvlp in the feces of homosexual men and report here on a prospective study for the presence of these particles in stool and serum specimens of patients belonging to a high risk group of aids. detailed clinical, parasitological, serological and immunologic data were available from homosexually or bisexually active males originating from germany and from one african male whose feces were screened for the presence of virus particles. two of them who showed systemic manitbstation of kaposi sarcoma were studied while under experimental rifn c~a therapy. one european and one african patient had opportunistic infections and met the criteria for aids [ ] . twelve patients had clinical signs compatible with the prodrome of aids (las) [t , ], whereas six had unexplained chronic enterocolitis. of the remaining cases, eight were hospitalized for acute hepatitis b and one for amebic liver abscess which was acquired during the patient's stay in the tropics. in five homosexuals, studied in detail, signs or symptoms of aids or las could be excluded. sixteen healthy heterosexual males (including medical staff taking care of patients with aids or related diseases) and two females with diarrhea (yersiniosis in one case, unexplained in the other case) were studied as controls and in parallel with patients' specimens. the routine laboratory profile included hematology, hemostaseology, blood chemistry, and urinary analysis. between one and three stool samples were examined on consecutive days for the presence of protozoa or helminths' eggs; stool cultures were performed to test for pathogenic bacteria, i.e., salmonella sp., shigella sp., yersinia sp., and campylobacter sp. in all symptomatic cases, a proctoscopy and a lymph node biopsy were performed. serological tests for hepatitis a, hepatitis b, cytomegalovirus, epsteimbarr virus, syphilis, and others were performed. patients evaluated prospectively were tested for cutaneous anergy by a multitest procedure (multitest m&ieux, lyon, france) for six different recall antigens. for the enumeration of t-lymphocyte subpopulations, mononuclear cells were separated by density medium centrifugation on ficoll-paque (pharmacia, freiburg, frg) and nonadherent lymphocytes were obtained after plastic adherence. the differentiation antigens were identified by indirect immunofluorescence using monoclonal antibodies a suspension of feces in distilled water (up to : v/v) was homogenized and centrifuged for rain at , g in order to remove debris and bacteria. the supernatant was further diluted : with water and the suspended material was pelleted at , g for min in a specially designed centrifuge tube onto pioloform coated grids [t ]. the specimens were negative stained with sodium-silico-tungstate and screened for the presence of virus particles using a philips em elecrron microscope. in the same way as feces, serum of nine homosexual and heterosexual males was cleared of subcellular debris and pelleted at , g for rain directly onto grids. equal areas of all specimens were screened electronmicroscopicatly for the presence of virus particles until they were considered negative in this respect. two stool sampts containing large numbers of cvlp were subjected to further characterization [ ] . one volume of the stool suspensions was mixed with nine volumes of a csc solution in phosphate-buffered saline (density . g/ml). after centrifugation at , g for h the clearly visible band was collected, dialyzed against . t tris buffer (ph . ) and used for negative contrast electronmicroscopic examination. for statistical evaluation all patients and controls were divided into three groups: group a, patients with aids or las; group b, homosexual men with or without clinical symptoms other than those of group a; group c, heterosexual patients and controls. data were analyzed using the chi-square test with yates' correction. group a was compared with groups b and c, and group b with group c. these two tests are orthogonal contrasts. additionally, the x table correlation coefficient was computed and tested. the clinical and immunologic findings presented at the time of investigation are shown in table . patients with aids or las are clearly distinguished by the inversion of the t /t ratio, the decrease in absolute t ÷ lymphocytes, and the elevation of the serum neopterin. cutaneous anergy was observed in of cases. in contrast, the remaining study population of homosexuals or heterosexuals failed to show such abnormalities. cultures of three consecutive stool samples examined for the presence of bacterial pathogens in symptomatic homosexuals excluded infections of salmonella sp., shigella sp., yersinia sp., and campylobacter sp. proctoscopy and mucosal biopsies were performed in symptomatic cases and only " cysts of the following protozoa were identified as joint agents: entamoeba histolytica, e. coli, e. hartmanni, endolimax nana, jodamoeba bfitschlii, and giardia lamblia b there is a significant difference ( c~< . ) of group a versus groups b and c, no statistical difference was observed between group b and group c. these tests are orthogonal contrasts a nonspecific irritation was observed. lymph node histology in all cases with lymphadenopathy revealed follicular hyperplasia. the serological, parasitological and virological investigations are concluded in table . a high proportion of patients with aids or las revealed antibodies against hepatitis a, hepatitis b, cytomegatovirus, and syphilis, but so also did homosexuals not belonging to these groups. the parasitological stool investigations revealed that % to % of homosexual men harbor cysts either of apathogenic intestinal protozoa, i.e., entamoeba coli, entamoeba hartmanni, endolimax nana, jodamoeba buetschlii, or of pathogenic intestinal protozoa, i.e. entamoeba histolytica or giardia lamblia (table ) . by the negative staining technique, distinct particles were visualized electronmicroscopically in i homosexual patients. these particles are to be classified as cvlp because of their typical pleomorphic appearance and their regular radiating projections (figs. i and ) . no other distinct structural entities resembling known viruses were found in any specimen. in order to distinguish the particles from cellular debris, the material was further characterized by csc density gradient centrifugation. a buoyant density of . g/ml was observed for those particles which clearly identifies cvlp. six patients were studied repeatedly over a period of months and cvlp could be identified in all samples re-examined. eight of patients ( %) with aids or las were found to excrete particles within the feces, a finding which is significantly . ) or with the immunologic findings of an inversed t /t ratio ( -= . , p< . ), whereas no correlation could be found with enteritic symptoms. among seven sera from homosexual males with aids or las, tested for the presence of such particles, one specimen contained a small number of cvlp, whereas no particles were found in heterosexual controls. our findings clearly show that homosexual men are preferentially exposed to a number of infectious or transmittable agents including apathogenic intestinal protozoa. with the exception of the clear immunologic aberrations seen in patients with aids or las, most of the homosexual males were found to have markers of presumably sexually transmitted diseases to a similar extent. in % of the patients with aids or las, however, we found structurally distinct viral particles in the feces by the negative staining technique. they showed the typical morphology of coronaviruses characterized by a corona of widely spaced radiating projections [ , ] and resembled a buoyant density (csc ) of . g/ml characteristic of cvlp [ ] . the sensitivity in detecting cvlp by our protocol of stool preparation and the em exploration is not known. however, the observed frequency must be considered as a minimum because samples with low numbers of particles might have been overlooked by the em method. human coronaviruses (strain e and oc ) are associated with lower respiratory tract disease and are responsible for % of common colds [ ] . these viruses are distributed world-wide and antibodies ware present with high prevalences [ , ] . in addition,some human coronaviruses may be associated with enteric infections [ , , ] . however, their causative role and their serological relationship to other human coronaviruses has not yet been demonstrated [ ] . two distinct groups of enteric coronaviruses can be differentiated: one is a minor group of enteric coronaviruses that has been reported from neonates associated with epidemic gastroenteritis [ ] , and the other occurs in babies in nursery homes and causes a necrotizing ulcerocolitis [ ] . the major group has been reported from many parts of the world in children and adults with gastrointestinal diseases, although a significant proportion of the unaffected population also shed these particles [ , ] . it is deduced that coronavirus infection might become endemic under low standard of personal hygiene as there is a high incidence found in the rural population in southern india [ ] and among australian aborigines [ ] . while no information is available with regard to the mode of transmission of enteric coronaviruses, similarities to other viral and microbial agents present in the homosexual population become obvious. the particular intimate contacts of homosexuals favor a fecal-oral route of transmission [ ] . in epidemiologic studies it has been shown that the enteric coronaviruses are occasionally excreted in the feces over a long period of time (up to months) [ ] . this was also found in our patients with las or aids, even during potent antiviral therapy with rifn ~a. however, the most striking finding was the presence of the virus in the blood of one patient with las and intermittent diarrhea. this illustrates that the organ tropism of most of the known animal or human coronaviruses [ ] might not be present in the examined group of homosexual males. in contrast to acute infections caused by most of the known animal and human coronaviruses, some murine and feline types involve multiple organs and have a strong tendency to establish persistent and chronic diseases [ , ] . it remains open to question whether the detection of cvlp in human feces and blood demonstrates the systemic spread and multiple organ tropism of an up until now unrecognized strain of the cvlp. it appears that cvlp might act as another infectious agent in homosexual men and that chronic infections might establish themselves because of the particular immunodeficient state characteristic of aids or diseases belonging to the aids-related complex. isolation of a t-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (aids) coronavirus propagated from a patient with non-bacterial gastroenteritis coronaviruses in humans epidemiologic aspects of the current outbreak of kaposi's sarcoma and opportunistic infections antibodies to a retrovirus etiologically associated with acquired immunodeficiency syndrome (aids) in populations with increased incidences of the syndrome association of coronavirus infection with neonatal necrotizing enterocolitis acquired immunodefiency syndrome in afi:ican patients lymphadenopathy associated virus infection of a blood donor-recipient pair with acquired immunodeficiency syndrome frequent detection and isolation of cytopathic retroviruses (htlv-iii) from patients with aids and at risk for aids the virology and pathogenesis of feline infectious peritonitis. brief review immunologische befunde bei homosexuellen mfinnern mit generalisierter lymphadenopathie. prodromalsta-note added in proof sera of patients were investigated for the presence of htlv iii antibodies by indirect immunofluorescence coronavirus-like particles as aetiological agents of acute non-bacterial gastroenteritis in humans human enteric coronaviruses macnaughton mr (t ) occurrence and frequency of coronavirus infections in humans as determined by enzymelinked immunosorbent assay pleomorphic virus-like particles in human feces coronaviruses: a comparative review the syndrome of unexplained generalized lymphadenopathy in young men elektronenmikroskopische partikelzfihlung in der virologie. i. zentrifugierr hrchen zur direkten sedimentation yon viren auf netztr~iger the polymicrobial origin of intestinal infections in homosexual men human t cell differentiation antigens characterizing a cytotoxic/suppressor t cell subset a radioimmunoassay for determination of d-erythro-neopterin two year serological surveillance of coronavirus infections in hamburg ) coronavirus-like particles in aboriginals and nonaboriginals in western australia pleomorphic, envelopped, virus-like particles associated with gastrointestinal illness in neonates the biology and pathogenesis of coronaviruses key: cord- -zht olyh authors: nkengasong, john n.; nsubuga, peter; nwanyanwu, okey; gershy-damet, guy-michel; roscigno, giorgio; bulterys, marc; schoub, barry; decock, kevin m.; birx, deborah title: laboratory systems and services are critical in global health: time to end the neglect? date: - - journal: am j clin pathol doi: . /ajcpmpsinq brmu sha: doc_id: cord_uid: zht olyh the $ billion comprehensive global health initiative (ghi) emphasizes health systems strengthening (hss) to tackle challenges, including child and maternal health, hiv/aids, family planning, and neglected tropical diseases. ghi and other initiatives are critical to fighting emerging and reemerging diseases in resource-poor countries. hss is also an increasing focus of the $ billion program of the us president’s emergency plan for aids relief and the global fund to fight aids, tuberculosis and malaria. laboratory systems and services are often neglected in resource-poor settings, but the funding offers an opportunity to end the neglect. to sustainably strengthen national laboratory systems in resource-poor countries, the following approaches are needed: ( ) developing integrative national laboratory strategic plans and policies and building systems to address multiple diseases; ( ) establishing public-private partnerships; ( ) ensuring effective leadership, commitment, and coordination by host governments of efforts of donors and partners; ( ) establishing and/or strengthening centers of excellence and field epidemiology and laboratory training programs to meet short- and medium-term training and retention goals; and ( ) establishing affordable, scalable, and effective laboratory accreditation schemes to ensure quality of laboratory tests and bridge the gap between clinicians and laboratory experts on the use of test results. and malaria. laboratory systems and services are often neglected in resource-poor settings, but the funding offers an opportunity to end the neglect. to sustainably strengthen national laboratory systems in resource-poor countries, the following approaches are needed: ( ) developing integrative national laboratory strategic plans and policies and building systems to address multiple diseases; ( ) establishing publicprivate partnerships; ( ) ensuring effective leadership, commitment, and coordination by host governments of efforts of donors and partners; ( ) establishing and/or strengthening centers of excellence and field epidemiology and laboratory training programs to meet short-and medium-term training and retention goals; and ( ) establishing affordable, scalable, and effective laboratory accreditation schemes to ensure quality of laboratory tests and bridge the gap between clinicians and laboratory experts on the use of test results. in may , president barack obama announced a $ billion comprehensive global health initiative (ghi) to focus attention on broad global health challenges, including child and maternal health, hiv/aids, family planning, and neglected tropical diseases, with cost-effective intervention. the ghi adopts an integrated approach to fighting diseases, improving health, and strengthening health systems. during the past years, the field of global infectious diseases has witnessed tremendous challenges and opportunities, including the continuous struggle to control and prevent the hiv/aids pandemic and to tackle emerging or reemerging infectious diseases, including multidrug-resistant and extensively drugresistant tuberculosis (tb), novel emerging infections such as severe acute respiratory syndrome, the avian influenza virus h n , and the current pandemic of novel influenza a (h n ) virus. these infections have been well contained in developed countries, thanks to well-established laboratorysupported surveillance systems. however, laboratory services and systems are weak in resource-poor countries (rpcs). the new ghi, together with the surge in funding and commitment for programs to fight hiv/aids, tb, malaria, and flu in rpcs (an estimated $ billion per annum is devoted to tackling the hiv/aids pandemic , ), offers a monumental opportunity to strengthen laboratory systems in rpcs that could be used to combat multiple diseases. health system strengthening is a key area of focus for some of the major programs, including the ghi. for example, in , the us president's emergency plan for aids relief (pepfar) dedicated $ . to $ . billion to supporting health systems, of which % is earmarked for strengthening laboratory systems. the global fund to fight aids, tuberculosis and malaria has also allocated a similar proportion to strengthening laboratory services. in addition, the world bank will be allocating $ . million to strengthen laboratory systems in a regional program in east africa. together these increased resources offer an unprecedented prospect to strengthen, in a holistic and integrated way, multiple challenges facing the appalling national laboratory systems (nlss) in rpcs. strengthened nlss will be critical to delivering reliable laboratory services to meet the millennium development goals (mdgs) for health; fight multiple existing, emerging, and reemerging diseases; and achieve president obama's ghi objectives. despite substantial evidence that nlss (comprising public health, government, private, and mission hospitals) are a key component of the overall health system; are needed to achieve the mdgs for health; are required for meeting universal access for treatment of hiv/aids, tb, and malaria; and are critical for achieving the objectives of the world health organization's (who) international health regulation (ihr), they remain one of the most neglected components of the health system in rpcs. , major challenges facing nlss in rpcs include a shortage of skilled and trained personnel, an inadequate infrastructure (eg, consistent supply of electricity and water, physical infrastructure), a lack of equipment, inadequate supply-chain management for consumables and reagents, poor equipment maintenance, lack of clear policies, and insufficient leadership. , consequently, clinicians lack confidence in laboratory results and often rely on clinical diagnosis and empirical treatment instead of laboratory-confirmed diagnosis. for example, few clinicians order sputum-smear microscopy for a tb diagnosis because the turnaround time for the results may be longer than the average hospital stay, and patients are often discharged or die before the results are received. in addition, clinical diagnosis without quality laboratory testing often results in significant misdiagnosis and overdiagnosis, leading to inadequate or inappropriate treatment, drug resistance, and increased mortality. , reyburn and colleagues found that among , patients admitted and treated for malaria in a tanzania hospital, fewer than % actually had malaria, as confirmed by blood smear. similarly, a study in ghana found that % of patients with a clinical diagnosis of malaria actually had bacterial sepsis, , and the correct diagnosis of malaria leads to better treatment. in january , the maputo declaration for a global commitment to strengthen laboratory services and systems in rpcs was issued and endorsed. , with the surge in funding, we believe that the following actions should be undertaken to strengthen nlss in a sustainable manner in rpcs. as illustrated in ❚figure ❚, countries and partners need to develop national laboratory policies and strategic plans as part of the overall health sector development investment. these plans should be comprehensive and not disease-specific and should integrate multiple diseases with the ultimate goal of establishing a functional tiered laboratory network in the country as proposed in ❚figure ❚. laboratory plans should also be considered a key component of implementing the who ihr, which is a legally binding agreement of all member states of who to help the international community ❚figure ❚ core cross-cutting elements of laboratory health systems that should be strengthened to support multiple diseases of public health importance. horizontal arrows indicate cross-cutting core elements that affect laboratories and need to be addressed in a national laboratory strategic plan, regardless of the disease. these core elements must be addressed at various levels of a tiered laboratory network. the vertical arrows are examples of major public health diseases that have seen a surge in funding that can drive the laboratory systems to be strengthened in resource-poor countries. prevent and respond to acute public health risks with a global impact, such as influenza, multidrug-resistant and extensively drug-resistant tb, and other diseases. as shown in figure , a comprehensive national laboratory strategic plan should focus on strengthening core cross-cutting elements of laboratory health systems, including the following: ( ) a framework for training, retaining, and career development of laboratory workers; ( ) infrastructure development; ( ) supply-chain management of laboratory supplies and maintenance of laboratory equipment; ( ) specimen referral systems in an integrated, tiered nls network; ( ) standards for quality management systems and accrediting laboratories and facilities; ( ) laboratory information system; ( ) biosafety and waste management; and ( ) a governance structure that will clearly address regulatory issues and define reporting structures, authority, and the relationship between private diagnostic and public health laboratories, to ensure a functional nls network as illustrated in figure . these regulatory frameworks are critical for guiding the implementation of laboratory quality management systems, accreditation of laboratories, defining certification process for technicians, and monitoring and evaluation. ❚figure ❚ is a proposed framework for strengthening laboratory systems in developing countries. if efforts are focused on strengthening core cross-cutting aspects of laboratory systems that are critical to ensure quality diagnostic services (microscopy, flow cytometry, molecular diagnosis, serology, clinical chemistry, and culture), sustainable nlss will emerge in rpcs that will benefit the fight against multiple emerging, reemerging, and existing diseases. in fact, because some hiv/ aids laboratory investments had strengthened laboratory core systems in some rpcs, they have been instrumental in the past in supporting the investigation of other disease outbreaks. moreover, with support from the world bank's aids program and pepfar, rwanda developed a functional integrated national reference laboratory that is currently used to combat multiple diseases, including tb, malaria, and epidemic-prone diseases (eg, cholera), and priority diseases. finally, laboratory plans should aim at strengthening infrastructure in health facilities outside the public sector, especially private and mission hospitals that are critical to achieving universal access to care and treatment in rpcs. in fact, a sizable portion of persons in africa receive health care in the private and rural settings in which, in some countries, % of all health care and more than % of care in rural areas is provided in mission hospitals. once developed, laboratory strategic plans can be implemented through a variety of ways. first, public-private partnerships (ppps) have been shown to be effective in strengthening ❚figure ❚ potential structure of a national laboratory network system in resource-poor countries. in this structure, clear lines of functions, authority, and responsibility are outlined from the central public health laboratory (cphl) to the primary health center (phc). for example, the cphl sets policy, conducts planning, and establishes appropriate quality management systems. in larger countries, regional public health laboratories may need to take on the responsibilities of the cphl so as to reach the phc. health systems in rpcs. therefore, ppps that focus on implementing established laboratory plans will be vital. in this respect, pepfar has entered into an $ million ppp agreement with becton dickinson, a private medical diagnostic company, to strengthen laboratory capacity in african countries in the areas of training, development of referral systems for transporting samples, and quality management schemes. similarly, the abbott fund in tanzania is developing laboratory infrastructure in the country, including a stateof-the-art reference laboratory in dar es salaam, and upgrading all regional hospital laboratories in the country. will be critical to developing laboratory services and systems in the private sector. increased funding to combat hiv/aids, tb, malaria, flu, and global infectious diseases means that multiple international partners and donors will be present in a given rpc. the unintended consequences of uncoordinated efforts can be fragmented laboratory health systems. to avoid this shortcoming, the maputo declaration calls for increased collaboration and coordination of donors and implementing partners' activities, based on their comparative advantages, within the context of countries' national strategic laboratory plans. therefore, host governments will need to show leadership and commitment by ensuring that laboratory plans are an integral part of the overall health systems strategy and investment for the country and that a functional department of laboratory services is established within the ministry of health, similar to other departments such as pharmacy and disease control. there is an acute shortage of a well-trained national laboratory workforce to meet the expanding hiv/aids, tb, malaria, and flu programs. the who estimates that to meet the mdgs, approximately million new health workers (including staff working in laboratories) will need to be trained and retained by the year . in this regard, the pepfar reauthorization legislation that aims to train , health care workers is a highly appropriate initiative. training and retention efforts for laboratory experts should focus on job redesign and use holistic approaches that address projected skill shortages, ie, based on an assessment and definition of critical gaps at the country or regional level. any effective training strategy must proactively involve stakeholders (eg, national governments, the private sector, development partners, and multilateral bodies). to partly address the short-term laboratory needs and support current ❚figure ❚ proposed framework for strengthening laboratory systems globally showing the core elements of a laboratory system that need to be strengthened, with the surge in hiv/aids and tuberculosis funding, to provide broad-based, integrated, quality laboratory services and ensure sustainability of global laboratory investments. this approach will be needed to combat multiple global disease program needs, especially for infections that do not have specific funding. for example, for serologic diagnosis of any disease to be effective in a resource-poor country, there is a need to adequately address issues related to quality management, training and retention, equipment procurement and maintenance, supply chain management, laboratory information systems, biosafety, and policy. program goals, centers of excellence are needed to provide specialized staff needs. with funding from pepfar, the national institute of communicable diseases in johannesburg, south africa, recently established the african center for integrated laboratory training (acilt). the acilt was created after in-depth consultation on laboratory training needs of several african countries, in collaboration with the who regional office for africa. the courses used a competency-based approach for the trainees to obtain knowledge and skills at the national institute of communicable diseases; attendees then returned to their countries and developed competencies while working under supervision and received follow-up visits by the core training staff of acilt. this training approach is similar to the short-course component of the us centers for disease control and prevention-supported field epidemiology training programs in several rpcs. in these programs, field epidemiologists and public health laboratory staff are jointly trained in long courses (ie, -year public health leadership training) and short courses (ie, -to -week public health implementer training) to acquire skills and develop competencies while providing a public health service. these were modeled on the us centers for disease control and prevention epidemic intelligence service. laboratory components of the field epidemiology training programs will need to be standardized and strengthened to address needs for technicians, managers, and policy makers. although implementing international laboratory standards, such as iso , has been shown to be possible in developing countries, implementation is not easily scalable in the laboratories of most developing countries. thus, the who regional office for africa stepwise laboratory accreditation program and the thai accreditation scheme, both described in this issue of the journal, offer practical and affordable approaches to quality management systems that can be implemented and scaled up in developing countries. there is need to establish continuous laboratory medical education (cmle) for clinicians so as to bridge the gap between laboratory testing and uptake for patient management. regional societies for laboratory medicine or clinical pathology could serve as the appropriate vehicle to meet these critical gaps, including implementing cmle and certification of training for medical technologists. the new obama ghi and the increased funding for hiv/ aids, tb, malaria, and flu programs provide a monumental opportunity to build integrated and sustainable nlss in rpcs, which will help advance the goals of the mdgs for health, support universal access to treatment, meet the objectives of the maputo declaration, and advance the who ihr. the efforts of rpc governments and partners should be focused on developing an integrated and functional tiered nls through a comprehensive national laboratory strategic plan and policy, establishment of ppps, leadership and commitment of host countries that is needed to effectively coordinate donors and implement the efforts of partners, establishment of centers of excellence to meet urgent human capacity needs, and implementation of practical and affordable laboratory accreditation schemes and cmle for physicians. global efforts should center on strengthening critical cross-cutting core elements of laboratory systems (figure ) that are vital to support multiple global health needs and will ensure sustainability. multidrug-resistant and extensively drug-resistant tuberculosis: a review identification of the novel coronavirus in patients with severe acute respiratory syndrome characterization of an avian influenza a (h n ) virus isolated from a child with a fatal respiratory illness severe respiratory disease concurrent with circulation of h n influenza the great funding surge hiv/aids: money matters aids: lessons learnt and myths dispelled cross-country laboratory network to raise east africa's defenses against disease are laboratory services coming of age in sub-saharan africa laboratory medicine in africa: a barrier to effective health care laboratory use in ghana: physician perception and practice achilles heel" of global efforts to combat infectious diseases diagnostic insufficiency in africa overdiagnosis of malaria in patients with severe febrile illness in tanzania: a prospective study high mortality of infant bacteraemia clinically indistinguishable from severe malaria overlap in the clinical features of pneumonia and malaria in african children improved diagnostic testing and malaria treatment practices in zambia world health organization. the maputo declaration on strengthening of laboratory systems critical role of developing national laboratory strategic plans as a guide to strengthen laboratory health systems in resource-poor settings outbreak news: avian influenza responding to the global human resources crisis public-private partnerships to build human capacity in low income countries: findings from the pfizer program the united states president's emergency plan for aids relief: bd and pepfar collaborate to strengthen laboratory systems in fight against hiv/aids and tb corporate volunteerism as a pilot approach to strengthening laboratory infrastructures in mbeya region abstract mopeg international health partnership: a welcome initiative health in africa fund holds first close on $ m united states. president bush signs hr , the tom lantos and henry j. hyde united states global leadership against hiv/ aids, tuberculosis and malaria reauthorization act of training programmes for field epidemiology key: cord- -lzybfwc authors: savarino, andrea; shytaj, iart luca title: chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in hiv/aids date: - - journal: retrovirology doi: . /s - - - sha: doc_id: cord_uid: lzybfwc the restoration of the immune system prompted by antiretroviral therapy (art) has allowed drastically reducing the mortality and morbidity of hiv infection. however, one main source of clinical concern is the persistence of immune hyperactivation in individuals under art. chronically enhanced levels of t-cell activation are associated with several deleterious effects which lead to faster disease progression and slower cd (+) t-cell recovery during art. in this article, we discuss the rationale, and review the results, of the use of antimalarial quinolines, such as chloroquine and its derivative hydroxychloroquine, to counteract immune activation in hiv infection. despite the promising results of several pilot trials, the most recent clinical data indicate that antimalarial quinolines are unlikely to exert a marked beneficial effect on immune activation. alternative approaches will likely be required to reproducibly decrease immune activation in the setting of hiv infection. if the quinoline-based strategies should nevertheless be pursued in future studies, particular care must be devoted to the dosage selection, in order to maximize the chances to obtain effective in vivo drug concentrations. the quest for clinical candidates to counteract immune activation has become a "hot topic" in aids research, because hiv infection is characterized by malignant immune hyperactivation which correlates with disease progression and poor response to antiretroviral therapy (art) [ ] [ ] [ ] [ ] [ ] . moreover, immune hyperactivation is also regarded as a major obstacle to a cure for aids [ ] . in the beginning of the millennium, an article authored by one of us launched chloroquine as a tool to inhibit viral replication and the related malignant immune activation associated with some viral diseases [ ] . this article sparked a new wave of studies, in that it extended a theory, previously designed for hiv/aids [ ] , to other viral diseases characterized by excessive immune activation. as will be discussed below, by accumulating in the acidic organelles, chloroquine exerts both direct antiviral effects on enveloped viruses and decreases activation of several cell types involved in the immune response. chloroquine has since shown promise in preclinical studies (both in vitro and in vivo), as a therapeutic agent against emerging viruses such as mers cov [ ] . of note, chloroquine has been indicated as a promising candidate for filovirus treatment [ ] , especially during the latest ebola epidemic [ , ] . in two studies out of three, chloroquine showed antiviral activity in mice at the maximum tolerated dose [ , , ] , thus rendering this drug an interesting agent for further testing of combination anti-ebola therapies. however, the effects of chloroquine and its hydroxyl analogue hydroxychloroquine, on hiv infection, i.e. the initial target for the repurposing of these drugs, have remained controversial. on the one hand, based on the results of some earlier clinical trials, chloroquine/hydroxychloroquine has been recently resuggested as a promising candidate to restrict the hivrelated immune activation [ , ] . on the other hand, the results from the latest clinical trials indicate that chloroquine/hydroxychloroquine has no beneficial effect on immune activation [ , ] . we here provide a state of the art of the studies investigating the use of chloroquine/hydroxychloroquine as a therapeutic tool for hiv/aids and suggest the possible biological grounds for the clinical results obtained. moreover, we describe the reasons why our group decided to proceed further with strategies based on another drug, i.e. auranofin, which shares with chloroquine an antirheumatic effect [ ] . several reviews have recently been published on immune activation in hiv infection [ , , , ] . briefly, immune hyperactivation, commonly measured as the expression levels on peripheral blood lymphocytes of markers such as hla-dr, cd , or cd correlates with, and also predicts, disease progression (reviewed in [ , ] ). immune activation gradually decreases following therapy initiation [ ] and is maintained high in immunological non-responders, who are individuals maintaining low cd counts despite prolonged exposure to art [ , ] . while the initial studies were focused on the relationship between disease progression and activation of cd + t-cells [ ] , later studies better concluded that there is a broader relationship between disease progression and immune hyperactivation, involving also cd + t-cells [ , ] and innate immunity [ ] . immune activation and viral replication are believed to be mutually enhanced in a vicious circle. the virus, recognized by the immune system as non-self, induces immune activation, which, in turn, fuels viral replication by furnishing to the virus material to synthesize the different viral components. for example, lymphocyte activation increases the cytoplasmic levels of deoxyribonucleotides necessary for viral dna synthesis by reverse transcriptase [ ] . this vicious circle may still persist in anatomical compartments incompletely penetrated by art. hiv-induced immune activation is not limited to specific immunity, but exerts its effects on innate immunity as well. hiv- was shown to activate plasmacytoid dendritic cells (pdcs), which, differently from myeloid dendritic cells (the most potent antigen-presenting cells in the body), induce innate antimicrobial immunity by producing type i interferons ( figure ) [ ] . pdcs internalize hiv- through viral envelope/cd interactions, and the internalized virus activates these cells mainly through toll-like receptor (tlr- ) signaling ( figure ). comparative pathology corroborates the hypothesis that over-stimulation of this pathway may be associated with deleterious effects. sooty mangabeys (cercocebus atys), which can be infected by a simian homolog of hiv (i.e. simian immunodeficiency virus, siv) but do not develop aids, display weak ifn-α production upon stimulation with tlr- antagonists [ ] . on the contrary, rhesus macaques (macaca mulatta), which do progress to aids, produce high amounts of ifn-α when their pdcs are subjected to the same stimuli [ ] . moreover, another species displaying nonpathogenic siv infection, i.e. the african green monkey (chlorocebus aethiops), is characterized by an efficient control of ifn-α production following acute infection [ ] . pdcs decrease in peripheral blood during progression to aids, because, upon activation, they migrate to the lymphoid tissue [ ] . as a huge number of cells reside in the gut-associated lymphoid tissue (galt), according to the microbial translocation theory, the intestinal mucosa damaged by the consequent inflammation may become permeable to products of the gut microbiome which further enhance hiv-related immune hyperactivation [ , ] . finally, immune activation is one primary driver of both generation and maintenance of the viral reservoir, which is mainly constituted by latently infected, central and transitional memory cd + t-cells (henceforth t cm and t tm , respectively) [ ] . also in this case, comparative pathology has provided clues for understanding this phenomenon. it was shown that cd + t cm cells from sooty mangabeys express, upon activation, low levels of ccr , the main coreceptor for virus entry into cells, thus limiting infection of this important cellular compartment [ ] . instead, activated t cm cells from aids-developing species, such as humans and rhesus macaques, up-regulate the levels of ccr to a higher extent than cells from sooty mangabeys, thus facilitating the generation of a consistent viral reservoir [ ] . after these cells become quiescent, viral replication switches off, and latently infected, hiv-reservoir cells proliferate through low-level antigenic stimulation (t cm ) or il- -driven homeostatic proliferation (t tm ) [ ] . both processes are enhanced by generalized immune activation. multiple in vitro effects of chloroquine could support its possible use as a modulator of immune activation in hiv/aids: . chloroquine and its hydroxyl analogue hydroxychloroquine were shown in several studies to inhibit hiv- replication (reviewed in: [ ] ). the effects of these quinolines, mainly due to the induction of a defect in the maturation of the viral envelope glycoprotein gp [ , ] , might mimic the effects of broadly neutralizing antibodies directed against the viral envelope, although the effects of these antibodies are weaker than those directed against the cd binding site [ ] . these effects are additive to those of non-nucleosidic reverse transcriptase inhibitors (nnrtis) and synergistic to those of protease inhibitors (pis) [ ] . as quinoline drugs accumulate in lymphoid tissues [ ] , they might decrease ongoing viral replication during art in anatomical sanctuaries and, consequently switch off one of the main drivers of immune activation. chloroquine is also an inhibitor of p-glycoprotein (p-gp) and multidrug resistance proteins (mrps) [ , ] , cell surface glycoproteins which extrude several antiretroviral drugs to the extracellular medium. in line with this evidence, chloroquine was shown to increase the intracellular levels of pis [ ] . the effects of chloroquine in com-bination with nrtis are instead controversial: some reported an additive effect [ ] , while others did not detect it [ ] . the combined effects of chloroquine and integrase inhibitors are as yet unknown. . chloroquine accumulates in phagosomes of pdcs and inhibits their hiv-induced activation [ ] . it might therefore impact on innate immunity-induced immune hyperactivation. . a recent study showed that hydroxychloroquine selectively induces apoptosis in the memory t-cell compartment (cd ra − cd ro + ) [ ] . as, upon activation, naïve t-cells (cd ra + cd ro − ) acquire a cd ra − cd ro + phenotype, the "antimemory" effect should limit immune activation (figure ) [ ] . there is growing consensus that induction of apoptosis in the memory t-cell compartment might have a detrimental effect on the viral reservoir [ ] [ ] [ ] . in this light, chloroquine/hydroxychloroquine should have an anti-reservoir potential. this view is supported by another recent study which shows that chloroquine sensitizes to apoptosis the latently infected cells upon viral reactivation, likely by removing the anti-apoptotic effect of the virus structural gag gene products [ ] . these effects are potentially interesting, since it has been well demonstrated that viral reactivation from latency does not necessarily result in cell death [ ] . the macaque aids model is an important tool for preclinical assessment of strategies aimed at treating hiv/ aids [ ] . to our knowledge, chloroquine has been tested in this model on two occasions. in a first study, chloroquine ( mg every other day for days, i.e. a cumulative dosage comparable to that administered to humans with rheumatioid arthritis) was administered to three chinese rhesus macaques infected with the simian hiv-homologue, sivmac [ ] . although a decrease in activated pdcs was shown, no effects were seen on viral load and cd + and cd + t-cell activation (measured as cd expression) [ ] . as the immune activation set point is established during acute infection [ ] , vaccari et al. [ ] treated with chloroquine ( . mg/day for consecutive days) seven sivmac -infected rhesus macaques during the viral load peak that characterizes acute infection. apart from an unexpected, although transient, increase in the comparison of the susceptibility to chloroquine/hydroxychloroquine and auranofin of the cellular subsets involved in hiv production and persistence. shown in the figure is a schematic depiction of a activation and b differentiation stages of cd + t-lymphocytes and their correlation with viral production, latency and viral reactivation. both chloroquine/hydroxychloroquine and auranofin can influence these transitions by exerting a pro-apoptotic effect, the efficacy of which is graphically exemplified by the intensity of the blue color in the corresponding rectangles. efficacy gradients are based on data derived from refs. [ , , ] . expression of interferon-regulated genes (perhaps not population-relevant as possibly driven by only one animal), no significant differences were reported in viral load and t-cell activation and proliferation (measured as expression of cd and ki , respectively) [ ] . a trend was however noticed for maintenance of decreased levels of ki , cd and ccr in the gut of the chloroquinetreated animals, although the differences with values from the control group did not reach statistical significance. the effect of chloroquine in this simian model in the presence of art is still unknown. chloroquine and hydroxychloroquine have so far been tested in several hiv clinical trials. the results summarized in figure support the hypothesis that the chloroquine/hydroxychloroquine dosage may be an important driver of at least partial clinical success. suppressive effects on immune activation by chloroquine were shown in the trial conducted by murray et al. [ ] . however, in this trial, the dosage administered was not the same for all individuals, some of them receiving mg/die instead of mg/die. it is thus possible that the statistical significance of the effects reported in this study was driven by the higher dosage of the drug. this view is supported by a later study which tested chloroquine at mg/die and failed to show any effect of the drug [ ] . in two clinical trials conducted in the s, sperber et al. reported suppressive effects on immune activation (measured at that time as il- production) and viral load in individuals treated with mg of hydroxychloroquine/day (bioequivalent to mg/day of chloroquine) [ , ] . the other clinical trials testing hydroxychloroquine at a lower dosage (i.e. mg/day) led to conflicting results. earlier studies [ , ] and the more recent study of piconi et al. [ ] reported significant effects on viral load [ ] , cd counts [ ] , and immune activation. [ ] . instead, a more recent clinical trial, randomized and double blind, showed disappointing results, even hinting at possibly deleterious effects of hydroxychloroquine on viral load and cd counts [ ] . this trial was conducted in the absence of art, and this might explain differences between this study and the study of piconi et al., which was conducted on individuals under art [ ] . another trial in art-treated patients is currently ongoing and will provide more information on the effects of hydroxychloroquine (clinicaltrials.gov identifier: nct ). the hydroxychloroquine levels show high inter-subject variability and, although individuals receiving the higher hydroxychloroquine dosages ( and , mg/day) also showed significantly higher blood levels of the drug than those receiving mg/die, the range of the blood concentrations was in part overlapping in the different dosage groups [ ] . chloroquine has similar pharmacokinetics [ ] ; therefore, not only the dosage but also individual differences in drug metabolism and distribution may explain the different conclusions of the aforementioned studies. a large clinical trial has recently been completed (clinicaltrials.gov identifier: nct ) and its results can help to better represent the response of a population, thus abolishing the bias due to limited sample size. in this trial, however, chloroquine has been tested at mg/day in the absence of art; thus, in light of the results of the aforementioned clinical trials and considerations derived from basic science (see next paragraph), it is not surprising that the preliminary results released so far for this trial (https://clinicaltrials.gov/ct / show/nct ) do not show any significant effect of chloroquine on immune activation, viral load and cd counts. chloroquine/hydroxychloroquine-treated individuals display blood concentrations that are highly variable and only rarely exceed or µm, respectively [ , ] . therefore, at the steady state levels, these blood concentrations only in part overlap those at which a therapeutic effect is expected. for example, the ec of chloroquine on pbmc proliferation upon activation is, in general, ≥ µm [ ] , and this value can explain the varying results obtained in the different clinical trials, with clearer effects associated with the higher drug dosages. similarly, the pro-apoptotic effect of hydroxychloroquine on the memory t-cells is only moderate at the concentrations reachable in blood, especially in the lower range [ , ] . the pro-apoptotic effect of chloroquine described by li et al. on latently infected cells upon viral reactivation is instead more marked, although still partial, at the upper range of clinically achievable blood concentrations ( - µm) [ ] . this effect could therefore be visible in vivo in terms of viral reservoir reduction, but only treating with high chloroquine dosages in the presence of suppressive art. moreover, to maximize the chances to obtain viral reservoir reduction in vivo, chloroquine treatment should be prolonged, as the events of virus reactivation from latency are rather rare (estimated as one event of transition from latency to productive infection every ml of blood each day) [ ] . the effect of chloroquine on pdc activation (see figure published clinical studies evaluating the effects of chloroquine/hydroxychloroquine administration, alone or in combination with other drugs, in hiv infected subjects. highlighted in blue, red or white are the studies that have reported a positive, negative, or neutral outcome of the therapy respectively. cq chloroquine, hcq hydroxychloroquine. [ ] . in this case, the in vitro effect is in line with the results of two in vivo studies [ , ] . the use of chloroquine-related compounds with increased potency is yielding promising results in vitro [ ] , and it will be interesting to test the best-performing candidates in the simian aids model. the effects of chloroquine/hydroxychloroquine on viral replication have been repeatedly shown in vitro at lower drug levels than those inducing the cellular effects [ , , , ] . the blood concentration/ec ratio is however much narrower than those shown by antiretroviral drugs [ ] . the antiretroviral effects of chloroquine/hydroxychloroquine may though become visible in anatomical sanctuaries of those individuals treated with pi-containing antiretroviral regimens. in any case, we recommend that chloroquine/hydroxychloroquine be tested at the highest recommended dosages in future hiv clinical trials. alternative/complementary interpretations of the results so far obtained are possible. for example, the effectiveness of the art regimen employed may play a role in determining the magnitude of the effects (if any) observed following chloroquine/hydroxichloroquine addition. the study of piconi et al. [ ] , showing some benefit in immunological non responders, may indicate that the effects of chloroquine may be visible only in some subsets of individuals with peculiar immunological characteristics, and that these effects can be hindered when immunologically non homogeneous cohorts are studied. in this regard, larger studies, with cohorts stratified according to immunological responsiveness to art, could provide further information on the effects of chloroquine/hydroxychloroquine. another open question remains the influence of the duration of drug exposure, as it has been shown that chloroquine/hydroxychloroquine has cumulative effects [ ] . as a proportion of hiv-infected patients in africa may already be on chloroquine medication to prevent malaria, it might be worth examining the long-term effects of this treatment. in this regard, an ongoing phase iii clinical trial will assess the long-term effects of chloroquine and trimethoprim-sulfamethoxazole phrophylaxis on survival and disease control in hiv-infected individuals with suppressed viral load and good clinical response to art [ ] . given the aforementioned problems in the pharmacokinetics of chloroquine/hydroxychloroquine, our group chose to follow a different, yet partly similar, approach to corroborate treatment of hiv/aids. based on the feedback received from basic science studies and clinical trials that have been published throughout the years, we decided to use drugs the desired effects of which be striking in vitro at concentrations lower than the trough plasma concentrations in vivo. we also decided to redirect our research on the basis of the plasma concentrations rather than on whole-blood concentrations (widely used for chloroquine/hydroxychloroquine), because we thought that the former might better mimic the tissue culture concentrations. the drug that we selected is the gold-based compound auranofin, the pharmacodynamics and pharmacokinetics of which are well known, due to its decade-long employment for treatment of rheumatoid arthritis [ ] . the main rationale for the use of auranofin in our studies was its ability to target the central/transitional memory cd + t-cell compartment ( figure ) [ , ] , which is known to harbor the main viral reservoir in patients receiving art [ ] . auranofin is drastically active at submicromolar (i.e. ≤ nm) concentrations, which are below those readily achievable in human plasma [ ] . the administration of auranofin ultimately led to a reduction of the viral reservoir in art-treated sivmac -infected macaques [ ] . a review on our preclinical studies has recently been published [ ] and the reader is addressed to it for further detail. not surprisingly for a drug effective against an autoimmune disease such as rheumatoid arthritis, auranofin may as well be beneficial in terms of reduction of cell activation. in particular, the downregulation of the cd molecule induced by auranofin can disrupt the co-stimulatory signal often crucial for lymphocyte activation [ ] . moreover, apart from memory cd + t-cells, auranofin also targets the memory cd + t-cell compartment [ ] , i.e. a cellular subset known to be hyperactivated during hiv infection [ ] . interestingly, as described for hydroxychloroquine [ ] , auranofin was shown to disrupt in various cell lines the tlr- signaling [ ] , which is activated by bacterial lipopolysaccharides and likely constitutes another source of immune hyperactivation. in vitro data indicate that the impact of auranofin on lymphocyte activation may be mediated, at least in part, by modulation of oxidative stress [ ] . of note, the addition of a potent pro-oxidant drug, such as buthionine sulfoximine (bso), increases the potency of auranofin, decreasing phytohemagglutinin-induced activation and expression of the α-chain of the il- receptor [ ] . this is in line with our preliminary data in sivmac -infected macaques, in which a combined regimen of art, auranofin and bso induced a functional cure-like condition following suspension of all therapies [ ] . these observations provide proof of concept that drastically decreasing immune hyperactivation arrests siv disease progression and turns the virus/immune system balance in favor of the latter. clinical trials will be required to assess the potential of auranofin to decrease immune activation in art-treated subjects. finally, other drugs used or proposed for treatment of rheumatoid arthritis might find a place in the treatment of hiv/aids. for example, the janus kinase inhibitors tofacitinib and ruxolitinib have shown a promising in vitro activity against hiv replication [ ] . the ongoing in vivo studies on these compounds could provide an opportunity to analyze the effects of this treatment on viral replication and immune activation. as and ils contributed to the ideas and to the interpretation of the data presented in the manuscript. as and ils contributed to manuscript drafting and preparation of the figures. both authors read and approved the final manuscript. cd + lymphocyte activation at human immunodeficiency virus type seroconversion: development of hla-dr+ cd − cd + cells is associated with subsequent stable cd + cell levels. the multicenter aids cohort study group increased numbers of primed activated cd + cd + cd ro+ t cells predict the decline of cd + t cells in hiv- -infected patients t cell activation is associated with lower cd + t cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy immune activation set point during early hiv infection predicts subsequent cd + t-cell changes independent of viral load relationship between t cell activation and cd + t cell count in hiv-seropositive individuals with undetectable plasma hiv rna levels in the absence of therapy immune activation and hiv persistence: considerations for novel therapeutic interventions effects of chloroquine on viral infections: an old drug against today's diseases? the potential place of chloroquine in the treatment of hiv- -infected patients screening of an fda-approved compound library identifies four small-molecule inhibitors of middle east respiratory syndrome coronavirus replication in cell culture a systematic screen of fda-approved drugs for inhibitors of biological threat agents ebola virus (ebov) infection: therapeutic strategies antiviral therapies against ebola and other emerging viral diseases using existing medicines that block virus entry [v ; ref status: awaiting peer review evaluation of ebola virus inhibitors for drug repurposing lack of protection against ebola virus from chloroquine in mice and hamsters immune responses during spontaneous control of hiv and aids: what is the hope for a cure persistent immune activation in chronic hiv infection: do any interventions work? hydroxychloroquine trial team: effects of hydroxychloroquine on immune activation and disease progression among hiv-infected patients not receiving antiretroviral therapy: a randomized controlled trial assessment of chloroquine as a modulator of immune activation to improve cd recovery in immune nonresponding hiv-infected patients receiving antiretroviral therapy comparison of phenytoin with auranofin and chloroquine in rheumatoid arthritis-a double blind study immune activation and hiv persistence: implications for curative approaches to hiv infection hiv-associated chronic immune activation residual immune dysregulation syndrome in treated hiv infection biomarkers of immune dysfunction following combination antiretroviral therapy for hiv infection positive effects of combined antiretroviral therapy on cd + tcell homeostasis and function in advanced hiv disease shorter survival in advanced human immunodeficiency virus type infection is more closely associated with t lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage endocytosis of hiv- activates plasmacytoid dendritic cells via toll-like receptor-viral rna interactions low levels of deoxynucleotides in peripheral blood lymphocytes: a strategy to inhibit human immunodeficiency virus type replication divergent tlr and tlr signaling and type i interferon production distinguish pathogenic and nonpathogenic aids virus infections nonpathogenic siv infection of african green monkeys induces a strong but rapidly controlled type i ifn response impaired restoration of plasmacytoid dendritic cells in hiv- -infected patients with poor cd t cell reconstitution is associated with decrease in capacity to produce ifn-alpha but not proinflammatory cytokines residual immune dysregulation syndrome in treated hiv infection microbial translocation in the pathogenesis of hiv infection and aids hiv reservoir size and persistence are driven by t cell survival and homeostatic proliferation low levels of siv infection in sooty mangabey central memory cd + t cells are associated with limited ccr expression inhibition of human immunodeficiency virus infectivity by chloroquine effect of chloroquine on reducing hiv- replication in vitro and the dc-sign mediated transfer of virus to cd + t-lymphocytes llama antibody fragments with cross-subtype human immunodeficiency virus type (hiv- )-neutralizing properties and high affinity for hiv- gp quinoline antimalarials as investigational drugs for hiv- /aids: in vitro effects on hiv- replication, hiv- response to antiretroviral drugs, and intracellular antiretroviral drug concentrations short communication: preferential concentration of hydroxychloroquine in adenoid tissue of hiv-infected subjects the effect of lysosomotropic agents and secretory inhibitors on anthracycline retention and activity in multiple drug-resistant cells reversal of mrp-mediated doxorubicin resistance with quinoline-based drugs antiretroviral treatment influence of quinacrine and chloroquine on the in vitro ′-azido- ′-deoxythymidine antiretroviral effect chloroquine modulates hiv- -induced plasmacytoid dendritic cell alpha interferon: implication for t-cell activation hydroxychloroquine preferentially induces apoptosis of cd ro + effector t cells by inhibiting autophagy: a possible mechanism for therapeutic modulation of t cells a cure for aids: a matter of timing? maintenance of cd + t-cell memory and hiv persistence: keeping memory, keeping hiv a candidate anti-hiv reservoir compound, auranofin, exerts a selective 'antimemory' effect by exploiting the baseline oxidative status of lymphocytes plasmodium infection reduces the volume of the viral reservoir in siv-infected rhesus macaques receiving antiretroviral therapy gag-mediated autophagy promotes cd t cell survival: a possible mechanism for hiv reservoir persistence. xx international aids conference, towards an hiv cure symposium stimulation of hiv- -specific cytolytic t lymphocytes facilitates elimination of latent viral reservoir after virus reactivation nonhuman primate models in aids research inhibitory effects of chloroquine on the activation of plasmacytoid dendritic cells in sivmac -infected chinese rhesus macaques transient increase of interferon-stimulated genes and no clinical benefit by chloroquine treatment during acute simian immunodeficiency virus infection of macaques reduction of immune activation with chloroquine therapy during chronic hiv infection hydroxychloroquine treatment of patients with human immunodeficiency virus type comparison of hydroxychloroquine with zidovudine in asymptomatic patients infected with human immunodeficiency virus type hydroxychloroquine, hydroxycarbamide, and didanosine as economic treatment for hiv- hydroxychloroquine, hydroxyurea and didanosine as initial therapy for hiv-infected patients with low viral load: safety, efficacy and resistance profile after weeks hydroxychloroquine drastically reduces immune activation in hiv-infected, antiretroviral therapy-treated immunologic nonresponders hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis chloroquine levels in blood during chronic treatment of patients with rheumatoid arthritis anti-hiv effects of chloroquine: mechanisms of inhibition and spectrum of activity modeling latently infected cell activation: viral and latent reservoir persistence, and viral blips in hiv-infected patients on potent therapy inhibition of human immunodeficiency virus type replication by hydroxychloroquine in t cells and monocytes modulation of hiv- -induced activation of plasmacytoid dendritic cells by -desfluoroquinolones hydroxychloroquine and chloroquine retinopathy: a systematic review evaluating the multifocal electroretinogram as a screening test immune suppression by myeloid cells in hiv infection: new targets for immunotherapy auranofin versus placebo in rheumatoid arthritis gold drug auranofin restricts the viral reservoir in the monkey aids model and induces containment of viral load following art suspension gold levels produced by treatment with auranofin and sodium aurothiomalate auranofin, as an anti-rheumatic gold compound, suppresses lps-induced homodimerization of tlr the interaction of auranofin and buthionine sulfoximine blocks activation of human peripheral t lymphocytes investigational treatment suspension and enhanced cell-mediated immunity at rebound followed by drug-free remission of simian aids ruxolitinib and tofacitinib are potent and selective inhibitors of hiv- replication and virus reactivation in vitro submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution submit your manuscript at www ils is supported by a fellowship from the "sapienza" university (rome, italy). the istituto superiore di sanità holds a us patent on the use of the auranofin for treatment of hiv/aids. as is the leading inventor of the patent. key: cord- - z gpg authors: ruocco, eleonora; ruocco, vincenzo; tornesello, maria lina; gambardella, alessio; wolf, ronni; buonaguro, franco m. title: kaposi’s sarcoma: etiology and pathogenesis, inducing factors, causal associations, and treatments: facts and controversies date: - - journal: clin dermatol doi: . /j.clindermatol. . . sha: doc_id: cord_uid: z gpg kaposi's sarcoma (ks), an angioproliferative disorder, has a viral etiology and a multifactorial pathogenesis hinged on an immune dysfunction. the disease is multifocal, with a course ranging from indolent, with only skin manifestations to fulminant, with extensive visceral involvement. in the current view, all forms of ks have a common etiology in human herpesvirus (hhv)- infection, and the differences among them are due to the involvement of various cofactors. in fact, hhv- infection can be considered a necessary but not sufficient condition for the development of ks, because further factors (genetic, immunologic, and environmental) are required. the role of cofactors can be attributed to their ability to interact with hhv- , to affect the immune system, or to act as vasoactive agents. in this contribution, a survey of the current state of knowledge on many and various factors involved in ks pathogenesis is carried out, in particular by highlighting the facts and controversies about the role of some drugs (quinine analogues and angiotensin-converting enzyme inhibitors) in the onset of the disease. based on these assessments, it is possible to hypothesize that the role of cofactors in ks pathogenesis can move toward an effect either favoring or inhibiting the onset of the disease, depending on the presence of other agents modulating the pathogenesis itself, such as genetic predisposition, environmental factors, drug intake, or lymph flow disorders. it is possible that the same agents may act as either stimulating or inhibiting cofactors according to the patient’s genetic background and variable interactions. treatment guidelines for each form of ks are outlined, because a unique standard therapy for all of them cannot be considered due to ks heterogeneity. in most cases, therapeutic options, both local and systemic, should be tailored to the patient’s peculiar clinical conditions. kaposi's sarcoma (ks) is an angioproliferative disease, with a viral etiology and a multifactorial pathogenesis hinged on an immune dysfunction. the name is bound to moritz kaposi ( kaposi ( - who described three fatal cases of multiple idiopathic pigmented hemangiosarcoma in elderly men at the university of vienna in . since then, ks has been defined as a malignant neoplasm of blood or lymph vessels presenting with multiple vascular nodules in the skin or other organs. the disease is multifocal, with a course ranging from indolent, with only skin manifestations, to fulminant, with extensive visceral involvement. since kaposi's description of the classic type clinicians have described four distinct types. although the classic type remains more prevalent among elderly men of mediterranean origin, it has been diagnosed worldwide and typically follows a benign course. the african endemic form of ks was first described in and occurs predominantly among young black men aged to years. there is also a lymphadenopathic subvariant of the african form that affects children at a mean age of years. in the s, a third form associated with immunosuppressant treatment was described among recipients of organ transplantation, patients on long-term corticosteroids for various disorders, and patients immunosuppressed as a result of other therapeutic regimens, including chemotherapy (iatrogenic form). , finally, in , an epidemic of ks among young men who had sex with men in the united states served as the harbinger of a new immunodeficiency syndrome, subsequently identified as being associated with hiv infection (epidemic form). as the hiv epidemic progressed, ks was found almost exclusively among homosexual men. due to epidemiologic data indicating the high incidence of ks among persons at greater risk for sexually transmitted infections, a further independent infectious agent was proposed in the etiology of epidemic ks. etiology and pathogenesis of ks from the viral etiology hypothesis to the hhv- discovery although the onset of ks ensues from complex and multifactorial events, including immunosuppression, a crucial role of viral agents has been supposed since the s. , in the s, a specific role for herpesviruses was proposed. giraldo and colleagues observed herpes-type viral particles in five of eight tissue culture cell lines from african patients with ks and subsequently cytomegalovirus genetic sequences were identified in those tumors. in , a major breakthrough in the etiology of ks was reported. chang and co-workers identified a new human herpesvirus, hhv- , by representational difference analysis and detected this virus in more than % of ks lesions, including those unrelated to hiv. subsequently, hhv- has been documented in more than % of ks patients of all four types of ks. hhv- , found in saliva and semen, may spread through contact with saliva and kissing, as well as sexual activity, similarly to what occurs with other herpesviruses. the prevalence of hhv- antibodies increases with age and shows wide fluctuations geographically. low rates (b %) of hhv- seroprevalence are reported in north europe and the americas, high rates ( %) in sicily,, and very high ( %) in botswana. the rates are usually related to the prevalence of ks. nevertheless, there are countries, such as brazil, gambia, ivory coast, and thailand, with high hhv- seroprevalence and low incidence of ks. phylogenetic studies performed on the well-conserved open reading frame (orf) (minor capsid gene) allowed the identification of eight distinctive subtypes designated as a/c, j, k/m, d/e, b, q, r, or n groups, which are diversely distributed in different geographical regions. in particular, four subtypes (b, n, q, and r) have been found almost exclusively among sub-saharan african samples, one (d/e) has been found only within indigenous south asian and polynesian (pacific rim) populations, and three (a/c, j, and k) have been identified almost exclusively in eurasian subjects (european, united states, north asian, and middle eastern). sequence analysis of the highly variable orf k region has allowed the identification of seven major hhv- subtypes (a, b, c, d, e, f, and z), comprising each several sub-clades, whose distribution in the world parallels that of orf variants: hhv- subtype b predominates in africa and f has been identified in ugandan bantu tribe, subtype d is present in the pacific islands; subtype e clusters in ancient populations, like brazilian amerindians, whereas a and c predominate in europe and the united states. [ ] [ ] [ ] [ ] [ ] it is still unclear whether different genotypes may have different pathogenic and tumorigenic properties associated with inverse rates of disease progression. [ ] [ ] [ ] [ ] the role of co-factors in ks pathogenesis pathogen-related diseases do not have the same clinical outcome in all infected patients with a subset developing chronic infections and a smaller subset progressing to cancer, suggesting that cofactors are needed for the different evolution, including genetic and environmental determinants. in the current view, all forms of ks have a common etiology in hhv- infection and their differences are due to the involved cofactors. hhv- infection, in fact, can be considered a necessary but not sufficient condition for the development of ks because further factors (genetic, immunologic, and environmental) are required. it is well known today that hhv- is a necessary cause for the development of ks, but given the heterogeneous distribution of the virus, the incidence of ks in different populations, and the datum that only a small percentage of hhv- seropositive patients develop ks, other genetic or environmental cofactors are clearly necessary for the development of this tumor. [ ] [ ] [ ] [ ] hhv- , similar to other dna oncogenic viruses, expresses viral genes that directly or indirectly perturb p protein functions and thereby mediate viral oncogenesis. the p protein plays a central role in cell cycle control for its ability to induce cell cycle arrest and dna repair, or senescence and apoptosis in response to a variety of stimuli such as stress signals, genotoxic agents, hypoxia and oncogene activation. the key function of p in oncogenesis as tumor suppressor protein is supported by the fact that tp is the most frequently mutated gene in a variety of human cancer of diverse histologic type. hhv- virus interferes with p pathway at several levels: ( ) the latency-associated nuclear antigen, encoded by orf of the hhv- genome, suppresses p transcription and transactivation activity, and interacts directly with the p protein inhibiting the ability of p to induce cell death , ; ( ) the viral interferon (ifn) regulatory factor (virf ), encoded by orfk /k . of hhv- , specifically interacts with and stabilizes murine double minute (mdm ) human homologue, a well-known negative regulator of p via proteasome-mediated degradation, leading to the consequent reduction of p levels and thereby concurring to the suppression of p -mediated apoptosis. , the relevance of the virf interference with mdm protein is strongly supported by its relevance in cell cycle control. a number of studies have shown that mdm is overexpressed in several human cancers. the higher expression levels of mdm are mutually exclusive in respect to p mutations suggesting that they may substitute for mutational inactivation of p . , a naturally occurring g to t sequence variation (single-nucleotide polymorphism [snp ]) in the second promoter-enhancer region of mdm gene has been shown to increase the binding affinity of the transcriptional activator sp resulting in high levels of mdm protein, formation of transcriptionally inactive p -mdm complexes and alteration of the p pathway. , these observations are consistent with an oncogenic function for the variant snp . the mdm snp polymorphism may be associated with earlier onset of breast cancer in li-fraumeni patients , , and with earlier onset of soft tissue sarcoma, diffuse large b-cell lymphoma, colorectal cancer, and non-small cell lung cancer particularly in women. [ ] [ ] [ ] in a recent study, a significant increase of the heterozygous mdm snp t/g genotype among white classic ks cases was reported. the homozygous mdm snp g/g genotype in classic ks, on the other hand, was lower ( . %) than observed in controls ( . %). the decreased frequency of mdm snp g/g genotype in cutaneous ks patients could have several explanations including that g/g carriers with hhv- infection could be at increased risk for developing visceral ks, or highly aggressive hhv- related lymphoproliferative disorders such as primary effusion lymphoma (pel) or multicentric castleman's disease. the analysis of seven pel cell lines for mutations and snps in genes involved in apoptosis and cell cycle regulation, including snp in mdm and codon in cdkn a genes has been demonstrated. interestingly, three ( . %) epstein-barr virus (ebv)-negative cell lines, namely bc , bcbl- and bcp, were homozygous for snp g, suggesting a major role of this polymorphic allele in cell transformation, particularly in the absence of ebv coinfection. future researches, however, are needed to accurately address this hypothesis. immune deficit and risk for ks systemic immunodeficiency. ks prevalence is tremendously higher in post-transplant and aids patients, being times and , times, respectively, greater than in the general population. the incidence of ks has changed markedly during aids epidemic, particularly across the african continent. before the hiv epidemic ks was a disease primarily affecting men, with extreme incidence variation among specific populations in different geographical regions. in uganda, from to and to , ks represented . % to . % of all male cancer patients, respectively, with rare female cases , ; however, from to , ks prevalence in male cancer patients rose to . % (incidence of . / , ), becoming the most frequently reported cancer in men, whereas prevalence in female cancer patients climbed to . % (incidence of / , ). since the hiv epidemic, ks has become as common in women as in men and has been prevalent also in many african countries where it was almost unknown, but where hhv- has been shown to be prevalent. these observations point to a role for other factors in the etiology of ks, including the possibility that different hhv- variants might spread during hiv/aids epidemic. local immunodeficiency. concerning immunity disorders, systemic immunodeficiency should be considered as well as conditions of local immune destabilization, such as lymphedema, caused by several agents, often environmental factors. in endemic ks, there is a relationship between ks and podoconiosis (non-filarial elephantiasis) and an increased prevalence of ks among rural peasants and cultivators toiling up highland soils containing volcanic clay minerals. walking barefoot on volcanic soils exposes pores and sweat glands in bare feet permits abrasions and allows aluminosilicates and possibly iron oxides to be taken up by lymphatics. the silicates can cause an obstacle to lymph flow, inflammation of regional lymph nodes, and disruption of the immune control in the feet and legs. as a result, these sites become an immunocompromised district, namely, a body region where chronic lymph stasis leads to an immune stasis, responsible for the local outbreak of opportunistic infections (parasitic, bacterial, fungal) or tumors, as paradigmatically ks is. the link between the impairment of lymph circulation and regional immune dysfunction in classical ks was first proven in . ks appeared on a lymphedematous leg of a patient with altered lymph drainage and lack of cell immune response confined to the lymphedematous limb. intradermal skin tests to common antigens performed on the four limbs (forearms and legs) revealed no immune responses on the affected limb versus normal or even strong responses on the three unaffected limbs. five years later, the same patient presented with lymphedema and new ks lesions on the other leg. on this occasion, skin tests were negative on both legs, whereas normal responses were still observed on the forearms. two years later, ks lesions also appeared on both the forearms: at this time, skin tests were negative on all four limbs. a lymphologic and immunologic investigation performed in patients with classical ks sensitized with dinitrochlorobenzene proved that the affected limbs presented concomitant alteration of the lymph drainage and of the immune response. the role of chronic lymphedema in facilitating the onset of ks was stressed in an unusual localization (penis) of the classical form and even in the epidemic aids-related type. although rarely emphasized in hiv-related ks, a variable degree of lymphedema (overt or subtle, a sort of microlymphedema) of the ks-involved areas is somewhat common in homosexual men and has a wide anatomic distribution, often without notable lymphadenopathy. , also a localized trauma may be responsible for facilitating the onset of ks lesions selectively on the traumatized area. , environmental cofactors and risk for ks in cancer pathogenesis, the possibility exists that following an initial stable, genetic damage (initiation event), a transient post-initiation insult (promotion event), nonsufficient by itself to induce a cancer, could contribute to increase cancer incidence. viruses, like chemicals, can act both as initiators as well as promoters, depending on their prevalent effects either mutagenic (eg, herpesviruses) or epigenetic (eg, papillomaviruses). [ ] [ ] [ ] viruses can interact with several co-carcinogens, which may act simultaneously or sequentially, continuously, repeatedly, or occasionally. these co-carcinogens may act directly on the potential cancer cell or indirectly by affecting other tissues of the host. ks can represent a good model of interaction between different oncogenic factors, useful to identify their role and their mechanisms. , the role of cofactors can be attributed to their ability to interact with hhv- , to affect the immune system, or to act as vasoactive agents (table ) . in aids-related ks, for instance, the use of large quantities of nitrite inhalants among gay men with aids was strongly associated with ks onset. several plausible biologic mechanisms of action have been proposed for nitrites and their metabolites, such as cholesteryl nitrite and nitrosamines to be carcinogenic. nitrite inhalant use might also contribute to the development of ks through immune suppression or affecting small blood vessels. , drugs as environmental cofactors for risk for ks: facts and controversies. some drugs proved to be associated with ks pathogenesis due to their immunomodulatory and proangiogenic effects. quinine and its analogues, -aminoquinolines, are drugs used for many years in malaria treatment. the link between these drugs and ks is based on a series of clues that take into account the geographical distribution and incidence of ks in patients taking these drugs. in fact, hhv- seropositivity and ks have a high prevalence in areas such as sub-saharan africa, italy, and greece and low in northern europe and asia, which reflects the same pattern of distribution of malaria. , there are regions of the world, such as brazil, gambia, ivory coast, and thailand, with high hhv- seroprevalence where ks and malaria are rare and the use of quinine derivatives is low, thus confirming the possible association of these drugs with ks development. in several regions of sub-saharan africa, despite the widespread resistance of plasmodium to quinolines and the availability of more efficacious antimalarial drugs, quinine and its analogues continue to be widely used in the treatment of malaria. in fact, since , african countries have recommended quinine as secondline treatment for uncomplicated malaria, as first-line treatment of severe malaria, and for treatment of malaria in the first trimester of pregnancy. in most of africa, quinine is still used as monotherapy, contrary to recommendations by the world health organization (who). quinine continues to play a significant role in the management of malaria in sub-saharan africa and other malaria endemic areas, and its use in routine practice may not be restricted to the stated who recommendations. in cameroon, quinine has continued to be used as first-line therapy, with % of adults receiving oral quinine for uncomplicated malaria. recent surveillance data from sentinel sites in uganda showed that quinine was prescribed for up to % of children younger than age years with uncomplicated malaria. furthermore, this drug and its analogs are widely distributed to healthy children as preventive treatment (prophylaxis campaigns). the still widespread use of antimalarials might contribute to the high incidence of ks in the geographic areas where both ks and malaria are endemic. in fact, ks and its causative agent, hhv- , have distinctive geographic distributions that are largely unexplained. for this reason, it has been put forward an "oncoweed hypothesis," which suggests that environmental cofactors (such as some plants and natural products deriving from them) present in ks endemic regions may cause frequent reactivation of hhv- in infected subjects, thus leading to increased viral shedding and transmission. , conversely, it has been hypothesized that quinine and its derivatives might better explain the epidemiology of ks than oncoweeds. this oncodrug hypothesis, specifically hints at quinine and its derivatives. in fact, it is worth noting that quinine, chloroquine, and hydroxychloroquine may affect the effectiveness of the immune response, being immunosuppressive drugs. it is well known that chloroquine and hydroxychloroquine are extensively used in the treatment of autoimmune diseases such as lupus erythematosus and rheumatoid arthritis. the immune-suppressive properties of these drugs may produce deleterious effects in the presence of viral infections or immunizations. for example, a randomized controlled trial to evaluate the antibody response of freshman veterinary students to intradermal human diploid-cell rabies vaccine administered concurrently with chloroquine have demonstrated that this drug taken in the dose recommended for malaria prophylaxis can reduce the antibody response to primary immunization with rabies vaccine. incidentally, one could reasonably think that the unusually severe course run by the spanish flu pandemic of - could have been facilitated by the documented large administration of quinine in flu patients, because at the time, quinine was considered the "specific" remedy for fever attacks. quinine is also used to "cut" heroin, which contributes to the widespread use of the drug among heroin addicts. in aids-related ks, drug addicts represent one of the main populations at risk; in these individuals, the use of quinine combined with heroin can pave the way for the onset of ks due to the interrelated anti-inflammatory and immunosuppressive effects of the two drugs. another category of drugs, angiotensin-converting enzyme (ace) inhibitors, have been widely associated with classic and iatrogenic ks onset. several cases reported in the literature would indicate that ace inhibitors might act as a trigger for the development of ks. , in fact, ace inhibitors have immmunomodulatory effects. the immunomodulatory action of ace inhibitors has been attributed to several mechanisms, including: ( ) inhibition of the production of pro-inflammatory cytokines such as tumor necrosis factor (tnf)-α, interleukin (il)- , il- , and il- produced by activated monocytes and dendritic cells, (b) antiproliferative activity, (c) inhibition of free radicals, (d) inhibition of metalloproteases and, (e) elevation of immunomodulatory prostaglandins. suppression of ace itself may explain immune alteration (possible immunosuppression) because ace has been shown to be involved in immune function and to be up-regulated in inflammatory conditions. furthermore, ace inhibition enhances angiogenesis through the activation of the b -receptor pathway. this proangiogenic effect may be associated with the upregulation of endothelial nitric oxide synthase (enos) expression, but would be independent by the vascular endothelial growth factor (vegf) pathway. other studies, however, have confirmed that the same enos up-regulation would be able to stimulate the vegf pathway, or to stimulate angiogenesis through the production of proinflammatory cytokines or activation of cyclooxygenase- . evaluating the role of cofactors in the outbreak of ks is not an easy task. for example, some contradictory data make it difficult to assess the relationship existing between antimalarial drugs and ks (table ) . chloroquine and hydroxychloroquine, quinine analogs, have recently being considered potential anticancer agents as well as chemosensitizer when used in combination with anticancer drugs, such as -fluorouracil in colon cancer cells or topotecan in lung cancer cells, possibly by inhibiting autophagy-dependent resistance to chemotherapy. , autophagy is an evolutionarily conserved cell survival pathway that has been implicated as a potential mechanism of resistance to anticancer agents. in fact, it can promote cell survival in the face of stress induced by chemotherapeutic agents by breaking down cellular components to generate alternative sources of energy. disruption of autophagy with chloroquine induces the accumulation of ubiquitin-conjugated proteins, stimulating apoptosis in several cancer cells. chloroquine and hydroxychloroquine also inhibit angiogenesis and production of proinflammatory cytokines such as il- β, il- , il- , vegf, fibroblast growth factors (fgf)- , tnf-α, transforming growth factor-β and ifn-β. most cytokines are involved in the reactivation of the hhv- lytic cycle and induction of the microenvironment necessary for lesion formation, which is characterized by a triad of inflammation, angiogenesis, and production of cytokines and chemokines. thus, these drugs can counteract the molecular targets by which hhv- is able to cause the disease and indirectly they can inhibit the action of the virus. , even more complex is the evaluation of the direct effects exerted by antimalarial drugs on hhv- . in fact, chloroquine and hydroxychloroquine are lysosomotropic amines, substances that are selectively taken up into lysosomes; owing to their accumulation, these drugs are able to increase the intracellular ph and inhibit ph-dependent steps of duplication of several bacteria (enterobacterium agglomerans, staphylococcus aureus) and replication of viruses including members of the flaviviruses, retroviruses, coronaviruses and herpesviruses through blockade of bacterial and viral entry via inhibition of endosomal acidification. [ ] [ ] [ ] [ ] several studies have shown that the same hhv- entry is blocked by inhibition of acidification of endosomes. also problematic is the role of tnf-α; in fact, this factor seems to play a key role for lytic cycle reactivation of the virus (hhv- itself stimulates tnf-α production) and to create the ideal environment for the genesis of the disease. antimalarial drugs seem able to exert a protective effect by inhibiting the production of tnf-α through inhibition of toll-like receptors; however, some studies have shown the outbreak of ks in patients taking tnf-α blockers such as infliximab; these cases have questioned the role of this factor in the genesis of the disease, especially regarding the role of its production or inhibition in the reactivation of hhv- lytic cycle and, in general, in ks pathogenesis. concerning ace inhibitors, some studies have suggested a protective role played by these drugs as a result of the improvement or regression of ks lesions in patients who were administered ace inhibitors. the matter is controversial because opposite mechanisms of action, protective or inducing, have been alleged (table ) . [ ] [ ] [ ] based on these assessments, it is possible to hypothesize that the role of cofactors in ks pathogenesis can move toward an effect either favoring or inhibiting the onset of the disease depending on the presence of other agents modulating the pathogenesis itself, such as genetic predisposition, environmental factors, drug intake, or lymphatic system disorders. it is possible that the same agents may act as either stimulating or inhibiting cofactors based on the patient's genetic background and their variable interactions. due to the ks heterogeneity, there are no standard therapeutic guidelines and several different therapeutic options are available for ks treatment. treatment decisions must take into consideration the extent and the rate of tumor growth, patient's symptoms, immune system conditions, and concurrent hiv-related complications. the best therapeutic results are obtained in the classic ks with only local treatment. iatrogenic ks usually regresses after withdrawal of the "culprit" drug(s). endemic ks may require a systemic therapy with cytostatic agents, which results in a variable outcome depending on the extent and severity of the disease. epidemic ks prevalence has decreased dramatically since the introduction of highly active anti-retroviral therapy (haart). therapeutic options can be distinguished in two groups: local and systemic therapy. local therapy allows for a safe, cost-effectiveness approach and is reserved for patients with minimal cutaneous disease or for nonresponders to systemic therapy who have rapidly progressive disease, as palliative therapy. intralesional vinblastine, oral etoposide, cryotherapy with liquid nitrogen, and excisional surgery may be feasible options. alitretinoid gel . % ( -cis-retinoic acid) may be applied two to four times daily in the affected areas. the overall response rates (orrs) range between % and % with cutaneous reactions. electrochemotherapy (ect) is an emerging treatment for cutaneous lesions of different tumor types. the combination of chemotherapy and electroporation enhances drug uptake radiotherapy is effective and often represents the best local treatment for palliation of pain, bleeding or edema, with response and complete remission rates of more than % and %, respectively. for patients with far advanced disease a single dose of gy is preferable. systemic therapy haart haart is indispensable in the treatment of epidemic ks in all patients, alone or in combination with systemic chemotherapy and local therapy. some antiretroviral drugs such as foscarnet, ganciclovir, cidofovir, and adefovir are alleged to have anti-hhv- activity. in patients with limited cutaneous lesions (t early-stage disease and/or slowly proliferating disease) an effective haart regimen may represent the first step of therapy for ks, with an orr of % to % and a complete remission rate of %. ks lesions typically start to decrease and disappear completely within a few weeks or months. frequently, ks may flare dramatically following the initiation of haart, which seems to be a manifestation of the immune reconstitution inflammatory syndrome (iris), that occurs in hiv-positive patients with initial low cd counts and an incontrollable viral load. at present, haart alone may represent the firstline therapy for t and t slowly progressive disease. haart with concomitant chemotherapy is indicated for visceral and/or rapidly progressive disease, whereas haart after systemic chemotherapy may be effective as anti-ks therapy after debunking chemotherapy (orr %). , systemic chemotherapy systemic chemotherapy is reserved for patients who do not respond to haart and/or have widespread, symptomatic, rapidly progressive, life-threatening disease with visceral involvement or an iris-associated flare. several single-agent therapies have been reported to be active in aids-related ks (vincristine, vinblastine, vinorelbine, etoposide, teniposide, adriamycin, epirubicine, bleomycin, docetaxel, and paclitaxel), with orrs ranging between % and %, although most were partial responses. liposomal anthracyclines (doxorubicin or daunorubicin) are now considered as first-line therapy for patients with advanced aids-ks. paclitaxel, a cytotoxic agent that exerts its antitumor activity by polymerizing microtubules and inhibiting cell division, is reserved for patients with recurrent or refractory aids-related ks after first-line chemotherapy. intravenous paclitaxel ( mg/m given every weeks as a -hour infusion) is associated with a response rate of % and duration of sustained response of months. high-dose ifn-α allows obtaining complete and partial response rates between % and %, if the cd + count is greater than /mm . current understanding of ks as a convergence of immune evasion, oncogenesis, inflammation, and angiogenesis has prompted investigators to develop a target therapy based on antiangiogenic agents, metalloproteinase, and inhibitors of cytokine signaling. this therapy may be an effective strategy for patients with epidemic ks that progressed despite chemotherapy and/or haart. irinotecan (cpt- ), a semisynthetic camptothecin derivative converted by decarboxylation into a biologically active form sn- ( -ethyl- hydroxycamptothecin), belongs to a recently established class of anticancer agents with a cytotoxic mechanism targeting the cellular enzyme dna topoisomerase i. the model of fibroblast growth factor-β-induced angiogenesis in mouse cornea suggests that irinotecan may be active also in ks. data from a gicat (gruppo italiano cooperativo aids e tumori) phase ii study show that intravenous cpt- ( mg/m day ; mg/m every days) plus haart including protease inhibitors is active and well tolerated in hiv-infected patients with ks relapse or progression during haart. matrix metalloproteinases (mmps), constitutively overexpressed in ks cells, are a family of zinc-dependent endopeptidases involved in the degradation of collagen iv, the major component of basement membranes, that facilitate tumor invasion and metastases. phase ii trial data have shown that mg col- , an mmp inhibitor that blocks in vitro activated neutrophil gelatinase and the expression of mmps in human colon and breast cancer cell lines in a dosedependent manner, administered orally once daily, produces a significant decline in mmps levels. the orr is %, with median duration of response of weeks. thalidomide ( mg/day for months) has been shown to block tnf-α production and to inhibit basement membrane formation and intercellular adhesion molecules. the inhibition of vascular endothelial cell proliferation induced by thalidomide occurs in association with a marked decrease in the activity of the transcription factor sp , which is involved in the extracellular matrix gene expression and moderate inhibition of nuclear factor-κb activation in nuclear extracts. il- , a cytochine that enhances type immunity, can down-regulate a constitutively active g protei-coupled receptor that is encoded by hhv- . according to the preliminary results from a phase i study on the combination of il- plus liposomal doxorubicin and haart, remission was obtained in a substantial percentage of patients with advanced ks. oral imatinib mesylate ( mg twice daily) inhibited activation of the platelet-derived growth factor and c-kit receptors, important targets in mediating the growth of aids-related ks. in the latest decades, the pathogenesis of ks has been greatly elucidated and new etiologic factors have been described, which has facilitated the development of more effective therapeutic approaches. many aspects of ks still remain unsolved, and further studies are needed on the matter. idiopathisches multiples pigmentsarkom der haut geographical and racial differences in the frequency of kaposi's sarcoma as evidence of environmental or genetic causes kaposi's sarcoma in renal allograft recipients association of kaposi's sarcoma with second primary malignancies: possible etiopathogenic implications kaposi's sarcoma in homosexual men-a report of eight cases kaposi's sarcoma among persons with aids: a sexually transmitted infection? kaposi's sarcoma: a natural model of interrelationships between viruses, immunologic responses, genetics, and oncogenesis kaposi's sarcoma: a new model in the search for viruses associated with human malignancies herpes-type virus particles in tissue culture of kaposi's sarcoma from different geographic regions kaposi's sarcoma and its relationship to cytomegalovirus (cmv). iii. cmv dna and cmv early antigens in kaposi's sarcoma identification of herpesviruslike dna sequences in aids-associated kaposi's sarcoma herpesviruslike dna sequences detected in endemic, classic, iatrogenic and epidemic kaposi's sarcoma (ks) biopsies hiv serodiscordant sex partners and the prevalence of human herpesvirus infection among hiv negative men who have sex with men: baseline data from the explore study human herpesvirus epidemiology: what we do and do not know human herpesvirus seroprevalence in blood donors and lymphoma patients from different regions of italy latent class analysis of human herpesvirus assay performance and infection prevalence in sub-saharan africa and malta geographic variation in the prevalence of kaposi sarcoma-associated herpesvirus and risk factors for transmission kaposi's sarcoma revisited evaluation of global clustering patterns and strain variation over an extended orf gene locus from kaposi's sarcoma herpesvirus high-level variability in the orf-k membrane protein gene at the left end of the kaposi's sarcoma-associated herpesvirus genome defines four major virus subtypes and multiple variants or clades in different human populations comparison of genetic variability at multiple loci across the genomes of the major subtypes of kaposi's sarcoma-associated herpesvirus reveals evidence for recombination and for two distinct types of open reading frame k alleles at the right-hand end human herpesvirus in brazilian amerindians: a hyperendemic population with a new subtype sequence analyses of human herpesvirus- strains from both african human immunodeficiency virus-negative and -positive childhood endemic kaposi's sarcoma show a close relationship with strains identified in febrile children and high variation in the k glycoprotein ugandan kaposi's sarcoma-associated herpesvirus phylogeny: evidence for cross-ethnic transmission of viral subtypes hhv a subtype is associated with rapidly evolving classic kaposi's sarcoma genotypic characterization of kaposi's sarcoma-associated herpesvirus in asymptomatic infected subjects from isolated populations human herpesvirus type variants circulating in europe, africa and north america in classic, endemic and epidemic kaposi's sarcoma lesions during pre-aids and aids era molecular epidemiology of human herpesvirus variants in kaposi's sarcoma from iranian patients kaposi's sarcoma: an update kaposi's sarcoma risk among transplant recipients in the united states ( - ) geographic heterogeneity of prevalence of the human herpesvirus in sub-saharan africa: clues about etiology risk of classic kaposi sarcoma with exposures to plants and soils in sicily a common genetic variant in fcgr a-v f and risk of kaposi sarcoma herpesvirus infection and classic kaposi sarcoma kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen induces chromosomal instability through inhibition of p function the p functional circuit tp mutations in human cancers: functional selection and impact on cancer prognosis and outcomes p inhibition by the lana protein of kshv protects against cell death kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor targets mdm to deregulate the p tumor suppressor pathway mdm and human malignancies: expression, clinical pathology, prognostic markers, and implications for chemotherapy regulation of the p protein by the mdm oncoprotein-thirty-eighth g.h.a. clowes memorial award lecture p mutation and mdm amplification in human soft tissue sarcomas a single nucleotide polymorphism in the mdm promoter attenuates the p tumor suppressor pathway and accelerates tumor formation in humans a chromatin-associated and transcriptionally inactive p -mdm complex occurs in mdm snp homozygous cells impact of the mdm snp and p arg pro polymorphism on age of tumour onset in li-fraumeni syndrome the single-nucleotide polymorphism in the mdm gene contributes to the li-fraumeni syndrome and related phenotypes mdm snp accelerates tumor formation in a gender-specific and hormonedependent manner association of a functional polymorphism in the promoter of the mdm gene with risk of nonsmall cell lung cancer association between mdm -snp and age at colorectal cancer diagnosis according to p mutation status mdm and cdkn a gene polymorphisms and risk of kaposi's sarcoma in african and caucasian patients lymphoid disorders associated with hhv- /kshv infection: facts and contentions mutational analysis of tp , pten, pik ca and ctnnb /beta-catenin genes in human herpesvirus -associated primary effusion lymphoma incidence rates of cancer in kyandondo county, uganda, - cancer in kyadondo county, uganda, - cancer in kampala, uganda, in - : changes in incidence in the era of aids review of the distribution of kaposi's sarcoma-associated herpesvirus (kshv) in africa in relation to the incidence of kaposi's sarcoma multifactorial etiology of kaposi' sarcoma: a hypothesis endemic kaposi's sarcoma in africa and local volcanic soils kaposi's sarcoma on a lymphedematous immunocompromised limb linfostasi: importante fattore patogenetico nel sarcoma di kaposi classico anomalies régionales des voies lymphatiques et de la réponse au d.n.c.b. dans le sarcome de kaposi classique penile kaposi's sarcoma preceded by chronic penile lymphoedema acquired immune deficiency syndrome-related hyperkeratotic kaposi's sarcoma with severe lymphoedema: report of five cases kaposi's sarcoma. a lymphologic perspective lymphedema: an immunologically vulnerable site for development of neoplasms kaposi's sarcoma after repeated surgical procedures in an immunocompetent patient: the lymphatic hypothesis kaposi's sarcoma restricted to an immunocompromised district viruses, chemicals and co-carcinogenesis viruses as tumor initiators and tumor promoters prospected etiopathogenic mechanisms of aids-associated tumors viruses and cancer kaposi's sarcoma and its associated herpesvirus nitrite inhalants: history, epidemiology, and possible links to aids mutagenicity of isobutyl nitrite vapor in the ames test and some relevant chemical properties, including the reaction of iso-butyl nitrite with phosphate kaposi's sarcoma: aetiopathogenesis, histology and clinical features kaposi sarcoma: a continuing conundrum who. malaria treatment guidelines treatment of malaria from monotherapy to artemisinin-based combination therapy by health professionals in rural health facilities in southern cameroon umsp sentinel site malaria surveillance report reactivation of kaposi's sarcoma-associated herpesvirus by natural products from kaposi's sarcoma endemic regions kaposi sarcoma and quinine: a potentially overlooked triggering factor in millions of africans re-evaluation of antimalarials in treating rheumatic diseases: re-appreciation and insights into new mechanisms of action antibody response to preexposure human diploid-cell rabies vaccine given concurrently with chloroquine does quinine facilitate aids? possible causal role of lisinopril in a case of kaposi's sarcoma kaposi's sarcoma in a patient with psoriasis vulgaris the non-thiol angiotensin-converting enzyme inhibitor quinapril suppresses inflammatory arthritis nitric oxide synthase modulates angiogenesis in response to tissue ischemia nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis bradykinin stimulates il- and il- production by human lung fibroblasts through erk-and p mapk-dependent mechanisms chloroquine potentiates the anticancer effect of -fluorouracil on colon cancer cells chloroquine enhances the cytotoxicity of topotecan by inhibiting autophagy in lung cancer cells autophagy: cellular and molecular mechanisms the influence of antimalarial treatment on il- beta, il- and tnf-alpha mrna expression on uvb-irradiated skin in systemic lupus erythematosus il- , il- , tnf-alpha and ifn-gamma mrna expression in epidermal keratinocytes of systemic lupus erythematosus skin lesions recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the st century quinine sulfate inhibits invasion of some bacterial skin pathogens antiviral effects of quinine sulfate on hsv- hacat cells infected: analysis of the molecular mechanisms involved quinine sulfate and hsv replication kaposi's sarcoma-associated herpesvirus (human herpesvirus ) infection of human fibroblast cells occurs through endocytosis implication of tnf receptor-i-mediated extracellular signal-regulated kinases and (erk / ) activation in growth of aids-associated kaposi's sarcoma cells: a possible role of a novel death domain protein madd in tnf-alpha-induced erk / activation in kaposi's sarcoma cells kaposi's sarcoma in a psoriatic arthritis patient treated with infliximab inhibition of angiogenesis in kaposi's sarcoma by captopril immunosuppressive action of captopril blocked by prostaglandin synthetase inhibitor tissue inhibition of angiotensin-converting enzyme activity stimulates angiogenesis in vivo angiotensin converting enzyme inhibitors suppress production of tumor necrosis factor-alpha in vitro and in vivo electrochemotherapy in the treatment of kaposi sarcoma cutaneous lesions: a two-center prospective phase ii trial radiotherapy in the management of kaposi's sarcoma aids-related malignancies: state of the art and therapeutic challenges recrudescent kaposi's sarcoma after initiation of haart: a manifestation of immune reconstitution syndrome use of liposomal anthracyclines in kaposi's sarcoma evidence of activity of irinotecan in patients with advanced aidsrelated kaposi's sarcoma randomized phase ii trial of matrix metalloproteinase inhibitor col- in aids-related kaposi's sarcoma: an aids malignancy consortium study activity of thalidomide in aids-related kaposi's sarcoma treatment of aids-related kaposi's sarcoma with interleukin- : rationale and preliminary evidence of clinical activity imatinib-induced regression of aids-related kaposi's sarcoma key: cord- -hs ntlok authors: atlan, h.; gersten, m. j.; salk, p. l.; salk, j. title: mechanisms of autoimmunity and aids: prospects for therapeutic intervention date: - - journal: research in immunology doi: . /s - ( ) - sha: doc_id: cord_uid: hs ntlok summary the network theory of autoimmunity is presented with recent experimental data relevant to the understanding of the pathogenesis of aids. schematically, effector t cells specific for self-antigens exist normally, but their activity is modulated and prevented by networks of regulatory t cells. as a result of mimicry between molecular components of microorganisms and self-antigens, autoimmune disease can be triggered by specific foreign pathogens which alter the state of activity of the network from suppression to activation. conversely, by a procedure known as t-cell vaccination, autologous effector t cells re-injected after in vitro stimulation and attenuation may alter the state of the network from an activation to a suppression. numerous observations are reviewed that support the concept of autoimmune activity in the destruction of non-infected t cells. such activity is presumed to be triggered by an antigen of viral origin, the most likely, but not the only one, being the envelope protein gp . based on this hypothesis, a t-cell vaccination procedure against effector t cells responsible for autoimmunopathic activity in hiv-seropositive patients is proposed, similar to the one known from experimental study of autoimmunity and presently being tested in human autoimmune diseases. its purpose would be to prevent t-cell loss and the onset of immunodeficiency disease in hiv-seropositive patients. apart from its potential therapeutic value, this procedure will have use as a therapeutic test from which insight will be gained about the immunopathogenesis of aids. in previous communications (atlan, ; atlan et al., ) , we have suggested that t-cell vaccination may be applied.to hiv-seropositive patients in order to prevent the development of aids. t-cell vaccination is a well-documented procedure designed as a specific cellular im- submitted december , , accepted february , (*) to whom correspondence should be sent. present address: service de biophysique, hbpital de i'hdtel dieu, place du parvis de notre dame, paris, france, munotherapy against autoimmunity (cohen, a) . t-cell vaccination has been effective in a number of experimental autoimmune diseases, and is presently being tested in humans affected by multiple sclerosis (hafler et al., ; zhang et al., ) and rheumatoid arthritis (van laar et al., ) with no toxic effects and encouraging preliminary results. several lines of evidence suggest that development of the acquired immunodeficiency syndrome (aids) in individuals infected with the human immunodeficiency virus (hiv) does not result solely from direct cytopathic effects of the virus (shearer, ; ziegler and stites, ; klatzmann and montagnier, ; klatzmann and gluckman, ; procaccia et al., ; ascher and sheppard, ; isaksson et al., ; kaplan et al., ; kopelman and zolla-pazner, ; schattner, ; martinez-a. et al., ; bacchetti and moss, ; duesberg, ; schnittman et al., ; ascher and sheppard, ; hoffman et al., ; maddox, ; hsia and spector, ; morrow ec al., ) . it is true that more sensitive pcr techniques have shown that the proportion of cd + t lymphocytes latently infected with hiv is much higher than originally thought, even during the clinical latency period (embretson et al., ) . however, the presence of viral dna in the genome of the cells is not lethal in itself in the absence of activation. therefore, the question remains open concerning the immunopathology of aids. the long and variable interval between infection with hiv and development of immunodeficiency disease (klatzmann and gluckman, ; isaksson et al., ; kaplan et al., ; bachetti and moss, ) , clinical and pathological similarities with known autoimmune disorders (procaccia et al., ; kopelman and zolla-pazner, ; eat = experimental autoimmune thyroiditis. i aa = adjuvant arthritis. aids = acquired immune deficiency syndrome. cm = cell-mediated immunity. cmv = cytomegalovirus. cl-l = cytotoxic t lymphocyte. dth = delayed-type hypersensitivity. eae = autoimmune encephalomyelitis. schattner, ; morrow et al., ) and the observation of genetic correlations with patterns of hiv disease progression (steel et al., ; jeannet et al., ; simmonds et al., ; puppo et al., ; louie et al., ) , all suggest more complex pathological processes involving the immune response of the organism to hiv infection. a number of immunopathic mechanisms with several features of autoimmunity have been proposed as contributing to the development of aids. these include cross-reactive recognition of self-mhc and a secondary antiidiotypic response to cd , to be found in the first large set of references mentioned above, elimination of infected t cells by virus-specific, hlarestricted cytotoxic lymphocytes (shearer, ; zinkernagel, ) , elimination of uninfected t cells by immune responses directed against hiv (klatzmann and gluckman, ; salk, ; lyerly et al., ; lanzavecchia et al., ; lanzavecchia, ; siliciano et al., ; israel-biet et al., ; morrow et al., ) and/or t cell antigens (stricker et al., ; martinez-a. et al., ; kowalski et al., ; zarling et al., ) , unrestricted t-cell activation by hiv-infected macrophages with consequent immune dysregulation and t-cell death sheppard, , ) , superantigen effects of hiv components leading to widespread deletion of t clones (imberti et al., ) , other non-specific immunosuppressive effects mediated by hiv components including gp (weinhold et al., ) and the tat gene product (viscidi et al., ) and inappropriate activation-induced t-cell death (apoptosis) in mature t cells (a process which is normally observed only in immature thymocytes) (ameisen and capron, ; terai et al., ; montagnier et al., ; groux et al., versus-host and host-versus-graft responses to allogeneic class ii mhc antigens, with consequent immune suppression, have also been suggested (shearer, ; klatzmann and gluckman, ; moser et al., ) . on the basis of observed cross-reactivity between mhc and hiv proteins, it has been suggested that hiv envelope antigens induce a chronic autoreactivity similar to graft-versus-host disease (habeshaw et al., ) . more recently, a highly plausible hypothesis on the immunopathology of the development of arc/aids has been proposed (pantaleo et al., ) . this hypothesis is based on the observation that large numbers of human immunodeficiency viruses and of hiv-infected cells are present in the lymphoid organs during the clinical latency period, associated with a progressive dysruption of the follicular dendritic cell (fdc) network in the lymph nodes. it is suggested that during the progression of the disease, most of the hiv-infected cd + t cells are no longer prevented from circulating in the peripheral blood by being destroyed in the lymph nodes, when the fdc network cannot continue to perform its normal functions of trapping and antigen presentation. then, further activation of large numbers of circulating infected cd + t cells would allow for viral replication and cell death responsible for the increased viraemia observed at the late stages of the disease. however, the critical event in this mechanism, namely the destruction of fdc, does not seem to be produced by a direct viral cytopathic effect, but again by an immunopathic response leading to activated cd + cytotoxic t lymphocytes (ctl) infiltrating the lymph node follicles. thus, on the one hand, immune responses to hiv infection might be immunoprotective through destruction of hiv-infected cells and neutralization of free virus. on the other hand, however, some aspects of the immune response might be autoimmunopathic and contribute to the development of immunodeficiency through destruction of both infected and uninfected t cells, and/or of follicular dendritic cells in the lymph nodes. the rate of tccell decline and hiv disease progression might thus reflect, in part, the balance between immunoprotective and autoimmunopathic facets of the anti-hiv immune response. in the present article, the first section will review the relevant experimental and theoretical background on autoimmunity and t-cell vaccination. recent developments in the network theory of autoimmunity (cohen, ; cohen and atlan, ; atlan and hoffer-snyder, ; cohen and young, ; atlan and cohen, ; cohen, a cohen, , b shed light on the nature of various autoimmunopathic mechanisms that might be operative in hiv disease and suggest ways in which such autoimmunopathic processes might be prevented or controlled. according to that theory, for example, molecular mimicry between a strong foreign epitope and a self-antigen may lead to the breaking of tolerance to the self-antigen through perturbation of a pre-existing regulatory network. autoimmunopathic destruction of t cells might thus result, in this case, from the destabilization of a self-tolerance-maintaining regulatory network by immune responses to hiv components with homologies to antigens normally present on t cells. another alternative would be that hiv antigens presented by cd + t cells or follicular dendritic cells would have a similar destabilizing effect by activating helpers and cytotoxic cells against those cells. in section ii, we shall examine existing evidence for autoimmunopathicity in hiv disease and discuss how the concepts developed in section i can be applied to a possible immunotherapy of hiv-seropositive patients. several models of how regulatory networks might be related to autoimmunopathicity in hiv disease and implications with respect to potential modes of intervention will be discussed. in section iii, we shall propose a detailed protocol for a first therapeutic test to be implemented. a general discussion will serve as a conclusion. i. -network theory of autoimmunity contrary to the global theories of the idiotypic network, initiated by the pioneering work of jerne ( ) , the network theory of autoimmunity is a local description of interactions between identified cell populations involved in the occurrence of specific autoimmune diseases (cohen and cohen, a) . according to its main concept, autoimmunity is "natural" (horton, ) and is present in healthy organisms. it is controlled by a network of regulatory t cells (and possibly lymphokines, b cells, antibodies) which prevents normally existing effector cells reactive to a given selfantigen from being activated. the balance between stimulating and suppressive effects depends on the connection structure of the network, i.e. the nature and the strength of the interactions between the network elements. depending on that structure, the network stabilizes in a normal or pathological state, where the effector cells directly responsible for the disease are activated or inactivated, respectively. however, the connections between the elements can be modified by external antigenic stimuli or internal regulatory signals produced by the network's own temporal evolution (atlan and hoffer-snyder, ) . thus, such a network, like neural networks in the central nervous system, is endowed with "cognitive" properties, i.e. self-organizing learning and adaptive capacities (atlan and cohen, ; cohen, a cohen, , b . relevant examples of those mechanisms will be discussed further (in section ii, parts b and ). the network theory of autoimmunity is based on the evidence that effector cells with specificity for self-antigens normally exist in vivo (guilbert et al., ; burns et al., ; cohen and young, ) . such effector cells are either prevented or not from exerting autoimmune effects. this depends on the state of activity of other, regulatory, cell populations, mainly (but not solely) antigen-specific and idiotypic-specific (ben-nun et al., a , holoshitz et al., lider et al., ; lider et al., ; kakimoto et al., ; lohse et al., ; roubaty et al., ) . when this finely tuned regulatory system is appropriately perturbed by the introduction of a foreign antigen, crossreactive with a given self-antigen or interfering with antigen presentation, the ensuing stimuli delivered to the various component cells of the network change the steady state of the network in such a way that expression rather than suppression of autoimmunity occurs. conversely, the regulatory network is enhanced or strengthened with respect to its ability to suppress autoimmunity by exposure to a non-pathogenic form of the relevant effector cells. such enhancement is learned and "memorized" in the structure of the network, so that subsequent exposure either to the pathogenic effector cells or to the potentially immunopathogenie antigen would not produce autoimmunity. this concept is particularly relevant to studies of t-cell vaccination as a prophylactic and therapeutic procedure against autoimmune diseases (ben-nun et al., a; cohen et al., ; cohen, cohen, ,c, a atlan and hoffer-snyder, ; roubaty et al., ; cohen and young, ; elias et al., ; beraud, ; atlan and cohen, ; hafler et al., ) . studies with experimental autoimmune diseases have provided most of the data underlying the network theory of autoimmunity. the best studied model has been experimental autoimmune encephalomyelitis (eae). this disease, characterized by the acute onset of paralysis in genetically susceptible animals following appropriate inductive stimuli, has been shown to be mediated by t effector cells specific for myelin basic protein (mbp) b) . spontaneous recovery may occur and is associated with the appearance of suppressor cells which react specifically with idiotypic determinants present on the anti-mbp t cells (ben-nun and cohen, ; ellerman et al., ) or with antigenic determinants on mbp lb) . these and other observations (lider et al., ; lohse et al., ) have led to the formulation of a model in which the onset, remissions and relapses of eae and other autoimmune diseases can be explained by changes in the interactions among an effector cell and two pairs of regulatory elements: (i) antigen-specific helper and suppressor cells, and (ii) idiotype-specific helper and suppressor cells (cohen and atlan, ) . according to this model, once a state of autoimmunity has resulted from a change in the normal balance among the various elements of a regulatory network, which has previously served to suppress an anti-self response, the autoimmune state may be stable and persist even after the agent which precipitated the change is no longer present. alternatively, if the host response to a foreign antigen induces the de nova formation of a regulatory network leading to autoimmunity, then the continued presence of cross-reactive self-epitopes may perpetuate the autoimmunopathic state of the network even after the precipitating antigen has been cleared. other experimental models of autoimmune disease suggest the existence of further levels of complexity in the regulation of autoimmunity. for example, adjuvant arthritis (aa) is an autoimmune disease which may be experimentally induced by injection of killed mycobacferium tuberculosis, which contains an antigenic protein cross-reactive with a joint cartilage proteoglycan . the disease may also be induced by inoculating cells from an anti-m. tuberculosis t clone which also recognize the proteoglycan (van eden et al., , . more recent investigation into the nature and dynamics of the regulatory network in aa suggests that at least one additional component may be involved karin, ; atlan and cohen, ) . the onset and severity of the autoimmune disease triggered by m. tuberculosis has been correlated with the presence of a population of non-specific cd + suppressor cells which downregulate the antiidiotypic regulatory cells to a greater extent than they do the cytolytic effector cells. according to the proposed network model (atlan and cohen, ) , this results in a net increase in effector activity. this contrasuppressive, pathogenic response is partially non-specific lohse et al., ; karin, ) , being directed not only against the specific antiidiotypic regulatory cells, but also against other anticlonotypic regulatory cells. the latter includes cells which control responses to different epitopes of the self-antigen and others which are involved in the regulation of unrelated autoimmune diseases, such as eae. it is thus conceivable that partially non-specific suppressor cells might exert contrasuppressive effects and facilitate the expression of autoimmunopathic res-ponses in other diseases. in this regard, it is interesting to note that a subpopulation of cd + suppressor cells acting via release of a soluble inhibitory factor has been observed in association with hiv infection (joly et al., ; sadat-sowti et al., ) . the pathogenesis of experimental autoimmune thyroiditis (eat) provides another example of additional network complexity. this disorder, which can be produced experimentally by inoculation of cells from a thyroglobulinspecific cytotoxic t-cell clone, may entail dysfunction of an immune regulatory network containing humoral as well as cellular components (roubaty et al., ) . in this regard, given the homologies that have been described between the hiv envelope glycoprotein (gp ) and immunoglobulins (bjork, ) , it is possible that anti-hiv responses, cross-reactive with selfimmunoglobulins, might non-specifically perturb the humoral arm of a bipartite cellular/humoral regulatory system and thereby contribute to the immunopathogenesis of aids. although the detailed mechanisms of network regulation of autoimmunity may be more complicated than presently understood, an appreciation of the dynamic aspect of regulatory networks is useful when considering means to perturb the system intentionally so as to strengthen or to restore the development of a nonimmunopathic state. network models suggest that vaccination with autoimmune effector cells (in a form or under conditions in which the cells are not capable of exerting pathogenic effects) should elicit antiidiotypic and other regulatory cells which might suppress an autoimmune effector cell response, thereby preventing or ameliorating autoimmune disease. an example of such a model is shown in figure , where a network of effector cells and five populations of regulatory cells account for complicated and paradoxical data on aa (atlan and cohen, ) . this example is particularly relevant since it involves the participation of a foreign pathogen (m. tuberculosis) working as an adjuvant in the triggering of autoimmunity. in the framework of the proposed hypothesis on aids, the role of hiv could be similar -as will be detailed below. h. atlan et al. (atlan and cohen, ) . full and dotted arrows represent activating and suppressive connections, respectively. higher doses of m. tuberculosis (mt) -a foreign pathogen working as an adjuvant in the onset of aa, probably because of mimicry with the self-antigen -produce more severe forms of the disease. t-cell vaccination with attenuated effector cells prevents the onset of the disease. experimental observations on the state of activity of the different cell populations under different conditions (healthy, diseased, vaccinated) are accounted for by the steady states of the network computed as functions of the connections. t-cell vaccination works as a learning process of the network, following given laws which modify the connections in such a way that further exposure to pathogenic doses of mt do not produce a diseased state (cohen and atlan, ; atlan and hoffer-snyder, ; atlan and cohen, ). this concept is consistent with the results of studies using t-cell vaccination in a number of experimental autoimmune diseases. vaccination with subpathogenic doses of effector t cells, or with large numbers of effecters attenuated by irradiation or treatment with glutaraldehyde, mitomycin c, hydrostatic pressure or other agents (cohen, (cohen, , a lider et al., ) , has been shown to elicit antiidiotypic (lider et al., (lider et al., , roubaty et al., ; elias et al., ) and/or antiergotypic (lohse et al., ; beraud, ) suppressor cells and to be effective in preventing and/or treating eae (ben-nun et al., a; lider et al., ; lohse et al., ) , aa (holoshitz et al., ; lider et al., ; , eat (roubaty et al., l!m) , collagen-ii-induced arthritis (kakimoto et al., ) , spontaneous autoimmune diabetes (elias et al., ) and experimental autoimmune uveitis (beraud, ) . in humans, clinical trials have been initiated to explore the use of t-cell vaccination for the treatment of some autoimmune diseases with no evidence of toxicity (hafler et al., ; zhang et al., ; van laar et al., ) . in patients treated for multiple sclerosis, it is still too early to make any assessment on possible clinical improvement, because of the slow evolution of the disease. however, as expected from abovementioned previous animal studies on eae (lider et al., ; lohse et al., ) , an antiidiotypic response has been observed after t-cell vaccination with myelin basic proteinspecific t-cell clones (zhang et al., ) . a similar procedure was achieved by a different group (van laar et al., ) on patients suffering from rheumatoid arthritis with variable disease duration. on average, a slight decrease in disease activity was observed, with an indication of a clearer improvement in patients with recent onset of the disease. in view of the foregoing, the first question to be asked concerning a given autoimmunopathic mechanism is the nature of the selfantigen involved. a given self-antigen must be identified as the target for autologous ctl and/or autoantibodies. then, the vaccination procedure will be aimed at strengthening deficient regulatory responses capable of suppressing the activity of those ctl, or antibodies. it has previously been suggested that the immunosuppression observed in aids might be in part attributed to an hiv-triggered immunopathic response directed against uninfected as well as infected t cells (kiatzmann and montagnier, ; klatzmann and gluckman, ; salk, ; lyerly et al., ; lanzavecchia et al., ; siliciano et al., ; lanzavecchia, ; israel-biet et al., ) . in that case, the antigen must be looked for in the membrane of cd + t cells themselves. however, as mentioned above, another alternative would be to consider the lymph node fdc as the target for cd + ctl activated by the hiv infection. in view of existing experimental evidence, we shall consider the implications of the two possible targets for autoimmunopathic responses -cd + t cells and fdc -as far as the identification of the antigen and regulatory network is concerned. from an autoimmunity viewpoint, the simplest assumption would be that the cd molecule itself is the self-antigen. however, viral molecules interacting with cd must be involved to trigger the immunopathicity against cd + t cells. therefore, the hypothesis of cd + t cells being the targets of immunopathic responses must be divided into two possible models, for which supporting data from the literature will be reviewed. in the first model, a viral antigen -the most likely being the envelope glycoprotein gp -is directly involved and plays the role of a "self''-antigen after it has been incorporated into the cd + t-cell membrane. in the second model, a true self-antigen, pre-existing in that membrane, is activated by hiv infection. a) the gp antigen model according to this view, autoimmunopathic destruction may occur as a result of anti-gp effecters killing both infected t cells expressing gp among other viral antigens on their membrane, and uninfected t cells which have bound free gp ( fig. a ). that such gp binding is likely to occur is supported by the high degree of gp shedding after infectious viruses are released (gelderblom et al., ; schneider et al., ) and by the detection of gp in sera of hiv-seropositive individuals (oh et al., ) . free gp bound by the cd molecule might well be internalized and, depending upon the route of metabolism, reexpressed in association with class i (making it a target for classical cd + cytotoxic t cells) or class ii mhc molecules. hoffenbach et al. ( ) detected mhc-restricted anti-env cd + cytotoxic lymphocytes in both seropositive and seronegative donors. since the frequency of these cells declined in seropositives with clinical deterioration, the authors hypothesized that this response was primarily immunoprotective. however, they also noted that these env-specific cytotoxic cells might be capable of causing autoimmunopathic t cell destruction through the mediation of bound env or molecular mimicry. siliciano et al. ( ) were able to precisely demonstrate such a potentially autoimmunopathic effect. they detected anti-gp cytotoxic cd + lymphocytes in normal seronegative individuals which could kill, in an antigen-specific, mhc-restricted manner, uninfected activated autologous t cells pulsed with gp . the presence of anti-gp cytotoxic cells in sufficient frequency would be expected, according to the network theory, to induce the formation of a network which would regulate the activity of these effector cells. given the persistence of hiv infection, and therefore the continued presence of hiv antigen, we postulate that the regulatory network established would be configured so as to favour stimulation of the antigp response. from the viewpoint of autoimmunity, however, such a network would be ineffective, insofar as it would fail to restrain the effecters of autoimmunopathic destruction. thus, in this model, autoimmunopathicity in aids would result from (i) gp bound to uninfected t cells coupled with (ii) a regulatory network configured to stimulate, rather than suppress, the anti-gp autoimmune effecters. the significance of the autoimmunopathicity would depend upon the relative balance between the protective aspect of the response (destruction of infected t cells and consequent reduction in viral proliferation) and the immunopathic aspect of the response (destruction of normal t cells and consequent reduction of residual immunological potential). b) the t -cell membrane self-antigen model the second model is more closely analogous to classical experimental autoimmune disorders. several findings suggest that one (or more) selfantigen might be normally present on the cd + cell membrane and that pre-existing suppressed ctl against that antigen would be activated by hiv infection. for example, zarling et al. ( ) have found such ctl in the blood of hivseropositive patients (and not of hiv-infected chimpanzees), capable of killing uninfected cd + cells from both hiv-seropositive patients and seronegative controls. israel-biet et al. ( ) have found cd + cells in hiv-infected patients able to kill allogeneic ebv-transformed b cells and cd + cell blasts from seropositive and from seronegative subjects. hoffenbach et al. ( ) and plata ( ) have observed an unusually high frequency of ctl precursors primed to hiv antigens -and not to other viruses -in the repertoire of normal humans in the absence of hiv infection. as in other instances of autoimmunity triggered by foreign pathogens (van eden et al., , morrow et al., ; karin, ; cohen and young, ; horton, ) , the triggering of a true autoimmune response by an hiv antigen could imply some mimicry between that antigen and the pre-existing self-antigen. class ii mhc antigen has been suggested as being the postulated self-antigen (hoffman et al., ) . however, in that case, one might expect aids to be characterized by a significant depletion of b cells and antigen-presenting cells, the primary expressors of mhc class ii antigen, rather than, or in addition to, t cell depletion. rather, one might hypothesize that t cells carry an additional unique marker which is crossreactive with gp (perhaps structurally or physiologically associated with cd on the t cell membrane), either directly or by complexing with mhc molecules. the detection by both hoffenbach et al. ( ) and siliciano et al. ( ) of anti-env specificities in cytotoxic lymphocytes of seronegative individuals might be postulated to be due to the existence of such a cross-reactive self-antigen. the inability of siliciano et al. ( ) to detect killing by such cells of uninfected autologous t cells not pulsed with gp might be related to a subthreshold level of surface expression of the self-antigen (marker) under the ambient conditions of the assay. in summary, according to the t cell membrane self-antigen model ( fig. b ), effecters specific for this putative cross-reactive selfantigen exist prior to hiv infection; but they are inactive, owing to a dominant suppressive effect exerted by a pre-existing regulatory network. this phenomenon would be similar e.g. to what is observed in experimental aa (van eden et al., , atlan and cohen, ) , where a foreign bacterial antigen in the adjuvant (from m. tuberculosis) is cross-reactive with a joint cartilage self-antigen. the bacterial antigen serves as a strong antigenic stimulus to a pre-existing regulatory network, quantitatively related to the amount injected. in the absence of adjuvant stimulation, the network is normally in a suppressive state, preventing the activity of cytotoxic effector cells against the joint cartilage. similarly, in our tqcell self-antigen model, the pre-existing regulatory network would be destabilized by the strong antigenic stimulation produced by the introduction of (foreign) gp . as a result, the network would be driven to a new steady state characterized by activated effector cells able to destroy (in viva) uninfected marker-bearing t cells, independent of the presence of bound and reexpressed gp . early in the course of hiv infection, these activated cytotoxic cells are still subject to some network regulation by the suppressor cells. therefore, only a mild form of autoimmune disease, typified by a moderate degree of killing of t cells, occurs. with time, however, the network moves into a more pathological state in which the suppressor cell activity is itself suppressed or insufficient. as in other instances of pathological autoimmunity, the progression of the disease may be explained by several mechanisms. for example, after the onset of an active state against the antigen, a progressive increase in the efficiency and diversification of antigen presentation may produce a reinforcement of the antigenic stimulus. such processes of alterations in self-antigen presentation, leading e.g. to the display of previously cryptic self-determinants (lehmann et al., ) , may explain the time course of autoimmune diseases, including virus-induced progressive states of autoimmunity, such as chronic active hepatitis (ohtani et al., ) and eaelike lesions induced with coronavirus (watanabe et al., ) . a "vicious circle of cytokine-driven upregulation of autoantigen presentation" (lehmann et al., ) may be produced by crossreactivity with viral antigens, but may also occur in the absence of cross-reactivity, leading to "ongoing t-cell stimulation, further t-cell recruitment and determinant spreading, greater cytokine production, and so forth". this process can be accelerated as intercurrent infectious and non-infectious stresses contribute to an increase in virus and viral antigen production, leading to a heightened activation of the effector and helper regulatory cells. particular intercurrent infections could also precipitate an increase in contrasuppression, as in aa, where the level of contrasuppressor activity varied directly with the dose of adjuvant mycobacterium administered (karin, ; atlan and cohen, ) . such a mechanism could contribute to the observation that certain opportunistic infections appear to accelerate the clinical progression of hiv/aids. in any case, as mentioned above, as far as the connection structure of the regulatory network is concerned, this kind of vicious circle would amount to a reinforcement mechanism of learning and distributed memory, well-known in neural network modeling (weisbuch, ; atlan and hoffer-snyder, ; atlan and cohen, ) . as a result, the earlier disease-free state of the network is destabilized and the network evolves towards more and more activating pathogenic states. c) common features of the two models; t-cell vaccination against anti-gpl ctl as a therapeu tic test in both models (sections la and lb), humoral participation in the onset of hiv-triggered autoimmunopathic response is possible, as in eat. this might be mediated, for example, through the reported homology between a gp epitope and immunoglobulins (bjork, ) , as well as cell surface proteins with a role in cd binding (beretta et al., ; golding et al., ; young, ) , which might result in the perturbation of a possible t-cell/b-cell regulatory network. in any case, the search for anticlonotypic cell populations being activated, and for increased concentrations of different antibodies and cytokines in response to the cell clone or line being used in the vaccination procedure, will in itself provide useful information on the nature of the antigen and the regulatory network. the different reinforcement mechanisms discussed in lb may also be operative in the model of section la since, as mentioned above, they can be triggered after the first immunopathic response has been induced even in the absence of cross-reactivity between pre-existing selfdeterminants and viral antigens. increased efficiency in gp antigen presentation by specific binding to cd and direct processing by cd + t cells has been reported by lanzavecchia et al. ( lanzavecchia et al. ( , . these authors have found that cd + cells can capture soluble gp and present it to gpl -specific mhc class-iirestricted clones. as in other well-established autoimmune disorders, an association between hla haplotype and disease incidence has been reported for development of arc/aids (steel et al., ; jeannet et al., ; simmonds et al., ; puppo et al., ; louie et al., ) . such an association would be consistent with either model for the development of autoimmunopathic disease consequent to hiv infection. however, as in other instances of autoimmunity triggered or facilitated by foreign pathogens, the observation of similar syndromes and cellular lesions occurring in the absence of viral infection -idiopathic cd + t-lymphocytopenia or "immunodeficiency without virus" (fauci, ; smith et al., ; ho et al., ) -on a small number of patients with genetic predisposition would be more strongly in favour of the second model. in theory, the two models, although not mutually exclusive, differ significantly in the prospects for "cure" through the therapeutic elimination of virus. in the first case, complete elimination of virus would also remove the source of the "simulated self-antigen", i.e. gp bound to t cells, and autoimmune destruction of t cells would be abrogated. in the second case, however, removal of the inciting cross-reactive foreign antigen, gp , would not necessarily result in a return of the immunoregulatory network to a predominantly suppressive mode. the new steady state of autoimmunity might be a stable state, sustained by the continued presence of bona fide tcspecific self-antigen. in practical terms, however, the possibility of completely eradicating an established hiv infection is unlikely, at least in the forseeable future. therefore, regardless of which model may prove to be correct, it would be useful to explore adjunctive interventions aimed specifically at controlling the autoimmunopathic destruction of t cells. in either case, t-cell vaccination using autologous cloned anti-gp cytotoxic cells would be expected to enhance (or induce) the antiidiotypic and other regulatory cells of the network, which would act to downregulate the activity of the anti-gp /anti-self cytotoxic cells. this should occur whether or not the viral infection is concurrently controlled or eliminated, because the focus of intervention is the autoimmunopathic destruction which occurs as a result of the host response to infection, rather than the virocytopathic destruction which occurs as a result of infection per se. an associated reduction in viral burden by independent means, however, would be expected to synergize in limiting autoimmunopathic destruction by reducing antigenic stimulation to the autoimmunopathic effector cell. to the extent that the autoimmunopathic destruction of t cells is a major factor in the development of hiv-associated disease, such t-cell vaccination should serve to enable the hivinfected host to live with, integrate and compensate for the perturbations induced by a persistent viral infection. under these conditions, hiv infection might be expected to come to resemble infection with other persistent viruses, such as ebv, cmv and hsv, which are relatively innocuous in most cases. in addition, from the response to the proposed intervention, it will be possible to test the validity of the hypothesis and to expand it, for example, by looking for in vivo activation of anti-antigp suppressor cells and for their tcr specificities. considering the above-mentioned observations on the progressive destruction of fdc (follicular dendritic cells) by ct + cytotoxic cells during the latency period (pantaleo et al., ) , we are still facing a tissular anti-self immune response. again, the question is raised as to the nature of the antigen which transforms fdc into targets for cd + ctl. in view of the observed concomitant accumulation of viruses in the lymph nodes, it is reasonable to assume that cd + ctl might be activated by the large numbers of viral antigens presented by fdc. in addition, the antigen presentation function of fdc in the microenvironment of lymphoid organs may be favorable to the onset of a vicious circle or reinforcement of antigen presentation (atlan and hoffer-snyder, ; atlan and cohen, ; lehmann et al., ) , whereby the strength of activation against various antigenic determinants increases continuously, as discussed above. however, contrary to the tccell target models, there is no direct documented experimental indication of possible specific mechanisms responsible for the activation of cd + ctl against fdc. therefore, since we do not want to produce an overall suppression of antiviral cellular response, these cd + anti-fdc cytotoxic cells should be first characterized by some antigen specificity before a t-cell vaccination procedure against those cells can be tested. in the meantime, the proposed procedure described in the following section might also turn out to be effective in the context of the fdc target model. that would be the case to the extent that anti-gp ctl might participate in immunopathic responses involving fdc, as well as in the direct destruction of cd + t cells discussed above (sections i and ii/l). in view of the foregoing considerations, we propose that t-cell vaccination be explored first as a strategy for reducing direct autoimmunopathic tccell destruction in hiv infection. the t-cell vaccination technique (cohen, a) would consist of reinjecting cloned autologous effector cytotoxic cells after in vitro activation and either irradiation or treatment with a crosslinking agent (such as glutaraldehyde) to prevent proliferation. thus, although the effector cells are presented to the regulatory network in an immunologically active form, they are both autologous and non-proliferative, hence not pathogenic. reinjection of these cells is intended to launch the network into a new stable state where the regulatory suppressor cells are strongly activated. the resulting change in connectivity of the network would suppress the development of active, pathogenic, effector or helper cells, and thereby suppress autoimmunopathicity. the key to the success of such an approach is identification of the responsible effector cell. as dis-cussed earlier, the working hypothesis is that cytotoxic effecters with specificity for gp are responsible for the immunopathic destruction of uninfected t cells that culminates in aids. however, it is still possible that autoimmunopathic destruction of t cells could be mediated by cytotoxic effecters with specificities directed against hiv antigens other than gp , against cellular antigens which are crossreactive with hiv antigens other than gp , or against cellular antigens which are not crossreactive with hiv (e.g. new cd epitopes exposed as a result of binding with gp (stricker et al., ; kowalski et al., ) ). the effects of t-cell vaccination with anti-gp cytotoxic effecters will be assessed by looking for desired induced modifications of the regulatory network, in the form of in vivo activation of anti-anti-gp suppressor cells and antibodies. qualitative and quantitative assessment of such responses will determine whether or not it is useful to pursue studies using effecters with other specificities. in the flow chart presented in table i, we outline a first protocol currently under development. we propose that studies be initiated in a small group of hiv seropositives with comparable viral burdens who have recently begun to manifest a decline in t cells. to facilitate the subsequent analysis, it will be preferable to study subjects who have been followed with serial t counts for at least months, whose t level is above , and who, at study entry, demonstrate a significantly negative t -cell slope. thus, a possible therapeutic effect could be subsequently assessed by looking for a slowdown of that slope. cell-mediated immune responsiveness will be assessed by standard skin test for delayed-type hypersensitivity (dth), since a correlation has been observed between favourable clinical history of hiv-seropositive patients and high dth response . the post-vaccination follow-up might indicate that dth response could be used as a criterion for future patient selection. peripheral blood t lymphocytes will be plated in limiting dilution with irradiated autologous antigen-presenting cells and gpl . cloning will be performed at the outset to permit calculation table i effectiveness of vaccination ; therapeutic efficacy (*) it is planned to prepare autologous ebv-transformed b cells into which are introduced the gene for gp or cd . this would provide a permanent source of stimulator and target cells for ctl generation and testing, as well as for growth expansion. (**) cd antigenicity should also be tested, since anti-cd ctl could also be activated through interactions of cd with molecules different from gp . of precursor frequencies prior to therapeutic intervention. responding hiv-uninfected clones will be expanded in vitro and then tested for antigen specificity, cytotoxicity, mhc restriction and cd / phenotype. we suggest that t-cell receptor (tcr) gene usage also be explored, since use of a restricted number of vp genes might permit the future development of a non-autologous and therefore generally applicable preparation (cohen, a) . this technique has been used successfully in some instances of experimental autoimmunity (howell et al., ; vandenbark et al., ; offner et al., ) . in eae (owhashi et al., ) and eat (texier et al., ) , monoclonal antibodies against tcr of antigen-specific effector t-cells produced a protective effect similar to that induced by vaccination against the effector cells themselves. moreover, in eae, tcr specific for the encephalitogenic determinant of mbp use similar va and v chains in two different species, although the m i-! c and antigenic determinants are different (burns el al., ) . similarly, in our case, a characterization of conserved tcr structures could dispense the technique with the need for cumbersome autologous preparations on a patient per patient basis. initially, however, autologous antigenspecific cytotoxic clones will be expanded and activated in vitro, followed by irradiation or treatment with a cross-linking agent, prior to reinoculation into the donor. it is anticipated that the effectiveness of vaccination may be evaluated by serial measurements of(i) dth responsiveness, (ii) the amlr (autologous mixed lymphocyte reaction) against the injected t-cell clone, (iii) levels of circulating t cells with idiotypic specifications identical to injected cells (anti-gp ), and (iv) levels of antiidiotypic and antiergotypic t-cell responses (anti-anti-gp ). on the other hand, measures of therapeutic efficacy would be monitored by following peripheral blood t cell counts (both absolute and as a percent of total t cells) and clinical indicators of disease progression. measures of static virus burden (hiv-dna pcr) and active virus burden (glycine-dissociated p antigen, hiv-rna pcr) might be included to monitor for secondary effects on virus clearance. the major thrust of aids research has been identification of the responsible virus and elucidation of its biology,. in the hope of discovering means by which the virus might be successfully controlled or eliminated. the underlying rationale has been that the virus, hiv, directly causes the disease syndrome known as aids. therefore, most strategies for vaccination have been based on the production of neutralizing antiviral antibodies. however, several lines of evidence indicate that antiviral antibody production could be counterproductive in favouring viral infection by preventing efficient cell-mediated immunity. this suspicion is based on ( ) the known antagonism between humoral and cellular response and ( ) the observed mimicry between hiv protein gp and immunoglobulins as well as self-epitopes in other components of the immune system (beretta el al., ; golding et al., ; young, ; bjork, ) which may enable the virus to escape a strong host-immune response (sastry and arlinghaus, ) . that is why an alternative strategy was proposed to develop anti-hiv vaccine that would elicit strong cell-mediated immunity (cmi) by virus-specific ctl in the absence of neutralizing antibody production (sastry and arlinghaus, ; shearer and clerici, ; salk et al., ) . however, as discussed earlier, it has become apparent that several aspects of hiv infection are difficult to reconcile with the notion that the virus itself is the sole direct and proximal cause of disease. moreover, some of the viral stimulation of ctl activity itself, in as much as it does not succeed in completely eradicating viral infection, may be maintained and diverted as a factor of autoimmunity directed against cd + t cells, both infected and non-infected, as well as against fdc in lymphoid organs. in other words, an autoimmunopathic disorder precipitated by hiv infection may be an important proximal cause of hiv-related disease. therefore, in parallel with a vaccine strategy aimed at developing early cm to prevent chronic hiv infection and conversion to seropositivity, a therapeutic-prophylactic strategy against these autoimmunopathic disorders is necessary for hiv-infected seropositive patients. the thesis presented above is that a major cause of the development of hiv-related disease is the destruction of t cells by anti-gp cytotoxic lymphocytes. experimental testing of this thesis is proposed because such cytotoxic lymphocytes have been detected in both seropositive and seronegative individuals. they are postulated to kill via gp on the surface of uninfected, as well as infected t cells, and also perhaps via a tcspecific self-antigen which is cross-reactive with gp . discussed within the context of network theory, this becomes a testable hypothesis, since t-cell vaccination with autologous anti-gp cytotoxic lymphocytes is expected to specifically abrogate the activity of such immunopathic effector cells. the success of such an approach will depend both upon the relative importance of immunoprotective as compared to autoimmunopathic effects of anti-gp effector cells and upon the existence of immunoprotective factors with specificities for other hiv antigens such as p and p . in addition, such direct cytotoxicity of anti-gp ctl against cd + t cells is certainly not the only possible autoimmunopathic effect which could be triggered by hiv infection. as discussed in the introduction and in section ii ( ), one might consider that fdc, rather than or in addition to t cells, could be the target of autoimmune mechanisms triggered by hiv infection. in other words, cytotoxic cd + cell activity against fdc would be triggered by hiv antigens and would be responsible for the observed destruction of the lymph node reticulum, leading to increased viraemia and tccell loss. if such putative anti-fdc-specific effector cells could be identified in seropositive patients and expanded in vitro, a t-cell vaccination procedure against those cells could be designed and attempted. in any case, a significant consequence of viewing aids in this manner is that it shifts the focus of emphasis from hiv alone to hiv in the context of the particular immune system into which it is introduced. the discovery of new facts and observations has rendered inadequate the classical clonal selection concept of a simple cause-and-effect relationship between exposure to a foreign antigen and the production of specific antibodies against that antigen. rather than a mere system of defence against foreign invaders, the immune system appears today as a complex dynamic network of interacting elements -effector cells, antigen-presenting cells and various regulatory cells -all modulated by genetic factors, cytokines and mutual recognition units. in particular, recent studies on autoimmunity (see e.g., in addition to the above mentioned, pereira et al., ; coutinho and bandeira, ; cohen, b) ) have shown that immune responses at the molecular and cellular level are normally triggered by selfconstituents (self-antigens, mhc molecules, idiotypes etc.), at least as much as by molecules or cells coming from the outer world. thus, as discussed elsewhere (atlan and cohen, a, b) , "problems of complexity, generation of diversity and self-organization have entered the field of immunology" and the immune system has emerged "as an evolving computing network or self-organizing entity -a non-programmed history of encounters with partially random internal and external antigenic stimuli is constantly integrated and serves to modulate and specify the more general initial genetic determinations". this shift in emphasis means that one must focus on the complex interactions between hiv as an incoming stimulus and the immune system as a pre-existing functional network similar to the nervous and neuro-endocrine systems, in a constant process of self-organization. whereas reduction of viral burden by an appropriate combination of chemotherapy, active immunization and passive administration of hyperimmune globulin may be useful and should be pursued, such measures may not be sufficient, and an autoimmunopathic component of the disease may need to be addressed independently. to this end, the goal of therapeutic intervention would be to help the immune system reorganize itself and retain or regain a functional state capable, if need be, of coexisting indefinitely with a persistent viral infection. such a goal is reminiscent of the use of bcg vaccination against tuberculosis in the pre-antibiotic era. drawing on the accumulated insights from other, better understood autoimmune disorders, it has been proposed that t-cell vaccination be investigated in hiv-infected individuals as a means to strengthen the host's immune regulatory network and its consequent control of autoimmunopathicity. its specific implementation has the advantage of not requiring a detailed understanding of mechanisms in order to be effective, since it emerges from the natural history of hiv/aids considered in the light of other autoimmune disorders precipitated by microorganisms. in fact, from the results of its application, it may be possible to learn more about the dynamics of the human immune system exposed to hiv. a more in-depth understanding of these dynamics, coupled with a precise identification of the specificity of the autoimmunopathic effector t-cell clones (by assessment of their tcr variable gene usage), should contribute much to the development of an effective therapeutic and potentially prophylactic vaccine against hivrelated disease. as discussed above, such a t-cell receptor vaccine would be more easily and broadly vaccine basis. applicable than the autologous t-cell implemented on a patient-by-patient par un antigene d'origine virale, le plus probable, mais non le seul, &ant la proteine d'enveloppe gp . sur la base de cette hypothese, les auteurs proposent d'appliquer une procedure de vaccination par cellules t contre des celhrles effectrices responsables d'une activite autoimmune pathologique chez des sujets seropositifs pour le vih. cette procedure est semblable a celle mise au point chez i'animal sur des modtles experimentaux d'autoimmunitt, actuellement testee chez l'homme sur des maladies autoimmunes. le but recherche est d'empkher la destruction de cellules t et l'installation de deficience immunitaire chez des sujets seropositifs pour le vih. mais en dehors de son efficacite cventuelle, cette procedure presente l'avantage d'un test therapeutique d'oh l'on est en droit d'attendre de nouvelles informations sur la pathologie immunitaire du sida. mats-cl&s: sida, autoimmunitt, lymphocyte t, immunotherapie; reseaux, vaccination par cellules t, immunopathogenese; revue. ceil dysfunction and depletion in aids: the programmed cell death hypothesis aids as immune system activation: a model for pathogenesis. c/in aids as immune system activation. -ii. the panergic amnesia hypothesis t cell vaccination of hiv-seropositives : a therapeutic test for the autoimmune component of aids preface, in "theories of immune networks introduction to immune networks paradoxical effects of suppressor t cells in the onset of adjuvant arthritis: neural network analysis can aids be prevented by t-cell vaccination? immunol simulation of the immune cellular response by small neural networks, in "theories of immune networks incubation period of aids in san francisco vaccination against autoimmune encephalitis with t-lymphocyte lines reactive against myelin basic protein the rapid isolation of clonable antigen-specific t lymphocyte lines capable of mediating autoimmune encephalomyelitis spontaneous remission and acquired resistance to autoimmune encephalomyelitis (eae) are associated with suppression of t-cell reactivity: suppressed eae effector t cells recovered as t-cell lines t-cell vaccination in autoimmune diseases hiv env glycoprotein shares a cross-reacting epitope with a surface protein present on activated human monocytes and involved in antigen presentation hiv-l : seven facets of functional molecular mimicry both rat and mouse tcrs specific for the encephalitogenic determinant of mbp use similar v, and vp chain genes even though the mhc and encephalitogenic determinants being recognized are different isolation of myelin basic protein-reactive t-cell lines from normal human blood regulation of autoimmune disease: physiological and therapeutic natural id-anti-id networks and the immunological homunculus t-cell vaccination and suppression of autoimmune disease physiological basis of t-cell vaccination against autoimmune disease t-cell vaccination in immunological disease the immunological homunculus and autoimmune disease, iq "molecular autoimmunity the cognitive principle challenges clonal selection the cognitive paradigm and the immunological homunculus network regulation of autoimmunity : an automaton model t-lymphocyte clones illuminate pathogenesis and affect therapy of experimental arthritis. arthritis rheum autoimmunity, microbial immunity and the immunological homunculus tolerize one, tolerize them all : tolerance is self-assertion human immunodeficiency virus and acquired immunodeficiency syndrome : correlation but not causation vaccination against autoimmune mouse diabetes with a t-cell epitope of the human -kda heat shock protein a suppressor t-lymphocyte cell tine for autoimmune encephalomyelitis analysis of human immunodeficiency virusinfected tissues by amplification and in situ hybridization reveals latent and permissive infections at single-cell-resolution cd + t-lymphocytopenia without hiv infection. no lights, no camera, just facts loss of envelope antigens of htlv-iii/lav, a factor in aids pathogenesis? identification of homologous regions in human immunodeficiency virus i gp and human mhc class ii bl domain activation-induced death by apoptosis in cd + t cells from human immunodeficiency virus-infected asymptomatic individuals naturally occurring antibodies against nine common antigens in human sera. -i. detection, isolation, and characterization does the hiv envelope induce a chronic graft-versus-hostlike disease? t-cell vaccination in multiple sclerosis: a preliminary report idiopathic cd + t-lymphocytopenia. immunodeficiency without evidence of hiv infection unusually high frequencies of hivspecific cytotoxic t lymphocytes in humans an idiotypic network model of aids immunopathogenesis lines of t lymphocytes induce or vaccinate against autoimmune arthritis natural autoimmunity vaccination against experimental allergic encephalomyelitis with t-cell receptor peptides human immunodeficiency virus dna is present in a high percentage of cd + lymphocytes of seropositive individuais selective depletion in hiv infection of t cells that bear specific t-cell receptor vp sequences aids two months after primary human immunodeficiency virus infection autoreactive cytotoxicity in hivinfected individuals hla antigens are risk factors for development of aids towards a network theory of the immune system cell-mediated suppression of hiv-specific cytotoxic t lymphocytes isolation of t-cell line capable of protecting mice against collagen-induced arthritis a six-year follow-up of hiv-infected homosexual men with lymphadenopathy : evidence for an increased risk for developing aids after the third year of lymphadenopathy the interactions between mycobacterium tuberculosis and the immune system leading to the development of autoimmune disease hiv infection: facts and hypotheses approaches to aids therapy association of human immunodeficiency virus infection and autoimmune phenomena antibodies to cd in individuals infected with human immunodeficiency virus type harming and protecting responses to hiv t cells can present antigens such as hiv gp targeted to their own surface molecules determinant spreading and the dynamics of the autoimmune t-cell repertoire therapeutic vaccination against adjuvant arthritis using autoimmune t-lymphocytes treated with hydrostatic pressure anti-idiotypic network induced by t-cell vaccination against experimental autoimmune encephalomyelitis control of experimental autoinimune encephalomyelitis by t cells responding to activated t cells influence of host genotype on progression to aids among hivinfected men human t-cell lymphotropic virus s glycoprotein (gp ) bound to cd determinants on normal lymphocytes and expressed by infected cells serves as target for immune attack aids research turned upside down immunological consequences of hiv infection: advantage of being low responder casts doubts on vaccine development new insights on the mechanisms of cd + lymphocytes depletion in aids aids virus infection and autoimmunity : a perspective of the clinical, immunological, and molecular origins of the autoallergic pathologies associated with hiv disease graft-vs-host reaction limited to a class ii mhc difference results in a selective deficiency in l t + but not in lyt- + t helper cell function t-cell receptor peptide therapy triggers autoregulation of experimental encephalomyelitis identification of hiv-l envelope glycoprotein in the serum of aids and arc patients autoantibodies against liver cell membrane detected by enzymelinked immunosorbent assay in acute and chronic liver disease protection from experimental allergic encephalomyelitis conferred by a monoclonal antibody directed against a shared idiotype on rat t-cell receptors specific for myelin basic protein the immunopathogenesis of human immunodeficiency virus infection v-region connectivity in t cell repertoires hiv-specific cytotoxic t lymphocytes igm, igg and iga rheumatoid factors and circulating immune complexes in patients with aids and aids-related complex with serological abnormalities major histocompatibility gene products and human immunodeficiency virus infection prevention of experimental autoimmune thyroiditis through the antiidiotypic network a lectin-binding soluble factor released by cd +cd + lymphocytes from aids patients inhibits t-cell cytotoxicity prospects for the control of aids by immunizing seropositive individuals a strategy for prophylactic vaccination against hiv a novel hiv vaccine strategy human immunodeficiency virus infection and autoimmune phenomena shedding and interspecies type seroreactivity of the envelope glycopolypeptide gp of the human immunodeficiency virus the reservoir for hiv-l in human peripheral blood is a t cell that maintains expression of cd acquired immune-deficiency syndrome (aids) : a consequence of allogeneic ia-antigen recognition aids: an autoimmune pathologic model for the destruction of a subset of helper t lymphocytes t helper cell immune dysfunction in asymptomatic, hiv-l seropositive individuals: the role of thl-th cross-regulation analysis of host-virus interactions in aids with anti-gpl t-cell clones : effect of hiv sequence variation and a mechanism for cd + cell depletion determinants of hiv disease progression : six-year longitudinal study in the edinburgh haemophilia/hiv cohorts unexplained opportunistic infections and cd + t-lymphocytopenia without hiv infection. an investigation of cases in the united states hla haplotype al b dr as a risk factor for hiv-related disease an aids-related cytotoxic autoantibody reacts with a specific antigen on stimulated cd + t cells apoptosis as a mechanism of cell death in cultured t lymphoblasts acutely infected with hiv-l protection from experimental autoimmune thyroiditis conferred by a monoclonal antibody to t-cell receptor from a cytotoxic hybridoma specific for thyroglobulin immunization with a synthetic t-cell receptor vregion peptide protects against experimental autoimmune encephalomyelitis arthritis induced by a t-lymphocyte clone that responds to mycobucterium tuberculosis and to cartilage proteoglycans cloning of the mycobacterial epitope recognized by t lymphocytes in adjuvant arthritis effects of inoculation with attenuated autologous t cells in patients with rheumatoid arthritis inhibition of antigen-induced lymphocyte proliferation by tat protein from hiv-l adoptive transfer of eae-like lesions from rats with coronavirus-induced demyelinating encephalomyelitis hiv-l gpl -mediated immune suppression and lymphocyte destruction in the absence of viral infection networks of automata and biological organization hiv and hla similarity hivinfected humans, but not chimpanzees, have circulating cytotoxic t lymphocytes that lyse uninfected cd + cells mhc-restricted depletion of human myetin basic protein-reactive t cells by t cell vaccination hypothesis: aids is an autoimmune disease directed at the immune system and triggered by a lymphocytic retrovirus virus-triggered aids: a t-cellmediated immunopathology? we are grateful to irun r. cohen, rene de vries, maurizio zanetti and joelle nataf for their helpful comments and fruitful discussions.the work of h.a. was supported by an ishaiah horowitz scholarship in residence at the hadassah university hospital, jerusalem. key: cord- -oxbmtend authors: naik, parvaiz ahmad; zu, jian; owolabi, kolade m. title: global dynamics of a fractional order model for the transmission of hiv epidemic with optimal control date: - - journal: chaos solitons fractals doi: . /j.chaos. . sha: doc_id: cord_uid: oxbmtend in this paper, a nonlinear fractional order epidemic model for hiv transmission is proposed and analyzed by including extra compartment namely exposed class to the basic sir epidemic model. also, the infected class of female sex workers is divided into unaware infectives and the aware infectives. the focus is on the spread of hiv by female sex workers through prostitution, because in the present world sexual transmission is the major cause of the hiv transmission. the exposed class contains those susceptible males in the population who have sexual contact with the female sex workers and are exposed to the infection directly or indirectly. the caputo type fractional derivative is involved and generalized adams-bashforth-moulton method is employed to numerically solve the proposed model. model equilibria are determined and their stability analysis is considered by using fractional routh-hurwitz stability criterion and fractional la-salle invariant principle. analysis of the model demonstrates that the population is free from the disease if [formula: see text] and disease spreads in the population if [formula: see text]. meanwhile, by using lyapunov functional approach, the global dynamics of the endemic equilibrium point is discussed. furthermore, for the fractional optimal control problem associated with the control strategies such as condom use for exposed class, treatment for aware infectives, awareness about disease among unaware infectives and behavioral change for susceptibles, we formulated a fractional optimality condition for the proposed model. the existence of fractional optimal control is analyzed and the euler-lagrange necessary conditions for the optimality of fractional optimal control are obtained. the effectiveness of control strategies is shown through numerical simulations and it can be seen through simulation, that the control measures effectively increase the quality of life and age limit of the hiv patients. it significantly reduces the number of hiv/aids patients during the whole epidemic. epidemiology mainly deals with the infectious diseases and predicts their occurrence, transmission as well as control in a population. it identifies the factors responsible for disease spread, facilitates treatment quality and health services, provides necessary measures for prevention, treatment, planning in order to improve the efficiency and effectiveness of health services [ ] . hiv is a retrovirus which is discovered in in usa among the gay community causes an aids a severe life intimidating ailment. at present, there is no vaccine or cure for aids, that makes it an incurable disease with high mortality rate (there are almost million deaths by aids per year worldwide), also it spread quickly affecting about , new case/day. the time duration for hiv to as an attractor. wang et al. [ ] studied a delayed fractional order sir model with saturated incidence and treatment functions. they have provided the sufficient conditions that guarantee the existence of equilibria and discussed the global stability results for both disease-free equilibrium as well as endemic equilibrium by constructing a suitable lyapunov functions. almeida [ ] in his paper studied a fractional seir epidemic model in presence of treatment. he analysed the model and his main focus was on the fractional differential equations in order to describe the dynamics of certain epidemics. further, he proved the local stability for both equilibria. carvalho et al. [ ] provided a hiv/hcv coinfection fractional order model to understand the impact of hiv viral load on the coinfection. their main motive in the model was to provide good fits to real data from patients suffering from several diseases such as hiv, hcv, dengue fever and many more. they have numerically suggested that the hiv viral load impacts impressively the severity of the hcv infection. also, by their results they showed that the treatment efficacy is also influential over the natural progression of hcv on the hiv/hcv coinfection. recently, kheiri and jafari [ ] analysed a multi-patch hiv/aids epidemic model with fractional order derivatives and investigated the effect of human movement on the spread of hiv/aids epidemic among patches. they derived the basic reproduction number r of the model and studied the local as well as global stability of the equilibria on the basis of r . they have shown that the system is stable if r < and it becomes unstable if r > . they also obtained the sufficient conditions under which the endemic equilibrium is unique and globally asymptotically stable. besides this, they formulated a fractional optimal control problem in which the state and costate equations are given in term of the left fractional derivatives. they incorporated in the model time dependent controls in order to control the spread of hiv/aids epidemics. they also derived the necessary conditions for the fractional optimal control in their proposed model. the effect of varying the fractional order on the disease spread is also studied in their model. researchers have continuously studied the fractional order models of hiv disease dynamics and provided many well-known mathematical techniques for the solution of these models for the dynamics of hiv epidemics [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . besides this, a number of studies on fractional order modeling of other infectious diseases can be found in the literature [ ] [ ] [ ] [ ] . the fractional order derivative not only find its application on modeling infectious diseases but in other fields as well like vibration equation [ ] and so on. the optimal control theory is developing fast and its various applications are extensively used in many fields of science and engineering [ ] . this theory for linear systems has been highly improved [ ] , however, the nonlinear optimal control problem (ocp) has become a strong topic and should be deeper investigated [ ] [ ] . jajarmi and baleanu [ ] proposed a new approach based on the modal series method and eigenvalue decomposition technique to solve a class of nonlinear optimal control problems. they have also investigated the convergence analysis of their suggested technique. jajarmi et al . [ ] proposed a new approach for the optimal control of time-varying delay systems with external persistent matched disturbances. in their internal model principle, they converted original time-delay model with disturbance into an augmented system without any disturbance. then, they selected a quadratic performance index for the augmented system to form an undisturbed time-delay optimal control problem. the necessary optimality conditions are then derived in terms of a two-point boundary value problem involving advance and delay arguments. at the end they finally provided a fast iterative algorithm for the latter advance-delay boundary value problem. they also investigated the convergence of the new iterative technique. the purpose of dealing with fractional order systems is the memory and hereditary properties which are the complex behav-ioral patterns of biological systems gives us more realistic way to model hiv/aids systems. in the fractional order models, the memory property allows the integration of more information from the past which predicts and translates the models more accurately. also, the hereditary property describes the genetic profile along with age and status of the immune system. because of such properties fractional order calculus have found wide applications to model dynamics processes in many well-known fields of science, engineering, biology, medicine and many other [ ] [ ] . saeedian et al. [ ] formulated sir epidemic model with the inclusion of memory effect and studied its behavior along the memory effect on the disease spread with the help of fractional derivatives. rihan [ ] provided a class of fractional order differential models of biological systems with memory, such as dynamics of tumor-immune system and dynamics of hiv infection of cd + t cells. communicable diseases have been a cause of global concern throughout the history of mankind. its outbreak severely affects the morbidity and the mortality rates across the globe. it is therefore important to implement the control measures to prevent and control the disease spread among the populations. kheiri and jafari [ ] formulated a fractional optimal control epidemic model of hiv/aids with random testing and contact tracing. in their model, they have incorporated the control measures of condom use and antiretroviral therapy for the control of spread of hiv/aids in the susceptible population. they have presented a forward-backword sweep numerical method based on adams-bashforth-moulton method for the solution of their model. agrawal [ ] formulated a fractional optimal control problem by using the reimann-liouville fractional derivatives and presented a numerical method for its solution. bashir et al. [ ] presented a fractional optimal control for a kinetic model and provided a numerical scheme for its solution. going by the antecedents, we have seen clearly that modeling of physical and real-life scenarios with the fractional order derivatives is much more accurate when compared with the integer order cases. this assertion has been demonstrated a number of research papers, monographs and books, see for example [ ] [ ] [ ] [ ] . in view of these achievements, we are motivated in this research work by modeling the control and analysis of sei i r dynamics of hiv disease transmission using the caputo fractional order operator which is most suited for modeling the biological and physical facts [ ] [ ] [ ] [ ] [ ] [ ] . the choice of using the caputo derivative is due to the fact that, if the given function is a constant, then the caputo derivative of that function gives zero. primarily, the caputo operator computes an ordinary differential equation, followed by a fractional integral to obtain the desired order of fractional derivative. more importantly, the caputo fractional differential equation (fdo) permits the use of local initial conditions to be included in the derivation of the model. in the present paper, we propose and analyze a fractional optimal control problem, in which the state and co-state equations are given in terms of the caputo fractional derivatives. this approach simplifies the use of fractional numerical methods to solve the state and co-state equations. fractional optimal control problems can be regarded as a generalization of classic optimal control problems for which the dynamics of the control system are described by fractional differential equations. we incorporate into the model time dependent controls such as condom use for exposed individuals, treatment for infected female sex workers, awareness about the disease among unaware infectives and behavioral change for susceptibles in order to reduce the risk of the spread of hiv/aids disease. conditions for fractional optimal control of the disease are derived and the state and co-state equations are characterized by caputo fractional derivatives. the numerical solution of the proposed fractional optimal control problem is obtained by using generalized adams-bashforth-moulton method. furthermore, the efficacy of order of fractional derivative, the control strategies and the value of objective functional is investigated. the structure of the paper is designed as: in the next section , some preliminary results required for the formulation of mathematical model is provided. development of the proposed mathematical model and its well-posedness is discussed in section . in section , we discuss the mathematical analysis of the proposed fractional order sei i r epidemic model along with equilibrium points and the stability of equilibrium points. in section , the fractional optimal control problem is formulated and discussed. also, in this section, the necessary conditions for the optimality of proposed fractional optimal control problem is provided. furthermore, in section , application of the generalized adams-bashforth-moulton method is performed on the proposed model and the numerical simulations are done to validate the analytical studies. in section , numerical results are given to illustrate the capability of generalized adams-bashforth-moulton method and the behavior of the obtained solutions is also discussed in this section. finally, section concludes all the major findings of the present research study. researchers have continuously extended the definitions of fractional order derivatives like the riemann-liouville, the caputo, caputo-fabrizio, atangana-baleanu, the grunwald-letnikov, the weyl, the marchaud, the riesz, and the miller and ross [ ] [ ] [ ] [ ] [ ] . recently, many new definitions of fractional derivative [ ] have hugely evolved, going from the derivatives with nonsingular kernel and new riemann-liouville fractional derivative without singular kernel to the two-parameter derivatives with non-singular and non-local kernel [ ] [ ] [ ] . definition . . a real function ψ( t ), t > is said to be in the space c η , η ∈ r , if there exists a real number l > η, such that ψ (t) = t l ψ (t) , where ψ ( t ) ∈ c [ , ∞ ) and it is said to be in the space where κ > and (.) is a well-known gamma function. ( ) definition . . the caputo fractional derivative of ψ( t ) order κ > is defined as where the operator c d κ t satisfies the following two basic properties: the definition . and definition . are not equivalent to each other, and their difference is expressed by the caputo operator c d κ t , has advantages for differential equations with initial values. in the case of riemann-liouville and caputo derivatives, respectively, the initial values are usually given as [ ] rl assume that the function d κ t ψ (t) , satisfies some smoothness conditions in every finite interval ( , t ), t ≤ t . choosing the grid = τ < τ < ... < τ n + = t = ( n + ) u, τ n + − τ n = u, and using the classical notation of finite differences, the laplace transform of the caputo fractional derivative of ψ( t ) order κ > is defined as definition . . the laplace transform of the function where e κ, κ is the two-parameter mittage-leffler function with κ, κ > . further, the mittage-leffler function satisfies the following equation [ ] e κ, κ to describe the transmission dynamics of hiv epidemics, we have generalized the basic sir epidemic model by including more compartments, to one in which population is divided into five sub-classes, the susceptible population s ( t ), the exposed population e ( t ), the infective population that don't know they are infected i ( t ), the infective population that know they are infected i ( t ), by means of medical screening or otherwise and recovered population r ( t ). the proposed model is considered as the generalization of the original kermack-mckendrick model [ ] , where only three compartments were considered, but here the exposed compartment is included contains those susceptible males in the population who have sexual intercourse with the female sex workers as a result by having sexual contact they are exposed to the infection. furthermore, the infected class is divided into two sub-classes namely infected female sex workers who are unaware about their disease status and the infected female sex workers who knows their disease status. thus, the model takes the following form [ , , ] . for the understanding of hiv disease dynamics, the total population n ( t ) is divided into five sub-population compartments namely susceptible, exposed, infected but unaware, infected but aware and recovered such that the following description is associated to the above classical model: the susceptibles are recruited at a rate , β is the per capita rate for susceptibles individuals with unaware infectives, β is the per capita rate for susceptibles individuals with aware infectives, λ is the natural death rate unrelated to aids, σ is the break through into infected class, θ is the rate of unaware infectives to become aware infectives by screening or testing, ρ is the rate by which types of infectives develop aids and d is the aids related death rate. it may further be noted that we further extend the above ordinary differential model to the following fractional order system of order κ, with σ , ρ > being the rate that exposed individuals become infectious and recovery rate, respectively and λ ≥ being the infection related death rate. the purpose of considering the fractional order case is the significant uniqueness of these varieties of fractional order systems with non-local characteristics (memory) and hereditary properties that have not been seen with the integer-order differential operators which widely exists in biology. also, using fractional order differential equations can help us to reduce the errors arising from the neglected parameters in modelling real life phenomena. in each case, we replace the ordinary derivative by a fractional derivative. thus, our proposed fractional order model for hiv disease transmission has the form subject to the initial conditions and if κ = , then system ( ) reduces to an integer order system ( ) . it is clear that the variable r ( t ) does not appear in the first four equations, thus it is meaningful to consider the reduced system ( ) as: ( ) subject to the positive initial conditions here, it is assumed that the functions and their caputo fractional derivatives are continuous at t ≥ . the existence, uniqueness, and non-negativity of the solution of system ( ) are analyzed. the schematic diagram of the proposed fractional order sei i r epidemic model ( ) is shown in fig. . in this section, we first prove the existence and uniqueness of positive solution, then the basic reproduction number and the existence conditions for both equilibria (disease-free equilibrium and endemic equilibrium) are obtained, finally, the conditions for the stability of both the equilibria are obtained. let us denote r for the proof of the main theorem about the non-negativity of the solutions, we recall the following lemma [ , , ] . this completes the proof. t for the initial value problem given by ( ) along initial conditions ( ) on t ≥ in ( , κ) and the solution will remain in r + . furthermore, the solutions are all bounded. proof. according to lin [ ] from the theorem . [ ] and remark . [ ] , we can determine the solution on ( , ∞ ) by solving the model ( ) along initial conditions ( ) which is not only existent but also unique. subsequently, we have to explain the nonnegative domain r + , is positively invariant region. from model ( ) , we find on each hyperplane bounding the non-negative orthant, the vector field points into r + . furthermore, from system ( ) thus, by lemma . , in the case of hiv infection, the total population n ( t ), i.e., the subpopulations s ( t ), e ( t ), i ( t ) and i ( t ) are bounded. by positivity means the population survives and boundedness refers as a natural restriction to growth as a consequence of limited resources. this completes the proof of the theorem . . therefore, the biologically feasible region for the system ( ) is for the equilibrium points, setting the right-hand side of the system ( ) equal to zero, we obtain equilibrium points as after simplification, the system ( ) gives the disease-free equi- thus, the proposed nonlinear fractional order sei i r epidemic model has at most two equilibria namely disease-free equilibrium in order to study the local stability of the disease-free equilibrium, we first compute the basic reproduction number by using next generation matrix method [ ] [ ] [ ] [ ] ( ) can be written as by the next generation matrix method, the matrices Ғ and Ѵ at the disease-free equilibrium point − d are obtained by where Ғ is non-negative and v is a non-singular m-matrix. therefore, the basic reproduction number denoted by r which is considered as the spectral radius of the next generation matrix v − at the disease-free equilibrium − d is thus given by it shows that if r < , then the disease does not spread in the population and the infection dies. on the other hand, if r > , then the disease persists in the whole population. now, we will discuss the local stability analysis of equilibrium points. for this, we state the results in the form of theorems and prove them. proof. to prove the above theorem . , the general jacobian matrix and the matrices corresponding to each equilibrium point will be obtained. therefore, the jacobian matrix is given by therefore, by the routh-hurwitz stability conditions for fractional order systems [ ] , the necessary and sufficient condition for various fractional order models. therefore, the disease-free equilibrium of system ( ) is asymptotically stable if all of the ( ) . hence, a sufficient condition for the local asymptotic stability of the equilibrium points is that the eigenvalues γ this confirms that fractional order differential equations are, at least, as stable as their integer order counterpart. by solving the characteristic equation, the eigenvalues can be obtained as the simplification allows us to get the following algebraic equation this implies, therefore, the roots of the characteristic equation are , satisfy the condition given by ( ) . therefore, all the eigenvalues have negative real parts if r < . this completes the proof of the theorem . . in the next theorem . , we discuss the local asymptotic stability of the endemic equilibrium of the system given by ( ) . proof. the jacobian matrix of the system ( ) evaluated at endemic equilibrium − d * is given as the characteristic equation of the linearized system is in the form now, the discriminant of the polynomial − p (γ ) = γ + ϑ γ + ϑ γ + ϑ is described by [ , , ] and using the construction of results by ahmed et al. [ , ] , following fractional routh-hurwitz conditions associated with are observed. we have the following result. i if d (− p ) > , then the necessary and sufficient condition for the equilibrium point to be locally asymptotically stable is ϑ > , the global existence of the solution of the fractional differential equation always becomes a most important concern, which is carry out in the following section. theorem . . [ , ] , assume that the function : r + × r → r satisfies the following conditions in the global space: ) the function ( t, ψ( t )) is lebesgue measurable with respect to t on r . ) the function ( t, ψ( t )) is continuous with respect to ψ( t ) on ( t, ψ ( t ) ) ≤ α + α ψ (t) , for all most every t ∈ r and all ψ (t) ∈ r . here α , α are two positive constants and has a unique solution. proof. from the theorem . , we obtain the unique solution on ( , ∞ ) by solving the system ( ) . firstly, lin [ ] discussed the proof of theorem and shows that the solution is not only exist but also unique. in theorem . , we already proved that the solution of model ( ) will remain in r + . ( [ , ] ) let ψ (t) ∈ r + be a continuous and derivable function. then, for any time instant t ≥ , and where κ ∈ ( , ). note that for κ = , the inequalities in ( ) and ( ) becomes equalities. now, we provide the global stability results of the equilibria in the following theorems by considering the lyapunov direct method. ( ) is globally asymptotically stable in , if r ≤ and unstable when r > . to prove this, we define a lyapunov function φ ( t ) given using the disease-free steady state condition of model ( ) , s = λ , we have from the equation ( ) as in addition, we know that c d κ t φ (t) | ( ) = , if and only if s(t ) = s and i (t) = .substituting i (t) = into ( ) , one can directly obtain e(t ) = . using i (t) = e(t ) = again in ( ) , then i (t) = . therefore, the maximum invariant set for { ( s, e, i , i ) ∈ : c d κ t φ (t) | ( ) = } is the singleton set -d . according to the lasalle's invariance principle [ ] [ ] [ ] [ ] , we know that all solutions in converge to -d .therefore, the disease-free steady state of model ( ) is globally asymptotically stable when r ≤ . this completes the proof of the theorem . . ( ) is globally asymptotically stable in , when r > . to prove this, we define a lyapunov function φ ( t ) given using the endemic conditions, therefore, φ ( t ) is bounded and non-increasing. further, the limit of φ ( t ) exits as t → ∞ . in addition, we know that c lasalle's invariance principle [ ] [ ] [ ] [ ] , we know that all solutions in * converge to − d * .therefore, the endemic equilibrium of proposed model ( ) is globally asymptotically stable when r > . this completes the proof of the theorem . . in this section, we extend the basic model ( ) by including some particular control measures aimed at controlling the spread of the hiv infection and formulate the fractional optimal control problem by proposing the control objectives. the aim of the control measures is to reduce the infection in the population and thus there is the need to formulate the optimal control problem to achieve this goal. the first control function v ( t ) represents the behavioral change for susceptibles which reduced the number of exposed by a factor ( − v (t) ) . the control v ( t ) is proposition of the susceptible individuals who change their sexual habits per unit of time. the second control function v ( t ) is the use of condoms to the exposed individuals who are going to have sexual interaction with the female sex workers. the third control function v ( t ) represent the enhancement of the strength of treatment for the infected individuals. the fourth control function v ( t ) is the awareness source among the unaware infectives about their disease status. under these control measures the proposed model ( ) all formulas and models should be left aligned . ( ) with the non-negative initial conditions the control is completely effective when v i (t) = and the control is not effective when v i (t) = , for i = , , , i.e., ≤ v i ( t ) < . our focus is to minimize the number of exposed individuals under the cost of applying control measures which can be done by consider the following fractional optimal control problem to minimize the objective functional given by subjected to the state system given in ( ) along non-negative initial conditions ( ) . in eq. ( ) , q represent the positive weight constant of the exposed population, while -p , -p , -p , and -p are positive weight constants for behavioral change, personal protection, treatment strategy and awareness source respectively. the subjected to the state system given in ( ) , where the control set is defined as the lagrangian Ɫ and hamiltonian h for the fractional optimal problem ( ) - ( ) are respectively given by [ , - ] ( ) and this further implies, where λ s , λ e , λ i , λ i and λ r are the adjoint variables. we have to prove the necessary conditions for the optimality of the fractional system ( ) . for the optimal control v ( t ), that minimizes the performance index ( ) subjected to the dynamical constraints ( ) with initial conditions π ( ) = π ( ) where π ( t ) and v ( t ) are the state and control variables, respectively, l and ω are differentiable functions, and < κ ≤ . we have the following theorem. if ( π , v ) is a minimizer of ( ) under the dynamic constraint ( ) and the boundary condition ( ) , then there exists a function λ such that the triplet ( π , v, λ) satisfies proof. for the proof of theorem . , readers are suggested to see [ , - ] , where the authors have given the proof in detail. this completes the proof of the theorem . . and r * be optimal state solutions with associated optimal control variables v * , v * , v * , v * for the optimal control problems ( ) and ( ) . then there exist adjoint variables λ s , λ e , λ i , λ i and λ r satisfying with transversality conditions or boundary conditions furthermore, the control functions v * , v * , v * and v * are given by all form ulas and mode ls shou ld be left alig ned . proof. the adjoint system ( ) i.e., λ s , λ e , λ i , λ i and λ r are obtained from the hamiltonian h as in this section numerical solution for the proposed fractional order sei i r epidemic model ( ) is presented. because no analytical solution to the nonlinear fractional system ( ) is available, we use the technique so-called generalized adams-bashforth-moulton method [ , , ] to obtain the numerical solution of the system ( ) . in this algorithm, we derive the predictor-corrector scheme for obtaining the numerical solution of the nonlinear fdes. to provide the estimated solution by means of this algorithm, consider the subsequent nonlinear fractional differential equation [ , , ] with the following initial conditions now, with operating by the fractional integral operator on the equation ( ) , we can obtain on the solution ψ( t ) by solving the following equation: this equation ( ) is equivalent to the volterra integral equation. diethelm et al. [ ] [ ] [ ] used the predictor-corrector scheme based on the adams-bashfort-moulton algorithm to integrate ( ) . setting h = t n , t n = nh and n = , , , ..., n ∈ z + , the equation ( ) can be discretized as follows: where a q,n + = all form ulas and mode ls shou ld be left alig ned . ( ) and the predicted value ψ p h ( t n + ) is determined by the error estimate is in which p = min ( , + κ ) . in this subsection, we solve numerically the nonlinear fractional sei i r epidemic model using the proposed method. in view of the generalized adams-bashforth-moulton method, the numerical scheme for the proposed model ( ) is given in the following form [ ] [ ] [ ] [ ] [ ] further, the quantities , r h ( t q )), are computed from the following functions, in addition, the quantities are computed from equations ( ) - ( ) respectively, at the points t n + , n = , , , ..., m. for the fractional optimal control problem ( ) discussed in section , similar procedure is followed for the numerical results. therefore with π = s, e, i , i , r and the control v . similarly, for the adjoint system we have the coefficients a q,n + , b q,n + are given by equations ( ) and ( ) respectively. in order to justify our theoretical findings, we introduced in this section some numerical experiments obtained for different instances of fractional power κ for the hiv epidemic model without control ( ) and with control ( ) along with adjoint variable systems and the control strategies. we present the numerical results for the model ( ) when all control measures are absent and also to examine the role of fractional order κ on the hiv disease spread. then, we simulate the fractional optimal control of the model and investigate the effect of the controls introduced in the model on the spread of epidemics. we use the generalized adams-bashforth-moulton method for the simulation of both the systems and use the values of parameters described in table . in this subsection, we present numerical results for fractional system ( ) and allow the values of κ to varies from k = . to k = as seen in the fig. . it is clear from the fig. that fractional order has significant effect on dynamic behavior of all the components. we observe that when the derivative order κ is reduced from , the memory effect of the system increases, and therefore the infection grows slowly and the number of hiv-infected population and aids people increases for a long time. also, undiagnosed hiv-infected population in some societies refuse to per-form hiv test for reasons such as stigma and fear of identification due to lack of knowledge about the disease. this results in a delay in identification of hiv-infected individuals, an increase in the undiagnosed hiv-infected population, fast progress of aids and an increase in people diagnosed with aids. on the other hand, the experience or knowledge of individuals about the disease causes susceptible and exposed individuals to take different precautions, such as behavioral change, vaccination, treatment and condom use, against infection transmission. this leads to a slow growth of infection among the population. therefore, from the numerical results in fig. , we conclude that the derivative order κ ( . ≤ κ ≤ ) can play the role of precautionary measures against infection transmission, treatment of infection and delay in accepting hiv test. existence of attractors for some fractional order κ for different population groups are given in fig. . thus, the results from fig. shows that there is tendency of each population class to exist and enter into permanence with time. numerical results for the difference of integer-order and fractional order are given in figs. - . it is clearly visible from figs. - that the differential equations with fractional order derivative have rich dynamics and describe biological systems better than traditional integer-order models. from the above discussion and numerical results in figs. - , we conclude that the derivative order κ can play the role of experience or knowledge of individuals about the past of the disease. therefore, the numerical results confirm that differential equations with fractional order derivative have rich dynamics and describe biological systems better than traditional integer order models. as a result, our numerical results are more logical than the results of other articles on the modeling of the hiv/aids epidemic and other models with integer-order derivative due to the presence of the fractional derivative order κ ( . < κ ≤ ). now, we investigate the effect of the control measures introduced in the model on the spread of the epidemic. we consider the following strategies and examine the corresponding numerical results. in this subsection, we present the numerical results for the model ( ) when all control measures are present. the results are obtained in different ways by applying control strategies in the following five ways. in the first control strategy, we set the control measures v = , v = and active the control measures v = . , v = . namely the behavioral change for susceptible individuals and condom use for the exposed individuals which is shown in fig. , for different values of fractional order κ. analysis of control strategy- predicts that susceptible and exposed individuals greatly decrease after implementing control measure v , v . in fig. , we observe that this control strategy results in a significant decrease in the number of undiagnosed hiv-infected population and aids people for a long time compared with the case without control. fig. shows that, by applying the strategy- , the value of r will be less than for more time when κ is reduced from . this means that by decreasing κ from , we can control the spread of disease over a longer period of time. therefore, the presence of the fractional derivative order κ in the model increases the use of condom control and behavioural control in the population. the control v is proportion of the susceptible individuals who change their sexual habits per unit time. the class r , the removed class, represents the number of people who have greatly changed their sexual habits such that they cannot easily be infected through sexual contact. people in the class r take on safe habits and keep these habits in the rest of their lives. the importance of class r is that it emphasizes the need for prevention for a disease like hiv that has no treatment. therefore, increasing the members of this class plays an important role in controlling the spread of disease. strategy- . using only condom use control in the second control strategy, we set the control measures v = , v = , v = and active the control measure v = . namely the condom use for the exposed individuals which is shown in fig. , for different values of fractional order κ. analysis of control strategy- predicts that exposed individuals greatly decrease after implementing control measure v . the results in fig. , further show that condom use is the main control measure which can be helpful in controlling the disease more properly. this is because the control is applied to exposed class which is the main source from which the virus can transmit and spread due to the fact that this class is easily available for virus during their sexual contact with infected female sex workers. strategy- . using only treatment control in the third control strategy, we set the control measures v = , v = , v = and active the control measure v = . namely the efficiency of treatment given to the aware infected individuals which is shown in fig. , for different values of fractional order κ. analysis of control strategy- predicts that infected individuals greatly decreases after implementing control measure v . this is due to the fact that treatment of diagnosed hiv-infected population results in an increase in the level of cd + t-cells of this class. therefore, this strategy prolongs the lifespan of hiv-infected patients and delays the onset of aids. fig. shows that differential equations with fractional order derivative have rich dynamics and describe biological systems better than traditional integerorder models. strategy- . using treatment control and awareness control in the fourth control strategy, we set the control measures v = , v = and active the control measures v = . , v = . namely the efficiency of treatment given to the aware infected individuals and the awareness source for unaware infected individuals which is shown in fig. , for different values of fractional order κ. analysis of control strategy- predicts that infected individuals greatly decreases after implementing control measures v and v . in fig. , we observe that this control strategy results in a signif-icant decrease in the number of aware infected hiv people and unware infected people compared with the case without control. in last control strategy, we activate all the control measures v = . , v = . , v = . and v = . namely the behavioral change for susceptible individuals, condom use for exposed individuals, efficiency of treatment given to the aware infected individuals and the awareness source for unaware infected individuals which is shown in fig. , for different values of fractional order κ. analysis of control strategy- predicts that susceptible individuals and exposed individuals decreases with the control measures v and v while infected individuals greatly decrease after implementing control measures v and v . by adding the behavioral change control v or condom use control v to the art treatment control v , we see from figs. - , that the strategies - result in a decrease in the hiv infected population and aids people compared with the case without control. with implementing all the control effort s, we observe that the strategy- results in a significant decrease in the hiv-infected population and aids people compared with the case without control. with comparison of the strategies, we see that the strategy- is better than the other strategies in control and reduction of the spread of hiv/aids epidemic. therefore, by applying the strategy- , we can increase the life time and the quality of life for those living with hiv and decrease significantly the number of hiv-infected population and aids people. on the other hand, in human societies, the process of evolution and control of the epidemic is associated with memory. when a disease spreads in a society, the experience or knowledge of individuals about the past of the disease helps susceptible individuals to take different precautions, such as behavioural change, treatment, awareness and condom use against infection transmission. also, the experience or knowledge can lead to the screening measures of entry and exit between different groups. it is noticeable from fig. that due to the memory property of fractional derivatives, the derivative order κ affects the values of the controls. we see that the maximum levels of the controls are reduced when κ limits to . on the other hand, the memory effect characterized by fractional derivative is reduced when κ limits to . therefore, by reducing the memory effect, the maximum levels of the controls are reduced. in the current study, we have introduced a nonlinear sei i r fractional order epidemic model for the transmission dynamics of hiv epidemics. the non-negative solution of the model is provided by using the generalized mean value theorem. we obtained the basic reproductive number r , which perform as a threshold parameter in the disease status. the existence of equilibria and their asymptotical stability results using fractional routh-hurwitz stability criterion is discussed. we established and investigated the stability analysis of the fractional order model with respect to the values of r . the disease-free equilibrium is locally asymptotically stable if r ≤ . for r > , using theorem . and corollary . , we investigated the local stability of the positive endemic equilibrium state − d * . meanwhile, global asymptotic stability of the disease-free and endemic equilibrium point is investigated by constructing a suitable lyapunov functions. additionally, we investigated the optimal control problem by the application of the optimal control theory. we used the pontryagin's minimum principle to provide the necessary conditions needed for the existence of the optimal solution to the optimal control problem. furthermore, generalized adams-bashforth-moulton method is applied to obtain a numerical solution of the proposed fractional order sei i r epidemic model ( ) and the fractional optimal problem ( ) . the re-sults obtained shown that the adams-bashforth-moulton method is an accurate and effective technique for obtaining the numerical solution of the proposed nonlinear fractional order sei i r epidemic model. lastly, the theoretical results are verified by numerical simulations to measure the efficacy and impact of controls on the transmission of the hiv/aids disease. from the numerical simulation, the size of the exposed population is significantly reduced under the controlled conditions. this proposes that if all four control measures v (behavioral change for susceptibles), v (condom use by the exposed individuals), v (strength of treatment for the infected individuals), v (awareness source among the unaware infectives) are employed for the same period of time and continue for a considerable period of time, the spread of hiv disease through prostitution could be restricted. in this manner, the fractional order optimal control method can progress the value of the necessary control measures. this recommends that personal precautional measures, periodic monitoring by medical professionals and researchers should be done to control the transmission of the hiv disease dynamics. the recently emerged virus namely novel coronavirus (covid- ) which has originated from wuhan the capital city of hubei providence of mainland china in december is a major threat to mankind at present in the whole world. application of fractional order derivatives to model the new outbreak of coronavirus and other trending diseases are left for future research. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. modeling the role of acquired immune response and antiretroviral therapy in the dynamics of hiv infection dynamics of an sir model with nonlinear incidence and treatment rate hiv/aids epidemic fractional-order model dynamic analysis of a delayed fractional-order sir model with saturated incidence and treatment functions analysis of a fractional seir model with treatment hcv coinfection model: a fractional-order perspective for the effect of the hiv viral load stability analysis of a fractional order model for the hiv/aids epidemic in a patchy environment contributions to the mathematical theory of epidemics. iii-further studies of the problem of endemicity a fractional-order differential equation model of hiv infection of cd + t-cells solving a fractional order model of hiv infection of cd + t cells a fractional-order model of hiv infection with drug therapy effect the modeling dynamics of hiv and cd + t-cells during primary infection in fractional order: numerical simulation applications of the extended fractional euler-lagrange equations model to freely oscillating dynamical systems local and global stability of fractional order hiv/aids dynamics model a fractional order seir model with vertical transmission numerical behavior of a fractional order hiv/aids epidemic model a fractional-order model for hiv dynamics in a two-sex population analysis and numerical solution of seir epidemic model of measles with non-integer time fractional derivatives by using laplace adomian decomposition method equilibrium points, stability and numerical solutions off fractional-order predator-prey and rabies models a new fractional model and optimal control of a tumor-immune surveillance with non-singular derivative operator a new fractional modelling and control strategy for the outbreak of dengue fever a new and efficient numerical method for the fractional modelling and optimal control of diabetes and tuberculosis co-existence a new fractional sirs-si malaria disease model with application of vaccines, anti-malarial drugs, and spraying on the analysis of vibration equation involving a fractional derivative with mittag-leffler law optimal control with engineering applications the optimal homotopy analysis method for solving linear optimal control problems online identifier-actor-critic algorithm for optimal control of nonlinear systems inverse optimal controller based on extended kalman filter for discrete-time nonlinear systems optimal control of nonlinear dynamical systems based on a new parallel eigenvalue decomposition approach a new approach for the optimal control of time-varying delay systems with external persistent matched disturbances fractional differential equations fractional-order nonlinear systems: modeling, analysis and simulation memory effects on epidemic evolution: the susceptible-infected-recovered epidemic model numerical modeling of fractional-order biological systems fractional optimal control of an hiv/aids epidemic model with random testing and contact tracing a general formulation and solution scheme for fractional optimal control problems optimal control of a fractional-order enzyme kinetic model fractional calculus: theory and applications, differentiation and integration to arbitrary order fractional integrals, derivatives -theory and applications. yverdon: gordon and breach science publishers mathematical modelling and analysis of love dynamics: a fractional approach numerical methods for fractional differentiation on the formulation of adams-bashforth scheme with atangana-baleanu-caputo fractional derivative to model chaotic problems numerical analysis and pattern formation process for spacefractional super diffusive system computational study of noninteger order system of predation behavioural study of symbiosis dynamics via the caputo and atangana-baleanu fractional derivatives mathematical analysis and computational experiments for an epidemic system with nonlocal and nonsingular derivative numerical simulation of fractional-order reaction-diffusion equations with the riesz and caputo derivatives a new definition of fractional derivative without singular kernel portraying the effect of calcium-binding proteins on cytosolic calcium concentration distribution fractionally in nerve cells properties of a new fractional derivative without singular kernel an introduction to the fractional calculus and fractional differential equations lyapunov functions for fractional order systems a new definition of fractional derivative analytical and numerical schemes for a derivative with filtering property and no singular kernel with applications to diffusion characterizations of two different fractional operators without singular kernel comparing the new fractional derivative operators involving exponential and mittag-leffler kernel a fractional order epidemic model for the simulation of out breaks of influenza a (h n ) global existence theory and chaos control of fractional differential equations estimating the approximate analytical solution of hiv viral dynamic model by using homotopy analysis method modeling the mechanics of viral kinetics under immune control during primary infection of hiv- with treatment in fractional order reproduction numbers and sub-threshold endemic equilibria for compartmental models of disease transmission the stability of dynamical systems global stability of infectious disease models using lyapunov functions the construction of nextgeneration matrices for compartmental epidemic models stability results for fractional differential equations with applications to control processing, computational engineering in systems and application on some routh-hurwitz conditions for fractional order differential equations and their applications in lorenz, rssler, chua and chen systems volterra-type lyapunov functions for fractional-order epidemic systems effect of partial immunity on transmission dynamics of dengue disease with optimal control differential equations: classical to controlled, mathematics in science and engineering an algorithm for the numerical solution of differential equations of fractional order analysis of fractional differential equations a predictor-corrector approach for the numerical solution of fractional differential equations spatiotemporal patterns in the belousov-zhabotinskii reaction systems with atangana-baleanu fractional order derivative new approaches to the fractional dynamics of schistosomiasis disease model optimal solutions for singular linear systems of caputo fractional differential equations on the formulation of adams-bashforth scheme with atangana-baleanu-caputo fractional derivative to model chaotic problems numerical solution of some fractional dynamical systems in medicine involving non-singular kernel with vector order the first author is very grateful to xi'an jiaotong university for the assistant professor position provided to him. also, the authors would like to thank the reviewers and editors of this paper for their careful attention to detail and constructive feedback that improved the presentation of the paper greatly. the study was supported by grants from the china postdoctoral science foundation (grant nos. m and m ), the national natural science foundation of china (grant nos. , , and ), the national science and technology major project of china (grant no. zx ) and grant from the natural science foundation of shaanxi province (grant no. jm- ). the funding body did not play any roles in the design of the study and in writing the manuscript. key: cord- -w fu c authors: dikman, andrew e.; schonfeld, emily; srisarajivakul, nalinee c.; poles, michael a. title: human immunodeficiency virus-associated diarrhea: still an issue in the era of antiretroviral therapy date: - - journal: dig dis sci doi: . /s - - -y sha: doc_id: cord_uid: w fu c over half of patients with human immunodeficiency virus (hiv) experience diarrhea that contributes negatively to quality of life and adherence to antiretroviral therapy (art). opportunistic infectious agents that cause diarrhea in patients with hiv span the array of protozoa, fungi, viruses, and bacteria. with global use of art, the incidence of diarrhea because of opportunistic infections has decreased; however, the incidence of noninfectious diarrhea has increased. the etiology of noninfectious diarrhea in patients with hiv is multifactorial and includes art-associated diarrhea and gastrointestinal damage related to hiv infection (i.e., hiv enteropathy). a basic algorithm for the diagnosis of diarrhea in patients with hiv includes physical examination, a review of medical history, assessment of hiv viral load and cd + t cell count, stool microbiologic assessment, and endoscopic evaluation, if needed. for patients with negative diagnostic results, the diagnosis of noninfectious diarrhea may be considered. pharmacologic options for the treatment of noninfectious diarrhea are primarily supportive; however, the use of many unapproved agents is based on unstudied and anecdotal information. in addition, these agents can be associated with treatment-limiting adverse events (aes), such as drug–drug interactions with art regimens, abuse liability, and additional gastrointestinal aes. currently, crofelemer, an antisecretory agent, is the only therapy approved in the usa for the symptomatic relief of noninfectious diarrhea in patients with hiv on art. advances in the treatment of human immunodeficiency virus (hiv) and acquired immunodeficiency syndrome (aids) have transformed this disease into a chronic illness [ ] . as a result, individuals with hiv have a longer life expectancy [ ] . when hiv is treated early and aggressively, life expectancy approaches that of uninfected individuals [ , ] . according to the centers for disease control and prevention (cdc), the annual incidence of hiv has remained stable during the past years [ ] . in , the prevalence of hiv in individuals aged over years was estimated to be about , , [ ] . although this number illustrates a dramatic increase in the prevalence of hiv since , it is largely due to the decreased mortality rate associated with the advent of antiretroviral therapy (art) [ ] . because most cases of diarrhea in the pre-art era were due to infectious pathogens, it was widely believed that successful treatment would reduce, or even solve, this problem [ , ] . although art has improved the survival and quality of life of patients with hiv, and even decreased the incidence of diarrhea in this population, diarrhea remains a common complaint among these patients and continues to negatively impact the quality of life [ ] [ ] [ ] [ ] . furthermore, while the burden of diarrhea in the hiv-infected population remains high, the causes of diarrhea have shifted toward noninfectious etiologies [ , ] . in one survey, * % of patients receiving art reported having the symptom of diarrhea in the previous month [ ] ; clinical trial data would suggest that up to % of these events may have been due to the effects of art itself [ ] . in support of this assertion, us historical data of hiv-infected patients with cd ? t cell counts \ cells/mm were investigated and demonstrated a decline in infectious diarrhea from to % over years ( ) ( ) ( ) ; this correlated with the introduction of art around [ ] . during that same period, the percentage of patients with noninfectious diarrhea increased from to % [ ] . a similar trend in etiologic differences has been observed in other countries for patients taking art versus those not taking art [ ] . this review explores some explanations for the continued burden of diarrhea among patients with hiv, discusses the diagnostic workup, and provides guidance on how hivassociated noninfectious diarrhea should be treated. gut-associated lymphoid tissue (galt) is the largest collection of lymphoid tissue in the human body [ ] . the gastrointestinal (gi) tract is regularly exposed to a complex and diverse assortment of antigens from both microbial and dietary sources [ ] . as a result, naïve b and t cells of the gut are constantly interacting with antigens that induce their maturation into plasma cells and memory t cells, respectively. this persistent stimulation of the immune system leads to a baseline inflammatory state that encourages the production of chemokines and adhesion molecules, which mediate the movement of lymphocytes into the mucosal tissues [ , ] . the gi tract is targeted during all phases of hiv infection, but the effects of hiv on the mucosal immune system are most apparent in the acute infection period. data from simian models with simian immunodeficiency virus [ ] and from patients with hiv [ , , ] show that within weeks of infection, the vast majority of mucosal lamina propria cd ? lymphocytes are depleted. this depletion occurs well before any decrease in cd ? t cells is seen in the periphery and likely reflects the greater expression of the cc chemokine receptor type (ccr ), which functions as the primary coreceptor for the majority of infective hiv strains, on mucosal cd ? t cells [ ] . the expression of the chemokine receptor on these cells supports the entry of the virus, but their state of physiologic activation is responsible for enhanced hiv replication in the mucosal compartment and subsequent mucosal cd ? t cell depletion. further, despite the use of potent antiretroviral medications, hiv persists within galt lymphocytes, even after repletion of cd ? t cells in the periphery [ ] . thus, in patients with chronic hiv infection, the mucosal environment contains a paucity of cd ? t cells but is overpopulated with cd ? t cells and b cells, giving the wrong impression of a healthy mucosal environment at the microscopic level [ ] . the etiology of diarrhea in hiv-infected patients can be divided into two major categories: noninfectious and infectious. as treatment of hiv has improved, the increase in peripheral cd ? t cell counts has resulted in a decline in the risk of infection and associated diarrhea (fig. ) [ ] . indicative of this shift, noninfectious etiologies of diarrhea have now surpassed infectious causes [ ] . noninfectious diarrhea is defined as pathogen-negative diarrhea and includes art-associated diarrhea, gi damage related to hiv infection (i.e., hiv enteropathy), and many causes mirroring those seen in gender-and age-matched patients without hiv infection. hiv enteropathy is an idiopathic form of diarrhea observed in patients with hiv in the absence of an infectious source with characteristic histologic features (table ) [ , [ ] [ ] [ ] . while the exact mechanisms by which these changes occur in the gi tract are unclear, hiv has been postulated to alter signaling and cellular structure, which may lead to architectural distortion [ ] . several studies have demonstrated crypt epithelial proliferation in response to hiv infection, leading to increased crypt height, subsequent crypt cell encroachment onto villi, and relative decreased villous height resulting in diarrhea and malabsorption [ , ] . a study by keating and colleagues that investigated monosaccharide absorption in patients with hiv and aids demonstrated that patients with diarrhea had significant malabsorption of all monosaccharides tested [ ] . evidence of malabsorption was reported in patients with both pathogen-negative (n = ) and pathogen-positive (n = ) diarrhea, suggesting that malabsorption may be involved in hiv enteropathy, as well as in pathogen-induced diarrhea. other hypotheses for the mechanism of hiv enteropathy include decreased transepithelial electrical resistance, decreased sodium-dependent glucose absorption, and increased intercellular permeability in hiv-infected cells [ ] . in vitro studies have demonstrated that gp , an envelope protein of hiv, induces microtubule disruption, decreases epithelial resistance, and promotes calcium signaling within the cell to affect these cytopathic changes [ , ] . however, there was no effect of gp on chloride secretion. hiv enteropathy may occur at all stages of hiv infection, from acute hiv to advanced aids [ ] . data suggest that hiv may be capable of infecting mucosal epithelial dig dis sci ( ) : - cells, resulting in direct effects on epithelial cell function [ ] . further, microscopic inflammation may be mechanistically involved in hiv enteropathy [ ] . while hiv rapidly and severely depletes mucosal t cells, the total mucosal t cell population remains largely unchanged [ ] . this reflects greater mucosal infiltration by activated cd ? t cells. these cells are primed to produce proinflammatory cytokines and chemokines, which may directly [ , ] defined by the acg as abdominal pain or associated with altered bowel habits over a period of c months defined by rome iii criteria as recurrent abdominal pain or discomfort for c days/month in the last months with symptom onset at c months before diagnosis and associated with c of the following: onset associated with change in stool frequency onset associated with change in stool form functional diarrhea [ ] defined by rome iii criteria as c % of stools that are loose (mushy) and without pain for c months with symptom onset c months before diagnosis reprinted with permission from [ ] acg american college of gastroenterology, gi gastrointestinal, hiv human immunodeficiency virus damage the mucosal barrier, resulting in decreased transepithelial resistance and diarrhea [ , ] . this has been shown to lead to malabsorption of vitamin b , bile acid, and monosaccharides; thus, hiv enteropathy can also be more specifically defined by its physiologic effect on small bowel function [ , ] . while diarrhea is an adverse effect of art, protease inhibitors seem to be most strongly associated with diarrhea ( table ) [ ] . in mouse models, protease inhibitors and reverse transcriptase inhibitors were found to significantly increase water and electrolyte secretion into the intestinal lumen in vivo [ ] . rufo and colleagues demonstrated that protease inhibitors in general and nelfinavir in particular potentiate signaling through muscarinic-and calcium-dependent receptors of intestinal cells, resulting in increased chloride secretion into the lumen [ ] . this study also showed that sodium and chloride concentrations in stool samples from patients with hiv taking nelfinavir were elevated, consistent with secretory diarrhea. in an in vitro study, bode and colleagues found that protease inhibitors induced apoptosis of human intestinal epithelium, compromising barrier function in the cells and thereby increasing water secretion in the gut lumen [ ] . wu and colleagues also investigated the mechanism by which protease inhibitors cause diarrhea and found that lopinavir and ritonavir (notably not amprenavir) induced endoplasmic reticulum dysfunction in the intestinal epithelial cells [ ] . when exposed to protease inhibitors, the cells were found to have decreased alkaline phosphatase activity and thereby an increase in unfolded proteins. the accumulation of defective proteins in the cytosol may persistently activate the cell's unfolded protein response, a specific signaling pathway that aims to return the cell's protein folding function back to normal. if the levels of unfolded proteins do not decrease, the cell may induce apoptosis. functional bowel disorders, such as irritable bowel syndrome (ibs), are additional conditions that may present with diarrhea [ ] . in a survey conducted in a veterans affairs outpatient setting, ibs was more common in hivpositive patients compared with hiv-negative patients [ ] . another cause of noninfectious diarrhea is small intestinal bacterial overgrowth (sibo) [ ] , a condition in which increased bacteria in the small intestine leads to multiple gi symptoms, including abdominal bloating and discomfort, diarrhea, and malabsorption [ ] . this condition may be more common in those with anatomic abnormalities and motility disorders, but does not appear to be a common cause of diarrhea in those with hiv [ ] . given the multitude of differences in standard of living among developed versus developing countries and differences in availability of care for patients with hiv, the incidence and type of various diarrhea-associated infections in immunocompromised patients may vary substantially by region [ , ] . in addition, diarrhea experienced by hiv-infected individuals can be caused by pathogens that are unique to the hiv population or by pathogens that cause diarrhea in the immunocompetent host [ , ] . for example, salmonella, shigella, campylobacter, escherichia coli, and enterotropic viruses cause diarrhea in both the immunocompetent and hiv-infected patients. in addition to these pathogens, patients with hiv who are profoundly immunosuppressed, with a cd ? t cell count \ cells/mm , are also susceptible to opportunistic infections [ ] . these opportunistic infections can be organized into four general categories of organisms: protozoa, fungi, viruses, and bacteria (table ) [ , [ ] [ ] [ ] [ ] . cryptosporidiosis is caused by an intracellular pathogen, cryptosporidium [ ] . infection with cryptosporidium parvum is a common cause of diarrhea worldwide [ ] . there is an estimated rate of * , cases of [ ] [ ] [ ] . it spreads from person to person or via contaminated water (e.g., drinking water or recreational water sites) [ ] . although the protozoa cause a mild, self-limited disease in immunocompetent individuals, it can manifest as severe, watery diarrhea in hiv-infected patients and it can also occasionally lead to a chronic infection [ ] . in the profoundly immunocompromised, cryptosporidium parvum can lead to a malabsorptive syndrome, severe dehydration, and electrolyte derangements [ , ] . other protozoal infections that commonly affect patients with hiv include microsporidia, isospora, cyclospora, and, less commonly, toxoplasma and leishmania species, which like cryptosporidium, affect the small intestine and can lead to malabsorptive diarrheal illnesses [ ] . similarly, giardia also is a very common protozoal pathogen in both hiv-infected and immunocompetent hosts and infects the small intestinal mucosa. entamoeba histolytica is a protozoal pathogen that can cause colitis in the severely immunocompromised hiv-infected patient and in rare and severe circumstances can lead to ulceration, hematochezia, and even toxic megacolon. cytomegalovirus (cmv) is the most common viral gi pathogen in patients with aids [ ] . cmv can affect the entire gi tract but classically leads to diarrhea by causing colitis characterized by rectal bleeding, abdominal pain, and systemic signs such as fevers and weight loss [ ] . hiv infection itself can cause a diarrheal illness as described below, and multiple other viruses have been implicated as diarrheal pathogens, including adenovirus, coronavirus, herpes simplex virus, rotavirus, and norovirus [ , ] . rarely have fungi been reported to cause diarrhea in hivinfected patients [ ] . of the infections associated with endemic fungi, histoplasmosis is the most common fungal infection requiring hospitalization and can affect any part of the gi tract, causing diarrhea, weight loss, and fever [ ] . mycobacterium avium complex (mac) typically causes diarrhea in patients with aids with profoundly suppressed immune systems (i.e., cd ? t cell count \ cells/mm ) [ ] . symptoms are varied, but they usually reflect the systemic nature of the disseminated infection and include fever and weight loss [ ] . mac usually involves the small intestine; however, it can affect the entire gi tract [ , ] . salmonella, shigella, campylobacter, and e coli are bacterial infections of the gi tract that can present with diarrhea [ ] . they are usually spread through food and water contamination. patients with an impaired immune system can become asymptomatic carriers of some pathogens (e.g., shigella, campylobacter). clostridium difficile should be investigated in patients who have recently taken antibiotics [ ] . it causes pseudomembranous colitis that can progress to toxic megacolon in severe infections. clostridium difficile is more common in patients with advanced aids (cd ? t cell count \ cells/mm ). in one study evaluating the incidence of bacterial diarrhea in patients with hiv, clostridium difficile was the most common identified culprit, accounting for . % of episodes of diarrhea that had a bacterial pathogen isolated [ ] . overall, protozoa, fungi, mac, and cmv gi infections are usually seen only in patients with hiv and other immunocompromised patients [ ] . as noted earlier, with improved therapy, patients infected with hiv are less prone to develop diarrhea due to infectious pathogens and are more prone to noninfectious causes [ ] . the basic algorithm for the diagnosis and evaluation of diarrhea in patients with hiv is similar to the examination of diarrhea in the immunocompetent host and starts with a thorough medical history [ ] . this includes the duration of the diarrhea, constitutional and systemic symptoms, the presence or severity of abdominal pain, and questions on the characteristics of diarrhea (e.g., large versus small volume; infrequent or nocturnal versus frequent) to help localize the source to the large or small intestine and narrow the differential diagnosis (fig. ) [ , ] . classically, diarrhea from pathology in the small intestine presents as voluminous and watery, occasionally associated with weight loss as well as signs and symptoms of malabsorption [ ] . bloating, nausea, and cramping may also indicate a small intestine source. diarrhea from the large intestine is typically characterized by smaller, more frequent bowel movements [ ] . if there is inflammation of the rectum and anus, patients may describe tenesmus and painful defecation, which may be associated with hematochezia. a careful review of medications, travel history, contact with ill individuals, recent ingestions, family history, surgical history, and social history is important in evaluating acute and chronic diarrhea in the patient infected with hiv [ ] . physical examination and medical history of a patient with hiv and diarrhea may help to evaluate the chronicity of the diarrhea and the severity of illness and thereby focus the differential diagnosis. nutritional status should be assessed by evaluating for bitemporal wasting, weight changes, skin turgor, and mucosal dehydration. basic vital signs and orthostatic vital signs are essential to gauge the severity of the patient's illness and the degree of the patient's volume depletion. documented fever may be an important clue of an infectious etiology, though the absence of fever in an immunocompromised host does not rule out the possibility of an infection. the gi examination may reveal tenderness to palpation, possibly indicative of pancreatic pathology or colitis. hepatosplenomegaly may represent mycobacterial infection, hepatitis, or fungal or malignant causes of diarrhea. a rectal examination is of integral importance because it may reveal signs of sexually transmitted infections, bleeding, tenderness, and masses, all of which may help to establish a diagnosis. a careful, comprehensive examination of the patient is essential to evaluate the severity of disease, narrow the diagnosis, and guide the management. further diagnostic evaluation may also aid in a diagnosis [ ] . laboratory tests should include comprehensive metabolic panel, complete blood count with cell differential, blood cultures, hiv viral load, and cd ? t cell count to gauge the level of immune suppression. stool examinations should include fecal lactoferrin, fecal leukocytes, fecal calprotectin, fecal occult blood, and clostridium difficile stool culture, as well as three separate samples of ova and parasites. infection with cryptosporidium parvum is most commonly diagnosed by microscopic identification or enzyme immunoassay of the organisms in the stool of patients but can also be made by biopsy of the gi tract or aspiration from the biliary tree during endoscopy. diagnosis of giardia can be made by immunoassay of the stool but, again, can be identified on endoscopic biopsy or on luminal aspiration during endoscopy. diagnosis of bacterial infections of the gi tract, such as salmonella, is made by stool culture. if no pathogen is identified, further workup is needed with an endoscopic examination [ ] . colonoscopy with biopsy is necessary for diagnosis of cmv and hsv and may reveal hemorrhage, colitis, and ulcers [ ] . there is some debate as to whether sigmoidoscopy or full colonoscopy would be beneficial; one colonoscopy study (n = ) showed that nearly % of patients with cmv-associated colitis had disease localized to the cecum [ ] . however, a prospective study comparing sigmoidoscopy and full colonoscopy showed that the sensitivity of a sigmoidoscopy was % for enteric pathogens and full colonoscopy only yielded a small increase in sensitivity to %, with no additional cases of cmv-associated colitis identified [ ] . diagnosis of mac infection within the gi tract requires endoscopy, which may identify ulcerations, erythema, or normal mucosa but may also reveal foamy macrophages and positive culture via biopsy [ ] . diagnosis of fungal infections may be made histologically from biopsies taken for endoscopy or colonoscopy [ ] . mucosal biopsy can also help diagnose inflammatory bowel disease. for patients with negative diagnostic results, the diagnosis of noninfectious diarrhea can be made. the treatment of infectious diarrhea is outside the scope of this article, and this section will focus on the treatment of noninfectious diarrhea. if no other cause of diarrhea is [ ] . noninfectious diarrhea can be managed by modifying art and controlling symptoms with medications and lifestyle modification. however, clinical guidelines for patients with hiv recommend careful evaluation of the symptoms and symptomatic management of art-related aes (e.g., diarrhea) before switching art, with supportive care (e.g., antidiarrheals) generally allowing for continuation of prescribed art therapy [ , ] . however, cessation of art (''drug holiday'') is generally not advised as a management strategy. antidiarrheal medications used in noninfectious diarrhea can be divided into several classes: adsorbents, antimotility agents, and antisecretory agents (table ) [ , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . adsorbent drugs bind bacterial toxins, fluids, and other compounds in the intestines to improve stool consistency [ ] . drugs in this category include bismuth subsalicylate, kaolin/pectin, and attapulgite (aluminum magnesium silicate purified from clay). data on the use of adsorbents in patients with hiv are limited to one study in which the efficacy of attapulgite was not better than placebo in the management of diarrhea [ , ] . antimotility agents include loperamide, diphenoxylate/ atropine, and tincture of opium [ ] . these agents act upon opioid receptors in the gut to slow motility by decreasing peristalsis and increasing tone in the large intestine. this allows for greater fecal transit time and therefore longer time for water absorption. the antimotility agent diphenoxylate crosses the bloodbrain barrier and can cause central effects analogous to other opioid agonists [ ] . to prevent the abuse of diphenoxylate, it is usually sold as a combination agent with atropine. loperamide does not cross the blood-brain barrier and does not have these adverse effects. one disadvantage to loperamide is that it may interact with art agents, such as ritonavir and saquinavir, which can limit its use for long-term therapy [ , ] . however, loperamide has been shown in a small trial to decrease the number of bowel movements in patients with protease inhibitor-induced diarrhea [ ] . the use of the combination of lowdose diphenoxylate/atropine may be efficacious for treating protease inhibitor-induced diarrhea; however, it appears that this combination had no beneficial effect in patients who were refractory to loperamide therapy [ ] . although not studied for the treatment of diarrhea in patients with hiv, tincture of opium is considered more effective than loperamide as an antimotility agent, and it can be titrated easily. tincture of opium may be considered early in the treatment algorithm for patients with severe hiv-associated diarrhea. art antiretroviral therapy, hiv human immunodeficiency virus. reprinted with permission from [ ] antisecretory agents, such as octreotide, racecadotril, and crofelemer, directly inhibit secretory processes within enterocytes [ , [ ] [ ] [ ] [ ] . the mechanism of action of octreotide, administered subcutaneously, is unclear, but it is believed to alter the binding of vasoactive intestinal peptide, therefore acting as an antimotility and antisecretory agent [ , , ] . published data conflict about the efficacy of octreotide in treating diarrhea in patients with aids [ , ] . oral racecadotril is an enkephalinase inhibitor, which decreases the breakdown of endogenous gut opioids, thereby decreasing the secretion of water and electrolytes into the gut lumen [ ] . racecadotril is not currently available in the usa. orally administered crofelemer is a dual inhibitor of camp-stimulated cystic fibrosis transmembrane conductance regulator (cftr) and calcium-stimulated calciumactivated chloride channels (cacc) in the gut [ ] . crofelemer is a minimally absorbed gi drug derived from the latex of the croton lechleri tree, and has reportedly been used by amazonian tribes for diarrheal relief [ ] . crofelemer is the only agent approved in the usa for the symptomatic relief of noninfectious diarrhea in patients with hiv on art [ ] . compared with placebo, crofelemer has been shown, in a randomized, double-blind, placebo-controlled trial with an open-label extension, to significantly reduce symptoms of noninfectious diarrhea in patients with hiv receiving art (percentage of patients with b watery stools per week for at least of weeks during placebo-controlled phase: . versus . %, respectively; p = . ) [ ] . in addition, crofelemer has no known drug interactions with art drugs, is minimally absorbed, and does not have a negative impact on the clinical immune parameters (e.g., hiv viral load and cd ? t cell counts) [ , , ] . diarrhea is a common complication of hiv infection that has substantial clinical ramifications. the differential diagnosis for diarrhea in patients with hiv is broad. while infection has historically been the major cause of diarrhea in patients with hiv, with the widespread use of art therapy, noninfectious diarrhea has become a burden in this population. medications used for noninfectious diarrhea include antimotility and antisecretory agents, including crofelemer, which has been shown to significantly reduce symptoms of noninfectious diarrhea. improved treatment of noninfectious diarrhea will likely improve hiv medication adherence and quality of life. hiv/aids review centers for disease control and prevention. hiv surveillance-united states all-cause mortality in treated hiv-infected adults with cd [/= /mm compared with the general population: evidence from a large european observational cohort collaboration life expectancy of recently diagnosed asymptomatic hiv-infected patients approaches that of uninfected individuals centers for diease control and prevention national center for hiv/ aids viral hepatitis std and tb prevention. hiv in the united states: at a glance the changing etiology of chronic diarrhea in hiv-infected patients with cd cell counts less than cells/mm prevalence and impact of diarrhea on health-related quality of life in hiv-infected patients in the era of highly active antiretroviral therapy etiology and pharmacologic management of noninfectious diarrhea in hiv-infected individuals in the highly active antiretroviral therapy era global impact of antiretroviral therapy-associated diarrhea the association of hiv/aids treatment side effects with health status, work productivity, and resource use risk factors for gastrointestinal adverse events in hiv treated and untreated patients enteric parasitic infections in hiv/aids patients before and after the highly active antiretroviral therapy the gastrointestinal tract in hiv- infection: questions, answers, and more questions! prn noteb the mucosal immune system and hiv- infection expression of the chemokine receptors ccr , ccr , and cxcr by human tissueinfiltrating lymphocytes gastrointestinal tract as a major site of cd ? t cell depletion and viral replication in siv infection primary hiv- infection is associated with preferential depletion of cd ? t lymphocytes from effector sites in the gastrointestinal tract mechanisms of gastrointestinal cd ? t-cell depletion during acute and early human immunodeficiency virus type infection enhanced levels of functional hiv- co-receptors on human mucosal t cells demonstrated using intestinal biopsy tissue persistence of hiv in gut-associated lymphoid tissue despite long-term antiretroviral therapy hiv infection and the gastrointestinal tract review article: the aetiology, investigation and management of diarrhoea in the hiv-positive patient the mucosal barrier and immune activation in hiv pathogenesis an evidencebased position statement on the management of irritable bowel syndrome jejunal enteropathy associated with human immunodeficiency virus infection: quantitative histology hiv enteropathy: crypt stem and transit cell hyperproliferation induces villous atrophy in hiv/microsporidia-infected jejunal mucosa intestinal absorptive capacity, intestinal permeability and jejunal histology in hiv and their relation to diarrhoea the virotoxin model of hiv- enteropathy: involvement of gpr /bob and galactosylceramide in the cytopathic effects induced by hiv- gp in the ht- -d intestinal cell line gp -induced bob/ gpr activation: a possible cause of human immunodeficiency virus enteropathy hiv infection in gastric epithelial cells clinical focus: evolving options for managing noninfectious diarrhea in hiv-infected patients. clinical care options Ò hiv evaluation of hiv protease and nucleoside reverse transcriptase inhibitors on proliferation, necrosis, apoptosis in intestinal epithelial cells and electrolyte and water transport and epithelial barrier function in mice diarrhea-associated hiv- apis potentiate muscarinic activation of cl-secretion by t cells via prolongation of cytosolic ca ? signaling the hiv protease inhibitors saquinavir, ritonavir, and nelfinavir induce apoptosis and decrease barrier function in human intestinal epithelial cells hiv protease inhibitors induce endoplasmic reticulum stress and disrupt barrier integrity in intestinal epithelial cells irritable bowel syndrome and hiv: a cross sectional study of the severity of gastrointestinal symptoms and hiv-infected subjects jejunal bacterial overgrowth and intestinal permeability in children with immunodeficiency syndromes gastrointestinal bacterial overgrowth: pathogenesis and clinical significance no relationship between gastric ph, small bowel bacterial colonisation, and diarrhoea in hiv- infected patients etiological agents of diarrhea in patients infected by the human immunodeficiency virus- : a review diarrhea in the immunocompromised patient bacterial diarrhea in persons with hiv infection idiopathic aids enteropathy and treatment of gastrointestinal opportunistic pathogens aids-related diarrhea-pathogenesis, evaluation and treatment early use of tips in patients with cirrhosis and variceal bleeding clostridium difficile in a hiv-infected cohort: incidence, risk factors, and clinical outcomes investigation of diarrhea in aids cryptosporidium pathogenicity and virulence foodborne illness acquired in the united states-major pathogens cryptosporidiosis and isosporiasis among hiv-positive individuals in south ethiopia: a cross sectional study risk factors for intestinal parasitosis among antiretroviral-treated hiv/aids patients in ethiopia waterborne transmission of protozoan parasites: review of worldwide outbreaks-an update cryptosporidium surveillance and risk factors in the united states diarrheal diseases associated with hiv infection disseminated histoplasmosis: clinical and pathologic correlations endoscopic appearance of gi mycobacteriosis caused by the mycobacterium avium complex in a patient with aids: case report and review gastrointestinal infections in patients infected with hiv- diarrhoea due to small bowel diseases cytomegalovirus colitis in aids: presentation in patients and a review of the literature a prospective study of endoscopy in hiv-associated diarrhea diarrhea in patients with aids department of health and human services department of health and human services antimotility agents for chronic diarrhoea in people with hiv/aids management of protease inhibitor-associated diarrhea imodium a-d, and imodium multi-symptom relief (loperamide and loperamide-simethicone) pa: mcneil consumer healthcare crofelemer for the treatment of secretory diarrhea efficacy and safety of crofelemer for noninfectious diarrhea in hiv-seropositive individuals (advent trial): a randomized, double-blind, placebocontrolled, two-stage study population pharmacokinetic (pk) analysis demonstrates no drug-drug interactions (ddi) between crofelemer, a novel treatment for noninfectious diarrhea in hiv? individuals, and antiretroviral therapy (art) therapeutic effect of activated attapulgite mormoiron in related diarrhea syndrome of acquired immunodeficiency (aids) the treatment (tx) of nelfinavir (nfv) induced diarrhea (nfvid) [abstract mechanisms of action of long-acting analogs of somatostatin octreotide therapy of large-volume refractory aids-associated diarrhea: a randomized controlled trial multicenter trial of octreotide in patients with refractory acquired immunodeficiency syndrome-associated diarrhea crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from croton lechleri, targets two distinct intestinal chloride channels crofelemer: a review of its use in the management of non-infectious diarrhoea in adult patients with hiv/aids on antiretroviral therapy acknowledgments technical editorial assistance was provided, under the direction of the authors, by pratibha hebbar, phd, synchrony medical communications, llc, west chester, pa. funding for this support was provided by salix pharmaceuticals, inc. open access this article is distributed under the terms of the creative commons attribution noncommercial license which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. key: cord- -fan sf authors: thacker, stephen b.; stroup, donna f.; sencer, david j. title: epidemic assistance by the centers for disease control and prevention: role of the epidemic intelligence service, – date: - - journal: am j epidemiol doi: . /aje/kwr sha: doc_id: cord_uid: fan sf since , the centers for disease control and prevention has responded to urgent requests from us states, federal agencies, and international organizations through epidemic-assistance investigations (epi-aids). the authors describe the first years of epi-aids, breadth of problems addressed, evolution of methodologies, scope of activities, and impact of investigations on population health. they reviewed epi-aid reports and eis bulletins, contacted current and former epidemic intelligence service staff, and systematically searched the pubmed and web of science databases. they abstracted information on dates, location, staff involved, health problems, methods, and impacts of investigations according to a preplanned protocol. they assessed the methods presented as well as the quality of reports. during – , a total of , investigations of health events were initiated by , epidemic intelligence service officers. in the early years, the majority were in response to infectious agents, although environmental problems emerged. investigations in subsequent years focused on occupational conditions, birth defects, reproductive health, tobacco use, cancer, violence, legal debate, and terrorism. these epi-aids heralded expansion of the agency's mission and presented new methods in statistics and epidemiology. recommendations from epi-aids led to policy implementation, evaluation, or modification. epi-aids provide the centers for disease control and prevention with the agility to respond rapidly to public health crises. in , the us congress established the communicable disease center (cdc) to support state health departments in controlling communicable diseases ( ) . a critical part of this support was technical assistance, initially in the form of laboratory expertise and vector control necessary to support the agency's initial mission to combat malaria in the southeastern united states. by , under the guidance of alexander d. langmuir, md, epidemiologic support became the critical consultative tool, and epidemic-assistance investigations (epi-aids) became the most visible program of the new agency. the system of epidemiologic support was formalized by langmuir in with establishment of the epidemic intelligence service (eis) program ( ) . although the cdc (now the centers for disease control and prevention) works with health agencies throughout the world in multiple ways, the term epi-aid refers to investigations of serious and urgent public health problems in response to formal requests for rapid assistance from states, federal agencies (e.g., the indian health service, the national institutes of health, the food and drug administration, and the us department of defense), international organizations (e.g., the world health organization), and ministries of health from other countries. certainly, extensive service is provided by eis officers (eisos) and other cdc staff outside the formal epi-aid mechanism, including the majority of the work performed by officers and staff assigned to states and international settings. for example, the investigation of polio vaccine contaminated with live virus involved essentially all eisos and was conducted both in the field and at cdc headquarters, yet it was never classified as an official epi-aid ( ) . two other studies illustrate such service in later years. a study led by an eiso using data from a multicenter casecontrol study documented the high risk of pelvic inflammatory disease for women using the dalkon shield intrauterine device and recommended that all women using the device have it removed ( ) . an investigation led by an eiso assigned to the state health department documented the transmission of cryptosporidium infection through the public water supply in milwaukee, wisconsin, that led to an outbreak of disease affecting more than , residents and subsequent modifications of water quality standards ( ) . nevertheless, this critical mechanism of response remains a symbol of the cdc and eis: rapid response to a public health need whenever and wherever it is detected. as inaugurated in , epi-aid responses still are documented by an initial announcement, the epi- , followed by a report of the investigation, the epi- (now called the epi aid trip report), and sometimes later reports (epi- s and epi- s), all of which are addressed to the cdc director and relevant staff at the requesting agency and at the site of the investigation ( ) . these documents are labeled for administrative use, limited distribution and not for publication because results are preliminary and might contain identifying information about patients, providers, and institutions. meanwhile, epi-aids provide a rich chronicle of the practice of field epidemiology at the cdc since and often are key events that marked the evolution of the agency and public health practice (refer to appendix table ). use of the epi-aid mechanism expanded dramatically after establishment of the eis program, which provided a pool of field epidemiologists in training who were available to depart immediately for an investigation anywhere in the world. the success of the eis program, in part enriched by the availability of the epi-aid mechanism, plus the expansion of the cdc mission over time has resulted in more than , epidemiologists being trained ( ) . the initial class of men included physicians and a sanitary engineer. in contrast, the majority of the and eis classes of - members are women and include at least foreign citizens. approximately % of the us citizens are members of racial/ethnic minorities, and % are physicians. the majority hold a master's or doctorate degree, and the others hold a mixture of doctorates in multiple disciplines or are veterinarians, dentists, and nurses. in this report, we describe the first years of epi-aids. we highlight the breadth of health problems as the cdc's mission expanded; the evolution of the epidemiologic, statistical, and information display tools; the national and global scope of activity; and the impact of these investigations on the health of communities. we reviewed bound copies of all epi-aid reports maintained by the cdc's public health library. in addition, we reviewed available copies of eis bulletins and contacted current and former eis supervisors and officers in an attempt to locate published reports based on the epidemiologic investigations. we also identified related publications through online searches of the pubmed and web of science databases (updated january , ). we abstracted information according to a preplanned protocol and included relevant dates, location, staff involved, and suspected or confirmed health problems (table ). in addition, we reviewed laboratory, statistical, and data presentation methods as well as recommendations and impacts on health resulting from the investigations. to assess the statistical and other methodological characteristics of eis investigations, we adapted a rubric for assessing published statistical practice ( ) . we used this rubric to code all reports on epi-aids according to statistical and other methods presented. types and frequencies of applied methods were classified systematically into categories ( table ). reports containing analyses beyond descriptive ones were classified as basic, intermediate, or advanced according to the sophistication of applied statistical techniques. reports using stratification, nonparametric methods, one-way analysis of variance, simple correlation, and regression were counted as intermediate analyses. reports containing any method of multivariate analysis, statistical modeling, advanced contingency table analysis, or survival analysis were categorized as advanced analysis. for this report, we did not implement a rigorous assessment of quality of statistical methods applied; however, we do comment on different aspects of methodological quality. during the years from through , eisos and their colleagues initiated investigations of , health problems in every state and globally (figures - ). during the early years, the geographic distribution of epi-aids was a function of location of the cdc facilities as well as population. since , the cdc facilities outside atlanta, georgia, have been located in alaska (current), arizona, california, colorado (current), kansas, maryland (current), montana, new mexico, north carolina (current), ohio (current), pennsylvania (current), puerto rico (current), texas, washington (current), west virginia (current), and washington, dc. the district of columbia and states did not invite the cdc for epi-aids during the first decade, including new york (the most populous state at the time), massachusetts, connecticut, rhode island, wisconsin, and south dakota, but all states and the district of columbia had one or more requests during each of the subsequent decades. the first response to a health concern outside the united states was after a flood in canada in . as the cdc's international presence became known, international requests for assistance followed from world regions ( figure ). first decade. during the initial decade, - , a total of of ( %) epidemic assistance requests were conducted after the eis program was established in july , and all but were conducted in response to infectious agents. interestingly, a investigation of dysentery in table . classification and number of health problems addressed in epi-aids, - - - - - - abbreviations: epi-aids, epidemic-assistance investigations; hiv, human immunodeficiency virus. a the numbers in parentheses are not included in the virus total. b these numbers also include epi-aids that were discontinued or consolidated into one investigation. year - - - - - - early epi-aids provided the foundation for later methodological developments to address emerging health problems and organizational decisions. in , a response to hepatitis in georgia included an innovative analysis of racial disparities. a investigation of diphtheria in montana resulted in a recommendation that a full-time health department be established in that state. we identified the first peerreviewed publication that resulted from a investigation of western equine encephalitis in colorado ( ). recommendations from an epi-aid to investigate impetigo in a laundry associated with a neonatal ward in provided the foundations for the cdc's hospital infection prevention activities. the first example of a health communication professional participating in an investigation occurred during a epi-aid addressing polio in ohio; this investigation subsequently was covered in life magazine ( ) . during that period, more diseases were identified as the cdc added programmatic responsibilities and increased laboratory capacity, and environmental problems began to be reported. for example, a epi-aid documents the death of a child at the mayo clinic in rochester, minnesota. the cause was ini-tially thought to be trichloroethylene exposure but later was determined to be caused by agranulocytosis from an unknown contaminant in raw milk. second decade. the number of epi-aids increased to during - . occupational conditions appeared in epi-aid files in , when workers in a garment factory suffered from heat exhaustion and anxiety. in , we have the first epi-aid concerning birth defects; in that same year, an outbreak initially reported as fatty degeneration syndrome was probably among the first reported cases of reye syndrome. forty-three outbreaks of suspected polio were confirmed in investigations during the decade after vaccine availability, often among vaccinated populations. the cdc responded with stockpiled oral polio vaccine. indeed, a epi-aid documented the highest recorded incidence of polio in west germany, probably attributable to live vaccine. in , the eis investigation of the first adverse reaction to live virus polio vaccine was reviewed by a blue-ribbon panel that included albert sabin. in , epi-aids involved eisos in the first isolation of the virus causing st. louis encephalitis from a bird in nature, the first outbreak of turkey ornithosis in which human cases occurred among persons not involved in processing work, and the first outbreak of hepatitis in the united states attributable to a municipal water supply. in , an epi-aid resulted in the first report of inhalation anthrax in modern world literature. the first identification of type e botulinum toxin came from an epi-aid in michigan in , and, in that same year, an epi-aid investigation of the first reported localized outbreak of neisseria meningitidis group b at a year - - - - - - - - - - - - california naval base demonstrated failure of antimicrobial prophylaxis. throughout the second decade, epi-aids thrust eisos into the midst of legal debate. for example, a investigation of hepatitis caused by drug toxicity was postponed because of legal concerns. in , an investigation of illness associated with an industrial cafeteria resulted in litigation brought by the employees against management, and an outbreak of foodborne illness resulted in a lawsuit against the grocery chain distributing the product. of note is that, as commissioned officers of the us public health service, eisos need permission from the us surgeon general to testify in a court of law, which limits their availability for testimony. third decade. during - , eisos and their colleagues investigated , reported health problems (figure ), an increase of more than % over the previous -year period. botulism was suspected in epi-aids; of these, were confirmed food botulism, were wound botulism, was a laboratory incident, and the other suspect cases were found to have multiple etiologies (e.g., guillain-barré syndrome). in of the botulism investigations, the father and mother of a family of moving from oklahoma to colorado were found dead in their car, and their -year-old daughter was comatose for days before recovery. apparently, the family had eaten contaminated meatloaf brought on the journey. other investigations of suspected botulism among people in a car in and ultimately were determined to have been caused by carbon monoxide poisoning; the investigations documented increased susceptibility to carbon monoxide among smokers. in a investigation, an outbreak of pneumonia at a washington, dc, hospital seemed to be caused by exposure to the hospital grounds, but no etiologic agent was identified. a investigation of an outbreak of febrile myalgia was determined to be related to the air-conditioning in the pontiac, michigan, health department, which also led to illness among the eisos; again, however, the etiologic agent was undetermined. (in , an epi-aid in pennsylvania led to identification of legionella pneumophila by the cdc laboratorians as the causal agent in all outbreaks, as well as a epi-aid in a minnesota meat-packing plant.) the cdc's role in the global smallpox eradication program had a profound and lasting effect on the agency. during - , domestic and international epi-aids were initiated for smallpox or cowpox; however, only in the international epi-aids was smallpox confirmed or surveillance activities initiated where disease was known to be prevalent. typically, the cause of the other cases was chickenpox or insect bites. smallpox eradication campaigns involved eisos in ghana, india, and yugoslavia. other international epi-aids required eisos to investigate emerging hemorrhagic fevers in germany (marburg virus, ) and sierra leone (lassa fever, ) . development of the cdc's chronic disease program evolved from a investigation of acute lymphocytic leukemia in illinois. interest in chronic disease persisted throughout the decade- cancer clusters were investigated (the vast majority were leukemia), as well as cardiomyopathy and diabetes. attention was directed toward broader aspects of reproductive health and family planning beginning in . investigations related to maternal death from abortion and increased incidence of abortion led to an evaluation of family planning services in new york in . during this decade, investigations involved aspects of reproductive health; others involved birth defects. also during the third decade, eisos moved into other fields of public health (e.g., the epidemiology of illicit drug use and violence, infectious complications of needle sharing by intravenous drug users ( and ) , and heroinrelated overdose deaths in georgia ( )). in , an eiso investigated homicides in atlanta. fourth decade. during - , eisos and their colleagues investigated a total of , reported health problems, a number comparable to that in the previous -year period, but with the size and complexity of the investigations reaching new levels. new infectious problems initially investigated as epi-aids included legionnaires disease in and ebola hemorrhagic fever in zaire and sudan in . in , an investigation of kaposi's sarcoma and pneumocystis carinii pneumonia represented the initial investigation of what would become known as acquired immunodeficiency syndrome, and, in , an epi-aid was conducted to study a cluster of deaths related to conjunctivitis among children, later termed brazilian purpuric fever. attention to social and behavioral aspects of health also evolved during this decade. for example, in , the asso-ciation of binge drinking with bacterial infections was noted among american indians. a analysis of health effects of drought in haiti included income as well as more innovative measures of socioeconomic status, and the investigator recommended that a refugee unit be established at the cdc. in the first epi-aid regarding unintentional injuries caused by motor vehicles in , increased mortality was related to -wheeled all-terrain vehicles in alaska. testimony before the consumer product safety commission led to a nationwide ban on these vehicles. eisos were dispatched to solve problems involving mysterious circumstances, including a investigation of cardiac deaths associated with a popular liquid protein diet, unexplained sudden deaths among hmong refugees in , and infant deaths from digoxin overdose associated with a hospital nurse in . fifth decade. the epi-aids conducted during - involved substantial and increasingly complex health problems. for example, a epi-aid involved more than , reported cholera cases in peru, the first time the disease had been discovered in that country during the th century and an event marking the beginning of a new cholera pandemic. also in , an epi-aid documented the first cholera outbreak in the united states associated with a commercial product, a coconut milk topping. during a decade highlighted by emerging infectious diseases, epi-aid investigations uncovered the first human case of salmonella enterica serotype newport associated with antibiotic use in animals ( ); the first occurrence of meat as a vehicle for listeria monocytogenes ( ); the first confirmed case of human ehrlichiosis ( ); and the first outbreak caused by escherichia coli o :h , a non-o , shiga-like toxin-producing e. coli ( ). investigation of a epidemic of cholera in guinea bissau confirmed that those who had eaten rice and fishmeal prepared by the same persons who had prepared an epidemic victim for burial were at increased risk. in , eisos discovered that apple cider can carry e. coli o :h , and, years later, an epi-aid identified hundreds of confirmed cases of bloody diarrhea and dozens of cases of hemolytic uremic syndrome caused by e. coli o :h associated with consumption of undercooked hamburgers sold at the jack-in-the-box (san diego, california) fast-food chain. in addition to these advances in infectious conditions, the percentage of epi-aids related to disabilities, injuries, environmental exposures, cardiovascular disease, and other chronic diseases increased. the first physical-activity-related epi-aid in assessed the impact of a community-based exercise program; a survey of tobacco outlets revealed that the majority of them sold to minors despite laws forbidding such sales. hurricane andrew stimulated an acute response in , with long-term follow-up the next year. an epi-aid in philadelphia, pennsylvania, confirmed more than deaths resulting from heat exposure in philadelphia in ; a year later, an investigation of heat-related deaths in states uncovered deaths in chicago, illinois, and in milwaukee during days. in , an epi-aid in georgia noted that . % of children aged years or younger were confirmed victims of child abuse or neglect, and, during an investigation of school violence in , approximately % of students reported having access to handguns and % of students favored using metal detectors in schools. increasingly, recommendations from epi-aids led to federal policy implementation, evaluation, or modification. a investigation of an epidemic of diarrhea linked to s. enterica serotype enteritidis contamination of commercial pasta led to a labeling change. the food and drug administration recalled l-tryptophan when a series of investigations in - linked it to eosinophilia-myalgia syndrome. a epi-aid evaluated a policy prohibiting tobacco sales to minors; in , another evaluated the effectiveness of anonymous human immunodeficiency virus testing and counseling. sixth decade. during - , fewer epi-aids (n ¼ ) were requested, probably reflecting increased state and local health department capacity as well as more field-based eisos, but an increase in multistate and nationwide investigations was also evident. two infectious disease events might have highlighted any other decade had they not been overshadowed by terrorism and disasters. the first was the introduction of west nile virus in new york city in and its subsequent systematic march across the country in ensuing years. the threat posed by this virus was anticipated in a epi-aid that identified more than suspect west nile virus cases in romania. during - , a total of west nile virusrelated epi-aids were conducted in new york, louisiana, mississippi, and arkansas. the second event, the devastation wrought by the newly identified coronavirus that causes severe acute respiratory syndrome led to epi-aids in the united states and in asia-vietnam, taiwan, and thailand. three multistate investigations confirmed the strong association (odds ratio ¼ ) between rotavirus vaccine and intussusception ( ), discovered the association between development of meningitis infection and cochlear implants ( ), and documented transmission of monkeypox from exotic animals sold as pets by a single distributor ( ) . the events of september , , were not the only criminal activities that involved eiso investigations. a epi-aid documented acute renal failure attributable to contaminated glycerin being added to acetaminophen syrup in haiti, resulting in deaths. that same year, epidemiologic data from an epi-aid supported a criminal investigation of abscesses in of patients treated with intramuscular adrenal cortex injections by a single physician. a investigation exposed intentional poisoning of texas hospital employees who had consumed tainted pastries in a break room, leading to shigellosis among persons. in , epi-aids were conducted in response to anthrax threats directed at california clinics performing abortions and in pennsylvania in response to a cluster of serratia marcescens cases associated with a respiratory technician tampering with equipment. food and waterborne disease investigations were more frequently national and international in scope, no doubt reflecting broader societal changes in both the sources of food and dietary preferences. a epi-aid linked cases of gastroenteritis to raspberries from guatemala contaminated with cyclospora and traced it to birds in the berry fields. a multistate outbreak investigation for the first time associated salmonella with cold cereal, and the largest outbreak of e. coli ever documented in the united states was investigated among an estimated , persons who became ill after eating at catered events. an investigation in of a multistate outbreak of cases of s. enterica serotype bareilly from contaminated bottled water convinced the food and drug administration to recall the product. in , eisos documented the first norovirus outbreak attributed to commercially prepared food (delicatessen-type meat). by this time in public health, diet, fitness, and recreation were well documented as being necessary for a healthy lifestyle, but eisos demonstrated that these efforts are not without risk. health consequences included herpes infection among wrestlers, methicillin-resistant staphylococcus aureus among football players, and cryptosporidiosis among swimmers. persons from countries and us states who participated in ecochallenge contracted leptospirosis, and campylobacter jejuni was identified among bike tour participants from states and canada in . in addition, military trainees suffered from muscular overuse injuries, and hockey players experienced carbon monoxide and nitrogen dioxide poisoning from incorrect use of an ice resurfacing machine. efforts to maintain a healthy diet were complicated by widespread salmonella epidemics associated with presliced tomatoes in and and with unpasteurized orange juice in , and by the largest hepatitis a foodborne outbreak in us history in , which was associated with green onions. an internet hoax claiming that necrotizing fasciitis was associated with bananas was disproven by a epi-aid. the first transmission of nipah virus from pigs to humans was reported in malaysia in , recurring in bangladesh in . in , the ebola hemorrhagic fever investigation team diagnosed cases and deaths in sudan and uganda, the largest documented outbreak of this disease and the first with an onsite laboratory. in , investigations of cases and deaths in kenya showed that they were related to hepatotoxicity caused by aflatoxin-contaminated maize. environmental hazards continued to challenge eisos as they evaluated allergic reactions to tattoo products in multiple states and assessed access to sidewalks, safety, and ease of walking in west virginia as part of their obesity prevention activities. epi-aids evaluated the effect of president clinton's welfare reform on access to prenatal care in new york city ( ) and the impact of legislation granting oregon adoptees aged years or older access to their birth records ( ) . the investigation of migrant deaths (most commonly from heat stroke) within years at the us-mexico border documented a serious consequence of illegal immigration. a epi-aid studied the health and behavioral repercussions of the electricity blackout in ohio, michigan, and new york. during early epi-aids, reported statistical methods were primarily calculations of rates and measures of central tendency (percentages, means, and modes). data display most often consisted of -or -way tables. the first use of a frequency distribution occurred in a epi-aid concerning suspected measles. also in that year, a report on hepatitis in kentucky contained the first mention of an analysis using punch cards; this report was also the first to use a map. a epi-aid report on encephalitis among florida horses provided an early cost-benefit analysis, noting in the recommendations that the price of a horse was less than the price of one dose of the recommended vaccine. a social network analysis was used in to investigate rabies among dogs. by the end of , we began to see sporadic, if not routine, use of epidemic curves. during - , a total of of ( %) reports included no statistical results. of the remainder, the most frequent statistical methods were summary measures of central tendency (e.g., mean, median, and percentage) or attack rates. of the epi-aids that reported any statistical methods, ( %) collected data through convenience survey methods or used existing surveillance data. rarely were measures of variability or confidence intervals reported. we located only one analysis that used stratification and no advanced methods. still, change was evident during the s. a statistician eiso introduced an innovative measurement of socioeconomic status as a risk factor for illness, and the first anthropologist in the eis used anthropologic methods in an investigation of polio in arizona in . perhaps as a result of increasing diversity of disciplines in eis, epidemiologic methods advanced as well. the first dose-response analysis occurred during a investigation of hepatitis in a texas housing project. a report of the association of breastfeeding with illness from an investigation of staphylococcus in a newborn nursery was the first to use exclusion criteria, a chi-square statistic, and a p value; the fatality rate was the highest reported to date in the united states. we begin to observe use of odds ratios ( ), stratified analysis ( ), and computers (the ibm (international business machines corporation, armonk, new york) method, ). randomization methods were reported first in as the cdc randomization technique. inferential methods appeared as the first use of an epidemic threshold ( ), and the first use of the t test in an epi-aid was reported in . in that same year, a pie chart was used for the first time in a report of an outbreak of polio in the marshall islands. influenced by langmuir, epi-aids often were initiated after review of surveillance data; this was documented in of , ( %) of all epi-aids conducted during [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . only ( %) provided no statistical methods compared with % during the previous decade. the most frequent statistical methods continued to be summary measures of central tendency or attack rates. however, during the third decade, data collection methodology in epi-aids shifted from convenience survey methods or case-series to case-control or cohort studies. we note the emergence of multivariate methods in regression ( ) in part, the increasing sophistication of statistical methods was a result of the increasing use of computers and software packages, as well as coverage of these topics in the eis introductory course. indeed, the first mention of sas (sas institute, inc., cary, north carolina) and spss (spss, inc., chicago, illinois) software in an epi-aid was in in an investigation of injuries during a prison riot. quality control for keypunching was reported first in a suicide study. the first use of a deterministic mathematical disease model in an epi-aid, the reed-frost model, was reported in a investigation of a measles outbreak. despite this sophistication in methods, we continue to observe reporting of personal identifiers as late as , the lack of statistical methods in ( . %) of , investigations during - , and a tendency to report p values without accompanying statistical methods in ( %) reports. new methods continued to be used in epi-aids during - , including time-series analysis to study food poisoning in peru ( ), capture-recapture methods to study school-related deaths ( ), record matching to study motor vehicle injuries among older drivers ( ), and generalized estimating equations to study dengue in palau ( ). case-control studies became the method of choice during this decade; epi-aid reports often used matching techniques. frequently, both risk ratios and odds ratios were reported. as computer software became more widely used, logistic regression began to replace mantel-haenszel adjustment for risk estimates. unfortunately, power calculations were reported rarely, and still p values often were given without explanation of methods. during - , eisos increasingly incorporated economic data into their investigations of disasters ( ), coxsackievirus infection ( ), hepatitis a ( ), meningitis ( ), program evaluation ( ), measles ( ), and coccidioidomycosis ( ) . again, during this decade, use of surveillance methods was prevalent; ( %) of epi-aids were initiated through review of surveillance data or used surveillance data for analysis. only ( %) epi-aids included no statistical methods in the report. eisos continued to explore new methods of analysis: a logic model ( ), walter's method ( ) for cluster analysis ( ) a method for repeated measures ( ) ( ) , calculations for an overcrowding rate ( ), and a time/ space method ( ). as during previous decades, the method for randomization was reported rarely. the data and stories included in the , epi-aids describe a fascinating history, a history elaborated in scientific publications, in multiple books, and frequently in the popular press, the last most notably in the pages of the new yorker magazine by berton roueché ( , ) . the importance of this history to the eis program and of the , eisos to the cdc and to public health is, however, the reason for summarizing the epi-aid story in this report. the reason for absence of epi-aids in some us states during certain years was not always clear. certainly, throughout the years, both state and local health departments developed increased epidemiology and laboratory science capacity. sometimes the reasons might have been based on local politics or legal considerations. at other times, the absence of epi-aids might be attributed to personality clashes or a perception that eisos or their supervisors did not respect the local needs and constraints. for example, no epi-aids occurred in new york state during - , and the state health officer, herman hilleboe, an assistant surgeon general temporarily assigned to the state, is reported to have said, ''i don't want any of langmuir's storm troopers in new york.'' more often, the resistance was less explicit and more passive. nonetheless, the legacy is one primarily of collaboration and mutual respect, and the data support this conclusion. during the years reported on here, , epi-aids were initiated by , eisos (many eisos participating in multiple investigations). the leveling off in the number of investigations since paralleled enhanced capacity of public health departments across the united states and increased complexity of investigations conducted by eisos (figure ). during this time, , epi-aids were completed in the united states and puerto rico ( figure ); were conducted in countries and territories ( figure ) . naturally, as the communicable disease center until , the cdc focused almost exclusively on infectious disease; only limited numbers of epi-aids were not directed to infections (table ) . sometimes, outbreaks of unclear cause led to new or unexpected etiologies. the pursuit of an infectious cause of cancers led to more than investigations of clusters during the s and s. no infectious causes were identified, but the effort formed the basis for development of a chronic disease program and, in , formation of the national center for chronic disease prevention and health promotion. similar efforts to apply epidemiology and surveillance to birth defects and to population concerns were highlighted by epi-aids, and programs in women's health and the cdc's national center for birth defects and developmental disabilities were established in . today, approximately % of the cdc's staff and budget remains devoted to combating infectious diseases around the world, but an increased proportion of the work and of the eis classes is focused on prevention and control of chronic diseases, injuries, environmental health exposures, and noninfectious conditions affecting women and children. the number of epi-aids directed to bacterial disease declined from a peak in the decade ending in but has remained at approximately since then. the number devoted to viral diseases declined at the same time and stabilized at approximately during the past decades, with a similar pattern for parasitic diseases. in contrast, epi-aids for mycobacteria, particularly tuberculosis, have increased during the past decades, as have those for chlamydia and fungal infections. the epi-aid mechanism has also been increasingly used for urgent program evaluations in those years. other than investigations of cancer clusters and problems related to women's and children's health, the epi-aid process has had limited application to chronic disease. similar to investigations of infectious diseases, urgent program evaluation using the tools of an epidemiologist has been adopted some in the past decades, particularly to evaluate laws and policies. in contrast, epi-aids for environmental health and injury events have been used more extensively, starting with the flood disaster in winnipeg, ontario; langmuir was the consulting epidemiologist. these investigations were often in response to natural and human-made disasters and led to development of standard practices that are now routine in response to floods, heat waves, hurricanes, tornadoes, and other widespread health events. similar epidemiologic and surveillance methods have been applied to injuries, both intentional and unintentional, with limited but increasing frequency during the past decades. the evolution of statistical methods in the acute setting of the epi-aid reflects a similar pattern in other public health settings ( table ). especially notable is the increased use of multivariate modeling beginning in the late s, paralleling advances in computer hardware, especially the laptop, and advances in computer software, most notable cdcsponsored epi info, an open-source software package developed in the s for practicing epidemiologists and now translated into other languages ( ) . epi-aids provide the cdc with a unique ability to respond immediately to public health crises throughout the united states and internationally. to many people, the cdc's capacity for rapid response symbolizes its, and more particularly the eis program's, special role in protecting the public's health. the scope and impact of the eis program since its inception in is reflected dramatically by these investigations. such investigations are only a part of what the agency and eisos do; nonetheless, they contribute considerably to the trust in the cdc expressed by the us public and the international community ( ) . the ability to adapt to new challenges in often uncertain and sometimes hazardous settings is chronicled in these reports. continuing success of the eis program and the cdc depends on the ability to retain that agility and anticipate new challenges. to do so, the cdc must continue to prepare its workforce adequately for future public health needs and to base all its work on the best science available. retired from the centers for disease control and prevention, atlanta, georgia (david j. sencer). sentinel for health: a history of the centers for disease control fifty years of epidemiology at the centers for disease control and prevention: significant and consequential the cutter incident. poliomyelitis following formaldehyde-inactivated poliovirus vaccination in the united states during the spring of . i. background type of intrauterine device and the risk of pelvic inflammatory disease a massive outbreak in milwaukee of cryptosporidium infection transmitted through the public water supply epidemiologic field investigations by the centers for disease control and epidemic intelligence service epidemic intelligence service of the centers for disease control and prevention: years of training and service in applied epidemiology the use of statistics in medical research: a comparison of the new england journal of medicine and nature medicine ecology of western equine and st. louis encephalitis viruses; a summary of field investigations in weld county, colorado, to health squad traces polio in ohio mapping mortality and morbidity patterns: an international comparison application of gee procedures for sample size calculations in repeated measures experiments the medical detectives ga: us department of health and human services usda get the highest ratings of thirteen federal government agencies. the harris poll author affiliations: office of surveillance, epidemiology, and laboratory services, centers for disease control and prevention, atlanta, georgia (stephen b. thacker); data for solutions, inc., decatur, georgia (donna f. stroup); and the authors are indebted to alexander d. langmuir for his contributions to the practice of field epidemiology and to the establishment of the epidemic intelligence service. they thank lisa pealer and meghan spall for their tireless efforts in collecting and organizing historical information about epi-aids and the eis program.the findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the centers for disease control and prevention.conflict of interest: none declared. key: cord- - obc k u authors: ahmed, ali; dujaili, juman; sandhu, anisha kaur; hashmi, furqan khurshid title: concerns of hiv-positive migrant workers in covid- pandemic: a call for action date: - - journal: journal of global health doi: . /jogh. . sha: doc_id: cord_uid: obc k u nan t he unaids set a goal to eradicate the acquired immunodeficiency syndrome (aids) epidemic worldwide by [ ] . the global coronavirus disease (covid- ) pandemic is deemed to pose a greater risk to patients with chronic diseases, including those that are affected by human immunodeficiency virus hiv/aids [ ] . during this time, it is crucial to properly identify hiv/aids patients to ensure that they continue to receive timely and equitable access to health care and health support as they are increasingly vulnerable to covid- consequences [ ] . covid- emerged in china at the end of spreading rapidly to infect over countries and territories worldwide resulting in more than confirmed cases and deaths as of th july [ ] . while it has been realized that patients with chronic conditions require additional health support to mitigate risk of covid- , it is also important to recognise the vulnerability of chronically-ill migrant populations whose health issues are often neglected [ ] . this is especially of concern in hiv/aids-infected migrant populations who avoid deportation and are considered illegal as immigration laws in various countries do not permit carriers of hiv infection to work or stay regardless of their legal status [ , ] . reports have confirmed that russia, middle-east and south-east asian countries usually deport migrant workers who test positive for hiv [ ] . reports have confirmed that until , approximately hiv-positive patients have been deported back to pakistan from the gulf countries [ ] . in a bid to escape deportation, these hiv positive migrants are often forced to obtain antiretroviral therapy (art) illegally through exploitation of informal channels, friends or family to continue treating their condition [ , ] . in other cases, these migrants are forced to buy expensively priced drugs (or in desperation, share the highly sought treatment with other migrants in order to afford it) [ ] . additionally, access to health care has been challenging during the covid- pandemic with governments globally opting to curb the spread of the virus by introducing different national measures including lockdown or movement control, self-isolation and social distancing [ ] . the lockdown and quarantine measures taken by most countries have been daunting for its hiv/aids-infected migrant population (legal or illegal) many of whom have been forced into unemployment and are unsure how to access appropriate health support, obtain essential medications or treatment [ ] . not only do these migrants face difficulties in accessing public and health services they may have depended on previously, but they also may be living in inadequate accommodation where they are unable to observe safe and appropriate social distancing and hygiene protocols [ ] . migrants living with hiv/aids often feel reluctant to inform their employers of their condition due to the social stigma associated with being a hiv/aids patient [ ] . hence, they continue to work, exposing themselves and others to risk [ ] . despite the increased risk of contracting covid- , hiv-infected migrants in the uk tend not to be eligible for financial employment assistance though they may be in unstable employment. hence, they face increasing difficulties in earning or receiving sufficient funds to afford art medication [ , ] . ensuring a migrants' good health is critical for the countries in which they originate from and move to [ ] however, reports globally show that migrants are often subject to health inequalities due to lack of access to adequate health care as a result of neglect, exclusion, discrimination, unfavourable employment conditions causing ill health, inadequate living conditions, financial constraints or lack of appropriate legal status [ ] . studies conducted in australia and europe respectively show that migrants are behind in fulfilling the unaids - - target (a strategy where % of hiv patients should be aware of their hiv status, receive sustained antiretroviral therapy and achieve viral suppression by the year ) and more prone to being lost to follow-up art treatment when compared to non-migrant population [ , ] . access to health care is also affected by a divide in the skill level of employment that migrants are hired for [ ] . highly-skilled professional foreigners, often referred to as 'expatriates', tend to experience better health care access when compared to migrants working in low-skilled employment [ ] . the pressures of social adjustment and poor health literacy also increase the migrant workers vulnerability to deteriorating health in times of a pandemic as they navigate through the difficulties of integrating into a foreign culture and language, while accepting the loss of their traditional values, beliefs and support systems [ ] . overall, these factors further expose a highly-vulnerable migrant population suffering from hiv/aids to the threat of contracting the covid- virus [ ] . hiv/aids patients are advised to observe precautions similar to general recommendations for cov-id- such as hand washing, cough and sneezing etiquettes, and social distancing [ ] . they should also be assured with a -day supply of art treatment as well as adequate supply of appropriate medications to treat other acute or chronic illnesses or addictions [ ] . while sufficient evidence is not available at present to link hiv/ aids patients undergoing art treatment to a higher susceptibility of covid- virus, nonetheless individuals with advanced-stage or poorly regulated hiv (low cd tlymphocytes count and high viral load) are at increased risk of infection, health complications and therefore, stand an increased chance of contracting covid- [ ] . studies have shown that migrants seldom bring infections that pose a threat to the population of the host country [ ] . in the past, outbreaks of hepatitis a, b, hiv and tuberculosis have occurred in non-endemic regions due to a lack of timely treatment provision to refugees [ ] . a study conducted by mendelsohn et al. in malaysia compared the adherence of art between refugees and the host population. it has been noted that, if asylum seekers are included in primary care, the high levels of compliance achieved (equal to those in the domestic population) have decreased onward hiv transmission [ ] . in short, most migrants (whether legal or illegal) lack adequate health entitlements and face health inequalities that prevent them from accessing health care in a safe, appropriate and fair manner [ ] . some countries, such as thailand and spain have ensured equal access to health care for all legal and illegal who need to issue advisory to all the countries for timely access of antiretroviral therapy to hiv positive migrants regardless of their legal status. photo: from the authors' own collection, used with permission. migrants in accordance with the human rights framework [ ] . the world health organization (who) should provide guidelines to all countries with hiv/aids infected migrants (whether legal or illegal) to adhere to so the migrant population continues to receive fair, assured and uninterrupted supply of art treatment during the covid- pandemic to maintain their immunity, health and decrease risk of co-vid- contraction. this will ensure another step is taken in a positive direction for the who to fulfil its slogan of "health for all". funding: we declare we received no direct or indirect funding from any institution or organization for this viewpoint. authorship contributions: aa conceived the idea, aks, fkh, and aa retrieved the data, did write up of viewpoint and finally jd reviewed and provided her inputs. all authors approved the final version of manuscript. competing interest: all authors completed the icmje form (available upon request from the corresponding author) and declare no conflict of interest. what is required to end the aids epidemic as a public health threat by ? the cost and impact of the fast-track approach redefining vulnerability in the era of covid- countries where covid- has spread migrants with hiv of concern in covid- era infectious diseases and migrant worker health in singapore: a receiving country's perspective i was waiting to die': in russia, hiv+ migrants fear death and deportation , migrants deported from gulf states due to hiv labour migrants in central asia deserve our attention migrants living with hiv during the coronavirus (covid- ) pandemic breaking down the barriers: understanding migrant workers' access to healthcare in malaysia gaps in the hiv diagnosis and care cascade for migrants in australia effect of legal status on the early treatment outcomes of migrants beginning combined antiretroviral therapy at an outpatient clinic in milan, italy healthcare is not universal if undocumented migrants are excluded is forced migration a barrier to treatment success? similar hiv treatment outcomes among refugees and a surrounding host community in kuala lumpur key: cord- -tuq z gm authors: weiss, robin a; mcmichael, anthony j title: social and environmental risk factors in the emergence of infectious diseases date: journal: nat med doi: . /nm sha: doc_id: cord_uid: tuq z gm fifty years ago, the age-old scourge of infectious disease was receding in the developed world in response to improved public health measures, while the advent of antibiotics, better vaccines, insecticides and improved surveillance held the promise of eradicating residual problems. by the late twentieth century, however, an increase in the emergence and re-emergence of infectious diseases was evident in many parts of the world. this upturn looms as the fourth major transition in human–microbe relationships since the advent of agriculture around , years ago. about new diseases have been identified, including legionnaires' disease, human immunodeficiency virus (hiv)/acquired immune deficiency syndrome (aids), hepatitis c, bovine spongiform encephalopathy (bse)/variant creutzfeldt-jakob disease (vcjd), nipah virus, several viral hemorrhagic fevers and, most recently, severe acute respiratory syndrome (sars) and avian influenza. the emergence of these diseases, and resurgence of old ones like tuberculosis and cholera, reflects various changes in human ecology: rural-to-urban migration resulting in high-density peri-urban slums; increasing long-distance mobility and trade; the social disruption of war and conflict; changes in personal behavior; and, increasingly, human-induced global changes, including widespread forest clearance and climate change. political ignorance, denial and obduracy (as with hiv/aids) further compound the risks. the use and misuse of medical technology also pose risks, such as drug-resistant microbes and contaminated equipment or biological medicines. a better understanding of the evolving social dynamics of emerging infectious diseases ought to help us to anticipate and hopefully ameliorate current and future risks. popular writing on emerging infectious diseases resounds with dire warnings about the threat of modern 'plagues' and losing the 'war against microbes.' this adversarial language obscures the fact that most of the microbial world is either neutral toward, or supportive of, human well-being and survival. indeed, we would not survive long without commensal microbes such as the beneficial strains of escherichia coli in our gut. that aside, the study of emerging infections is more than a passing fad. the recent rate of identification of such infections, the impact of the sars outbreak, the devastation caused by aids, and the ever-present threat of a new influenza pandemic indicate that we cannot control our disease destiny. nor are emerging infections unique to humans; the irish potato famine in and the english foot-and-mouth disease epidemic in underscore the consequences for human societies of disease emergence in crops and livestock. emerging infectious diseases in humans comprise the following: first, established diseases undergoing increased incidence or geographic spread, for example, tuberculosis and dengue fever; second, newly discovered infections causing known diseases, for example, hepatitis c and helicobacter pylori; and third, newly emerged diseases, for example, hiv/aids and sars. this perspective will discuss the human ecology of both the (apparently) new and re-emerging diseases. interest in infectious disease has itself recently re-emerged. in , burnet and white commented, "the most likely forecast about the future of infectious disease is that it will be very dull. there may be some wholly unexpected emergence of a new and dangerous infectious disease, but nothing of the sort has marked the past fifty years" . today, we may criticize the short-sightedness of our mentors' generation, yet in demographic terms they were essentially correct because the proportion of deaths from infectious disease has fallen throughout the twentieth century , (fig. ) . humankind currently faces neither apocalyptic extinction nor even a population reduction such as occurred in europe during the black death of the fourteenth century. rather, overpopulation in relation to environmental resources remains a more pressing problem in many developing countries, where poor economic and social conditions go hand-in-hand with infectious disease. in industrializing countries during the nineteenth century, a major reduction in enteric infections was achieved by separating drinking water from sewage-an environmental change that probably saved more lives than all the twentieth century vaccines and antibiotics together. today, however, the growth of shanty towns without sanitation around the megalopolis cities of asia, africa and south america is recreating similar conditions, and in the past years cholera has made a remarkable re-emergence through its longest ever (seventh) pandemic . in most countries, life expectancy has risen over the past years (fig. ) . the most important exception is those regions where hiv infection is rife. moreover, during the past years, falling living standards in some african countries and the breakdown of public health infrastructure in ex-soviet nations has aided the re-emergence of transmissible diseases like tuberculosis , . further, severe outbreaks such as the - influenza a pandemic temporarily reversed the decline of deaths caused by infectious disease. the million estimated deaths from that pandemic represented about % of the global population at that time, and is twice as many as the cumulative aids mortality of the past years. the next influenza pandemic may be just around the corner, and may spread even faster , if access to appropriate vaccines and drug treatment is not available , . for other newly emerging infections that make headlines, such as sars, ebola or vcjd, it is important to keep a sense of demographic proportion. placing these emerging infections on a 'richter' scale of human mortality (box ) shows that they elicit scarcely detectable minor tremors in numbers of fatalities -despite the fear they invoke. we do not know, however, which one might leap to the top of the scale like hiv has done; indeed, it may be a completely unknown agent, as the sars coronavirus was two years ago. a major challenge is to predict which infection presages the next big quake, hopefully allowing preventive action. like any other animal or plant species, humans have been prone to infection by pathogens throughout their evolutionary history. such ancient infections by helminth and protozoan parasites, bacteria, fungi and viruses are endemic, eliciting a range of effects from a heavy burden of disease (e.g., malaria) to being essentially commensal in immunocompetent hosts (e.g., most types of herpesvirus and papilloma virus). other infections depend on an animal reservoir for their maintenance; their infection of humans may be pathogenic, but it has little part in the evolving ecology of the microbe or parasite. an estimated % of the , species of infectious organisms known to be pathogenic in humans are transmitted by animals , for which the human represents a dead-end host. occasionally, however, a zoonotic infection adapts to human-to-human transmission and diversifies away from its animal origin. epidemic diseases are generally caused by infections that are directly transmissible between humans. hiv is a recent example of a long line of human infections initiated by a switch of host species, stretching back to the origins of measles and smallpox. free-living microbes may also find a human niche that suits their lifestyle, such as the lung for legionella pneumophila and the gut for vibrio cholerae. legionnaires' disease, first recognized in philadelphia in , is the environmental equivalent of a zoonosis. it is seldom passed directly from person to person but it was human ingenuity in designing warm, aerated, humid 'artificial lungs' called air-conditioning systems that allowed the microbe to proliferate and become an opportunistic colonizer of the human lung. cholera, which was unknown beyond the ganges delta before it spread widely in asia and the middle east during the period - , at around that time horizontally acquired a toxin gene and other factors in a genetic package that helped it to colonize the gut; the resultant diarrhea aids dispersal of the microbe , . human society has undergone a series of major transitions that has affected our pattern of infectious disease acquisition and dissemination . these transitions illustrate the interrelationship between environmental, social and behavioral influences on the emergence and subsequent spread of infectious disease. some infections were acquired when our australopithecine ancestors left their arboreal habitat to live in the savannah. this ecological change included exposure to new species of mosquito and tick as vectors for infection. after the emergence of homo sapiens, the eventual migration of neolithic hunter-gatherers out of africa , to , years ago exposed them to new infections in distant regions. the first major transition of prehistoric/early historic times gave rise to the epidemic, or 'crowd,' infections. this change must have started in the millennia following the advent of agriculture-from around , years ago-as agriculturally based society developed larger, denser populations. the domestication of livestock and the rich dividends available in human settlements to other animals (e.g., rodents, dogs and various insects) provided further opportunities for pathogens to move between species. sometimes such a pathogen (or a mutant strain thereof) would have been well suited to humans as a new host species, and, if human numbers were adequate, could therefore persist indefinitely as a human infection. thus, measles emerged about , years ago, probably from rindepest of cattle, and diverged to become an exclusively human infection when population size and density became sufficient to maintain the virus without an animal reservoir. similarly, smallpox became epidemic about , years ago, possibly evolving from camelpox, its closest phylogenetic relative. the next two transitions were primarily to do with great extensions in the spread of infectious diseases, entering distant populations as 'new infections.' thus, the second historical transition occurred in classical times as large eurasian civilizations came into commercial and military contact. they inadvertently exchanged their pools of infections, and vectors such as rats and fleas, across the mediterranean basin, the middle east, india and china. the plague of athens in bce during the peloponnesian war vividly described by thucidides may represent the first report of typhus. this rickettsial infection is transmitted from rats to humans and thence among louse-ridden humans. typhus frequently accompanies human conflict and deprivation, as seen in a recent outbreak among rwandan refugees in burundi . the justinian plague of ce devastated the eastern mediterranean region and probably extended as far as china like the black death years later (and both are attributable to yersinia pestis ). the third historical transition accompanied the era of worldwide exploration and colonization by europeans from circa ce onward. a contemporary account by one of hernan cortes' fellow conquistadors, bernal diaz, recalls that they might well have failed to overthrow the mighty aztec empire had they not been aided by a raging epidemic. this was possibly a combination of smallpox and measles, both wholly unknown to the new world population. curiously, the columbian exchange was unidirectional regarding infectious diseases; the one contentious possible exception being syphilis. the new world is believed to have had substantially fewer human zoonotic infections , , and vector-borne infections like chagas' disease did not travel in the absence of an appropriate vector. two centuries later, captain cook unwittingly repeated the decimation of indigenous peoples through syphilis, measles and tuberculosis in many of the pacific islands, whereas lord jeffrey amherst deliberately attempted to spread smallpox among 'hostile' native americans, one of the better documented cases of germ warfare . the transmission dynamics of infections in naive populations is markedly different from those in which the majority of adults are immune . onboard the beagle, charles darwin observed with his customary acuity, "wherever the values are approximate global death rates for the year , taken from the world health organization (who) and other sources. hbv and hcv, hepatitis b and c viruses; rsv, respiratory syncytial virus; hpv, human papilloma viruses; vcjd, variant creutzfeldt-jakob disease. two major, novel causes of mortality top the list: cigarette smoking and hiv infection; they emerged in the twentieth century and continue to increase in many developing countries. among the chronic and re-emerging infections, malaria and tuberculosis are near the top, so it becomes apparent why there is a need for the global fund for malaria, tuberculosis and aids. accidental injuries, particularly road deaths, continue to rise, with % occurring in developing countries . although was the year of the sars outbreak , , less than , people actually died as a result of sars coronavirus infection despite the collateral damage to daily life, psychological wellbeing and economic activity in the affected cities. this richter scale represents a snapshot in time. twenty years ago, hiv was three logs further down the scale, whereas polio was three logs higher. fifty years ago, malaria was finally eradicated from europe, where it had formerly been widespread, including in england (shakespeare's 'ague'). bacterial respiratory diseases used to have a more important role in human mortality and, despite concern over multi-resistance to antibiotics , , the situation is considerably better than in the era before the advent of antibiotics. common bacterial infections of childhood, such as diphtheria and whooping cough, have become rarities in the developed world, largely through vaccination. viral diseases have similarly been reduced. thanks to effective immunization policies of the who, smallpox was eradicated in ; polio and measles viruses, which have no animal reservoir, may soon be eliminated in the same way. the european has trod, death seems to pursue the aboriginal …most of the diseases have been introduced by ships and what renders this fact remarkable is that there might be no appearance of the disease among the crew which conveyed this destructive importation." today we are living through the fourth historical transition of globalization. urbanization, dense and usually impoverished peri-urban settlements, social upheaval, air travel, long-distance trade, technological developments, land clearance and climate change all influence the risks of infectious disease emergence and spread. although some of the apparent increase in infectious disease may be attributable to better diagnostic methods and surveillance, there seems little doubt that more incidents are occurring, and have the potential to spread more widely than years ago, as outbreaks and spread of infections like nipah virus and sars would not have passed unnoticed. as humans encroach further into previously uncultivated environments, new contacts between wild fauna and humans and their livestock increases the risk of cross-species infection . this process will only diminish as wild species become rarer and eventually endangered, like the great apes today. an example of such contact followed the establishment of piggeries close to the tropical forest in northern malaysia, where, in , the nipah virus first crossed over from fruit bats (flying foxes, pteropus spp.) to pigs and thence to pig farmers . destruction of natural forest has also encouraged fruit bats to relocate nearer human habitation, like the large colony in the botanic gardens in the heart of sydney. indeed, in , hendra, a related paramyxovirus of australian fruit bats , fatally infected a veterinarian examining a sick horse. rodents continue to be sources of re-emerging infections, as witnessed in the s with hantaviruses in the united states. rodentborne hantavirus is prevalent in agricultural systems in south america and east asia, in arid grasslands in north america and elsewhere. in mid- , an unexpected outbreak of acute, sometimes fatal, respiratory disease occurred in humans in the southwestern united states . this 'hantavirus pulmonary syndrome' was caused by a previously unrecognized virus, maintained primarily within the native deermouse, and transmitted through excreta. the - el niño event, with unseasonal heavy summer rains and a proliferation of piñon nuts, hugely amplified local rodent populations which led to the outbreak , . in south america, there have been several outbreaks of hantavirus and arenavirus infections linked to forest clearance and the growth of rodent populations in the new grasslands . habitat destruction is not the only cause of increased human infection, however. dengue virus is extending its range and prevalence because its mosquito vector breeds rapidly in the urban environment . in the united states, nature conservation and increased woodland in the eastern states has led to the emergence of lyme disease. this disease is caused by a tick-borne spirochete and the presence of tick-infested deer near suburban homes leads to ticks residing on bushes adjacent to baseball diamonds and gardens. intensification of production of meat and meat products has led to new infections . most notorious is vcjd in the uk arising from consumption of contaminated food products of cattle affected by bse . bse, or 'mad cow disease,' emerged in british cattle in because of industrialized cannibalism, whereby rendered neural tissue and bone meal from slaughtered cattle were recycled into cattle feed, as well as into pies and hamburgers for human consumption . originally, infectious prions from scrapie in sheep were the suspected source, but it now seems more likely that it arose from a bovine with sporadic prion disease. the extent of the human epidemic remains unclear. although natural transmission is unsustainable (r < in both cattle and humans), there are concerns that vcjd might be transmissible through blood transfusions . without effective diagnostic tests for presymptomatic vcjd infection, this situation is extremely unfortunate. other recently emergent food-borne infections include e. coli o :h , which is harmless to cattle but toxic to humans, and salmonella enteriditis in chickens. better hygiene in abattoirs, butchers and domestic kitchens can greatly reduce the incidence of infection. in theory, closed and intensive farming of a single species should reduce the risk of cross-species infection (fig. ) . but it also allows large-scale epidemics to emerge, as seen recently for avian influenza strains in southeast asia and the netherlands , . ancient dietary taboos, such as those of hindus, muslims and jews regarding pork as unclean, doubtless had their roots in protection from infectious disease. today, an increasing demand for consumption of exotic and wild animals raises new risks of infectious diseases such as sars (box ). changing patterns of human behavior and ecology affect two distinct steps in the emergence of new infectious disease. the first is an increased opportunity for animal-to-human infection to occur owing to greater exposure, which may be necessary but not sufficient to lead to the emergence of a new human infection. the second step is the opportunity for onward transmission once a person has become infected. for each novel epidemic, such as the - influenza pandemic or aids, there are probably thousands of failed transfers. some infections simply do not take in the new host. innate hostspecific restrictions on viral replication have recently become evident for primate lentiviruses , which may explain why certain species that harbor simian immunodeficiency virus, but not others more commonly in contact with humans, gave rise to hiv- and hiv- . even in the case of hiv- , only one pedigree of three independent chimpanzee-tohuman crossover events has given rise to the aids pandemic, whereas the other two smolder as poorly transmissible infections. fatal pathogenesis is not necessarily coupled with infectiousness , which is evident for h n avian influenza in humans . but genetic reassortment between avian and human influenza viruses could easily give rise to a new, rapidly spreading strain . a poorly infectious pathogen may not spread at all from the index case, as is usual with rabies, or may only infect close contacts and soon peter out, as seen with lassa fever and ebola virus. sars nearly became self-sustaining but was brought under control. some of the most insidious infections are those with long, silent incubation periods during which the person is infectious. these emerge surreptitiously so that when the new disease is eventually recognized, as aids was in , the infection has already spread far beyond control. like the ships of centuries past, the speed of modern air travel works wonders for the dispersal of infectious diseases. sars was eventually constrained by quarantine and strict adherence to infection control guidelines in hospitals, but not before it quickly traveled from guangzhong to hong kong and on to toronto. if ebola broke out in a city with a busy international airport, it might also travel across continents in a similar manner. brockmann has modeled how rapidly such infections can move once they reach a major airport hub; closing the hubs becomes an immediate imperative. we cannot be sure what the initial vector was for the arrival of west nile virus into north america in : a migratory bird blown off course, an infected human with a valid air ticket or a stowaway mosquito on a similar flight. whatever the means of entry and early colonization of crows in new york, it has taken less than four years to reach the pacific coast . thus, west nile virus has found a new reservoir in american birds, just as yellow fever virus reached new world primates years earlier. microbes frequently capitalize on situations of ecological, biological and social disturbance. biologically weakened and vulnerable populations-especially if also socially disordered and living in circumstances of privation, unhygienic conditions and close contact-are susceptible to microbial colonization. the severity of the bubonic plague (black death) in mid-fourteenth-century europe seems to have reflected the nutritional and impoverishment consequences of several preceding decades of unusually cold and wet weather with crop failures compounding the incipient destabilization of the hierarchical feudal system. many of the rapid and marked changes in human social ecology in recent decades have altered the probabilities of infectious disease emergence and transmission. these changes include increases in population size and density, urbanization, persistent poverty (especially in the expanding peri-urban slums), the increased number and movement of political, economic and environmental refugees, conflict and warfare. political ignorance, denial and obduracy often compound the risk of infectious disease transmission-as has been tragically observed with hiv/aids in parts of africa, where widespread poverty, a culture of female disempowerment and political instability further "if there is any conceivable way a germ can travel from one species to another, some microbe will find it," wrote william mcneill in his classic text plagues and peoples . for millennia, small farmsteads accommodated mixed species living closely with humans-goats, pigs, cattle, ducks, geese, chickens and perhaps a water buffalo or a donkey-and exchanged infections. when species are raised separately but are sold together, the opportunity for cross-infection moves from the farm to the marketplace. the outbreak of avian influenza in hong kong occurred in mixed markets, where live chickens, quail and ducks were stacked together in close quarters with humans. the h n virus that emerged may have been derived by recombination between those of different avian hosts . after , mixed species were separated into different areas of the markets. but this year's h n virus is spreading among intensively reared chickens across southeast asia. the increasing predilection for meat of exotic species has exacerbated the risk of exposure to infections not previously encountered, and this situation probably triggered the sars epidemic . although we are still not sure of the natural reservoir species of sars coronavirus, the live markets and restaurants in guangzhong sold small carnivores, and several species of civet cat, racoon dog and ferret badger captured in china, laos, vietnam and thailand, were brought into close proximity . clearly, some of the palm civet cats were infected with sars-related viruses, but it is less clear whether they represent the original source species. there is a danger in incriminating the wrong species; if the true reservoir resides in the rodent prey of these carnivores, then culling the predators may be counterproductive. stopping the exotic meat trade altogether would seem to be a simple solution to prevent the reappearance of sars, but once the taste for it has been established, that may prove no more practical than attempting to prohibit the tobacco trade. in africa, bushmeat also poses a serious problem for emerging infectious diseases, as well as for nature conservation. sick animals may be more easily captured. for example, human deaths owing to ebola virus infection ensued from the butchering of a single chimpanzee . hiv has crossed from chimpanzees to humans on at least three occasions, and a higher number of zoonotic events from sooty mangabeys are indicated for hiv- (ref. ). whether these cross-species infections arose from butchering the animals or from keeping them as pets is unknown, but a recent survey of primate hunters in africa showed that they are susceptible, like handlers of primates in captivity, to infection (though not disease) from foamy retroviruses . the escalating intercontinental trade in exotic pets can lead to unexpected infectious disease outbreaks. the united states has only recently imposed more stringent regulations and quarantine following cases of monkeypox in humans and in prairie dogs introduced by rodents imported from africa as pets . exacerbate the problem , . but we have little understanding of why the prevalence of hiv infection varies so greatly between cities in sub-saharan africa . the urban environment has only recently become the dominant human habitat. urbanism typically leads to a breakdown in traditional family and social structures, and entails greater personal mobility and extended and changeable social networks. these features, along with access to modern contraception, have facilitated a diversity of sexual contacts and, hence, the spread of sexually transmitted diseases . this risk is further amplified by the growth in sex tourism in today's internationally mobile world, which capitalizes on the desperation and ignorance of poverty, combined with exploitative behaviors, in developing countries. more generally, cities often function as highways for 'microbial traffic' . rapid urbanization boosts certain well established infectious diseases, such as childhood pneumonia, diarrhea, tuberculosis and dengue, and facilitates dissemination of various 'emerging' diseases-as occurred for sars in the high-rise housing of hong kong. crowded and dilapidated public housing can potentiate infectious disease transmission through drug abuse and sexually transmitted infections . technological advances in medicine and public health can also inadvertently promote the emergence and spread of infectious disease. it has become commonplace to quip that you go to the hospital at the peril of acquiring an intractable nosocomial infection such as methicillin-resistant staphylococcus aureus , and such infections killed around times as many people as sars did in (box ). multidrug-resistant tuberculosis has also become a major problem, and, paradoxically, regions with health programs that reduced wildtype tuberculosis strains can develop into 'hot zones' for multidrugresistant tuberculosis . by far the most effective medical vector of infectious disease has been the syringe and needle. drucker et al. have charted the massive increase in the use of injecting equipment over the past years. individuals with hemophilia treated with pooled clotting factors became almost universally infected with hepatitis b and c viruses before diagnostic screening tests were developed. over % of such affected individuals also became infected with hiv , and more recently, transmission of west nile virus by blood transfusion and by organ transplantation has been reported , . the use of contaminated needles among intravenous drug users has had similar consequences. infectious diseases have also been amplified by the use of nonsterile medical injections in developing countries . egypt has the highest prevalence of hepatitis c infection in the world because of the use and reuse of syringes and needles in an earlier public health campaign to reduce bilharzia by medication given by injection. the transmission of cjd through contaminated surgical instruments is another example of iatrogenic spread of infection . biological medicines produced from animal-cell substrates present an inherent potential hazard for introducing new infections. great care must be taken to ensure that live attenuated vaccines grown in animal cells or eggs are devoid of pathogens ; for example, several early batches of live and inactivated polio vaccine unwittingly contained live sv virus, a polyoma virus of macaques. after sv was discovered in , polio vaccine production shifted to virus propagation in primary kidney cells of african green monkeys. these cultures were free of sv but possibly contained sivagm, a relative of hiv that fortunately does not infect humans . the irony of the sv story is that the united states food and drug administration prohibited the use of well known, permanent cell lines demonstrably free of adventitious infectious agents, for fear that such immortalized cells might exert oncogenic properties on the vaccine. there is no epidemiological evidence of increased tumor incidence in those populations who are known to have received sv -contaminated polio vaccine. but there have been a number of recent claims of an association of sv dna sequences in a variety of human malignancies , although these findings remain controversial . the ultimate medical means of introducing animal viruses into humans is xenotransplantation. the implantation of animal cells or tissues into immunosuppressed individuals seems to be a perfectly designed way to encourage cross-species infection. it is astonishing that trials were started without much thought about the consequences for potentially emerging pathogens, for example, porcine retroviruses . the generation of genetically modified knockout or transgenic animals to prevent hyperacute rejection of donor tissues may exacerbate the infection hazard , . happily, there is no evidence so far of retrovirus infection in individuals who were exposed to living pig cells , and clinical xenotransplantation is now stringently regulated; so it seems all the more extraordinary that cellular therapies with fetal lamb cells and extracts continue to be practiced with impunity in alternative medicine clinics in europe and the far east. novel infectious diseases can emerge in any part of the world at any time. hiv and ebola came out of africa, avian influenza and sars from china, nipah virus from malaysia, bse/vcjd from the uk and hantavirus pulmonary syndrome from the americas. it is difficult to predict what new disease will come next or where it will appear, but changing ecological conditions and novel human-animal contacts will be useful clues as to which horizons require scanning with most scrutiny. we must expect the unexpected. as a codicil, another factor that needs to be taken into account is the potential impact of the hiv pandemic on the emergence of other infectious diseases . we already know that persons with aids act as 'superspreaders' of tuberculosis, and we can only speculate what course the sars outbreak might have taken had someone incubating the disease flown to durban rather than toronto . people with aids may persistently harbor infections that would otherwise be transient, and this could hamper the eradication of measles and polio. multivalent pneumococcus vaccines are ineffective in hiv-infected people with cd + lymphocyte levels below /µl, whereas live 'attenuated' vaccines such as vaccinia can cause virulent disease in the immunocompromised host. immunodeficient persons living at high density could also be the seed-bed for microorganisms that are initially ill adapted to human infection to evolve into transmissible human pathogens. thus, an infection from a zoonotic or environmental source-for example, the mycobacterium avium intracellulare complex-could conceivably emerge as the tuberculosis of the twenty-first century, although direct transmission between individuals with aids of such opportunistic infections have not been documented so far. we shall give girolamo frascatoro the last word on emerging and re-emerging infectious diseases by quoting from his treatise de contagione, published almost years ago, "there will come yet other new and unusual ailments in the course of time. and this disease [syphilis] will pass way, but it later will be born again and be seen by our descendents." we are grateful to m. e. chamberland, h. w. jaffe and s. leff for critically reading the manuscript. natural history of infectious disease human frontiers, environments and disease. past patterns, uncertain futures the challenge of emerging and re-emerging infectious diseases environmental and social influences on emerging infectious diseases: past, present and future mortality trends and setbacks: global convergence or divergence? betrayal of trust: the collapse of global public health (hyperion updating the accounts: global mortality of the - "spanish" influenza pandemic molecular constraints to interspecies transmission of viral pathogens influenza: old and new threats antivirals and antiviral strategies risk factors for human disease emergence virulence and pathogenesis the cambridge world history of human disease jail fever (epidemic typhus) outbreak in burundi plagues and peoples (penguin genotyping, orientalis-like yersinia pestis, and plague pandemics germs and steel. a short history of everybody for the last , years smallpox and the indians in the american colonies infectious diseases of humans: dynamics and control unhealthy landscapes: policy recommendations on land use change and infectious disease emergence fatal encephalitis due to nipah virus among pig-farmers in malaysia newly discovered viruses of flying foxes the hantavirus epidemic in the southwest: rodent population dynamics and the implications for transmission of hantavirus-associated adult respiratory distress syndrome (hards) in the four corners region climatic and environmental patterns associated with hantavirus pulmonary syndrome, four corners region, united states emerging flaviviruses: the spread and resurgence of japanese encephalitis, west nile and dengue viruses deaths due to unknown foodborne agents a new variant of creutzfeldt-jakob disease in the uk how the cows turned mad transfusion transmission of vcjd: a crisis avoided transmission of h n avian influenza a virus to human beings during a large outbreak in commercial poultry farms in the netherlands in defense of the cell: trim α interception of mammalian retroviruses aids as a zoonosis: scientific and public health implications dynamics of epidemics spread across airline networks rethinking the african aids epidemic ecological and individual level analysis of risk factors for hiv infection in four urban populations in sub-saharan africa with different levels of hiv infection sexual behaviour in britain: partnerships, practices, and hiv risk behaviours factors in the emergence of infectious diseases urban unfinished business methicillin-resistant staphylococcus aureus in europe modeling the emergence of the 'hot zones': tuberculosis and the amplification dynamics of drug resistance the injection century: massive unsterile injections and the emergence of human pathogens mortality before and after hiv infection in the complete uk population of haemophiliacs transmission of west nile virus through blood transfusion in the united states in transmission of west nile virus from an organ donor to four transplant recipients cell and molecular biology of simian virus : implications for human infections and disease sv in human cancers-an endless tale? infection of human cells by an endogenous retrovirus of pigs transgenic pigs and virus adaptation reduced sensitivity to human serum inactivation of enveloped viruses produced by pig cells transgenic for human cd or deficient for the galactosyl-α( - ) galactosyl epitope gulliver's travels in hivland what have we learnt from sars? mission now possible for aids fund research on preventing road traffic injuries in developing countries is needed severe acute respiratory syndrome antimicrobial resistance worldwide: causes, challenges and responses animal origins of sars coronavirus: possible links with the international trade in small carnivores zoonoses and haemorrhagic fever. in safety of biological products prepared from mammalian cell culture naturally acquired simian retrovirus infections in central african hunters human monkeypox: an emerging zoonosis the authors declare that they have no competing financial interests. key: cord- -kahi cbc authors: miller, robert f.; lipman, marc c.i. title: pulmonary infections date: - - journal: clinical respiratory medicine doi: . /b - - . - sha: doc_id: cord_uid: kahi cbc nan it is hard to believe that the first consistent reports of acquired immunodeficiency syndrome (aids) were only years ago. since then, respiratory and general physicians have become accustomed to dealing with an extraordinary range of esoteric and previously unheard of conditions. pneumocystis carinii (now known as pneumocystis jirovecii) pneumonia is frequently part of the differential diagnosis of treatment-nonresponsive pneumonic illness. human immunodeficiency virus (hiv) testing is almost routinely offered as a "rule out" test in clinical cases that defy simple diagnosis. in many parts of the developing world, advanced hiv disease is unfortunately the likeliest reason for seeking medical care. the change this has wrought on people, countries and their economies is huge and depressing. the isolation of hiv from patients with aids in the mid s paved the way for intensive research with the ultimate development of drugs directed against this chronic infection. however, despite such advances, the methods by which hiv infection leads to severe immune dysregulation and clinical disease are still not fully defined. the introduction in , in the developed world, of highly active antiretroviral therapy, also known as combination antiretroviral therapy (cart) hereto referred to as haart, has altered the natural history of this extraordinary condition. before haart, defined as a combination of medications that usually includes at least three potent anti-hiv agents, treatment largely consisted of specific opportunistic infection management and less effective antiretroviral therapy. the clinical consequences of this change are enormous. the relative hazard for development of pneumocystis pneumonia (pcp) in an hivinfected individual has fallen by more than %. drug therapy does have a down side. it has significant unwanted effects, as well as major interactions with other medication (e.g., rifamycins used in treating tuberculosis). the profound change in immunity induced by haart may also lead to disease (the immune reconstitution inflammatory syndrome [iris] ). notwithstanding haart, respiratory disease remains an important cause of morbidity and mortality. much of the world cannot afford such medication, and more than two thirds of hiv-infected individuals have at least one respiratory episode during the course of their illness. in the early stages of hiv infection, when patients have relatively preserved immune responses, individuals have the same infections found in the general population, although at a greater incidence. with progressive hiv disease, subjects are at an increased risk of opportunistic disease. for example, the north american prospective study of pulmonary complications of hiv infection (pspc), a multicenter cohort drawn from all hiv risk groups at various stages of immunosuppression, revealed over an -month study period that of approximately subjects who were not using haart: % reported an upper respiratory tract infection % had an episode of acute bronchitis % had acute sinusitis % had bacterial pneumonia % had pcp develop the immune dysregulation that arises from hiv infection means that bacteria, mycobacteria, fungi, viruses, and protozoa can all cause disease in subjects with advanced infection. table - shows the organisms that typically infect the lung in hiv disease. of these, bacterial infections, tuberculosis, and pcp are the most important. in the west, % of aids diagnoses are due to pcp. this chapter provides a brief general overview of the epidemiology and pathogenesis of hiv infection before concentrating on hiv and its infectious pulmonary complications. it is reported that by the end of , . million individuals worldwide had acquired hiv infection (figure - ). of these, more than % are thought to have had aids develop (for definition of aids, see tables - and - , and box - ). globally, . million individuals acquired hiv infection in , and over this time . million died of aids. the developing world has been most affected. sub-saharan africa is the current epicenter of the pandemic (two thirds of all infections); here, one in five adults is hiv infected. south and southeast asia are responsible for almost a fifth of the estimated hiv global burden. in central-eastern europe and central asia, there are currently . million hivinfected individuals. in the developed world, north america and western europe account for approximately . million and , infections, respectively. most of these are spread through sexual contact, although vertical (mother-to-child) and bloodborne infections are also common. in the developing world, heterosexual transmission is the norm; however, in north america and europe, homosexual and bisexual men constitute the largest group of infected individuals. hiv was first isolated in from patients with symptoms and signs of immune dysfunction. two subtypes (hiv- and hiv- ) have subsequently been identified. hiv- (hereafter referred to as hiv) is responsible for most infections, has a more aggressive clinical course, and is the focus of this chapter. hiv is a human retrovirus belonging to the lentivirus family. cell-free or cell-associated hiv infects through attachment of its viral envelope protein (gp ) to the cd antigen complex on host cells. the cd receptor is found on several cell types, although the t-helper lymphocyte is the main site of hiv infection in the body. hiv gp must also bind to a cell surface protein coreceptor called chemokine receptor (ccr ) or to other co-receptors, including cxcr , depending on the host cell type. polymorphisms in genes for ccr may affect disease progression by reducing the ability of hiv to enter and infect cells. however, at a population level, this effect is small. once hiv is inside the cell, it can, by use of the enzyme reverse transcriptase (rna-dependent dna polymerase), transcribe its hiv rna into a dna copy that can translocate to the nucleus and integrate with host cell dna by use of its viral integrase. the virus (as proviral dna) remains latent in many cells until the cell itself becomes activated. this may arise from cytokine or antigen stimulation. the viral genetic material is then transcribed into new rna, which, in the form of a newly created virion, buds from the cell surface and is free to infect other cd -bearing cells. hiv infection directly attacks the immune system and in particular the t-helper cells that are central to a coordinated immune response. this leads to progressive immune dysfunction and an inability to resist opportunistic disease. the pathogenic process is not well defined, although it is thought that at the time of primary infection, hiv spreads to the lymph nodes, circulating immune cells, and thymus. this is a massive viral infection of the human host; and although there seems to be a relatively potent immune response, in fact, this initial onslaught is so devastating (targeting as it does specific memory t cells responsible for sustaining long-term protective immunity) that the scene is set for progressive immune failure. this occurs through a combination of direct cell killing by hiv replicating within cells, as well as the negative effects of chronic immune activation. ultimately, these lead in most individuals to immune system destruction and dysfunction. this is reflected not only by clinical disease indicating profound immunosuppression but also by a measurable reduction in the circulating absolute cd cell count, the percentage of t cells expressing cd markers, and in the progressive reduction in cd /cd t-cell ratio. the use of haart, as well as preventative (prophylactic) therapies for opportunistic infections, has changed the clinical picture of hiv disease in countries where these interventions are available. death rates have fallen to one sixth of their previous levels. however, in the absence of such treatments, the median interval between hiv seroconversion and progression to aids in the developed world has been estimated to be years, although rather less in resource-poor countries. almost all individuals have aids develop if untreated, and without haart, % of these will die within years. in many parts of the world, the main causes of death in patients with hiv infection include bacterial pneumonia, tuberculosis, and pcp. the course of hiv infection can be divided clinically into several distinct periods: acquisition of the virus seroconversion, with or without a clinical illness (primary hiv infection) clinically silent period, lasting several months to years development of symptoms and signs indicating some degree of immunosuppression aids (where the subject has opportunistic disease implying profound immunosuppression [e.g., pcp]) the time from acquisition of hiv infection to development of detectable antibodies (the "window" period) is usually approximately - weeks. between and % of individuals who become infected will have a seroconversion illness. hiv antibody is normally present within - weeks of these symptoms, although this can take longer. hiv rna in peripheral blood is detectable before this and is often used to confirm infection. the nonspecific features of primary hiv infection are almost always self-limiting, and typically seroconversion mimics a "flulike" illness or glandular fever. most individuals with primary hiv infection recover from the acute symptoms within weeks. a proportion may have persistent symmetric generalized lymphadenopathy. there is no difference in prognosis in this group compared with asymptomatic hiv-positive individuals. although a proportion of individuals remain completely well without any treatment for an extended period (approximately % after years), many hiv-infected individuals have minor symptoms and signs suggesting immune dysfunction. examples of these include new or worsening rashes (including herpes simplex), tiredness, cough, and low-grade anemia. certain clinical symptoms and signs provide important prognostic information. most studies have shown that oral candidiasis and constitutional symptoms (e.g., malaise, idiopathic fever, night sweats, diarrhea, and weight loss) are the strongest clinical predictors of progression to aids. the term aids was created as an epidemiologic tool to capture those conditions that early in the hiv epidemic seemed to suggest significant immune destruction. over time, it has been modified to incorporate the expanding spectrum of recognized diseases affecting immunosuppressed individuals, such as cervical carcinoma and recurrent bacterial pneumonia (see box - ). the centers for disease control and prevention (cdc) classification included an immunologic criterion for aids (cd count < cells/ml or cd percentage < % of total lymphocytes) regardless of clinical symptoms (see table - ). these data are used to define a point at which the risk of severe opportunistic infection rises dramatically. an example of this can be seen in the multicenter aids cohort study (macs) of homosexual and bisexual men without aids, which found that the incidence of pcp in subjects who did not use prophylaxis rose from . % at months in men with a baseline cd count > cells/ml to . % in those with a cd count < cells/ml. apart from cervical carcinoma, aids indicator diseases differ little between men and women. injecting drug users have a high incidence of wasting syndrome, recurrent bacterial pneumonia, and tuberculosis. geographic differences in diseases occur that reflect the opportunistic pathogens present in the local environment (e.g., histoplasmosis or visceral leishmaniasis usually occur only in patients from endemic areas). in the developed world, sexual, racial, and hiv risk factor survival differences after an aids diagnosis mainly arise from variation in ease of access to medical care. it is certainly the case, however, that better treatment outcomes are associated with genuine specialist care provided by people with extensive experience in the field. in countries where haart is available, the spectrum of hiv-related disease has changed. in the eurosida cohort (a pan-european prospective study of hiv infection), between and , opportunistic infections associated with very low cd counts (e.g., cytomegalovirus [cmv] retinitis and mycobacterium avium-intracellulare complex [mac] infection) were observed less frequently over time. malignant disease, such as non-hodgkin lymphoma, increased as an aids-defining event between and . although death rates have fallen in haart-treated populations, there has been a rise in the proportion of non-aids deaths. in some series, this accounts for most events. causes include liver disease (often caused by viral hepatitis) and cancer, as well as cardiovascular disease and drug-related toxicity. in such circumstances, aids deaths usually occur among patients who have not accessed medical care regularly and who are initially seen with advanced hiv disease. a new manifestation of opportunistic infection has been described in patients commencing haart. the immune reconstitution disease, iris, may cause severe, if temporary, clinical illness as the individual's immunity recovers. patients will appear to develop a relapse of their original (and partially treated) disease. this is often seen in mac infection, tuberculosis, hepatitis b, cmv retinitis, and herpesviral infection. metabolic complications of haart, such as ischemic heart disease and diabetes, are a potential problem in hiv practice in the developed world. a significant number of individuals taking haart also experience drug toxicity. an increasing number of patients are also surviving to manifest symptoms associated with chronic hepatitis b and c infection. hivassociated nephropathy (often with chronic kidney disease) is common in black africans and is a significant cause of long-term morbidity. laboratory markers and clinical symptoms (e.g., oral thrush) can independently reflect the immune changes that lead to serious disease. staging systems have been developed that can predict the risk of progression to severe opportunistic disease (aids). the fall in absolute blood cd t-lymphocyte count is the most widely used prognostic marker, although cd counts may be affected by a number of factors apart from hiv, including intercurrent infection, cigarette smoking, exercise, time of day, and laboratory variation. the percentage of cd cells and ratio of cd /cd cells are more stable measures and may be used if the cd absolute counts seem to vary widely from visit to visit. measurement of plasma hiv rna "viral load" provides important prognostic information that can both guide therapy and suggest long-term outcome. it has a particular value in subjects who are clinically well and have high cd counts, because it can give some indication of the expected speed of clinical progression. it is clear from the frequency with which hiv-related respiratory disease occurs that the pulmonary immune response is profoundly dysregulated. however, the mechanism underlying this has not been fully explained. in part, this is because the alterations that arise reflect the complex interplay between systemically derived hiv and other circulating antigens trafficking through the pulmonary vasculature, local immune cells, and airborne antigen. most studies investigating the pulmonary immune response have used in vitro cell culture systems that seek to mimic the pulmonary environment or in some cases bronchoscopy and bronchoalveolar lavage (bal) to recover lung cells from infected individuals. until recently, these have been performed on symptomatic patients who required bronchoscopy as a diagnostic procedure. such subjects generally have advanced hiv infection, are often taking a number of different drugs (including antiretrovirals), and may have any number of different pathogens causing their pulmonary disease-which by themselves can influence the immune findings. finally, the question of whether bal fluid truly represents the site of the immune response (the lung parenchyma) remains unclear. for all these reasons, reported data should be interpreted with some care. an individual's risk for respiratory disease is determined by his or her medical history (e.g., receipt of effective preventative or antiretroviral therapy), place of residence and travel history (e.g., the influence of geography on mycobacterial and fungal disease), and state of host immunity. falling blood cd counts or high plasma rna "viral loads" increase the chance of respiratory infection, with an increased spectrum of potential organisms responsible for infection in the more immunosuppressed individual. for example, hiv-infected individuals with a cd count < cells/ml are four times more likely to have one episode of bacterial pneumonia per year than those with higher cd cell counts. more exotic organisms are found in subjects with very low cd counts. these include bacteria such as rhodococcus equi and nocardia asteroides and fungi such as aspergillus species and penicillium marneffei. just as with p. jirovecii, this reflects the importance of t-cell depletion and macrophage dysfunction in the loss of host immunity (a process that has been confirmed by animal experiments). among hiv-infected patients, injecting drug users are at greatest risk for development of bacterial pneumonia and tuberculosis. individuals who have had previous respiratory episodes (pcp or bacterial pneumonia) seem to be at increased risk of further disease. whether this relates to host or environmental factors is not certain, although it seems likely that structural lung damage and abnormal pulmonary physiology would, in part, contribute to this. this argument is supported by the increased rates of pneumonia in hiv-infected smokers compared with nonsmokers. recent work has shown chronic obstructive pulmonary disease (copd) and lung cancer occur more frequently among hiv-infected individuals compared with the general population. given that a large number of hiv-infected individuals smoke heavily, there is a pressing need to target this population for smoking cessation. this is reinforced by the association demonstrated in some (but not all) studies between smoking and a more rapid progression to first aids illness and death. the presentation mimics bacterial exacerbations of chronic obstructive lung disease; most patients have a productive cough and fever. the pathogens commonly identified are similar to those in the general population (i.e., streptococcus pneumoniae and haemophilus influenzae). however, patients with advanced disease may be infected with pseudomonas aeruginosa or staphylococcus aureus. response to appropriate antibiotic therapy in conventional doses is good, although relapses frequently occur. bronchiectasis is increasingly recognized in hiv-infected patients with advanced hiv disease and low cd lymphocyte counts. it probably arises secondary to recurrent bacterial or p. jirovecii infections. the diagnosis is most often made by high-resolution/fine-cut computed tomography (ct) scanning. its prevalence has not been accurately determined, although with improved survival from both opportunistic infections and hiv disease, it is likely that it will be increasingly common in clinical practice. the pathogens isolated in patients with bronchiectasis are those seen in bronchitis. in addition, pseudomonas cepacia and moraxella catarrhalis have been described. community-acquired bacterial pneumonia occurs more frequently in hiv-infected patients than in the general population. it is especially common in hiv-infected injecting drug users. the spectrum of bacterial pathogens is similar to that in non-hiv-infected individuals (see table - ). s. pneumoniae is the most common cause, followed by h. influenzae. hiv-infected individuals with s. pneumoniae pneumonia are frequently bacteremic. in one study, the rate of pneumococcal bacteremia in hiv-infected individuals was times that of an hiv-negative population. more recent work has confirmed this to be the case for all causes of hiv-related bacterial pneumonia. typically, blood cultures have a -fold increased pickup rate in hiv-positive patients. the widespread use of haart has led to some decrease in rates of bacterial pneumonia and bacteremia, although they are still considerably higher than those seen in a non-hiv-infected population. bacterial pneumonia has a similar presentation in hivinfected and uninfected individuals. chest radiographs are frequently atypical, mimicking pcp in up to % of cases ( figure - ). by contrast, radiographic lobar or segmental consolidation may also be seen in a wide range of bacterial organisms (figure - ); these include s. pneumoniae, p. aeruginosa, h. influenzae, and mycobacterium tuberculosis. pcp may also present with lobar or segmental consolidation. in subjects with more advanced hiv disease and low cd lymphocyte counts, p. aeruginosa and s. aureus also cause pneumonia. complications of bacterial pneumonia frequently occur, and pleural effusions are twice as likely in hiv infection (often occurring with s. aureus infection); empyema and intrapulmonary abscess formation are present in up to % of patients. inevitably, the mortality rate is high (approximately %). nocardia asteroides infection. this has been reported in patients with advanced hiv disease and low cd lymphocyte counts. the widespread use of trimethoprim/sulfamethoxazole (tmp/smx) for prophylaxis of pcp may have reduced the incidence of infection. the clinical presentation is often indistinguishable from that of other bacterial infections. chest radiographic appearances may mimic tuberculosis (see later), with upper lobe consolidation, cavitation, interstitial infiltrates, pleural effusion, and hilar lymphadenopathy. the diagnosis is made by identification of the organism in sputum/bal fluid or lung tissue. rhodococcus equi. r. equi usually produces pneumonia in patients who have advanced hiv infection and have been in contact with farm animals or with soil from fields or barns where animals are housed. the presentation is subacute, with - weeks of cough, dyspnea, fever, and pleuritic chest pain. the chest radiograph typically shows consolidation with cavitation. pleural effusions are common. the diagnosis is usually made by culture of sputum or blood; bronchoscopy with bal or pleural aspiration may be necessary in some cases. bartonella henselae. b. henselae is a gram-negative bacillus that causes bacillary angiomatosis in hiv-infected patients. clinically, the cutaneous lesions may mimic kaposi sarcoma, from which they may be distinguished by demonstration of organisms in tissue with warthin-starry silver stain. bacillary angiomatosis may also infect the lungs, where it produces endobronchial red or violet polypoid angiomatous lesions, which may resemble kaposi sarcoma. biopsy is necessary to confirm a diagnosis. tuberculosis hiv infection is associated with at least a -fold increased risk of an individual having active tuberculosis develop compared with noninfected subjects. taken together with its ability to infect both the immunosuppressed and immunocompetent, tuberculosis is perhaps, therefore, the single most important disease associated with hiv infection. it is estimated that there are at least million individuals with hiv-tuberculosis coinfection. as such, tuberculosis is a major cause of hiv-related morbidity and mortality. it is also a major driver in both resource-rich and resource-poor countries for the current overall increase in tuberculosis rates. where hiv infection is endemic, tuberculosis control at a population level is almost impossible if treatment for both infections is not available. in the united kingdom, many centers routinely offer hiv antibody testing to all patients with tuberculosis, regardless of risk factors for hiv infection. in the united states, the cdc now recommends hiv testing as a routine part of health care for all patients aged - accessing medical services. the advantage of this is that individuals who are found to be hiv infected can be given haart. furthermore, strategies to modify high-risk behavior and reduce ongoing hiv transmission may be offered. active tuberculosis can occur at any stage of hiv infection, and unlike almost every other hiv-related infection, may do so despite effective antiretroviral therapy. in the united states, united kingdom, and most european countries, reporting of tuberculosis in both hiv-infected and non-hiv-infected individuals is mandatory. clinical disease in hiv-infected patients may arise in several different ways: by reactivation of latent tuberculosis, by rapid progression of pulmonary infection, and by reinfection from an exogenous source. pulmonary disease is the most common presentation; and clinical manifestations are related to the level of an individual's cell-mediated immunity. for example, subjects with early hiv disease have clinical features similar to "normal" adult postprimary disease (table - ). symptoms typically include weight loss, fever with sweats, cough, sputum, dyspnea, hemoptysis, and chest pain. these patients may have no clinical features to suggest associated hiv infection. the chest radiograph frequently shows upper lobe consolidation, and cavitary change is common (figure - ) . the tuberculin skin test (purified protein derivative [ppd] ) is usually positive, and the likelihood of spontaneously expectorated sputum or bal fluid being smear positive for acid-fast bacilli is high. in individuals with advanced hiv disease (i.e., low cd lymphocyte counts and clinically apparent immunosuppression), it may be difficult to diagnose tuberculosis. the clinical presentation here is often with nonspecific symptoms. fever, weight loss, fatigue, and malaise may be mistakenly ascribed to hiv infection itself. in this context, pulmonary tuberculosis is often similar to primary infection, with the chest radiograph showing diffuse or military-type shadowing ( figure - ), hilar or mediastinal lymphadenopathy, or pleural effusion; cavitation is unusual. in up to % of patients the chest radiograph may appear normal; in others, the pulmonary infiltrate can be bilateral, diffuse, and interstitial in pattern, thus mimicking pcp. hilar lymphadenopathy and pleural effusion may also be produced by pulmonary kaposi sarcoma or lymphoma, with which m. tuberculosis may coexist. the tuberculin skin test is usually negative, and spontaneously expectorated sputum and bal fluid are often smear negative (but culture positive). in addition to pulmonary tuberculosis, extrapulmonary disease occurs in a high proportion of hiv-infected individuals with low cd lymphocyte counts (< cells/ml). mycobacteremia and lymph node infection ( figure - ) are common, but involvement of bone marrow, liver, pericardium, meninges, and brain also occurs. evidence of extrapulmonary tuberculosis should be sought in any hiv-infected patient with suspected or confirmed pulmonary tuberculosis, by culture of stool, urine, and blood or bone marrow. traditional solid phase culture and speciation techniques may take - weeks. liquid culture methods (e.g., bactec, becton dickinson) that detect early growth may provide a diagnosis in only - weeks. molecular diagnostic tests that use m. tuberculosis genome detection (e.g., by polymerase chain reaction [pcr] ) offer the possibility of yet more rapid diagnosis (within hours), but are not yet in routine clinical use. they are also less useful in primary samples with low bacterial load (e.g., smear negative sputum)-which is often when they will be most needed in hiv-coinfected patients. the recent description of simple, but highly sensitive and specific, methods that use the inoculation of large quantities of, for example, sputum onto microscopic plates with subsequent rapid detection (in days) of both mycobacterial growth and resistance patterns (mods) is of great potential significance. until the results of culture and speciation are known, acidfast bacilli identified in respiratory samples, biopsy tissue, an aspirate, or blood in an hiv-infected individual, regardless of the cd lymphocyte count, should be regarded as being m. tuberculosis, and conventional antituberculosis therapy should be commenced. if culture fails to demonstrate m. tuberculosis and instead another mycobacterium (see later) is identified, treatment can be modified. multiple drug-resistant (mdr) tuberculosis-that is, m. tuberculosis that is resistant to isoniazid and rifampicin (rifampin), with or without other drugs, is now an important clinical problem in hiv-infected individuals in the united states, where it is responsible for approximately % of all tuberculosis in hiv-infected patients. outbreaks of mdr tuberculosis have occurred in both hiv-infected and non-hiv-infected individuals in the united states in prison facilities, hostels, and hospitals. similar outbreaks have also been documented among hiv-infected patients in europe. inadequate treatment (including case management and supervision of medication) of tuberculosis and poor patient compliance with antituberculosis therapy are the most important risk factors for development of mdr tuberculosis. other cases have arisen because of exogenous reinfection of profoundly immunosuppressed hiv-infected patients who are already receiving treatment for drug-sensitive disease. despite antituberculosis therapy, the median survival in hiv-infected individuals with mdr-tuberculosis was initially only - months. recently this has improved, largely because of an increased awareness of the condition with early initiation of suitable therapy as determined by drug sensitivity testing. extensively drug-resistant (xdr) tuberculosis-that is, m. tuberculosis resistant to isoniazid and rifampicin (rifampin), plus any fluoroquinolone and one or more of the three injectable second-line drugs (capreomycin, kanamycin and amikacin)-is an increasingly important clinical problem. originally described in south africa in association with hiv infection, xdr tuberculosis has also been identified in most parts of the world. as of march , countries had reported at least one case; although in many places, testing for fluoroquinolone sensitivity is not standard practice; this number may be, in fact, a huge underestimate. what is of concern about xdr tuberculosis is that, despite specific therapy, mortality is high among hiv-infected individuals. the current picture seems to mirror early reports of mdr tuberculosis in hiv infection: in the original south african study from kwazulu natal, survival was less than weeks from the time of receipt of the first sputum sample. mycobacterium avium-intracellulare complex. before the widespread availability of haart, disseminated mac infection developed in up to % of hiv-infected patients. it remains a problem in patients with advanced hiv disease not receiving antiretroviral therapy and who have cd lymphocyte counts < cells/ml. clinical presentation is nonspecific and may be confused with the effects of hiv itself. fever, night sweats, weight loss, anorexia, and malaise are common. anemia, hepatosplenomegaly, abdominal pain, and chronic diarrhea are frequent findings. the diagnosis of disseminated mac infection is based on culture of the organism from blood, bone marrow, lymph node, or liver biopsy specimens. also, mac is frequently identified in bal fluid, sputum, stool, and urine, but detection of the organism at these sites is not diagnostic of disseminated infection. evidence of pulmonary mac infection is not usually obtained from a chest radiograph, which may be negative or show nonspecific infiltrates. rarely, focal consolidation, nodular infiltrates, and apical cavitation (resembling m. tuberculosis) have been reported. mycobacterium kansasii. mycobacterium kansasii is the second most common nontuberculous opportunistic mycobacterial infection in hiv-infected individuals and usually appears late in the course of hiv infection in patients with cd lymphocyte counts < cells/ml. the most frequent presentation is with fever, cough, and dyspnea. in approximately two thirds of those who have m. kansasii infection, the disease is localized to the lungs; the remainder have disseminated disease that affects bone marrow, lymph node, skin, and lungs. the diagnosis is made by culture of the organism from respiratory secretions or from bone marrow, lymph node aspirate, or skin biopsy. focal upper lobe infiltrates with diffuse interstitial infiltrates are the most common radiographic abnormalities; thin-walled cavitary lesions and hilar adenopathy have also been reported. mycobacterium xenopi. mycobacterium xenopi may occasionally be isolated from sputum or bal fluid samples, but its significance is uncertain. patients have low cd counts, and m. xenopi is usually accompanied by isolation of a copathogen, such as p. jirovecii. treatment of the latter condition is associated in most cases with resolution of symptoms. there is some evidence that starting haart prevents disease recurrence, provided there is an adequate immune response. pneumocystis jirovecii pneumonia. the development of pcp is largely related to underlying states of immunosuppression induced by malignancy or treatment thereof, organ transplantation, or hiv infection. in in the united states, united kingdom, europe, and australasia, pcp is largely seen only in hiv-infected individuals unaware of their serostatus or in those who are intolerant of, or noncompliant with, anti-p. jirovecii prophylaxis and haart. until recently, p. jirovecii was regarded taxonomically as a protozoan, on the basis of its morphology and the lack of response to antifungal agents such as amphotericin b. the organism has now been ascribed to the fungal kingdom. the demonstration of antibodies against p. jirovecii in most healthy children/adults suggests that organisms are acquired in childhood and persist in the lungs in a dormant phase. subsequent immunosuppression (e.g., as a result of hiv infection) allows the fungus to propagate in the lung and cause clinical disease. however, this "latency" hypothesis is challenged by several observations: p. jirovecii cannot be identified in the lungs of immunocompetent individuals. "case clusters" of pcp in health care facilities suggest recent transmission. different genotypes of p. jirovecii are identified in each episode in hiv-infected patients who have recurrent pcp. genotypes of p. jirovecii in patients who have pcp correlate with place of diagnosis and not with their place of birthsuggesting infection has been recently acquired. taken together, these data suggest that pcp arises by reinfection from an exogenous source. the clinical presentation of pcp is nonspecific, with an onset of progressive exertional dyspnea over days or weeks, together with a dry cough with or without expectoration of minimal quantities of mucoid sputum. patients often complain of an inability to take a deep breath, which is not due to pleurisy (table - ) . fever is common, yet patients rarely complain of temperatures or sweats. in hiv-infected patients, the presentation is usually more insidious than in patients receiving immunosuppressive therapy, with a median time to diagnosis from onset of symptoms of more than weeks in those with hiv compared with less than week in non-hiv-infected patients. in a small proportion of hiv-positive individuals, the disease course of pcp is fulminant, with an interval of only - days between onset of symptoms and progression to development of respiratory failure. in others, it may be much more indolent, with respiratory symptoms that worsen almost imperceptibly over several months. rarely, pcp may present without respiratory symptoms as a fever of undetermined origin. clinical examination is usually remarkable only for the absence of physical signs; occasionally, fine, basal, end-inspiratory crackles are audible. features that would suggest an alternative diagnosis include a cough productive of purulent sputum or hemoptysis, chest pain (particularly pleural pain), and signs of focal consolidation or pleural effusion (see table - ). it should be noted that infection with more than one pathogen occurs in almost one fifth of individuals, and thus symptoms may be the product of several agents. the chest radiograph in pcp is typically unremarkable initially. later, diffuse reticular shadowing, especially in the perihilar regions, is seen and may progress to diffuse alveolar consolidation that resembles pulmonary edema if untreated or if the patient is seen late in disease. at this stage, the lung may be massively consolidated and almost airless (figure - ) . up to % of chest radiographs are atypical, showing lobar consolidation, honeycomb lung, multiple thin-walled cystic air space formation (pneumatoceles), intrapulmonary nodules, cavitary lesions, pneumothorax, and hilar and mediastinal lymphadenopathy. predominantly apical changes, resembling tuberculosis, may occur in patients who have pcp develop having received anti-p. jirovecii prophylaxis with nebulized pentamidine (figure - ). all these radiographic changes chest radiograph early: perihilar "haze" or bilateral interstitial shadowing late: alveolar-interstitial changes or "white out" (marked alveolar consolidation with sparing of apices and costophrenic angles) arterial blood gases pao : early, normal: late, low paco : early, normal or low; late, normal or high are nonspecific, and similar changes occur with other pulmonary pathogens, including pyogenic bacterial, mycobacterial, and fungal infection, as well as kaposi sarcoma and nonspecific interstitial pneumonitis. respiratory symptoms in an immunosuppressed, hiv-infected individual with a negative chest radiograph should not be discounted, because over an interval of - days radiographic abnormalities may appear. the diagnosis of pcp is made by demonstration of the organism in induced sputum, bal fluid, or lung biopsy material by use of histochemical or immunofluorescence techniques. the early promise of molecular diagnostic techniques has not been borne out. many fungal infections of the lung are confined to specific geographic regions, although with widespread travel, they may present in patients outside these areas. candida, aspergillus, and cryptococcus species are ubiquitous and occur worldwide. in contrast to infections of the oropharynx and esophagus, candidal infection of the trachea, bronchi, and lungs is rare in hiv-infected patients, as are candidemia, disseminated candidiasis, and deep focal candidiasis. the clinical presentation of pulmonary candidal infection has no specific features. chest radiography is equally nonspecific-it may be negative or show patchy infiltrates. isolation of candida from sputum may simply represent colonization and does not mean the patient has candidal pneumonia. indirect evidence may be obtained from positive cultures or rising antibody titers. however, in hivinfected patients, a high antibody titer alone is a less reliable indicator, and antibodies may be absent in proven cases of invasive candidal infection. some correlation occurs between identification of large quantities of candida species in bal fluid and candida species as the cause of pneumonia. definitive diagnosis is made by lung biopsy. by contrast with patients immunosuppressed and rendered neutropenic by systemic chemotherapy, infection with aspergillus species is relatively rare in hiv-positive individuals. risk factors for aspergillosis are neutropenia, which is commonly drug induced (zidovudine or ganciclovir), or patient's receipt of corticosteroids. fever, cough, and dyspnea are the most common presenting symptoms, but pleuritic chest pain and hemoptysis are found in approximately one third of patients. patterns of pulmonary disease include cavitating upper lobe disease, focal radiographic opacities resembling bacterial pneumonia, bilateral diffuse and patchy opacities (nodular or reticular-nodular in pattern), pseudomembranous aspergillosis, which may obstruct the lumen of airways, and tracheobronchitis. diagnosis of pulmonary aspergillosis is made by the identification of fungus in sputum, sputum casts, or bal fluid associated with respiratory tract tissue invasion ( figure - ). the role of antigen testing (such as galactomannan assays), which is commonplace in hematology patients at risk of invasive aspergillus, has not been clearly defined in hiv-infected individuals. infection may present in one of two ways: either as primary cryptococcosis or complicating cryptococcal meningitis as part of disseminated infection with cryptococcemia, pneumonia, and cutaneous disease (umbilicated papules mimicking molluscum contagiosum; figure - ). primary pulmonary cryptococcosis presents in a very nonspecific way and is frequently indistinguishable from other pulmonary infections. in disseminated infection, the presentation is frequently overshadowed by headache, fever, and malaise (caused by meningitis). the duration of onset may range from only a few days to several weeks. examination may reveal skin lesions, lymphadenopathy, and meningism. in the chest, signs may be absent or crackles may be audible. arterial blood gas tensions may be normal or show hypoxemia. the most common abnormality on the chest radiograph is focal or diffuse interstitial infiltrates. less frequently, masses, mediastinal or hilar lymphadenopathy, nodules, and effusion are noted. the diagnosis of cryptococcal pulmonary infection ( figure - ) is made by identification of cryptococcus neoformans (by staining with india ink or mucicarmine, and by culture) in sputum, bal fluid, pleural fluid, or lung biopsy. cryptococcal antigen may be detected in serum by use of the cryptococcal latex agglutination (crag) test. titers are usually high but may be negative in primary pulmonary cryptococcosis, in which case bal fluid (crag) is positive. in patients with disseminated infection, c. neoformans may also be cultured from blood and cerebrospinal fluid. the mortality rate is high in this disseminated form (up to %). the endemic mycoses caused by histoplasma capsulatum, coccidioides immitis, and blastomyces dermatitidis are found in hiv-infected patients living in north america (especially the mississippi and ohio river valleys). histoplasmosis is also found in southeast asia, the caribbean islands, and south america. coccidioidomycosis is endemic in the southwest united states (southern california), northern mexico, and in parts of argentina and brazil. blastomycosis has a similar distribution, with an extension north into canada. progressive, disseminated histoplasmosis in patients with hiv typically presents with a subacute onset of fever and weight loss; approximately % of patients have mild respiratory symptoms with a nonproductive cough and dyspnea. hepatosplenomegaly is frequently found on examination, and a rash (similar to that produced by cryptococcus species) may be seen. rarely, the presentation may be rapidly fulminant, with clinical features of the sepsis syndrome, including anemia or disseminated intravascular coagulation. the chest radiograph may be unremarkable (in up to one third of patients), although characteristic abnormalities are bilateral, widespread nodules - mm in size. other radiographic features are nonspecific and include interstitial infiltrates, reticular nodular shadowing, and alveolar consolidation. histoplasmosis may disseminate to the central nervous system and produce meningoencephalitis or mass lesions. the diagnosis is made reliably by identification of the organism in wright-stained peripheral blood or by giemsa staining of bone marrow, lymph node, skin, sputum, bal fluid, or lung tissue. it is important that identification is confirmed by detection of h. capsulatum var. capsulatum polysaccharide antigen by radioimmunoassay, which has a high sensitivity. false-positive results may occur in patients infected with blastomycosis and coccidioides species. tests for histoplasma antibodies by complement fixation or immunodiffusion may be negative in immunosuppressed, hiv-positive patients. the clinical presentation of coccidioidomycosis is variable. the chest radiograph may show focal pulmonary disease with focal alveolar infiltrates, adenopathy, and intrapulmonary cavities or, alternately, diffuse reticular infiltrates. diagnosis is made by isolation of the organism in sputum or bal fluid. disseminated disease is identified by isolating the fungus in blood, urine, or cerebrospinal fluid. serologic tests may also be used for diagnosis. blastomycosis presents in patients who have advanced hiv infection, when cd lymphocyte counts are usually less than cells/ml. clinical symptoms include cough, fever, dyspnea, and weight loss. patients may present late in respiratory failure. disseminated disease can occur with both pulmonary and extrapulmonary features. there is frequently multiple involvement of the skin, liver, brain, and meninges. chest radiographic abnormalities include focal pneumonic change, miliary shadowing, or diffuse interstitial infiltrates. diagnosis is made by culture from bal fluid, skin, and blood. in this infection, cytologic or histologic diagnosis is important for early diagnosis, because culture of the organism may take - weeks. the mortality rate is high in patients with disseminated infection. p. marneffei infection is particularly common in southeast asia. most hiv-infected patients present with disseminated infection and solitary skin or oral mucosal lesions, or with multiple infiltrates in the liver or spleen, or bone marrow (leading to presentation with pancytopenia). pulmonary infection has no specific clinical features, and chest radiographs may be negative or show diffuse, small nodular infiltrates. diagnosis is made by identifying the organism in bone marrow, skin biopsy samples, blood films, or bal fluid. the differential diagnosis of p. marneffei infection includes both pcp and tuberculosis. these occur with equal frequency in hiv-infected and non-hiv-infected patients; however, respiratory complications after influenza infection are increased in patients affected with underlying conditions such as cardiac or pulmonary disease and immunosuppression. in prospective studies of hivinfected patients undergoing bronchoscopy for evaluation of suspected lower respiratory tract disease, the communityacquired respiratory viral infections (i.e., influenza, parainfluenza, respiratory syncytial virus, rhinovirus, coronavirus and adenovirus) are found only rarely, if at all. cmv chronically infects most hiv-infected individuals, and up to % of homosexual hiv-infected men shed cmv intermittently in urine, semen, and saliva. clinical disease may be caused by cmv in patients who have advanced hiv infection and cd counts < cells/ml. chorioretinitis is most frequently encountered, but encephalitis, adrenalitis, esophagitis, and colitis are also seen. frequently, cmv is isolated from bal fluid, being found in % of samples from patients with cd counts < cells/ml. however, the role of cmv in causing disease in this context is unclear (see later). in patients who have cmv as the sole identified pathogen, clinical presentation and chest radiographic abnormalities (usually diffuse interstitial infiltrates) are nonspecific. diagnosis of cmv pneumonitis is made by identifying characteristic intranuclear and intracytoplasmic inclusions, not only in cells in bal fluid but also in lung biopsy specimens (figure - ). pulmonary involvement with leishmania species may rarely occur as part of the syndrome of visceral leishmaniasis in hiv-infected patients. patients usually have advanced hiv disease with cd lymphocyte counts less than cells/ml and present with unexplained fever, splenomegaly, and leukopenia. respiratory symptoms are often absent. diagnosis of visceral leishmaniasis is most often made by staining a splenic or bone marrow aspirate and subsequent culture. occasionally, the parasite is found by chance in a skin or rectal biopsy or bal fluid taken for other purposes. the chest radiograph may be negative or show reticular-nodular infiltrates. toxoplasma gondii infection in patients who have aids usually occurs as a result of reactivation of latent, intracellular protozoa acquired in a primary infection. patients are invariably systemically unwell, with malaise and pyrexia. clinical disease in association with hiv infection is most commonly seen in the central nervous system, where it produces single or multiple abscesses. multisystem infection with t. gondii is uncommon in patients who have hiv infection. toxoplasmic pneumonia is frequently difficult to distinguish from pcp. nonproductive cough and dyspnea are the symptoms most commonly reported. chest radiographic abnormalities include diffuse interstitial infiltrates indistinguishable from those of pcp ( figure - ) , as well as micronodular infiltrates, a coarse nodular infiltrate, cavitary change, and lobar consolidation. the diagnosis is made by hematoxylin-eosin or giemsa staining of bal fluid that reveals cysts and trophozoites of t. gondii. staining of bal fluid is not always positive; the diagnostic yield is increased either by staining of transbronchial biopsy material or by performing nucleic acid amplification procedures such as pcr to detect t. gondii dna in bal fluid. the most frequent manifestation of infection with cryptosporidium species in hiv infection is a noninflammatory diarrhea that may be of high volume, intractable, and life threatening. cryptosporidium species may colonize epithelial surfaces, including the trachea and lungs, occasionally resulting in pulmonary infection. most cases of pulmonary cryptosporidiosis have co-pathology such as pcp or bacterial pneumonia; ascertaining the exact role of cryptosporidiosis as the cause of respiratory symptoms may be difficult. diagnosis is made by ziehl-neelsen or auramine-rhodamine staining of bal fluid or transbronchial biopsy specimens. pulmonary microsporidia infection may occur as part of systemic dissemination from gastrointestinal infection with septata intestinalis or encephalitozoon hellem. the organism may be identified by conventional staining in bal fluid. electron microscopy is necessary to distinguish the two species. the nematode strong yloides stercoralis is endemic in warm countries worldwide. in immunosuppressed patients, the organism has an increased ability to reproduce parthenogenetically in the gastrointestinal tract without the need for repeated exposure to new infection-so-called autoinfection. this results in a great increase in worm load and a hyperinfective state ensues; massive acute dissemination with s. stercoralis may occur in the lungs, kidneys, pancreas, and brain. although infection with s. stercoralis is more severe in immunocompromised patients, it is no more common in patients who have hiv infection. presentation with hyperinfection may be with fever, hypotension secondary to bacterial sepsis, or disseminated intravascular coagulation. the clinical features of respiratory s. stercoralis infection are nonspecific. s. stercoralis in sputum or bal fluid (figure - ) may be identified in hiv-positive patients in the absence of symptoms elsewhere; this can predate disseminated infection and, as such, requires prompt treatment. it is apparent from the foregoing discussion that hiv-related pneumonia of any cause may present in a similar manner. a wide range of investigations is available to aid diagnosis. these are listed in table - . if the subject is producing sputum, it is important to obtain samples for bacterial and mycobacterial detection. in up to one third of cases, these will assist in diagnosis. three samples on consecutive days (preferably either with overnight or early morning production) is the critical first step in the diagnosis of pulmonary tuberculosis. this is considerably easier and safer for health care personnel than obtaining hypertonic saline-induced sputum or bal fluid. blood cultures are also important, because very high rates of bacteremia have been reported in both bacterial and mycobacterial disease (see earlier). a patient who is initially seen with symptoms and signs consistent with pneumonia should have chest radiography and arterial oxygen assessments performed at his or her first consultation. the question at this stage is usually whether this infectious episode is due to bacterial infection, tuberculosis, or pcp. in general, alveolar and interstitial shadowing is taken as evidence for pcp, although important caveats apply. transcutaneous pulse oximetry and arterial blood gas analysis are useful tests for hypoxemia. they can be used to distinguish an alveolar condition (i.e., pcp) from bacterial pneumonia. the alveolitis produces a greater impairment of oxygen transfer (especially during exercise), such that for a given clinical situation there will be more hypoxemia and a wider alveolararterial oxygen gradient (a-ao ) in those with pcp. with pulse oximetry, this manifests as low oxygen saturations at rest that decrease further with exercise. in general, more information can be obtained from arterial blood gas analysis, although this advantage is offset by the need for direct arterial puncture. of patients with pcp, fewer than % have a normal pao and a normal a-ao . these measures are sensitive, although not particularly specific for pcp, and similar results may occur with bacterial pneumonia, pulmonary kaposi sarcoma, and m. tuberculosis infection. the diagnostic value of identifying exercise-induced desaturation, measured by transcutaneous oximetry, has been validated only in hiv-infected patients who have pcp and a normal or "near normal" appearance on chest radiographs. the test's value has not been confirmed in patients with abnormal chest radiographs because of pcp or other pathogens. exercise-induced desaturation may persist for many weeks after treatment and recovery from pcp, even in the absence of active pulmonary disease. abnormalities of lung function are well documented with hiv infection. the most common of these relate to tests measuring gas exchange, rather than the size of the conducting airways. in general, an overall reduction in diffusing capacity for carbon monoxide (dlco) occurs at all stages of hiv infection, with the largest changes found in hiv-infected patients with pcp. thus, to some extent, patients who have probable pcp can be differentiated and treatment guided. a normal dlco in an individual who has symptoms but a negative or unchanged chest radiograph makes the diagnosis of pcp extremely unlikely. data from the north american pspc cohort study suggest that individuals with rapid rates of decline in dlco are at an increased risk for development of pcp. recent work suggests that hiv-infected smokers are at increased risk of early-onset emphysema. smoking history must, therefore, be taken into account when assessing a patient's lung function results in the context of possible pcp. high-resolution (fine-cut) ct scanning of the chest may be helpful when the chest radiograph is normal, unchanged, or equivocal. the characteristic appearance of an alveolitis (i.e., areas of ground-glass attenuation through which the pulmonary vessels can be clearly identified) may be present, which indicates active pulmonary disease (figure - ). this feature, however, is neither sensitive nor specific for pcp, although its sensitivity can be improved if evidence for reticulation and/or small cystic lesions is added to this. hence, a negative test result implies an alternative diagnosis. in the context of an hiv-infected patient who is seen with an acute or subacute pneumonitis, an elevated serum lactate dehydrogenase (ldh) enzyme level is strongly suggestive of pcp. when interpreting such results, it is important to remember that other pulmonary disease processes (e.g., pulmonary embolism, nonspecific pneumonitis, and bacterial and mycobacterial pneumonia) and extrapulmonary disease (castleman disease and lymphoma) may also cause elevations of ldh and may need to be considered in the correct clinical context. from the previous information, it is evident that noninvasive tests cannot reliably distinguish the different infecting agents from each other but may be useful in excluding acute opportunistic disease. thus, the clinician is left with either proceeding to diagnostic lung fluid or tissue sampling (by either induced sputum collection or bronchoscopy and bal with or without transbronchial biopsy table - ) or treating an unknown condition empirically. haart has also altered the investigation of respiratory disease. the numbers of invasive procedures performed are falling and tend to be in patients spontaneously expectorated sputum is inadequate for diagnosis of pcp. sputum induction by inhalation of ultrasonically nebulized hypertonic saline may provide a suitable specimen (see table - ). the technique requires close attention to detail and is much less useful when samples are purulent. sputum induction must be carried out away from other immunosuppressed patients and health care workers, ideally in a room with separate negative-pressure ventilation, to reduce the risk of nosocomial transmission of tuberculosis. although very specific (> %), the sensitivity of induced sputum varies widely ( - %), and therefore a negative result for p. jirovecii prompts further diagnostic studies. the use of immunofluorescence staining enhances the yield of induced sputum compared with standard cytochemistry. fiberoptic bronchoscopy with bal is commonly used to diagnose hiv-related pulmonary disease. when a good "wedged" sample is obtained, the test has a sensitivity of more than % for detection of p. jirovecii (figure - ). just as with induced sputum, fluorescent staining methods increase the diagnostic yield, which makes it the procedure of choice in most centers. more technically demanding (both of the patient and the operator) than induced sputum collection, bronchoscopy and bal have the advantage that direct inspection of the upper airway and bronchial tree can be performed and, if necessary, biopsies taken. transbronchial biopsies may marginally increase the diagnostic yield of the procedure. this is relevant for the diagnosis of mycobacterial disease, although the relatively high complication rate in hiv-infected individuals (pneumothorax and the possibility of significant pulmonary hemorrhage in up to %) outweighs the advantages of the technique for routine purposes. samples of bal fluid are examined for bacteria, mycobacteria, viruses, fungi, and protozoa. inspection of the cellular component may also provide etiologic clues-cooperation of a pathology department with experience in opportunistic infection diagnosis is vital. the drug interactions associated with antiretroviral protease inhibitor (pi) therapy mean that special care should be exercised when sedation is used with either benzodiazepine or opiate drugs. prolonged sedation and life-threatening arrhythmias have been reported. a diagnostic strategy, therefore, includes sputum induction and, if results are nondiagnostic or if the test is unavailable, bronchoscopy and bal. if this does not yield a result, consideration is given to either a repeat bronchoscopy and bal with transbronchial biopsies or surgical biopsy. the latter can be performed as either an open lung or thoracoscopic procedure. surgical biopsy has a high sensitivity. although empirical therapy is usually reserved for the management of presumed bacterial pneumonias, and at first sight may seem unwise when dealing with possible opportunistic infection, in reality pcp is almost invariably a diagnosis of exclusion, and certain clinical and laboratory features may guide the assessment of an hiv-infected individual's risk for this condition. the likelihood that p. jirovecii is the causative organism increases if the subject is not taking effective anti-pneumocystis drug prophylaxis or has a previous medical history with clinical or laboratory features that suggest systemic immunosuppression (i.e., recurrent oral thrush, longstanding fever of unknown cause, clinical aids, or blood cd count < cells/ml). hence, some centers advocate use of empirical therapy for hiv-infected patients who are seen with symptoms and chest radiographic and blood gas abnormalities typical of mild pcp, without the need for bronchoscopy. invasive measures are reserved for those with an atypical radiographic presentation, those who fail to respond to empirical therapy by day , and those who deteriorate at any stage. most clinicians in north america and the united kingdom would seek to obtain a confirmed diagnosis in every case of suspected pcp. in practice, both strategies seem to be equally effective, although a number of caveats should be borne in mind when empirical treatment is given for pcp. patients who have pcp typically take - days to show clinical signs of improvement, so a bronchoscopically proven diagnosis ensures that the treatment being given is correct, particularly in the first few days of therapy, when it may not be well tolerated. in addition, the diagnosis of pcp has implications for the infected individual, because it may influence the decision to start either haart or anti-pneumocystis prophylaxis. finally, empirical therapy requires the patient to be maximally adherent to treatment, because nonresolution of symptoms may be seen as failure of therapy rather than of compliance. molecular biologic techniques (such as pcr) are increasingly used in the diagnosis of respiratory disease. two examples of this are dna amplification of loci of the p. jirovecii and m. tuberculosis genomes. the advantages of molecular methods are that the diagnosis may be made by use of samples that are more readily obtained than bal fluid (i.e., expectorated sputum or nasopharyngeal secretions) and also that these methods are rapid (the answer may be available within a working day, compared with conventional mycobacterial culture, which may take weeks). despite encouraging results in the research setting (sensitivity and specificity have been reported as - % and - %, respectively), problems persist when these techniques are applied to routine diagnostic samples. these include extraction of nucleic acid from clinical material, cross-contamination with the products of previous assays, and clinical interpretation of a test result. currently, treatment individuals infected with hiv, compared with the non-hivinfected general population, have an increased likelihood of adverse reactions to therapy. this includes tmp/smx (see later) and other antibacterial and antimycobacterial agents. in addition, there are complex drug interactions with other medications, particularly components of haart. before instituting therapy for any infectious complication in an hivinfected individual, it is important to consult with a physician experienced in the care of patients with hiv infection and to seek advice from a specialist pharmacist. the main organisms causing pneumonia in hiv-infected individuals are similar to those found in the general population with community-acquired pneumonia. thus, bacterial pneumonia in hiv-infected patients should be treated in a similar manner to that in hiv-negative individuals, by use of the published american thoracic society (ats) and british thoracic society (bts) guidelines. in addition, expert advice on local antibiotic resistance patterns should be sought from infectious disease or microbiology colleagues, because treatment is usually begun on an empirical basis before the causative organism is identified and antibiotic sensitivities known. the same clinical and laboratory prognostic indices that are described for the general population apply to hiv-infected patients and should be documented on presentation. response to appropriate antibiotic therapy is usually rapid and is similar to that seen in the non-hiv-infected individual. early relapse of infection after successful treatment is well described. those hiv-infected patients who have presumed pcp and are being treated empirically with high-dose tmp/ smx, and who have infection with either s. pneumoniae or h. influenzae rather than p. jirovecii, may also improve. in addition, in those patients who are treated with benzylpenicillin for proven s. pneumoniae pneumonia but do not respond, and penicillin resistance can be discounted as the cause, it is important to consider whether there is a second pathologic process, such as pcp. co-pathogens are reported in up to % of cases of pneumonia. before instituting treatment, assessment of the severity of pcp should be performed on the basis of history, findings on examination, arterial blood gas estimations, and chest radiographic abnormalities. patients can then be stratified into those with mild, moderate, or severe disease (table - ) . this is important, because some drugs are of unproven benefit and others are known to be ineffective for the treatment of severe disease. in addition, adjuvant glucocorticoid therapy may be given to patients with moderate or severe pneumonia. patients with glucose- -phosphate dehydrogenase deficiency should not receive tmp/smx, dapsone, or primaquine, because these drugs increase the risk of hemolysis. several drugs are effective in the treatment of pcp. tmp/ smx is the drug of first choice (tables - and - ). overall it is effective in - % of individuals when used as firstline therapy. adverse reactions to tmp/smx are common and usually become apparent between days and of treatment. neutropenia and anemia (in up to % of patients), rash and fever (up to %), and biochemical abnormalities of liver function (up to %) are the most frequent adverse reactions. hematologic toxicity induced by tmp/smx is neither attenuated nor prevented by coadministration of folic or folinic acid. furthermore, the use of these agents may be associated with reduced therapeutic success. during treatment with tmp/ smx, full blood count, liver function, and urea and electrolytes should be monitored at least twice weekly. it is not known why hiv-infected individuals, especially those with higher cd counts, have such a high frequency of adverse reactions to tmp/smx. the optimum strategy for an hiv-infected patient who has pcp and who becomes intolerant of high-dose tmp/smx has not been established. many physicians "treat through" minor rash, often adding an antihistamine and a short course of oral prednisolone ( mg every h, reducing to zero over days). if treatment with tmp/smx fails, or is not tolerated by the patient, several alternative therapies are available (see tables - and - ). the combination of clindamycin and primaquine is widely used for treatment of pcp whatever the severity, although there is no license in the united kingdom or united states for this indication. the combination is as effective as oral tmp/smx and oral trimethoprim-dapsone for the treatment of mild and moderate-severity disease. as a second-line treatment it is effective in up to % of patients. methemoglobinemia caused by primaquine occurs in up to % of patients. if mg four times daily of primaquine is used, rather than mg four times daily, the likelihood of methemoglobinemia is reduced. diarrhea develops in up to % of patients receiving clindamycin. if this occurs, stool samples should be analyzed for the presence of clostridium difficile toxin. this oral combination is as effective as oral tmp/smx and oral clindamycin plus primaquine (see earlier) for treatment of mild and moderate-severity pcp. the combination has not been shown to be effective in patients who have severe pcp. most patients experience methemoglobinemia (caused by dapsone), which is usually asymptomatic. up to one half of patients have mild hyperkalemia (< . mmol/l) caused by trimethoprim. a methotrexate analog, trimetrexate, is given intravenously together with folinic acid "rescue" to protect human cells from trimetrexate-induced toxicity. in patients who have moderate regimen recommended by cdc/ nih/idsa, widely used in usa methylprednisolone iv at % of dose given above for prednisolone methylprednisolone prednisolone iv q h, days - . iv days - then g po q h reducing to , days - nb, none of these regimens for adjuvant glucocorticoid therapy have been compared in prospective clinical trials. to severe disease, trimetrexate-folinic acid is less effective than high-dose tmp/smx, but serious treatment-limiting hematologic toxicity occurs less frequently with trimetrexate-folinic acid. atovaquone is licensed for the treatment of mild and moderate-severity pcp in patients who are intolerant of tmp/ smx. in tablet formulation (no longer available), this drug was less effective but was better tolerated than tmp/smx or intravenous pentamidine for treatment of mild or moderateseverity pcp (see tables - and - ). there are no data from prospective studies that compare the liquid formulation (which has better bioavailability) with other treatment regimens. common adverse reactions include rash, fever, nausea and vomiting, and constipation. absorption of atovaquone is increased if it is taken with food. intravenous pentamidine is now seldom used for the treatment of mild or moderate-severity pcp because of its toxicity. intravenous pentamidine may be used in patients who have severe pcp, despite its toxicity, if other agents have failed (see tables - and - ). nephrotoxicity develops in almost % of patients given intravenous pentamidine (indicated by elevation in serum creatinine), leukopenia develops in approximately half, and up to % have symptomatic hypotension or nausea and vomiting. hypoglycemia occurs in approximately % of patients. given the long half-life of the drug, this may occur up to several days after the discontinuation of treatment. pancreatitis is also a recognized side effect. for patients who have moderate and severe pcp, adjuvant glucocorticoid therapy reduces the risk of respiratory failure by up to half and the risk of death by up to one third (see tables - and - ). glucocorticoids are given to hivinfected patients with confirmed or suspected pcp who have a pao < . kpa (< mmhg) or an a-ao of > . kpa (< mmhg). oral or intravenous adjunctive therapy is given at the same time as (or within h of starting) specific anti-p. jirovecii therapy. clearly, in some patients treatment is commenced on a presumptive basis, pending confirmation of the diagnosis. in prospective studies, adjuvant glucocorticoids have not been shown to be of benefit in patients with mild pcp. however, it would be difficult to demonstrate this, given that survival in such cases approaches % with standard treatment. patients with mild pcp may be treated with oral tmp/smx as outpatients if they are able to manage at home, willing to attend the outpatient clinic for regular review, and that there is clinical and radiographic evidence of recovery. if the patient is intolerant of oral tmp/smx despite clinical recovery, either the treatment is given intravenously or treatment may be changed to oral clindamycin plus primaquine. all patients with moderate and severe pcp should be hospitalized and given intravenous tmp/smx or intravenous clindamycin and oral primaquine (plus adjuvant steroids). patients with moderate or severe disease who show clinical and radiographic response by day - of therapy may be switched to oral tmp/smx to complete the remaining days of treatment. if the patient has failed to respond within - days or deteriorates before this time while receiving tmp/smx, then treatment should be changed to clindamycin and primaquine or trimetrexate plus folinic acid. deterioration in a patient who is receiving anti-p. jirovecii therapy may occur for several reasons (table - ) . before ascribing deterioration to treatment failure and considering a change in therapy, these alternatives should be evaluated carefully. it is also important to consider treating any co-pathogens present in bal fluid, to perform bronchoscopy if the diagnosis was made empirically, to repeat the procedure, or to carry out open lung biopsy to confirm that the diagnosis is correct. most centers advocate admission to the icu for pcp with respiratory failure and for acute severe deterioration after bronchoscopy. the prognosis for severe pcp in such circumstances has improved over the past decade. this is likely because of a greater understanding of successful general icu management of respiratory failure and acute respiratory distress syndrome (ards) rather than specific improvements in pcp care. factors associated with poor outcome include increasing patient age, need for mechanical ventilation, and development of a pneumothorax. the latter reflects both the association between this complication and pcp, as well as the subsequent difficulty in successful mechanical ventilation of such individuals. the treatment of hiv-related mycobacterial disease is complex. not only do individuals have to take prolonged courses of relatively toxic agents, but also these antimycobacterial drugs have side effects similar to those of other prescribed in the developed world, isoniazid-related peripheral neuropathy is rare in hiv-negative subjects taking pyridoxine. the nucleoside reverse transcriptase inhibitors (rti) didanosine and stavudine, which are now less frequently used in the united states and the united kingdom but which remain a mainstay of haart in the developing world, can also cause a painful peripheral neuropathy. this complication develops in up to % of patients if stavudine and isoniazid are coadministered. rash, fever, and biochemical hepatitis are common adverse events with rifamycins, pyrazinamide, and isoniazid (occurring more frequently in patients with tuberculosis who have hiv infection with hepatitis c coinfection). the nonnucleoside rti drugs (e.g., nevirapine) have a similar toxicity profile. if treatment for both hiv and tuberculosis is co-administered, ascribing a cause may be problematic. drug-drug interactions between medications used to treat tuberculosis and hiv infection occur because of their common pathway of metabolism through the hepatic cytochrome p- enzyme system. rifampin is a potent inducer of this enzyme (rifabutin less so), which may result in subtherapeutic levels of nonnucleoside rti and pi antiretroviral drugs, with the potential for inadequate suppression of hiv replication and the development of resistance to hiv. in addition, the pi class of antiretroviral drugs inhibits the metabolism of rifamycins, which leads to increases in their plasma concentration and is associated with increased drug toxicity. the nonnucleoside rti drugs are inducers of this enzyme pathway. coadministration of rifabutin with efavirenz requires an increase in the dose of rifabutin to compensate for the increase in its metabolism induced by efavirenz (see later). the optimal duration of treatment of tuberculosis, by use of a rifamycin-based regimen, in a patient who has hiv infection is unknown. current recommendations (joint tuberculosis committee of the bts and the ats/cdc/infectious disease society of north america [idsa]) are to treat tuberculosis in hiv-infected patients in the same way as for the general population (i.e., for months for drug-sensitive pulmonary tb). in addition, ats/cdc/idsa guidelines recommend that treatment be extended to months in those who have cavitation on the original radiograph, continuing signs, or a positive culture after months of therapy. recent work has highlighted the increased risk for development of rifampin monoresistance in hiv-infected individuals on treatment. this is especially so if intermittent regimens are used and may arise from a lack of efficacy of the other drugs present in the combination (e.g., intermittent isoniazid). hence, daily medication regimens are recommended and should be closely supervised in all hiv-positive patients. it should be remembered that although rifabutin is usually given three times a week with ritonavir-boosted protease inhibitors, this seems to achieve adequate rifamycin levels; there have been no reports of this leading to rifamycin resistance in patients who are appropriately adherent. directly observed therapy (dot) is an important, although fairly labor-intensive, strategy that has the support of the world health organization. the best time to start therapy in patients being treated for tuberculosis is unknown. decision analyses show that early treatment with antiretroviral therapy leads to a marked reduction in further opportunistic disease. against this is balanced the risk of needing to discontinue antituberculosis therapy or hiv therapy because of drug toxicity or drug-drug interactions. iris is reported to be more likely if the treatments are started at the same time as each other. pragmatically, delaying the start of antiretroviral therapy simplifies patient management and may reduce or prevent adverse drug reactions and drug-drug interactions and may also reduce the risk of iris. on the basis of current evidence, patients with cd counts > cells/ml have a low risk of hiv disease progression or death during months of treatment for tuberculosis. in these patients, the cd count should be closely monitored, and antiretroviral therapy may be deferred until treatment for tuberculosis is completed. in patients who have cd counts from - cells/ml, many centers currently delay starting antiretroviral therapy until after the first months of treatment for tuberculosis have been completed; patients are given concomitant pcp prophylaxis. in patients who have cd counts of < cells/ml, antiretroviral therapy is started as soon as possible after beginning treatment for tuberculosis. this is based on evidence that shows a significant short-term risk of hiv disease progression and death in this patient group if antiretroviral therapy is delayed. two options exist for starting antiretroviral therapy in a patient already being treated for tuberculosis. first, the rifampin-based regimen is continued, and antiretroviral therapy is commenced, for example, with a combination of two nucleoside rtis and a non-nucleoside rti, such as efavirenz (if the patient weighs < kg, the efavirenz dose is often increased to mg once daily to compensate for rifampin-induced metabolism of efavirenz). alternately, the rifampin is stopped and rifabutin is started: antiretroviral therapy is given, with a combination of two nucleoside rti drugs and either a single ritonavir-boosted pi or a nonnucleoside rti. here the dose of rifabutin is adjusted to take into account the pharmacokinetic effect of the co-administered drug. with a boosted pi, it is usually prescribed at a dose of mg three times weekly and with efavirenz it is increased to mg once a day. before the advent of antiretroviral therapy, it was recognized by tuberculosis physicians that patients who were apparently responding to their antimycobacterial treatment would sometimes have a short period of clinical deterioration develop. this "paradoxical reaction" (in the face of overall treatment response) was seen as an interesting and probable immunebased phenomenon of generally little consequence. the widespread introduction of haart has led to an increased awareness by clinicians of similar, but generally more severe, events in hiv-infected individuals. in the context of hiv, these are termed iris, or immune reconstitution disease. they can present in a number of ways and with a range of opportunistic conditions. perhaps the most common of these is similar to a paradoxical reaction. here, after initiation of antiretroviral therapy in a patient being treated for tuberculosis, for example, there arises the return of the original or the development of new symptoms and signs. these are often of a systemic nature and may be associated with marked radiographic changes. examples of this include fever, dyspnea, lymphadenopathy, effusions, parenchymal pulmonary infiltrates, or expansion of cerebral tuberculomas. this form of iris is seen most frequently with mycobacteria (commonly tuberculosis or mac), fungi (notably, cryptococcus), and viruses (hepatitis and herpes viridae). iris develops in up to one third of hiv-infected patients being treated for tuberculosis when antiretroviral therapy is started. the median onset of tuberculosis-related iris is approximately weeks from beginning antituberculosis treatment or weeks from commencing haart. it seems to be more likely in patients who have disseminated tuberculosis (and hence presumably more antigen present as well as more potential for significant inflammatory reactions) and a lower baseline blood cd count. a rapid fall in hiv load, as well as a large increase in cd counts in response to haart, may also predict iris. the relationship between early use of haart and low blood cd counts suggests that care must be taken when starting antiretrovirals in patients with tb at sites where rapid expansion of an inflammatory mass could be life threatening. examples of this would include cerebral, pericardial, or peritracheal disease (figure - ) . it is important to note that iris is currently a diagnosis of exclusion. there is no laboratory test available to assist with this; it should be made only after progressive or (multi) drug-resistant tuberculosis, poor drug adherence (to either antituberculosis or antiretroviral agents) and drug absorption, or an alternative pathologic process have been excluded as an explanation for the presentation. criteria have been drawn up that seek to provide clinical diagnostic criteria (table - ) . the mechanism leading to iris is unclear. it is not due to failure of treatment of tuberculosis or to another disease process; if anything, it is most likely to represent an exuberant and uncontrolled response to mycobacterial antigens (from both dead and live organisms). current treatments include nonsteroidal antiinflammatory drugs or glucocorticoids. the latter are undoubtedly effective, although they can lead to hyperglycemia and hypertension. recent preliminary data suggest that the leukotriene receptor antagonist montelukast may be of benefit in iris (this drug is unlicensed for this indication). recurrent aspiration of lymph nodes or effusion may also be needed. although iris is often self-limiting, it may persist for several months. rarely, temporary discontinuation of antiretroviral therapy is required. in this situation there may be precipitous falls in cd counts; patients are at risk of other opportunistic infections. attention has also focused on what is possibly more of a concern-the form of iris referred to as "unmasking phenomenon." here, individuals with presumably latent tuberculosis infection who start haart have systemic active (and often infectious) tuberculosis develop within a -month period. although it is likely that the patient's disease would have presented in time anyway and that some of the reported cases may, in fact, represent ascertainment bias, the current view is that this is real and represents an adverse effect of haart. given that the people most at risk live in countries with limited facilities for pre-haart screening, this has major implications for antiretroviral therapy roll-out programs in resource-poor areas. combination antimycobacterial therapy by itself does not cure mac infection. a commonly used regimen is oral rifabutin, mg once daily, with oral ethambutol, mg/kg once daily, and oral clarithromycin, mg once daily or every h. if clarithromycin is not used, oral rifabutin, mg once daily, is given-the lower dose adjusting for yet more drug-drug interactions. use of three drugs has no impact on overall outcome, although it reduces the risk of resistance and possibly enhances early mycobacterial killing. in patients severely compromised by symptoms, intravenous amikacin, . mg/kg once daily for - weeks, is also given. trough blood levels must be measured to ensure toxic accumulation of amikacin does not occur. fluoroquinolones such as moxifloxacin or levofloxacin may be extremely useful, because they have good antimycobacterial activity with limited side effects. at present, many of these agents are not licensed for this indication. given the concerns over xdr tuberculosis, it is important to ensure that patients are adherent to such treatments, and hence reduce the risk of fluoroquinolone resistance developing. a frequently used regimen includes rifampin, isoniazid, and ethambutol in conventional doses; all drugs are given by mouth. the treatment regimens for fungal infections complicating hiv infection are shown in table - . after initial treatment of cryptococcal infection, there is a high likelihood of relapse of infection; hence, lifelong secondary preventative therapy is needed unless antiretroviral therapy is commenced and results in sustained improvements in cd counts (> cells/ml) and suppression of hiv load in peripheral blood. secondary prophylaxis is most often oral fluconazole - mg four times daily. just as with mycobacterial disease, "late" iris events can occur after months or even years. these should be investigated to exclude active disease and other conditions. oral itraconazole, mg twice daily, is the current treatment of choice. the dose is adjusted to achieve blood trough drug levels that are above the standard lowest effective concentration. there are no data on the impact of antiretroviral therapy on which to base decisions about discontinuation of secondary prophylaxis. treatment of this infection is difficult. after initial treatment with amphotericin b, itraconazole or fluconazole may be given for long-term suppression. the overall prognosis is poor, with a % mortality rate despite therapy. there are no data on the impact of antiretroviral therapy on which to base decisions about discontinuation of secondary prophylaxis. oral itraconazole has now replaced amphotericin b as the treatment of choice for p. marneffei infection, apart from the subgroup who are acutely unwell. fluconazole is less effective than itraconazole. after initial treatment, lifelong suppressive therapy with itraconazole is needed. there are no data on the impact of antiretroviral therapy on which to base decisions about discontinuation of secondary prophylaxis. the treatment regimens are shown in table - . a combination of sulfadiazine and pyrimethamine is the regimen of choice for t. gondii infection. the most frequent dose-limiting side effects are rash and fever. adequate hydration must be maintained to avoid the risk of sulfadiazine crystalluria and obstructive uropathy. alternate regimens are given in table - . once treatment is completed, lifelong maintenance is necessary to prevent relapse, unless antiretroviral therapy achieves adequate immune restoration (blood cd count > cells/ml and undetectable hiv load). visceral leishmaniasis is usually treated with liposomal amphotericin b, although this is still associated with a high rate of relapse. second-line therapy (or first-line in resourcepoor environments) is to use sodium stibogluconate (see table - ) . phenomena temporally associated with starting haart. this includes, but is not limited to: . new or enlarging lymphadenopathy, cold abscesses, or other focal tissue involvement . new or worsening central nervous system disease . new or worsening radiological features of tuberculosis . new or worsening serositis (pleural effusion, ascites, pericardial effusion, or arthritis. . new or worsening constitutional symptoms such as fever, night sweats, and/or weight loss . retrospective review indicating that a clinical or radiologic deterioration occurred with no change having been made to tuberculosis treatment c. immune restoration, e.g., a rise in cd lymphocyte count in response to haart d. a fall in hiv "viral load" in response to haart alternative diagnoses to be excluded progressive underlying infection treatment failure due to drug resistance (mdr or xdr) treatment failure from poor adherence adverse drug reaction another diagnosis coexisting (e.g., non-hodgkin lymphoma) the treatment of choice is ivermectin. risk of treatment failure with thiabendazole in hiv-infected individuals is higher than that in non-hiv-infected patients. cytomegalovirus pneumonitis is treated with intravenous ganciclovir, mg/kg every h, for days. drug-induced neutropenia is managed with granulocyte colony-stimulating factor. some centers use valganciclovir, an oral formulation of ganciclovir, at a dose of mg orally every h, to treat cmv pneumonitis. side effects and their management are as for ganciclovir. there are no data that demonstrate efficacy for cidofovir for treatment of cmv pneumonitis, but this agent is used as second-line therapy in many centers. phosphonoformate (foscarnet) can be used for treatment of cmv endorgan disease (e.g., pneumonitis), although it has an extensive toxicity profile. it is also a moderately effective antiretroviral agent. this effect is occasionally used as an adjunct in controlling nonresponsive viral infections. within the past few years, drug therapy has radically altered the depressingly predictable nature of progressive hiv infection. combinations of specific opportunistic infection prophylaxis and antiretroviral therapy can reduce both the incidence and the mortality associated with common conditions. the observational north american macs cohort demonstrated that the risk of pcp in individuals with blood cd counts of < cells/ml can be reduced almost fourfold if both specific prophylaxis and haart are taken (from % to %). however, as common conditions are prevented, so other less treatable illnesses may arise. the initial impact of p. jirovecii prophylaxis was a reduction in the incidence of pcp at the expense of an increase in cases of disseminated mac infection, cmv infection, esophageal candidiasis, and wasting syndrome. new prophylactic therapies targeting those conditions associated with high morbidity and mortality (in particular mac) have further improved survival. it has become apparent that specific infection prophylaxis may also confer protection against other agents. this "cross- prophylaxis" is particularly seen with the use of tmp/smx for pneumocystis, which also provides cover against cerebral toxoplasmosis and several common bacterial infections (although not s. pneumoniae) and with macrolides for mac infection, which further reduce the incidence of bacterial disease and also pcp. use of large amounts of antibiotic raises the possibility of future widespread drug resistance. this is clearly of concern, and recent reports suggest that, indeed, in some parts of the world the incidence of pneumococcal tmp/smx resistance is rising. current preventive therapies pertinent to lung disease focus on p. jirovecii, mac, m. tuberculosis, and certain bacteria (table - ). numerous studies have demonstrated the greatly increased risk in subjects who do not take adequate drug therapy with blood cd counts < cells/ml. clinical symptoms are also an independent risk factor for pcp, and hence the current guidelines recommend lifelong prophylaxis against p. jirovecii in hiv-infected adults who have had prior pcp, cd counts < cells/ml, constitutional symptoms (documented oral thrush or fever of unknown cause of < . c that persists for more than weeks), or clinical aids. the importance of secondary prophylaxis (i.e., used after an episode of pcp) becomes clear from historical data, which indicate a % risk of relapse in the first months after infection. the increase in systemic and local immunity that occurs with haart has led to several studies evaluating the need for prolonged prophylaxis in individuals with sustained elevations in blood cd counts and low hiv rna load. in summary, it seems that both primary and secondary pcp prophylaxis can be discontinued once cd counts are > cells/ml for more than months. a caveat to this is that the patient should have a low or undetectable hiv rna load, that the cd percentage is stable or rising and is > %, and that the individual plans to continue haart long term with good adherence. the risk of pcp recurrence is real if the cd count falls below cells/ml. if this does happen, pcp prophylaxis should be restarted. similar algorithms have been successfully used for all the major infections except tuberculosis. they all rely on an estimation of the general blood cd count above which clinical disease is highly unlikely. for example, secondary prophylaxis of mac may be discontinued once the blood cd count is consistently > cells/ml. this is a general guideline, however, and patients must be assessed on an individual basis. as with treatment strategies, tmp/smx is the drug of choice for prophylaxis (table - ) . it has the advantages of being highly effective for both primary and secondary prophylaxis (with -year risk of pcp while on the drug being . and . %, respectively). it is cheap, can be taken orally, acts systemically, and provides some cross-prophylaxis against other infections, such as toxoplasmosis, salmonella species, staphylococcus species, and h. influenzae. its main disadvantage is that adverse reactions are common (see earlier), occurring in up to % of individuals taking the prophylactic dose. the standard dose of tmp/smx is one double-strength tablet ( mg trimethoprim, mg sulfamethoxazole) per day. other regimens have been tried; these include one "double-strength" tablet three times weekly and one single-strength tablet per day. in general, when used for primary prophylaxis, these regimens are tolerated well (if not better than the standard) and seem as efficacious as one double-strength tablet per day. the data are less clear on secondary prophylaxis, in which subjects are at a much higher risk of recurrent pcp. attempts to desensitize patients who are intolerant of tmp/ smx have met with some success. in patients who cannot tolerate tmp/smx, dapsone is a safe and inexpensive alternative. it has been studied in a number of trials as both primary and secondary prophylaxis and is effective at an oral dose of mg/day. when combined with pyrimethamine ( mg three times weekly), it provides a degree of cross-prophylaxis against toxoplasmosis. before starting dapsone, patients are tested for glucose- -phosphate dehydrogenase deficiency. nebulized pentamidine has largely fallen from use as a prophylactic agent. this is despite it being better tolerated and having a similar efficacy to tmp/smx for primary preventive therapy. however, its breakthrough rate is higher in subjects who have lower cd counts (i.e., < cells/ml) and in those who take it as secondary prophylaxis. other disadvantages include equipment costs and complexity (alveolar deposition is crucial, and hence the nebulizer system used is important), the risk of transmission of respiratory disease (e.g., tuberculosis) to other patients and staff during the nebulization procedure, an alteration in the clinical presentation of pcp while on pentamidine (increased frequency of radiographic upper zone shadowing, increased incidence of pneumothorax), and a lack of systemic protection against pneumocystis and other infectious agents. there is also an acute bronchoconstriction effect during nebulization. long-term follow-up studies have not demonstrated any significant negative effect on lung function. atovaquone oral suspension is used as a second-line prophylactic agent in subjects intolerant of tmp/smx. it seems to have similar efficacy to dapsone (given together with weekly pyrimethamine), with a reduced incidence of side effects, of which the most frequent are rash, fever, and gastrointestinal disturbance. azithromycin is used in many centers as a third-line prophylactic agent. it is given at a dose of mg once weekly, and may provide protection against some bacterial infections, as well as mac. a low blood cd count (< cells/ml) is the current best laboratory predictor of prophylaxis failure. this is not particularly surprising given that the median blood cd count of subjects not on prophylaxis who have pcp develop is below cells/ml. persistent fever of unknown cause is an important clinical risk factor for pcp. used as preventive therapy, tmp/ smx significantly reduces the chance for development of pneumocystis. it is, therefore, vital that subjects who are most vulnerable be encouraged to use this drug on a regular basis. the pspc cohort study revealed that % of subjects with a cd count < cells/ml were not receiving any form of pcp prophylaxis. the effective and safe (i.e., replication incompetent) bacterial vaccines that are available would be expected to be widely used to prevent hiv-related disease. in fact, uptake of both pneumococcal and the h. influenzae type b (hib) vaccines is poor (current estimates for the former are at most only % of the infected population with the recommended -valent vaccine). one reason for this may be that the protection conferred by vaccination ( %) in the general population is not seen in immunosuppressed hiv-infected individuals, reflecting their inability to generate adequate memory b-cell responses (especially those subjects with cd counts < cells/ml). however, in north america, cdc/idsa recommend the pneumococcal vaccine as a single dose as soon as hiv infection is diagnosed, with a booster at years, or if an individual's blood cd count was < cells/ml and subsequently increased on haart. several studies show pneumococcal immunization reduces the risk of invasive pneumococcal infection in this population. this does not seem to be the case in a developing world setting, where not only is the -valent vaccine ineffective against both invasive and noninvasive pneumococcal disease, but the overall incidence of pneumonia is increased. infection with h. influenzae type b is much less common in hiv-infected adults and, therefore, immunization with hib vaccine is not routinely recommended. there is little evidence to suggest that the high frequency of bacterial infections in the hiv population is related to bacterial colonization. therefore, continuous antibiotics are rarely indicated, although both tmp/smx and the macrolides (clarithromycin and azithromycin) given as long-term prophylaxis for opportunistic infections have been shown to reduce the incidence of bacterial pneumonia, sinusitis/otitis media, and infectious diarrhea. the use of tmp/smx also confers a survival advantage in many studies performed in resource-poor settings. there is little evidence, however, that tmp/smx protects against pneumococcal infection. the interaction between hiv and tuberculosis is of fundamental importance, because the annual risk for the development of clinical tuberculosis in a given individual is estimated to be - % (i.e., similar to a non-hiv-infected subject's lifetime risk). hiv-infected individuals with pulmonary tuberculosis are less likely to be smear positive than their hiv-negative counterparts, although they can still transmit tuberculosis. thus, within a community, tuberculosis prevention involves case finding and treatment of active disease, as well as specific prophylactic drug therapies for those exposed. if possible, hiv-positive subjects should make every effort to avoid encountering tuberculosis (e.g., at work, homeless shelter, health care facility). one of the problems with standard methods of tuberculosis contact tracing in hiv infection is that both tuberculin skin test results and chest radiology may be unreliable. however, in the absence of bacillus calmette-guérin (bcg) immunization, a positive ppd (e.g., < mm induration with tuberculin units) indicates a greatly increased risk ( -to -fold compared with nonanergic, ppd-negative, hiv-infected subjects) of future active disease. the chance that hiv-infected subjects may contract disseminated infection if given bcg means that (having excluded active infection) the only option in these circumstances is to use a preventative drug regimen. options include at least months of isoniazid (together with pyridoxine to prevent peripheral neuropathy). this is safe and well tolerated, although compliance is a problem (especially with regimens longer than months), and dot may need to be instituted (e.g., mg isoniazid twice weekly). there is little evidence to suggest that this single-agent regimen leads to isoniazid resistance, which probably reflects the low mycobacterial load present in such individuals. attempts to shorten the length of treatment for latent infection have produced variable results. recent studies used rifampin and pyrazinamide for short-course prophylaxis ( months). this was as effective as months of isoniazid in hiv-coinfected individuals, although it was associated with fatal hepatotoxicity (almost exclusively in the hiv-negative population). hence, it is currently out of favor. if used, liver function should be closely monitored, and it is recommended that this regimen not be given to patients with preexisting liver disease (e.g., because of alcohol or viral hepatitis). because rifampin should not be used by subjects taking pis, this may also limit widespread application of the two-drug regimen. the same applies to combinations of isoniazid and rifampin taken for at least months, which are also effective in hivnegative individuals. alternate protocols also exist for subjects thought to be resistant to first-line prophylactic agents. these have not been widely clinically evaluated. it is recommended that hiv-infected subjects who have had close contact with an active case of tuberculosis should also receive prophylaxis. there is little evidence to suggest that anergy confers an increased risk for development of clinical disease. however, patients who have not had bcg, have a negative skin test, and have started haart may benefit from regular skin tests, because some studies suggest that cutaneous responses may return with increasing cd counts, and that this may help in identifying newly infected individuals requiring prophylaxis. in populations where the prevalence of tuberculosis is low and bcg may be given during childhood or adolescence (e.g., the united kingdom), the value of ppd testing is more limited. here, an arbitrary cutoff of mm for tuberculin reactions is used to define who should receive preventive therapy. the introduction of immune-based blood tests that can accurately distinguish between bcg vaccination and tuberculosis infection may be helpful when screening for evidence of latent tuberculosis. the two currently available commercial tests use fairly specific cd -directed mycobacterial antigen responses with consequent production of detectable interferon-g. the need for reasonably intact cd function means that they may, in fact, be less useful in hiv infection, especially in those subjects with very low blood cd counts, who are possibly at greatest risk of developing active tuberculosis. secondary tuberculosis prophylaxis may be important, because studies indicate a high rate of relapse in endemic areas. here, no specific guidelines exist, although months of isoniazid and rifampin after a full treatment course shows a greatly reduced risk of relapse within the subsequent years. whether this is enough to prevent clinical disease (which may also arise from reinfection in areas of high tuberculosis prevalence) without concomitant antiretroviral therapy is unclear. in the developed world, secondary prophylaxis is usually not recommended. the use of haart also can reduce the risk of tuberculosis in endemic areas. work in south africa indicates that this is most beneficial in patients with advanced disease and leads to a reduction in rr of at least %. data from north america indicate that the prevention of disseminated mac infection has an effect on survival ( % reduction in mortality rate in subjects taking clarithromycin). the us guidelines advise prophylaxis with a macrolide (either clarithromycin, mg orally twice per day, or azithromycin, mg orally, once a week) in all hiv-infected individuals with blood cd counts > cells/ml. in europe, where the prevalence of disseminated mac infection is probably lower (perhaps because of previous bcg vaccination), this may be less relevant. here, surveillance cultures of blood may be more cost-effective in the at-risk hiv population with low cd counts. routine stool and sputum cultures probably do not add much to this strategy, because disseminated mac is much more common than isolated organ disease. single-agent prophylaxis may lead to antibiotic resistance. this does not seem to be reduced by the addition of a second drug (rifabutin) to the prophylactic regimen. the latter is now a second-line prophylactic agent, largely as a result of its rather worse protective effect and its adverse interaction profile with pis. as mentioned earlier, if an individual sustains a rise in cd count > cells/ml for > months, it is safe to discontinue prophylaxis. several clinical and laboratory features have prognostic significance in hiv-infected individuals with pcp (box - ). a severity score on the basis of the serum ldh levels, the a-ao , and the percentage of neutrophils in the bal fluid can predict survival reasonably accurately, with the highest scores indicating the worst outcome. other workers have shown that increased age (< years) leads to an increased mortality rate-in part as a result of late, "unsuspected" diagnosis. the overall mortality rate from an episode of pcp is approximately % and has not changed since the advent of haart. among individuals with access to haart, post-pcp survival has improved. in , the median survival after pcp was months. by , this had risen to months. the introduction of haart has led to a further improvement, with survival in the period up to year of months. in those without access to haart and/or prophylaxis, survival post-pcp, unfortunately, remains poor. in general, mortality from bacterial respiratory infection in hiv-infected individuals is similar to that seen in the general population. clinical and laboratory markers of disease severity that have been defined in the adult general population (e.g., those described in the ats or the bts guidelines for the management of community-acquired pneumonia in adults) apply to hiv-infected patients. these are confusion, raised respiratory rate, abnormal renal function, and low blood pressure. recurrent pneumonia is common (reported in up to % of cases) and may lead to chronic pulmonary disease (see earlier). although tuberculosis normally responds to standard multipledrug therapy, work from africa has highlighted the increased mortality rate in hiv-infected compared with non-hivinfected individuals. a relationship has also been described between mortality and declining blood cd count: hivinfected patients with cd counts < cells/ml have a mortality rate of % compared with % in those with cd counts from - cells/ml. compared with hiv-infected individuals without tuberculosis, the main effect on mortality is seen in patients with higher cd counts (> cells/ml), where the relative risk of death is three times that of the nontuberculous population. several case-controlled studies have indicated that in the absence of effective treatments, mac-infected patients have a reduced survival compared with blood cd level-matched control subjects (approximately months vs months, respectively). currently available treatment regimens may reduce this difference, although severe anemia seems to be an independent predictor of mortality. the presence of cmv in bal fluid also containing p. jirovecii has been related to outcome (see earlier). the mortality rate at and months after bronchoscopy is greater in those with cmv detected at bronchoscopy. however, cmv recovered as a sole pathogen does not impact on survival. the effect of antiretroviral therapy on opportunistic infections the introduction of haart, together with the wide availability of accurate methods of determining plasma rna viral load, has led to profound changes in both clinical practice and hiv outcome. although it is still the case that respiratory disease remains above non-hiv infected background levels, in particular, bacterial pneumonia, tb, and lung cancer are more common, despite apparently effective haart, in hiv-infected subjects. overall data indicate that clinical progression is rare in subjects who are able to adhere rigorously to at least % of their antiretroviral drug regimen. mortality rates have fallen by % for almost all conditions, and it seems that a damaged immune system can, to a clinically significant extent, be reconstituted for a period of at least several years. hence, clinicians need to consider not only opportunistic infection or malignancy within their diagnostic workup but also the effects of drug therapy itself. the side effect profile of haart (e.g., metabolic and mitochondrial toxicities, liver damage, and neuropsychiatric disorders), as well as the large number of drug-drug interactions, makes this a very complex area of management. the best example of this is hiv-related tuberculosis. here, not only is there overlapping toxicity and pharmacologic interaction, but iris is common. research is needed to address this area. studies should inform the decision on when to start haart in patients already on antituberculosis medication. other work needs to focus on understanding box - prognostic factors associated with poor outcome in pneumocystis jirovecii pneumonia on admission patient's age no previous knowledge of hiv status tachypnea (respiratory rate > /min) second or subsequent episode of pneumocystis jirovecii pneumonia poor oxygenation À pao < . kpa (< mmhg) or a-ao > . kpa (> mmhg) low serum albumin (< g/dl) low hemoglobin (< . g/dl) peripheral blood leukocytosis (> . Â /l) elevated serum lactate dehydrogenase levels (> iu/l) cd count < cells/ml marked chest radiographic abnormalitiesdiffuse bilateral interstitial infiltrates with or without alveolar consolidation medical comorbidity (e.g., pregnancy) at bronchoscopy . in bronchoalveolar lavage fluid detection of a. copathology cmv bacteria b. neutrophilia (> %) . detection of pulmonary kaposi sarcoma serum lactate dehydrogenase levels that remain elevated development of pneumothorax high apache ii score on admission to the icu need for mechanical ventilation why full pulmonary immunity is not restored. this may reflect abnormalities in the innate immune response, which is currently poorly described in hiv infection. despite the benefits of haart, it is likely that in the long term many patients will progress to severe disease. there is currently little research in this area. research should focus on correlating clinical and laboratory findings. an example of this would be assessing the risk of an individual for development of active tuberculosis. it is clear that much of the excess mortality in hiv-tuberculosis coinfection occurs early in hiv infection. thus, if tests can be devised that indicate who has latent tuberculosis infection (and who is, therefore, most likely to have clinical disease develop), steps can be taken to prevent illness. as discussed previously, immune-based tests have shown promise in immunocompetent individuals with tuberculosis infection. if these can be refined to work consistently in patients with hiv infection at a reasonable cost, there is the possibility of targeting those at risk of future tuberculosis, or of tuberculosis "unmasking" after starting haart. the other role for a test such as this would be in rapid diagnosis of active tuberculosis. it is common to be faced with a patient who has nonspecific symptoms and a wide differential diagnosis. often treatment is multiple and empirical. a quantitative test would help resolve some of these dilemmas by indicating the chance of the condition being caused by a particular disease. an example would be the patient from an endemic tuberculosis area, with low cd counts, who has both pulmonary and central nervous system disease. is this tuberculosis, toxoplasmosis, cryptococcosis, or viral or bacterial infection? any such test for tuberculosis would also have to distinguish between the different states of old (treated), old (inactive), old (latent), and active. although not insurmountable, at present, this is not possible. rapid diagnostic assays that assess organism viability are also important. if a clinician can receive early feedback on whether treatment is producing a suitable killing effect, therapy can be tailored to the individual. this enables regimens to be "dose adjusted" as needed and removes the element of concern that is often present when patients are slow to respond. examples of this would be in the treatment of pcp or mycobacterial disease. the frequency of bacterial infection (often recurrent) with its attendant sequelae makes effective strategies for vaccination an important priority. it is uncertain why there is a differential response to vaccination; even in the united states, african americans do not seem to derive the same benefit as whites. this needs further research, together with more emphasis on identifying the local immune response present in the lung in such individuals. bacterial infections may be clinically indistinguishable from other pathogens, and only two thirds of all respiratory infections are formally diagnosed. there is a need for improved methods to assist with this. the use of rapid antigen tests may be one way forward. this is especially so given the high incidence of (potentially fatal) bacteremia present in such populations. for maximum benefit, this needs to use a system that is simple and cheap, and hence suitable to both resourcerich and resource-poor countries. m. tuberculosis is globally the most important hiv-related pathogen. strategies of control and prevention are vital to ensure that millions of people do not become coinfected and that those who are do not go on to have clinical disease develop. rapid diagnostics are critical. the encouraging reports of the simple and cheap method of mods to both diagnose tuberculosis and then provide resistance data in field settings (see earlier) argues for large-scale roll out and evaluation. beyond public health measures, such as dot, fixed-dose combination drugs, case management, and education, research needs to improve on current drug therapy. long-acting preparations such as rifapentine show promise but, as the problem with rifampicin monoresistance demonstrates, there is still much work to be done. for the first time in many years, there are several antimycobacterial drugs that are in various stages of clinical trials. all are promising, and several have novel mechanisms of action. the global alliance and the who "stop tb" campaigns have been crucial in this regard. the fluoroquinolones, moxifloxacin and gatifloxacin, are closest to the market. they are potent drugs with considerable ability both to kill and also sterilize mycobacteria-infected sites. trials of treatment-shortening regimens are ongoing worldwide. vaccination against m. tuberculosis with bcg has understandably not been widely used in an immunosuppressed hiv-infected population. however, a safe vaccine may be the only affordable way of protecting large parts of the world from tuberculosis. so far there seems to be more success in vaccines to either enhance or replace the primary protective effects of bcg. the use of immunotherapy (e.g., with heat-killed mycobacterium vaccae) in combination with chemotherapy has been disappointing in clinical trials. newer methods of diagnosis (e.g., pcr tests on saliva) may prove invaluable for quick and easy disease confirmation, although their applicability to routine samples needs further evaluation. p. jirovecii prophylaxis was the first important hiv treatment widely available. however, despite the efficacy of tmp/smx, compliance remains a problem. regimens that use a gradual increase in dosage when starting prophylaxis may help. one concern with widespread use of prophylaxis is that resistance will start to occur to tmp/smx. reports have indicated that there are mutations in the p. jirovecii dihydropteroate synthase gene that confer resistance. these seem to be increasing over time, although they do not seem to be present in many patients who fail treatment for pcp with tmp/smx. the implications of this are uncertain but could include a greater likelihood of treatment failure and the possibility of worsening patterns of global bacterial drug resistance. hiv-infected populations in the developed world have high rates of smoking. the evidence that this is harmful above those effects seen in the general population continues to accrue. the accelerated course of both obstructive lung disease and cancer, together with the increased risk of respiratory infection in smokers, persuasively argues the case for targeted smoking cessation. that hiv infection and haart have profound (and probably negative) effects on blood lipids and insulin resistance further support the need to reduce smoking rates in this population. it seems that we are starting to see increased rates of cardiovascular disease in this now aging population. the natural history of hiv-related respiratory disease continues to evolve. haart and newer therapeutic strategies have made a significant impact on morbidity and mortality. yet individuals continue to become hiv infected, progress, and die from an ever-expanding range of conditions. p. jirovecii remains the most common aids-defining event in the developed world, whereas m. tuberculosis is globally the most common cause of death. bacterial respiratory infection is not far behind. given the huge number of individuals with hiv infection, the only effective way to manage this disease is to find simple ways of treating hiv itself, and thus contain the worst ravages of this illness. treating opportunistic infections among hiv-infected adults and adolescents revised recommendations for hiv testing of adults, adolescents, and pregnant women in healthcare settings treatment of hiv-related tuberculosis in the era of effective antiretroviral therapy treatment and prophylaxis of pneumocystis carinii pneumonia immune reconstitution disease associated with mycobacterial infections in hiv-infected individuals starting antiretroviral therapy immune reconstitution inflammatory syndrome in hiv guidelines for preventing opportunistic infections among hiv-infected persons- on behalf of the bhiva guidelines writing committee pneumocystis and trypanosoma cruzi: nomenclature and typifications oxford: blackwell scientific aids and respiratory medicine key: cord- - jiaghrb authors: brondani, m.; donnelly, l. title: the hiv and sars-cov- parallel in dentistry from the perspectives of the oral health care team date: - - journal: jdr clin trans res doi: . / sha: doc_id: cord_uid: jiaghrb objectives: the aim of this study was to unravel the professional and social consequences of covid- as compared with the aids pandemic according to oral health care providers, staff, and administrators. methods: an exploratory qualitative inquiry via at-a-distance, semistructured interviews engaged a purposefully recruited sample of oral health care team workers in british columbia. interviews took place between april and may , ; they were audio recorded, transcribed verbatim, and deidentified for interactive thematic analysis. an inductive process of coding was used to identify themes, subthemes, and categories of information. results: forty-five interviews were conducted with dentists, dental hygienists, certified dental assistants, and administrators; were females. interviews each lasted an average of min. after the transcripts were coded, subthemes emerged: ) personal protective equipment and universal precautions as commonsense approaches to care during both pandemics; ) an (un)collapsed world in terms of global lockdowns; and ) social unrest in terms of the potential for stigma and discrimination caused by both pandemics. these subthemes made up the covid- –aids parallel theme. conclusion: this study explored the extent to which the current covid- pandemic is leading to professional and social consequences when a parallel is drawn with the aids pandemic. this is the first qualitative study that identifies the potential social unrest of the pandemic from the perspective of oral health care providers and administrators. future studies should include other providers across canada, as well the patients receiving oral health care during this pandemic. knowledge transfer statement: the covid- pandemic has unraveled potential societal implications in a parallel to the hiv/aids era from the perspectives of oral health care providers and their staff. such implications are changing the way that oral health care is delivered; it may also be leading to social unrest in the form of stigma and discrimination. this study discusses some of these implications from the perspective of oral health care providers and administrators. although virus outbreaks continue to emerge and threaten public health across the globe, the current novel coronavirus disease pandemic caused by sars-cov- (severe acute respiratory syndrome coronavirus ; zhu et al. ) is perhaps the only infection in modern history to bring oral health care to a halt, probably because of its route of transmission via respiratory and saliva droplets (proffitt ) . covid- also seems to be bringing sweeping changes to personal protective equipment (ppe), universal precautions (ups; mccarthy ) , and the way that oral health care is delivered via new clinical protocols and procedures that minimize or do not generate aerosols (coulthard ) . these changes can be compared with the modifications that hiv (human immunodeficiency virus)-implicated in the development of aids (acquired immunodeficiency syndrome)-brought to the practice of oral health care back in the s (depaola ) . although the current ppe and ups were introduced in dentistry as a response to the hiv outbreak, the hiv/aids era brought to the surface a much more grim reality: the stigma and discrimination (mawar et al. ) still faced by many individuals around the world and in canada when accessing oral heath care brondani, phillips, et al. ; jessani et al. ) . similarly, stigma is currently faced by certain populations due to sars-cov- (hanasoge et al. ; logie and turan ; nature ) . however, the extent to which covid- has affected access to professional oral health care and led to societal implications from the perspectives of providers and administrators remains unknown. the main objective of this study was to unravel the potential professional and social consequences of covid- according to oral health care providers, staff, and administrators in british columbia, canada. of note, the study presented herein is part of a larger qualitative project entitled "structural preparedness during the covid- pandemic and the provision of urgent oral health care." although that project was not designed from the outset to explore the covid- -aids parallel, the issue frequently emerged during interviews with members of the oral health care team and is reported accordingly. the university of british columbia's behavioural research ethics board approved this study (h - ). we employed a qualitative inquiry method via individual interviews with dentists, dental hygienists, certified dental assistants, and staff (e.g., administrators and front desk personnel) from across british columbia between april and may , . participants were purposefully informed about the study via an email distributed to a provincewide professional list and through snowball sampling via word of mouth. inclusion criteria covered any of the target audience that was unemployed (e.g., offices or practices were closed) or continued to work to treat dental emergencies after the curtailment of oral health care services in british columbia on march , (bc dental association ). inclusion criteria targeted participants of any gender and with various years of experience; however, we attempted to establish a somewhat even representation for professional roles (e.g., dentists, dental hygienists), gender, and years of experience in that role (e.g., < y and > y) whenever possible. participants contacted the first author, who then shared information about the study, the interview process, and the informed consent. the interviews where scheduled in the order in which the emails were received, and they were conducted at a distance via phone, zoom video communication, or microsoft skype platform at a day and time convenient for the participant, given the recommendations for physical distancing during the pandemic. interviews were conducted by one of the authors or by a hired research assistant; interviewers were calibrated by interviewing the first participants in a group format to refine the interview guide. interview questions included but were not limited to the following: ) "what do you know about the covid- outbreak?" ) "what do you know about the transmission of the virus?" ) "why is this pandemic relevant to oral health care?" ) "what do you understand by being prepared to provide oral health care during the pandemic?" while we did not plan to ask questions about hiv/aids in particular, the nature of qualitative inquiry allowed us to probe for that information after participants willingly compared the pandemics from various perspectives. it is important to note that participants used "hiv" and "aids" interchangeably, even though hiv is the virus implicated in the development of aids and not all patients carrying hiv develop aids. a total of dentists ( females), dental hygienists ( females), certified dental assistants (all females), and administrators ( females) participated, ensuring saturation of the information with interviews. interviews lasted an average of min, led to h of audio recordings, and generated > pages of transcripts. participants received a $ honorarium in appreciation for their time. demographic data on gender, profession, work location, and years of practice were documented for information only. audio recordings were transcribed verbatim, deidentified in the order in which they were completed, and analyzed interactively; transcripts were explored for codes and themes concomitantly with the interviews (smith ) . between april and may , , the authors independently analyzed transcripts each after round of interactive coding of the first transcript to increase rigor of the audit trial. as the authors independently coded and conducted the thematic analyses of different transcripts, they met constantly via conference calls to discuss the codes, categories, and themes identified for consensus. figure presents an example of this coding process in excerpt from of the transcripts, as we have done previously (brondani et al. ; donnelly et al. ; feng et al. ) . as shown in the figure, "coding" refers to an inductive process of identifying specific ideas or labels in the form of a word or words (e.g., "type of virus," "originated in china," "lockdowns") within sentences or excerpts from the transcripts. similar and related codes are then grouped to represent a specific category or subtheme (e.g., "knowledge"). related categories or subthemes are clustered to represent a main theme, including "origin of the virus." this study opted for an inductive coding process grounded on the qualitative data, rather than a deductive process based on a predefined set of codes, so that important ideas were not overlooked (smith ) . from the interviews, participants discussed hiv/aids in one way or another, which allowed us to identify subthemes: ) ppe, ups, and common sense; ) an (un)collapsed world; and ) social unrest. these subthemes were identified under the covid- -aids parallel as the main theme and are presented in figure . to contextualize the themes, the professional role, work location, and years of experience are added to the excerpts from the transcripts when applicable. across all the interviews, there was no question that the current practice of dentistry and dental hygiene could not be envisioned without the use of protective gloves and masks as a minimum: "we take the necessary precautions to promote a safe environment for us and our patients by removing gloves and masks after every appointment" (dental hygienist with y of practice in the interior of british columbia). specifically, participants took the opportunity during their interview to draw parallels between hiv and sars-cov- in terms of ppe and ups. for a certified dental assistant working for > y in the same office in northern british columbia, barehand dentistry was the norm until the arrival of hiv: when i first started we didn't use masks or gloves. but that all changedwe were all tested for hiv. and we were very mindful of that and that was when we started wearing glasses, and masks and gloves. now you would never consider working on somebody without any of it. the idea of pre-hiv era barehand dentistry was highlighted by other participants. for other participants, including a dentist who was practicing in vancouver island in the s, the parallel between covid- and aids surfaced when commenting on the sterilization of instruments: i think it's just like when hiv/aids happened in the s. we used to disinfect our hand instruments with cavicide, and there was not a big deal. then [autoclaves] became mandatory. now [with covid- ] i think it's going to definitely be changes in a lot of the sterilization again. in the words of a dentist who worked on vancouver island for decades, "i remember in the s we used to wash any linen, apron, or towel when we were concerned about hiv because we didn't have enough knowledge. we washed them in the washing machine under extremely hot water." however, for many participants, unrest around covid- was related to the way that the virus can be transmitted during an appointment: "if before we were worried about hiv and blood, now we will be much more concerned with aerosols and droplets, and they are everywhere, every time care is provided" (certified dental assistant working in vancouver for > y). this unrest seems to be predominantly influenced by a lack of a full understanding about transmissibility and the perceived impact of the virus on the cost and time associated with minimizing or eliminating the risk of transmission within a dental setting. all interviewees acknowledged that covid- has affected their lives in one way or another. according to a senior administrator working for almost y at a community dental clinic in the greater vancouver, "this covid- pandemic is impacting both the demand and supply sides of dental care, and has also major implications in the lives of our patients who might have lost their jobs, and locked at home, and are now struggling to feed their families." in fact, the lockdown experienced by many cities and countries worldwide due to the covid- pandemic was questioned by a dental hygienist who started working in the s in the greater vancouver area, as she recalled what happened when hiv/aids emerged: hiv has infected millions of people and if you remember back then, nothing shut down because of aids. the whole world didn't shut down, right. i mean, it was definitely awful, but it wasn't like the whole world pandemic that we now have with covid- . while considering the lockdown, participants, including a junior dentist < y into practice in northern british columbia, brought up the issue of travel bans: "it seems intuitive to close the border if you want to prevent the spread of a disease and contain the infection. but at what cost? i'm not sure it is even working the way it should." a similar yet unparalleled reality was drawn among the sars outbreak in the early st century, hiv, and covid- according to a senior dental hygienist: for one, canada did not do well with sars because there was just not enough understanding, there wasn't enough response. with hiv, we just treated everybody as infected. but now there is a huge earthquake in our lives that this is causing. one of the participating dentists who started practicing in a small city in british columbia in the earlier hiv pandemic mentioned the issue of transmission of the virus when drawing an (un)parallel between covid- and hiv: i do not think they are comparable, no. what comes to mind is that hiv is [a] blood-and other body fluids-borne disease. it is almost impossible to get in the dental office compared to covid- through saliva droplets, which is everywhere. for other participants, the relative unrest around covid- will likely be transient as it was for hiv, and some of the changes might compose a new norm for years to come. the comparison between covid- and hiv also surfaced in terms of profiling and stereotyping those who might have the disease, as mentioned by participants. the following dialogue between the interviewer and a junior practicing dentist in the interior of british columbia for y exemplifies this: for numerous participants, the professional duty remains to make all patients comfortable in the dental chair regardless of who they are or what they have. for a dental hygienist with > y of experience working in the vancouver area, it was a matter of welcoming all patients: "with aids i felt confident and i wanted to welcome all patients. . . . i didn't want them to feel stigmatized, and the same with covid patients now." we were also told, "we just treat everybody the same way. [it] is that simple, and it should also be the same now" (dental hygienist working on vancouver island since ). the protocol of doubling gloves and masks during the hiv outbreak might come back during the covid- pandemic according to a senior dentist working for > y in the interior of british columbia. he told us that covid- "is going to bring back that piece of protocol [with] the double gloving during aids." another (un)parallel was related to the way that the viruses implicated in the development of those diseases are transmitted. we were told by a dentist with y of experience in vancouver that hiv, it is of low [transmission], if any, in a dental office, with our current universal precautions. as a blood-borne disease, it is much more difficult to get in the dental office, for example, compared to this one that is much easier via saliva droplets and aerosols. according to a young practicing dentist, the almost identical parallel between covid- and hiv/aids was based allegedly on the origin of the viruses: this information is coming from everywhere. what i know is that is about a virus, allegedly from a live animal meat market in wuhan, china. isn't that the same history behind hiv back in the s, from slaughtering monkeys in the [african] jungles, that was transmitted to us? our main objective with this qualitative inquiry was to unravel the potential professional and social implications of the covid- pandemic according to members of oral health care teams from across british columbia, canada. figure shows the intertwined relationship of the covid- -aids parallel with subthemes identified from transcripts: ) ppe, ups, and common sense (from barehand dentistry to education and awareness); ) an (un)collapsed world (from lockdowns to a new reality); and ) social unrest (from unknown to welcoming patients). these subthemes might overlap in meaning and relevance and are mapped in relation to the main theme indicated via single solid arrows. subtheme are composed of their respective codes. while some of these codes are linked with the subtheme via solid double arrows to denote a mutable relationship (e.g., an [un]collapsed world and "lockdown"), others are linked within themselves to portray interdependency (e.g., barehand dentistry with "awareness and education" and "shift in protective equipment"). the dashed double arrow shows a reversible relationship between codes, such as "virus transmissibility" and "lockdown": as new information and a better understanding about the transmission of the virus emerge, some lockdowns may be eased. as acknowledged by many participants, the arrival of hiv at a time when dentistry was practiced mostly barehanded introduced the concept of ppe and ups (mccarthy ) as providers became more aware and educated about infection control (depaola ; mccarthy ) . ppe and ups are now part of a commonsense approach to infection control that treats every patient and one's bodily fluids as infectious for any blood-borne pathogen, even when the patient is unaware of the infection or is asymptomatic. hiv transmissibility is now widely known, and the development of aids has been successfully curtailed by medications (hulla and montaner ) , which is not yet the case for covid- as of july (rabby ; sanders et al. ) . participants also discussed the fact that awareness and education around hiv/ aids helped them to better understand the risks of transmission of that disease in the context of a dental office. the same can be said about covid- , as new information about disease transmission can only increase professional knowledge and improve practice skills in providing care to patients who are sars-cov- positive . unlike covid- , the aids era did not cause a global collapse and lockdowns, as the diseases have very different transmissibility pathways, via respiratory droplets (zhu et al. ) and bodily fluids (shaw and hunder ) , respectively. although transmission seems to be heightened by a potential airborne transmission route relevant for the spread of sars-cov- (setti et al. ) , travel bans and restrictions have been widely criticized (petersen et al. ) , given that they failed to effectively affect the epidemic's trajectory (chinazzi et al. ) when used at random without careful risk assessment (devi ). however, unlike the travel bans for individuals who are covid- positive that are being lifted < mo after the initial outbreak, > countries still impose travel restrictions on those living with hiv almost decades after the first cases were reported in north america (unaids ). in fact, it has been only y since the united states lifted a -y restriction on immigration and travel for those living with hiv/aids (winston and beckwith ) . these few months of social/physical distancing, self-isolation, and travel restrictions due to covid- have already decreased the workforce across all economic sectors, have caused job loss levels not seen since the s great depression, and have created economic crises and recessions globally (nicola et al. ) . although physical distancing interventions seemed to reduce the covid- incidence across many countries (islam et al. ) , there is a harsh social reality emerging. as voiced by at least participants, the covid- pandemic is leading to a number of hate crimes and to anti-asian sentiment, as china is being blamed for the outbreak (chen and trinh ; schild et al. ) . the way that the covid- pandemic is fueling racism and discrimination against asian individuals is unsettlingly, similar to the constant prejudice that gay men still face in association with hiv/aids (mawar et al. ) , particularly when accessing oral health care donnelly et al. ; jessani et al. ) . such stigma, discrimination, and prejudice are a constant for certain ethnicities and religious groups that have been experiencing xenophobia (suleman et al. ; hanasoge et al. ) and anti-semitism (kogan ) . as advocated by chen and trinh ( ) , "if we can unite to overcome a pandemic of epic proportions, certainly we can also confront the socioracial issues [from it]." the idea brought forward by participant to double glove when treating patients with covid- does not ease the experience of stigma, and it is probably unjustified given the transmission route of sars-cov- . despite double-gloving techniques being suggested as an effective means of infection control for high-risk medical surgical procedures involving patients who may have blood-borne infections (padhye et al. ; lipson et al. ) , some patients who are hiv positive may feel stigmatized if they see the dentist overusing this measure (patel et al. ) . additionally, in terms of the origin of both viruses, participants made reference to the fact that sars-cov- and hiv are zoonotic in nature (sharp and hahn ) , albeit from different animals and a consequence of cross-species infections. however, the extent to which the parallels regarding the origin of the diseases are implicated in the current social unrest discussed by our participants remains unknown. as voiced by the participants of this study, the covid- pandemic has unraveled potential societal implications in a parallel to hiv/aids. such implications are likely changing the way that oral health care is delivered for the time being, and it may be leading to social unrest in the form of stigma and discrimination. saturation helped to achieve rigor in this qualitative study, as no new information was provided on the issue under investigation after interviews (saunders et al. ) . rigor was also attained by conducting member checking at different stages of the study, where participants were given the opportunity to read their transcripts and/or the thematic analysis and/or the final report (birt et al. ) ; however, only participants provided member checking on the thematic analysis, and they did not suggest any changes. our study has several limitations. the focus on british columbia may prevent generalization despite the data reaching saturation. this qualitative research was also highly contextual, as it took place within western canada in a specific period during a worldwide pandemic and might not be readily duplicated. the remote mode of the interviews might have been impersonal when compared with the commonly employed face-toface method and might have prevented us from assessing essential nonverbal cues; yet, it gave us the opportunity to engage with participants from across the province without the need to travel. the honorarium paid to the participants may have attracted those who might have expressed their ideas in a more socially desirable manner. however, the interviewers let the participants be at ease and openly discuss their thoughts. although we tallied the number of times that hiv-related information, codes, and subthemes were assigned within the transcripts, we did not perform any statistical evaluation of these frequencies, nor did we interpret such frequency as a sign of relevance or importance necessarily. future studies are necessary to include the opinions of a larger group of oral health care providers in british columbia and across canada, given the interprovincial differences in professional regulations and population composition. the perspectives of the patients themselves should be sought, particularly around the social unrest experienced as recipients of oral health care during this pandemic. last, follow-up inquiries should explore the roots of covid- stigma, how prior destigmatizing interventions can contribute to tackle the discrimination related to sars-cov- , and how different stigmatizing conditions influence one another. this study explored the extent to which the current covid- pandemic is leading to consequences, socially and in terms of professional practice, when a parallel is drawn with the aids pandemic, according to the views of oral health care providers and administrators. the interactive thematic analysis revealed the major theme as the covid- -aids parallel with subthemes: common sense around ppe and ups, a world that is collapsed in some ways but not others, and a potential social unrest surfacing in terms stereotyping certain patients. this is the first qualitative study that identifies the potential implications of the pandemic when compared with the hiv/aids era to the practice of oral health care. future studies should include oral health care providers across canada, as well as the patients receiving oral health care during this pandemic. m. brondani, contributed to conception, design, data acquisition, analysis, and interpretation, drafted and critically revised the manuscript; l. donnelly, contributed to data analysis and interpretation, critically revised the manuscript. both authors gave final approval and agree to be accountable for all aspects of the work. covid- information for dental patients member checking: a tool to enhance trustworthiness or merely a nod to validation? elders' assessment of an evolving model of oral health i'm not hiv positive, i'm undetectable": community forum views of people living with hiv/aids and issues of self-stigma stigma experienced by people living with hiv when accessing oral care anti-asian sentiment in the united states-covid- and history the effect of travel restrictions on the spread of the novel coronavirus (covid- ) outbreak dentistry and coronavirus (covid- )-moral decision-making managing the care of patients infected with bloodborne diseases travel restrictions hampering covid- response stigma experiences in marginalized people living with hiv seeking health services and resources in canada evaluating point-of-care hiv screening in dental hygiene education settings: patient, faculty, and student perspectives visibility challenges for asian scientists hiv treatment as prevention: the key to an aids-free generation physical distancing interventions and incidence of coronavirus disease : natural experiment in countries dental care utilization: patterns and predictors in persons living with hiv in british columbia anti-semitism and xenophobia covid- : the need for continuous medical education and training practice and attitudes regarding double gloving among staff surgeons and surgical trainees how do we balance tensions between covid- public health responses and stigma mitigation? learning from hiv research the third phase of hiv pandemic: social consequences of hiv/aids stigma and discrimination and future needs universal precautions stop the coronavirus stigma now the socio-economic implications of the coronavirus and covid- pandemic: a review efficacy of double gloving technique in major and minor oral surgical procedures: a prospective study hiv-related stigma in the dental setting: a qualitative study covid- travel restrictions and the international health regulations-call for an open debate on easing of travel restrictions what will be the new normal for the dental industry? current drugs with potential for treatment of covid- : a literature review pharmacologic treatments for coronavirus disease (covid- ): a review saturation in qualitative research: exploring its conceptualization and operationalization go eat a bat, chang!" an early look on the emergence of sinophobic behavior on web communities in the face of covid- airborne transmission route of covod- : why meters/ feet of inter-personal distance could not be enough origins of hiv and the aids pandemic hiv transmission. cold spring harb perspect med interactive qualitative analysis: a systems method for qualitative research xenophobia as a determinant of health: an integrative review no end to aids without respecting human rights the impact of removing the immigration ban on hivinfected persons a novel coronavirus from patients with pneumonia in china the authors are in deep gratitude to all participants who engaged into a conversation around their ideas, struggles, concerns, and life-changing experiences. the authors acknowledge the other members of the research team: drs. fernanda almeida, kavita mathu-muju, hsingchi von bergmann, and tala maragha and the trainees, denise cua and melody shayanfar. a special thanks goes to dr. angela tether for editorial contributions. the authors confirm that this study is original and has not been submitted for publication elsewhere, and they approve all aspects of the research, including this article. the authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: funding for this study was obtained via the genome bc rapid response funding for covid- research and innovation project (cov ). key: cord- -nattdect authors: ejima, k.; koizumi, y.; yamamoto, n.; rosenberg, m.; ludema, c.; bento, a. i.; yoneoka, d.; ichikawa, s.; mizushima, d.; iwami, s. title: hiv testing by public health centers and municipalities, and new hiv cases during the covid- pandemic in japan date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: nattdect background: during the covid- outbreak, medical resources were primarily allocated to covid- , which might have reduced facility capacity for hiv testing. further, people may have opted against hiv testing during this period to avoid covid- exposure. we investigate the influence of the covid- pandemic on hiv testing and its consequences in japan. methods: we analysed quarterly hiv/aids-related data from to the second quarter of using an anomaly detection approach. the data included the number of consultations that public health centers received, the number of hiv tests performed by public health centers or municipalities, and the number of newly reported hiv cases with and without aids diagnosis. as sensitivity analyses, we performed the same analysis for two subgroups: men who have sex with men (msm) and non-japanese. findings: the number of hiv tests ( , vs. , in the year-before period) and consultations ( , vs. , ) performed by public health centers significantly declined in the second quarter of , while the proportion of hiv cases with aids diagnosis among all hiv cases ( . % vs. . %) significantly increased after removing the trend and seasonality effects. the number of hiv cases without aids diagnosis numerically decreased ( vs. ), although the reduction was not significant. we confirmed similar trend for the msm and non-japanese groups. interpretation: the current hiv testing system including public health centers misses more hiv cases at the early phase of the infection during the pandemic. given that the clear epidemiological picture of hiv incidence during the pandemic is still uncertain, continuously monitoring the situation as well as securing sufficient test resources using self-test is essential. evidence before this study before this study, we searched pubmed, medline, and google scholar on oct , , for articles investigated the number of hiv test and hiv cases during the covid- pandemic in japan, using the search terms "novel coronavirus" or "sars-cov- ", and "hiv" or "aids", and "japan", with no time restrictions. we found no published work relevant to our study. during the covid- pandemic in japan, the public health centers and municipalities temporarily suspended facility-based hiv testing to concentrate their limited resources to covid- testing. we investigated the impact of the covid- pandemic on the number of hiv tests in public health centers and municipalities, and on the number of hiv cases with and without aids diagnosis. we confirmed that the number of the test declined in the second quarter (april to june) of , and the proportion of hiv with aids diagnosis among all hiv cases increased during the same period. providing sufficient hiv testing opportunities even during the pandemic, when facility-based testing is challenging, is necessary for better clinical and public health outcomes. self-testing and home specimen collection (e.g. dried blood spot or oral fluid test) could be a key to fill the gap between the need for hiv testing and the constraints related to the covid- outbreak. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . https://doi.org/ . / testing and its consequences in japan. we analysed quarterly hiv/aids-related data from to the second quarter of using an anomaly detection approach. the data included the number of consultations that public health centers received, the number of hiv tests performed by public health centers or municipalities, and the number of newly reported hiv cases with and without aids diagnosis. as sensitivity analyses, we performed the same analysis for two subgroups: men who have sex with men (msm) and non-japanese. the number of hiv tests ( , vs. , in the year-before period) and consultations ( , vs. , ) performed by public health centers significantly declined in the second quarter of , while the proportion of hiv cases with aids diagnosis among all hiv cases ( · % vs. · %) significantly increased after removing the trend and seasonality effects. the number of hiv cases without aids diagnosis numerically decreased ( vs. ), although the reduction was not significant. we confirmed similar trend for the msm and non-japanese groups. the current hiv testing system including public health centers misses more hiv cases at the early phase of the infection during the pandemic. given that the clear epidemiological picture of hiv incidence during the pandemic is still uncertain, continuously monitoring the situation as well as securing sufficient test resources using self-test is essential. japan society for the promotion of science, japan science and technology agency, japan agency for medical research and development. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . . https://doi.org/ . / introduction the ongoing covid- pandemic has had broad influences on lifestyle and health issues beyond covid- . there have been positive impacts, such as a curtailed / influenza season in japan ( ), which could be partially explained by measures taken to constrain the covid- outbreak. due to reduced economic activity and human mobility during lockdown, air pollution, which is a risk factor of pulmonary diseases, was temporally improved in china ( ). however, there are many problems caused by risk mitigating interventions for covid- , many of which are under investigation. fear and anxiety about this new disease and changed lifestyle have been stressful for many people, which has worsened mental health ( ) ( ) ( ) . further, during this pandemic period, non-covid- diseases have been at a lower priority for treatment because medical resources have been disproportionately allocated to treat covid- patients in many health care facilities and the capacity to care for non-covid- disease has been limited. moreover, health care facilities need to balance the benefits of providing care for non-critical conditions with minimizing the risk of covid- infections for both health care professionals and patients ( ). people living with hiv infections have better outcomes with early diagnosis and connection to antiretroviral treatment. early diagnosis is also key to preventing onward transmission because early infection is characterized by high viral load and receiving an hiv diagnosis facilitates behavioural change. however, lagat et al. reported a decline in hiv test volume in kenya due to many barriers related to covid- , such as lack of funds to visit clinics and fear of covid- infection at clinics ( ). to increase hiv testing opportunities, in the united states the cdc is recommending self-testing of hiv or home specimen collection (e.g. dried blood spot or oral fluid test) to avoid covid- infection risk associated with face-to-face testing service ( ). in japan, the number of self-collection-based hiv tests has increased, though the majority of tests are still conducted at public health centers and clinics (i.e., facility- based testing). however, during the pandemic, public health centers and clinics have been overwhelmed by covid- pcr testing and administrative work and many have temporally suspended or limited hiv testing. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint aids is usually diagnosed by the specific symptoms and the average incubation period is years ( , ). therefore, the impact of the pandemic on the number of reported hiv cases with aids diagnosis will not be substantial in a short-term period (< year). in contrast, the median time interval between hiv infection to the diagnosis without aids symptoms is · years in tokyo, japan ( ) without aids diagnosis in japan. we further extracted the data of hiv cases with and without aids diagnosis for the following two subgroups: men who have sex with men (msm) and non-japanese, because msm accounts for about % of the newly reported hiv cases ( ), and foreigners are considered vulnerable during disasters due to language barriers ( ). the data on the number of tests and consultations for these subgroups were not available. note that hiv cases with aids diagnosis here represent new cases of hiv identified at late-stages, compatible with an aids diagnosis. thus, this number does not include hiv cases with aids diagnosis that were previously diagnosed and progressed to aids. to rephrase, the new hiv cases here are divided into two categories: early diagnosis (hiv cases without aids diagnoses) and late diagnosis (hiv cases with . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint aids diagnoses). hiv tests at clinics/hospitals and self-testing are also available in japan. thus, the number of hiv testing performed by public health centers or municipalities was used to examine the trend of facility-based tests, rather than capturing the total number of hiv tests or examining the proportion of hiv positive cases among all the hiv tests. we applied an anomaly detection approach to those longitudinal data to identify the period when the number figure shows the observed data points and the computed normal range (the shaded area). we observed a significant downward trend in hiv cases with or without aids diagnosis (figure ab) , all the hiv cases (figure c) , and the number of consultations (figure e ) over the period examined (from the first quarter of to the second quarter of ). the trend in number of tests was not significant during the period ( figure d) . the proportion of hiv cases with aids diagnosis among all the hiv cases showed a significant downward trend during the period (figure f) , suggesting that more hiv cases have been diagnosed in the early phase of infection recently. regarding anomaly by the last quarter of (i.e., . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint before the covid- pandemic), there are a couple of data points that significantly deviated from the normal range. however, the magnitude of the deviation of those numbers was modest. we did not observe deviation in any numbers in the first quarter of . however, in the second quarter, the numbers of hiv tests and hiv consultations significantly declined (figure de) , which is compatible with a public health infrastructure overwhelmed by covid- related work. in contrast, the proportion of hiv cases with aids diagnosis among all hiv cases significantly increased ( figure f) . intriguingly, the number of hiv cases with aids diagnosis in the second quarter of showed the same trend as before ( figure b) . the number of hiv cases without aids diagnosis numerically decreased in the second quarter of (figure a) , however it was not significant. it is worth noting that the number of hiv cases without aids diagnosis did not decline as much as the number of tests (the former dropped . %, whereas the latter dropped . % compared with the year-before period). this might be because more hiv cases with acute symptoms (i.e., fever) visited clinics for viral test for sars-cov- and hiv infection was subsequently diagnosed. as a sensitivity analysis, we examined the longitudinal data of hiv cases with and without aids diagnosis of two subgroups: men who have sex with men (msm) and non-japanese. we confirmed the same downward trend for the msm population as for the total population (figure a-c) in terms of newly reported hiv cases with and without aids diagnosis. on contrary, the hiv cases without aids diagnosis and all hiv cases among non-japanese were in upward trend ( figure ac ). the number of hiv cases without aids diagnosis numerically decreased, whereas hiv cases with aids diagnosis numerically increased or were in the same trend as before in these two populations in the second quarter of ( figure ab and ab). as a result, the proportion of hiv cases with aids diagnosis among all positive cases also numerically increased in the second quarter of in these two subgroups (figure d and d) ; however, they were not significant, which might be due to the small sample size. the proportion of hiv cases among msm and non-japanese populations relative to total hiv cases was consistent over time including the second quarter of (figure e and e) . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . we need to interpret the results carefully. first, we have analyzed the number of tests performed by public health centers and municipalities. however, this type of test accounts for less than half of the tests performed in japan. for example, self-collection-based tests (mostly using dried blood spot) are increasing, and tests are available in clinics and hospitals; however, the count of those tests was not available. it is probable that the number of different types of hiv test has increased during the same period as compensation for the reduction in the number of tests performed by public health centers and municipalities. second, we do not know the full picture of the impact of the pandemic on hiv epidemiology. we have used the number of reported hiv cases; however, there is likely a substantial proportion of undiagnosed cases, and it is uncertain whether the number and the proportion of undiagnosed cases changed during the pandemic. it is possible that the incidence increased (or decreased) during the pandemic. therefore, even though the number of new hiv cases did not change dramatically, it does not indicate that the number of tests is sufficient to identify all hiv patients. indeed, the number of reported hiv positive cases without progressed to aids in the second quarter of was the lowest in the last five years and the proportion of hiv cases with aids diagnosis significantly increased. it raises a concern that the testing opportunities might not be sufficient to fully capture the epidemiological situation of hiv/aids during the pandemic in japan. because most of the hiv cases with aids diagnosis are identified in clinics or hospitals due to specific symptoms, hiv cases with aids diagnosis are less prone to being affected by healthcare avoidance . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint even under the pandemic. indeed, the number of hiv cases with aids diagnosis was in the same trend as before the pandemic. we need to keep monitoring the situation as well as adapting testing strategies to work in these unusual circumstances. as the pandemic continues, we do not know how long the hiv testing opportunities provided by public health centers could be disrupted and how it could affect hiv spread. given that early detection and treatment initiation for hiv is lifesaving, providing sufficient hiv testing opportunities is important. unaids has a proposed treatment target, " - - " to control the hiv epidemic ( ). a part of the target is that "by , % of all people living with hiv will know their hiv status." if the covid- pandemic continuously disrupts testing opportunities, diagnosing % of people living with hiv might be difficult to achieve. self-testing and home specimen collection could be a key to fill the gap between the need for hiv testing and the constraints related to the covid- outbreak. the strength of this study is that we used the quarterly hiv/aids reports in japan, which include all the diagnosed cases as physicians are required to report all diagnosed cases under the infectious diseases control law( ). further, the cases reported as hiv cases with aids diagnosis include only the cases of newly diagnosed hiv infection co-occurring with aids. therefore, we could quantify the proportion of patients presenting with aids at the time of diagnosis, which captures late-presentation for diagnosis and is more likely if testing resources are not accessible. a limitation of this study is that we were not able to account for the heterogeneous epidemiology of hiv between different regions. higher hiv incidence has been observed in urban areas such as tokyo and osaka compared with rural areas. thus, public health centers in urban areas have allocated budgetary resources towards hiv testing, whereas this has not been prioritized in rural areas. during the pandemic, the testing opportunities in rural areas may have declined even further than urban areas. our study mainly focused on hiv cases with and without aids diagnosis and testing regardless of the patients' characteristics. one of the concerns in this pandemic is that more vulnerable populations, such as sex workers, low-income populations, younger population, in addition to foreigners, may have experienced disproportionate harms. further studies should focus on these populations and identify barriers to testing. we used only the number of tests performed by public health centers and municipalities, thus self-tests and home specimen collection, . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . https://doi.org/ . / which are increasingly popular, and tests performed in clinics and hospitals were not counted. further investigation is necessary to focus on these types of tests to fully understand the response of the hiv cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . range. the observed data outside of the normal rage is considered abnormal and red colored. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . . https://doi.org/ . / seasonal influenza activity during the sars-cov- outbreak in japan the short-term impacts of covid- lockdown on urban air pollution in china how mental health care should change as a consequence of the covid- pandemic. the lancet psychiatry mental health and the covid- pandemic depression and loneliness during covid- restrictions in the united states, and their associations with frequency of social and sexual connections centers for disease control and prevention. hiv self testing guidance incubation period of aids in san francisco the incubation period of aids estimating hiv- incidence in japan from the proportion of recent infections disproportionate impact of the covid- pandemic on immigrant communities in the united states stl: a seasonal-trend decomposition procedure based on loess non parametric statistics for the behavioral sciences percentage points for a generalized esd many-outlier procedure overview of infectious disease surveillance system in japan international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted the copyright holder for this preprint this version posted october , . . https: //doi.org/ . //doi.org/ . / the authors declare that they have no competing interests. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review)the copyright holder for this preprint this version posted october , . . https://doi.org/ . / key: cord- -yo cp vs authors: nan title: kapitel infektionskrankheiten date: - - journal: innere medizin doi: . /b - - - - . - sha: doc_id: cord_uid: yo cp vs zur orientierung infektionskrankheiten werden durch pathogene verursacht, die sich im wirt vermehren: ektoparasiten, helminthen, protozoen, pilze, bakterien, viren, prionen. infektionskrankheiten können alle organe bzw. organsysteme befallen. entstehung und verlauf werden durch faktoren beeinflusst, die sich grob einteilen lassen in erreger- und wirtsfaktoren. die kenntnis und richtige einschätzung dieser faktoren sind entscheidend für diagnostik und therapie dieser erkrankungen. oft ist die unterscheidung zwischen infektiösen und nichtinfektiösen erkrankungen mit einer entzündlichen komponente schwer. andererseits können z. b. bei patienten mit immundefekten symptome oder zeichen trotz bestehender infektion fehlen. hautveränderungen als symptom viele infektionskrankheiten zeigen eine mitbeteiligung der haut, mit fokalen läsionen bei bakterieller endokarditis oder als exanthem bzw. enanthem bei viruserkrankungen. hautveränderungen können pathognomonisch sein, so bei meningokokkensepsis und den damit verbundenen petechialen blutungen und später großflächigen ekchymosen. hautveränderungen, auch im zeitlichen verlauf, können wichtige differentialdiagnostische hinweise liefern. der erste schritt ist die beurteilung des klinischen zustandes (› abb. . ). bei kritisch kranken patienten muss zunächst parallel zu supportiven maßnahmen eine rasche empirische antiinfektive therapie erwogen und ggf. begonnen werden. die diagnostik kann aber meist ohne zeitverlust in den ablauf integriert werden. infektionskrankheiten, die einen kritischen zustand eines nicht immundefizienten patienten verursachen, sind vor allem bakterielle sepsis, meningitis und bakterielle pneumonie, aber auch malaria tropica. anamnese hier sind mögliche erregerexpositionen, der zeitliche ablauf der erkrankung und die prädisposition des wirts zu beachten. • nicht für alle infektionen ist eine besondere exposition eruierbar (› tab. . ). kontakte zu anderen erkrankten, reiseanamnese, nahrungsaufnahme, berufsanamnese, freizeitbeschäftigungen, tierkontakte inklusive insektenstiche, vorherige erkrankungen und deren therapie, medikamenten-, drogen-sowie sexualanamnese müssen berücksichtigt werden. • der zeitliche ablauf der krankheitsentwicklung muss geklärt werden. nahezu alle infektionserreger haben charakteristische zeitintervalle zwischen exposition und erkrankung (inkubationszeiten). so sind bakterielle erreger durch inkubationszeiten von einigen tagen gekennzeichnet, während viruserkrankungen meist inkubationszeiten von einigen wochen haben (viele ausnahmen!). zusätzlich treten bei vielen erregern saisonale häufungen auf. • die prädisposition des wirts als dritte komponente umfasst die frühere anamnese (speziell infektionen, vorgenommene impfungen), andere erkrankungen oder organschädigungen und die beurteilung des klinischen status, z. b. die integrität von haut und schleimhäuten. spezifische untersuchungen blutkulturen müssen bei allen kritisch kranken, bei allen systemisch kranken und/oder fiebernden patienten entnommen werden. hierbei sind eine rasche und frühe entnahme (vor antibiotikagabe), ausreichende blutmenge pro flasche (mind. - ml je nach system), eine ausreichende zahl von blutkulturen (mindestens zwei, je als aerob-anaerobes paar von blutkulturen) und sterile abnahme wichtig. die weitere diagnostik richtet sich nach den symptomen oder befunden, z. b. sputum-, urin-, abstrichuntersuchungen untersuchungen von organpunktaten. bei allen untersuchungen ist auf entnahmetechnik, aufbewahrung und richtigen transport zu achten. sputum z. b. muss vor der ersten gabe von antibiotika entnommen und innerhalb weniger stunden aufgearbeitet werden, ansonsten sind pathogene nicht mehr nachweisbar. der rationale einsatz von serologischen untersuchungen wie auch die aufbewahrung von serumproben zur späteren untersuchung von initial-und rekonvaleszentenserum kann zur diagnostik sinnvoll sein wie auch spezielle verfahren z. b. polymerasekettenreaktion-untersuchung einer biopsie. wirts-und pathogenitätsfaktoren beeinflussen entstehung und ablauf von infektionskrankheiten. wirtsfaktoren lassen sich einteilen in unspezifische (angeborene) und spezifische (erworbene, › tab. . ). zu den unspezifischen faktoren gehören barrieremechanismen von haut und schleimhäuten, aber auch mechanismen, mit denen erreger aktiv bekämpft werden können. spezifische funktionen des immunsystems sind gegen einzelne erreger gerichtet. beide systeme weisen eine vielzahl von interaktionen auf. mit pathogenität wird die eigenschaft eines mikroorganismus bezeichnet, eine erkrankung auslösen zu können. virulenz ist der grad der pathogenität innerhalb einer spezies. notwendige bedingungen für die pathogenität eines erregers sind: . in gewebe oder zellen anhaften oder eindringen zu können, . im körper zur replikation fähig zu sein. epithelbarrieren und -läsionen haut und schleimhaut haben mehrere barrieren, um ein eindringen von pathogenen zu erschweren oder vermeiden. dazu gehören neben den anatomischen auch chemische barrieren, z. b. die fettschicht der epidermis, aber auch antibakterielle substanzen, wie das in mukosalen sekreten vorhandene lysozym. monozyten und makrophagen, granulozyten und natural-killer(nk)-zellen sind die wichtigsten zellpopulationen dieses systems. die zellen des monozyten-makrophagen-systems und granulozyten weisen moleküle auf, mit denen erregerspezifische strukturen (z. b. lipopolysaccharide, bestimmte dna-sequenzen oder doppelsträngige rna) erkannt werden können. diese strukturen werden als pathogen-assoziierte molekulare pattern (pamp) bezeichnet. ein beispiel für solche rezeptoren sind die nach einer homologie mit einem rezeptor der drosophila-fliege bezeichneten tlr (toll-like-rezeptoren). die bindung von erregerspezifischen strukturen an diese moleküle führt zur raschen aktivierung einer entzündungskaskade. natural-killer-zellen sind lymphozyten, die durch antigen-antikörper-komplexe oder durch zellen, die keine mhc-(major-histocompatibility-complex)-moleküle auf der oberfläche exprimieren, aktiviert werden können. die proteine des komplementsystems können nach aktivierung im blut zirkulierende erreger lysieren. störungen des komplementsystems führen zu infektionen mit polysaccharidbekapselten erregern, z. b. pneumokokken und meningokokken. als akute-phase-reaktion wird die produktion von proteinen und peptiden bezeichnet, die nach einer infektion oder entzündungsreaktion abläuft. involviert sind makrophagen, die vor allem interleukin (il- ), tnf-α, interferon-α, il- und eine reihe von prostaglandinen und arachidonsäuremetaboliten produzieren. eine kooperation dieser beiden systeme findet bei jeder lokalen entzündungsreaktion statt. aktivierte granulozyten und makrophagen produzieren chemotaktische substanzen, aktivieren adhäsionsmoleküle in den lokalen endothelien und sorgen so für eine verstärke einwanderung von entzündungszellen (› abb. defekte des unspezifischen immunsystems • verletzungen von epithelien begünstigen die invasion von erregern, z. b. nach zytostatischer therapie mit abschilferung der intestinalen schleimhaut. der aktive partikeltransport des flimmerepithels des respirationstraktes ist bei rauchern und bei patienten mit zystischer fibrose gestört. in beiden fällen ist die rate von infektionen des respirationstraktes deutlich erhöht. • neutropenie oder funktionsstörungen der granulozyten führen zu häufigen bakteriellen erkrankungen und invasiven mykosen. • das fehlen von natural-killer-zellen führt u. a. zu schweren infektionen mit herpesviren. die wesentlichen mechanismen sind die bildung von antikörpern durch b-zellen sowie spezifischer t-effektorzellen. beide zellsysteme haben eine hohe genetische plastizität und können eine hohe zahl spezifischer antigene erkennen. t-lymphozyten repräsentieren die spezifische zelluläre immunität. die wichtigsten funktionellen gruppen sind t-helferzellen und zytotoxische t-zellen. damit antigene durch die effektorzellen erkannt werden können, sind eine prozessierung und präsentierung durch zelluläre mechanismen notwendig. präsentation von antigen bakterielle oder virale proteine werden intrazellulär in oligopeptide zerlegt, und über mhc-(major-histocompatibility-complex)-moleküle auf der zelloberfläche präsentiert. "professionelle" antigenpräsentierende zellen nutzen mhc-klasse-ii-, alle anderen zellen mhc-klasse-i-moleküle. t-lymphozyten der kontakt von "naiven" t-helferzellen mit präsentiertem antigen führt zur aktivierung, reifung und klonalen expansion der betreffenden t-helferzellen. diese stimulieren die bildung von spezifischen zytotoxischen t-zellen und immunglobulinproduzierenden b-zellen. die zentrale rolle in der stimulierung der effektorzellen der spezifischen abwehr hat dieser zellgruppe ihren namen gegeben. die eigentlichen effektorzellen sind die zytotoxischen t-zellen. sie erkennen infizierte zellen durch die kombination der mhc-klasse-i-moleküle mit den erregerpeptiden und töten sie ab. die initale phagozytose von erregern und nachfolgende antigenpräsentation durch makrophagen mit der ausbildung einer spezifischen zellulären immunität durch t-lymphozyten ist ein beispiel für das zusammenwirken unspezifischer und spezifischer immunmechanismen. der kontakt des passenden antigens mit dem noch unreifen oberflächenimmunglobulin auf b-lymphoyzten führt zur ausbildung und selektion von plasmazellen, die entweder iga, ige oder igg mit höherer spezifität und avidität produzieren. immunglobuline können erreger (z. b. viren) und toxine neutralisieren und die phagozytose und lyse von erregern erleichtern. das spezifische immunsystem bildet außerdem ein gedächtnis für vorangegangene infektionen und reagiert mit einer besseren abwehr oder sogar immunität bei reexposition. beim erstkontakt mit dem erreger kommt es nach rascher aktivierung, reifung und expansion von t-und b-lymphozyten auch zur bildung von gedächtniszellen beider gruppen. defekte des spezifischen immunsystems können angeboren (agammaglobulinämie, kombiniertes immundefektsyndrom) und erworben (aids) sein. bei immunglobulinmangel kommt es vor allem zu infektionen mit polysaccharidbekapselten erregern, bei störungen des t-zellulären systems zu schweren infektionen z. b. mit intrazellulären erregern (z. b. toxoplasma gondii und herpesviren). viren sind obligat intrazelluläre erreger, die keinen eigenen stoffwechsel besitzen. zur replikation sind sie auf zelleigene enzyme angewiesen. zwei bedingungen müssen für virale pathogenität erfüllt sein: . das virus muss eine oberflächenstruktur besitzen, mit der es an eine zielzelle binden und dann eindringen kann. . durch die replikation in der zelle muss entweder eine störung der zellfunktion oder eine immunreaktion auf die infektion erfolgen. ein pathogenitätsmechanismus ist die möglichkeit, eine latente infektion zu erzeugen. so besitzen z. b. humane herpesviren die fähigkeit, das genom in einer inaktiven, aber reaktivierbaren form in zellen einzubauen. die mechanismen, die das gleichgewicht zwischen latenz und produktiver infektion steuern, sind nur unvollständig bekannt. die einfache kultivierung klonaler populationen und die manipulation von umgebungsbedingungen ermöglichen die untersuchung bakterieller pathogenitätsfaktoren. zusätzlich haben sequenzierung von bakteriellen genen und deren gezielte manipulation das wissen über pathogenitätsmechanismen entscheidend vermehrt. genetische regulation von pathogenitätsfaktoren neben der chromosomalen form kann dna als plasmid oder phage vorliegen. diese "mobilen" genetischen elemente erlauben eine genetische diversifizierung. chromosomale gene und externe gene können für pathogenitätsfaktoren kodieren, deren expression einer komplizierten regelung unterliegen kann. adhäsion, toxinbildung und immunevasion von bakterien wichtige pathogene mechanismen von bakterien sind adhäsion an epithelien oder die bildung von toxinen und immunevasion: • pili oder fimbrien bei escherichia coli werden nach dem identifizierten gen-p(ap)-pili genannt. die expression dieser pili wird durch umgebungsbedingungen (ph-wert und temperatur) so moduliert, dass sie vor allem in den ableitenden harnwegen produziert werden, wo sie zur besseren adhäsion führen. • häufig ist die produktion von toxinen -ebenso wie die von adhäsionsmechanismen -an plasmide oder phagen gebunden. zur produktion des diphtherietoxins muss der betreffende stamm mit einem phagen infiziert sein. andere pathogene toxine sind exotoxine von staphylococcus aureus und der gruppe-a-streptokokken, die z. b. für die toxic-shock-syndrome verantwortlich sind. • immunevasionsstrategien richten sich gegen abwehrmechanismen. beispiele: neisseria gonorrhoeae und haemophilus influenzae entziehen sich durch iga-spezifische proteasen der vernichtung auf der schleimhaut. legionella pneumophila kann nach beladung durch komplementproteine leichter in zellen eindringen. vor allem keime mit intrazellulärem vermehrungszyklus haben oft die fähigkeit, der phagozytose durch makrophagen zu entgehen. • das patientengut ändert sich mit einem ständig steigenden anteil an intensivpflegepatienten und abwehrgeschwächten patienten. • das repertoire an zur verfügung stehenden chemotherapeutika wird immer größer. • die resistenz von bakterien gegen antibakterielle chemotherapeutika nimmt sowohl quantitativ als auch qualitativ zu. jeder arzt, der eine antibakterielle chemotherapie durchführen will, muss wichtige grundprinzipien beherrschen wie auch in wesentlichen zügen das spektrum der antibakteriellen substanzen kennen. indikationsstellung antibakterielle chemotherapeutika sind ursächlich wirksame medikamente und nicht primär gegen symptome, wie z. b. fieber, gerichtet. die gabe solcher substanzen setzt also eine exakte indikationsstellung voraus, es muss mit sehr hoher wahr-scheinlichkeit eine durch bakterien verursachte infektionskrankheit vorliegen. die indikation wird naturgemäß zunächst klinisch gestellt. hierfür genügen in aller regel anamnese, befunde der klinischen untersuchung sowie einige klinisch-chemische und radiologische zusatzbefunde. gleichzeitig erfolgt die materialentnahme zur mikrobiologischen erregerdiagnose, um dadurch die indikation abzusichern. die therapie wird meist vor erhalt der endgültigen erregerdiagnose und des antibiogramms begonnen. man spricht dann von einer kalkulierten chemotherapie, d.h., es wird eine empirische therapie nur auf basis der klinischen befunde eingeleitet. hieraus sollte es in vielen fällen schon möglich sein, die zu erwartenden erreger einzugrenzen, aber auch die zu erwartende resistenzsituation sowohl generell als auch lokal zu kalkulieren. wenn dann mikrobiologische befunde -erregerdiagnose und antibiogramm -vorliegen, die mit der klinik korrelierbar sind, kann eine gezielte chemotherapie durchgeführt werden. das heißt, die kalkulierte chemotherapie muss überprüft und evtl. geändert werden. für die auswahl der chemotherapeutika müssen klinische, mikrobiologische und pharmakokinetische kriterien herangezogen werden. von seiten der klinik sind eventuelle grundkrankheiten zu berücksichtigen, ferner die infektionslokalisation und die tatsache, ob es sich um eine außerhalb (ambulant) oder innerhalb des krankenhauses (nosokomial) erworbene infektionskrankheit handelt. die zu beachtenden bakteriologischen kriterien betreffen das wirkspektrum der jeweiligen antibiotika und deren aktivität innerhalb dieses spektrums. entscheidend ist auch, ob der wirkeffekt bakterizid (keimabtötend) oder nur bakteriostatisch (proliferationshemmend) ist. eine ganze reihe von pharmakokinetischen eigenschaften der jeweiligen substanzen wie säurestabilität, enterale resorption, art der metabolisierung bzw. elimination, penetration in körperkompartimente und -gewebe beeinflusst ebenfalls in der individuellen klinischen situation die festlegung des chemotherapeutikaregimes. nicht zuletzt spielen toxikologische gesichtspunkte (s. u.) eine wichtige rolle. die durchführung der chemotherapie folgt im prinzip den allgemeinen grundsätzen der internistischen pharmakotherapie (› kap. ), hier nur die zusätzlich besonderen aspekte der antibiotikatherapie. dosierung die dosis des chemotherapeutikums muss ausreichend hoch sein, um den gewünschten wirkeffekt sicher zu erreichen. dauer es lassen sich keine allgemein gültigen regeln aufstellen. so können unkomplizierte harnwegsinfektionen mit einer einmalgabe eines potenten antibiotikums behandelt werden, während für die therapie einer osteomyelitis eine mehrmonatige therapiedauer erforderlich sein kann. applikationsart die parenterale applikation stellt grundsätzlich den sichersten applikationsweg dar. bei schweren und schwersten infektionsverläufen ist daher dieser weg zumindest bei beginn der therapie immer zu wählen. bei einer umstellung von einer parenteralen auf eine orale therapie (= sequentialtherapie) ist darauf zu achten, ob dies mit der parenteral begonnenen substanz überhaupt möglich ist, d.h., ob sie enteral resorbierbar ist. eine orale folgetherapie mit einem anderen antibiotikum kann nur dann erfolgen, wenn es das gleiche spektrum wie das zuvor verwandte parenterale antibiotikum hat. für die orale chemotherapie ist die compliance des patienten entscheidend. applikationsintervall die pharmakodynamischen eigenschaften (= beziehung von serumspiegel, halbwertszeit und wirkaktivität gemäß minimaler hemmkonzentration) eines antibiotikums entscheiden über einmalgabe, mehrfachgabe oder dauergabe. die kombinationstherapie mit zwei oder mehreren substanzen hat in der kalkulierten chemotherapie zum ziel, ein breiteres spektrum möglicher erreger abzudecken. in der gezielten chemotherapie kann eine synergistische wirkung angestrebt werden, erwiesenermaßen sinnvoll nur für die gabe von β-lactam-antibiotika bzw. glykopeptidantibiotika mit aminoglykosiden bei grampositiven kokken als häufigste angewandte kombination. weitere gründe für die gabe einer kombination liegen vor, wenn die dosiserhöhung einer substanz aus toxikologischen gründen nicht mehr möglich ist oder bei einer mischinfektion mehrere erreger therapiert werden müssen. für die kombinierbarkeit verschiedener antibiotika gibt es keine verbindlichen regeln. "drug-monitoring" antibiotika, die bei nierenfunktionsstörungen schnell kumulieren können, wie aminoglykoside und vancomycin, müssen dann gemäß serumspiegelkontrolle dosiert werden. bezüglich allergischer und toxischer nebenwirkungen unterscheiden sich antibiotika nicht von anderen substanzen. je nach spektrum der potenziellen nebenwirkungen, das für die einzelnen chemotherapeutika sehr unterschiedlich sein kann, müssen entsprechende klinische bzw. laborchemische oder auch funktionelle kontrollen erfolgen. die besonderheiten einer antibakteriellen chemotherapie liegen darin, dass sog. biologische nebenwirkungen (folge der hauptwirkung) auftreten können: • selektion resistenter bakterien. das versagen einer antibakteriellen chemotherapie kann mehrere gründe haben. die häufigste ursache ist die primäre oder sekundäre resistenz der verursachenden bakterien. primäre resistenz bedeutet, dass alle bakterien z. b. einer spezies oder gattung gegenüber einem bestimmten antibiotikum von natur aus resistent sind. sekundäre resistenz beinhaltet, dass ein klon einer primär empfindlichen spezies durch mutation oder akquirierung eines resistenzgens (z. b. auf einem plasmid) resistent wird. unter der persistenz eines erregers versteht man das Überleben des erregers am infektionsort während einer antibiotikatherapie. hierzu kommt es, wenn der erreger vorübergehend von der wachstumsphase in eine ruhephase übertritt, z. b. bedingt durch verschiedene physikalisch-chemische ursachen am infektionsort. da die meisten gebräuchlichen chemothera-peutika nur auf proliferierende keime wirken, werden sie nicht eliminiert und können daher nach absetzen der antibiotikatherapie zum rezidiv führen. die ineffektivität einer antibiotikatherapie kann natürlich auch durch einen wechsel des ätiologisch bedeutsamen erregers während der therapie bedingt sein, aber ebenso durch fehler in der durchführung der chemotherapie (s. o.). die prophylaktische gabe von antibakteriellen chemotherapeutika hat nur wenige, eingeschränkte indikationsgebiete! hierzu gehört z. b. die perioperative antibiotikagabe zur verhinderung von postoperativen wundinfektionen und septikämien, deren sinn bei bestimmten operativen eingriffen erwiesen ist. in seltenen fällen kann eine expositionsprophylaxe mit antibiotika durchgeführt werden, akzeptiert sind hier die pertussis-und die meningokokkenmeningitis-prophylaxe bei besonders gefährdeten personen, wenn in deren umgebung ein erkrankungsfall aufgetreten ist. heute steht eine große anzahl von antibakteriellen chemotherapeutika aus verschiedensten substanzgruppen zur klinischpraktischen anwendung zur verfügung. › tabelle . gibt einen orientierenden Überblick über die unterschiedlichen substanzgruppen mit beispielen von einzelsubstanzen. hieraus lassen sich in geraffter form das antibakterielle wirkspektrum, wichtige pharmakologische eigenschaften und bedeutende potenzielle nebenwirkungen ablesen. diese klassifizierung folgt klinischen anwendungsgesichtspunkten und nur z. t. der exakten chemischen einteilung. wegen der großen anzahl der zur verfügung stehenden chemotherapeutika musste dabei eine auswahl erfolgen, die sich an deren praktischer bedeutung orientiert. der infektiologisch nicht spezialisierte arzt sollte sich auf ein standardrepertoire von wenigen substanzen beschränken, bei deren therapeutischem einsatz er dann eigene erfahrungen gewinnt. z u s a m m e n f a s s u n g • es steht außer zweifel, dass eine antivirale chemotherapie möglich und die gabe mancher substanzen in bestimmten klinischen situationen bereits absolut indiziert ist. • eine vielzahl von substanzen wird schon seit jahrzehnten regelmäßig in vielen laboratorien auf antivirale wirkung geprüft. aids hat zur verstärkten suche und für erheblich mehr publizität gesorgt. die wirkprinzipien werden im labor und z. t. bereits in klinischen studien anhand vieler substanzen unterschiedlicher chemischer natur untersucht. in der tat stößt z. b. die planung ausreichend kontrollierter studien zur antiviralen therapie bei aids selbst in den usa bereits auf das problem des mangels an studienfähigen patienten. th. mertens die künftigen entwicklungen in der antiviralen chemotherapie betreffen sowohl die charakterisierung neuer ziele (engl.: targets) für antivirale interventionen und die entwicklung antiviral wirksamer substanzen als auch die durch studien begründbaren empfehlungen für die anwendung vorhandener therapeutika. viren unterscheiden sich hinsichtlich struktur und vermehrungsweise grundsätzlich von allen anderen infektionserregern. sie sind für ihre vermehrung vollständig auf die energiegewinnung und syntheseleistung ihrer wirtszelle angewiesen. voraussetzung für eine antivirale chemotherapie ist somit, dass moleküle und biochemische prozesse identifiziert werden, die nur in virusinfizierten zellen vorkommen. der begriff virusselektivität beschreibt die fähigkeit einer substanz, die virusvermehrung zu hemmen, ohne die wirtszelle zu schädigen. viele viren haben strategien entwickelt, um im einmal infizierten organismus zu persistieren. in diesen fällen kann es zu infektionszuständen ohne virusvermehrung kommen (z. b. latenz der herpesviren). da alle bislang verfügbaren antiviralen substanzen im vermehrungszyklus angreifen, entziehen sich persistierende infektionen ohne virusvermehrung derzeit einer antiviralen therapie. die verfügbaren therapeutika haben ein begrenztes wirkspektrum, und es gibt bislang keine "breitbandmedikamente". antivirale therapie setzt somit eine virustypdiagnose voraus. bei akuten viruserkrankungen entscheidet darüber hinaus ein frühzeitiger therapiebeginn über den erfolg, was eine rasche diagnosestellung notwendig macht. bei patienten mit schwerster angeborener (scid), erworbener (aids) oder iatrogener (transplantation) immundefizienz ist es häufig trotz adäquater antiviraler therapie nicht möglich, die virusvermehrung zu beenden, solange es nicht zu einer verbesserung der immunsituation kommt. therapieindikation, -beginn und -dauer allgemeine regeln zur therapie sollten nur auf der grundlage klinischer studien festlegt werden (evidence-based). wesentliche allgemeine kriterien, die berücksichtigt werden müssen, sind die immunsituation des patienten, das risiko schwerer erkrankung, folgeerkrankung oder chronifizierung, die vermeidung unerwünschter arzneimittelwirkungen (uaw) und die vermeidung von resistenzentwicklung. die probleme mögen folgende fragen verdeutlichen, deren antworten z. t. in letzter zeit gegeben wurden (s. u.): muss eine akute hepatitis b oder c therapiert werden? welches ist der optimale zeitpunkt zum beginn einer antiretroviralen therapie bei hiv-infektion? wie soll man hiv-infizierte schwangere behandeln? müssen windpockenerkrankungen oder eine gingivostomatitis herpetica behandelt werden? bei schwerst immunsupprimierten wird zur verhinderung lebensbedrohlicher virusinfektionen vielfach eine antivirale prophylaxe durchgeführt. diese medikamentengabe vor beginn einer aktiven infektion führt natürlich bei etlichen patienten zur unnötigen gabe teils toxischer substanzen. der begriff der präemptiven therapie bezeichnet eine antivirale behandlung nach virologischer diagnose einer aktiven infektion ohne vorliegen von symptomen und ist abzugrenzen von der therapie einer infektionskrankheit. die therapieentscheidung erfordert den nachweis des vorteils einer vorgehensweise für die jeweilige patientengruppe. die optimale dauer der therapie ist in vielen fällen noch nicht durch studien bestimmt worden. resistenzvermittelnde mutationen treten bei jeder virusvermehrung spontan auf. bei längerfristiger anwendung antiviraler chemotherapeutika und damit vor allem bei den erheblich immunsupprimierten patienten mit langdauernder massiver virusvermehrung kann es dann relativ rasch zur selektion resistenter viruspopulationen kommen. diese virusvarianten besitzen mutationen in der viralen polymerase (rt bei hiv), der viralen kinase (herpesviren) oder anderen viralen genen, welche für zielstrukturen der antiviralen substanzen kodieren. voraussetzung für die selektion der spontan auftretenden resistenten virusvarianten ist somit virusvermehrung unter dem selektionsdruck einer antiviralen substanz. klinisch relevante virusresistenzen gegen nukleosidanaloga treten nach bisherigen erfahrungen bei kurzzeitiger therapie bzw. therapie immungesunder patienten nicht auf. vielmehr ist resistenz meist ein problem der langzeittherapie (> - monate), wenn es nicht gelingt, die produktive virusinfektion durch die therapie zu stoppen (hsv, cmv, hiv). resistenz-vermittelnde mutationen bedingen manchmal einen vermehrungsnachteil für das mutierte virus gegenüber dem wildtyp, wenn der selektionsdruck entfällt. in einigen fällen sind resistente virusvarianten (herpesviren, hiv) weniger pathogen als die wildviren. dies ist aber leider keinesfalls die regel. aufgabe der kliniker ist es, therapieversagen anhand klarer kriterien zu definieren, und den virologen obliegt es, standardisierte tests zur raschen phänotypischen oder genotypischen resistenztestung von viren bereitzustellen. manche zunächst wenig gravierende oder asymptomatische virusinfektionen können folgeerkrankungen auslösen (z. b. immunpathogenese), bei denen die viren dann keine entscheidende rolle mehr spielen und somit eine antivirale therapie zu spät kommt. ansatzpunkte für antivirale substanzen › tabelle . zeigt, dass die hemmung der virusvermehrung doch an vielen stellen möglich ist. diese frühesten vorgänge bei jeder virusinfektion, die bindung der viren an ihre wirtszelle und bei umhüllten viren die fusion mit der äußeren wirtszellmembran, lassen sich experimentell durch blockade der verantwortlichen rezeptorstrukturen auf seiten der viren oder der zellen hemmen. auch spezifische antikörper wirken auf dieser stufe der infektion. die molekularen vorgänge bei diesen frühen prozessen der infektion sind äußerst komplex und erfordern z. b. bei hiv etliche regulierte strukturelle veränderungen des viralen rezeptors. die hemmung der fusion ist bei hiv durch peptidische fusionsinhibitoren (t ), die an rezeptorstrukturen des virus binden, bereits möglich. auch die hemmung der korezeptorbindung ist denkbar. grund eines durch die strukturproteine gebildeten tiefen oberflächeneinschnittes (canyon) einlagern. dadurch wird die bindung an den zellrezeptor behindert und die zur freigabe der nukleinsäure notwendige, bei einigen virustypen ph-abhängige endosomale, intrazelluläre desintegration der viralen proteinhülle verhindert. bei einigen picornaviren wird die rezeptorbindung wenig behindert, aber das viruskapsid doch so stabilisiert, dass kein uncoating stattfinden kann. es gibt resistenz gegen diese substanzen, aber erstaunlicherweise sogar virusmutanten, die nur noch in anwesenheit dieser substanzen vermehrungsfähig sind. die faszination dieser entdeckung bestand auch darin, dass es plötzlich möglich wurde, aufgrund der kenntnis der molekularen struktur-wirkungs-beziehung antiviral wirksame moleküle sozusagen am reißbrett zu entwerfen (› tab. . ) . therapeutisch einsetzbare substanzen erstes und bislang einziges für die systemische therapie verfügbares medikament, das nach diesem mechanismus die picornavirus-replikation hemmt, ist pleconaril. einer der beiden wirkmechanismen von adamantanderivaten gegen influenza-a-viren beruht ebenfalls auf einer hemmung der freisetzung des ribonukleoproteins aus intrazytoplasmatischen vesikeln und des uncoatings durch blockade eines m -virusprotein-abhängigen ionenkanals. therapeutisch einsetzbare substanzen amantadin und rimantadin stehen seit vielen jahren für die systemische therapie von influenza-a-virus-infektionen zur verfügung. die biologische besonderheit der retroviren besteht darin, dass, beginnend mit dem eindringen des viruscores (nukleokapsid) in die zelle und weiter nach der freisetzung des diploiden einzelsträngigen viralen rna-genoms, zuerst eine doppelsträngige dna hergestellt werden muss. dies geschieht in einem komplexen syntheseprozess über den zwischenzustand eines rna-dna-hybridmoleküls. zwei moleküle der hierfür notwendigen reversen transkriptase (rt) werden bei hiv im viruspartikel mitgebracht. neben der polymerasefunktion besitzt die rt in einer zweiten domäne noch eine enzymatische rnase-h-aktivität, die für die entfernung des rna-stranges vom rna-dna-hybridmolekül erforderlich ist. diese doppelsträngige dna-kopie der viralen rna wird danach als sog. provirales genom kovalent in das wirtszellgenom integriert. hierfür ist ebenfalls ein viruspartikelassoziiertes enzym, die integrase, erforderlich. substanzen zur hemmung der integration der proviralen dna eines retrovirus in das wirtszellgenom (hiv) befinden sich in der klinischen prüfung (integrasehemmer) und werden künftig möglicherweise ein weiteres standbein der antiretroviralen therapie bilden. therapeutisch einsetzbare substanzen die reverse transkriptase (rt) von hiv ist das zielmolekül für die meisten antiretroviralen medikamente. diese werden nach ihrer chemischen struktur unterteilt in nukleosidanaloge rt-hemmer und nicht nukleosidanaloge rt-hemmer (nnrti). eingriffsmöglichkeiten in virusspezifische funktionen ergeben sich während der transkription der viralen genetischen information. vorwiegend typ-i-interferone (ifn) hemmen die replikation verschiedener viren in unterschiedlichem ausmaß, wobei einer der vielfältigen mechanismen (s. u.) in der degradation viraler mrna besteht. einer der antiviralen wirkmechanismen von ribavirin beruht auf der hemmung der mrna einiger viren. therapeutisch einsetzbare substanzen verschiedene humane αund β-interferone stehen für die systemische therapie (chronische hepatitis-b-virus-und hepatitis-c-virus-infektion) und auch topische therapie (papillomaviren) zur verfügung. das relativ breit wirksame nukleosidanalogon ribavirin wird als kombinationstherapeutikum bei chronischer hcv-infektion und zur monotherapie bei rsv-und parainfluenzavirusinfektionen schwer kranker kinder, aber auch bei lassavirusinfektionen eingesetzt. abhängig von der art des vom virus in die wirtszelle eingeschleusten genoms (einzelstrang-rna/dna, doppelstrang-rna/dna) und des zur virusvermehrung erforderlichen genetischen informationsflusses bedarf es besonderer enzyme, die entweder vom virus -im partikel verpackt -mitgebracht (viruspartikelassoziiert, s. o. bei hiv) oder in der infizierten zelle synthetisiert werden (viruskodiert). beispiel für ein viruskodiertes enzym, welches in uninfizierten zellen nicht vorkommt, ist die rna-abhängige rna-polymerase der picornaviren, deren hemmung die wirkung mancher substanzen erklärt ( -[α-hydroxybenzyl]-benzimidazol, enviroxime). viele andere viruskodierte polymerasen von dna-viren unterscheiden sich von zellulären isoenzymen hinsichtlich der akzeptanz und bindung von nukleosidanaloga so weit, dass virusselektive nukleosidanaloga möglich sind. therapeutisch einsetzbare substanzen die vier derzeit gegen herpesviren einsetzbaren nukleosidanaloga, das na-phosphonat cidofovir und auch das pyrophosphatanalogon foscarnet hemmen letztlich alle die viruskodierten polymerasen. die blockierung viraler mrna durch kurze synthetische "antisense"-oligonukleotide ist eine vom konzept her sehr elegante und naturgemäß spezifische möglichkeit der hemmung der viruskodierten proteinsynthese. probleme bereiten die auswahl der geeigneten sequenzen und die chemische modifikation der oligonukleotide, die die aufnahme in die zelle ermöglichen müssen und die stabilisierung in der zelle bei erhaltener wirksamkeit sicherstellen müssen. interferone können die translationsinitiation hemmen. therapeutisch einsetzbare substanzen eingang in die therapie der zytomegalievirusretinitis hat ein intraokulär zu applizierendes antisense-phosphothioat gefunden. zur topischen therapie von herpes-simplex-virus-infektionen stehen ältere nukleosidanaloga zur verfügung mit geringerer virusselektivität. bekanntestes beispiel sind die proteasehemmer zur kombinationstherapie der hiv-infektion. der wirkmechanismus dieser substanzen beruht auf der hemmung der posttranslationalen spaltung der retroviralen gag-(gruppenspezifisches antigen) und gag-pro-pol-polyproteine durch hemmung der homodimeren "aspartatprotease" des virus. es werden unreife, nichtinfektiöse viruspartikel gebildet. auch andere posttranslational nötige modifikationen viraler proteine, z. b. glykosylierung, könnten ein ziel antiviraler substanzen sein. an dieser stelle im replikationszyklus greifen die neuen neuraminidasehemmer ein, die in der lage sind, die korrekte ausschleusung von influenzaviren zu inhibieren. während ihrer untersuchungen zur bereits bekannten interferenz von virusinfektionen entdeckten alick issacs und jean lindenmann einen übertragbaren virushemmenden faktor, den sie interferon nannten. in einem schlüsselexperiment stellten sie fest, dass zellen, die mit uv-inaktivierten influenzaviren behandelt worden waren, etwas in das gewebekulturmedium abgaben, das die infektion weiterer zellen verhinder-te. in den folgenden jahren der erforschung dieses phänomens wurde ein gewaltiges netzwerk von interaktoren und interaktionen aufgedeckt. trotz vieler erkenntnisse besteht auch heute noch längst kein vollständiges bild aller zusammenhänge und wirkungen. die antivirale wirkung ist dabei nur eine von vielen, und sie ist eine folge regulatorischer funktionen der interferone in der zelle. als folge des schrittweisen erkenntniszuwachses ist auch die nomenklatur schwierig und teilweise redundant. ifn gehören nach heutiger nomenklatur zu den zytokinen. zur unterscheidung der interferone gibt › tabelle . eine Übersicht. alle ifn sind relativ kleine moleküle, die in ihrer reifen form aus - aminosäuren bestehen. für die antivirale therapie spielen derzeit nur die typ-i-ifn, und hier die α-ifn, eine wesentliche rolle. die induktion kann auf verschiedenen wegen erfolgen. virusinfektionen, vor allem durch rna-viren, führen zur raschen induktion der ifn, die nach wenigen stunden wieder beendet wird. die induktion erfolgt über mehrere positiv regulatorische domänen, aber auch durch negative regulation, die zur verminderung der repressorproteine und einer gesteigerten ifn-gen-expression führt. die ifn werden von den zellen, in denen sie gebildet wurden, freigesetzt. natürliche α-ifn werden von lymphozyten, monozyten, makrophagen und einigen zelllinien gebildet. quelle für β-ifn sind fibroblasten und einige epitheliale zellen. mittlerweile werden die zur antiviralen therapie eingesetzten ifn meist als rekombinante ifn gentechnisch hergestellt. die ifn binden über spezifische zellrezeptoren an die zellen, in denen sie ihre antivirale und andere wirkungen entfalten. diese ifn-rezeptoren sind bekannt, und ihre expression unterliegt wiederum regulatorischen prozessen. viele (> ) proteine werden durch ifn in den zellen reguliert, von denen etliche auch in die antivirale wirkung eingebunden sind. die stimulation der no-synthetase führt zur no-bildung und damit zu einer eher unspezifischen antiviralen wirkung hemmung der virusreifung ifn aktivieren eine gykosyltransferase, wodurch einerseits die notwendige posttranslationale modifikation mancher viraler proteine gehemmt und andererseits der normale ausschleusungsprozess (budding) behindert wird. bei systemischer anwendung gibt es z. t. erhebliche nebenwirkungen: neben den erwähnten zielen antiviraler therapeutika sind viele weitere denkbar. hinzuweisen ist in diesem zusammenhang auf die möglichkeit der hemmung regulatorischer proteine (z. b. tat oder rev bei hiv) oder auf die hemmung der genomreifung bei herpesviren und die genomverpackung bei im kern replizierenden umhüllten viren. die substanz wird parenteral und oral eingesetzt, auch prophylaktisch bei immunsuppression. die orale bioverfügbarkeit von acv ist allerdings nicht gut und unsicher, so dass bei schweren erkrankungen immer eine i.v. therapie angezeigt ist. die therapeutisch wirksame dosierung liegt bei dem wesentlich langsamer replizierenden vzv deutlich höher als bei hsv, was möglicherweise an der kurzen intrazellulären halbwertszeit von acv-triphosphat liegt. valaciclovir (valacv) ist ein valinester des acv. die substanz wird oral wesentlich besser resorbiert, so dass eine orale bioverfügbarkeit von ca. % erreicht wird. valacv wird bei der resorption und bei der ersten leberpassage praktisch vollständig in die wirksame substanz acv umgewandelt. mit einführung des valacv ist es möglich geworden, acv-serumkonzentrationen durch orale valacv-gabe zu erhalten, die ansonsten nur durch i.v. applikation von acv erreicht werden können. resistenzentwicklung acv-resistente hsv-mutanten mit mutationen/deletionen im thymidinkinase(tk)-gen und/ oder polymerase-gen können isoliert werden und sind bei immunsupprimierten u.u. klinisch relevant. tk-minus-mutanten sind nicht neuropathogen, allerdings sind resistente hsv durchaus nicht immer tk-minus-mutanten. in der regel führen tk-mutationen zu kreuzresistenz gegenüber anderen nukleosidanaloga, die durch die tk aktiviert werden müssen (s. u. und ganciclovir). resistenz aufgrund von polymerasemutationen ist seltener, führt aber meist zu breiter kreuzresistenz gegenüber nukleosidanaloga (s. u.). bvdu wird ebenfalls selektiv durch die viralen thymidinkinasen von hsv- und vzv zu monophosphat und diphosphat phosphoryliert. die phosphorylierung zu diphosphat kann von der hsv- -tk nicht geleistet werden, da deren thymidylatkinase-aktivität wesentlich geringer ist, was die geringe wirksamkeit von bvdu gegenüber hsv- erklärt. die wirksamkeit von bvdu bei vzv-infektionen (varizellen und zoster) immunkompromittierter patienten ist durchaus sehr gut und vergleichbar der von i.v. verabreichtem aciclovir, jedoch fällt die nutzen-risiko-betrachtung insgesamt auch bei vzv-therapie zu gunsten von aciclovir aus, da bvdu eher mutagen zu sein scheint und nicht zusammen mit -fluorouracil (zytostatikum) gegeben werden darf. penciclovir (pcv) pcv ist strukturell dem ganciclovir sehr ähnlich und ebenfalls oral sehr schlecht resorbierbar im gegensatz zu famciclovir (fcv), einer oral sehr gut resorbierbaren substanz (bioverfügbarkeit bis > %). nach resorption wird fcv rasch und vollständig in pcv, das wirksame pro-drug, umgewandelt. pcv wird ähnlich wie acv durch die thymidinkinasen von hsv und vzv phosphoryliert. wesentliche indikationen genitale hsv-primärinfektionen sollten möglichst frühzeitig systemisch behandelt werden, auch mit dem ziel, möglicherweise die spätere rezidivhäufigkeit zu verringern. Ähnliches gilt auch für die primäre gingivostomatitis herpetica. rekurrierende mukokutane hsv-infektionen können je nach beschwerden und beeinträchtigung, vor allem bei genitalen manifestationen (u.u. patientengesteuert), systemisch behandelt werden. in besonderen fällen mit häufigen genitalen rekurrenzen ( - pro jahr) oder mit schwerer psychischer beeinträchtigung kann eine suppressionsbehandlung durchgeführt werden. nach absetzen der therapie treten erneut rekurrenzen auf. topisch kann mit verschiedenen nukleosidanaloga (s. o.) behandelt werden. bei hautmanifestationen ist zwischenzeitliches betupfen der läsionen mit Äther oder alkohol sinnvoll. bei schweren systemischen infektionen (enzephalitis, neugeborenensepsis) mit hsv oder vzv oder bei infektionen erheblich immunsupprimierter mit diesen viren muss mit einer sofortigen i.v. acv-therapie begonnen werden. das behandlungsergebnis hängt entscheidend von einem frühzeitigen behandlungsbeginn ab. liegt zum zeitpunkt der geburt eine hsv-infektion im geburtskanal der mutter vor, so besteht die gefahr einer konnatalen infektion des neugeborenen mit der folge einer unbehandelt oft tödlich verlaufenden hsv-sepsis (› kap. . . ). in diesen fällen kann nach heutiger kenntnis eine therapie der schwangeren zur vermeidung einer schnittentbindung durchaus erwogen werden. ebenso muss die möglichkeit der antiviralen therapie in das optimale management der perinatalen vzv-infektion einbezogen werden. bei vzv-exposition eines seronegativen immunsupprimierten patienten (meist kinder) ist die sofortige gabe eines varizellen-hyperimmunglobulins ( , ml/kg körpergewicht) indiziert, ggf. in kombination mit antiviraler therapie. bei vzv-manifestationen bei immunsupprimierten patienten (auch zoster) ist eine antivirale therapie indiziert. es gibt durchaus gute argumente für eine generelle antivirale therapie bei varizellen, jedoch wird sie in der praxis kaum durchgeführt. in den letzten jahren hat sich gezeigt, dass acv bei cmv-erkrankungen therapeutisch nicht einsetzbar ist, dass jedoch bei prophylaktischer gabe an erheblich immunsupprimierte transplantatempfänger auch eine gewisse prophylaktische wirkung gegen cmv-erkrankungen nach endogener reaktivierung vorhanden ist. die substanz kann nur i.v. und topisch angewendet werden. pfa wird systemisch bei cmv-erkrankungen immunsupprimierter eingesetzt, wenn eine gcv-resistenz vorliegt, und stellt dann eine alternative zu cidofovir dar. pfa kann topisch erfolgreich bei herpes labialis und genitalis eingesetzt werden. bei den anderen humanen herpesviren sind z. t. gute effekte der oben genannten substanzen in vitro beschrieben worden. in klinischen studien konnte durch anwendung von acv bei ebv-infektionen auch die virusausscheidung deutlich vermindert werden, ein wesentlicher einfluss auf den krankheitsverlauf ließ sich nicht erreichen. dies gilt ebenfalls für die übrigen humanen herpesviren und hängt wohl auch mit der pathogenese der jeweiligen erkrankungen zusammen. das humane hbv ist ein sehr kleines dna-virus mit einer teilweise doppelsträngigen zirkulären dna von ca. bp. im partikel ist eine polymerase verpackt, die den während der replikation notwendigen, für ein dna-virus sehr ungewöhnlichen schritt einer reversen transkription ermöglicht. dies geschieht an einer prägenomischen rna. angesichts dieser biologischen Ähnlichkeiten mit einem retrovirus und auch der homologien der hbv-polymerase mit der reversen transkriptase von retroviren ist es nicht erstaunlich, dass gegen retroviren wirksame substanzen in vitro und in vivo auch gegen hbv wirksam sind. hauptindikation für die antivirale therapie ist heute die chronische hepatitis b wegen der spätkomplikationen: leberzirrhose und hepatozelluläres karzinom. interferone natürliche und auch rekombinant hergestellte humane α-interferone inhibieren die hbv-replikation sehr effektiv und waren für etliche jahre einzige standardtherapeutika bei der behandlung der chronischen hepatitis b. dies war auch die erste indikation, bei der interferone in großem umfang zur antiviralen therapie eingesetzt wurden. virologisch und histopathologisch findet sich bei etwa einem drittel der patienten, die monate lang dreimal wöchentlich mio. ie α-interferone erhielten, eine deutliche besserung der chronischen hbv-infektion. die hbv-dna-konzentrationen im blut nehmen signifikant ab oder fallen -auch in abhängigkeit von der empfindlichkeit der eingesetzten nachweismethodikunter die nachweisgrenze ab. bei etwa % der patienten kam es zur normalisierung der transaminasen und zum therapiebedingten verlust von hbeag. leider persistiert dieser positive effekt nach beendigung der interferontherapie nur bei wenigen der ursprünglich erfolgreich behandelten patienten. andererseits machen die bekannten nebeneffekte der therapie (s. o.) eine wirkliche dauertherapie unmöglich. lamivudin ( tc) das nukleosidanalogon tc, welches zunächst in der hiv-therapie eingesetzt wurde, hat sich auch bei der hbv-therapie bewährt. nach einjähriger therapie mit täglich mg zeigten in einer studie % der patienten eine histologisch nachweisbare verbesserung der hepatitis und sogar % eine anhaltende normalisierung der transaminasen (alt). nach fortgesetzter -jähriger therapie fanden sich bei einem drittel der behandelten antikörper gegen hbeag. tc führt nach lebertransplantation aufgrund einer hbv-induzierten zirrhose zu einer reduktion der neuinfektionen des transplantates, wobei die standardprophylaxe die fortgesetzte gabe von anti-hbs-haltigen hyperimmunglobulinpräparaten ist. verschiedene resistenzvermittelnde mutationen treten in der hbv-polymerase in sehr ähnlichen, konservierten bereichen wie bei hiv in abhängigkeit von der therapiedauer auf. die auswirkungen auf den grad der resistenz einerseits und die verbleibende vermehrungsfähigkeit der mutanten andererseits sind wie bei hiv unterschiedlich. neue nukleosidanaloga (entecavir) finden derzeit mit erfolg eingang in die therapie der chronischen hbv-infektion. langzeittherapie scheint die erfolge zu verbessern, solange keine resistenzen auftreten. es liegt nahe, dass alle in der erprobung befindlichen antiretroviralen nukleosidanaloga auch hinsichtlich ihrer hbv-wirksamkeit und kreuzresistenzen geprüft werden. hcv-infektionen stellen eine besondere therapeutische herausforderung dar, weil ein sehr hoher anteil ( - %) der infizierten eine chronische infektion entwickelt, die dann nach jahren eines relativ symptomarmen verlaufs plötzlich in eine leberzirrhose und auch ein karzinom übergehen kann. der zunächst klinisch eher milde verlauf führt dazu, dass die therapiebereitschaft der patienten in den asymptomatischen phasen häufig nicht allzu groß ist. bei hcv handelt es sich um ein völlig anderes virus als bei hbv, um ein einzelsträngiges rna-virus mit plusstrang-polarität. das genom dieses flavivirus umfasst ca. nukleotide. Ähnlich wie bei picornaviren ist das primäre translationsprodukt ein polyprotein, das bei hcv posttranslational in zehn struktur-und nicht-struktur-proteine gespalten wird. eines der nicht-struktur-proteine, das ns a, ist offenbar für die interferonempfindlichkeit des virus verantwortlich. bei hcv unterscheidet man genotypen mit verschiedenen subtypen. diese genotypen α sind geographisch unterschiedlich verteilt. die erfolgsrate einer α-interferon-therapie ist vom genotyp abhängig. in deutschland ist mit ca. % der genotyp (subtypen a und b) am häufigsten vertreten, welcher leider die geringste ansprechrate bei α-interferon-therapie aufweist. Ähnlich wie bei hiv ist die viruspopulation in einem patienten genetisch nicht einheitlich, sondern stellt ebenfalls eine quasi-spezies dar. das ausmaß der heterogenität der viruspopulation vor therapie und die veränderung unter therapie scheinen prognostische bedeutung zu besitzen. α-interferone die zunächst angewendete -monatige monotherapie mit dreimal mio. ie α-interferon pro woche erbrachte je nach studie und bei einschluss aller genotypen nur bei etwas über % der patienten einen anhaltenden erfolg. dieser war definiert als mindestens monate nach therapieende anhaltende normalisierung der transaminasen und verschwinden der hcv-rna aus dem blut. in den folgenden jahren konnte durch steigerung der α-interferon-dosis, durch tägliche gaben und verdoppelung der therapiedauer der erfolg verbessert werden. peg-gekoppelte interferone und kombinationstherapie mit ribavirin zwei weitere therapeutische neuerungen, einerseits die anwendung von polyethylengekoppeltem α-interferon a (sog. pegyliertes interferon) und andererseits die kombinationstherapie mit dem nukleosidanalogon ribavirin, konnten die ergebnisse unabhängig voneinander nochmals deutlich verbessern. durch anwendung von peg-α-ifn a wird bei nur einmal wöchentlicher gabe ( mg) ein wesentlich gleichmäßigerer ifn-spiegel erreicht. der therapieerfolg liegt bei anwendung von peg-α-ifn a bei etwa % (genotyp ) und % (alle genotypen) mit vergleichbaren nebenwirkungen wie nach α-ifn-therapie. die ergebnisse mit der kombinationstherapie α-ifn + ribavirin liegen in der gleichen größenordnung. auch hier lassen sich durch dosissteigerungen und verlängerte therapie verbesserungen erreichen. interessant ist die tatsache, dass frühere studien mit einer ribavirin-monotherapie zwar eine verbesserung der leberhistologie und der transaminasen gezeigt haben, aber keine verminderung der viruslast im blut. die naheliegende kombination von peg-ifn und ribavirin hat die ergebnisse weiter verbessert. eine reihe weiterer kombinationen befindet sich in der erprobung. die langzeitprognose der erfolgreich behandelten patienten ist gut und mittlerweile scheint sogar klar zu sein, dass auch chronisch hcv-infizierte patienten mit leberzirrhose, abhängig vom hcv-genotyp, gemessen an virologischen, klinischen und auch histologischen parametern, von der antiviralen therapie profitieren. therapiebestimmende faktoren derzeit sind retroviren bekannt, die für die pathogenese von erkrankungen des menschen bedeutsam sind: • beide erreger von aids, hiv- und hiv- • htlv- als erreger der adulten t-zell-leukämie und der tropischen spastischen paraparese. zielmoleküle der meisten verfügbaren antiretroviralen therapeutika sind partikelgebundene viruskodierte enzyme, die reverse transkriptase (rt) und die protease. die substanzen lassen sich einteilen in nukleosidanaloge reverse-transkriptase-hemmer, nicht nukleosidanaloge reverse-transkriptase-hemmer (nnrti) und proteasehemmer. seit der erstzulassung des ersten rt-hemmers azt in den usa im jahr sind mehr als medikamente in deutschland zugelassen worden. zanamivir muss i.v. oder als aerosol verabreicht werden, wohingegen das analoge "pro-drug" oseltamivir oral verabreicht werden kann. da die beiden substanzen an unterschiedlichen stellen der funktionellen domäne der neuraminidase binden, besteht keine absolute kreuzresistenz zwischen beiden pharmaka. h n -infizierte patienten sind teilweise mit erfolg behandelt worden. neben den etablierten antiviralen therapeutika und therapieindikationen gibt es andere viren, bei denen die therapie am menschen erprobt wurde, aber noch eher experimentellen charakter hat. die therapie von enterovirus-und rhinovirusinfektionen ist seit mehreren jahrzehnten gegenstand wissenschaftlicher forschung und auch von therapieversuchen mit chemischen substanzen, antikörpern und interferonen. eine gruppe von sog. win-substanzen hemmt durch spezifische bindung an das viruskapsid die adsorption des virus an die zielzelle und das intrazelluläre uncoating. in den usa ist ein vertreter dieser substanzen, das pleconaril, klinisch erprobt worden. es ist gegen viele picornaviren ( %) wirksam und hat sich bei der behandlung der aseptischen meningitis und respiratorischer infektionen in kontrollierten studien bewährt. ob pleconaril bei der enterovirusmyokarditis eingesetzt werden kann, ist noch nicht klar. derzeit laufen bei dieser indikation versuche mit interferontherapie. adenoviren sind weltweit verbreitet und besitzen ein erhebliches pathogenes potenzial. insbesondere bei systemischen infektionen immunsupprimierter stellen sie ein schwieriges the-rapeutisches problem dar. zwei in vitro gegen verschiedene adenovirustypen wirksame substanzen, die für andere indikationen zugelassen sind, werden zur experimentellen therapie eingesetzt: cidofovir und ribavirin. für beide substanzen gibt es positive kasuistische mitteilungen, aber der therapeutische wert beider substanzen ist derzeit noch nicht klar. wie bereits erwähnt, zeichnet sich das nukleosidanalogon ribavirin durch ein relativ breites wirkungsspektrum aus. bereits vor knapp jahren wurde es zur behandlung von rsv-infektionen der lunge bei schwer kranken intensivpflichtigen kindern zugelassen. in studien konnte bei aerosolanwendung eine senkung der letalität nachgewiesen werden. auch die intravenöse anwendung ist mit erfolg möglich, und derzeit wird die kombination von ribavirin mit einer etwa gleich wirksamen antikörpergabe evaluiert. auch beim masernvirus, einem weiteren paramyxovirus, ist über einzelne erfolge bei der behandlung von pneumonien immunsupprimierter mit ribavirin berichtet worden. interessanterweise ist ribavirin auch mit gutem erfolg bei schweren hämorrhagischen lassavirusinfektionen eingesetzt worden und gilt als therapie der wahl. auch bei dem verwandten, in südamerika vorkommenden junin-virus konnte die letalität von ca. auf % gesenkt werden. leider ist die substanz nicht ausreichend liquorgängig, um einen therapeutischen effekt bei zns-manifestationen zu erreichen. bei der durch jc-virus hervorgerufenen progressiven multifokalen leukoenzephalopathie (pml) wurden bei gabe von cidofovir, aber auch α-interferon klinische besserungen beobachtet. eine reihe mehr oder weniger spezifisch wirksamer substanzen (auch interferone) ist für die topische therapie von papillomen erprobt worden. in jüngster zeit konnte in einer ersten studie gezeigt werden, dass auch hier eine topische applikation von cidofovir wirksam ist. die zunächst mit großen erwartungen durchgeführten studien zur behandlung der juvenilen larynxpapillomatose mit interferonen haben nicht zufrieden gestellt. diagnostik die diagnose einer katheterassoziierten infektion ist häufig schwierig. zur definitiven diagnose einer katheterassoziierten infektion ist der nachweis desselben erregers von der katheterspitze und aus der blutkultur notwendig. bei liegendem katheter kann die diagnose mit der sogenannten "differential time to positivity" (dttp) gestellt werden: im falle einer katheterassoziierten infektion wird eine aus dem katheter entnommene blutkultur mindestens h früher positiv als eine gleichzeitig aus einer peripheren vene entnommene probe. als klinische hinweise können eine entzündung an der einstichstelle, fehlende andere ausgangsherde für eine bakteriämie sowie der nachweis typischer erreger, z. b. staphylokokken, angesehen werden. therapie es werden antibiotika verabreicht und der katheter entfernt. bei implantierten verweilkathetern ist vor der entfernung je nach vorliegendem pathogen ein antibiotischer behandlungsversuch gerechtfertigt. die wichtigste allgemeine maßnahme zur verhinderung nosokomialer infektionen ist das händewaschen. besonders in bereichen mit erhöhtem risiko, wie z. b. in infektions-, intensivund hämatologisch-onkologischen stationen, müssen vor und nach jedem patientenkontakt die hände gewaschen werden, . syndrome und spezifische probleme um eine nosokomiale ausbreitung von erregern zu vermeiden. daneben sind bei einigen erkrankungen spezielle maßnahmen erforderlich (s. o.). desinfektionen von medizinischen geräten sind heute durch gesetzliche bestimmungen und hygienevorschriften so geregelt, dass bei richtiger anwendung hierdurch keine erreger übertragen werden können. die liegedauer von intravasalen oder urinkathetern sollte möglichst kurz sein, d.h., jeder katheter, der nicht unbedingt benötigt wird, sollte entfernt werden. wo immer möglich, sollten therapieregime bevorzugt werden, bei denen medikamente oral statt intravenös gegeben werden. infektionen bei immunsupprimierten patienten sind häufig, verlaufen atypisch und können zu schweren komplikationen führen. art der immunsuppression und ausprägung und qualität der immunitätsfaktoren bestimmen spektrum und verlauf von infektionen wesentlich und sind für diagnostisches und therapeutisches vorgehen entscheidend. praxisfall ii eine -jährige frau wird wegen einer akuten myeloischen leukämie mit einer hochdosischemotherapie behandelt. am tag nach beginn der chemotherapie sind die leukozyten auf < /μl gefallen, sie klagt über kopfschmerzen und wirkt apathisch. nach einer halben stunde steigt die temperatur auf , °c an, blutkulturen werden abgenommen und eine empirische antibiotikatherapie begonnen. der klinische zustand bessert sich rasch, die patientin ist h nach deren beginn fieberfrei. zu diesem zeitpunkt ist e. coli als erreger in der blutkultur isoliert und identifziert worden. die empirische therapie ist adäquat und wird für weitere tage • prognostisch ungünstigste kategorie: patienten mit lungeninfiltraten. nur bei - % aller patienten finden sich positive blutkulturen, die eine gezielte antibiotische therapie ermöglichen. pilzinfektionen sind oft schwer zu diagnostizieren, da kulturelle verfahren wenig sensitiv sind. als nachweismethoden dienen heute in erster linie blutkulturen für candida-und die hochauflösende computertomografie des thorax sowie der galactomannan-test im serum für aspergillus-infektionen. therapie die behandlung eines neutropenischen patienten mit fieber muss unmittelbar nach auftreten der klinischen symptome, vor dem eintreffen mikrobiologischer befunde erfolgen. sie ist deshalb empirisch und kann später, bei erfolgter erregeridentifizierung, modifiziert werden. • initialtherapie und frühe eskalation: als primäre therapie kommen eine kombination aus einem breitspektrum-(ureido-)penicillin mit einem β-lactamase-hemmer, ein pseudomonas-wirksames cephalosporin oder ein carbapenem in frage. tritt nach - tagen keine entfieberung auf, sollte eine erneute diagnostik insbesondere mit hinblick auf pilzinfektionen erfolgen. • antimykotische therapie: wegen der gefahr von invasiven pilzinfektionen wird bei neutropenie (insbesondere bei patienten mit pulmonalen infiltraten) frühzeitig, spätestens jedoch nach - fiebertagen eine antimykotische therapie eingesetzt. zur empirischen therapie eignen sich caspofungin oder liposomales amphotericin b, beim nachweis von lungeninfiltraten ist voriconazol mittel der wahl. • fokussanierung: sie ist in der regel nur bei lokalisierten hautinfektionen möglich oder auch sinnvoll. die chirurgische therapie einer neutropenischen kolitis ist nur bei bildung von intraabdominellen abszessen oder einer offenen perforation sinnvoll, ansonsten erfolgt die therapie konservativ. prophylaxe wegen der hohen inzidenz von infektionen bei neutropenischen patienten werden verschiedene maßnahmen zur infektionsprophylaxe angewandt. diese maßnahmen zielen auf eine verminderung der endogenen keimflora und vermeidung der exposition gegenüber pathogenen organismen. • innerhalb einiger wochen erfolgt offenbar durch die immunantwort eine partielle kontrolle der hiv-replikation. die virämie nimmt ab und stellt sich auf ein individuell unterschiedlich hohes niveau ein. die höhe der virämie in dieser phase (messbar durch die quantitative bestimmung der hiv-rna) ist maßgeblicher parameter der weiteren prognose. patienten mit niedriger hiv-rna (< genomkopien/ml blut), haben eine deutlich längere Überlebenszeit als solche mit höheren werten. obwohl in dieser phase (klinische latenzphase) meist keine beschwerden vorhanden sind, besteht eine ungeheure dynamik der hiv-replikation, die schließlich zur erschöpfung des immunsystems führt. pro tag werden ca. virionen produziert. Über % werden dabei in den cd + -lymphozyten gebildet, die infolge der infektion zerstört werden. es kommt so zum stetigen abfall der t-helferzell-zahl im blut, der sich meist über viele jahre hinzieht. das verhältnis von cd + -zellen zu cd + -zellen (suppressor-und zytotoxische t-zellen) kehrt sich um (normalerweise cd + : cd + > ). wenn die zahl der cd + -zellen unter eine kritische schwelle von /μl blut sinkt, kommt es zum auftreten von aids-typischen opportunistischen infektionen. bereits vorher können die patienten symptome aufweisen (z. b. oraler soor), die auf einen nahen zusammenbruch des immunsystems hindeuten. die hiv-infektion führt zur unspezifischen stimulation des humoralen immunsystems. dies äußert sich in einer vermehrten bildung von immunglobulinen. neben der infektion lymphatischer zellen werden auch frühzeitig langlebige makrophagen und gliazellen des zns befallen. diese zellen spielen für die dynamik der hiv-infektion keine so große rolle wie die cd + -lymphozyten, sind aber therapeutisch schwerer erreichbar und bereiten daher probleme. symptome je nach stadium der erkrankung treten unterschiedliche symptome auf. • akutes retrovirales syndrom: bei bis zu % der infizierten kommt es wenige wochen nach der ansteckung zum akuten krankheitsbild, dem sog. akuten retroviralen syndrom. wegen der klinischen Ähnlichkeit mit der mononukleose wird das krankheitsbild auch als "mononukleoseähnliches syndrom" bezeichnet. typische symptome sind fieber, nachtschweiß, allgemeines krankheitsgefühl, lymphknotenschwellungen, pharyngitis und exantheme. vereinzelt treten auch schwere neurologische erkrankungen auf (z. b. guillain-barré-syndrom). während dieses akuten stadiums kommt es zum deutlichen abfall der t-helferzell-zahl, die hiv-rna im blut und damit auch die infektiosität ist sehr hoch. nach einigen tagen bis wochen bilden sich diese klinischen veränderungen wieder zurück. • asymptomatisches stadium (klinische latenz): die meisten hiv-infizierten haben über mehrere jahre keine beschwerden, die hiv-infektion wird in diesem stadium oft nur durch zufall entdeckt. als klinisches symptom können generalisierte lymphknotenschwellungen vorhanden sein (daher die frühere bezeichnung "lymphadenopathiesyndrom"). bei relativ konstantem wert der hiv-rna im plasma findet sich ein unterschiedlich rascher abfall der cd + -zeilen. • symptomatisches stadium: kennzeichnend ist die zunehmende immunschwäche, die sich im auftreten von opportunistischen infektionen äußert (cdc-kategorien b und c). die zahl der cd + -zellen ist stark abgefallen, es findet sich meist ein hoher wert der hiv-rna im plasma. die schweren aids-definierenden erkrankungen treten meist dann auf, wenn die cd + -zell-zahlen < /μl gesunken sind (› kap. . . ). abb. . hiv im elektronenmikroskopischen bild. gut erkennbar ist die virushülle (pfeil) mit den knopfartig erscheinenden oberflächenantigenen, die an den cd -rezeptor anbinden können, ferner das zylinderförmige viruskapsid (doppelpfeil), das aus dem hauptcoreprotein p aufgebaut ist (aufnahme: h. gelderblom, berlin). klassifikation die derzeitig gültige klassifikation kommt von den amerikanischen centers for disease control (cdc-klassifikation) und wurde zuletzt revidiert (› tab. . ). sie führt die aids-definierenden erkrankungen auf. ferner gibt sie eine stadieneinteilung der hiv-infektion an, die sich an klinischen und immunologischen parametern orientiert. alle patienten, die eine klinische aids-definition erfüllen, werden in die kategorie c eingestuft (› tab. . ). virologische diagnostik die diagnostik der hiv-infektion erfolgt meist durch nachweis virusspezifischer antikörper. als screening-test bei verdacht auf hiv-infektion dient ein eli-sa mit sehr hoher sensitivität und spezifität je > %. bei positivem elisa muss ein bestätigungstest erfolgen. meist ist dies ein westernblot, ggf. auch ein immunfluoreszenztest. jeder hiv-test muss nach aufklärung und mit dem einverständnis des patienten erfolgen und bei positivem ausfall durch eine . blutentnahme und erneute untersuchung bestätigt werden. zwischen infektion und bildung messbarer antikörper vergehen einige wochen (diagnostisches fenster). - monate nach infektion weisen fast alle infizierten antikörper auf. in der frühen phase vor einsetzen der antikörperbildung ist also bei negativem hiv-antikörpertest eine Übertragung der infektion möglich. in besonderen fällen, wenn eine sichere frühzeitige entdeckung der infektion notwendig ist, kann ein direkter nachweis der viralen rna oder proviralen dna durch pcr erfolgen. diese wird z. b. bei kindern hiv-infizierter mütter eingesetzt. mit dieser oder anderen diagnostischen verfahren (nasba = "nucleic acid squence-based amplification"; bdns = "branch-chain dns) kann ferner ein quantitativer nachweis der hiv-rna (viruslast) im blut erfolgen. dieser test spielt heute eine sehr große rolle für die beurteilung der prognose und als kontrolle der antiretroviralen therapie. immunologische diagnostik die zahl der cd -lymphozyten im blut stellt den entscheidenden immunologischen parameter für die verlaufsbeurteilung der hiv-infektion dar. die bestimmung erfolgt mittels der facs-methode. begleitende diagnostik durch die hiv-infektion können einige sekundäre laborveränderungen hervorgerufen werden. häufig finden sich anämie, leukozytopenie, thrombozytopenie und erhöhte immunglobuline. viele infizierte haben zusätzliche infektionen. besonders nach hepatitis b und c, lues, toxoplasmose und zytomegalievirus-infektion muss gesucht werden. differenzierungsmaßnahme akute hiv-infektion: klinische kategorien ( • hemmung der protease • hemmung der integration. mittlerweile stehen mehr als substanzen aus verschiedenen klassen für die therapie zur verfügung (› tab. . ), medikamente mit weiteren neuen therapieprinzipien (ccr -antagonisten, integrasehemmer, maturationshemmer) werden derzeit klinisch erforscht. die therapie der hiv-infektion erfolgt heute immer als kombinationstherapie. diese wird auch als "hochaktive antiretrovirale therapie" (haart) bezeichnet. typischerweise besteht sie aus der kombination von nrti mit einem proteasehemmer (pi) oder einem nnrti. durch keine bisher bekannte therapie wird die vollständige elimination von hiv erreicht. daher muss eine einmal begonnene und effektive antiretrovirale therapie unbegrenzt fortgeführt werden, da es sonst erneut zur ungehemmten virusvermehrung kommt. aus unterschiedlicher motivation ist in den letzten jahren die auswirkung von therapiepausen untersucht worden. die erhofften positiven effekte (verbesserung der immunantwort gegen hiv) traten hierunter nicht ein, dagegen konnte ein vermehrtes risiko für schwerwiegende komplikationen gezeigt werden. therapiepausen sind daher nicht zu empfehlen. wiegen. bei einer cd + -zahl von > /μl wird deshalb meist zunächst abgewartet. eine gesicherte behandlungsindikation besteht für alle patienten mit einer symptomatischen hiv-infektion unabhängig von der zahl der cd + -zellen und der hiv-rna. eine besondere herausforderung ist die behandlung hiv-infizierter schwangerer frauen. im ersten trimenon sollte wegen des möglichen teratogenen potenzials keine antiretrovirale therapie erfolgen bzw. eine begonnene therapie ausgesetzt werden. für eine antiretrovirale therapie mit zidovudin ab der . schwangerschaftswoche bis zur entbindung mit anschließender -wöchiger nachbehandlung des kindes ist eine verringerung der vertikalen hiv-Übertragung nachgewiesen. viele frauen werden heute auch in der schwangerschaft mit einer kombinationstherapie behandelt, wobei bisher kaum daten zur fruchtschädigung durch einzelne medikamente vorliegen. wegen seiner teratogenität ist efavirenz auf jeden fall kontraindiziert. therapieziele ziele einer antiretroviralen therapie sind die lebensverlängerung und eine besserung vorhandener symptome und der lebensqualität. bei asymptomatischen patienten können nur die viruslast und der immunstatus als parameter für die wirksamkeit einer therapie herangezogen werden. es sollte heute eine absenkung der hiv-rna unter die nachweisgrenze ultrasensitiver tests (< kopien/ml) angestrebt werden. je nach höhe der ausgangsviruslast wird dieses ziel meist nach - monaten erreicht. durch eine effektive antiretrovirale therapie steigt die zahl der cd + -zellen an. normalwerte werden jedoch meist nur von patienten mit relativ guten ausgangswerten erreicht. probleme der antiretroviralen therapie diese therapie war zunächst mit erheblichen einschränkungen und belastungen behaftet ( von der akuten hiv-infektion bis zum auftreten von aids vergehen bei unbehandelten im durchschnitt ca. jahre. die mittlere zeitspanne von der diagnose aids bis zum tod beträgt dann knapp jahre. ein geringer anteil aller hiv-infizierten (< %) zeigt auch nach mehr als -jähriger dauer der infektion keine anzeichen eines immundefektes (long-term non-progressor). es ist bisher nicht bekannt, ob diese personen jemals an aids erkranken werden. bei allen anderen führt die hiv-infektion unbehandelt unweigerlich zur ausbildung von aids und zum tod. durch die antiretrovirale kombinationstherapie hat sich die prognose der hiv-infektion dramatisch verbessert. die meisten können damit ein normales leben führen, und die prognose ist günstig. die mittlere lebenserwartung eines patienten unter antiretroviraler therpaie lässt sich heute noch nicht sicher angeben, dürfte sich aber der normalen lebenserwartung annähern. da die hiv-infektion zur unheilbaren, tödlichen erkrankung führt und eine schutzimpfung nicht zur verfügung steht, kommt der prävention eine zentrale rolle zu. das risiko einer sexuellen Übertragung der hiv-infektion kann durch vermeidung riskanter sexualpraktiken vermindert werden. die konsequente benutzung von kondomen ist eine entscheidende maßnahme zur verminderung des Übertragungsrisikos. bei drogenabhängigen konzentrieren sich präventive strategien auf die suchttherapie sowie auf die kontrollierte verabreichung von ersatzdrogen ("methadon-programm"). eine weitere präventive maßnahme ist die ausgabe steriler spritzen an drogenabhängige. allgemeine vorsichtsmaßnahmen angehörige medizinischer berufe sind beim umgang mit hiv-patienten einer infektionsgefahr ausgesetzt. ein relevantes infektionsrisiko existiert allerdings nur beim kontakt mit infiziertem blut. die höchste gefahr besteht bei stichverletzungen mit hohlnadeln, die blut enthalten: in , - , % kommt es zur Übertragung von hiv. daher müssen unbedingt vorsichtsmaßnahmen eingehalten werden. am wichtigsten ist die vermeidung von prozeduren, die ein hohes verletzungsrisiko beinhalten ("re-capping" von kanülen!). scharfe gegenstände müssen immer aus dem unmittelbaren arbeitsbereich entfernt und sofort in spezielle container entsorgt werden. da eine infektion prinzipiell auch über schleimhäute und verletzte haut erfolgen kann, müssen in allen situationen, in denen blutkontakt möglich ist, schutzhandschuhe getragen werden. vorgehen bei nadelstichverletzung ist es trotz vorsichtsmaßnahmen zur nadelstichverletzung gekommen, müssen sofort folgende maßnahmen ergriffen werden: blutung anregen und die möglichst gespreizte wunde mit einem desinfektionsmittel auf alkoholbasis gründlich desinfizieren (ca. min). bei hautkontakt ebenfalls desinfizieren oder gründlich mit seife und viel wasser waschen. handelt es sich um eine verletzung mit hohem risiko (injektion von größeren mengen blut, intramuskuläre verletzung mit großlumiger nadel), sollte eine antiretrovirale kombinationstherapie rasch begonnen (optimal innerhalb von - h nach verletzung) und für tage durchgeführt werden. bei verletzungen mit geringerem risiko (z. b. subkutane verletzung) sollte eine individuelle beurteilung und beratung durch jemanden mit spezieller erfahrung in diesem bereich erfolgen. wichtig sind in allen situationen, in denen ein infektionsrisiko aufgetreten ist, eine psychologische betreuung der betroffenen personen und die exakte dokumentation des unfallhergangs einschließlich der hiv-tests (zeitpunkte , wochen, und monate), damit ansprüche des betroffenen im falle einer infektion gewahrt bleiben. als folge der durch hiv ausgelösten immunschwäche kommt es zum auftreten so genannter opportunistischer infektionen. typisch für viele opportunistische erreger ist, dass sie weit verbreitet sind und nach einer primärinfektion, die bereits vor der hiv-infektion stattfindet, zu latenten infektionen führen. diese erreger werden erst durch die immunschwäche zu pathogenen (daher die bezeichnung opportunistisch). alle organe können von diesen infektionen betroffen werden. am häufigsten treten erkrankungen der haut, der mundhöhle, des gastrointestinaltraktes, der lunge, des auges und des nervensystems auf. einige der opportunistischen infektionen kommen bereits vor, wenn die cd + -zellen noch nicht maximal erniedrigt sind (zwischen und /μl). beispiele hierfür sind die candida-Ösophagitis und die pneumocystis-carinii-pneumonie. andere erkrankungen sind charakteristisch für das endstadium der immundefizienz (cd + -zelien < /μl). neben infektionen treten auch verschiedene tumoren gehäuft auf (kaposi-sarkom, non-hodgkin-lymphome). ii ein -jähriger, der bis dahin nie krank war, stellt sich in der notaufnahme vor. seit wochen bemerkt er fieber, das in den letzten wochen täglich °c überschreitet. er klagt über quälenden reizhusten mit wenig auswurf, der auch nachts sehr heftig sei. in den letzten wochen habe er kg gewicht abgenommen (von auf kg). bis zum vortag habe er gearbeitet, was ihm in den letzten tagen sehr schwer gefallen sei. bei nachfrage gibt er an, homosexuelle kontakte zu haben, ein hiv-test sei nie durchgeführt worden. bei der untersuchung fallen eine tachypnoe ( /min) und eine ausgeprägte periphere zyanose auf. auskultation und perkussion sind unauffällig. im mund besteht ein soor. zervikal, inguinal und axillär lassen sich vergrößerte lymphknoten (bis , cm) tasten. ansonsten keine auffälligkeiten. labor: hb , g/dl; leukozyten /μl; ldh u/l; in der arteriellen blutgasanalyse po mmhg, pco mmhg, ph , ; sonst keine weiteren auffälligkeiten. röntgen-thorax: ausgeprägte interstitielle infiltrationen in beiden lungenflügeln, z. t. auch alveoläre verschattungen. klinische diagnose: interstitielle pneumonie, dringender verdacht auf pneumocystis-carinii-pneumonie. therapie: sofortige behandlung mit hochdosiertem cotrimoxazol und mit ceftriaxon; ferner gabe von prednison. symptomatisch verabreichung von o per nasensonde, behandlung des soors mit amphotericin-b-suspension. weiterführende diagnostik: hiv-serologie im elisa und westernblot positiv; hiv-rna im plasma copies/ml; cd + -lymphozyten /μl, cd + -lymphozyten /μl; in der bronchoalveolären lavage nachweis von pneumocystis carinii. verlauf: allmählicher rückgang der klinischen symptomatik; nach diagnosesicherung der pcp absetzen von ceftriaxon und behandlung mit co-trimoxazol über wochen. danach einleitung einer antiretroviralen therapie, fortführung der co-trimoxazol-gabe in prophylaktischer dosierung und entlassung in deutlich gebessertem zustand. ii das spektrum der hautveränderungen im rahmen der hiv-infektion umfasst: • infektiöse veränderungen • allergische reaktionen • sog. idiopathische hauterkrankungen. häufig sind herpes-simplex-virus-infektionen, die als harmlose infektionen, aber auch als schwere, chronische ulzerationen imponieren können. varicella-zoster-virus-reaktivierungen (gürtelrose) treten typischerweise schon in frühen stadien der hiv-infektion auf und erstrecken sich häufig über mehrere dermatome. die behandlung der herpesvirusinfektionen kann mit aciclovir, valaciclovir, famciclovir oder brivudin erfolgen. eine andere häufige virusinfektion sind die dellwarzen (mollusca contagiosa), die sehr charakteristisch sind und oft ausgedehnte körperareale befallen (› kap. . ). im analbereich kommen gehäuft feigwarzen (condylomata acuminata) vor. die infektionen mit herpes-simplex-und varicella-zoster-virus werden mit aciclovir behandelt. bei dellwarzen und feigwarzen müssen kürettagen angewendet werden. bakterielle infektionskrankheiten, die bei hiv-infizierten vermehrt diagnostiziert werden, umfassen pyodermien, lues und bazilläre angiomatose. letztere wird durch die erst kürzlich entdeckten erreger bartonella henselae und quintana verursacht und äußert sich in form rötlicher, papulöser hautveränderungen. es kann ferner ein disseminierter organbefall vorkommen. die therapie erfolgt mit penicillin (lues), mit staphylokokken-wirksamen antibiotika (pyodermie) und mit makroliden (bazilläre angiomatose). allergische reaktionen und andere hauterkrankungen neben allergischen reaktionen treten gehäuft psoriasis vulgaris, seborrhoisches ekzem, xerodermie und papulöse dermatitiden auf. außer durch dermatologische lokalbehandlung bessern sich diese erkrankungen oft durch verbesserung der immunsituation im rahmen einer erfolgreichen antiretroviralen therapie. die symptomatik reicht von asymptomatischen veränderungen bis zu schmerzhaften läsionen, die eine nahrungsaufnahme fast unmöglich machen (therapie siehe oben). erkrankungen des gastrointestinaltraktes sind häufig bei fortgeschrittener hiv-infektion. im folgenden sind die häufigsten opportunistischen erkrankungen aufgeführt. hinzu kommen einige seltene infektionen und andere erkrankungen, die nicht spezifisch für die hiv-infektion sind. häufigste aids-definierende opportunistische infektion des gastrointestinaltraktes. symptome dysphagie und retrosternale schmerzen, meist auch candida-beläge in der mundhöhle. diagnostik Ösophagoskopie mit dem makroskopischen bild weißer schleimhautbeläge und mikrobiologischer oder histologischer nachweis von candida. therapie fluconazol. nach erfolgreicher behandlung treten häufig rezidive auf. dann ist eine prophylaktische behandlung mit fluconazol indiziert. bei den seltenen fällen einer fluconazol-resistenz wird voriconazol eingesetzt. diese infektionen treten meist bei sehr weit fortgeschrittenem immundefekt (cd + -zellen < /μl) auf und betreffen v. a. gastrointestinaltrakt und auge. erkrankungen des gastrointestinaltraktes durch cmv können in allen abschnitten vorkommen: als Ösophagitis, gastritis, enteritis, kolitis und als proktitis. symptome die Ösophagitis verursacht eine dysphagie. bei der cmv-gastritis stehen oberbauchschmerzen im vordergrund. die cmv-enterokolitis manifestiert sich mit durchfällen und bauchschmerzen. bei der cmv-proktitis sind defäkationsschmerzen und blutbeimengungen im stuhl die führenden symptome. diagnostik endoskopische untersuchung mit biopsie. makroskopisch sieht man eine entzündung der schleimhaut und ulzerationen, die wie ausgestanzt wirken. histologisch ist der nachweis von intranukleären einschlusskörperchen in vergrößerten zellen (eulenaugen-zellen) typisch. die abgrenzung von anderen viralen infektionen ist durch die immunhistologie (nachweis viraler antigene) möglich. der nachweis des cmv-pp -antigens im blut und die cmv-pcr aus dem blut geben hinweise auf die diagnose. therapie zurzeit sind substanzen verfügbar: ganciclovir, cidofovir und foscarnet. sie müssen intravenös verabreicht werden und sind in ihrer wirksamkeit vergleichbar. unterschiede bestehen in den nebenwirkungen: ganciclovir ist hämatotoxisch (leukopenie, anämie), während bei foscarnet und cidofovir die nephrotoxizität im vordergrund steht. in schweren fällen können ganciclovir und foscarnet kombiniert gegeben werden kryptosporidien sind protozoen, die bei tieren und bei menschen durchfallerkrankungen auslösen können. sie werden vor allem durch kontaminiertes wasser übertragen. bei immunkompetenten kommt es zu einer milden, selbstlimitierten diarrhö. symptome hiv-patienten mit ausgeprägter immunschwäche erkranken an schwersten wässrigen durchfällen, die den patienten häufig tag und nacht quälen. infolgedessen kommt es zur auszehrung ("wasting syndrom"). diagnostik die kryptosporidien finden sich an der oberfläche des darmepithels und können dort histologisch nachgewiesen werden. nachweis von oozysten im stuhl, darstellbar mit spezialfärbungen. therapie nicht bekannt. besserung erfolgt meist mit der einleitung einer antiretroviralen therapie. symptomatische maßnahmen (loperamid, opiumtinktur) müssen häufig angewandt werden. mikrosporidien sind obligat intrazelluläre, sporenbildende protozoen. von den mehr als spezies sind bisher als menschenpathogen bekannt. spezies stehen bei hiv-infektion im vordergrund: enterocytozoon bieneusi infiziert darm und gallengänge. die symptome sind von denen bei der kryptosporidien-infektion nicht unterscheidbar. encephalitozoon verursacht eine allgemeininfektion. die diagnose einer mikrosporidiose erfordert spezielle techniken (fluoreszenztest) und ist aus stuhl oder abstrichen und sekreten möglich. die speziesdifferenzierung ist durch elektronenmikroskopie oder pcr möglich und von therapeuti-scher bedeutung: während encephalitozoon auf eine therapie mit albendazol anspricht, ist für enterocytozoon bieneusi keine wirksame therapie bekannt. das wasting-syndrom ist definiert durch eine gewichtsabnahme von mehr als % des ausgangsgewichtes, verbunden mit anhaltendem fieber oder chronischer diarrhö ohne erregernachweis. diagnostik behandelbare opportunistische infektionen müssen ausgeschlossen werden. therapie die antiretrovirale therapie führt meist zur besserung. wie alle opportunistischen infektionen sind lungenmanifestationen in den letzten jahren seltener geworden. nach wie vor stellt die pneumocystis-pneumonie als akut lebensbedrohliche infektion häufig die erstmanifestation von aids dar. die tuberkulose ist weltweit die häufigste todesursache hiv-infizierter menschen. epidemiologie weltweit ist die tuberkulose mit abstand die häufigste opportunistische infektion im rahmen der hiv-infektion. ihre größte verbreitung hat sie in den unterentwickelten ländern. aber auch in südeuropa kommt sie sehr häufig vor. an tuberkulose ist besonders zu denken bei drogenabhängigen und bei patienten aus ländern der dritten welt. die lunge ist meist betroffen, doch handelt es sich bei der tuberkulose hiv-infizierter oft um ein disseminiertes krankheitsbild mit befall unterschiedlichster organe. symptome unspezifisch mit fieber, nachtschweiß, gewichtsabnahme und husten. röntgenologisch finden sich an der lunge typische verläufe im sinne einer reaktivierung mit kavernösen veränderungen und atypische verläufe mit flächenhaften infiltraten und mediastinalen lymphknotenschwellungen. diagnostik eine tuberkulose muss bei allen pulmonalen infiltraten bei hiv-infizierten patienten ausgeschlossen werden. die definitive diagnose wird mit der sputumuntersuchung durch den nachweis säurefester stäbchen gestellt, evtl. ferner untersuchung des magensekrets oder bronchoskopie. zur unterscheidung von ubiquitären mykobakteriosen (mycobacterium-avium-komplex) ist eine mikrobiologische differenzierung nötig. therapie dieselben substanzen wie bei nicht-hiv-infizierten patienten (› kap. . ) meist über insgesamt monate, bei komplizierten fällen auch länger. das ansprechen auf die therapie ist allgemein gut. multiresistente tuberkuloseerreger kamen in einigen amerikanischen großstädten bei hiv-infizierten gehäuft und mit sehr hoher letalität vor. in deutschland sind solche infektionen bisher nicht aufgetreten. wichtigste maßnahme zur verhütung von resistenzbildungen ist eine konsequente und effektive therapie. hervorgerufen durch den ubiquitär vorkommenden pilz (früher als protozoon klassifiziert) pneumocystis jiroveci (früher pneumocystis carinii, daher die abkürzung pcp). bereits im kindesalter besteht fast hundertprozentige durchseuchung, so dass das risiko einer erkrankung nur vom ausmaß des immundefektes abhängt. ohne prophylaktische maßnahmen beträgt die inzidenz für patienten mit cd + -zellen < /μl ca. diagnostik ein klinischer verdacht auf pcp muss sofort weiter abgeklärt werden. bei der körperlichen untersuchung finden sich häufig zyanose und tachypnoe. der auskultationsbefund ist aber typischerweise normal. im röntgenbild des thorax sieht man eine interstitielle zeichnungsvermehrung, in schweren fällen können auch alveoläre verschattungen auftreten (› abb. . ). obligate blutuntersuchungen sind die bestimmung der ldh (erhöht) und eine arterielle blutgasanalyse (erniedrigung des po ), da beide parameter prognostische aussagekraft haben. die leukozyten sind meist nicht vermehrt. bei patienten mit den aufgeführten diagnostischen kriterien kann die klinische diagnose einer pcp gestellt werden. die definitive diagnose wird durch den erregernachweis (immunfluoreszenz oder andere färbetechniken) aus der bronchoalveolären lavage (bal) gestellt. therapie bei verdacht auf pcp muss sofort eine therapie eingeleitet werden. dies steht einer späteren diagnosesicherung nach wenigen tagen nicht im wege. mittel der wahl ist co-trimoxazol in hoher dosierung ( mg trimethoprim, mg sulfamethoxazol/kg kg und pro tag). die therapiedauer beträgt normalerweise wochen. bei schweren unverträglichkeitserscheinungen (allergie) muss auf intravenös verabreichtes pentamidin ausgewichen werden. eine pcp mit arteriellem ausgangs-po von mmhg oder weniger muss zusätzlich mit prednison ( -mal mg/d) behandelt werden, da so die letalität vermindert wird. unbehandelt ist eine pcp immer letal. auch bei optimaler behandlung handelt es sich um eine ernste erkrankung. ungünstige prognostische parameter sind eine ausgeprägte erniedrigung des po und eine starke erhöhung der ldh. patienten mit beatmungspflichtiger respiratorischer insuffizienz haben eine schlechte prognose. bakterielle pneumonien treten schon bei einer helferzellzahl über /μl auf, werden aber mit zunehmendem immundefekt häufiger. drogenabhängige sind öfter betroffen als homosexuelle patienten. häufigste erreger sind pneumokokken, haemophilus influenzae, staphylokokken und gramnegative erreger. symptome wie bei pneumonien bei immunkompetenten personen (› kap. . . ). diagnostik von der pcp ist die bakterielle pneumonie bei typischem verlauf durch raschen beginn, purulentes sputum, positiven auskultationsbefund und durch die röntgenuntersuchung abzugrenzen. es gibt aber häufig atypische verläufe, die eine klinische unterscheidung unmöglich machen. therapie bei leichtem verlauf mit cephalosporin der . generation bzw. ampicillin plus lactamasehemmer, bei schwerem verlauf kombinationstherapie mit cephalosporinen der . generation und einem makrolid oder mit einem chinolon mit pneumokokken-wirksamkeit (moxifloxacin, levofloxacin). bis zum ausschluss einer pcp sollte bei schweren pneumonien auch co-trimoxazol gegeben werden. pneumonien durch pilze kommen insgesamt selten bei hiv-infizierten vor. aspergillus-pneumonien treten im endstadium des immundefektes auf und haben eine schlechte prognose. infektionen mit kryptokokken manifestieren sich gelegentlich an der lunge, meist jedoch erst bei weiterer disseminierung als fungämie oder meningitis. andere pulmonale pilzinfektionen sind in europa sehr selten. candida-pneumonien werden bei hiv-infizierten nicht beobachtet. virale pneumonien sind ebenso sehr selten. zytomegalievirus wird zwar häufig in der lunge nachgewiesen, es handelt sich aber fast immer um eine infektion ohne krankheitswert. symptome des zentralen und des peripheren nervensystems treten im rahmen der hiv-infektion sehr häufig mit sehr vielgestaltigen ursachen auf. neurologische symptome können durch hiv selbst, durch opportunistische erkrankungen oder als unerwünschte wirkungen therapeutischer maßnahmen auftreten. die differentialdiagnose ist daher sehr schwierig. ca. % der bevölkerung sind mit dem protozoon toxoplasma gondii infiziert. als opportunistische infektion im rahmen der hiv-infektion tritt die toxoxplasmose aber nur bei schwer eingeschränktem immunstatus auf (cd + -zellen < /μl). als zeichen der früher erfolgten infektion finden sich antikörper im serum. bei fehlenden igg-antikörpern ist eine toxoplasmose sehr unwahrscheinlich. symptome die zerebrale toxoplasmose äußert sich in fieber, kopfschmerzen, neurologischen ausfällen und epileptischen anfällen. diagnostik nachweis von typischen veränderungen in der kernspintomografie oder computertomografie des schädels möglich (› abb. . ). therapie pyrimethamin und sulfadiazin. bilden sich die veränderungen hierunter zurück, ist die diagnose bestätigt. eine prophylaxe mit verminderter dosis ist wegen hoher rezidivgefahr anzuschließen. wenn sich die erkrankung unter der therapie nicht bessert, sollte eine stereotaktisch gewonnene biopsie erfolgen zum ausschluss anderer erkrankungen (z. b. lymphom). durch den hefepilz cryptococcus neoformans kann eine meningitis ausgelöst werden. diese infektion kommt v. a. in afrika und den usa häufig vor, bei uns ist sie seltener. symptome kopfschmerzen und fieber, oft über wochen progredient. diagnostik bestimmung des kryptokokken-antigens im serum mit sehr hoher sensitivität. zum ausschluss einer anderen meningitisform muss eine punktion des liquor cerebrospinalis durchgeführt werden, in dem sich die kryptokokken durch ein tuschepräparat nachweisen und kulturell anzüchten lassen. therapie amphotericin b und flucytosin und zusätzlich evtl. fluconazol. ca. / der erwachsenen patienten und / der kinder weisen symptome einer hiv-enzephalopathie auf. sie wird vermutlich durch direkte infektion des zns mit hiv verursacht und führt zu psychomotorischen störungen unterschiedlichen schweregrades. symptome das klinische bild ist sehr variabel. meist stehen konzentrations-und gedächtnisstörungen bis hin zur ausgeprägten demenz im vordergrund, aber auch epileptische anfälle und wesensveränderungen kommen vor. diagnostik nur durch den ausschluss anderer zns-manifestationen möglich. im liquor finden sich nur unspezifische veränderungen, in der kernspintomografie kann eine hirnatrophie erkennbar sein. therapie antiretrovirale behandlung. dabei gibt es verschiedenartige verläufe von der vollständigen rückbildung bis hin zur weiteren progredienz der veränderungen. die progressive multifokale leukenzephalopathie (pml) ist eine meist innerhalb von wochen bis monaten zum tode führende erkrankung des zns, die durch polyoma-viren (jc-virus) ausgelöst wird. charakteristisch sind zunehmende neurologische störungen bei meist erhaltenem bewusstsein und ausgedehnte läsionen im marklager, die sich am besten in der kernspintomographie darstellen. die diagnose kann durch pcr aus dem liquor oder durch hirnbiopsie gestellt werden. unter hochaktiver antiretroviraler therapie kommt es bei einem teil der patienten zur besserung. die cmv-enzephalitis ist eine meist rasch progredient verlaufende zerebrale infektion, die klinisch nicht von anderen enzephalitiden zu unterscheiden ist. die diagnose kann durch eine pcr aus dem liquor untermauert werden, die therapie erfolgt mit foscarnet oder ganciclovir. das zerebrale lymphom ist eine opportunistische erkrankung im endstadium der hiv-infektion. die diagnose kann heute mit hoher wahrscheinlichkeit durch den nachweis von ebv-dna im liquor cerebrospinalis mittels pcr erfolgen. eine definitive sicherung ist nur durch hirnbiopsie möglich. kurzfristige therapieerfolge können mit dexamethason erzielt werden. eine systemische chemotherapie ist nicht wirksam, und auch eine bestrahlung führt meist nur zur sehr kurzfristigen remission. bei der polyneuropathie handelt es sich um eine erkrankung, die sehr häufig in späten stadien der hiv-infektion auftritt. neben einer direkten neuropathischen wirkung des hiv kommen toxische wirkungen von medikamenten ursächlich in frage. die diagnose wird meist klinisch gestellt, elektroneurografische untersuchungen können ggf. zusätzlich erfolgen, ist die polyneuropathie medikamentös ausgelöst, kommt es nach absetzen zur besserung. andernfalls bestehen die beschwerden meist fort. die therapie ist symptomatisch (gabapentin, amitriptylin, carbamazepin). neurotoxische substanzen (d t, ddi) müssen abgesetzt werden. die zytomegalievirus(cmv)-retinitis tritt bei patienten mit sehr schwerem immundefekt auf (cd + -zell-zahlen unter /μl). symptome verschwommenes sehen und sehminderung. unbehandelt führt die erkrankung zur erblindung. diagnostik spiegelung des augenhintergrundes mit charakteristischem befund. therapie intravenöse infusionen von ganciclovir, foscarnet oder cidofovir werden eingesetzt. viele der infektionen, die bei aids-patienten auftreten, verlaufen als disseminierte infektionen. dies gilt auch für einen teil der oben beschriebenen erkrankungen (z. b. cmv-infektion, tuberkulose). im folgenden werden diejenigen infektionen vorgestellt, die primär als generalisierte erkrankung durch den erregernachweis im blut diagnostiziert werden. in der regel manifestieren sich diese infektionen als sepsis, d.h mit klinischen symptomen (fieber, tachykardie, tachypnoe) und nachweis von bakterien im blut (bakteriämie). oftmals treten bakteriämien im zusammenhang mit intravenös platzierten kathetern auf. hier spielen vor allem staphylokokken, aber auch gramnegative keime wie pseudomonas aeruginosa eine rolle. pneumokokken-bakteriämien kommen im zusammenhang mit pneumonien vor. eine aids-definierende, selten auftretende komplikation ist die rezidivierende salmonellen-sepsis. diagnostik die blutkultur ist entscheidende maßnahme. therapie die behandlung erfolgt jeweils mit wirksamen antibiotika (antibiogramm). prognose neben der rechtzeitigen diagnose und der antibiotika-sensitivität des erregers ist der allgemeinzustand des patienten ausschlaggebend. mycobacterium avium und intracellulare bilden den mycobacterium-avium-komplex und kommen ubiquitär in der umwelt vor. bei immunkompetenten verursachen sie nur ganz selten infektionen. dagegen ist die disseminierte mac-infektion eine der schwersten infektionen bei hiv-patienten mit hochgradigem immundefekt (cd + -zellen < /μl). die aufnahme des erregers erfolgt entweder über den magen-darm-trakt oder über die lunge. hier kommt es zunächst zur kolonisierung und im weiteren verlauf zur disseminierung. der nachweis des erregers aus sputum oder stuhl beweist noch keine disseminierte infektion. symptome die disseminierte infektion äußert sich durch fieber, nachtschweiß, gewichtsabnahme, durchfälle, lymphknotenschwellungen, bauchschmerzen und eine hepatosplenomegalie. diagnostik die laborwerte zeigen meist eine anämie und eine erhöhung der alkalischen phosphatase. die diagnose lässt sich durch die anzüchtung des erregers aus der blutkultur oder anderen sterilen materialien (knochenmark, lymphknoten, leber) sichern. im gegensatz zur tuberkulose sind lungeninfiltrate durch mac selten. therapie auf die herkömmlichen antituberkulotika kann man nicht zurückgreifen, da der erreger gegen die meisten dieser mittel primär resistent ist. am wirksamsten ist eine kombination aus clarithromycin und ethambutol (eventuell zusätzlich mit rifabutin). als hiv-assoziierte tumoren (kategorie cdc c) werden das kaposi-sarkom (s. o.), das non-hodgkin-lymphom und das invasive zervixkarzinom gezählt. non-hodgkin-lymphome (nhl) treten bei ca. - % aller aids-patienten auf. histologisch handelt es sich meist um hochmaligne b-zell-lymphome. ein disseminierter und extranodaler befall liegt häufig vor. symptome entsprechend dem befallsmuster: lymphknotenschwellungen und allgemeinbeschwerden (fieber, nachtschweiß) sind häufig; bei knochenmarkbefall kommt es zur panzytopenie, bei befall des magen-darm-traktes zu bauchschmerzen und gewichtsabnahme. im labor findet sich oft eine erhöhung der ldh. bei zns-befall kommt es zum auftreten neurologischer herdsymptome (anfälle, lähmungen). eine besonderheit ist das auftreten primärer zerebraler lymphome, die immer durch ebstein-barr-virus (ebv) ausgelöst sind (diagnostik durch nachweis von ebv-dna mittels pcr im liquor). therapie durchführung einer standard-chemotherapie (chop-schema: cyclophosphamid, adriamycin, vincristin, prednison). ziel ist heute die komplette remission und heilung auch in fortgeschrittenen stadien und bei fortgeschrittenem immundefekt. hierzu werden zunehmend auch aggressive therapieschemata eingesetzt. prognose nicht gut (heilung in < %). maligne tumoren, die durch humane papillomaviren (hpv) induziert werden, wurden bei hiv-patienten gehäuft beobachtet. hierzu zählen das zervixkarzinom der frau und plattenepithelkarzinome der analregion. außerdem wurde über vermehrtes auftreten von hodgkin-lymphomen berichtet. die prophylaxe von infektionen bereits vor deren erstem auftreten (primärprophylaxe) oder nach der ersten episode (sekundärprophylaxe) ist weiterhin eine wichtige aufgabe bei der betreuung hiv-positiver patienten, auch wenn opportunistische infektionen durch die antiretrovirale therapie insgesamt seltener geworden sind. klinisch von bedeutung ist die prophylaxe der pcp bei einer cd + -zell-zahl von < /μl mit cotrimoxazol. die beste vorbeugung aller opportunistischen infektionen ist eine wirksame antiretrovirale kombinationstherapie (haart). durch die verbesserte funktion des immunsystems ist ein schutz gegen opportunistische infektionen vorhanden. in vielen studien wurde nachgewiesen, dass patienten mit supprimierter viruslast ein sehr niedriges risiko für opportunistische infektionen aufweisen. steigen die cd -zellen dauerhaft auf > /μl an, können meist primär-und sekundärprophylaxen abgesetzt werden. patienten, die trotz antiretroviraler therapie deutlich unter helferzellen/μl bleiben, müssen dagegen weiter prophylaktisch behandelt werden. viren erreichen den zustand der persistierenden infektion durch unterschiedliche strategien. beim herpes-simplex-virus (humanes α-herpesvirus) kommt es z. b. nach primärinfektion an haut oder schleimhäuten mit lokaler virusvermehrung (produktive infektion) zur zunächst ebenso produktiven infektion zugehöriger sensibler ganglienzellen. im ganglion geschieht dann die "umschaltung" in eine latente infektion, die durch fehlende virusproduktion und jegliches fehlen von viruspartikeln gekennzeichnet ist. das virale dna-genom bleibt extrachromosomal bei minimaler expression einzelner gene in den ganglien. durch bestimmte triggermechanismen (son- bei zytozidaler virusinfektion kommt es am ende des virusvermehrungszyklus zum tod der wirtszelle. es gibt persistierende und nicht persistierende viren, bei denen aus der weiterhin vitalen wirtszelle nachkommen-viruspartikel ausgeschleust werden. während die folgen einer zytozidalen infektion für den organismus entsprechend dem "alles-odernichts-prinzip" wesentlich von art und anzahl der direkt zerstörten zellen abhängen, kommt es bei nichtzytozidalen virusinfektionen eher zu störungen der wirtszellregulation (z. b. embryopathie oder onkogenese) oder auch sekundär zur immunpathogenese. viele viren sind in der lage, durch gezielte modulation der wirtszell-genexpression abwehrmechanismen der zelle und des organismus (immunsystem, apoptose) zu unterlaufen (sog. immunevasion). . und › abb. . ). die größe der einzelnen gruppen ist je nach erreger, prophylaktischen maßnahmen (z. b. impfungen) und therapiemöglichkeiten sehr verschieden. vereinzelt können persistierend mit hepatitis-b-virus infizierte patienten noch nach jahren die infektion beenden (serokonvertieren) und so aus der gruppe der persistierend infizierten in die gruppe der immunen wechseln. aus der gesamtpopulation (gelb) treten individuen nach infektion in die gruppe der akut infizierten (rosa). der weitere verlauf hängt davon ab, ob viren persistenzmechanismen entwickelt haben, und von der fähigkeit des wirts, eine protektive immunantwort zu bilden. die manifestationsrate bestimmt den anteil der erkrankten und die letalität den der verstorbenen. bei verlust der spezifischen immunität aufgrund einer immunsuppression können zuvor immune in die erneut infizierbare gesamtpopulation oder selten sogar bei einigen viren (z. b. hepatitis-b-virus) in die gruppe der persistent infizierten zurückkehren. viele infektionen verlaufen beim immungesunden subklinisch. primärinfektionen und rekrudeszenzen können aber auch vielfältige erkrankungen hervorrufen. patienten mit immundefekten sind durch diese viren besonders bedroht. erstaunlicherweise sind die krankheitsbilder bei primärinfektion und reaktivierung nicht nur abhängig vom ausmaß, sondern auch von der art der immunsuppression. als beispiel sei die cmv-infektion genannt, die beim immunkompetenten meist asymptomatisch verläuft. bei hiv-infizierten patienten tritt cmv dagegen in erster linie als retinitis und gastroenteritis, beim knochenmarktransplantierten patienten als interstitielle pneumonie und beim nierentransplantierten als nephritis mit gefahr der abstoßung auf. herpesvirusinfektionen sind mit ausnahme von epstein-barr-virus (ebv) und hhv- bis hhv- der therapie durch verschiedene verfügbare antivirale substanzen gut zugänglich. das herpes-b-virus des rhesusaffen ist auch hochpathogen für den menschen (enzephalitis). herpes-simplex-virus typ und (hsv- , hsv- ) beschreibung und einteilung es handelt sich eigentlich eher um varianten eines serotyps, da serologisch erhebliche kreuzreaktionen bestehen. virusisolate sind relativ leicht typisierbar und inzwischen kann man auch zwischen hsv- -und hsv- -antikörpern unterscheiden. epidemiologie die primärinfektion mit hsv- findet mit gipfeln in der frühen kindheit und im jungen erwachsenenalter meist oral statt. die durchseuchung erwachsener mit hsv liegt weltweit je nach sozioökonomischer situation bei - %. die primärinfektion (erster kontakt eines organismus mit hsv) kann auch durch sexualkontakt, dann meist mit hsv- , erfolgen. bei bestehender oraler hsv- -infektion mit latenz in kranialen ganglien ist die erste infektion im genitale mit hsv- keine primärinfektion, sondern eine klinisch milder verlaufende exogene zweitinfektion (initiale infektion). die prävalenz von hsv- -antikörpern ist bei erwachsenen in verschiedenen kollektiven sehr unterschiedlich, aber stets geringer als bei hsv- . die virusvermehrung auf der schleimhaut (infektiosität) beginnt vor dem auftreten der symptome, und die virusausscheidung erfolgt durchschnittlich - tage lang (max. bis tage). im gegensatz zur hsv- -primärinfektion kommt es bei hsv- offenbar auch zur virämie. Ätiologie und pathogenese während der virusvermehrung auf der schleimhaut werden bereits frühzeitig auch nervenendigungen infiziert. Über axonalen transport ( der chronische, lokal destruierende mukokutane herpes simplex ist eine aids-manifestation; es entstehen z. b. größere perianale ulzera, die in der differentialdiagnose der klassischen venerischen infektionen durch ihre schmerzhaftigkeit von der lues abzugrenzen sind und einen belegten, weichen ulkusgrund aufweisen. die weitaus häufigste hsv-erkrankung ist der rekurrierende orale oder genitale herpes. beide haben beim immungesunden eine gute prognose, können aber zu erheblichen psychischen belastungen, bis hin zum suizid, führen. orale und genitale primärinfektionen können zu schweren erkrankungen führen, die frühzeitig und intensiv systemisch behandelt werden sollten. die rekurrierende ulzerative herpeskeratitis führt häufig zum visusverlust -ggf. mit der notwendigkeit einer hornhauttransplantation. enzephalitis, konnatale infektion und infektionen immunsupprimierter können sehr rasch zu lebensbedrohlichen erkrankungen führen und müssen daher schnellstmöglich intensiv behandelt werden. die virologische diagnose kann sehr schnell gestellt werden, wenn das geeignete material mit geeigneten methoden untersucht wird. in der akuten phase der mononukleose können - % der zirkulierenden b-zellen ebv-infiziert sein (polyklonale transformation). es treten teils heterophile autoantikörper auf, was diagnostisch genutzt wird (paul-bunnell-test). im regelfall werden die ebv-infizierten b-zellen durch das intakte immunsystem (t-zellen) eliminiert, dies gelingt aber nicht vollständig, sondern es verbleiben einige latent infizierte b-zellen mit der möglichkeit der reaktivierung im späteren leben (s. u.). eine assoziation des burkitt-lymphoms mit ebv ist aufgrund molekularbiologischer und seroepidemiologischer daten gesichert. ebenso eindeutig ist der zusammenhang zwischen ebv und dem nasopharynxkarzinom (npc), das endemisch in einigen gegenden afrikas und v. a. in südchina vorkommt. mit zunehmendem alter wird das bild der infektiösen mononukleose (im) häufiger beobachtet: sie geht einher mit fieber, pharyngitis und tonsillitis mit gräulichen belägen, generalisierter oder zervikookzipital betonter lymphadenopathie, exanthem (selten enanthem), hepatitis und splenomegalie. das fieber dauert ca. - tage an und fällt wieder ab. es besteht eine kutane anergie wie beim morbus boeck, bei fortgeschrittener hiv-infektion und anderen schweren krankheitsbildern (disseminierte tuberkulose). eine restsymptomatik (subfebrile temperaturen, müdigkeit) kann monatelang anhalten. eine produktive ebv-infektion ist häufig als orale haarleukoplakie am seitlichen zungenrand bei aids und anderen schweren immundefekten nachweisbar. chronisch aktive ebv-infektionen mit lang anhaltenden, rezidivierenden organsymptomen wurden mit familiärer häufung beschrieben. es ist bislang unklar, ob in diesen fällen ein genetischer defekt oder eine besondere virusvariante verantwortlich ist. erkrankungen der blutzellen und immunorgane eine massive b-zell-proliferation mit nachfolgender kontrolle durch induzierte spezifische t-zellen gehört zum krankheitsbild der im. beim "duncan-syndrom" sind die patienten aufgrund eines genetischen defektes nicht in der lage, diese proliferation zu kontrollieren. die latente ebv-infektion wird durch nicht produktiv infizierte b-lymphozyten aufrechterhalten, die durch den nachweis von ebna- (ebv-nukleäres antigen) charakterisiert sind. proteine, die von latent infizierten zellen gebildet werden können, sind für die rolle des ebv in der entstehung von tumoren verantwortlich. sehr gefürchtet ist das lymphozyten-proliferationssyndrom bei immunsupprimierten nach transplantation. ebv ist in b-zell-lymphomen bei hiv-infektion, nach organtransplantation und beim morbus hodgkin nachzuweisen. vor allem in asien kommt es gelegentlich zu einer ebv-induzierten überschießenden t-zell-aktivierung, die letztlich zum hämophagozytotischen syndrom führt. weitere organbeteiligungen eine beteiligung von ebv an erkrankungen, die von infektionen des lungenepithels im rahmen einer chronisch aktiven ebv-infektion ausgehen, bis hin zur beteiligung an der idiopathischen lungenfibrose ist vielfach diskutiert worden. myokarditiden können bei im auftreten und die bestimmenden beschwerden während der rekonvaleszenz sein. die pro gnose ist insgesamt gut. die benigne hepatitis mit mäßig erhöhten transaminasen ist typisch bei der primären ebv-infektion. vielfach werden chronische ebv-reaktivierungen als ursache von anhaltenden gastrointestinalen beschwerden und gelegentlich auch hepatopathien angenommen. inwieweit ein kausaler zusammenhang besteht, ist aber meist unklar und auch schwer zu klären, da ebv-reaktivierungen auch bei anderen grunderkrankungen vorkommen. besondere klinische bedeutung hat cmv für alle immuninkompetenten (untergewichtige frühgeborene, transplantatempfänger, tumorpatienten, aids-patienten). es existieren befunde, wonach cmv evtl. auch bei immungesunden in zellen der gefäßwände durch modulation der zellulären genexpression veränderungen hervorruft, die zur entstehung der atherosklerose und zur entwicklung der restenose beitragen. bei immundefizienten und immunsupprimierten hängt die schwere der erkrankung vom ausmaß der beeinträchtigung des immunsystems ab. mit zunehmender dysfunktion der t-zellen nehmen cmv-reaktivierungen und persistierende aktive cmv-infektionen zu. diese kündigen sich noch vor der klinischen manifestation einer cmv-erkrankung durch lang anhaltende intermittierende oder kontinuierliche cmv-ausscheidung meist im urin an. asymptomatische infektionen die primärinfektion verläuft bei immungesunden älteren kindern und erwachsenen in ca. % asymptomatisch. symptomatische infektionen sind klinisch von einer infektiösen mononukleose nicht zu unterscheiden. endogene reaktivierungen mit virusausscheidung, die von zeit zu zeit in abhängigkeit von der aktuellen immunkontrolle der infektion durch den organismus ablaufen, werden im allgemeinen nicht bemerkt. die infektion verläuft bei reifen neugeborenen auch asymptomatisch, ist aber von einer u.u. langen cmv-ausscheidung begleitet. hno-erkrankungen ca. % aller klinisch diagnostizierten mononukleosen sind cmv-bedingt. die klinischen zeichen treten nach einer inkubationszeit von - tagen auf. der verlauf ist gutartig; neben fieber, lymphadenopathie, pharyngitis bzw. tonsillitis, hepatitis, splenomegalie und exanthem treten selten blutbildveränderungen (leukopenie, relative lymphozytose mit lymphomonozytären reizformen, thrombopenie) und gelegentlich eine parotitis (dd mumps) auf. cmv bei immunsuppression und aids bei aids-patienten war die infektion vor der intensiven antiretroviralen therapie (haart) am häufigsten mit einer cmv-retinitis (› abb. . ) assoziiert, gefolgt von gastrointestinalen erkrankungen und enzephalitis. die aktiven cmv-infektionen bei - % der aids-patienten sind meist folge einer cmv-reaktivierung. die in anderen klinischen situationen bedeutsame diagnostische unterscheidung zwischen primärinfektion und reaktivierung spielt daher bei aids-patienten keine rolle. cmv-enzephalitiden wurden v. a. bei aids-patienten vor einführung von haart häufiger beobachtet. auch die interstitielle pneumonie ist eine der typischen cmv-erkrankungen, die meist bei erheblich immunsupprimierten transplantatempfängern auftritt. cmv-bedingte hepatitis ist häufig bei konnataler infektion, aber auch möglich bei virusreaktivierungen bei immunsupprimierten. gastrointestinale infektionen mit typischen, teils blutenden schleimhautulzera waren vor einführung der intensiven antiretroviralen therapie eine häufige erkrankung bei aids-patienten und werden gelegentlich bei anderen risikopatienten gefunden. ulzerationen können in allen abschnitten des gastrointestinaltraktes auftreten, vom Ösophagus bis zum enddarm (› abb. . ). cmv spielt eine wesentliche rolle bei nierentransplantierten. neben lang anhaltenden asymptomatischen virusausscheidungen mit dem urin kommt es zu nephritiden und transplantatabstoßungen. eine primäre und sekundäre thrombozytopenie, aber auch trizytopenie ist typisches symptom bei konnataler infektion und häufig erstes symptom einer cmv-reaktivierung bei knochenmarktransplantierten patienten. intrauterine und perinatale infektionen das krankheitsbild der konnatalen zytomegalie umfasst die in › tabelle . angegebenen symptome. hinzu kommen können weitere symptome, so auch zahnbildungsschäden. cmv ist heute hauptursache einer intrauterinen infektion des fetus ( , - , %). etwa % der intrauterin infizierten kinder zeigen das typische bild einer konnatalen zytomegalie (cid mit einschluss des zns: letalität bis % und häufig bleibende schäden). die prognose dieser kinder ist schlecht (gesamtletalität %). spätschäden (neurologische defizite, hörverlust) sind zu erwarten. weitere % der intrauterin infizierten haben geringfügige symptome bei der geburt, die prognose ist sehr viel besser, in % ist auch hier mit spätschäden zu rechnen (› tab. . ). fetale infektionen nach reaktivierter infektion bei der mutter führen sehr selten zu klinischen manifestationen, und wenn, dann mit deutlich schwächer ausgeprägter symptomatik als bei primärinfektionen und ohne spätfolgen. bei untergewichtigen frühgeborenen besteht auch nach postnataler infektion (z. b. durch muttermilch) ein hohes risiko, an einer schweren systemischen cmv-infektion zu erkranken. diagnostik bei verdacht auf eine cmv-pneumonie ist die röntgenologische untersuchung wichtig. für die diagnose einer aktiven cmv-infektion, aber auch für die bestimmung der prognose und für therapieindikation und -kontrolle stehen heute quantitative nachweismethoden für virale antigene und dna zur verfügung. • virusnachweis: die cmv-isolierung aus urin, bronchiallavage, speichel u.Ä. ist in humanen fibroblasten möglich, sie braucht im gegensatz zu hsv aber viel länger. hier kann der nachweis von early-virus-antigen -bereits vor dem erscheinen des zytopathischen effekts in der infizierten zellkultur -die diagnostik beschleunigen (shell vial culture). eine typische histopathologische veränderung sind die eulenaugenzellen, deren nachweis zwar sehr spezifisch, aber wenig sensitiv ist (› abb. . ). • nachweis viraler antigene: der quantitative nachweis von cmv-pp -antigen in polymorphkernigen leukozyten eignet sich zur früherkennung einer systemischen cmv-reaktivierung. das pp -antigen (s. o.) ist v. a. bei systemischen infektionen immunsupprimierter während der phase der antigenämie überwiegend in polymorphkernigen leukozyten (pmnl) und zirkulierenden endothelzellen zu finden und damit von großer diagnostischer bedeutung. • das verfahren zur isolierung von hhv- entspricht dem vorgehen beim versuch der retrovirusisolierung. hhv- wurde erstmals beim gesunden isoliert. mittlerweile ist gesichert, dass in allen untersuchten populationen erwachsene zu - % mit hhv- und hhv- infiziert sind, dass beide viren auch aus gesunden isoliert werden können und die durchseuchung in früher kindheit beginnt. offenbar erfolgt die hhv- -serokonversion später. die Übertragung geschieht sehr effektiv über den speichel: - % aller hhv- -infizierten scheiden hierüber das virus aus. im Übrigen dienen auch hier die lymphozyten als virusreservoir. die geschichte von hhv- zeigt einmal mehr, wie vorsichtig man bei der ätiologischen verknüpfung des nachweises eines ubiquitären virus mit spezifischen symptomen oder syndromen sein muss. Ätiologie und pathogenese Ätiologisch sind hhv- b und hhv- bei kindern verantwortlich für das exanthema subitum (dreitagefieber). ferner gibt es beschreibungen von schwereren krankheitsfällen. denkbar ist, dass, wie bei den anderen herpesviren, bestimmte immunologische voraussetzungen zu besonderer pathogenität führen. die klinische bedeutung von hhv- a ist noch unklar. bei immunkompetenten kindern ist das dreitagefieber oder exanthema subitum (es) eine der klassischen "kinderkrankheiten": nach dreitägiger fieberphase kommt es gleichzeitig mit der entfieberung zum stammbetonten kleinfleckigen exanthem. das es ist häufiger begleitet von Übelkeit, erbrechen und auch durchfall. bei erwachsenen kann es zum mononukleoseähnlichen krankheitsbild mit langer rekonvaleszenz kommen. bei immunsupprimierten kommen neurologische, pulmonale und hämatologische komplikationen vor. diagnostik im labor ist eine leukopenie mit relativer lymphozytose zu erkennen, eine thrombopenie kann ebenfalls vorliegen. • nachweis viraler genome: hhv- -dna kann während der akuten infektion durch pcr leicht aus lymphozyten und speichel nachgewiesen werden: nach Überstehen der primärinfektion geht die zahl der latent infizierten lymphozyten erheblich zurück, so dass die pcr im peripheren blut nur noch in % aller fälle ein positives ergebnis zeigt. durch quantitative pcr lässt sich ein reaktivierungsereignis diagnostizieren. • antikörpernachweis: die serodiagnostik ist in ihrer aussage durch die hohe durchseuchung von ca. % im . lebensjahr eingeschränkt. für die frische infektion kommen daher die igg-serokonversion und der igm-nachweis in frage -jedoch sind viele igm-nachweisverfahren qualitativ nicht zufrieden stellend. • virusisolierung: aus speichel und lymphozyten kann hhv- durch kokultivierung mit stimulierten nabelschnurlymphozyten isoliert werden: die anzucht ist auf wändig, gelingt aber auch bei gesunden virusträgern -und hier eher aus speichel als aus peripherem blut. therapie obwohl die wirksamkeit verschiedener nukleosidanaloga in vitro gezeigt werden konnte, gibt es keine guten daten zur klinischen wirksamkeit. symptomatische therapie. therapieversuche mit foscarnet oder nukleosidanaloga sind bei schweren erkrankungen immunsupprimierter patienten u.u. angezeigt. durch die entdeckung von hhv- und hhv- wurde endlich das alte rätsel des dreitagefiebers gelöst, von dem man schon seit langem annahm, dass es sich um eine infektionserkrankung handeln könnte. beim immungesunden erwachsenen kommt es gelegentlich zu schwereren, lang dauernden, mononukleoseähnlichen erkrankungen. einzelne fulminante hepatitiden wurden beobachtet. hhv- kann zu verschiedenen komplikationen bei immunsupprimierten patienten (pneumonie, enzephalitis) führen. beschreibung und einteilung humanes herpesvirus typ (hhv- ) wurde zunächst über pcr als herpesvirusspezifische genetische information in einem aids-assoziierten kaposi-sarkom (ks) entdeckt. es ließ sich dann als freies virus aus hhv- -assoziierten b-zell-lymphomen isolieren und als gamma-herpesvirus charakterisieren. epidemiologie antikörper gegen hhv- sind im elisa bei fast allen kaposi-sarkom-trägern, bei % der hiv-positiven homosexuellen und zum geringen prozentsatz bei blutspendern nachweisbar. damit ist hhv- offensichtlich nicht so verbreitet wie andere herpesviren. die antikörperprävalenz macht es wahrscheinlich, dass hhv- überwiegend durch sexualkontakte übertragen wird. pathogenese gamma-herpesviren wirken potenziell transformierend. hhv- -genom wird mit der pcr inzwischen auch in kaposi-sarkomen von therapeutisch immunsupprimierten transplantationspatienten, in spontanen kaposi-sarkomen und den relativ seltenen hhv- -assoziierten body-cavity-lymphomen nachgewiesen. kaposi-sarkome bestehen typischerweise aus einem gemisch proliferierender spindel-und endothelzellendie zur entstehung führenden mechanismen sind noch ungeklärt. enterovirusinfektionen kommen bei uns ganz überwiegend im sommer und herbst vor ("sommergrippe"). die aus-scheidung der enteroviren beginnt - tage nach infektion. sie kann einige tage lang oral erfolgen und für mehrere wochen fäkal. bei der Übertragung handelt es sich generell um eine enterale "schmutz-schmierinfektion", wobei in den ländern mit hohem hygienestandard die Übertragung durch rachensekrete bedeutsamer ist. sehr selten werden bei schweren immundefekten (z. b. bei agammaglobulinämie) dauerausscheider beobachtet. die paralytische poliomyelitis konnte während der letzten jahre in den westlichen industrieländern durch impfung im rahmen des who-eradikationsprogramms drastisch vermindert werden (europa - : ca. fälle jährlich, deutschland ist seit frei von infektionen, s. u.). die seroprävalenz der hepatitis-a-antikörper hat in deutschland seit dem zweiten weltkrieg ebenfalls stark abgenommen (kriegsgeneration bis zu % seropositiv, studenten heute < %); die bedeutung der hepatitis a als reiseerkrankung (entwicklungsländer) nimmt demzufolge zu. das hepatitis-a-virus wird im gegensatz zu anderen picornaviren, die auch oral ausgeschieden werden, nur fäkal und v. a. in der späten inkubationsphase ausgeschieden. pathogenese picornaviridae führen zu unterschiedlich stark ausgeprägter zytozidaler virusvermehrung, also in der regel zu nicht persistierenden infektionen. die partikelproduktion erfolgt zunächst in epithelzellen des nasen-rachen-raums bzw. magen-darm-trakts und in den regionalen lymphknoten und findet erst danach bei einigen picornaviren in typi- poliovirusinfektionen (je nach endemischer oder epidemischer situation - %) unterscheidet man verlaufsformen: • bei der abortiven poliomyelitis kommt es nach der inkubationszeit nur zu einer - tage anhaltenden "grippesymptomatik" (minor illness), wie sie viele enterovirustypen hervorrufen können. nach einer -bis -tägigen besserung kann es dann zu plötzlicher verschlechterung kommen (hauptkrankheit). • die meningitische poliomyelitis verläuft unter dem bild der prognostisch günstigen aseptischen meningitis, die ebenso durch viele andere enteroviren verursacht werden kann (sehr selten ist die perakute, letal verlaufende enzephalitis). zweiterkrankungen durch rhinoviren sind möglich, verlaufen aber milder. obwohl rhinovirusinfektionen bekanntlich gutartig verlaufen, besitzen sie angesichts der erkrankungshäufigkeit erhebliche ökonomische bedeutung ( bekannte serotypen und möglichkeit der reinfektion!). jeder mensch macht viele picornavirusinfektionen durch, meist subklinisch oder als milde erkrankung. schwere krankheitsbilder kommen -auch altersabhängig -vor. picornaviren verursachen einige charakteristische erkrankungen und viele uncharakteristische symptome und syndrome. enteroviren und hepatitis-a-virus hinterlassen eine belastbare typenspezifische immunität. bei rhinoviren sind symptomatische reinfektionen bekannt. picornaviren können bei kardiomyopathien und dem juvenilen diabetes mellitus ätiologisch beteiligt sein. viele picornaviren sind leicht isolierbar. die serologie ist wenig aussagekräftig. einige der vielen tierpathogenen picornaviren können den menschen infizieren. beschreibung und einteilung adenoviren sind nackte und sehr umweltresistente ikosaedrische partikel von - nm durchmesser (› abb. . ). sie enthalten doppelsträngige lineare dna. im genus der mastadenoviren gibt es subgenera a-f mit den zunächst serologisch definierten humanpathogenen virustypen - (hadv , … ). später wurde auch eine genotypische abgrenzung nach homologie der nukleotidsequenz festgelegt. diagnostik je nach manifestation (auge, gastrointestinaltrakt) müssen andere mikrobiologische erreger abgegrenzt werden. die diagnose stützt sich auf virusisolierung und kaum auf die serologie. • virusnachweis: die meisten adenoviren sind aus rachenspülwasser, augenabstrich, stuhl, urin, liquor und anderen proben leicht in zellkulturen zu isolieren. die schwer anzüchtbaren hadv und werden elektronenmikroskopisch oder im antigen-elisa nachgewiesen, der auch schon eine subgenusdiagnose ermöglicht. • nachweis viraler genome: die pcr ermöglicht den nachweis der virus-dna direkt aus klinischen materialien und sogar eine genotypspezifische diagnose. • antikörpernachweis: die serologie (komplementbindungsreaktion, kbr) gestattet die diagnose einer frischen infektion bei nachweis eines antikörperanstiegs, bei gastrointestinalen infektionen kommt es aber nicht immer zu diesem antikörperanstieg. differentialdiagnose picornaviren, aber auch andere respiratorische und gastrointestinale viren. wichtig ist die frühzeitige abgrenzung zur streptokokkentonsillitis. bei schweren adenoviruserkrankungen, v. a. auch bei immunsupprimierten, ist ein therapieversuch mit cidofovir oder ribavirin möglich und indiziert. ribavirin scheint vorwiegend wirksam gegen viren des subgenus c. komplikationen bei angeborenen oder erworbenen immundefekten können adenoviren auch sehr schwere disseminierte infektionen induzieren, die lunge, gastrointestinaltrakt, leber und zns betreffen und fatal verlaufen. adeno-und rotaviren können vereinzelt auch nach ende einer akuten infektion ausgeschieden und bei gesunden nachgewiesen werden, teils gemeinsam mit enteroviren. adenovirusausbrüche auf neugeborenenstationen können sehr schwer, mit hoher letalität verlaufen. • röteln • echo-virus- -infektion therapie und prophylaxe die therapie mit ribavirin wurde vereinzelt beschrieben und kann bei immundefekten sinnvoll sein. impfung die masern-lebendimpfung, gemäß impfkalender als mumps-masern-röteln-tripelvakzine (mmr) im . bis . lebensmonat und mit wiederholung im . lebensjahr, hat die zahl der masernfälle in deutschland im jahr auf zurückgehen lassen. der grad der durchimpfung reicht mit % aber nicht aus, um die mensch-zu-mensch-Übertragung ganz erlöschen zu lassen. das ziel der who, in europa bis zum jahr die masern auf weniger als erkrankung/ einwohner zu senken und den tod an masern auszurotten, erfordert immunitätsraten von > %, die mit einer einmaligen mmr-impfung nicht erreicht werden können. kürzlich ist es auch in deutschland wieder zu größeren masernausbrüchen gekommen. bei masernexposition ungeschützter personen ist ferner die passive immunisierung mit standard-serum-immunglobulin hilfreich (› kap. . ). angesichts der pathogenese ist es verständlich, dass die moderne masern-lebendimpfung auch vor der sspe schützt. häufigkeit masernpneumonie (als direkte folge der maserninfektion oder als folge einer bakteriellen superinfektion des geschädigten flimmerepithels) die disseminierung während der inkubation führt bei % zur klinisch und labormäßig fassbaren, aber prognostisch günstigen aseptischen meningitis, selten auch zur zerebellaren ataxie. eine enzephalitis ist selten und geht mit psychiatrischen und neurologischen spätschäden einher (verhaltensstörungen, krampfleiden, taubheit, retrobulbärneuritis, hydrozephalus). diagnostik der typische verlauf erleichtert die diagnose. • antikörpernachweis: serologisch lässt sich der antikörperanstieg mit hilfe der kbr nachweisen. die "kbr-antikörper" fallen allerdings - monate nach erkrankung unter die nachweisgrenze und sind daher zur immunitätsbestimmung ungeeignet. die frage der immunität wird durch nachweis virushüllenspezifischer antikörper im mumps-igg-elisa beantwortet. bei diagnose einer frischen infektion ist die untersuchung auf mumps-igm-antikörper im elisa die methode der wahl. • nachweis viraler genome: rt-pcr weist quantitativ hcv-rna nach und damit die aktive infektion. hcv-spezifische antikörper beweisen eine akute oder chronische, evtl. auch ausgeheilte infektion. der nachweis von hcv-genomen zeigt eine frische infektion, aber auch chronische carrier-zustände mit virusreplikation an; bei ausgeheilten hcv-infektionen wird die pcr negativ. die akute hcv-erkrankung ist meldepflichtig. therapie und prophylaxe therapie der chronischen hcv-infektion durch kombination von pegylierten alpha-interferonen mit nukleosidanaloga (› kap. . . ) . durch untersuchung von blut-und organspendern, ggf. auch von angehörigen von hochrisikogruppen auf hcv-antikörper kann die verbreitung des virus eingeschränkt werden. die symptomatische therapie (analgetika bei arthralgien) ist möglich. impfungen sind nur gegen gelbfieber, fsme und die japanische enzephalitis verfügbar. ein impfstoff gegen dengue-virus müsste alle serotypen erfassen, da teilimmunität gegen nur typ negative auswirkungen (immunenhancement) bei wildvirusinfektion mit einem weiteren serotyp haben kann. komplikationen bei dengue-fieber kommt es v. a. bei sequentieller infektion durch verschiedene serotypen zu schweren krankheitsverläufen. die affenpocken verlaufen beim menschen ähnlich, meist mit viel ausgeprägterer lymphadenopathie. beim ausbruch / in kongo/zaire waren von erkrankungen ca. % durch sekundäre mensch-zu-mensch-infektionen verursacht. das virus kann sich offenbar für begrenzte zeit in der fremden spezies mensch ausbreiten. andererseits war die rate an todesfällen unter den infizierten mit , % viel niedriger als die noch in den er jahren beobachtete rate von %, so dass die who zurzeit eine wiederaufnahme der auch vor affenpocken schützenden vakzinierung ablehnt. haut-und schleimhauterkrankungen das molluscum contagiosum (dellwarze) ist eine harmlose, auf den menschen beschränkte infektion der epidermis, die höchstens kosmetisch bedeutsam ist. nach einer inkubationszeit ( - wochen) wachsen meist multiple, wachsfarbene papeln von - mm durchmesser heran, die bindegewebig gut abgegrenzt sind und nach - monaten spontan zurückgehen. die voll ausgebildeten knötchen haben zentral eine pore, aus der sämiges, weißliches material ausgepresst werden kann. dieses enthält die elektronenoptisch nachweisbaren viren. sehr häufig erkranken kinder und immunsupprimierte (aids). die Übertragung, auch autoinokulation, erfolgt durch direkten kontakt oder durch gemeinsame handtuchnutzung. bei kindern findet man die veränderungen meist im gesicht und an den extremitäten, bei erwachsenen angesichts der sexuellen Übertragung am genitale und dessen umgebung. dellwarzen mit längerer persistenz werden mittlerweile häufig bei aids-patienten beobachtet. melkerknotenvirus (kuh) und orf-virus (schaf) sind primär tierische poxviren, mit denen sich andere tierspezies undmeist bei beruflicher exposition -auch menschen infizieren können. kuhpocken-und melkerknotenvirus (beide sind nicht antigenverwandt) werden von tieren durch direkten kontakt auf den menschen übertragen. betroffen sind meist die hände, wobei das kuhpockenvirus vesikuläre veränderungen, das melkerknotenvirus derbe, oft geschwürig zerfallende knoten verursacht. allgemeinsymptome und lymphangitis sind bei den kuhpocken häufiger. diagnostik bei klinischem verdacht kann der erreger leicht elektronenmikroskopisch als quadervirus aus der vesikelflüssigkeit dargestellt werden. vaccinia-, affen-und kuhpockenvirus lassen sich gut auf der chorioallantoismembran anzüchten und differenzieren. der nachweis von dellwarzen bei erwachsenen ist ungewöhnlich und weist auf eine störung der immunabwehr hin; ggf. sollte eine hiv-infektion ausgeschlossen werden. therapie und prophylaxe keine spezifische antivirale therapie bekannt. die pockenimpfung gegen variola major ist nach ausrottung der humanen pocken weltweit ausgesetzt worden. die pocken waren eine der großen menschheitsseuchen und stellen die . infektionskrankheit dar, die durch den menschen weltweit ausgerottet wurde. beschreibung und einteilung die ehemalige familie der papovaviridae (› abb. . ) wurde in selbstständige virusfamilien aufgeteilt, die papillomaviridae (durchmesser nm, genom kb) und polyomaviridae (durchmesser nm, genom kb). es handelt sich bei beiden um nackte, ikosaedrische partikel mit doppelsträngiger zirkulärer, superhelikaler dna. einige tierische papillomaviren induzieren tumoren, v. a. wenn sie in spezies inokuliert werden, die nicht natürliche wirte sind. epidemiologie die vermehrung der papillomaviren in konventionellen zellkulturen ist nicht möglich und eine typenspezifische serologie war nicht möglich. lange war dagegen bekannt, dass sie übertragbare warzen des menschen verursachen (› abb. . ). erst die molekulare genetik ermöglicht pathogenetische untersuchungen und molekulare epidemiologie. die papillomavirustypen sind so als genotypen definiert (< % sequenzhomologie = neuer typ). bisher unterscheidet man > hpv-genotypen, die vielfach den krankheitsbildern zugeordnet werden können. polyomaviren sind in form einer latenten infektion bei den meisten menschen vorhanden. pathogenese humane papillomaviren (hpv) verursachen persistierende infektionen. die ätiologische beteiligung bestimmter hpv-typen an der entstehung anogenitaler malignome ist gesichert. die primäre infektion mit den polyomaviren bkv und jcv bleibt meist unerkannt. sie verläuft häufig als milder respiratorischer infekt und führt bei bkv zur latenz in der niere, während das eher neurotrope jcv im zns -weniger ausgeprägt auch in der niere -latent wird. symptome, verlauf und prognose asymptomatische primärinfektionen mit polyomaviren sind die regel und mit papillomaviren sehr häufig. haut-und schleimhauterkrankungen warzen entstehen nach relativ langer inkubationszeit durch produktive virusinfektion mit hpv in den epithelzellen, wobei die virusvermehrung an differenzierung und keratinisierung der zellen gebunden ist. die normalen hautwarzen sind eine selbstlimitierende erkrankung. die seltene, familiär gehäuft auftretende epidermodysplasia verruciformis, assoziiert mit hpv und , zeigt beetartig verschiedene warzenformen, die in - % in ein plattenepithelkarzinom übergehen. hno-erkrankungen die juvenile larynxpapillomatose (hpv , ) ist eine hartnäckige und gefürchtete erkrankung, die möglicherweise auf einer infektion im infizierten geburtskanal der mutter beruht. die durch jcv bedingte progressive multifokale leukoenzephalopathie (pml) tritt bei schwer immunsupprimierten (maligne lymphome, v. a. morbus hodgkin, aids, transplantationspatienten) auf und spielt eine rolle in der differentialdiagnose der zerebralen non-hodgkin-lymphome und anderer demyelinisierender erkrankungen (multiple sklerose, lupus erythematodes mit zns-befall). es kommt an mehreren orten zu herden, die meist keine verdrängungserscheinungen verursachen, aber zu großen entmarkungsherden zusammenfließen können. die patienten zeigen zunehmende wesensveränderungen und kognitive störungen, die erkrankung führt monate nach den ersten neurologischen ausfällen zum tode. weitere erkrankungen schwere immundefekte können zur virurie und zystitis durch bkv führen. papillomavirusinfektionen führen zu spitzen kondylomen (hpv , , u. a.) und intraepithelialen dysplasien der cervix uteri und der vagina (hpv , , ). vergleichbare dysplasien sind auch am penis möglich. diagnostik warzen und kondylome werden klinisch leicht erkannt. anders hpv-assoziierte präkanzerosen, die als epitheldysplasien charakteristische zytologische veränderungen im abstrichpräparat ergeben (› abb. . ). hier können dna-und rna-hybridisierung hinweisend auf latente oder aktive infektion durch bestimmte hpv-typen sein. eine pml wird zunächst nach kernspintomographie vermutet und virologisch durch jcv-pcr im liquor oder sicherer im biopsat durch pcr oder elektronenmikroskopie diagnostiziert. bkv-infektionen sind häufig mit nierenerkrankungen assoziiert und werden durch pcr leicht und spezifisch im urin nachgewiesen, so dass eine partikelisolierung entbehrlich ist. bei pml kann die niedrig dosierte chemotherapie mit cytosinarabinosid zum rückgang der symptome führen, aber nur bei relativ intakter zellvermittelter immunität. bei transplantierten mit pml ist daher die therapeutische immunsuppression zurückzunehmen -die prognose der pml bleibt insgesamt schlecht. komplikationen die kausale assoziation bestimmter hpv-genotypen (z. b. hpv , , insgesamt hpv-genotypen von der cervix nachgewiesen) mit weiblichen genitalkarzinomen hat dazu geführt, dass die hpv-diagnostik mehr eingang in die vorsorgeuntersuchung bei der frau gefunden hat. der nachweis von hpv-genotypen der hochrisikogruppe führt zumindest zur engmaschigen kontrolle oder zum aktiven vorgehen bei gleichzeitigen zytologischen veränderungen. die in der westlichen hemisphäre bei pferd, rind und schwein vorkommenden vesiculoviren können als zoonose beim menschen zu grippeähnlichen infekten, myalgien und auf schleimhäuten zu herpetiformen bläschen mit hoher partikelzahl führen. pathogenese das tollwutvirus bleibt nach infektion für stunden bis wochen im bereich der eintrittspforte in der peripherie; es vermehrt sich wahrscheinlich auch in den zellen der quergestreiften muskulatur oder persistiert in makrophagen. dabei kommt es nicht zur nennenswerten protektiven immunantwort. nach eindringen in die peripheren nervenendigungen gelangt es mit dem axoplasmastrom (ca. mm/h) ins zns. nach erreichen des gehirns verursacht es eine enzephalitis, die histologisch (negri-körperchen) nicht sehr ausgeprägt sein muss, und kehrt dann in verschiedene organe in der peripherie "zurück" (z. b. speicheldrüsen) und auch in verschiedene periphere nervenzellen. durch die intrazelluläre entwicklung innerhalb des nervensystems kommt es erst sehr spät zum effektiven kontakt mit dem immunsystem, so dass neutralisierende und diagnostisch verwertbare antikörper in serum und liquor anfangs fehlen können. die inkubationszeit ist umso kürzer (spanne zwischen tagen und mehreren jahren; durchschnitt: - monate) und die erkrankungswahrscheinlichkeit umso höher, je näher die verletzung am zns liegt (bein: %, gesicht: %) und je schwerer sie ist. • . phase: neurologisch-psychiatrische symptome (verstärkte speichelsekretion, reizbarkeit). "stille wut" mit aufsteigender paralyse, "wilde wut" mit starker unruhe und charakteristischer hydrophobie in - % (muskelspasmen im mund-, rachen-und larynxbereich), anfangs beim versuch zu trinken, später schon bei der visuellen wahrnehmung von wasser oder anderen akustischen und taktilen reizen. die wilde wut verläuft rascher progredient ( - tage) als die stille (bis tage). • . phase: präfinales koma ( - tage). bei intensivmedizinischer versorgung mit beatmung kann der verlauf viel länger sein. inwieweit unterschiedliche virusstämme für verschiedene verläufe verantwortlich sind, ist noch unklar. es gibt berichte über überlebte erkrankungen, wobei alle patienten vorgeimpft waren, so dass es sich eher um impfversagen handelte. die rate tatsächlich erfolgter, aber asymptomatischer infektionen ist nicht bekannt. • virusnachweis: immunfluoreszenznachweis des virusantigens im abdruckpräparat der kornea. postmortale diagnose durch genomnachweis mittels rt-pcr und histopathologisch am gehirn (negri-körperchen) oder durch immunhistologie. die virusisolierung in mäusen und neuroblastomzelllinien aus speichel ist möglich. • nachweis des viralen genoms: über rt-pcr als standardmethode • antikörpernachweis: die serologische diagnose der tollwut (ift, elisa) ist unzuverlässig. therapie und prophylaxe jede tollwutexposition bedeutet lebensgefahr und erfordert beim ungeimpften eine sofortige postexpositionelle, kombinierte aktive und passive immunisierung. nach ausbruch der erkrankung gibt es keine spezifische therapie -die rabies des menschen verläuft tödlich. virostatika zeigten keinen einfluss, doch sind zytokine wie il- evtl. interessant. intensivmedizinische maßnahmen wegen hypoxischem zns-Ödem und gestörter thermoregulation. bei beruflicher gefährdung (u. a. tierärzte, förster) ist die aktive schutzimpfung indiziert. biss-und kratzwunden mit evtl. tollwutexposition müssen chirurgisch gereinigt, gründlich desinfiziert und mit rabies-immunglobulin umspritzt werden. präventiv lebenswichtig ist die schnelle postexpositionsimpfung (› kap. . ) mit inaktivierten vakzinen und bald evtl. gentechnologisch erzeugten impfstoffen. das risiko bei htlv- -infektion, einen tumor zu entwickeln, liegt bei ca. % ( - % bekommen insgesamt symptome der infektion). die bedeutung von htlv- für erkrankungen des menschen ist unklar, obwohl einiges für eine beteiligung bei leukämien spricht. hautmanifestationen im sinne eines kutanen lymphoms sind häufig im rahmen einer adulten t-zell-leukose (atl), an deren entstehung htlv- oft beteiligt ist. jedoch ist die inkubationszeit der atl mit - jahren lang. atl geht einher mit opportunistischen infektionen durch immunsuppression, lymphadenopathie, hepatosplenomegalie, lungeninfiltraten und osteolysen. das zellbild im peripheren blut kann sehr unterschiedlich sein. bei einigen verläuft die erkrankung eher unter dem bild eines lymphoms. htlv- ist selten ursache der tropischen spastischen paraparese (langsam fortschreitende myelopathie mit pyramidenbahnzeichen). diagnostik analog zu hiv durch antikörpernachweis und nachweis viraler rna. antikörper treten evtl. erst spät nach infektion auf. die differenzierung zwischen htlv- und htlv- bedarf manchmal zusätzlicher tests. inwieweit und in welchen ländern blutspender generell auf htlv- getestet werden sollten, muss immer wieder aufgrund der epidemiologischen situation geprüft werden. in › abbildung . (s. ) ist der verlauf einer infektionskrankheit schematisch auf einer zeitskala durch die begriffe infektion und beginn der erkrankung veranschaulicht. die zeitliche differenz ist die inkubationszeit, die bei vielen infektionskrankheiten ein charakteristisches merkmal darstellt. es wurden frühzeitig erkrankungen des zentralnervensystems beschrieben, bei denen es nicht gelang, ein viruspartikel oder endogene virale nukleotidsequenzen zu identifizieren. heute gilt als sicher: prionen sind erreger von übertragbaren, chronischen, degenerativen, stets letalen erkrankungen des zentralen nervensystems. sie kommen mit ähnlichen erscheinungsformen als subakute enzephalopathien bei menschen und anderen wirbeltieren (rind, schaf, ziege, katze, hirsch, nerz u. a.) vor. beim menschen unterscheidet man folgende krankheitsbilder: • creutzfeldt-jakob-disease (cjd) • neue variante creutzfeldt-jakob-disease (vcjd) • gerstmann-sträussler-scheinker-syndrom (gss) • fatale familiäre insomnie (ffi) • kuru. bei tieren sind hier insbesondere scrapie beim schaf und die bovine spongiforme enzephalopathie (bse) beim rind aufzuführen. m e r k e allen krankheiten ist gemeinsam: • es werden keine entzündlichen prozesse, kein fieber und keine immunantwort beobachtet. • es gibt ein breites spektrum von symptomen, das für das jeweilige krankheitsbild einen charakteristischen schwerpunkt hat. • eine therapie ist gegenwärtig nicht verfügbar, alle erkrankungen führen zum tod. prionen sind nach ansicht der meisten forscher nukleinsäurefreie proteine. der name prion wurde von stanley prusiner aus der bezeichnung "proteinaceous infectious particles" abgeleitet. die assoziation von prionprotein als wesentlichem bestandteil des infektiösen agens ist zweifelsfrei bewiesen. eine alternative vorstellung geht von einer konzeptionell noch unklaren beteiligung von nukleinsäuren aus, um die existenz von varianten sowie hereditäre aspekte analog zur genetisch determinierten situation etwa in viralen systemen zu erklären. allen bisher bekannten prionen ist gemeinsam, dass es sich um glykosylierte proteine mit ca. aminosäuren, entsprechend molekülmassen von - kda handelt, die von zellulären genen kodiert werden. transkription und translation sind im gesunden wie im krankhaften zustand unverändert. soweit sequenzdaten vorliegen, handelt es sich um ein evolutionär insgesamt hoch konserviertes molekül insbesondere im bereich der aminosäurepositionen - . die tatsächlich vorhandenen abweichungen in der aminosäuresequenz von prionen verschiedener spezies definieren zusammen mit anderen faktoren (s. u.) die sog. speziesbarriere für eine heterologe infektion. die höhe der Übertragungsbarriere ist für sequenzierte prionen im vergleich zueinander zumindest abschätzbar (unterschiede ausgedrückt als zahl der voneinander abweichenden aminosäuren: schaf -rind , rind -mensch > , maus -mensch ). das gen für das menschliche prion (prnp) befindet sich auf dem kurzen arm von chromosom und kodiert für ein primäres genprodukt prp c mit aminosäuren. der index c steht für "cellular". das protein trägt am n-und am c-terminus signalsequenzen ( bzw. aminosäuren), die posttranslational durch zelluläre peptidasen entfernt werden. an das cterminale ende wird anschließend ein gpi-anker (glykosylphosphatidyl-inositol) für die befestigung in der zellmembran angehängt. diese form des prionproteins ist durch zelluläre proteasen leicht abbaubar. im gegensatz dazu lassen sich aus gehirnen von an übertragbarer spongiformer enzephalopathie (tse) erkrankten menschen und tieren isoformen des prionproteins isolieren, die trotz ihrer mit prp c identischen aminosäuresequenz wegen der spezifischen faltung unlöslich und in vitro nur bis auf den c-terminalen rest von aminosäuren (positionen bis ) abbaubar sind. dieses restmolekül wird auch als prp - bezeichnet und stellt den proteaseresistenten, aber immer noch infektiösen anteil von prp tse dar. die räumliche struktur von prp c enthält nach modellrechnungen drei α-helices und nur geringe β-faltblatt-bereiche, während der nicht spaltbare prp sc -anteil bis zu % β-faltblätter und nur einen geringen gehalt an α-helices aufweist. eine klassifizierung der prionen analog oder ähnlich derjenigen der viren gibt es gegenwärtig nicht. sinnvoll ist zurzeit lediglich die unterscheidung aufgrund der betroffenen wirte unter beachtung der tatsache, dass in tiermodellen mehr als verschiedene stämme von prp sc identifizierbar sind, die sich durch die inkubationszeit, den von der krankheit betroffenen bereich der gehirne und das spektrum der klinischen symptome unterscheiden. interessant ist der befund, dass sich verschiedene klinisch definierte phänotypen von cjd verschiedenen fragmentierungsmustern nach unvollständiger proteinase-k-spaltung zuordnen ließen. fragment-und glykosylierungsmuster von cjd und bse lassen nach experimentellen Übertragungen auf transgene mäuse eine definition von prionenstämmen zu. insbesondere ergaben sich nach inokulation von wildtypmäusen mit vcjd bzw. bse identische glykosylierungsmuster, d.h., die beiden krankheiten wurden mit hoher wahrscheinlichkeit durch den gleichen prionenstamm hervorgerufen. aggregatbildung und ablagerung der proteaseresistenten prp sc -moleküle werden als pathogenes prinzip angesehen, das mit dem krankheitsbild der spongiformen enzephalopathie assoziiert ist. als mechanismus der aggregation wird spontane autokatalytische bzw. durch prp sc vermittelte umfaltung zellulärer "gesunder" prp c -moleküle in die schwer abbaubaren, aggregierenden tse-prionen angenommen. im gegensatz zu viruserkrankungen kommt es nicht zum einbringen, exprimieren und vervielfältigen eines genetischen programms, sondern zur kumulativen ausbreitung einer strukturform innerhalb einer population bereits bestehender moleküle. die prionenstruktur macht krank! dies ist ein grundsätzlich neues pathogenes prinzip. creutzfeldt-jakob-disease (cjd) cjd ist die am besten bekannte tse-erkrankung, die von hans g. creutzfeldt bzw. von alfons jakob beschrieben wurde. gegenwärtig wird sie unter aspekten der entstehung diskutiert als • sporadisch auftretend (spcjd) • genetisch beeinflusst (gcjd) • iatrogen hervorgerufen (icjd) • und neuerdings als variante form (nvcjd), durch aufnahme boviner prionen erzeugt. sporadisch kommt cjd weltweit mit einer inzidenz von etwa fall pro mio. einwohner pro jahr vor. abweichungen resultieren vornehmlich aus der nichtvergleichbarkeit der erhebungsmethoden in den einzelnen ländern. die altersgruppe der -bis -jährigen ist am häufigsten betroffen. der bisher jüngste patient in deutschland war jahre alt, der älteste jahre, niemals jedoch war ein kind erkrankt. beide geschlechter scheinen gleichermaßen betroffen zu sein. nach dem auftreten erster symptome (kopfschmerz, müdigkeit, schlaf-und appetitlosigkeit, depression) folgt das bild einer rasch voranschreitenden generellen enzephalopathie mit verlust der bewegungskoordination sowie mit demenz. die krankheitsdauer beträgt in etwa % der fälle < monate. eine sichere diagnose kann bislang letztlich nur durch neuropathologische untersuchungen gestellt werden. genetisch bedingte creutzfeldt-jakob-krankheit (gcjd) familiäre häufungen von cjd sind bereits in den er-jahren des vorigen jahrhunderts beobachtet worden. von zentraler bedeutung scheint der polymorphismus zu sein, der durch das vorkommen der aminosäuren methionin (m) oder valin (v) an der aminosäureposition im prionprotein charakterisiert ist. in england liegt bei % der spcjd-fälle homozygotie mm vor, im gegensatz zu % in der normalbevölkerung. dagegen sind nur % der erkrankten heterozygot mv bei einem %igen anteil in der normalbevölkerung. alle bekannten nvcjd-fälle sind mm-homozygot (s. u.)! die aminosäureposition befindet sich innerhalb des prionmoleküls an einer Übergangsstelle zwischen der zweiten α-helix und dem β-faltblatt und könnte daher von wesentlichem einfluss auf die faltung des moleküls sein. das klinische bild wird bezüglich krankheitsbeginn und -dauer stark von der genetischen disposition in bezug auf die codons , und geprägt. weitere punktmutationen und insertionen sind ebenfalls von bedeutung. in den familiären fällen ist die inzidenz der erkrankung stark erhöht und geographisch auf bestimmte regionen begrenzt. so findet sich eine jüdische, aus libyen stammende population in israel mit -fach häufigerem auftreten von cjd. charakteristisch ist hier der aminosäureaustausch glu lys. neben der histopathologischen abklärung ist die sequenzierung des prnp-gens zur sicherung der diagnose gcjd erforderlich. iatrogene Übertragung erfolgte nach neurochirurgischen eingriffen, durch verwendung unvollständig sterilisierter neurochirurgischer geräte und elektroden, nach transplantationen von kornea und dura mater von verstorbenen sowie nach der verwendung von aus leichen gewonnenem humanem wachstumshormon (hgh) bzw. hypophysen-gonadotropin. das klinische bild entspricht demjenigen von spcjd, in die diagnose ist die krankengeschichte einzubeziehen. im jahr trat der erste todesfall auf, der einer neuen variante der cjd zuzuordnen ist. bezüglich des krankheitsbildes liegen ähnliche symptome wie bei den anderen formen vor, jedoch sind das niedrige patientenalter ( als medianes alter für den krankheitsbeginn, gesamtintervall - jahre) sowie die epidemiologisch wichtige erkenntnis der fast ausschließlichen geographischen beschränkung auf großbritannien hervorzuheben. im mai waren weltweit fälle bekannt, davon in großbritannien, in frankreich und in irland. klinisch stehen bei krankheitsbeginn hier eher psychiatrische als neurologische symptome im vordergrund, wie depression, angst, erregung, halluzinationen und schmerz, aber auch neuropsychologische auffälligkeiten wie aphasie oder alexie. später kommen die üblichen sensorischen symptome wie ataxie, parese und demenz hinzu. im gegensatz zu spcjd finden sich neuropathologische besonderheiten. es liegen keinerlei hinweise auf familiäre häufungen vor. die Übertragung erfolgt mit großer wahrscheinlichkeit durch den genuss von "infektiösen" nahrungsmitteln. durch die normale zubereitung von speisen werden prionen vermutlich nur unvollständig inaktiviert. das auftreten von nvcjd-prionen im gehirn und in den tonsillen ist ein sicheres diagnostisches merkmal. biologische typisierungen von prionen in versuchstieren sind zeitaufwändig und teuer und nicht für diagnostische zwecke geeignet. epidemiologische untersuchungen zeigten allerdings, dass bislang keine risikofaktoren wie berufszugehörigkeit (landwirte, veterinäre, schlachter, abdecker etc), essgewohnheiten oder geographische nähe zu bse-belasteten landwirtschaftlichen betrieben erkennbar sind. diese tse-erkrankung ist mit der inzidenz von einem fall unter mio. einwohnern pro jahr äußerst selten und mit wenigen sporadischen ausnahmen wohl ausschließlich genetisch determiniert. der erbgang ist autosomal-dominant. im vordergrund steht eine punktmutation mit der konsequenz des aminosäureaustausches von prolin durch leucin (pro leu). hinzu kommen weitere punktmutationen und ein spektrum von oktapeptid-insertionen, die in zusammenwirken mit dem polymorphismus an der position einfluss auf die klinischpathologischen aspekte der amyloidbildung im gehirn haben. erste symptome von gss sind uncharakteristische beschwerden, wie schlafstörungen, psychische veränderungen, gedächtnisverlust, aphasie und alexie, gefolgt von dem spektrum der anderen tse-symptome, die nach völliger dezerebration einige monate bis jahre nach auftreten der ersten symptome zum tode führen. das erkrankungsalter liegt zwischen und jahren. die diagnose erfolgt anhand der neuropathologischen befunde und ggf. durch sequenzanalysen des prnp-gens. gss ist ausschließlich als hereditär anzusehen, die vertikale weitergabe des gss-spezifischen prnp-gens sollte nicht als Übertragung eines krankheitserregers bezeichnet werden. es handelt sich um eine äußerst seltene genetisch bedingte erkrankung, die zuerst bei mitgliedern einer italienischen familie entdeckt wurde. der erbgang ist autosomal-dominant, scheint jedoch nur eingeschränkt penetrant zu sein, da mehrere familienmitglieder die entscheidende prnp-mutation mit der folge des aminosäureaustausches asp asn aufwiesen, jedoch symptomlos blieben. die gleiche mutation ist auch bei der familiären form der creutzfeldt-jakob-krankheit (gcjd) von zentraler bedeutung, was zu intensiver diskussion der beiden klinisch-pathologisch sehr unterschiedlichen situationen geführt hat. auch hier ist das codon von bedeutung. das zentrale klinische bild der ffi ist geprägt durch einen stark gestörten schlafrhythmus und entsprechende veränderungen in eeg-schlafmustern und endokrinen zirkadianen stoffwechselleistungen. die erkrankung tritt zwischen dem . und . lebensjahr auf und führt nach - monaten zum tode. nach zunächst uncharakteristischen stadien liefert die neuropathologische untersuchung astrogliose, vakuolenbildung und amyloidablagerungen. kuru ist der klassische fall einer horizontal übertragenen spongiformen enzephalopathie. sie wurde zuerst von gajdusek und zigas beschrieben als eine degenerative krankheit des zentralnervensystems in isolierten populationen in neuguinea. seit dem verbot des dort praktizierten rituellen kannibalismus ende der er jahre ist die erkrankung im verschwinden begriffen und heute praktisch ausgelöscht. homozygotie für methionin an der codonposition des prnp-gens ist charakteristisch für die erkrankung, die mit hoher wahrscheinlichkeit durch die horizontale Übertragung von infektiösem material eines an spontaner creutzfeldt-jakob-krankheit verstorbenen entstanden und durch die kannibalistischen beerdigungsriten epidemisch verbreitet wurde. die infektion ist vermutlich über den intestinaltrakt verlaufen. eindringen der kuru-prionen durch verletzungen während des eröffnens des leichnams und damit verbundene hautkontaminationen sowie konjunktivale und nasale schmierinfektionen sind als Übertragungswege ebenso denkbar. die krankheit beginnt mit unspezifischen beschwerden und führt nach neurologischen ausfällen mit ataxie, schweren lähmungen, damit verbundener unterernährung und letztlich völliger motorischer unfähigkeit zum tode. im fall von iatrogener cjd, kuru und nvcjd ist die Übertragbarkeit von infektiösen prionen sehr wahrscheinlich bzw. nachgewiesen. seit jahrzehnten wird tiermehl weltweit als zuschlagstoff in der tierfütterung eingesetzt. in großbritannien wurden ende der er-bis anfang der er jahre in verschiedenen produktionsanlagen unterschiedliche Änderungen des herstellungsprozesses vorgenommen, die offensichtlich eine minderung der inaktivierungseffizienz zur folge hatten. heute wird unter dem eindruck der bse-epidemie eine -minütige erhitzung auf °c bei bar Überdruck als norm gefordert. zur inaktivierung von prionen an chirurgischen instrumenten, die nicht autoklavierbar sind, wird eine einstündige behandlung mit natronlauge oder natriumhypochlorid empfohlen. um risiken inadäquater dekontaminierung zu vermeiden, wird die benutzung von lediglich einmal zu verwendendem material empfohlen. mit zunehmendem verständnis der pathogenitätsmechanismen ergeben sich hinweise auf mögliche therapiestrategien. so ist es denkbar, in den umwandlungsprozess der prp c -konformation direkt einzugreifen. behinderung von eintritt in den wirtsorganismus und transport von prp sc in das zns ist eine weitere möglichkeit. im fall tierischer erkrankungen wären genetische und züchterische maßnahmen denkbar, etwa die aufzucht von tieren, die von individuen abstammen, die künstlich negativ homozygot für das priongen (prp -/-) gemacht wurden. diese tiere sind nicht infizierbar, da sie selbst keine zellulären prionen synthetisieren können, die dann nach dem eindringen von prp sc in die pathogene konformation umgefaltet werden könnten. da die natürliche funktion des genproduktes des zellulären prp-gens und damit die folgen seines verlustes jedoch nicht bekannt sind, ist dieser weg risikoreich und vorerst nicht gangbar; beim menschen ist er sowieso ausgeschlossen. die konventionelle züchtung nicht erkrankender schafe ist gelungen und hat wohl dazu geführt, dass mittlerweile england, neuseeland und australien scrapie-frei sind. von der invasiven mykose ist die systemische mykose abzugrenzen, die nur infolge hämatogener streuung auftritt. invasive mykosen werden durch etwa verschiedene pilzarten hervorgerufen. sie betreffen nahezu ausschließlich abwehrgeschwächte patienten. prädisponierende faktoren sind abdominalchirurgie, zentrale venenkatheter, störung der normalen flora durch breitspektrum-antibiotika, herabsetzung der abwehr durch kortikosteroide, immunsuppressiva und zytostatika, hiv-infektion, diabetes mellitus, transplantation solider organe oder allogener stammzellen. epidemiologie die meisten pilze leben saprophytär. einige können aber in geringer zahl auf haut und schleimhäuten sowie im darmtrakt vorhanden sein, ohne krankheitserscheinungen hervorzurufen. bei einem pilznachweis in entsprechenden materialien stellt sich daher oft die frage nach ihrer relevanz als erreger. liegen keine der oben genannten risikofaktoren vor, so ist der nachweis von hefepilzen im stuhl klinisch nicht relevant. Ätiologie und pathogenese die adhärenz der pilze an die wirtszellen ist notwendige bedingung für eine infektion. sie wird durch wechselwirkungen zwischen kohlenhydrat-und proteinstrukturen der pilzzellwand und der wirtszelle verursacht. es können zell-und gewebsschädigende sekretorische proteasen und phospholipasen gebildet werden. außerdem spielen spezielle morphologische eigenschaften der pilze eine rolle, wie z. b. das "switching", der Übergang von der sprosspilzform in die hyphenform bei dimorphen pilzen. für die wirtsabwehr gegen die meisten opportunistischen pilze -insbesondere bei den am häufigsten vorkommenden gattungen candida und aspergillus -sind zahl und funktion der neutrophilen entscheidend. makrophagen und monozyten wird zunehmend bedeutung beigemessen, während die t-zell-vermittelte immunität hauptsächlich für die abwehr der obligat pathogenen pilze und von cryptococcus neoformans relevant ist. diagnostik das klinische bild der meisten pilzinfektionen ist uncharakteristisch, damit ist der erregernachweis besonders bedeutend. beweisend ist die kultur aus physiologisch sterilem material (blut, liquor, biospie) oder die histologie an paraffinschnitten. in allen materialien lassen sich pilze mit optischen aufhellern (blankophoren), giemsa-färbung oder gram-färbung (grampositiv) nachweisen. für die genaue identifizierung der pilze ist die kulturelle anzüchtung erforderlich. hierfür werden als selektive medien z. b. sabouraud-agar und chrom-agar verwendet. als weitere diagnostische möglichkeiten gibt es für einige pilze antigennachweise, z. b. galactomannan für aspergillus und β- , -d-glucan für candida, aspergillus und andere. serologische untersuchungsverfahren weisen spezifische antikörper nach und sind generell weniger verlässlich. molekularbiologische nukleinsäurenachweise sind nicht ausreichend standardisiert und der kultur in der identifizierung des erregers unterlegen. therapie zur therapie invasiver pilzinfektionen stehen substanzklassen zur verfügung, deren charakteristika in › tabelle . wiedergegeben sind. aus der gruppe der sprosspilze kommen krankheitserreger vor allem in der gattung candida vor. trichosporon und blastoschizomyces sind sehr viel seltener. candida verursacht bei schleimhautbefall weißliche beläge, den soor (engl.: thrush). dieser kann bei vorliegen von risikofaktoren zu invasiven infektionen (organbefall, fungämie) führen. eine weitere sprosspilzart, cryptococcus neoformans, verursacht nach einem flüchtigen lungeninfiltrat eine meningoenzephalitis bei abwehrgeschwächten, z. b. hiv-infizierten patienten. praxisfall ii ein -jähriger befindet sich zur diabeteseinstellung eher zufällig im krankenhaus, klagt über plötzlich einsetzende bauchschmerzen und wird bewusstlos. es liegt ein rupturiertes bauchaortenaneurysma vor, das notfallmäßig operiert wird. seit tagen liegt er beatmet auf der intensivstation, ein perioperativ diagnostiziertes akutes nierenversagen erfordert die dialyse über einen shaldon-katheter. er fiebert auf, blutkulturen werden abgenommen, eine breitspektrumantibiotika-therapie beginnt. drei tage diagnostik im ct der lunge und des kopfes werden uncharakteristische raumforderungen gesehen, die in verbindung mit der grunderkrankung an diese differentialdiagnose denken lassen sollten. eine histologische sicherung ist zwingend erforderlich. therapie neben der radikalen und ggf. wiederholten chirurgischen sanierung besteht die medikamentöse therapie der wahl in liposomalem amphotericin b. die empfehlungen zur dosierung gehen auseinander: - mg/kg. ist der patient diabetiker, dann wird sich die nierenfunktion unter dieser therapie sehr bald verschlechtern. einzige alternative ist posaconazol × mg. die therapiedauer kann nicht genau abgegrenzt werden, beträgt aber zumindest - jahre. nach ende der therapie ist eine regelmäßige nachsorge nötig. verlauf und prognose der verlauf hängt von der erfolgreichen behandlung der grundkrankheit und damit im falle eines diabetes von der adhärenz des patienten ab. wird ein diabetes optimal therapiert, kann die infektion überlebt werden. die gesamtsterblichkeit beträgt - %. nach - jahren kann unter engmaschiger kontrolle eine therapiepause versucht werden. • malaria tertiana und quartana: bei p. vivax-, p. ovale-und p. malariae-infektionen kommt es ungefähr woche nach krankheitsausbruch zur synchronisation der parasitenvermehrung im blut, d.h., die parasiten wachsen synchron heran und zerstören gleichzeitig ihre wirtserythrozyten (p. vivax und p. ovale an jedem ., p. malariae an jedem . tag). diese synchronisation bedingt die regelmäßigen und charakteristischen fieberanfälle. p. vivax und p. ovale hinterlassen sog. hypnozoiten in der leber, die monate und jahre später zu rezidiven führen können. • malaria tropica: p. falciparum neigt nicht zur synchronisierten vermehrung. eine weitere wichtige besonderheit der malaria tropica ist die veränderung der erythrozytenoberfläche durch die heranwachsenden formen von p. falciparum. die befallenen roten blutkörperchen gewinnen dadurch eine besondere affinität zum gefäßendothel. vor allem in den kapillaren bleiben sie am endothel "kleben" (sequestration) und verstopfen sie. die folge sind hypoxie und metabolitenstau im abhängigen gewebebezirk (› abb. . ). diese einzigartige eigenschaft der tropica-parasiten bedingt die gefährlichkeit der malaria tropica, die infolge der zunehmenden ischämie in wichtigen organen (gehirn, lunge, niere, herz) innerhalb weniger tage zum tod führen kann. • erysipel: pathognomonisches a-streptokokken-krankheitsbild, das auch tiefere hautschichten betrifft. beginnt mit lokalisiertem erythem mit schwellung, das sich rasch ausbreitet und klar vom normalen umgebenden gewebe abgrenzbar ist begleitet von hohem fieber, schüttelfrost und allgemeinem toxischem krankheitsgefühl. im gesichtsbereich ist es meist selbstlimitierend, bei anderer lokalisation kann es nur durch gezielte therapie geheilt werden. • akutes rheumatisches fieber: nach durchgemachter streptokokkenpharyngitis mit einer latenzzeit von ca. - tagen. es kommt zu fieber, schmerzhaften schwellungen der großen und mittleren gelenke und zur pankarditis (v. a. als endokarditis: endocarditis verrucosa). nach längerer latenzzeit evtl. syndrom im zns-bereich (chorea minor). andere spätfolgen sind: erythema nodosum und erythema anulare rheumaticum. man führt den gesamtkomplex des rheumatischen fiebers auf eine immunpathogenese zurück. nur bestimmte m-typen von a-streptokokken verursachen diese folgeerkrankung, solche stämme kommen zurzeit bei uns nicht autochthon vor. häufiger betroffen sind (bei uns meist türkische) patienten aus mediterranem gebiet. • akute glomerulonephritis: tritt auch nach hautinfektionen auf. gute prognose v. a. bei kindern. diagnostik einige der erkrankungen (z. b. erysipel und scharlach) sind schon klinisch pathognomonisch. wichtigste mikrobiologisch-diagnostische maßnahme ist der erregernachweis aus blutkultur und abstrich-und punktionsmaterialien. im verlauf stellt man meist serologisch eine titerbewegung der antikörper gegen streptolysin o (aso-, asl-titer) und/oder bei antikörpern gegen dnase b (adb-, streptodornase-titer) fest. faustregel: der asl-titer steigt v. a. bei infektionen im respirationstrakt, der adb-titer meist bei hauterkrankungen an. asl spielt in der diagnostik des rheumatischen fiebers nur eine geringe rolle, adb hat in der diagnostik der akuten glomerulonephritis größere bedeutung. die adb-werte können hier extrem hoch ansteigen. differentialdiagnose extrem hohe asl-bzw. adb-werte treten auch bei plasmozytomen mit entsprechender antikörperspezifität auf. differentialdiagnostisch kommen bei den pyogenen a-streptokokken-infektionen v. a. infektionen durch s. aureus in frage. dies gilt auch für das toxic shock syndrome. beim erysipel muss, v. a. bei immunsupprimierten, eine aeromonasspp.-Ätiologie ausgeschlossen werden (cave: andere antibiotikatherapie!). bei streptokokken-folgeerkrankungen müssen auch autoimmunerkrankungen in die differentialdiagnose einbezogen werden. therapie penicillin g als mittel der wahl. dosierung und dauer hängen von manifestation und klinischer fulminanz ab. bei der streptokokkenpharyngitis reicht eine orale therapie über tage (tagesdosis bei - mega), bei fulminanter sepsis sind tagesdosen bis zu mega nötig, alternativ evtl. cephalosporine. bei penicillinallergie sind makrolidantibiotika bzw. vancomycin alternativen. bei einigen krankheitsbildern (z. b. phlegmone, fasciitis necroticans) sind ferner schnelle und offensive chirurgische maßnahmen nötig. bei streptokokken-folgeerkrankungen spielt auch die antiphlogistische behandlung eine wichtige rolle und evtl. kortikosteroidgabe. ferner ist eine rezidivprophylaxe mit penicillin oder erythromycin für mind. - jahre indiziert. bei den übrigen a-streptokokken-erkrankungen keine spezifischen prophylaktischen maßnahmen, was auch für die expositionsprophylaxe mit antibiotika bei scharlachausbrüchen gilt. hämolysierende streptokokken der serologischen gruppe b verursachen v. a. peripartale infektionen bei neugeborenen, bis h post partum eine sepsis und - tage post partum meningitis. zunehmend findet man sie auch bei pyogenen infektionen geriatrischer patienten. hämolysierende streptokokken der gruppen c und g verursachen auch pharyngitis oder wundinfektion. systemisch-septische infektionen fast ausschließlich bei abwehrgeschwächten patienten. vergrünende bzw. nicht hämolysierende streptokokken haben ihren natürlichen standort im oropharynx des menschen, s. bovis im darm von mensch und tier. sie werden als orale streptokokken bezeichnet. sie verursachen: • karies und parodontitis • nativklappen-("endocarditis lenta") und spät-prothesenendokarditis (› kap. . . ). bei nachweis von s. bovis in der blutkultur muss eine kolonerkrankung (karzinom, divertikulitis) ausgeschlossen werden! diagnostik erregernachweis in entsprechenden materialien. pneumokokken sterben wegen ihres starken autolysesystems auf dem transport rasch ab. wichtig sind -vor allem bei pneumonie -blutkulturen. in der meningitisdiagnostik spielen der mikroskopische erreger-und der spezifische antigennachweis (kapselpolysaccharid) eine zunehmende rolle in der spezifischen schnelldiagnostik. der antigennachweis aus sputum oder trachealsekret ist oft unspezifisch. therapie penicillin g. andernorts schon sehr häufig (spanien!) isolierte penicillin-g-resistente pneumokokken wurden bei uns bisher nur selten gefunden. stämme mit nur mäßiger empfindlichkeit gegen penicilline sind auch bei uns häufiger. eine resistenztestung ist daher durchzuführen. alternative substanzen: cephalosporine der . generation (z. b. cefotaxim) oder carbapeneme. es besteht die möglichkeit zur aktiven immunisierung. die vakzine beinhaltet die wichtigsten, vor allem bei septischen verlaufsformen vorkommenden kapseltypen. die impfung ist regelimpfung nach stiko für kinder und ältere menschen. epidemiologie natürlicher standort ist der darm von mensch und tier. der infektionsweg ist endogen-hämatogen nach translokation aus dem darm, auch exogene schmutz-schmierinfektionen sind möglich. klinische bilder e. faecalis ist erreger akuter harnwegsinfektionen und adnexitiden (innerhalb einer mischinfektion) der frau. von größerer bedeutung ist die enterokokkenendokarditis (ca. %). ferner spielen enterokokken eine rolle als wundinfektionserreger. diagnostik erregernachweis in entsprechenden materialien, v. a. in der blutkultur (endokarditis). • enterokokken-harnwegsinfektionen: aminopenicilline • enterokokkenendokarditis: auch alternativ mezlocillin. grundsätzlich immer kombinierte behandlung mit gentamicin in den ersten wochen. die therapiedauer liegt bei - wochen. bei penicillinallergie oder bei stämmen mit "high-level"-resistenz (> mg/l mhk) gegen gentamicin gabe von glykopeptiden (v. a. teicoplanin). gegen glykopeptidresistente enterokokken wirken linezolid und daptomycin. die wichtigsten sind meningokokken und gonokokken der gattung neisseria. branhamella catarrhalis (früher neisseria catarrhalis, kokkoide stäbchen) gehört zur physiologischen rachenflora, kann aber infektionen des oberen und unteren respirationstrakts verursachen. moraxella-und kingella-arten (kokkoide stäb-chen) werden mitunter als opportunistische infektionserreger isoliert. selten werden veillonellen (anaerob) aus pyogenen mischinfektionen isoliert. man unterscheidet die zyklischen allgemeininfektionen typhus und paratyphus von den mit Übelkeit, erbrechen und durchfällen einhergehenden enteritissalmonellosen. die Übertragung erfolgt überwiegend auf oralem infektionsweg. definition die gattung salmonella hat einen sehr großen arten-bzw. serovarreichtum. es handelt sich um gramnegative stäbchen aus der familie der enterobakterien. nach heute gültiger, aber umstrittener exakter taxonomie ist der einzige humanmedizinisch bedeutende vertreter die spezies salmonella enterica bzw. die subspezies salmonella enterica subspecies enterica mit einer großen vielfalt an serovaren (zur abgrenzung von speziesnamen werden die serovare mit großbuchstaben gekennzeichnet). unter klinischen gesichtspunkten hat sich folgende einteilung bewährt: s. typhi (die abgekürzte form von s. enterica subsp. enterica serovar typhi) ist klassischer erreger des typhus, s. paratyphi (s. enterica subsp. enterica serovar paratyphi) der erreger des paratyphus, unterteilt in die gruppen a, b und c. wichtigste erreger von enteritissalmonellosen sind s. typhimurium (s. enterica subsp. enterica serovar typhimurium) und s. enteritidis (s. enterica subsp. enterica serovar enteritidis). die übrigen enteritissalmonellen werden aufgrund ihrer oberflächenantigene (o-gruppen) und geißelantigene (h-gruppen) typisiert. sie werden aufgrund der antigenformel benannt oder mit einem speziellen namen, der meist nach dem ersten nachweisort erfolgt (z. b. s. coeln). diese repräsentieren dann serovare und keine (!) spezies oder subspezies. diagnostik bei entsprechender reiseanamnese und typischem fieberverlauf lässt sich häufig klinisch die verdachtsdiagnose stellen. richtungweisend sind das auftreten von roseolen, eine leukopenie, das fehlen eosinophiler leukozyten im differentialblutbild mehrerer blutausstriche und eine relative bradykardie. die kulturelle erregerdiagnose gelingt im sehr frühen krankheitsstadium evtl. noch im stuhl, meist aber in der . und . krankheitswoche nur in der blutkultur, zur erhöhung der sensitivität sollten multiple blutkulturen abgenommen werden. die kulturelle untersuchung von knochenmark ist besonders sensitiv. am ende der . krankheitswoche lässt sich der erreger meist wieder aus dem stuhl isolieren. der antikörpernachweis ist für die akutdiagnostik wenig hilfreich. wegen der schwierigen isolierungsbedingungen (selektivnährböden nötig!) kann dies mehrere tage erfordern. ab ende der . bzw. beginn der . krankheitswoche kommt es zur messbaren antikörperbildung, hohe titer werden ab der . woche erreicht. dann kann die diagnose serologisch (widal-reaktion) bestätigt werden. bei sehr früh begonnener antibiotischer therapie kann der antikörpernachweis negativ bleiben. zur differentialdiagnose siehe auch › tabelle diagnostik erregernachweis aus stuhl, operationsmaterial und evtl. aus der blutkultur. antikörpernachweisverfahren (mikroagglutination, elisa, westernblot) spielen in der diagnostik der akuten enterokolitiden keine wesentliche rolle. bei subakut oder chronisch verlaufenden pseudoappendizitisformen und postinfektionssyndromen sind sie dagegen ausschlaggebend. therapie meist selbstlimitierende erkrankung, keine antibakterielle chemotherapie nötig. bei schwerem oder septischem verlauf behandlung mit tetrazyklinen, chinolonen, co-trimoxazol oder aminoglykosiden. definition erkrankungen durch y. pseudotuberculosis sind zooanthroponosen. ein fäkal-oraler infektionsweg wird angenommen, infektionsquelle sind infizierte tiere oder kontaminierte tierische nahrungsmittel. eine besonderheit scheint die affinität von y. pseudotuberculosis zum lymphatischen gewebe im abdominellen bereich zu sein. wichtigste klinische manifestation ist die pseudoappendizitis (mesenteriale lymphadenitis, akute terminale ileitis), die ihren häufigkeitsgipfel in der altersgruppe von - jahren hat. symptome fieber und schmerzen im rechten unterbauch. extrem selten septischer verlauf, dann v. a. bei stark abwehrgeschwächten patienten. begleitende krankheitserscheinungen sind reaktive arthritis und erythema nodosum. diagnostik erregernachweis aus schleimhautbiopsien, operationsmaterial, seltener aus stuhl. die serologische diagnostik (titerverlauf im mikroagglutinationstest) spielt jedoch eine wichtige rolle. therapie meist keine antibakterielle chemotherapie erforderlich. nur bei schwerem septischem verlauf antibiotikatherapie mit ampicillin, tetrazyklinen oder aminoglykosiden. Ätiologie eine der ältesten und gefährlichsten zooanthroponosen, hervorgerufen durch y. pestis. nagetiere, v. a. ratten, sind wichtigstes erregerreservoir, flöhe die wichtigsten vektoren. epidemiologie kommt in europa nicht mehr vor. sporadische fälle werden aus dem nördlichen und südlichen afrika, aus den usa, südamerika und weiten teilen asiens berichtet. jährlich werden weltweit mehrere tausend krankheitsfälle gemeldet. wegen der relativ kurzen inkubationszeit sind auch touristisch eingeschleppte fälle extrem selten (zur meldepflicht s. ifsg nach § abs. nr. ). • beulenpest: befall der regionalen lymphknoten im abflussbereich der bissstelle des infizierten flohs mit schwerer allgemeinsymptomatik • lungenpest: aerogene Übertragung von mensch zu mensch mit hoher letalität. therapie gut behandelbar mit antibiotika (gentamicin oder doxycyclin). die pest verursachte in den letzten jahren nur selten größere epidemien und hat viel von ihrem früheren schrecken verloren. definition die familie der enterobacteriaceae zeichnet sich durch großen artenreichtum aus. viele gattungen besitzen auch humanmedizinische bedeutung. während den salmonellen, shigellen und yersinien überwiegend spezielle krankheitsentitäten zugeordnet werden können, ist dies für die meisten anderen gattungen nicht möglich. daher werden diese enterobacteriaceae-arten als fakultativ pathogene erreger gesondert betrachtet (› tab. in speziellen fällen (z. b. zur sicheren diagnose der lues connata) ist der nachweis spezifischer igm-antikörper in der indirekten immunfluoreszenz erforderlich. bei neurosyphilis wird eine autochthone intrathekale anti-treponemen-antikörperproduktion nachgewiesen. therapie bedeutsam sind frühzeitige diagnose und therapiebeginn im ., spätestens im . stadium. therapie der wahl ist penicillin g oder ceftriaxon, bei penicillinallergie doxycyclin oder azithromycin. zur vermeidung der frühen neurosyphilis muss die therapie hoch dosiert (procain-penicillin g, , mio. e i.m.) für tage durchgeführt werden, um ausreichend hohe liquorspiegel zu erreichen. bei patienten mit gleichzeitiger hiv-infektion, bei tertiärer syphilis und bei neurosyphilis wird × mio. e penicillin i.v., alternativ × g ceftriaxon für tage verabreicht. der verlauf der erkrankung und vor allem der effekt der therapie müssen durch regelmäßige serologische aktivitätskontrollen (vdrl-test, cardiolipin-kbr) überprüft werden. prophylaxe eine impfung existiert nicht. eindämmung der Übertragungswege durch möglichst lückenlose aufklärung und Überwachung der risikogruppen. abb. . syphilis. a) primäraffekt an der glans penis. b) luesexanthem im stadium ii an den fußsohlen. c) alopecia areata, ebenfalls stadium ii. infektionsschutzgesetz: kommentar und vorschriftensammlung . kohlhammer dolin: principles and practice of infectious diseases, th edn ., vols klinische infektiologie . urban & fischer just-nübling: antibiotikatherapie, anthrax antibiotic associated colitis bacillary dysentery bartonellenerkrankungen botulism botulismus brucellosis chlamydial diseases cholera coagulase-negative staphylococci diphtherie enteric e . coli infections enteric fever enteritissalmonellose enterococci epidemic typhus erysipeloid fakultativ pathogene enterobacteracea gas gangrene/edema gonorrhoe gonorrhoea group a streptococci haem . influenzaerkrankungen hwi infektionen durch staphylokokken infektionen durch streptokokken legionärskrankheit legionellosis legionnaires' disease leprosy leptospirose leptospirosis listeriose-pneumokokken listeriosis lyme-borreliose-stadien lyme-borreliosis lyme disease meningococcal meningitis/sepsis mykoplasmenübertragung nocardiosis oculo-genital infections ornithose ornithosis pertussis pint plague pontiac fever pneumococci pseudomonas psittacosis q-fieber relapsing fever rickettsien rickettsial diseases salmonella foodborne disease salmonellose shigellose staphylococcal diseases streptococcal/enterococcal diseases swine erysipelas verfügbare zubereitungsformen aktivimpfstoffe enthalten impfantigene zur aktivierung des immunsystems mit erregerspezifischer bei einzelnen impfungen sind antikörpergrenzwerte für den optimalen impfschutz bekannt. jedoch kann nicht immer von antikörperkonzentration auf effektiven, sicheren schutz vor infektion geschlossen werden • zellvermittelte immunantwort: routinemäßig schwer zu testen. t-lymphozyten haben für die induktion humoraler antikörperantworten (z. b. gegen proteinantigene) große bedeutung und tragen zur bildung des immunologischen gedächtnisses (memory-zellen) bei. der effekt t-zell-abhängiger impfungen lässt sich z. b. durch bestimmung der masern-, mumps-und röteln-antikörper nach mmr-lebendimpfung abschätzen bei der aktiven immunisierung zum aufbau eines dauerhaften impfschutzes unterscheidet man: • lebendimpfstoffe: vermehrungsfähige, attenuierte (abgeschwächte vollkeim-impfstoff) oder in mehr oder minder reiner form immunologisch relevante antigene des erregers (spalt-impfstoff, extrakt-impfstoff, toxoid-impfstoff, subunitvakzine) durch geeignete spenderkontrolle, herstellungsverfahren von infektionskrankheiten hergestellt. beispiel: humanisierter antikörper palivizumab, zum schutz von frühgeborenen unter bestimmten indikationen (z. b. chronische lungenkrankheit) vor der infektion mit dem respiratory syncytial virus (rsv) stuhl kontaminierte) wunden, verletzungen mit gewebszertrümmerung und reduzierter sauerstoffversorgung oder eindringen von fremdkörpern jede auffrischimpfung mit td sollte anlass sein, eine mögliche indikation einer pertussis-impfung zu überprüfen und ggf. einen kombinationsimpfstoff (tdap) einzusetzen im allgemeinen werden ie verabreicht, die dosis kann auf ie erhöht werden; tig wird simultan mit td/t-impfstoff angewendet dosis), wenn seit der letzten impfung mehr als jahre vergangen sind wenn seit der letzten impfung mehr als jahre vergangen sind quelle: rki: empfehlungen der ständigen impfkommission (stiko) am robert-koch-institut/stand: juli ein patient stellt sich tage nach durchführung des . zyklus einer ambulanten chemotherapie nach dem chop-r-schema im -tägigen abstand mit fieber in der notaufnahme vor. bei der untersuchung des blutbildes zeigt sich eine leukozytenzahl von /μl. a. welche untersuchungen werden neben einer ausführlichen körperlichen untersuchung veranlasst? wie wird der patient initial behandelt? seine körperliche leistungsfähigkeit habe abgenommen, vor allem beim treppensteigen komme er leicht "aus der puste". er wisse seit , jahren, dass er hiv-positiv sei, habe sich aber bislang nicht weiter untersuchen lassen heute habe er deswegen kaum noch etwas zu sich nehmen können. bei der körperlichen untersuchung fällt ihnen auf, dass der rachen des patienten weiße beläge aufweist, die teilweise abstreifbar sind. am hals finden sich beidseits mehrere, bis zu cm im durchmesser große indolente lymphknoten, von denen der patient angibt, dass diese schon seit jahr unverändert bestünden ihr verdacht bestätigt sich. was empfehlen sie dem patienten? welche sind die wichtigsten antimykotika-substanzklassen? welche candida-spezies sind immer oder häufig gegen fluconazol resistent? werden sprosspilzinfektionen endogen oder exogen erworben? was ist die pathogenetische bedeutung der besiedlung der unteren atemwege mit candida species? ist die candidapneumonie eine häufige erkrankung? wie lange muss die therapie einer candidämie durchgeführt werden? . werden fadenpilzinfektionen endogen oder exogen erworben? welche erkrankungen der lunge durch aspergillus species werden unterschieden? ein junger mann berichtet, dass er seit wochen unter leibschmerzen und durchfällen, gelegentlich auch unter obstipation leide. die beschwerden seien das erste mal aufgetreten, als er noch in brasilien war, wo er für seine ethnologische doktorarbeit bei urwaldindianern material gesammelt habe. auf befragen gibt er an welche frage ist zunächst zu stellen? b. welche untersuchungen werden durchgeführt? c. wie wird der patient behandelt? d. was wird dem patienten gesagt? er gibt an, er habe seit tagen fieber bis , °c, außerdem kopfschmerzen, inappetenz, abdominelle schmerzen und Übelkeit. er habe keine malariaprophylaxe eingenommen, da man ihm gesagt habe, dass im januar wegen der tiefen nachttemperaturen in nordindien kein malariarisiko bestehe sie gibt an, sich seit gestern stark unwohl gefühlt zu haben, wie in letzter zeit schon öfter während ihrer regelblutung. im büro heute morgen habe sie dann begonnen stark zu schwitzen, verbunden mit hitze-kälte-wallungen, schließlich sei ihr "schwarz" vor augen geworden. befunde der orientierenden untersuchung: rr / liegend, puls , temperatur , °c rektal. a. wie lautet ihre verdachtsdiagnose? b. welche untersuchungen veranlassen sie zunächst? c. welche therapeutischen maßnahmen sind angezeigt? d die e.-granulosus-larve bildet in der regel eine mit flüssigkeit gefüllte zyste (› abb. . ), die langsam verdrängend wächst und einen durchmesser von cm und mehr erreichen kann: zystische echinokokkose.im gegensatz dazu bildet die e.-multilocularis-larve komplizierte, schwammartige, gallertig gefüllte schläuche und hohlräume von wenigen millimetern durchmesser: alveoläre echinokokkose. der parasit wächst infiltrativ destruktiv, ähnlich wie ein bösartiger tumor; metastasierungen in alle organe können vorkommen.symptome für beide echinokokkosen werden inkubationszeiten von mehreren jahren, bei der alveolären echinokokkose sogar von mehr als jahren angenommen. die symptome sind von der ausdehnung des organbefalls und von der wachstumsgeschwindigkeit des parasiten abhängig. häufig sind oberbauchschmerzen, tastbarer tumor im bereich der leber mit verdrängungsgefühl oder schmerzen, seltener gallenstau und aszites. oft werden die zysten auch nur zufällig entdeckt. bei lungenbefall kommt es zu hämoptyse, atelektasen und bronchiektasen. nicht selten sind allergische reaktionen an haut und schleimhäuten, gelegentlich asthma bronchiale.diagnostik für die diagnostik der beiden echinokokkoseformen sind vor allem sonographie und computertomographie von großer bedeutung. werden zystische veränderungen in der leber oder lunge festgestellt, muss durch anwendung serologischer verfahren versucht werden, eine diagnose zu stellen. werden zwei antikörperbestimmungen unterschiedlichen aufbaus nebeneinander verwandt, so lässt sich in den meisten fällen eine klärung erreichen. die alveoläre echinokokkose lässt bei den verschiedenen bildgebenden verfahren in der regel keine zystische struktur erkennen, zentrale nekrosen im parasitengewebe können diese allerdings vortäuschen. verkalkungen sind häufig. und eiweißerhöhung; sepsis: leukozytose mit linksverschiebung, crp-, procalcitoninerhöhung) wider. therapie entscheidend ist die frühzeitige penicillin-g-therapie in hoher dosierung ( - mega/tag). alternativen (vor allem bei penicillinallergie) sind carbapeneme oder cephalosporine der . generation. die therapie dauert mind. [ ] [ ] [ ] [ ] [ ] tage; von anfang an durchgeführte liquorkontrollen müssen keimfrei sein. prophylaxe eine präventive schutzimpfung für die serotypen a und c zur eindämmung von großepidemien ist möglich (ausnahme: säuglinge). gegen neisseria meningitidis typ b gibt es bisher keine impfung. expositionsprophylaxe mit rifampicin wird personen empfohlen, die intensiven kontakt zu einem erkrankten hatten (familie, kindertagesstätten). die erkrankung ist meldepflichtig (s. ifsg nach § abs. nr. ). verursacht durch neisseria gonorrhoeae (gonokokken), ist sie die häufigste bakterielle geschlechtskrankheit. außerhalb der genitalschleimhaut sterben die bakterien relativ schnell ab. therapie bei erwachsenen gabe von penicillin oder chinolonen (evtl. nur eine dosis!), bei kindern cephalosporine der . generation. diphtherie definition erreger ist corynebacterium diphtheriae, und zwar nur diphtherietoxin-bildende stämme. die Übertragung erfolgt durch tröpfcheninfektion oder direkten kontakt mit erkrankten oder gesunden keimträgern. epidemiologie gab es in deutschland zum bisher letzten mal gruppenerkrankungen bzw. kleinepidemien. einzelfälle (meist eingeschleppt aus epidemiegebieten, zurzeit russland, ukraine) kommen immer wieder vor. da bei uns der impfschutz bei älteren jugendlichen und erwachsenen (nicht durchgeführte wiederimpfungen) durch die aktive impfung stark abnimmt, ist ein epidemieartiges auftreten der diphtherie jederzeit möglich.manifest erkranken ca. % der infizierten. pathogenese pathogenetisch entscheidend ist das diphtherietoxin, bestehend aus den untereinheiten a (letal zytotoxisch) und b (vermittelt zelleinschleusung) und kodiert von einem prophagen.das toxin wird am ort der infektion produziert und gelangt per continuitatem oder hämatogen zu anderen gewebsbereichen bzw. organen. rachendiphtherie hauptsächliche manifestation mit rötung und schwellung von rachenschleimhaut bzw. tonsillen und schwerem allgemeinem krankheitsgefühl nach bis zu tagen inkubationszeit. hohes fieber ist selten, dann oft zeichen einer primär-toxischen diphtherie. im weiteren verlauf bilden sich nach wenigen stunden weiße beläge auf der schleimhaut, aus denen die bräunlichen pseudomembranen aus fibrin, entzündungszellen und nekrotischen epithelzellen gebildet werden (› abb. . ), die fest auf den wundflächen haften. eine instrumentelle ablösung führt daher zu blutungen (wichtiges diagnostisches kriterium!). von diesen pseudomembranen kann ein sehr charakteristischer fötid-süßlicher geruch ausgehen. die zugehörigen regionären lymphknoten sind deutlich geschwollen. klinischer höhepunkt nach - tagen. dieser kann im sekundär-toxischen verlauf mit spätkomplikationen, aber auch unter entfieberung in die hei lungsphase übergehen. selten hämatogene metastasierung der erreger.abb. . meningokokken (pfeile) im liquor, umgeben von granulozyten. (aus: thomas, ). • nasendiphtherie (mit eitrig-blutiger sekretion), augendiphtherie (konjunktivitis) und nabeldiphtherie: vorrangig bei säuglingen definition grampositive fadenbakterien, die in verzweigten geflechten wachsen (strahlenpilze). man unterscheidet anaerobe (gattung actinomyces und arachnia) von aerob wachsenden aktinomyzeten (gattung nocardia). nokardien leben im erdboden, die anaeroben aktinomyzeten auf der menschlichen oropharyngealschleimhaut. therapie nach entnahme von material zur mikrobiologischen diagnostik kalkulierte therapie mit antibiotika mit wirksamkeit gegenüber enterobakterien. häufig wird hierzu ein breitspektrum-β-lactam (z. b. piperacillin oder drittgenerations-cephalosporin), ein fluorchinolon oder ein carbapenem eingesetzt (› kap. . . ). grundlage für eine gezielte chemotherapie ist das ergebnis der antibiotikaresistenzprüfung. weltweit wird bei enterobakterien eine zunehmende resistenzentwicklung beobachtet, von der neben älteren substanzen (ampicillin, co-trimoxazol) zunehmend auch fluorchinolone (v. a. bei e. coli) betroffen sind. hinzu kommt das zunehmende auftreten von stämmen, die "extended spectrum"-β-lactamasen (esbls) bilden, die zur resistenz gegenüber allen β-lactam-antibiotika mit ausnahme der carbapeneme führen. besondere therapiemaßnahmen bei septischem krankheitsverlauf (z. b. gabe von antikörpern, kortikosteroiden oder aktiviertem protein c) und supportive therapiemaßnahmen werden an anderer stelle beschrieben. prävention bisher keine spezifischen maßnahmen. die verhinderung nosokomialer infektionen durch fakultativ pathogene enterobacteriaceae beruht v. a. auf präventiven hospitalhygienischen maßnahmen und dem rationalen umgang mit antibiotika. bestimmte darmpathogene e.-coli-stämme können enteritiden und kolitiden verursachen (› tab. symptome -phasiger verlauf nach -bis -wöchiger inkubationszeit mit charakteristischen, wochenlang anhaltenden hustenanfällen im . stadium.diagnostik pcr-basierte nachweisverfahren zum nachweis des pathogenetisch bedeutsamen, von b. pertussis produzierten pertussis-toxins stehen im vordergrund. andere verfahren zum nachweis von b. pertussis (direkte immunfluoreszenz, kultureller erregernachweis, serologischer antikörpernachweis) sind heute von geringerer bedeutung.therapie chemotherapie mit erythromycin: geringer einfluss auf den krankheitsverlauf, verkürzt aber die erregerausscheidungsdauer. nach durchgemachter erkrankung besteht eine lang dauernde, aber nicht unbedingt lebenslange immunität.die aktive impfung erfolgt nicht mehr mit dem klassischen "ganzzell"-impfstoff, sondern mit einer "azellulären" pertussis-vakzine mit hoher effektivität und geringen nebenwirkungen (› kap. . ). therapie wie bei ornithose. die mögliche ätiopathogenetische bedeutung von c. pneumoniae bei der entstehung arteriosklerotischer gefäßerkrankungen und folgekrankheiten wie z. b. khk und herzinfarkt wird kontrovers diskutiert. eine rolle in der kopathogenese (entzündung!) erscheint möglich, eine monospezifische bedeutung sehr unwahrscheinlich. auf jeden fall rechtfertigt die bisher vorliegende studienevidenz keine spezifischen therapeutischen konsequenzen (antibiotikatherapie). die serovare l -l von c. trachomatis sind für die klassische geschlechtskrankheit lymphogranuloma venereum verantwortlich mit manifestation im genitalbereich und den benachbarten lymphknoten.die serovare a-c von c. trachomatis, die weltweit aber vorrangig in warmen gebieten vorkommen, verursachen die in stadien fortschreitende keratokonjunktivitis, das trachom, die häufigste einzelursache für blindheit weltweit.natürliche habitate der serovare d-k von c. trachomatis sind die zervix die frau und die urethra des mannes. infektionen erfolgen daher stets von dort aus, perinatal oder durch geschlechtsverkehr.klinische bilder krankheitsbilder bei infektionen mit den serovaren d-k sind v. a. infektionen des genitaltrakts: beim mann nichtgonorrhoische und postgonorrhoische urethritis. symptome sind dysurie, urethralschmerzen und -ausfluss. komplizierend kann eine prostatitis bzw. epididymitis hinzukommen.bei der frau verlaufen infektionen oft symptomlos bzw. als urethral-oder dysuriesyndrom, mehr durch unpässlichkeit denn als richtige krankheit gekennzeichnet. daraus kann eine adnexitis bis zum tuboovarialabszess entstehen. ausgehend von ersterer kann sich eine perihepatitis (fitz-hugh-curtis-syndrom) entwickeln mit entsprechender oberbauchsymptomatik. als folge der adnexitis kann es durch verwachsungen zum tubenverschluss mit sterilität bzw. zur extrauteringravidität kommen. nach perinataler infektion kann es zur typischen chlamydienerkrankung des neugeborenen kommen, der sog. einschluss(körperchen)konjunktivitis. die entsprechende erkrankung des erwachsenen (schwimmbadkonjunktivitis) ist heute viel seltener (chlordesinfektion der schwimmbäder).bei schwer immunsupprimierten ist eine c.-trachomatis-pneumonie möglich.als komplikation nach einer c.-trachomatis-infektion gilt eine reaktive arthritis bei bevorzugter betroffenheit von hla-b -trägern. therapie chemotherapie bei erwachsenen mit tetrazyklinen oder chinolonen (evtl. partnerbehandlung!), bei kindern mit makroliden. synonym: rickettsiosen definition rickettsia species sind kokkoide gramnegative stäbchenbakterien. die bis vor kurzem auch hierzu gerechneten coxiella species werden aufgrund neuer molekulargenetischer untersuchungen heute mit den legionellen in einer eigenen ordnung geführt. dies gilt auch für die ehrlichia species, die mit anderen gattungen die familie anaplasmatacea bilden, und deren zellwand kein lipopolysaccharid und peptitglykan, sondern cholesterin enthält. alle haben einen obligat intrazellulären lebenszyklus und werden mit ausnahme von coxiella bumetii durch arthropoden übertragen. diagnostik pcr-verfahren und serologische tests. an mögliche doppelinfektionen denken (borreliose, fsme; zecken!). therapie tetrazykline, vor allem doxycyclin, und rifampicin. bartonellen sind gramnegative pleomorphe stäbchenbakterien, die früher z. t. als gattung rochalimaea in der familie rickettsiaceae geführt wurden. sie werden heute in einer eigenständigen familie (bartonellaceae) als gattung bartonella eingeordnet. im gegensatz zu den klassischen rickettsien (s. o.) können sie auf spezialmedien in etwa woche kulturell angezüchtet werden. die pathogenese von bartonella-infektionen ist noch weitgehend unbekannt. eine seltene, aber gefährliche manifestation ist die neuroretinitis mit akutem mono-oder bilateralem visusverlust mit papillitis, retinaler vaskulitis und/oder makulaödem. eine weitere wichtige manifestation ist die bazilläre angiomatose mit sepsis, die nur bei immundefekten (hiv!) auftritt. charakteristisch sind generalisierte gefäßproliferationen an haut und schleimhäuten, kombiniert mit septischen zuständen.eine seltene manifestation ist die bazilläre peliosis, gekennzeichnet durch zystische, mit blut gefüllte läsionen in leber und milz.diagnostik mikrobiologisch durch mikroskopischen und kulturellen erregernachweis im spezialverfahren. wichtiger sind immunfluoreszenz-und elisa-verfahren und auch die pcr.therapie tetrazykline und makrolide. impfindikationen und -empfehlungen hängen von folgenden zielen ab:• ausrottung eines erregers (z. b. pocken, aktuell: poliomyelitis (who))• herdenimmunität: manche erreger können in einer bevölkerung nicht mehr epidemisch auftreten, wenn ein bestimmter mindestanteil der bevölkerung ausreichend immun ist.• individualschutz. die impfpolitik eines landes hängt von den epidemiologischen verhältnissen, der verfügbarkeit von impfstoffen und der impfstrategie ab. in deutschland gibt es von der ständigen impfkommission (stiko) öffentliche empfehlungen, d.h. definitionen von regel-oder standardimpfungen. eine gesetzliche impfpflicht besteht hier nicht. allgemein empfohlene standardimpfungen sollen nach einem von der stiko jährlich aktualisierten impfplan bereits im frühen säuglingsalter (ab dem vollendeten . lebensmonat; › tab. für aktualisierungen siehe auch www.rki.de * abstände zwischen den impfungen mindestens wochen; abstand zwischen vorletzter und letzter impfung mindestens monate ** generelle impfung gegen pneumokokken für säuglinge und kleinkinder bis zum vollendeten . lebensjahr mit einem pneumokokken-konjugatimpfstoff; standardimpfung für personen ≥ mit polysaccharid-impfstoff und wiederimpfung im abstand von jahren *** mindestabstand zwischen den impfungen wochen **** jährlich mit dem von der who empfohlenen aktuellen impfstoff ***** jeweils jahre nach der letzten vorangegangenen dosis meningokokken (serogruppe c). bei erwachsenen sind auffrischimpfungen gegen tetanus und diphtherie in abständen von jahren vorgesehen. für alle erwachsenen nach vollendetem . lebensjahr wird eine standardimpfung gegen influenza und pneumokokken empfohlen, aber selten umgesetzt. für personen ohne individuelles risiko, wird in deutschland z. b. bei reisen in länder mit endemischem auftreten der poliomyelitis eine routinemäßige auffrischung der poliomyelitisimpfung nach dem . lebensjahr nicht mehr empfohlen.bei den nach § abs. des infektionsschutzgesetzes (ifsg) öffentlich empfohlenen impfungen ist eine kostenübernahme durch die krankenkassen nicht automatisch gegeben, jedoch werden die kosten für diese schutzimpfungen in der regel nach verhandlungen über die umsetzung der stiko-empfehlungen von den verschiedenen kostenträgern übernommen (kassenleistungen nach § abs. sgb v). bei anerkanntem impfschaden nach einer "öffentlich empfohlenen" impfung werden die kosten zur entschädigung und versorgung durch die bundesländer übernommen.neben den standardimpfungen (regelimpfungen) und den zugehörigen auffrischimpfungen gibt es indikationsimpfungen für risikogruppen (z. b. bei bestimmten grunderkrankungen, individuell erhöhtem expositions-bzw. beruflich erhöhtem risiko). wichtig ist die kenntnis der indikationen für reiseimpfungen (z. b. cholera, fsme, gelbfieber, hepatitiden a und b, influenza, meningokokken, tollwut, typhus). die in den stiko-empfehlungen mit r gekennzeichneten reiseimpfungen werden nicht von den krankenkassen übernommen. indikationen bei den regelimpfungen ist die indikation generell gestellt. indikationsimpfungen erfolgen zum individualschutz prä-oder postexpositionell. als domäne der postexpositionellen impfung wird üblicherweise die passive immunisierung empfänglicher (nicht immuner) angesehen, z. b. standardimmunglobulingabe nach masernexposition bei schwangeren, oder hyperimmunglobulingabe nach varizellen-exposition bei immunsupprimierten oder schwangeren. postexpositionelle aktive impfungen (inkubationsimpfungen) bei immungesunden sind möglich und werden allein (z. b. masern, hepatitis a) oder als kombinierte aktiv-/passivimmunisierungen praktiziert (z. b. tollwut, hepatitis b, tetanus, ggf. hepatitis a). die verbreitete furcht vor inkubationsimpfungen hat ihre wurzeln weniger in der immunologie als in der sorge um schadenersatzansprüche bei trotz impfung schwer verlaufender bzw. nicht vermeidbarer erkrankung. impfabstände zeitliche abstände zwischen impfungen mit totimpfstoffen sind nicht erforderlich. lebendimpfungen müssen simultan oder mit -wöchigem abstand verabreicht werden. die empfehlungen zu zeitlichen abständen zwischen auffrischimpfungen sind sinnvolle richtschnur für individuelle impfentscheidungen. eine begonnene, aber nicht vollständig durchgeführte grundimmunisierung kann jederzeit fortgeführt und muss nicht von neuem begonnen werden ("jede impfung zählt."). zur konkreten planung und verschreibung von impfungen siehe produktinformationen der hersteller und gültige rote liste (› tab. impfstoffe sinnvoll und anzustreben sind polyvalente extrakt-impfstoffe, die gereinigte kapselpolysaccharide von möglichst vielen infektionsrelevanten kapseltypen enthalten (› tab. . ). so gibt es eine polysaccharidvakzine aus verschiedenen polysaccharidantigenen der ca. bekannten pneumokokkentypen. polysaccharid-impfstoffe führen jedoch bei kindern < jahren zu keiner ausreichenden immunantwort. zur bekämpfung schwerer systemischer pneumokokkeninfektionen war daher die entwicklung von pneumokokken-protein-konjugat-vakzinen ein großer fortschritt, da mit einer bei diesen konjugaten gegebenen t-zell-abhängigen immunisierung auch säuglinge effektiv gegen pneumokokken geschützt werden können. indikationen nach eindeutigen erfolgen in den usa wurde ein -valenter pneumokokken-konjugat-impfstoff in deutschland zunächst für die höchstgefährdeten frühgeborenen zugelassen. im juli wurde dieser erstmals als standard für alle kinder < jahren empfohlen (› tab. . ). die verabrei-chung des pneumokokken-polysaccharid-impfstoffes (immunantwort t-zell-unabhängig) an personen > jahre ist seit jahren standard. im sinne einer indikationsimpfung sollte bei kindern und erwachsenen mit erhöhter morbidität und mortalität durch pneumokokken eine immunisierung durchgeführt werden. besonders gefährdet sind patienten mit folgenden grunderkrankungen: . angeborene oder erworbene immundefekte mit t-und/ oder b-zellulärer restfunktion: -hypogammaglobulinämie, komplementdefekte -asplenie oder nach splenektomie -krankheiten der blutbildenden organe -zustand nach organtransplantation -sichelzellenanämie -hiv-infektion -neoplastische erkrankungen. . chronische krankheiten:-herz-kreislauf-krankheiten -krankheiten der atmungsorgane -diabetes mellitus und andere stoffwechselkrankheiten -chronische nierenkrankheiten -neurologische krankheiten -liquorfistel. durchführen der impfung säuglinge sollen die pneumokokken-konjugat-impfung parallel zu den anderen standardimpfungen nach vollendetem ., . und . lebensmonat ebenso wie die . impfung ab vollendetem . lebensmonat erhalten. bei ca. % der vollständig immunisierten kinder in den usa lag eine schützende immunantwort gegen alle verabreichten serotypen vor. auch in europa ist trotz der epidemiologischen verbreitung unterschiedlicher serotypen ein erheblicher rückgang von invasiven pneumokokken-infektionen durch die generelle einführung der konjugatvakzine zu erwarten. nebenwirkungen insgesamt gute verträglichkeit der konjugat-impfung, bisher keine berichteten bleibenden schäden. vereinzelt wurden fieberkrämpfe infolge eines raschen temperaturanstieges beobachtet. lokale schmerzen an der injektionsstelle wurden von ca. % der geimpften beklagt. der polysaccharidimpfstoff gegen pneumokokken ist wegen seiner zum teil erheblichen lokalen nebenwirkungen (schmerzen, schwellung) vor allem bei auffrischimpfungen in zu kurzen intervallen bekannt, gilt aber als effektiv und sicher. impfstoff von den in deutschland relevanten serogruppen a, b und c können nur a und c durch einen impfstoff erfasst werden. eine impfstoffentwicklung gegen die häufigste serogruppe b war wegen einer strukturähnlichkeit des kapselpolysaccharids mit der n-acetyl-neuraminsäure in gehirnzellen und dadurch bedingter immuntoleranz bisher nicht erfolgreich (› kap. . . ). jedoch wurde in den letzten jahren u. a. in großbritannien ein meningokokken-konjugat-impfstoff gegen die serogruppe c erprobt und so eine deutliche reduktion schwerer meningokokken-typ-c-infektionen erzielt. indikationen die stiko hat im juli erstmals die impfung aller kinder zu beginn des . lebensjahres mit einer einmaligen meningokokken-typ-c-konjugat-gabe empfohlen. die umsetzung in der pädiatrischen praxis und der erhoffte epidemiologische erfolg mit verminderung der lebensbedrohlichen meningokokken-infektionen sind kritisch zu verfolgen. indikation zur meningokokkenimpfung gegen die serogruppen a, c, w und y mit einem quadrivalenten polysaccharidimpfstoff besteht bei:• besonderer gesundheitlicher gefährdung (angeborene oder erworbene immundefekte mit t-und/oder b-zellulärer restfunktion, z. b. komplementdefekte, hypogammaglobulinämie, asplenie)• gefährdetem laborpersonal • reisen in endemiegebiete (entwicklungshelfer, medizinisches personal, pilger). nebenwirkungen insgesamt gute verträglichkeit, gelegentlich lokalreaktionen, selten fieber. impfstoff der impfstoff (kühlkettenversand!) wird in embryonierten hühnereiern hergestellt und enthält daher hühnereiweiß (cave: hühnereiweißallergie!). indikationen die indikationsimpfung ist von einigen afrikanischen ländern für reisen in endemiegebiete vorgeschrieben. für reisende nach asien, die aus endemiegebieten einreisen wollen, besteht ebenfalls impf-oder quarantänezwang. die hinweise der who zu gelbfieber-infektionsgebieten sind zu beachten.die gelbfieberimpfung darf nur in von den gesundheitsbehörden zugelassenen gelbfieber-impfstellen durchgeführt werden. die impfung von kindern < monaten gilt als kontraindiziert. schwangere dürfen, besonders im . trimenon nur bei strenger indikationsstellung geimpft werden. eine allergie gegen hühnereiweiß stellt eine kontraindikation dar, evtl. kann bei verdacht darauf durch die intrakutane gabe von , ml des lebendimpfstoffes vorgetestet werden. der impfschutz ist hervorragend ( %) und hält wahrscheinlich lebenslang an. das internationale impfzertifikat ist jedoch nur jahre gültig, d.h., bei reisen in entsprechende länder ist eine wiederimpfung nach jahren nötig, um den rechtlichen vorschriften zu genügen.neben der bekämpfung der vektoren (insekten) ist die impfung der einzige schutz vor gelbfieberepidemien und urbanem gelbfieber. nebenwirkungen sehr gute verträglichkeit, gelegentlich lokale rötungen, vereinzelt kurzfristige grippeähnliche symptome am .- . tag nach der impfung. impfstoff die derzeit in deutschland zugelassenen impfstoffe zur oralen oder parenteralen applikation vermitteln eine schutzrate von - % (kein schutz gegen paratyphusinfektionen) für - jahre. indikationen• reisen in endemiegebiete • beruflicher umgang mit infizierten oder dem erreger.kontraindikationen diese sind für den oralen lebendimpfstoff gegeben bei:• darminfektionen zum zeitpunkt der impfung • antibiotikaeinnahmen vor dem . tag nach beendigung der impfung • kindern im . lebenshalbjahr (kapsel).geimpfte scheiden für einige tage den impfstamm aus. die gleichzeitige einnahme von malariaprophylaxe, antibiotika oder laxanzien kann den impfschutz beeinträchtigen. nebenwirkungen ausgezeichnete verträglichkeit, gelegentlich leichte gastrointestinale beschwerden oder kopf-und gliederschmerzen nach den einnahmen. • reisen (entwicklungshelfer) in endemiegebiete, die indikation sollte von fall zu fall, je nach art der reise, gestellt werden.• bei choleraepidemien.durchführen der impfung die derzeit in deutschland zugelassene impfung erfolgt subkutan mit altersabhängiger dosis in form von impfungen im abstand von - wochen. bei fortbestehender exposition erfolgen auffrischimpfungen im abstand von - monaten. dauer und schutzwirkung der zugelassenen choleraimpfung sind begrenzt: der schutz beträgt - % für nur ca. monate. daher wurde sie von der who aus den internationalen gesundheitsvorschriften im reiseverkehr herausgenommen.nebenwirkungen heftige lokale beschwerden (rötung, schwellung, schmerzhaftigkeit) sind häufig, systemische reaktionen mit fieber, kopfschmerzen, gastrointestinalen beschwerden selten. die indikationen ergeben sich aus reiseziel, aktuellen epidemiologischen bedingungen und hygienischen verhältnissen. für die zeitplanung ist entscheidend, ob lebendimpfungen und evtl. nachzuholende grundimmunisierungen oder auffrischimpfungen nötig sind (› tab. . ).man kann und soll bei vielen grundimmunisierungen und genug zeit bei der reiseplanung die injektionstermine der totimpfstoffe entflechten. die . injektion der grundimmunisierung z. b. gegen hepatitis b kann nach der rückkehr oder im reiseland erfolgen. key: cord- -dtxtjtfo authors: kasoka, kasoka title: autonomy in hiv testing: a call for a rethink of personal autonomy in the hiv response in sub-saharan africa date: - - journal: med health care philos doi: . /s - - -y sha: doc_id: cord_uid: dtxtjtfo the author reviews various conceptions of autonomy to show that humans are actually not autonomous, strictly speaking. he argues for a need to rethink the personal autonomy approaches to hiv testing in sub-saharan africa (ssa) countries. hiv/aids has remained a leading cause of disease burden in ssa. it is important to bring this disease burden under control, especially given the availability of current effective antiretroviral regimens in low- and middle-income countries. in most ssa countries the ethic or value of personal autonomy or self-determination is promoted as primary in hiv testing decision-making. ssa policymakers have an ontological and moral duty to adopt hiv testing policies that reflect human and medical realities, relationships, local contexts, and respect human rights for both individuals and others who are affected by hiv in society. without rethinking the value of autonomy in hiv testing decision-making, the article cautions that attainment of the sustainable development goal (sdg) and the unaids fast-track strategy that explicitly call to end the epidemic by will not be feasible for ssa. the case of covid- pandemic has more than ever presented to the world that individual autonomy in society is at best conditional and relational. the coronavirus intrusive measures taken to contain the virus expose the fundamental problem in metaphysics-the issue of what makes a person the same over a period of time-and the moral dilemma posed in bioethics by the fact that an individual who lives in society with others is promoted as a sovereign of her own body, medical choices and life. this dilemma might otherwise be expressed: 'what makes a person the selfsame person today as who he or she was yesterday' (ndete ) , and what does autonomy mean to an individual whose exercise of self-governance has inescapable ramifications on the wellbeing and rights of others. thus, should there be a need to rethink the personal autonomy premising of informed consent requirements in hiv testing in most sub-saharan african (ssa) countries, since informed consent requirements in hiv testing are mainly premised on personal autonomy? childress / ; fraser ; united nations ; naidoo and vernillo ) . or there isn't a need to rethink because humans are, as kantian and related notions of autonomy tell us, normatively and narratively sovereign selves? in this article i seek to show that personal autonomy, strictly speaking, is an illusion, and its primacy in healthcare ethics is morally problematic. in most of ssa countries the hiv prevalence has stabilised at high rates. the ssa region carries a disproportionate hiv burden, accounting for % of the worldwide burden of infection (bulstra et al. ) . hiv/aids is a leading cause of morbidity and mortality in the region (dwyer-lindgren, et al. ). this is despite that major scientific breakthroughs (availability of effective hiv therapy) that have shifted the hiv paradigm that was once was considered a death sentence are now mostly available in the region. even with the availability of hiv medication in ssa countries like zambia, aids still remains the most common cause of death. and yet, individual citizens are still celebrated and told through hiv laws or policies that they have a right to refuse hiv testing because they are sovereigns of their own health, life and destiny (castell v. de greef ; southern africa litigation centre ) . therefore, does this temptation and pursuit to view ourselves as autonomous hiv testing decision-makers blind us to an observable reality that shows that as humans we are interdependent and inextricably social and socialised beings? three decades into the hiv epidemic, hiv still poses a real health challenge from which no country in the world is immune, particularly ssa countries. according to unaids' factsheet, at the end of . million people worldwide were living with hiv (unaids a, b, c) . the same source indicates that . million people as of the end of became infected with hiv since the beginning of the epidemic. of the . million infected, million have since died from aids-related illnesses. this makes hiv/ aids one of the major causes of morbidity and mortality in the world. hiv/aids is the second leading cause of death in ssa (business insider ). given the threat of the epidemic, it is not surprising that all the united nations member states agreed to reach certain targets in response to the disease (suthar et al. ). these targets were set to be achieved by . some of the targets included the reduction of sexual and parental transmission of hiv by %, elimination of vertical hiv transmission, reduction of tb deaths among people living with hiv by %, and delivery of art to million people (suthar et al. ; udjo and lalthapersad-pillay ) . it was noted that the achievement of such goals requires that people test for hiv since it is only through knowledge of one's serostatus that one can be linked to prevention, treatment and care services (suthar et al. ) . it is encouraging to note that such efforts have led to significant degrees of progress in response to hiv. overall, hiv infections are approximated to have been reduced by % between and , with . million people globally reported to have been receiving art as of june (united nations ) . at present, new worldwide efforts are being made to end the epidemic by . on june united nations general assembly (unga) member states adopted, also in the light of the agenda for sustainable development and other, a new political declaration that seeks to end aids by (un general assembly ; un news centre ). the declaration includes a set of time-bound targets to fast-track response to reach three identified milestones by this year ( ). the milestones being: reduction of new hiv infections globally to less than , ; ensure that % of people infected with hiv know their hiv status, % of people who know their status are on put on art, and % of those on art have suppressed viral load (unaids (unaids , un news centre ) . according to unaids, scale-up of art has put the reach of the global commitment to end hiv by on track (unaids ) . moreover, kharsany and karim state that the substantial declines in hiv infections are the result of hiv testing scale-up and widespread coverage of art (kharsany and karim , p. ) . thus, it is apparent that the above unga targets can only be achieved if there is an increased uptake of hiv testing and counselling (htc), and increased access to hiv prevention and care services (suthar et al. , p. ) . recognising the critical importance of hiv testing, indeed one of unaids' - - targets is that % of of all persons living hiv will know their hiv status (unaids a, b, c) . as of , % of all plhiv knew their hiv status (unaids a, b, c) . the importance of hiv testing uptake cannot be overemphasised. its advantages include: being able to initiate early treatment for those who test positive at the time their immune system is still strong; early diagnosis improves long-term survival rates; knowledge of one's hiv status helps in prevention of hiv transmission to one's sexual partners, foetuses, babies, caregivers and other; knowledge of one's hiv status prevents re-infections, and; a positive test even for those who have been diagnosed later means one can still have access to life-saving treatment (st maarten aids foundation ) . put differently, 'an hiv test opens the door to accesing a range of hiv prevention options available depending on a person's hiv status to keep themselves and their loved ones hiv-negative' (unaids n.d.) . hiv testing is indeed critical as an entry point for hiv treatment and care. unaids one of the principles of the fast-track approach also calls for change; that is, among other things, stopping what does not work when it comes to the hiv response 'and scaling-up proven programmes' (unaids , p. ). 'hiv testing services (hts) are the entry point for diagnosis and access to life-saving antiretroviral therapy (art). early diagnosis and initiation of art have been shown to drastically decrease viral load, which reduces individual morbidity and mortality, and limits onward hiv transmission. hts can also offer a pathway for primary prevention interventions, including programs that deliver pre-exposure prophylaxis, voluntary medical male circumcision, and prevention of mother-to-child transmission ' (al., ) . and who have confirmed that adherence to an effective art regimen can result in reduction (by %) of the risk of transmitting the virus to an uninfected sexual partner, and can cause viral suppression that will lead to a plhiv living a normal lifestyle and longer life expectancy. without art, plhiv develop aids as a result of a compromised immune system, thereby exposing them to development of infections, certain cancers, and other severe clinical manifestations (unaids ; un-desa ) . in this vein, i am in favour of programmes such as the 'who test and treat' policy in ssa. those countries in ssa which have already adopted and implemented this approach are therefore to be commended. the introduction of 'test and treat' programmes have significantly contributed to an increase in the number of people accessing treatment (skovdal et al. ; avert, a, b; unaids, a, b, c) . ssa governments can alocate money, including requesting for hiv programmes funding from international donors, purchase mobile clinics and hire testing community workers to go door-to-door in communities and educate people about hiv prevention and the importance of hiv testing to an individual and common good, and then offer counselling and on-the-spot hiv testing and art initiation whenever individuals consent (egpaf ; sulat et al. ; silberner ) . this should be done in combination with routine hiv testing in healthcare facilities. without further delay, before the preparation of this article, i was aware that issues surrounding personal autonomy in hiv testing are multifaceted -therefore they cannot be all explored in this article. thus, the scope of this article is limited. firstly i have not explored various cultural conceptions of autonomy in this article (for such see the position of, mbiti ; gaylin and jennings ; woods woods - traphagan ; song ) who have suggested that the primacy of the value of autonomy has its roots in western liberalism (particularly american). i have only mentioned in passing the ssa traditional ontological outlook and its potential impact on hiv healthcare ethics. secondly, the scope of the present review does not include a review of issues surrounding autonomy in clinical practice, including whether it is even possible to actualise informed consent requirements in medical practice (for this see, the position of manson and o'neill ) . thirdly, i have not explored in detail issues surrounding personal autonomy, hiv stigma and discrimination, and hence, some may argue, the importance of personal autonomy in healthcare practice. i am persuaded that the subject area of stigma versus personal autonomy deserves a critical exploratory article of its own. nonetheless, i have written this article having bourne in mind existing study findings and reports on stigma and discrimination (april ; stangl and grossman ) , which, by implication, indicate that humans are social beings affected by the social environment. extensive studies that have found that fear for hiv stigma compromise hiv testing uptake and/or art adherence are also arguably an indictment on how respect to personal autonomy in hiv healthcare should be viewed. if indeed humans are self-rulers and rational players, why should social stigma prevent them from making self-rational and moral decisions in directing their own hiv medical therapy for their own good, and direct their lives as they deem fit? why should patients be declared and imputed with personal autonomy and yet at the same time blame the impact of social stigma on preventing potential hiv service-users from seeking medical attention? is this not conceptually and practically conflicting? and lastly, this paper does not explore whether the approach to hiv testing and treatment should be different from how we approach cancer, malaria, tuberculosis, covid- , etc., even in light of hiv treatment universal health coverage. for my positions on this, i agree with hiv exceptionalism conclusions that criticise the subjectivism tendency to separate hiv response approaches from broader health systems (de cock and johnson ; april ; oppenheimer and bayer ; smith and whiteside ; benton ) . i agree that hiv exceptionalism was necessary before access to and effective art was made available in ssa. indeed, the hiv exceptionalism force is losing its original power as hiv has become less threatening (smith and whiteside ) due to accessible and effective hiv medication-treatment which has now been made available for the majority of affected populations in ssa. 'through the combined efforts of people living with hiv, national public health programmes, global donors and a broad community basing autonomy on guarding against stigma can be problematic. among other things, april ( ) arguing for opt-out hiv testing versus the issue of stigma noted: 'under an opt-in programme, ….[a person] remains oblivious of her infection and avoids any immediate repercussions from her community. yet, this only delays the consequences -she will inevitably progress to aids. in societies with high hiv prevalence, as in much of sub-saharan africa, it is all but certain that her community will find out the cause of her suffering. it will be precisely at the time of her greatest physical ailing and need for emotional support that she will suffer the burden of hiv stigma and discrimination. in the case of an opt-out programme, although her decision to test may not have been borne of her own initiative, her decision not to decline testing will empower her to control the circumstances of her disclosure and formulate a plan for addressing her disease'. of stakeholders, the number of people on antiretroviral therapy (art) rose rapidly across ssa, going from about , in to . million by the end of ' (nash et al. , p. ). hence, almost all countries in ssa have adopted hiv national policies to treat all persons, regardless of cd cell count (ssa has an hiv prevalence of . million people) (nash et al. ) . the massive expansion of art treatment in ssa has continued to save millions of lives, hence a need to even advance more appropriate hiv testing ethics. the scope of this article therefore concerns itself with a review whether a person who can test for hiv and have access to art is an autonomous patient who should be encouraged to choose her own medical therepy for her own good. the chief aim of this article is to show by reviewing procedural, substantive, ontological and socio-relational autonomy theories that capacity or achievement of autonomy in human society is an illusion, strictly speaking. thus, premising informed consent requirements of hiv testing testing on personal autonomy is problematic, philosophically and ethically. i have demonstrated that since humans don't exist in a vacuum, but are born into society and live in families and communities with fellow human beings, the promotion of primacy of personal autonomy over the common good is inappropriate. the value of autonomy has been recognised as the core of medical ethics and has been validated by court judgments as a primary good in a free society (faden and beauchamp ; planned parenthood v. casey ; airedale nhs trust v. bland ; c v minister of correctional services ; lewanika v. frederick chiluba ; huri -laws v. nigeria ; diau v botswana building society ; southern africa litigation centre ) . for example, emphasising its primacy, the south african high court even held that '[i]t is, in principle, wholly irrelevant that [the patient's] attitude is, in the eyes of the entire medical profession, grossly unreasonable, because her rights of bodily integrity and autonomous moral agency entitle her to refuse medical treatment' (castell v. de greef ) . compounding this, the worldwide media through television dramas and documentaries foster this perception that individual choices or wishes are/ought to be sovereign in medical decision-making (english et al. ) . the individual or health service-user's medical judgment is celebrated as a right to be make one's own decisions for one's own health, body and life (southern africa litigation centre ). the individual is held to be a master of her own body and destiny, and is free to resist any violations to her autonomy (diau v. botswana building society ) against others of whom she lives with in society. behind the promoted freedom, autonomy, choice, and personal rights now stands a particular vision of what is entailed in being a human being; social relationships and arrangements are only recognised as far as they are able to nurture the atomistic self (gaylin ) . and behind this vocabulary of a sovereign human being is the belief that human behaviour is voluntarily chosen, and that other people's conduct can be modified through rational argument (gaylin ; gaylin and jennings ) . the case of the covid- crisis shows otherwise. my article interrogates the personal autonomy arguments and reaches a conclusion that the philosophy surrounding the value is problematic, as well as, it is silent on the ethics of the actual implications of an autonomous decision in hiv testing (selemogo ) . this article is, therefore, composed of three themed sections. it begins by giving a brief overview of the origin of the word 'autonomy' and its evolution, and its relationship to informed consent in healthcare ethics. the second section analyses the various conceptions of autonomy. thirdly, an alternative conception of autonomy is reviewed and advanced (a review of whether autonomy is social as opposed to individual). the paper concludes by referencing the implication of a social view of autonomy on hiv testing in ssa where hiv is an epidemic. jones ( ) more in discussing the impact of the coronavirus crisis, tobias jones observes: 'it has been fascinating to see the speed at which other attitudes have changed. the indignation expressed towards people not respecting social distancing (from those who would never normally describe themselves as moralists) has been understandably shrill: here too we've suddenly realised that the wellbeing of the group is endangered by indifferent individuals, and that community -for which we've yearned for so long -means originally simply a pooling of duties…. [t]he philosopher and activist simone weil wrote that "the notion of obligations comes before that of rights. it's a complicated, but convincing case, and it seems to me that in the last month there has been a radical shift in the balance between rights and responsibilities that has changed the timbre of our lives. i've never seen so many news items about applause, or so many social media posts accompanied by clappy emojis. before, "in the absence of adversity", the psychiatrist and philosopher iain mcgilchrist said this month: "we grew flabby, selfish. we manufactured grievances that now can be seen for what they were." now, when people meet their obligations to us we're obliged' (jones ) . in east and southern africa, % of adults and % of children living with hiv are on art (avert a, b) . in this article, i have used the word 'common good' to mean 'the sum of those conditions of social life which allow social groups and their individual members relatively thorough and ready access to their own fulfillment' (velasquez et al. ). the ' "common good" refers to those facilities-whether material, cultural or institutional-that' individual 'members of a community provide to all members in order to fulfill a relational obligation they all have to care for certain interests that they have in common' (hussain ) . and as john finnis held, 'respect for human rights is a requirement of justice and that "the maintenance of human rights is a fundamental component of the common good"' (finnis , cited in hussain recently argued that what the coronavirus public health responses worldwide have shown us is that 'wellbeing isn't individual but social', and that humans 'are not actually independent at all'. the origin of autonomy, its relationship with informed consent, and hiv testing in ssa jackson ( ) explains that the word autonomy is from the greek words autos (self) and nomos (rule), which originally was used to refer to cities' independent self-rule. feinberg ( ) , among others, also have noted that the word has a greek origin which comes from the greek for 'self' and 'law', meaning the making of one's own laws. in tracing the roots of personal autonomy, taylor ( ) suggests that individual self-authorship has its roots in the romantic liberalism of john stuart mill ( ) , in which free development of individuality was promoted. feinberg ( ) states that personal autonomy has interrelated meanings, from one's capacity to govern oneself, to the sovereign authority to govern oneself. o'neill ( ) provides that the original view of autonomy in antiquity-meaning self-legislation-never referred to persons, but to property. that is, ancient autonomous citystates made their own laws, colonies being given laws by the colonising parent cities (o'neill , p. ) . so, unlike its original cities' self-rule application, autonomy has now been extended to indicate the self-governance of rational independent individuals. this extension to an autonomous human has been adopted in medical ethics, and universalised, incuding in ssa. patient autonomy is promoted through informed consent requirements. informed consent has become one of the fundamental principles in medical ethics and law (dhai ) . individuals are held to have inviolable bodily and psychological integrity. this body-mind integrity right is violated when a patient is afforded medical intervention: without informing her in a language she understands the nature of the therapy; she has not been told about associated benefits and risks; available options in respect to an intervention have not been disclosed, and; she has not been informed that she has a right to refuse (mcquoid-mason ) . unlawful medical interventions that do not respect patient autonomy can constitute assault at law (dove et al. ) . in common law, free and informed consent means an inclusive recognition and respect of a: patient's capacity (and competence) to consent; disclosure of information to a patient related to the nature and extent of risks incident to a medical intervention; patient understands risks involved; patient is informed about available medical options, and; patient voluntariliy consents to (or to refuse) a medical intervention (beyleveld and brownsword ; mcquoid-mason ) . put differently, the legal and ethical elements of informed consent are: capacity; disclosure; understanding, and; voluntariness (dhai ) . a healthcare professional who by commission or omission fails to respect these requirements may be held responsible for any injury resulting therefrom. in this vein, '[t]he traditional hippocratic belief that one could do almost anything on a patient as long as the principles of beneficence (best interests) and nonmaleficence (no harm) were upheld has been considerably' stamped by rational and moral individuals whose autonomous actions or choices take precedence (dhai , p. ) . the principle of informed consent in clinical practice is primarily a negative right of non-interference (schermer ; clarke ) . '[i]t is closely connected to a particularly western, post-enlightenment idea that an adult person is a bounded individual who is able to live her life freely in accordance with her self-chosen plan, and ideally independently from controlling influences' (dove et al. , p. ) . its underpinnings can be traced to the influential kantian and millan conceptions of autonomy-or humans as rational self-legislators who are ends in themselves (selemogo ) . thus, 'in the domain of western biomedicine, the epitome of personal autonomy is a patient expressing a decision that she has come to autonomously and independently' (dove et al. , p. ) . to this effect, potential hiv service-users are told that they have the right to 'make choices that meet with their own interests according to their own will…[because humans have] capacity to understand substantial information, form a judgment according to their own values and communicate with the physician freely about their wishes' (song , p. ) . in this article, i have not questioned the importance of informed consent in healthcare conduct, and in hiv testing in particular. what i question is the premising of informed consent requirements on personal autonomy. i hold that grounding informed consent on autonomy distracts attention from observable human reality-which is that there are various important aspects of and factors in life that obstruct and pose challenges to realisation of personal autonomy in society. thus, instead of promoting personal autonomy, i advance a promotion of greater cooperation between patient, healthcare professional and one'a family and community. beauchamp and childress' definition of an autonomous patient who has freedom from controlling influences is mistaken. different schools of thought have advanced various conceptions of what autonomy means. o'neill ( ) has enumerated such definitions: dignity, integrity, individuality, independence, responsibility and self-knowledge; liberty; self-assertion; knowledge of one's interests; freedom from obligations; absence of external causation; choosing one's own moral position and accepting responsibility for one's own choices; self-mastery, voluntariness; privacy; and choosing freely. in the following review, much reference has therefore been made to killmister's ( ) thoughts on autonomy because the author identifies critical aspects of autonomy that have been overlooked in various theses by celebrated luminaries. killmister's structure and analysis of the subject matter is instructive for the present review. hence, the current analysis will be restricted to a critical review of feminist accounts; kantian accounts of autonomy which have been embraced by a number of feminist thinkers will therefore be reviewed. although feminists reject kantian and rawlsian notions of autonomy due to the former's argument that autonomy is relational, there are still different theses within the feminist school of thought which are arguably similar to kantian conceptions-the only major difference being that such feminist scholars advance a relational account of autonomy due to their rejection of self-sufficiency of human beings. besides marina oshana's socio-relational theory being arguably a more persuasive feminist account of autonomy, other accounts arguably embrace kantian and rawlsian rational choice theories. i commence by considering the reflective or historic endorsement accounts of frankfurt ( ) , dworkin ( ) and christman ( ) . the theses of these great thinkers indicate that an individual's capacity for autonomy lies in her psychological dispositions. nonetheless, christman's reflective endorsement theory has been credited as an account that is placed to address the problem of socialisation-it is argued that his theory overcomes the inadequacies identified in procedural models such as those of dworkin ( ) and frankfurt (killmister ) . in fact, christman has argued that gerald dworkin and harry frankfurt's first and second-order desire theories overlook the autonomycompromising nature of manipulation. being autonomous, according to dworkin and frankfurt, is synonymous with a capacity to critically evaluate firstorder values, desires and preferences by referencing them to one's second-order preferences, values, and desires. thus, one's capacity 'to accept or attempt to change these in light of higher-order preferences and values' makes one autonomous (dworkin , p. ) . it is held that by exercising such a capacity under second-order desires, persons define their nature, give meaning and coherence to their lives, and take responsibility for the kind of person they are (dworkin , p. ) . under this theory, second-order values ought to take priority over first-order ones; second-order values are considered to be an individual's realm of autonomous decision-making. i wish to argue that dworkin and frankfurt's second-order accounts are philosophically and, consequently, morally problematic. philosophically, this rational thesis of autonomy fails to convincingly account for the problem of socialisation of values, desires and preferences, internalisations of which compromise second-order values. a person's socalled second-order desires can be a product of socialisation. effective manipulation can reach all the way to second-order desires. thus, indeed 'to judge as autonomous individuals who are hypnotized, brain-washed, or otherwise manipulated into developing second-order desires…is to misunderstand the very nature of autonomy' (killmister , p. ). holton has illustrated: 'to see this [philosophical problem of second-order thesis], suppose that i implanted a second order desire in you by hypnosis… then surely you wouldn't have free will if you got your desires to conform to that; but frankfurt's account seems to have the consequence that you would' (holton , p. ) . 'a first order desire is a desire for anything other than a desire; a second order desire is a desire for a desire. so, for instance, you might have a first order desire to smoke a cigarette; and a second order desire that you desire not to smoke a cigarette… thus [another example], i might wish that i wanted to give all money to charity, since i might think that having such a desire would show me to be an excellent person; but i might nonetheless not actually want that desire to be effective… but when a person does want the first order desire to be effective, when they want it to be their will, frankfurt calls this a second order volition' (holton , p. ) . it can be inferred from this thesis that a person can act autonomously through identification with second-order desires. that is, a person is seen to have autonomy in so far as she has second order volitions and can bring her first order desires into line with second order volitions or desires. thus, according to this account, dogs and children don't have autonomy because they lack second-order desires or volitions (holton ) . they don't have autonomous second-order desires which can be used to control first-order desires. first order values can, for example, be values which form the edifice of a given moral system. thus, common good morality can be situated in first-order values (ockham's beard ) . frankfurtian and dworkinian accounts possess a great potential to declare someone who is acting on internalised values to be autonomous. such accounts seem to neglect the fact that external conditions (in the form of, e.g., societal rewards and punishments, and limiting human biological factors) have a tendency to make humans conform to certain behaviours (gaylin and jennings ) . this can be seen in the present case of coronavirus where, due to fear of receiving fines or fear of being viewed as social deviant, among other reasons, people who would otherwise wish to open their entertainment venues, go to clubs, restaurants, bars and other social facilities, or go on holidays cannot now do so. internalised first-order desires have consequences on second-order desires. internalised ideas, fears, and values which we later mistakenly come to identify as our own have inescapable consequences on our daily choices or preferences (lanier and henry ) . a good example of internalised preference can be inferred from the -year-old student theorised by benson ( ) . benson explores the case of an -year-old whom through internationalisation of the hollywood idea that appearance is a criterion of self-worth ends up regarding beauty and fashion as essential for her self-worth. first and second-order autonomy accounts fail to explain away this lived social reality. although it is possible to hold individuals to have acted autonomously by virtue of fulfilling frankfurtian or dworkinian first and second-order requirements, it can also be argued that morally this thesis of autonomy may be amoral because it has the potential to ignore that well-being can only be achieved when both individuals and others in society act responsibly towards each other. the common good values which sustain and advance the well-being of society can be denigrated through such outlooks, and the consequences of this would be the annihilation of millions of human beings and the end of human civilisation as we know it, as each individual acts according to their own second-order values. what about christman's theory of autonomy which killmister claims is more persuasive? does christman, who criticises frankfurtian theories of autonomy, provide a more realistic perspective? according to christman's view, for an individual to claim autonomy 'necessary endorsement must be directed at the process of desire-formation, rather than the desire itself' (christman ; killmister , p. ). christman's theory of autonomy to me is equally an internalist or rational theory of autonomy. stoljar explains: for christman, preferences or desires will be nonautonomous only if they fail either a competence condition or a hypothetical reflection condition. competency corresponds to the capacity of the agent to form effective intentions relative to a desire as well as to reflect critically about the desire. the hypothetical reflection condition employs the notion of non-alienation to characterize authenticity and hence autonomy. (stoljar , p. ). killmister has illustrated and differentiated christman's account from other procedural accounts of autonomy as follows: for instance, we can take an individual who desires to eat a slice of cheesecake. rather than asking, as dworkin and frankfurt would, whether the individual desires to desire to eat a slice of cheesecake, christman asks how she would feel about her desire, were she to be aware of how the desire were formed. if the desire were implanted by a hypnotist, and knowledge of this process caused the individual to feel alienated from the desire, then that desire [according to christman] would not be autonomous. (killmister , p. ). for christman, for an action to be autonomous the individual must personally identify with the desire through a feeling of non-alienation. like frankfurtian and dworkinian visions of autonomy, i wish to argue that christman's endorsement account is unpersuasive. endorsement accounts of autonomy fail to account for internalisation of norms, values which an individual may mistakenly endorse or identify to be her own. indeed, the problem with christman's theory is not the 'inclusion of a historical version of reflective endorse-ment…, but rather that this condition is insufficient to determine the autonomy of an individual' (killmister, p. ). christman's hypothetical reflection account fails to appreciate that due to deeply ingrained traditional values, imparted through oppressive (and i add non-oppressive) ideological socialisation over many years of one's life, individuals can identify with deformed desires and not feel alienated (stoljar ) . effects of ideological socialisation and environmental changes can cause one to treat stereotypes and acquired feelings as natural to oneself and thus formulate one's desires and plans based on such ingrained nonautonomous desires (gaylin and jennings ) . recipients of socialised ideologies 'are unlikely to experience alienation from either the 'one of the more astonishing features of current political debates on autonomy and coercion is the naïve underlying assumption about rationality and human motivation. psychology -whether based on behaviourism or on its diametric opposite and antagonist, freudianism (or any of the splinter of these two dominant branches) -views few pieces of human conduct as rational choices selected at the moment. rather, modern motivational psychology tends to see most human behaviour as being "conditioned" or "unconsciously determined," a consequence or product of life experiences that tend to make responses to certain stimuli automatic and unchosen…' (gaylin and jennings , pp. - ) . norms that they have internalized or the preferences formed on the basis of the norms' (stoljar , p. ). mele's ( ) external historical account is a hypothetical counter-example to procedural accounts (killmister ). mele dismisses psychological (internalistic) accounts of autonomy (christman ) as insufficient. he advances that, if all individual human beings were like athena or a god, procedural accounts of autonomy would indeed capture what amounts to autonomy, and therefore his (mele's) historical account of autonomy would be unnecessary. however, because humans are not athenas, he argues that his alternative account is therefore valid or convincing and necessary (mele ) . i actually find mele's account of autonomy more persuasive than frankfurt, dworkin and christman's accounts put together. for mele, for an agent to be autonomous her actions must not be compelled by another: it is a historical property of agents required for responsibility for the possession of a pro-attitude. a necessary condition of an agent s's authentically possessing a pro-attitude p (e.g., a value or preference) that he has over an interval t is that it be false that s's having p over that interval is, as i will say, compelled -where compulsion is not arranged by s. (mele , p. ). the implication of mele's theory is that pro-attitudes can violate an individual's autonomy. to this effect, mele's theory implies that second-order desires (explained above) must not be a product of pro-attitudes or compulsion. he predicates his theory on an understanding that humans are susceptible to acting on socialised values (compelled or instilled pro-attitudes ). according to mele, compelled pro-attitudes, therefore, make individuals non-autonomous (mele ) . put differently, an agent's choices are nonautonomous, according to mele's exposition, when: an agent comes to have a pro-attitude because of an external force, rather than via exercise of her skills for critical reflection and evaluative judgment; (ii) the instilled pro-attitude is one she is unable (in the absence of radical counterfactuals) to eradicate or attenuate; (iii) she did not arrange the by-passing herself; and (iv) she does not, nor did she earlier, possess other pro-attitudes that would support her endorsing the instilled pro-attitude. (killmister , p. ) the implication of this understanding of autonomy is that human motivation is susceptible to socialised pro-attitudes that are difficult to efface. mele's exposition of autonomy makes more sense as it touches on external factors that internalist accounts of autonomy fail to account for. indeed, a fully competent individual who is able or capable of acting rationally upon desires (values which she has critically reflected upon) cannot necessarily by this very token be safely considered autonomous, as the pro-attitudes (which she considers to be her own) could have been socialised earlier in life. however, i do not completely agree with mele's thesis regarding what he then advances as constituting autonomy. this disagreement lies in mele's advancement of an alternative theory of self-control as being a mechanism through which one can achieve autonomy. this theory (capacity for autonomy by virtue of self-control) appears to water down the fact that both inculcated cognitive biases and environmental changes can compose the very mechanics of self-control. mele's self-control theory does not satisfactorily explain how the problem of socialisation of pro-attitudes acquired since childhood can be qualified in the assessment of what amounts to one's autonomous self-control. studies have established that babies do not have competent mental capacities for reflection during early childhood-a period when they acquire pro-attitudes. killmister has argued that there is a problem in mele's theory if it is to be used as a guide for identifying 'autonomy-inhibiting socialization' (killmister , p. ). mele's approach would rule out most early childhood education directed at developing the very necessary mental capacities. killmister postulates that 'if the relevant capacities are inoperative or not yet developed, as they will be in very young children, mele takes them to have been bypassed' (killmister , p. ) . a pro-attitude is a person's mental attitude (a feeling or opinion about someone or something) directed toward an action under a certain description; pro-attitudes may include moral views, desires, urges, aesthetic principles and economic prejudices (bunnin and yu ) . despite an individual 'being perfectly able to appraise critically and act upon her desires and values, the perfectly self-controlled person may nevertheless be acting on desires and values that have been implanted into her by artificial means, ones whose development has bypassed normal reflection and awareness' (christman , p. ) . 'human beings are born biologically premature, so that unlike most mammals, many of our neurological and physical functions and all of our behavioral capacities exist at birth in potential form only. to come to fruition, these potentials must be molded by a social environment' (gaylin and jennings , p. ) . the conditions which influence our everyday adult conduct are set by our parents and culture early in life through a conflation of coercion, parental encouragement, emotional intimidation, conditioning, and other mechanisms (gaylin and jennings ). mele has nonetheless acknowledged that bypassing is common in infants but argues that such bypassing is not sufficient for compulsion unless the pro-attitude is also practically non-sheddable. to this, killmister has responded that many people have pro-attitudes (traceable to early childhood socialisation) that they are practically unable to shed. she claims that even our attitudes towards evidence, reason, and reflection are both presumably inculcated and nearly unsheddable: the problem here is that one of the central roles of socialisation is to inculcate the very pro-attitudes that are required for the kind of self-control mele sees as necessary for autonomy. to be self-controlled is to believe and desire on the basis of an assessment of evidence. this will rely upon having the appropriate pro-attitudes towards evidence and reasons, which must at some point have been instilled in the child. (killmister , p. ) . in our early development each of us is subjected to physical and social forces of which we are largely ignorant, over which we have no control, yet from which we acquire values, beliefs, motivations, and capacities for rational evaluation that subsequently guide our choices and actions. these forces "destroyed" any capacity to become a different sort of person with selfcontrol regarding any unsheddable pro-attitude that we happen to have. consequently, every unsheddable proattitude is compelled, and anyone with firm unshakeable principles of action ends up being inauthentic and non-autonomous. (kapitan , p. ). stoljar rejects procedural approaches to autonomy by replacing them with a substantive account (stoljar (stoljar , . she argues that procedural conceptions fail to appreciate that people who have been subjected to false and oppressive internalised norms cannot be autonomous. according to her thesis, oppressive socialisation can lead an individual to internalise false beliefs which the victim may later come to endorse as her own. decisions made on the basis of internalised false beliefs are therefore not autonomous, she declares. stoljar's thesis indicates that mere possession of false/ oppressive beliefs makes an individual non-autonomous. i wish to agree with killmister's observation that stoljar's theory is initially promising as it acknowledges that 'the question for all theories is what kinds of socialisation are incompatible with autonomy' (killmister , p. ) . i, however, find stoljar's account unpersuasive. what is problematic about stoljar's theory is that it reduces autonomy to an individual who is free from false/ oppressive socialisation (killmister ) . such a perspective fails to consider that for an individual to be autonomous she does not only necessarily need to choose her own moral position but also enjoys the absence of any form of external influences on her self-determination capacity. that an autonomous individual is a self-ruler, or a law unto herself, no matter what form of socialisation she underwent, should not be ignored. an autonomous individual freely acts in accordance with a self-chosen plan by virtue of self-law and/ or morality (kant ; gaylin and jennings ) . what the preceding arguments entail is that even nonoppressive internalised norms can still be non-autonomous, provided they were instilled or regulated by another or something external to the individual claiming autonomy. if to be autonomous is to be self-governing or self-directing or, in other words, to act on motives, values, and reasons that are one's own, then how can we restrict non-autonomous action to only false/oppressive socialisation? moreover, the fact that the person who is supposed to be a law unto herself is at the mercy of false/oppressive socialisation shows a lack of sovereignty, like that of the christian god, hence the illusion of autonomy. the dialogical theses by westlund ( ) and benson ( ) view a person to be a social self. according to these accounts, a person's answerability to others becomes the key condition for autonomy. in other words, autonomy is synonymous with a person's ability to have normative power or authority over one's decisions (mackenzie ) . autonomy thus becomes dispositional. what is encouraging about dialogical approaches is that they indicate that human beings are interconnected-in other words, social selves. as will be shown below, however, the thesis of dispositional autonomy is unconvincing because this theory propounds that a capacity for autonomy is premised on an individual's mental capacity. westlund argues that autonomy should not be understood in terms of an individual's psychology or history; rather it is constituted by a particular kind of disposition. her theory suggests that an agent's answerability to others is a key condition for autonomy. she rejects psychological accounts which designate an autonomous agent as one who critically reflects in an appropriate way in evaluating one's preferences, desires and motives. in other words, westlund rejects rational choice accounts of autonomy because such theories merely argue that autonomy is achieved when an individual engages in critical reflection or if an individual acts or chooses to act in accordance with desires which she has self-reflectively endorsed (friedman ; christman ). according to westlund, one's autonomy is instead undermined if one is unable to give reasons in defence for one's actions or choices (westlund ; killmister ) . so, an individual who readily answers for herself constitutes a self-governor or autonomous person, she suggests. according to benson, an autonomous act is achieved when a selfregarding attitude is expressed in one's willingness to take responsibility for one's actions (benson ) . in this case, if an agent claims authority over her own actions, then such an agent can be considered autonomous. these accounts suggest that certain emotional states and attitudes towards oneself are necessary conditions for autonomy. such approaches appear to require that reliance on critical reflection and judgment for autonomy is only possible if a person can endure criticism of her own sense of basic competence and worth. i wish to state that dialogical accounts of autonomy are philosophically and morally problematic. they are philosophically unpersuasive because such approaches ground autonomy on a person's ability to offer reasons for her choices. and these accounts are morally problematic because they are individualistic in outlook-such outlooks appear to promote autonomy on the basis of meeting moral obligations to self. although westlund criticises psychological accounts of autonomy, i wish to argue that dialogical accounts of autonomy are equally psychological or internalist in substance. thus, the criticisms of rational choice accounts of autonomy can to a larger degree equally be applied to dialogical ones; both approaches clearly ignore or brush aside the reality of socialisation and environmental conditioning. kantian psychological or rational conceptions of autonomy often erroneously portray agents as causally and psychologically independent of environmental conditioning. westlund regards someone as non-autonomous if they defer to something or someone rather than providing their own reasons in choice-making; however, she appears to ignore the fact that defending a choice with plausible reasons is not necessarily synonymous with being its author, or authentically identifying or individually valuing a given choice. an agent can defend, for example, oppressive values, not because that is what the agent desires, but because it is required. external circumstances can cause an agent to embrace oppressive values and yet still be in a position to stand behind a given decision as their own. thus, being answerable to one's choices or behaviour does not make one autonomous, but potentially makes one accountable to socialised values which one's external environment through interpersonal and environmental conditions have imposed upon or inculcated into the agent who is claiming autonomy. a person can give a convincing or persuasive reasoned answer to something not because she necessarily has chosen the value and identifies with it, but because of environmental conditioning and limitations. an agent is capable of defending inculcated or internalised oppressive values through adaptive preference formation (elster ) . expressed differently, the problem with westlund and benson's conception of autonomy is that individuals can stand behind decisions or actions which are paradigmatically non-autonomous. this is especially true seeing that it is widely accepted that 'we humans are very good at inventing post-facto explanations of our actions, even to ourselves' (moll , cited in killmister . killmister ( ) concludes by suggesting that we do not have absolute autonomy, but 'degrees of autonomy'. i hesitantly agree! one agrees in a strict sense that 'degrees of autonomy' can be in the form of restricted autonomies in which individuals have been placed under laws where boundaries have been drawn on how far they can conduct themselves. one may as well call this 'permitted autonomy'. it is within the boundaries of laws (natural or positive), ethics, regulations and conventions where one can agree that 'degrees of autonomy' are apparently found. thus, yes, we humans have no absolute autonomy. for example, the current covid- lockdown and social distancing rules indicate that human autonomy is not absolute. being the law unto oneself is limited to what governments proclaim are boundaries within which individuals can be allowed to rule themselves. however, founding autonomy on limited or relative autonomy also crumbles when the whole picture of human motivations, in light of the ever-changing environment, is closely examined. thus, can killmister convincingly enumerate in what circumstances exactly an agent can enjoy this limited autonomy, circumstances which are excluded from the susceptibility to socialisation, internalisation, biological influences or environmental changes? gaylin ( ) has established that human motivation and behaviour is highly susceptible to environmental influences. therefore, he argues that protagonists of autonomy are mistaken in believing that human behaviour is voluntary. gaylin submits that present behaviour is moreover significantly determined by past treatment (gaylin ) . he suggests that human behaviour is less rational than we are willing to admit. he advances that our behaviours are influenced by our emotions, which are usually more effective than logical argument, and adds that shame, fear, guilt, greed and pride influence human behaviour. the implication of this analysis is that a combination of societal morality (morality which can be internalised through effective socialisation), the institution of law in society which defines the boundaries of human behaviour, and human natural susceptibility to emotions (as drivers of decisions) makes the argument for capacity for individual autonomy, even in limited circumstances, problematic. discussing the stifling nature of our biological make-up on human decision-making, morison ( ) has observed that besides historical influences human 'agency' is encumbered with genetic or environmental factors which subtly motivate our day-to-day choices. for morison, much of our human behaviour is significantly influenced by events over which we as individual have little or no control. he quotes melvin konner's the tangled wing: biological constraints on the human spirit ( ) work as an extraordinary book which identifies, among others, the roles genes and the environment play towards behaviours and choice: it requires only a little reflection to realise… that our choice is strictly limited to the possibilities displayed before our conscious in real time including those we can call up from memory or create by synthesizing bits and pieces of previous experience… not nearly so clear is the degree to which the final choice is also so conditioned or "shaped" by genetic patterning or by previous experience of which we are no longer conscious. my hunch is that such influences are much more numerous than we imagine and that autonomy in any strict sense is an illusion. (morison , p. ). my review of autonomy so far agrees with feminist relational accounts to the extent that feminists generally highlight 'that agency cannot be separated from interdependence, since large swaths of our lives, especially during the formative years, are spent dependent on others, and those relationships function to inform our preferences, our values, and our understanding of our selves' (wenner ) . hence, i have contended above that autonomy cannot be conceptually explained without convincingly explaining away the impact of human social embeddedness and environmental change on human capacity for autonomy. i have thus shown that feminists' relational account analyses are only insufficient to the degree that they theorise that humans can be autonomous by virtue of a psychological state of mind. in the following discourse, i will show that autonomy is a social phenomenon. crittenden ( ) has observed that critics of liberalism, and even some liberal theorists, have criticised the emphasis of autonomy by liberalists. indeed, internalist conceptions of autonomy are not only conceptually unconvincing, but also, since they are associated with self-sufficiency, they exude 'the worst aspects of atomistic individualism, insulation, social isolation, and an indifference to society's values and interests' (crittenden ) . the fact that humans are born into society, are interdependent, co-exist, and therefore have to act in solidarity for the common good is almost ignored in rational theories. humans in psychological theories of autonomy become laws and morality unto themselves. crittenden, like gaylin, acknowledges that human beings by nature are interdependent and interconnected. hence, he argues that a conception of autonomy which is premised on self-sufficiency does not represent a fulfilment of autonomy but its abandonment. he submits that autonomy has a social nature and explains that autonomy develops through sociality, and it also requires sociality for its exercise. crittenden quotes anthony arblaster, who has noted that it is not normal or even desirable for a human to be self-sufficient (arblaster ) . he also invokes jennifer nedelsky, who submits that 'the perfectly autonomous man is thus the most perfectly isolated' (nedelsky ) . for crittenden, autonomy does not entail isolation from the presence of the influence of others or a necessary rejection of societal values, but the very concept of autonomy depends on these very factors. 'the social nature of autonomy appears to undergird a communitarian notion of the self as socially situated' (crittenden , p. ) . the author argues, among other reasons, that he believes autonomy is social because humans are not born with autonomy, but that autonomy requires psychosocial development. he also argues that 'autonomy is social because we can only be autonomous when we know we are acting autonomously; and we can only know that when we give an account to others of how we arrived at a decision or action' (crittenden , p. ) . according to crittenden, the only autonomous person is one who is able to remove herself from the social matrix. he argues that since no person is born autonomous; we may konner has demonstrated that man's behaviour is influenced by nature and nurture (konner ) . only be autonomous through socially distancing ourselves from the social matrix. he suggests that self-autonomy, provided one was born and lives in society, is impossible: any kind of introspection or reflection must be done in and through language, and the language we use is itself a cultural or social inheritance. we do not create it, and in this sense also autonomy has a social side… to make our actions and judgments intelligible to ourselves, we not only translate them into language, but also form them through language. the only language we have available by and through which to think rationally and self-reflectively, is one based on cultural tradition… there is implicit in every language, as part of that cultural tradition, a system of norms and standards that determine proper use. (crittenden , p. ). i agree with crittenden's theory of social autonomy, even though there are issues which arise from a further reading of his account which i do not necessarily agree with. when crittenden suggests that an autonomous person is one who is able to distance oneself from the social matrix-a matrix which one earlier identified with-this perspective appears to suggest that an individual is capable of extricating herself from the social context, and from her genetic make-up. if crittenden means that an individual can extricate herself from the environment (a reality which has made that person who she is), i argue that doing so is not possible in reality due to biological constraints, interdependence, common human frailty, and socialisation. in other words, because all human beings have internalised pro-attitudes, it is impossible for them to disown or separate themselves from what they are personally disillusioned to believe are their own personal values and aspirations, if they later on choose to live by themselves. that is, even if a person later decides to live alone, like the asocial koala which only has social intercourse with other koalas during the breeding season, that person very likely already has embedded pro-attitudes which they will inadvertently carry with them, unless they were nursed by a koala as a baby and have since lived alone in the jungle. feminist theorist marina oshana grounds autonomy on a socio-relational premise. oshana submits that autonomy is equivalent to self-governance (she states that the synonyms for self-governing are: 'free-standing', to be independent (self-sufficient), to be separate, and to be self-ruling and sovereign) (oshana ) . she rejects psychological conceptions of autonomy and advances an externalist account. she invokes both the internalist (psychological) and externalist (socio-relational) perspectives in her conceptualisation of what autonomy is. oshana submits that individual self-governance is in reality social. for oshana, 'autonomy is a condition of persons constituted, in large part, by external, social relations people find themselves in (or in the absence of certain social relations)' (oshana , p. ) . in this sense oshana's conception is to some extent similar to crittenden's theory. however, unlike crittenden, oshana adds that manipulation, coercion, subjection to the dominant will of others, and also 'the internal phenomena native to the individual such as captivity to desires or physical impulses, psychological neuroses, or weakness of the will' compromise the capacity for autonomy (oshana , p. ) . oshana criticises dworkinian, frankfurtian and christmanian accounts of autonomy as inadequate because these accounts are internalist. indeed, as shown above, rational accounts of autonomy premise capacity for autonomy on the 'structural and/or historical character of a person's psychological states and dispositions, and on an agent's judgments about them' (oshana , p. ) . for oshana, an individual does not become non-autonomous merely by being born in an environment where one has no control, but one becomes non-autonomous by virtue of the effects of the conditions of a given environment. she maintains that choice does not guarantee autonomy. this is because a person who may be exercising what appears to be genuine choice may be compelled to do so by others, and endorsing such choices from within does not guarantee autonomous agency (oshana ) . in regards to the assumption that critical reflection in a procedurally independent fashion makes one's choice an autonomous one, oshana argues that 'being able to engage in critical reflection, to take stock of oneself and to shape oneself on the basis of this evaluation, does not guarantee that whatever state of affairs ensues from this activity will be one of autonomy' because autonomy does not exclusively depend on circumstances descriptive of an individual's psychology (oshana , p. ). oshana has therefore advanced four conditions necessary for autonomy: critical reflection, procedural independence, access to a range of relevant options, and the condition of social-relational properties. she argues that an individual cannot be autonomous if: (i) one cannot engage in critical reflection or objective appraisal of one's motives or actions, and the environment in which one's putative values develop; (ii) if she is, in fact, influenced or restricted by others in ways that constrain autonomy (such influences can be by way of manipulation or coercion); (iii) that autonomy becomes questionable when a person claims that their decision was autonomous in circumstances where they were lacking in access to an adequate range of options; and, (iv) an individual who is in society (having relations with others) does not limit herself to relations which enable her to pursue her goals in a context of social and psychological security (oshana ) . she submits that these four conditions for autonomy are not mutually exclusive; they must all be satisfied for an individual to claim autonomy. for oshana, her account of autonomy has three benefits: it recognises the human condition; it recognises the status of humans as moral agents; and, that a socio-relational account of autonomy 'can easily explain how persons might be selfgoverning even when manifesting external or communal virtues that might appear to reduce autonomy' (oshana , p. ) . the socio-relational conception of autonomy is more convincing, philosophically and morally. it not only appreciates that humans are unique, but also recognises that humans are only able to exercise their uniqueness or the 'self' in a socialised world encumbered by fear, emotions, the need for social validation, a changing environment, and the need to act responsibly in order to protect and promote the common good for mutual well-being and survival. ravven ( , pp. - ) has shown that mounting data from history of ethics and neuroscience demonstrate that a human being is in reality the 'i that is we'. she states that neurobiological and other evidence have shown that the body-mind boundaries ethics celebrated as inviolable by millan and kantian ontological theses are mistaken. ravven demonstrates that the dimension of the human self extend beyond the scope of the body-mind, and that human investment in others in the world is finally what ethics is all about, and should be acknowledged as such. we are made for togetherness. throughout, her analysis, she convincingly demonstrates how locating the self as distributed beyond our skins and brains can provide a more plausible and appropropriate ethical and moral approach to hiv testing decisionmaking ethics. for ravven, 'the scope of the self as a moral agent, of who is performing a given moral action, can be distributed beyond the individual to groups, and even extend at times to whole contexts'. this indicates that hiv testing decision-making is in reality complex. firstly, by citing the work of clark ( ), ravven has demonstrated that the self as we understand it is joined to society and is one with the world. this is in contrast to individualised informed consent requirements which advance a self self. according to clark ( ), reported by ravven, 'at least some aspects of human cognition… [are] realised by the ongoing work of the body and/or the extraorganismic environment,' so that the 'physical mechanisms of the mind… are not all in the head' or in other central nervous system. ' ravven explains that our attraction to selfhood fails to account for an observable reality that demonstrates that as humans we are not 'locked-in' agents-as beings whose minds and physical abilities are fixed quantities apt (at best) for mere support and scaffolding by…[our] best tools and technologies.' instead, 'our minds and bodies are essentially open to episodes of deep and transformative restructuring in which new equipment (both physical and 'mental') can become quite literally incorporated into the thinking and acting systems that we identify as our own minds and bodies.' she emphasises and advances that humans do not only discover the world within their selves, but also discover themselves as parts of it. this entails that humans ought not to conceive themselves as the whole story of the whole, but as part of the story that makes the whole story complete. this outlook is similar to ssa ontological perspective that situate a human as 'a part of the organic whole' (mbiti ; menkiti ; diop ; tutu ; nussbaum ; woods woods - molefe ) . therefore, an hiv testing regime that locates hiv as a shared reality will also adopt appropriate ethics and human rights that intergrate this reality. current hiv testing ethics and human rights on decision-making in ssa have not reflected this human reality (eba ) . secondly, ravven shows how a person is an 'i that is we' by invoking co-consciousness empirical findings that have demonstrated that 'the self as a fully aware self-aware includes perspectives that were initially 'other': third person perspectives now taken in as one's own have relocated the self outside itself and in another'. she suggests that as humans we create a shared self-a self that is both mine and yours-when we unconsciously integrate our people's values and perspectives with our first person perspectives. she therefore concludes that humans are at best relational selves who discover the self through other's eyes with whom they have a shared reality, and a shared world. ravven indicates that humans share an environment of inescapable embeddedness. thus, ethicists, including hiv policymakers in ssa, should begin to acknowledge and accept that the self cannot exist in a social vacuum. the discovery that the self is not atomistic therefore 'heralds the end of the…cherished illusion… namely the illusory goal of independence, self-sufficiency, and free autonomy' promoted in hiv testing ethics which seek to disintegrate the self from her social embeddedness: at any given time the self is constructed by a relation to another person. 'people have as many selves selves as they have significant others.' these selves emerge from the early relationships with parents, siblings, extended family members, and others who have an impact on one's life, and they profoundly affect motivation and emotions. unconsciously perceived similarity triggers the relational patterns to take hold, without our conscious awareness or even the ability to control the process… the other and the relationships are necessary for the feeling of 'me' of this 'me'… heinz koht [a psychoanalyst]… held that it is through 'expanding its selfexperience to include the whole surround' that an infant comes to be able to ( ) feel itself confirmed as a self, ( ) pursue its ambitions, and ( ) pursues its ideals. (ravven , pp. - ) . thirdly, describing findings from neurobiological experiments, ravven reports that research by thomas metzinger and olaf blanke have also demonstrated that the boundaries of the self transcends the boundaries of our bodies and minds: we mistake the feeling of the self as our interior, a soul-thing, a solid bounded essence that is our true self that we alone know and disclose to the world. but that is a false picture. we are more like verbs than nouns; we make parts of the world feel like the self, and we fill our feeling with our engagemnets in the world. (ravven , p. ) . fourthly, ravven turns to neurochemistry discoveries, like the one by donald w pfaff, that have also illustrated that the self transcends body-mind. and suggests that ethics should be grounded on relational autonomy: pfaff shows that the feeling of the self and where we draw the line between the self and other, self and the world, depend upon particular neurochemicals. these chemicals that produce the self-other divide, he says, are sometimes turned off, and when they are we experience others as if they were ourselves. the neurochemistry that produces the feeling of self as extending into others, he argues, underlies ethics. he says the chemicals that turn off the feeling of self-other boundary operate in fear and in love, in empathy and in aggression, and in other situations. these chemicals create a sense of shared experience and even of merger. pfaff believes that this mechanism produces ethical action by creating empathetic responses to others. (ravven, , p. ). the dominant, individualistic understanding of autonomy that features in' bioethics and medical ethics underpin the idea that individuals are 'in their ideal form, independent, self-interested and rational gain-maximising decision-makers' (dove et al. , p. ) . my review of autonomy in this article demonstrates that such a view is erroneous as it does not convincingly account for both external and internal (influences of biology on decision-making) environmental factors. this individualistic conception of an autonomous patient is inconsistent with lived human life-it does not capture the breadth of lived human reality that shows the 'i that is we'. conceptions of autonomy, especially in clinical practice, 'should accommodate the fact that people are rarely, if ever, fully independent individuals' (dove et al. , p. ) , hence, as an example, the challenge posed by hiv stigma to hiv testing uptake. as humans, we are social, cultural and biological beings whose decisions, including in healthcare, are shaped by a conflation of powerful social, cultural and biological forces that often times are beyond us (konner ; gaylin and jennings ; ravven ; sapolsky ) . this is the more reason why we need each other as humans: as opposed to atomising ourselves. hiv testing ethics in ssa should be premised on the human reality of a self beyond itself, as this approach captures the physiological, biological, pyschological, sociological and cultural aspects of human condition; unlike the kantian and millan conceptions of personal autonomy which are largely abstract psychological ontologies. instead of advancing abstract ethics of a self within self and unto self, ssa hiv policymakers have also something to learn from ssa traditional and moral analysis that view a person as 'a person through other persons' (mbiti ; menkiti )-an outlook that was developed in the light of ssa's unique experiences and lived reality, besides ontological deliberations. this ssa outlook is consistent with the conclusion of my analysis in this article that suggests that humans are incapable of being autonomous-they are social creatures who constantly, also unconsciously, simulate the values of their socio-cultural environments as their own. drawing ethics that recognise and reflect environmental impacts, including of love, empathy, fear and hate, on individual decision-making, will therefore be a good starting point for reconfiguring individualised hiv testing informed consent requirements in ssa. hiv testing policymakers in africa should cease ignoring the impact of the illusion of personal autonomy on our shared humanity. rather, they should explore their own lived experiences and reality, review studies that indicate that as human we are part of the organic whole, explore potential ethics grounded on the recognition of social attachments as evidenced in sexual and parental love, and even in friendship, resist the illusion of autonomy, and advance realistic ethics where the individualised cold isolated person is restored to who she really is: a unique part of an organic whole. 'parent love and especially motherly love, 'take the blurring of identity between two living beings to new heights,'… [ -] the upshot of all this is that the various mechanisms that induce sexual and parental attachment can be harnessed and be recruited for all kinds of prosocial behaviours and attachments' (ravven , p. ) , as opposed to surrendering hiv testing ethics to the seduction of autonomy. to this end, i wish to invite ssa hiv policymakers to consider basing hiv testing on altruism, or what ravven ( ) terms, an ethic of: 'shared selves'-'a sefiness that loses the boundaries of the skin and is extended and distributed to others'. a self who is born into society, is interdependent, interrelated, and shares with others shared human frailty and vulnerability. recognising this kind self can lead to an appropriate reconfiguration of hiv testing ethics. hiv testing ethics, in particular informed consent requirements that are now premised on personal autonomy, should reflect a human being who is unique and yet a creature of the inescapable inculcating environment that makes her the 'i that is we'. according to ssa traditional and moral thought, 'i am because we are', and 'we are because i am'. ravven states: mounting data from neurosciences show that evil is rooted in the failure to see others as ourselves. in the case of genocides such as the holocaust, it is a collective failure of society-wide proportions. the self-other boundary beyond the skin is of central importance to rethinking of ethics, to a deeper understanding of both good and evil. (ravven , p. ) personal autonomy cannot provide a sufficient and persuasive starting point for bioethics (o'neill (o'neill , , in particular hiv testing decision-making. it is necessary for ssa countries to reconfigure their healthcare ethics and place them within the overall compass of human condition, and in the light of the setting of ssa's unique socio-economic and cultural background (wood (wood - ravven ; joseph et al. ) . it is appropriate to get rid of abstract liberal and libertarian concepts of an autonomous patient and reconsider the observable and lived situation of the relationship between patients and their environments. the emphasis on primacy of patient autonomy distracts attention from important aspects of life and healthcare: 'wellbeing is social'. it is crucial to eradicate the man-made autonomy versus medical intervention crisis and move towards greater cooperation. hiv testing informed consent requirements should be premised on ethics of love, honesty, empathy, sympathy, friendship, togetherness and solidarity. personal autonomy is an illusion. a review of the universalised dominant western liberal view of personal autonomy demonstrates that the general agreement that informed consent in hiv testing is required to respect personal autonomy 'and that autonomy is a basic ethical value, is more apparent than real' (manson and o'neill , p. ) . personal autonomy, strictly speaking, is an illusion. human lived experience and reality show that our lives and decisions are encumbered by combined forces of socialisation, genetics and changing external environmental factors that make the idea of an ability or capacity for autonomy resemble a fantastic dream which, when we wake up, we realise was just a dream and not something achievable in a real, civilised and striving society. in this vein, universalised ethics which continue to premise informed consent requirements in hiv testing on personal autonomy are inappropriate. human beings are not asocial or atomistic that they can be a law unto themselves; they are individuals who are enmeshed in complex social realities of reciprocity, mutual obligations, and responsibilities for amicable co-existence, well-being and survival. moreover '[h]uman behaviour is less 'voluntary' than libertarians and theorists of autonomy would have" us believe (gaylin and jennings , pp. - ) . as indicated in the analysis, "human behaviour is less rational than most of us would like to believe it is', in that 'fear, greed, shame, guilt, and pride fuel the machinery of' our decision-making and choices (gaylin and jennings , pp. - ) . it is these aspects which should also be acknowledged and reflected in hiv testing informed consent requirements in ssa. like what has been shown in the covid- pandemic response, persons living in ssa countries should be made aware that as social beings and living in complex relations with others in society, they have a duty to test for hiv because hiv is an epidemic that affect the lives of both people living with hiv and others (especially, close family members). the hiv epidemic not only affects the person living with hiv, but causes suffering, and some instances even death, to family members and people in the community. hiv testing, like the involuntary covid- lockdowns and social distancing, is a common good. in other words, the effects of aids are often corporately felt within the arena of the 'i that is we'-especially in the ssa setting where relational autonomy is articulated (woods (woods - . in conclusion, whenever we as humans are faced with the temptation to celebrate our 'individual autonomous right', we should pause, consider, and remember that we are because of the humanity of others: our birth came through others; our name was given to us by others; we have been educated by others; the respect we demand is given by others; the first bath we had was given to us by others when we were born; our last bath will be given by others; our funeral and potentially dignified burial will be organised and conducted by others; and everything we have owned will be inherited by others once we are dead. we are simply not autonomous as individuals; we are but interdependent and interconnected social creatures. therefore, we should act in solidarity towards each other by formulating appropriate hiv testing ethics and encouraging people to test for hiv so those who need it can access appropriate therapy. the covid- crisis has taught us that 'wellbeing isn't individual but social' (jones ) . this indicates that ssa countries may not be able to achieve the sustainable development goal (sdg) (united nations ), together with the unaids' fast-track strategy that explicitly call to end the epidemic by (unaids ), if hiv testing policies in ssa continue to ignore that humans are social beings (gaylin and jennings ) and 'wellbeing isn't individual but social' (jones ) . it is up to hiv policymakers in these countries to re-examine personal autonomy in hiv testing, and hopefully identify appropriate bioethics and human rights policies which are reflective of natural human condition and are suitable for the ssa socio-cultural setting and hiv epidemic reality. rethinking hiv exceptionalism: the ethics of opt-out hiv testing in sub-saharan africa the rise and decline of western of western liberalism who test & treat policy and change in art uptake principles of biomedical ethics autonomy and opressed socialisation narrative self-understanding and relational autonomy: comments on mackenzie c. poltera, j, 'narrative integration, fragmented selves, and autonomy'. symposia on gender hiv exceptionalism: development through disease in sierra leone mapping and characterising areas with high levels of hiv transmission in sub-saharan africa: a geospatial analysis of national survey data tocno de?id=g _chunk _g _ss - #citat ion hiv/aids is no longer the leading cause of death in africa all sa (cc) at (s. afr moral principlism alone is insufficient, and traditional moral theories remain important for practical ethics reviewed work(s): autonomous agents: from self-control to autonomy by alfred r. mele the politics of person: individual autonomy and social-historical selves autonomy and adaptive preferences the social nature of autonomy from exceptionalism to normalisation: a reappraisal of attitudes and practice around hiv testing civilisation or barbarism: an authetntic anthropology beyond individualism: is there a place for relational autonomy in clinical practice and research the theory and practice of autonomy mapping hiv prevalence in sub-saharan hiv-specific legislation in sub-saharan africa: a comprehensive guman rights analysis communities benefit from door-to-door hiv testing sour grapes: studies in the subversion of rationality autonomy and its limits: what place for the public good a history and theory of informed consent harm to self: the moral limits of criminal law the importance of what we care about ethics of hiv testing in general practice without informed consent: a case series worshiping autonomy the perversion of autonomy: coercion and constraints in a liberal society introduction to philosophy: free will ii afr. comm'n on hum. & peoples' rts the common good. the stanford encyclopedia of philosophy medical law: text, cases and materials the penny has dropped that wellbeing isn't individual but social. the guardian groundwork of metaphysic of morals in nous supplement; philosophical perspectives, . action and freedom hiv infection and aids in sub-saharan africa: current status, challenges and opportunites autonomy and the problem of socialisation the tangled wing: biological constraints on the human spirit essential criminology relational autonomy, normative authority and perfectionism rethinking informed consent in bioethics african religions and philosophy an introduction to aspects of health law: bioethical principles autonomous agents: from self-control to autonomy person and community in african traditional thought on liberty, utilitarianism, and other essays the biological limits of autonomy ethical and legal issues on hiv testing, policy and the practice of dentistry treating all people living with hiv in sub-saharan africa: a new era calling for new approaches aristotelian reconstruction of the concept of personal identity. sophia reconceiving autonomy: sources, thoughts and possibilities african culture and ubuntu: reflections of a south african values and moral pragmatism the inaugural address: autonomy: the emperor's new clothes the rise and fall of aids exceptionalism personal autonomy and society ; s.ct. ; l the self beyond itself: an alternative history of ethics, the new brain sciences, and the myth of free will autonomy in medical ethics: issues of informed consent evaluating the right to autonomy argument in the debate on coercive antenatal hiv testing in south africa they thought this hiv strategy couldn't work. but it did opportunities and challenges for 'test-andtreat': insights from eastern and southern africa ethical dilemmas concerning autonomy when persons with dementia wish to live at home: a qualitative, hermeneutic study the history of aids exceptionalism autonomy and intervention in medical practice southern africa litigation centre testing: a priority in aids prevention xsom gzau k. accessed global action to reduce hiv stigma and discrimination autonomy and the feminist intuition autonomy and adaptive preference formation the impacts of community-based hiv testing and counselling on testing uptake: a systematic review towards universal voluntary hiv testing and counselling: a systematic review and meta-analysis of community-based approaches kantian personal autonomy rethinking autonomy: a critique of principlism in biomedical ethics no future without forgiveness assessing the achievements of the millenium development goals in southern africa resolution adopted by the general assembly on un general assembly adopts popitical declaration to fast-track progess on ending aids fast-track: ending the aids epidemic by understanding fast-track: accelerating action to end the aids epidemic by unaids. . - - : an ambitious treatment target to help end the aids epidemic unaids. a. global hiv & aids statistics- fact sheet test and treat showing results in uganda and zambia the benefits of knowing your hiv status report of the special rapporteur on the right of everyone to the enjoyment of the highest attainable standard of physical and mental health-a/ / united nations united nations division for social policy and development, indigenous peoples united nations department of economic and social affairs (un-desa) the common good non-domination and the limits of relational autonomy rights as slogans: a theory of human rights based on african humanism acknowledgements this paper was prepared thanks to study support from birkbeck, university of london, uk during the author's phd studies. the author is also grateful to prof. matthew weait, deputy vice-chancellor -university of hertfordshire for his supervisory support during research on the subject matter examined in this article. funding none.data availability not applicable.code availability none. conflict of interest the authors declared that they have no conflict of interest. key: cord- -nehorqhi authors: o’brien, stephen j.; troyer, jennifer l.; roelke, melody; marker, laurie; pecon-slattery, jill title: plagues and adaptation: lessons from the felidae models for sars and aids date: - - journal: biological conservation doi: . /j.biocon. . . sha: doc_id: cord_uid: nehorqhi abstract research studies of infectious disease outbreaks in wild species of the cat family felidae have revealed unusual details regarding forces that shape population survival and genetic resistance in these species. a highly virulent feline coronavirus epidemic in african cheetahs, a disease model for human sars, illustrates the critical role of ancestral population genetic variation. widespread prevalence of species specific feline immunodeficiency virus (fiv), a relative of hiv–aids, occurs with little pathogenesis in felid species, except in domestic cats, suggesting immunological adaptation in species where fiv is endemic. resolving the interaction of host and pathogen genomes can shed new light on the process of disease outbreak in wildlife and in humankind. the role of disease in endangered populations and species is difficult to access as opportunities to monitor outbreaks in natural populations are limited. conservation management may benefit greatly from advances in molecular genetic tools developed for human biomedical research to assay the biodiversity of both host species and emerging pathogen. as these examples illustrate, strong parallels exist between disease in human and endangered wildlife and argue for an integration of the research fields of comparative genomics, infectious disease, epidemiology, molecular genetics and population biology for an effective proactive conservation approach. it is becoming increasingly clear that understanding the components of disease processes, particularly infectious disease, will be critical for understanding the survival or demise of free ranging mammalian species. genomic variation of both host species and infectious agent is of critical importance in the outcome of a disease outbreak, and even more so in endangered species. species with reduced genetic variation, particularly in genes involved with disease resistance, may be less able to mount an effective immune response against an emerging pathogen. representing carnivores, the cat family felidae offers numerous examples of reduced genetic var-iation in natural populations common to endangered species including asian lion (panthera leo persica) (gilbert et al., ) , cheetah (acinonyx jubatus) (menotti-raymond and o'brien, ) , tiger (p. tigris) (luo et al., ) , leopard (p. pardus) (uphyrkina et al., ; uphyrkina et al., ) and the north american populations of puma (puma concolor) (culver et al., ; roelke et al., ) that may signify increased susceptibility to opportunistic infectious disease. in addition, the pathogens themselves evolve, constantly developing new genetic based strategies to overcome or abrogate the immune defenses of the host species. the consequence of the co-evolution of pathogen and host are a dynamic ratchet of constantly improving virulence of the agent and resistance of - /$ -see front matter Ó elsevier ltd. all rights reserved. doi: . /j.biocon. . . the host. both the pathogens and the host are survivors of ancient deadly struggles and the exquisite strategies that have been retained are only now being deciphered. conservation management of endangered carnivores has limited opportunities to detect, monitor and contain emergent pathogens due to logistic concerns involved with the continued monitoring of the health status of natural populations. as a result, we know most about disease processes in humans, homo sapiens (garrett, ) , so understanding human-pathogen interactions can help us correctly interpret examples from wildlife. there are far more people and more human medical researchers than there are for most large charismatic mammals, so more human disease outbreaks have been tracked. tools of molecular biology, genetics, immunology and epidemiology were developed with human disease in mind, but they work very well in other mammals. thus, efforts in characterizing the genetics, evolution, and pattern of transmission of pathogens, and the resultant conservation implications for the host species, benefit directly from advances in human genomic research. one of the most significant advances in the genomics era integral to conservation genetics is the whole genome sequence of a score of mammals. starting with human, mouse, rat, and chimp, these projects now capture the phylogenetic divergence across all the orders of placental mammals by inclusion of dog, cat, elephant, cow and others (nhgri website: www.genome.gov). further, a subset of orthologous genes sequenced in representatives of species determined conclusively the evolutionary pattern of divergence of placental mammals during the last my (murphy et al., a; murphy et al., ; murphy et al., b; o'brien et al., a) . the utility of the mammalian phylogeny in conservation ranges from defining taxonomic units to using the evolutionary tree as a reference guide to detect patterns of mutation, adaptation, and selection in endangered species. for example, whole genome sequences of human, chimpanzee (pan troglodytes), mouse (mus musculus) and dog (canis familiaris) indicate that not only do genomes evolve at different rates (cooper et al., ) , but also categories of genes experience different regimes of selection to either diversify or maintain function among primates, rodents and carni- a t u c o r c a t u c o r c a n e a y h d e t t o p s a l u v r a p e l a g o l e h e s o o g n o m f r a w d s a t t a c i r u s a t a c i r u e t a c i r u s x o r e f a t c o r p o t p y r c a s s o f s u t i d o r h p a m r e h s u r u x o d a r a p t e v i c m l a p a t t e n e g a t t e n n e g t e n t a c d l i w n a e p o r u e t a c d l i w n a c i r f a t a c t r e s e d e s e n i h c t a c d n a s t a c d e t o o f -k c a l b t a c e l g n u j t a c s a l l a p t a c d e t t o p s -y t s u r t a c d r a p o e l n a i s a t a c g n i h s i f t a c d e d a e h -t a l f a m u p i d n u o r a u g a j h a t e e h c x n y l n a i r e b i x n y l n a i s a r u e x n y l n a i d a n a c t a c b o b t o l e c o y a g r a m t a c n i a t n u o m n a e d n a t a c s a p m johnson et al., . shown is the maximum likelihood tree using the gtr +i model of sequence evolution from , bp of data from autosome, x and y linked genes. terminal nodes are labelled with three-letter codes, scientific name, common name and grouped in to eight major lineages within felidae. vores. in addition, human and chimpanzee, separated by only - my of evolution (enard and paabo, ) exhibit profound differences in chromosome recombination (winckler et al., ) , gene expression (hill and walsh, ) and differential selection for biological function (clark et al., ) . further, adaptive evolution of genes involved with the immune response to infectious disease can be estimated only by comparison across species. for example, the major histocompatibility complex (mhc) is a large multi-gene complex responsible for adaptive immune response in mammals and is integral to host resistance to emerging pathogens (kumanovics et al., ) . whole genome sequence of mhc reveals differences in gene composition, gene order and putative gene function between primates, rodents and carnivores (belov et al., ; kumanovics et al., ; yuhki et al., ) . thus, conservation genetic strategies for targeting informative genes benefit from a wealth of sequence data defining unique differences for these gene families among taxonomic groups. our ongoing research into host-pathogen interactions in the cat family felidae offers additional insights on how the application of molecular genomic technologies to non-human animal species not traditionally studied in research laboratories holds real promise in conservation. there are species of felids nearly all of which are listed as threatened or near threatened with extinction (www.iucnredlist.org). recently, we have defined the pattern of divergence of the eight major lineages of cats from a common origin in asia and a series of global migration events over the past my (johnson et al., ) (fig. ) which provides an important evolutionary context for the analysis of host-pathogen adaptation. in the following, we illustrate how our investigations into the genomic, evolutionary and population studies of endangered cats species reviewed in o'brien and uncovered feline disease that resembled those in human and vice versa. the first involves the sars epidemic that devastated human populations in east asia in and a parallel outbreak in the cheetah (a. jubatus) years before (pearks wilkerson et al., ) . the second focuses on the lentivirus genus, which a generation ago (korber et al., ) leapt from chimpanzee to humans-likely through the bush meat trade in western africa sharp et al., ; sharp et al., ) , and precipitated perhaps the most deadly scourge in recorded history, hiv-aids . the cat family felidae is afflicted with a close relative of hiv, feline immunodeficiency virus (fiv). in domestic cat felis catus, fiv infection results in disease progression and outcome similarly to that of hiv in humans, and offers a natural model to aids (bendinelli et al., ) . here, we compare and contrast fiv genetics among additional cat species to yield new perspectives on host-pathogen adaptation. the impact of emerging pathogens in felids in these cases provides a cautionary tale of the importance of disease outbreaks in free-ranging species. the unpredictable nature of these outbreaks argues for conservation management strategies to guard against the introduction of disease by domestic animals or introduction of infected individuals into naïve populations. however, these cases show how in humans, rapid genetic and genomic characterization of both pathogen and host has been effective in development of treatment, intervention, and therapy, and offers a paradigm for disease research in conservation of endangered species. sars (severe acute respiratory syndrome) first appeared as a flu-like disease caused by a new human coronavirus in guangdong province in southern china (drazen, ; drosten et al., ; holmes, ) . in the space of nine months the virus traveled to countries, infected over people, and caused nearly deaths (cdc, ) . the virus spread with alarming speed among health care workers, through casual contacts, and across the globe, causing human suffering and huge economic costs. published reports indicate a virus phylogenetically close to the sars virus was discovered in samples collected in chinese food markets from himalayan palm civets paguma lavarta (guan et al., ) . further screening of wildlife has now identified one or more species of bat as the presumptive host reservoir for sars-like coronaviruses (sl-cov); li et al., ; poon et al., ) . the epidemic subsided by may , presumably consequent of draconian quarantine measures. there is still little clear understanding of the precise mode of transmission, and while there are promising advances in research of sars protease inhibitors (savarino, ; wei et al., ) there is still no vaccine or efficacious treatment for infected patients. the sars outbreak caught many by surprise, since human coronaviruses are well known as the cause of one third of common colds and are rarely deadly. further, veterinary virologists have commonly studied coronaviruses in livestock, dogs, cats and poultry and find these viruses seldom cause fatal diseases (holmes, ) . however, exceptions have occurred, for example in pigs, where a single nucleotide variant of porcine coronavirus leads to virulent pathogenic enteric coronavirus (ballesteros et al., ; sanchez et al., ) . the second exception involved a devastating feline coronavirus outbreak in cheetahs a. jubatus documented in a wild animal park, wildlife safari, in rural winston, oregon (heeney et al., ; o'brien et al., ) . wildlife safari was then the most prolific a. jubatus breeding facility in the world, holding some cheetahs. in may , two young cheetahs arrived from the sacramento zoo in california and rapidly developed symptoms of fever, severe diarrhea, jaundice, and neurological spasms. both died and were diagnosed at necropsy with the wet form of feline infectious peritonitis (fip) a disease caused by feline coronavirus in domestic cats (heeney et al., ) . within six months, every cheetah in the park developed antibodies to the fip virus (fipv), and exhibited diarrhea, jaundice, weight loss, gingivitis, and renal and hepatic pathology (fig. ) . within two years % of the cheetahs had died of fip (evermann et al., ; heeney et al., ) . to our knowledge, this was the worst outbreak of fip in any cat species. in reported domestic cat outbreaks, mortality seldom exceeds % (foley et al., ) . the winston fip outbreak preceded pcr and advanced molecular phylogenetic methods, but when sars appeared in , archival specimens were revisited to characterize the nature of the cheetah coronavirus (pearks wilkerson et al., ) . sequences of three viral genes from five cheetahs were pcr amplified. phylogenetic analyses of the cheetah strains and other known coronaviruses placed the cheetah fipv within the monophyletic group i lineage as close relatives of domestic cat fipv, porcine transmissible gastroenteritis virus (tgev) and canine coronavirus (ccov) (fig. a) . furthermore, the polyphyletic arrangement of the cheetah strains interspersed with domestic cat fipv suggested few differences between the deadly cheetah virus and the more innocuous domestic cat virus (fig. b) . given the high genetic similarity between domestic cat fipv and cheetah fipv, and the fact that several lions (p. leo) at winston park became infected with the virus simultaneously but did not succumb to fip, we suggested the reason for the extremely high morbidity and mortality was due to host genetics. the cheetah is one of the most genetically homogeneous species within the cat family. the cheetah has as its closest relatives two north and south american species of puma (p. concolor) and jaguarondi (p. yagouaroundi) and together form the puma lineage (fig. ) . fossil records indicate that cheetah once had a nearly global distribution, compared with its current distribution of sub-saharan africa and a relict population in iran (nowell and jackson, ) . a series of genetic studies of cheetah populations describe a species depauperate in genomic variation and this loss in genetic heterogeneity was most likely due to a severe population bottleneck that felled scores of large mammal species in north america, europe, asia and australia , - , years ago menotti-raymond and o'brien, ; o'brien et al., ) . the near extirpation led to generations of close inbreeding during the cheetah's ancestry reducing overall genomic diversity - -fold (menotti-raymond and o'brien, ) . this reduction included variation in the immune response genes within the major histocompatibility complex (o'brien et al., ; o'brien and yuhki, b; yuhki and o'brien, ) . the genetic basis for disease resistance is that inherent population genetic diversity provides a broad moving target for evolving pathogens. thus, when a microbe evolves a strategy to abrogate immune defenses of an individual, the genetically diverse population may still be protected. however, once virulence was achieved in the first cheetah, the conditions were set for transmission, pathogenesis and morbidity in the other individuals within the population made vulnerable by shared genetic and immunologic homogeneity. the parallels and lessons for sars have relevance to conservation of biodiversity in wildlife. first, the deadly coronaviruses in both human and cheetah represent profound consequences that may accompany viral emergence into a new host. phylogenetic analyses of genetic data clearly define the domestic cat origin of cheetah fipv (fig. a, b) and that the virus appeared to be highly pathogenic upon entering the new host. the similarity of the pattern of high pathogenicity with sars infection of humans suggests that the virus is potentially more benign in the reservoir species of bats, albeit this remains unconfirmed li et al., ) . even so, the pattern of genetic changes within the pathogen among fig. from heeney et al., ) . titers are based on immunofluorescent assay of cultured cells. numbers are from the north american cheetah studbook numbers for individual cheetahs (marker and o'brien, ) . arrows represent date of death by aju-cov for each animal. the intermediate host of palm civet p. lavarta was very similar to those observed in human strains, and is consistent with the expectation of rapid evolution in the pathogen to adapt to the new host immune response (song et al., ) . second, while mortality in humans with sars symptoms (cdc, ) and in house cats with fipv (foley et al., ) was low ( % in humans, % in cats), infected cheetahs exhibited the opposite extreme with % morbidity and over % mortality (fig. ) . as for cheetahs, the combined evidence suggests that genetic uniformity makes epidemics much worse. it is likely that variation in immune defense genes of humans and domestic cats protected them from a deadly disease, to which most exposed and genetically impoverished cheetahs succumbed (fig. ) . thus, genomic characterization of both pathogen and host are key for conservation of biodiversity and prevention of disease outbreak. lastly, fipv in cheetahs and sars in humans are highly contagious, spreading rapidly in close quarters in weeks, if not days ( fig. ; (shaw, ) ). this inherent ability of emergent pathogens to rapidly infect endangered populations should be an integral consideration for management strategies of re-introduction. aids had first appeared in humans in the early s as a clustering of patients from homosexual communities in los angeles and new york city with a rare cancer, kaposi's sarcoma, and pneumonia. aids is caused by a lentivirus, a genus within the family retroviridae, termed human immunodeficiency virus or hiv that infects and destroys cd bearing t-cells. there are two forms of hiv (types and ) and since its recognition in the early s, hiv- has spread across the globe infecting million people and killing over million (www.unaids.org). aids is potentially the most deadly disease in recorded history because it is a disease with no vaccine and a treatment that slows the virus but does not clear it from sequestered cellular reservoirs, and has infected million and continues to infect new cohorts within the world populations (rathbun et al., ) (www.unaids.org). the origin of the ongoing hiv- pandemic is recent and the virus entered humans early in the th century, originating from a subspecies of chimpanzee p. troglodytes troglodytes in central west africa . wild chimpanzees are infected with sivcpz (simian immunodeficiency virus) and genetic study affirms this strain is the closest genetic relative to hiv . additional evolutionary studies indicated these cross-species transmission events occurred more than once between chimpanzee and human to form hiv- subtypes m, n and o and at least once between sooty mangabey (cercocebus atys) and humans to form hiv- (gao et al., ) . in total, primate lentiviruses infect at least species and like sivcpz are host-specific sharp et al., ; sharp et al., ) . all naturally occurring siv are in african primates and these species seem resistant to aids-like pathology. by contrast, asian species are fig. -prevalence and distribution of fiv seroreactivity in free-ranging, and captive but wild-born, animals (troyer et al., ) the dark portion of the bar represents seropositives and the white represents seroindeterminates, giving conservative and liberal estimates of total seroprevalence of fiv. the number of animals tested for each species is given in parentheses. a black star indicates that pcr verification has been obtained from at least one free-ranging individual for that species. a white star indicates that pcr verification has been obtained from at least one captive, but wild-born individual for that species. (a) percent seroreactivity in african carnivores (excluding african golden cat, sand cat, and black footed cat, for which there were no wild-born samples). (b) percent seroreactivity in american felids (excluding kodkod and canadian lynx, for which there were no wild-born samples). (c) percent seroreactivity in eurasian felids (excluding lynx, bay cat, rusty spotted cat and chinese dessert cat, for which there were no wild-born samples). naïve, and do develop aids when infected with the siv from african primates (hirsch, ) . the sole naturally occurring model for aids disease in humans is the feline homologue of hiv, feline immunodeficiency virus (fiv). although related lentiviruses are found in other species such as sheep and goats (caprine arthritis encephalitis virus -caev), horse (equine infectious anemia virus -eiav), and cattle (bovine immunodeficiency virus -biv), only fiv in domestic cats causes aids-like disease. fiv was first discovered in in a house cat with a wasting-like disease (pedersen et al., ) . currently, fiv is epidemic among feral domestic cats throughout the world and is associated with an aids-like syndrome of immune depletion, increased susceptibility to rare cancers and opportunistic disease, and death (bendinelli et al., ; willett et al., ) . fiv has a small viral rna genome of about nucleotides that is similar in sequence, gene content, and gene arrangement to that of hiv- (miyazawa et al., ) . as with primate lentiviruses, fiv naturally infects multiple species of cat in the wild. western blot screening of antibodies against fiv in free-ranging non-domestic cat species (fig. ) revealed that several were exposed to the virus (carpenter and o'brien, ; olmsted et al., ; olmsted et al., ; troyer et al., ) . a recent comprehensive survey of serum and lymphocyte specimens from individuals within felidae and hyenidae species used three fiv antigens isolated from domestic cat, lion, and puma as targets of western blot plus pcr-based fiv genome sequence amplification as a validation of fiv infection (troyer et al., ) . those results revealed that at least free ranging felidae species harbor fiv antibodies and fiv viral genomes (fig. ) . these species are distributed across africa including lion, leopard (p. pardus), and cheetah along with two hyenidae species of spotted hyena (crocuta crocuta) and striped hyena (hyaena hyaena). fiv positive species occur in north and south america including puma, jaguaroundi (p. onca), jaguarondi, ocelot (leopardus pardalis), margay (l. weidii), geoffroy's cat (l. geoffroyi), tigrina (l. tigrina) and in asia with pallas cat (otocolobus manul). eight other species had western blot signals of antibodies, but did not yield fiv sequences using multiple pcr primers which is likely due to divergence within the primer binding sites, exceedingly low proviral load, or both (fig. ) . overall, inclusion of fiv western blot results from captive individuals indicates that as many as species of cat are susceptible to fiv infection and may harbor species specific viruses or be infected with non-native virus (troyer et al., ) (fig. ) . further, the distribution of fiv is not uniform among cat species, being endemic in africa and north and south america, but rare in species from europe and asia (fig. ) . phylogenetic analyses of the pol-rt region ( bp) isolated in felidae species reveal the sequences form species-specific monophyletic clades (fig. ) . this monophyletic pattern suggests that fiv does not spread among species easily. rather, fiv infected an ancestor of each host and then evolved within that species. there have been exceptions to this finding, but only in captive animals and these occur rarely. for example, the captive snow leopard (p. uncia) fiv sequence is well within the african lion fiv clade a (fig. ) . another example is a captive puma infected with a domestic cat strain of fiv (carpen-ter et al., ) . however, in the wild, opportunities for interspecies transmission are limited and thus the virus becomes adapted to its particular host. this evolutionary pattern resembles that of naturally occurring siv in african primates, where siv forms monophyletic lineages that are specific to each species (allan et al., ; sharp et al., ) and are host-dependent. yet, fiv transmission may have a geographic component whereby species in close proximity share more similar fiv strains. this is suggested in the common node shared by leopard fiv and cheetah fiv (fig. ) . clinical consequences for fiv infection in most nondomestic felidae species is not known, and there has been little convincing acute disease or patterned disease symptoms associated with fiv infection as is observed consistently for domestic cats. only one example of fiv-related mortality has been documented in a species other than domestic cat, a captive lion . the lack of documentation of clinical signs of fiv infection in wild populations may reflect logistic obstacles and expenses in routine physicals for these species. alternatively, these species-specific fiv strains may have undergone a prolonged period of co-adaptation with their respective host and may be less pathogenic as a consequence carpenter and o'brien, ) . in the following study with lions, we describe how current conservation efforts with endangered cat species are integrating genetic studies of fiv in natural populations. natural populations of african lions represent one of the longest running studies of fiv infected felids in the wild (brown et al., ; troyer et al., ) . a western blot survey of lions throughout africa (fig. ) indicates fiv antibody seroprevalence can range from % (in namibia and kalahari) to > % in the serengeti in tanzania and kruger park in south africa. this east-west discordance in fiv seroprevalence may be a consequence of geographic barriers such as the kalahari desert. however, it is not clear whether these geographic differences in fiv prevalence (most were sampled only once) reflect an ongoing spread or a stable restriction of fiv spread in the low incidence regions. phylogenetic analysis of fiv rt-pol sequences in lions reveal the persistence of at least six principal viral clades or subtypes (a-f) represented in different populations of lions in africa. some are unique to certain populations (e.g. subtype e in botswana, subtype c in the serengeti and subtype f in kenya) while others are present in multiple populations (fig. ) . the genetic distances among these lion fiv subtypes are as great as the distance observed between fiv isolates from different cat species (figs. , ) . this level of separation would suggest that the clades evolved in isolation. the common monophyletic node uniting all lion fiv strains suggests that fiv infected a common ancestor early in lion population history. the virus subtypes then evolved in isolation with specific lion populations as observed with subtypes c, d, and e. in the case of subtype a and b, it is likely that these evolved in formerly geographically isolated lion populations that recently came together allowing the transmission of the virus subtypes currently observed. because there is little known of disease associations with fiv infection in lions it is difficult to know whether there are now (or ever were) virulence distinctions among the clades. one of the most detailed lion population studies is that of the serengeti in tanzania. this large panmictic population over individuals has provided many useful insights into lion pride structure, population dynamics, and transmission of infectious diseases (gilbert et al., ; hofmann-lehmann et al., ; muller-graf et al., ; munson et al., ; packer et al., ) . long-term surveillance of lions in the serengeti has not revealed any evidence of aids like illnesses, decreased viability, or decreased fecundity in this population where seroprevalence among adult lions is %. these observations of (relatively) benign infection are similar to those for fiv in north american puma (biek et al., ; biek et al., ) and consistent with the notion that fiv has persisted in these host species longer than in domestic cat and that significant host adaptation has already occurred carpenter and o'brien, ) . however, recently we have shown that lions infected with fiv have significantly lower cd counts than uninfected animals suggesting that there may be sub-clinical immunological effects associated with fiv-infection in this population (roelke et al., in press) . at one stage we also suspected that infection with one clade of fiv might be a natural vaccine against infection with another or the mutational occurrence of a virulent deadly fiv variant (carpenter and o'brien, ) . however, troyer et al. ( ) inspected the pattern of fiv subtype distribution among serengeti lion prides and discovered multiple clade infections (i.e., two or three subtypes of virus present in the same lion) in % of the infected lions, an observation that would argue against acquired immunity by infection with a single strain. in , the serengeti lions became the target of a deadly infectious disease outbreak that caused whisker twitches, neurological seizures, and death to over lions, a third of the population. fiv was excluded as the primary cause since several afflicted lions were fiv negative (roelke-parker et al., ) . the etiological agent was a hyper-virulent form of a canine distemper virus (cdv) a virus previously known to infect but seldom cause morbidity in felidae species (roelke-parker et al., ) . this time, in the most deadly reported outbreak of the cdv among african carnivore species, a virulent transmissible cdv variant spread from domestic dogs living around the serengeti park to hyena, bat eared foxes otocyon megalotis, and to lions (carpenter et al., ) . although fiv was not the primary explanation for the serengeti lion mortality, it may have played a supporting role. hiv infection in humans causes increased susceptibility to opportunistic infections of normally benign infectious agents (like hhv /kaposi's sarcoma, pneumocystis carnii pneumonia or cytomegalovirus) as a consequence of cd t-lymphocyte depletion and immune collapse (levy, ) . nearly all the lions in the serengeti carried fiv, and fiv has been shown to be associated with depleted cd -lymphocyte counts of cells/ll compared with counts of - cells/ll in uninfected individuals (roelke et al., in press ). one could speculate that adult lions may have done better in defending against cdv had they not been afflicted with lentivirus that depletes their principal defense against viruses, the cd lymphocyte population. while there were fiv-negative animals that died, these were all juveniles (roelke-parker et al., ) and it is possible that their immature immune system may have accounted for their susceptibility to the new virus. the african lion study provides some useful insights on the impact of infectious disease in endangered populations. development of detection methods and effective monitoring of the health of animals in the wild is problematic, and as in the case of the cdv outbreak, was documented only due to the presence of researchers already in place to collect samples and observe the final outcome. although this cdv outbreak was marked by relatively high mortality estimates (roelke-parker et al., ) , subsequent outbreaks were less virulent within the same population. until we fully understand the immunological effects of infection with prevalent fiv strains, the interaction of pathogens such as cdv and fiv, and the role of the host immune system in modulating these viral infections, the question of their importance and collaborations in pathogenesis will continue. one approach is to continue to adapt and apply new technologies developed from human biomedical research to conservation of wildlife. for example, the massive research effort into understanding hiv in humans offers new technologies to apply towards related viruses such as fiv in endangered cat species. recognition that fiv causes aids-like disease in domestic cat and that this is a natural model for hiv in humans, has led to extensive surveillance of fiv in other species (biek et al., ; biek et al., ; carpenter et al., ; carpenter and o'brien, ; olmsted et al., ; troyer et al., ; troyer et al., ) , an essential step in determining the genetic diversity of the pathogen. knowledge of key amino acid motifs in the env gene of hiv linked with evading host immune surveillance (wyatt and sodroski, ; yusim et al., ) is in turn targets for comparative genomic research of virulence in fiv (de parseval et al., ) . understanding how genetic diversity within mhc in humans is linked with either resistance to hiv or increased susceptibility (carrington and o'brien, ) provides an incentive to sequence mhc in multiple mammalian taxa, including cats (yuhki et al., ; yuhki and o'brien, ) . the links between hiv in humans and fiv in endangered cat species illustrate the utility of biomedical approaches and discoveries that is directly applicable to elucidating the role of disease in endangered species. tion. the advances in molecular biology, immunology and genetics provide a diverse collection of effective tools for unraveling the secrets to survival. as the tools that are used in human medicine become available to wildlife research, new approaches and understanding of disease outbreaks and effective host control of infection are increasingly possible. unfortunately, in wildlife populations, few disease outbreaks are followed from start to finish and the vast majority remain completely unobserved and undocumented [but see randall et al. on ethiopian wolves and other papers in this special edition]. for this reason, our understanding of the effects of population demographics, genetics, mating and migration patterns on the spread of (and ultimately clearance of and/or adaptation to) disease is limited. these examples of fipv and fiv illustrate a critical need for consistent programs designed to monitor and survey endangered populations. conservation strategies that incorporate biological sampling yield invaluable genetic profiles of disease and disease resistance within endangered species. genomic analyses provide insight into the history of a population and its pathogen(s) that can assist in documenting patterns of co-evolution and adaptation. yet, these examples underscore the unpredictable aspects of epidemics within natural populations of threatened or endangered species and there is need for much more comprehensive and longterm data. finally, conservation management would clearly benefit from a better knowledge of viral evolution, adaptation, and cross-species infections to plan protected areas, inform strategies of re-introduction and relocation, and provide effective interventions in cases of potential disease epidemics. by resolving the root causes of human and animal outbreaks and their outcomes, we shall continue to learn lessons such as the cats have shared on sars and aids. species-specific diversity among simian immunodeficiency viruses from african green monkeys two amino acid changes at the n-terminus of transmissible gastroenteritis coronavirus spike protein result in the loss of enteric tropism marsupial mhc class ii beta genes are not orthologous to the eutherian beta gene families feline immunodeficiency virus: an interesting model for aids studies and an important cat pathogen epidemiology, genetic diversity, and evolution of endemic feline immunodeficiency virus in a population of wild cougars a virus reveals population structure and recent demographic history of its carnivore host a lion lentivirus related to feline immunodeficiency virus: epidemiologic and phylogenetic aspects coadaptation and immunodeficiency virus: lessons from the felidae genetic and phylogenetic divergence of feline immunodeficiency virus in the puma (puma concolor) genetic characterization of canine distemper virus in serengeti carnivores the influence of hla genotype on aids update: severe acute respiratory syndrome -worldwide and united states inferring nonneutral evolution from human-chimp-mouse orthologous gene trios characterization of evolutionary rates and constraints in three mammalian genomes genomic ancestry of the american puma (puma concolor) sequential cd -cxcr interactions in feline immunodeficiency virus (fiv): soluble cd activates fiv env for cxcr -dependent entry and reveals a cryptic neutralization epitope sars -looking back over the first days genomic microsatellites as evolutionary chronometers: a test in wild cats severe acute respiratory syndrome: identification of the etiological agent comparative primate genomics biological and pathological consequences of feline infectious peritonitis virus infection in the cheetah risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus human infection by genetically diverse sivsm-related hiv- in west africa origin of hiv- in the chimpanzee pan troglodytes troglodytes the coming plague. penguin analytical dna fingerprinting in lions: parentage, genetic diversity, and kinship isolation and characterization of viruses related to the sars coronavirus from animals in southern china aids as a zoonosis: scientific and public health implications prevalence and implications of feline coronavirus infections of captive and free-ranging cheetahs (acinonyx jubatus) molecular insights into human brain evolution what can natural infection of african monkeys with simian immunodeficiency virus tell us about the pathogenesis of aids? prevalence of antibodies to feline parvovirus, calicivirus, herpesvirus, coronavirus, and immunodeficiency virus and of feline leukemia virus antigen and the interrelationship of these viral infections in free-ranging lions in east africa sars -associated coronavirus the late miocene radiation of modern felidae: a genetic assessment timing the ancestor of the hiv- pandemic strains genomic organization of the mammalian mhc severe acute respiratory syndrome coronavirus-like virus in chinese horseshoe bats hiv and host immune responses in aids pathogenesis bats are natural reservoirs of sars-like coronaviruses phylogeography and genetic ancestry of tigers captive breeding of the cheetah (acinonyx jubatus) in north american zoos ( - ) dating the genetic bottleneck of the african cheetah the genome of feline immunodeficiency virus epidemiology of an intestinal parasite (spirometra spp.) in two populations of african lions (panthera leo) genetic diversity affects testicular morphology in free-ranging lions (panthera leo) of the serengeti plains and ngorongoro crater molecular phylogenetics and the origins of placental mammals evolution of mammalian genome organization inferred from comparative gene mapping mammalian phylogenomics comes of age status survey and conservation action plan, wild cats. international union for conservation of nature and natural resources big cat genomics comparative genome organization of the major histocompatibility complex: lessons from the felidae genetic basis for species vulnerability in the cheetah east african cheetahs: evidence for two population bottlenecks the promise of comparative genomics in mammals nucleotide sequence analysis of feline immunodeficiency virus: genome organization and relationship to other lentiviruses worldwide prevalence of lentivirus infection in wild feline species: epidemiologic and phylogenetic aspects viruses of the serengeti: patterns of infection and mortality in african lions ecological change, group territoriality, and population dynamics in serengeti lions coronavirus outbreak in cheetahs: lessons for sars isolation of a t-lymphotropic virus from domestic cats with an immunodeficiency-like syndrome lentivirus infection in an african lion: a clinical, pathological, and virologic study identification of a novel coronavirus in bats current hiv treatment guidelines -an overview the consequences of demographic reduction and genetic depletion in the endangered florida panther a canine distemper virus epidemic in serengeti lions (panthera leo) targeted recombination demonstrates that the spike gene of transmissible gastroenteritis coronavirus is a determinant of its enteric tropism and virulence expanding the frontiers of existing antiviral drugs: possible effects of hiv- protease inhibitors against sars and avian influenza origins and evolution of aids viruses simian immunodeficiency virus infection of chimpanzees the sars outbreak and its impact on infection control practices cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human patterns of feline immunodeficiency virus multiple infection and genome divergence in a free-ranging population of african lions seroprevalence and genomic divergence of circulating strains of feline immunodeficiency virus among felidae and hyaenidae species phylogenetics, genome diversity and origin of modern leopard, panthera pardus conservation genetics of the far eastern leopard (panthera pardus orientalis) the n-terminal octapeptide acts as a dimerization inhibitor of sars coronavirus c-like proteinase fiv infection of the domestic cat: an animal model for aids comparison of fine-scale recombination rates in humans and chimpanzees the hiv- envelope glycoproteins: fusogens, antigens, and immunogens dna variation of the mammalian major histocompatibility complex reflects genomic diversity and population history comparative genome organization of human, murine, and feline mhc class ii region clustering patterns of cytotoxic t-lymphocyte epitopes in human immunodeficiency virus type (hiv- ) proteins reveal imprints of immune evasion on hiv- global variation we are just now beginning to understand the complex interplay of host genetic background, immune competence, and pathogen evolution that contribute to the course of an epidemic when a disease agent enters a new species or popula- key: cord- - a aky i authors: zhang, lei; fung chow, eric pui; zhang, jun; jing, jun; wilson, david p title: describing the chinese hiv surveillance system and the influences of political structures and social stigma date: - - journal: open aids j doi: . / sha: doc_id: cord_uid: a aky i china’s public health surveillance system for hiv was established in late s and has evolved significantly during the past three decades. with the gradually changing mode of hiv transmission from sharing of intravenous injecting equipment to sexual exposure and the rapid spread of hiv infection among chinese homosexual men in recent years, an efficient and comprehensive population-level surveillance system for describing epidemics trends and risk behaviours associated with hiv acquisition are essential for effective public health interventions for hiv. the current review describes the overall strength of the chinese hiv surveillance system and its structural weaknesses from a political and social perspective. the hiv surveillance system in china has undergone substantial revamping leading to a comprehensive, timely and efficient reporting system. however, large data gaps and lack of quality control and sharing of information obstruct the full performance of the system. this is largely due to fragmented authoritarianism brought about by the underlying political structure. social stigma and discrimination in health institutes are also key barriers for further improvements of hiv diagnosis and surveillance in china. by the end of it was estimated that , ( . - . million) people in china were living with hiv [ ] . this estimate was obtained by using the workbook method recommended by unaids based on the numbers of newly diagnosed hiv cases and applying related mortality rates reported by the current hiv sentinel surveillance system. the overall national hiv prevalence is estimated to be . % ( . - . %) among the chinese population [ , ] . however, data from the national sentinel surveillance for hiv/aids indicated magnitudes and trends in hiv prevalence vary substantially across different at-risk populations: e.g. . % hiv prevalence among female sex workers (fsw) in [ ] and increases from . % in to . % in among men who have sex with men (msm) [ , ] , and from . % in to . % in among injecting drug users (idu) [ , ] . the profile of hiv epidemics in china have also been gradually changing in mode of transmission. in the early s, the main driver of hiv transmission was needle sharing among idu [ ] [ ] [ ] [ ] ; however, sexual transmission has now become the primary mode of transmission in recent years [ , [ ] [ ] [ ] . the proportion of newly diagnosed hiv cases due to sexual transmission increased from . % in to . % in and newly diagnosed cases attributed to homosexual contact has substantially increased from . % in to . % in [ , ] . effective public health interventions for hiv rely on accurate and timely information on the extent and patterns of *address correspondence to this author at the cfi building, corner of west and boundary streets, darlinghurst, sydney nsw , australia; tel: + ; fax: + ; e-mail: lzhang@nchecr.unsw.edu.au spread of infection. as such, an efficient and comprehensive population-level surveillance system for describing epidemics trends and risk behaviours associated with hiv acquisition are essential [ ] . previous studies have provided reviews of the current hiv surveillance system in china, mainly from a functional and epidemiological perspective [ ] [ ] [ ] . in contrast, the current review aims to describe the overall strength of the chinese hiv surveillance system and its structural weaknesses from a political and social perspective. prior to , newly diagnosed hiv/aids cases were reported through the national disease reporting system (ndrs) (see table for a list of reportable items in china). the system consists of multiple level of reporting. villages, being the lowest level of administrative, collected hiv epidemiological data in their allocated areas and reported to prevention units in township hospitals. from the prevention units, hiv data were further sent through county health and epidemic-prevention stations (eps) to provincial centers and forwarded to the chinese academy of preventive medicine. with the support from the ministry of health and cooperation of provincial centers of health and epidemic prevention, a computerized system had worked effectively to network the monitoring of hiv epidemics at various levels in china and information transfer experienced no substantial changes for about years. however, all communicable disease surveillance systems in china underwent significant upgrade in . the severe acute respiratory syndrome (sars) outbreak in - exposed the great deficiencies in both timeliness and completeness of infectious disease reporting in ndrs [ ] . this substantially changed the landscape of infectious diseases surveillance in china. just months after the sars epidemic subsided, the china center for disease control (china cdc) launched the china information system for disease control and prevention (cisdcp) [ ] . the system is an information platform constructed mainly with an infectious diseases orientation, aiming to improve timeliness of case reports, completeness and accuracy of surveillance data, ability for early detection of outbreaks and to provide direct information sharing among various levels of cdcs and health authorities, replacing the previous ndrs. the upgrade of overall infectious disease surveillance systems in china directly led to the construction of web-based hiv/aids case reporting system. under this reporting system, grassroot hospitals remain the primary source of hiv epidemiological information. all diagnosed and confirmed hiv-infected cases admitted to hospitals are obliged to report through the web-based reporting system to china cdc. improving from the previous step-wise hierarchical reporting framework, the new web-based reporting system provided the ability for direct reporting of diagnosed hiv cases from the grassroot hospitals to the centralised database in chinese moh through cisdcp (fig. ) . that is, once disease cases are entered into the system, all levels of cdc can acquire the data 'live' according to their assigned access privileges [ ] . this substantially reduced the average reporting period from - days to less than days. in addition to their assumed responsibility for authenticating the hiv disease information in their administrative regions, municipal and provincial cdcs are required to report to their corresponding department of health (dohs) and bureau of health (bohs) and to form networks with local research bodies, universities and other health organisations. at the top of the hierarchy, the national center for hiv/aids prevention and control (ncaids) of china cdc is the overseeing organisation for assembling and analysing all hiv disease information and then presenting a final report to china moh. china moh remains the only legitimate office to disseminate hiv/aids-related information to the public, but provincial and municipal cdcs are also authorised to release information under the supervision and approval of china moh [ , ] . china moh enacts health policies, designs prevention guidelines and intervention strategies based on the surveillance reports provided by ncaids, once a consensus agreement is established between moh and the chinese government, feedback recommendations and policies are issued to all lower levels of moh for execution. since the feedback information does not go through the webbased information pool, hospitals at grassroots level may have to wait for a considerable period of time to receive recommendations and guidelines from china moh. by the year , laboratories ( screening laboratories, confirmatory laboratories, confirmatory central laboratories and national aids reference laboratory) and laboratories hospitals are capable of carrying out cd and hiv viral load testing in china [ ] . confirmed diagnosed hiv cases were reported back to referring clinical sites then further integrated into the central database through cisdcp. the hospital-based surveillance in china has cumulatively diagnosed , people living aids and a total of , people are currently receiving art in [ ] , which accounted for . % of the aids cases [ ] . the hospital-based surveillance relies on plhiv to attend hospital to be diagnosed and cases subsequently reported. complementing this passive reporting, active surveillance for hiv was adopted in and further expanded in to include second generation behavioral surveillance in china according to who recommendations [ , ] . while the existing hospital-based diagnosis system provides hiv diagnosis and treatment data, sentinel surveillance collects information on hiv prevalence, incidence and the risk behaviours of at-risk populations. in china, hiv sentinel surveillance is collaboratively supervised by the chinese moh and who. in , surveillance pilot sites targeting idu, fsw, male clients and the general female population were established in fujian, xinjiang, guangxi, shanxi, yunnan and sichuan. the approach utilised surveillance points in these provinces and from every surveillance point people are sampled twice each year to estimate the prevalence, incidence rate and risk behaviours of the targeted population [ ] . the sampling and reporting for each round is completed within weeks. in , china issued "standards for hiv surveillance and hiv/aids" and "std comprehensive surveillance guideline" to provide guidelines to standardise the practice of hiv surveillance. in , the number of sentinel sites in china increased to , covering at-risk population groups [ , , ] . since the establishment of the web-based hiv reporting system in , sentinel surveillance data is integrated with disease information reported from hospitals. this approach established a comprehensive database for data collection, analysis and sharing and enables high-level comparison and integration of epidemiological and behavioural surveillance data [ ] . this further allows the conduct of evaluation and forecasting activities for guiding the formulation of public health intervention strategies. hiv sentinel surveillance has detected the changing trends and patterns of hiv epidemics in china, from transmission related to injecting practices to sexual transmission, especially homosexual transmission. further, surveillance data have revealed that the proportion of idu among all drug users has increased from % in [ , ] to % in [ , ] and % in [ ] . in addition, during - , the proportion of idu who report sharing needles increased from % to % [ ] . among fsw, consistent condom use in commercial sexual contacts in the last month increased from % in to % in , and the proportion who reported never using condoms decreased from . % to . % during the same period [ , ] . the current hiv surveillance system in china appears to have improved in its timeliness and effectiveness for providing useful hiv disease information and regular behavioural monitoring of at-risk populations in china. however, under-utilisation and lack of transparency of information outside certain authorised channels are possibly the greatest hindrances to optimal use of the current system. since accessibility to health data in china is largely limited to a small group of authorised personnel at the top of the administrative hierarchy, it often requires extensive bargaining and bureaucratic procedures to obtain epidemiological and behavioural indicators that are commonly accessibly in other countries. hence, large amount of surveillance data remains in cisdcp and cannot be utilised widely for the purpose of hiv public health research, broader program evaluation and planning of control strategies. a transparent hiv surveillance system across all stakeholders, including policy makers, health officials, community health organisation leaders and hiv researchers, is beneficial for the entire hiv sector in the evaluation and implementation of hiv prevention and intervention strategies [ ] . to understand barriers to optimal utilisation of available systems it is essential to first understand the political structure in china and its influences on surveillance. although hiv surveillance is considered as a purely public health issue in many countries, issues related to hiv in china are highly sensitive and politically motivated [ , , ] . authoritarianism describes any political structure in which overall authority is concentrated in the hands of a single leader or a small group of elite. prior to economic reform in china, the ultimate political powers were mastered by the chairman of state, who is simultaneously the president of the party and chief commander of the army. political fig. ( ) . schematic diagram of flow of information for hiv surveillance in china. decisions and national policies were implemented strictly "from top to bottom" through a pyramidal administrative structure (fig. a) . during the process of political decentralisation initiated by the economic reform in china, provincial governments and ministerial institutions were given high degrees of autonomy to stimulate economic growth. although the central government remains at the peak of the power hierarchy, opportunities for competition and bargaining between governments and institutions became possible. this phenomenon was coined "fragmented authoritarianism" by lampton in [ ] . as a result of fragmented authoritarianism, government authority below the very peak of the beijing central government is fragmented and disjointed [ , ] . as the highest administrative body, the central government does not generally dictate the execution of policies by provincial governments. between equal level governments or governmental institutions, and even between local and central governments, there exists a large space for competition and cooperation, which leads to extensive bargaining concerning policy execution and project development of common interests (fig. b) . fragmented authoritarianism in china can be viewed as the mixed product of traditional authoritarianism and demands for increase in political freedom triggered by the economic reform. the fragmented authoritarian political structure directly affects the hiv surveillance system in china. first, fragmented authoritarianism leads to the absence of accountability in vertical administration of cdcs and lack of cooperation among cdcs on the same level. in this structure, the central china moh cannot exercise direct supervision over the provincial mohs, which retain the authority of personnel appointment, organisation structure and budget distribution. conversely, policy immobility in inferior governments can only be overcome by the intervention of a superior government with the authority to resolve conflicting interests. in other words, lower-level governments tend to shift their policy overload to the upper levels in order to avoid assuming accountabilities [ ] . consequently, a large number of responsibilities and agenda items accumulate at the upper end of the political hierarchy. therefore, china cdc, as a subordinate organisation of china moh, is caught in an uneasy position whereby it is unable to exercise its designated authority and simultaneously overloaded with responsibilities which it is not designated to bear. this is reflected by the large amount of collected but unanalysed hiv data accumulated in ncaids in central china cdc. as pointed out by sun, et al., the amount of hiv surveillance data from diagnoses, treatment, laboratory tests and behavioural surveillance overflows the organizational capacity of ncaids [ ] . apart from key indicators that require to be distributed to moh and the general public, most of the surveillance data is under-utilised [ ] . although the web-based hiv reporting system provides an advanced technology base for data reporting and collection, the dissemination of related summary and policy to direct hiv prevention and care strategies remain slow and inefficient. in addition, such a fragmented system makes it difficult to authenticate the quality of the data, as intermediate levels of cdcs do not assume accountability for the accuracy of reported data. an evaluation of hiv surveillance systems by loo et al., indicated that although the chinese hiv surveillance system obtained high scores for flexibility and timeliness across in its surveillance activities, representativeness and completeness of data are poor in its case reporting [ ] . discrepancies are found between the hiv laboratory testing algorithm stated in protocols and the actual procedures implemented, which results in gaps in the data and reductions in quality [ ] . second, a fragmented authoritarian political structure inevitably leads to a fragmented information system with little openness and systematic mechanisms for synthesis. as fig. ( ) . change of political relationship between institutions at the same and different administrative levels in china prior to, and post, economic reform. previously analysed, lower-level cdcs can only access hiv information within its own jurisdiction, which represents only a subset of the information pool of the higher-level cdcs. as there is little information sharing, even between neighbour cdcs on the same level, these information subsets become isolated information islands which can only be integrated by their superiors. in this way, the central china cdc at the top of the administration pyramid has the ultimate authority of data collection, assembling, analysis and distribution. hence, information openness is strongly and solely dependent on the decision of central china cdc and there exists little monitoring mechanisms to ensure the accuracy of both the reported and published information. in the current political structure, all levels of government are only accountable to their upper-level administrations, but not to the general public. the absence of genuine engagement of civil society groups, including the media and the scientific communities, and the expectations and pressures from higher-level authorities, often results in a results-oriented policy implementation, such that local officials tend to manipulate nonscientific and arbitrary results to satisfy their superiors perfunctorily [ ] . in this view, ensuring the accuracy of reported disease information should be a high priority in the future development of hiv surveillance in china. social stigma against plhiv is common in china. misconceptions about hiv transmission and prejudice towards plhiv are widespread among the general population. hiv-positive individuals are often denied employment, education and necessary medical services [ ] and are thus more likely not to disclose their hiv status [ , ] . a recent study by zhou in shows that the healthcare expenses for hiv-positive individuals were greatly elevated by social discrimination, and their available social resources were substantially reduced in the presence of social stigma [ ] . the study further indicated that plhiv often perceive healthcare institutions as an indispensable source of social support and one of the few places where they may be willing to disclose their hiv-positive status [ ] . however, a separate survey among health workers in hospitals demonstrated that hiv stigmatisation remains as the major health-seeking barriers for plhiv in china [ ] . according to a unaids study in , % of surveyed participants indicated that their hiv status was disclosed by health-care professionals to others without their consent [ ] . according to the latest available statistics, there have been , cumulative hiv/aids cases in china, including , deaths, by the end of [ ] . this accounts for only % of the estimated number of plhiv at that time. the percentage of undiagnosed cases cannot be improved upon if the barrier of stigma against plhiv from health institutions is not removed. in addition, plhiv that belongs to at-risk groups, especially msm, are subjected to greater social stigma due their identity and sexual orientation. recent study indicated that only - % of chinese msm underwent hiv testing in the past months during - [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . also, it is estimated that only - % of hiv-positive msm are diagnosed based on an estimate among msm in yunnan province in [ ] . due to the hidden nature of msm, sentinel surveillance targeting msm was also required to substantial scale-up. although the number of sentinel surveillance sites targeting msm has increased from in to sites in [ , ] , both epidemic and behavioural surveillance for msm remains insufficient and limited in many parts of china. reducing social stigma and discrimination is necessary in improving hiv surveillance in china. in summary, the hiv surveillance system in china has undergone substantial revamping that leading to a comprehensive, timely and efficient reporting system. however, large data gaps and lack of quality control and sharing of information obstruct the full performance of the system. this is largely due to fragmented authoritarianism brought about by the underlying political structure. social stigma and discrimination in health institutes are also key barriers for further improvements of hiv diagnosis and surveillance in china. the insufficient biological and behavioural surveillance for chinese msm may result in underestimation of the actual prevalence and disease burden among this population. the study was funded by vice chancellor fellowship, the university of new south wales, - . estimating the number of people living with hiv/aids in china: - ministry of health of the people's republic of china hiv/aids epidemiology and prevention in china hiv prevalence is increasing among men who have sex with men in china: findings from a review and meta-analysis sexual behaviors and hiv/syphilis infection among men who have sex with men: a meta analysis of data collected between and in the chinese mainland risk of hiv/aids in china: subpopulations of special importance office of the state council working committee on aids china. progress on implementing ungass declaration of commitment in china comparing the cost-effectiveness of hiv prevention interventions injection drug use and hiv/aids in china: review of current situation, prevention and policy implications ministry of health of the people's republic of china sex, drugs, and hiv/aids in china the changing face of hiv in china china aids policy implementation: reversing the hiv/aids epidemic by the development of hiv/aids surveillance in china hiv/aids epidemic and the development of comprehensive surveillance system in china with challenges current challenge of aids epidemic surveillance in china overview on sars in asia and the world a sampling survey on syringe exchange and methadone maintenance treatment among drug abusers in yunnan province brief introduction of chinese infectious disease detection and reporting information system information release guidelines for infectious diseases epidemic and public health contigencies encyclopedia on the prc state secrets law. changchun: jilin people's publishers quality assurance in the hiv/aids laboratory network of china joint united nations programme on hiv/aids, world health organization geneva: world health organization and joint united nations programme on hiv regional differences in hiv prevalence among drug users in china: potential for future spread of hiv? group on hiv/aids in china. hiv/aids: china's titanic peril - update of the aids situation and needs assessment report hiv prevalence among populations at risk, using sentinel surveillance data from to in china heterosexual transmission of hiv in china: a systematic review of behavioral studies in the past two decades national hiv/aids sentinel surveillance report in . beijing: china cdc & national sentinel surveillance group injection drug use and hiv/aids transmission in china systematic review of hiv and hcv infection among drug users in china situations and trends of hiv and syphilis infections among drug users in china surveillance of aids among female sex workers in china improving hiv surveillance systems: country experiences and a proposal for evaluation framework quantitatively monitoring aids policy implementation in china living with hiv/aids in china policy implementation in post-mao china the sars epidemic and its aftermath in china: a political perspective evaluation of the guangdong hiv/aids surveillance system, china building a better infectious disease surveillance system for china: an evaluation from a political perspective discrimination against people with hiv persists in china disclosure of hiv status: cultural issues of asian patients disclosure of hiv status is a family matter: field notes from china help-seeking in a context of aids stigma: understanding the healthcare needs of people with hiv/aids in china hiv/std stigmatization fears as health-seeking barriers in china the china stigma index report evaluation of effect of community-based hiv/aids interventions among men who have sex with men in eighteen cities, china which chinese men who have sex with men miss out on hiv testing? investigation on the infection of hiv, hcv, syphilis and hbv among msm in dalian city in possible increase in hiv and syphilis prevalence among men who have sex with men in guangzhou, china: results from a respondent-driven sampling survey surveillance on the high risk behaviors among men who have sex with men prevalence and correlates of hiv and syphilis infections among men who have sex with men in chongqing municipality survey of the knowledge, attitude, and practice on aids among msm population in urumchi the next era of hiv in china: rapidly spreading epidemics among men who have sex with men the authors confirm that this article content has no conflicts of interest. key: cord- - cvtoc j authors: jaiswal, j.; loschiavo, c.; perlman, d. c. title: disinformation, misinformation and inequality-driven mistrust in the time of covid- : lessons unlearned from aids denialism date: - - journal: aids behav doi: . /s - - -y sha: doc_id: cord_uid: cvtoc j nan during a pandemic about which too little is known, public health is facing a crisis on multiple levels, including regarding covid- related-health messaging. with the federal government's inadequate, inconsistent and largely nonevidence-based response [ ] [ ] [ ] , and the far reach of social media "armchair experts" [ , ] , tremendous uncertainty, fear, and anger has emerged with respect to the origins, treatments and prevention methods regarding covid- . much of the evidence needed to fully inform clinical and public health responses is not yet available, making covid- uniquely vulnerable to a proliferation of disinformation, misinformation, and medical mistrust, including what are often called "conspiracy beliefs" [ , ] . disinformation (strategically and deliberately spread false information), misinformation (false information, not necessarily with intent to mislead), and mistrust (more than the lack of trust; suspicion of ill intent) are multi-faceted phenomena, with heterogeneous underlying motivating factors. the purpose of this commentary is to suggest that understanding the etiologies of disinformation, misinformation, and medical mistrust must be an important component of the public health response to covid- . this is especially critical when considering how the pandemic has affected communities of color, including asian communities who have been blamed for the introduction of sars-cov- to the u.s. [ , ] and black communities who have been blamed for higher fatality rates among black populations [ ] . we propose that two main forms of pushback against dominant scientific evidence have become prominent during covid- : ( ) disinformation propagated at the institutional/federal government level to preserve power and undermine already marginalized groups, and ( ) inequality-driven mistrust among communities that have been made vulnerable by historical and ongoing structural inequities. while these two forms do not constitute a strict dichotomy, this distinction can help inform strategies to address erroneous information and mistrust and inform public health messaging. "conspiracy beliefs," characterized as "attempts to explain the ultimate cause of an event…as a secret plot by a covert alliance of powerful individuals or organizations, rather than as an overt activity or natural occurrence" [ ] , feature prominently in disinformation, misinformation, and inequality-driven mistrust. it can be difficult to persuasively present evidence to refute these types of ideas, especially because experts are often seen as part of the conspiracy [ ] , and new pieces of contrary evidence can be rationalized into an existing narrative [ ] . for example, a pew research center survey conducted in march found that % of americans believed that sars-cov- was developed intentionally in a lab [ ] , with many pointing to wuhan, china as the source [ ] ; president trump has given this theory institutional legitimacy [ ] , despite scientific consensus [ ] [ ] [ ] [ ] and the consensus of the u.s intelligence services that sars-cov- is not human-made [ ] . this strategic disinformation has served several agendas: casting doubt on evidence presented by dr. anthony fauci, the director of the national institute of allergy and infectious diseases and member of the white house coronavirus task force, validating and reinforcing pre-existing xenophobia and racism [ ] , and redirecting attention away from the white house's inadequate and delayed response to covid- . state-sanctioned disinformation has proven disastrous in the past. in south africa during thabo mbeki's presidency ( - ), aids denialism was institutionalized at the highest levels of government. this disinformation delayed official recognition of hiv as the etiology of aids and the accessibility of life-saving anti-retroviral therapy, which directly contributed to more than , preventable deaths [ ] [ ] [ ] [ ] . these examples of disinformation share some commonalities: assertions and preservations of power, authoritarianism, fear mongering, scapegoating to deflect blame, and the creation or reinforcement of states of collective shock, which can be used to facilitate the implementation of political and economic agendas that are more difficult to achieve during periods of stability [ ] . covid- disinformation appears to reflect agendas of white supremacy [ , ] , anxiety over social and economic instability [ ] , opportunistic unrestrained capitalism, and the cult of personality regarding the president [ , ] . this is a contrast to the inequality-driven mistrust held by people who continue to experience disenfranchisement [ ] . in the covid- pandemic, beliefs about deliberately withheld vaccines [ , ] and the intentional human-made origins of sars-cov appear to be emerging in some black communities [ ] . while disinformation and inequality-driven mistrust may result in similar or even shared fallacious beliefs, understanding their different origins is vital to delivering effective public health messaging. government officials promulgating disinformation about the origins of covid- or possible therapies-whether rooted in racism and xenophobia, or whether motivated by goals of deflecting responsibility and accountability-is fundamentally different from marginalized individuals or groups endorsing the same beliefs, for whom mistrust is rooted in ongoing trauma and direct memories of real betrayals [ ] . medical mistrust is well documented among black people and other populations placed at risk for disproportionate harm [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . for example, endorsement of hiv-related "conspiracy beliefs" is associated with worse hiv-related outcomes among some black populations [ ] [ ] [ ] . this manifestation of hiv-related mistrust can include the beliefs that the u.s. federal government was involved in creating or disseminating hiv as a form of genocide against people of color, that anti-retroviral therapies are harmful, and that a cure is available but is being secretly withheld by the government and pharmaceutical companies [ , ] . referring to these ideas as "conspiracy beliefs" frames these beliefs as being irrational or even paranoid, yet for populations made socially and economically vulnerable by interlocking structures of inequality [ ] , these ideas are often intergenerational in nature and can resonate strongly with ongoing stigmatizing and exclusionary experiences with healthcare, government, law enforcement, and criminal justice systems [ , [ ] [ ] [ ] . similarly, inequality-driven mistrust around covid- may deter or prevent individuals from seeking covid- -related medical care or adhering to evidencebased covid- prevention guidelines, such as physical distancing and self-quarantining. this is a critical consideration, as black, native, and latinx populations have been disproportionately affected by covid- infection, morbidity, and mortality [ ] [ ] [ ] [ ] [ ] [ ] ] , are disproportionately arrested for physical distancing violations [ , ] , and appear to be less likely to receive covid- testing [ ] . more effective public health messaging is urgently needed to address these inequities. we suggest the following recommendations: the onus is on researchers and clinicians to better understand these beliefs and to more effectively bridge the mistrust gaps [ ] . a social determinants of health framework [ ] can help public health and medical professionals address the impact of population-level inequalities on health outcomes in addition to facilitate enhanced understandings of how social and economic conditions engender inequalitydriven mistrust. it is vital to consider how people, as individuals and as members of groups, experience and interpret social and economic inequality, and how those experiences affect their trust in or mistrust of evidence-based public health messaging, as well as their readiness to accept any promulgated misinformation or disinformation [ ] . public health and medicine must address structural racism directly [ ] . effective public health responses to the pandemic, and to its disproportionate impact on communities of color and other vulnerable populations, must recognize the complex dimensions of mistrust. this requires attention to the issues of structural racism and systematic discrimination which create, perpetuate, and sustain mistrust and influence people's acceptance or rejection of misinformation or disinformation. the failure to fully address differential risk at the community and structural level, and differential risk among various populations placed at greatest risk for harm, further drives mistrust, which then reinforces mistrust arising from people's daily lived experiences of racism, classism, and stigma [ ] . anti-racism education as well as training on research with and care for marginalized populations, must be more fully integrated into public health and medical education [ ] . avoiding terms like "conspiracy beliefs" may position us to better understand, and thus more effectively address disinformation, misinformation and inequality-driven mistrust that has emerged during this pandemic. referring to ideas as "conspiracy beliefs" risks obscuring and denying meaningful aspects of people's lived experiences, particularly regarding inequality-driven mistrust, and is an ethical and strategic mistake for public health [ , ] . thus, we propose that public health abandon this term and instead endeavor to identify and distinguish the underpinnings of such beliefs, highlighting how false information may be driven either by agendas of power and racism, or instead driven by mistrust deriving from ongoing social and economic exclusion. this distinction will avoid placing blame on communities that are structurally placed at risk for disproportionate harm by elucidating the role of historical and ongoing social and economic inequalities, while recognizing the forces underlying propagated disinformation and holding accountable those with structural power. distinguishing between disinformation and inequalitydriven mistrust and shifting language away from "conspiracy beliefs" can help avoid pushing people further toward endorsing misinformation and disinformation. moreover, language without the negative connotations of "conspiracy beliefs" may leave rhetorical space for marginalized populations to express concerns shaped by historical and current trauma, and for public health to better understand why some people endorse such beliefs. public health and medical professionals have a responsibility to communicate science in an effective, accurate and accessible manner, without bias-and with the understanding that structural racism and other forms of oppression are root causes of inequality-driven mistrust. while erroneous beliefs may appear to similar in nature, the critical distinction is in the source of and paths to those beliefs. misinformation during a pandemic americans immersed in covid- news; most think media are doing fairly well covering it associated press. out of people arrested for coronavirus-related offenses in nyc have been black or hispanic the dangerous rise of covid- influencer and armchair epidemiologists please, let's stop the epidemic of armchair epidemiology why uncertainty about coronavirus breeds opportunity for misinformation. pbs news hour coronavirus misinformation and disinformation regarding coronavirus in social media asian americans are blamed by some for covid- outbreak. national public radio blame and discrimination attached to covid- -an faq for us elected leaders and health officials stop blaming black people for dying of the coronavirus: new data from states confirm the extent of the racial disparities the hidden impact of conspiracy theories: perceived and actual influence of theories surrounding the death of princess diana advances in conspiracy theor dead and alive: beliefs in contradictory conspiracy theories nearly three-in-ten americans believe covid- was made in a lab covid- conspiracy theories: was sars-cov- made in a lab? psychology today a timeline of the covid- wuhan lab origin theory. forbes genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding full-genome evolutionary analysis of the novel corona virus ( -ncov) rejects the hypothesis of emergence as a result of a recent recombination event the proximal origin of sars-cov- statement in support of the scientists, public health professionals, and medical professionals of china combatting covid- office of the director of national intelligence. intelligence community statement on origins of covid- . odni news the foreignness of germs: the persistent association of immigrants and disease in american society. milbank q aids and the scientific governance of medicine in post-apartheid south africa lessons from south africa's experience of hiv/aids there is no proof that hiv causes aids": aids denialism beliefs among people living with hiv/aids denying aids: conspiracy theories, pseudoscience, and human tragedy screen new deal. the intercept white supremacist groups are recruiting with help from coronavirus-and a popular messaging app coronavirus outbreak revives dangerous race myths and pseudoscience. nbc news coronavirus perceptions and economic anxiety the relation between media consumption and misinformation at the outset of the sars-cov- pandemic in the us all the president's lies about the coronavirus. the atlantic towards a more inclusive and dynamic understanding of medical mistrust informed by science nearly one-third of americans believe a coronavirus vaccine exists and is being withheld, survey finds. usa today tuskegee always looms in our minds": some fear black americans, hardest hit by coronavirus, may not get vaccine study: nearly a third of americans believe a conspiracy theory about the origins of the coronavirus medical apartheid: the dark history of medical experimentation on black americans from colonial times to the present ubiquitous yet unclear: a systematic review of medical mistrust medical mistrust and prep perceptions among transgender women: a cluster analysis the association of cultural and structural factors with perceived medical mistrust among young adult latinos in rural oregon medical mistrust, racism, and delays in preventive health screening among african-american men does discrimination breed mistrust? examining the role of mediated and non-mediated discrimination experiences in medical mistrust medical mistrust and less satisfaction with health care among native americans presenting for cancer treatment the effect of conspiracy beliefs and trust on hiv diagnosis, linkage, and retention in young msm with hiv the health and sociocultural correlates of aids genocidal beliefs and medical mistrust among african american msm conspiracy beliefs about hiv are related to antiretroviral treatment nonadherence among african american men with hiv the need for multi-level mitigation of medical mistrust among social network members contributing to antiretroviral treatment nonadherence in african americans living with hiv: comment on bogart medical mistrust is related to lower longitudinal medication adherence among african-american males with hiv hiv-related 'conspiracy beliefs': lived experiences of racism and socio-economic exclusion among people living with hiv mapping the margins: intersectionality, identity politics, and violence against women of color like i have no choice": a qualitative exploration of hiv diagnosis and medical care experiences while incarcerated and their effects the transgenerational consequences of discrimination on african-american health outcomes rumors and realities: making sense of hiv/aids conspiracy narratives and contemporary legends black americans face alarming rates of coronavirus infection in some states. the new york times questions of bias in covid- treatment add to the mourning for black families. the new york times age-adjusted rates of lab confirmed covid for native americans, covid- is "the worst of both worlds at the same time doctors without borders dispatches team to the navajo nation for latinos and covid- , doctors are seeing an 'alarming' disparity. the new york times in-some-ofohi osmost-popul ous-areas -black -peopl e-were-at-least - -times -as-likel y-to-be-charg edwit h-stay-at-home-viola tions -as-white s the coronavirus doesn't discriminate, but u.s. health care showing familiar biases. national public radio whose responsibility is it to dismantle medical mistrust? future directions for researchers and health care providers social determinants of health inequalities there's never been a more urgent moment to build black americans' trust in the medical system structural racism and supporting black lives-the role of health professionals prior experiences of racial discrimination and racial differences in health care system distrust a call for critical race theory in medical education dissecting the social body: social inequality through aids counternarratives racial capitalism: a fundamental cause of novel coronavirus (covid- ) pandemic inequities in the united states. health edu behav key: cord- -q a aogo authors: sun, xinhua; lu, fan; wu, zunyou; poundstone, katharine; zeng, gang; xu, peng; zhang, dapeng; liu, kangmai; liau, adrian title: evolution of information-driven hiv/aids policies in china date: - - journal: int j epidemiol doi: . /ije/dyq sha: doc_id: cord_uid: q a aogo background as china continues to commit to universal access to hiv/aids prevention, treatment and care services, its hiv/aids policies have become increasingly information driven. we review china’s key national-level hiv/aids policies and discuss policy gaps and challenges ahead. methods we conducted a desk review of key national-level policies that have had a major impact on china’s hiv/aids epidemic, and examined recent epidemiological data relevant to china’s hiv response. results national-level policies that have had a major impact on china’s hiv/aids response include: ‘four frees and one care’; -year action plans; and hiv/aids regulation. these landmark policies have facilitated massive scaling up of services over the past decade. for example, the number of drug users provided with methadone maintenance treatment significantly increased from in to in ; almost a -fold increase. the ‘four frees and one care’ policy has increased the number of people living with aids on anti-retroviral treatment from some patients in to over in . however, stigma and discrimination remains major obstacles for people living with hiv/aids trying to access services. conclusions china’s current national policies are increasingly information driven and responsive to changes in the epidemic. however, gaps remain in policy implementation, and new policies are needed to meet emerging challenges. in april , the state council of the people's republic of china officially announced the lifting of its travel ban on people living with hiv/aids wishing to enter the country. this ban was implemented years ago as one of china's first key policies for hiv/aids control and prevention. the announcement reflects china's current approach to hiv/aids: pragmatic solutions to a changing epidemic based on sound scientific information. china has made significant progress in its hiv response over the past decade. china now has each of the 'three ones' recommended by the united nations program on hiv/aids (unaids) as key elements supporting a results-based hiv response, ( table ). in addition to the 'three ones', china has put into effect key laws that have created an enabling environment for china's national hiv response, such as the hiv/aids prevention and treatment regulations. moving forward, china faces an array of new and ongoing challenges that will need to be addressed in its new -year action plan for the containment and control of hiv/aids . we review key national policies that have guided china's hiv response at various stages. we also discuss gaps in policy implementation, and challenges ahead as china continues its efforts to achieve universal access to hiv prevention, treatment and care services. we performed a desk review of all hiv/aids policies issued by the chinese government since the beginning of the epidemic. we limited our review to nationallevel policies that have been put in place or revoked over the past years. we also reviewed available data relevant to selected policies. data were collected from government reports and papers published in peer-reviewed journals. an overview of aids policies issued against specific hiv/aids epidemic phases are summarized in table . the chinese government has issued hundreds of hiv/aids policies over the past years. we focused on national-level policies that have had a significant impact on china's hiv/aids response. the landmark policies include: the implementation and revocation of china's travel ban on people living with hiv/aids; the blood donation law of ; china's -year action plans for the containment and control of hiv/aids; the 'four frees and one care' policy to improve access to treatment and care services; the creation of high-risk behavioural intervention outreach teams; and the aids regulation. these key policies were put in place during different phases of the hiv/aids epidemic in china (figure ). in june , the first hiv-infected patient, a us citizen, was diagnosed and reported in china. later that same year, four haemophiliacs were confirmed to have been infected with hiv due to the use of imported blood products. by , a total of seven provinces, municipalities and regions had reported hiv/aids cases; most of them were foreigners or chinese residents returning from overseas. the chinese government issued a series of early policies focused mainly on blood product safety, case identification and preventing the spread of hiv from infected foreigners entering the country. the first hiv/aids policy document entitled 'the joint notice on preventing hiv from entering china by restricting import of blood products' was issued on september . in , the ministry of health classified hiv/aids as a class b infectious disease notifiable through the national infectious disease reporting system. to prevent hiv-infected foreigners from entering into china, a series of policies were issued. foreign students and research scholars visiting and living in china for months had to submit to hiv testing procedures month after entry into the country. other foreigners residing or living in china for months had to provide health certificates and were asked to specify if they were infected with hiv/ aids. foreigners found to be hiv infected at chinese cross-border and customs checkpoints were forced to leave the country and were placed under quarantine before departure. , [ ] [ ] [ ] to enforce this between late and early , outbreaks of hiv infection were identified among commercial plasma donors in regions of central and eastern china. , the scale of transmission and the resulting devastation led to one of the worst tragedies of the global hiv pandemic. early small-scale surveys indicated that the epidemic was serious, but the true scope of transmission was largely unknown until , when a large-scale survey was carried out among plasma donors in fuyuan, anhui province, showing an hiv prevalence of . %. to respond to this crisis, china's blood donation law was drafted in and enacted in . the most important components of the law highlight voluntary donation and prohibit repeated commercial donation. at same time, nationwide blood collection facilities were established and manual collection of blood or plasma was prohibited. since since , hiv spread more quickly throughout china. by , all provinces, municipalities and autonomous regions in mainland china reported hiv cases. to respond to the changing hiv/aids epidemic, several key ministries, including health, finance, public security, justice, and the development commission, met to discuss instituting supportive policies for condom promotion, needle exchange and methadone maintenance programmes. the language of early documents was carefully selected to avoid condoning 'social evils', such as prostitution and drug use. terms such as condom social marketing, needle social marketing and community-clinic-based therapeutic treatment for drug users were used to describe hiv prevention measures that were incorporated into china's first -year action plan ( - ). china's first -year action plan was a policy milestone in terms of supporting effective policies for condom promotion, methadone maintenance and needle exchange. one of most important policy directions laid out in the first -year action plan was pilot testing of harm reduction strategies, including methadone maintenance treatment (mmt) and needle exchange programmes. , however, implementation of the plan was not adequately budgeted, weakening its impact, particularly in the first years, between and . after the severe acute respiratory syndrome outbreak in , public health rose to the top of china's policy agenda, and funding for the hiv/aids -year action plan increased. china's second -year action plan ( - ) was drafted in a more supportive political environment in which public health was given a higher priority. first, there was much stronger political commitment and financial commitment for controlling hiv/aids from chinese central government. in , a new administration led by president hu jintao, premier wen jiabao and vice premier and the then health minister wu yi put the implementation of evidence-based hiv policies high on the national agenda. secondly, china's 'four frees and one care' policy to increase access to anti-retroviral therapy (art) was announced in late and had greatly facilitated implementation of hiv prevention, treatment and care and support. the second -year action plan set more specific and ambitious targets, particularly for prevention programmes for marginalized groups, such as drug users, female sex workers and men who sex with men. for example, one of the targets was for hiv prevention programmes to achieve % coverage of the 'floating population' (such as migrant workers) and people with high-risk behaviours. another target was set to establish mmt clinics in counties and cities with more than drug users registered with the public security bureau, and for % of opiate users to receive mmt services. this target has greatly facilitated the scaling up of the mmt programme in china; for example, the number of drug users receiving methadone increased from in to in , almost a -fold increase. other targets included: achieving % coverage of needle and syringe exchange programmes; reducing the needle/syringe sharing rate among idus to < %; increasing the proportion of people with high-risk behaviour who have basic hiv knowledge to at least %; increasing the condom usage rate to % among high-risk groups. the plan also set specific targets for treating aids patients. some of these targets included: at least % of aids patients satisfying the treatment criteria should have received art by ; mother-to-child transmission prevention services should be available in % of cities and counties; and more than % of hiv-positive mothers should have received prevention of mother-to-child transmission (pmtct) services. the evaluation of the second -year action plan will take place next year. china's ungass country progress report suggested that china's aids programme is approaching specific targets set in its second -year plan. the 'four frees and one care' policy the massive outbreaks of hiv infection that occurred in central china among paid plasma donors around the mid- s led to a huge demand for hiv/aids treatment and care services as more and more people became ill and died. at the united nations high-level special meeting in september , the chinese government announced five commitments in the fight against hiv/aids, later known as the 'four frees and one care' policy. these commitments included: ( ) free anti-retroviral drugs to aids patients who are rural residents or people without insurance living in urban areas; ( ) free voluntary counselling and testing; ( ) free drugs to hiv-infected pregnant women to prevent mother-to-child transmission, and hiv testing of newborn babies; china. first, it resulted in a significant increase in the number of people being tested for hiv . before , less than newly identified hiv infections were reported each year. after , over newly identified hiv infections were reported each year ( figure ) . secondly, it resulted in a significant increase in the number of aids patients receiving free anti-retroviral treatment; for example, increased from in to over in , and it helped reduce aids mortality among those on art. thirdly, it increased the number of pregnant women screened for hiv infection and receiving pmtct services. fourthly, all aids orphans have been taken care of by either relatives, or neighbour or local government social welfare programmes. the 'four frees and one care' policy has also significantly reduced stigma in local communities, particularly in areas where the epidemic was driven by contaminated plasma collection. high-risk behavioural intervention outreach teams in , as the primary mode of hiv transmission began to shift from injecting drug use to high-risk sexual behaviours, the chinese ministry of health announced the establishment of high-risk behavioural intervention teams at all levels of the public health system. the primary function of these teams is to conduct an outreach programme among sex workers, men who have sex with men, and migrant labourers to reduce the risk of hiv sexual transmission among these high-risk groups. intervention teams have increased the reach of hiv prevention programmes. on average, these teams have reached about female sex workers and men who sex with men per month. national hiv/aids regulation in early , the chinese government issued the national hiv/aids regulation to define the roles and responsibilities of government, civil society and people living with hiv/aids. this was the first law in china to highlight protection of human rights of people living with hiv/aids, including the right to marry, to access health-care services, to enjoy equal employment opportunities and to receive schooling. the regulation has laid a legal base for effective but sensitive prevention measures, such as condom promotion, mmt and needle exchanges. however, implementation of hiv/aids regulation varies in different articles and in different places. the most significant gap relates to stigma-related rights for receiving medical services and employment. on august , the first case of a law suit concerning hiv-related stigma for employment was reported and has generated great discussion and concern. the most frequent cases of discrimination that people living with hiv/aids face are when seeking medical care in clinical settings. there is still a long way to go to achieve the goal of zero stigmas in chinese society, though hiv/aids regulation is in place. china now has national laws, policies, action plans, surveillance systems and monitoring and evaluation systems in place to support its hiv/aids response, as well as a government body with the authority to coordinate different sectors. hiv/aids policies and action plans are responsive to the increasing wealth of epidemiologic data available, and a massive scaling up of services has taken place over the past decade. though efforts have been made to achieve universal access to prevention, treatment, care and support services, a number of important gaps exist in the implementation of china's hiv/aids policies. first, despite the increased coverage of hiv testing services, too many people remain unaware of their hiv status. by the end of , there were cumulative cases of hiv/aids reported, and an estimated people living with hiv/aids in china. this means that less than half of the people living with hiv/aids are aware of their hiv status, and hence unable to receive needed hiv prevention, treatment and care services. secondly, aids mortality remains a major problem despite expanded art programmes because too many people are receiving hiv testing services after they have already progressed to aids. deaths related to hiv/aids increased from in to in and in . , , the majority of reported deaths occurred among people who had progressed to aids by the time they were tested for hiv, and hence many missed the opportunity to use life-saving art. thirdly, many people remain unwilling to be tested for hiv. after china launched its mass screening campaign in - , it was presumed that most of people infected with hiv via plasma donation or transfusion were already identified. however, there have been between and hiv cases and - aids cases newly identified and reported each year between and . , , fourthly, important gaps remain in the implementation of national policies at the provincial and sub-provincial levels. some local governments do not fully implement national hiv/aids policies. , interventions among high-risk groups often lack sufficient coverage, depth and frequency to have an impact on the course of the epidemic. fifthly, in some places, the rate of consistent condom use is low among sex workers and their clients. sixthly, coverage of pmtct services and art programmes remain too low, and the quality of services needs to be improved. ii international journal of epidemiology seventhly, the involvement of civil society needs to be increased. non-governmental organizations alone lack the necessary capacity and experience to respond to the hiv/aids epidemic, but they can play a vital role in the hiv response. enterprises and individuals have often limited understanding of the importance of hiv/aids and are not fully motivated to participate in hiv/aids activities. new policies are needed to achieve the goals of universal access and respond to the changing dynamics of china's hiv epidemic. new policy areas of special emphasis in china's new -year action plan should include reducing stigma and discrimination, encouraging greater civil society participation, hiv routine testing, partner notification, management of opportunistic infections and co-infections with tuberculosis and hepatitis, and treatment of the mobile population. recent data have shown that hiv transmission is gradually shifting away from being caused by injecting drug use and more by sexual contact. in , the proportion of estimated hiv infections associated with sexual transmission exceeded that of injecting drug use. hiv prevalence among men who have sex with men is increasing rapidly. between and , the proportion of hiv infections associated with male-to-male sexual transmission increased from . to %, representing a -fold increase. to address these challenges, the strategies and policies for hiv/aids response at the grass-roots level are being explored and strengthened in several ways. policies and mechanisms that encourage grass-roots governmental department support are being promoted. the participation of grass-roots social and civil society groups is encouraged. improvements are being made on the social security system, grass-roots health-service system, and basic health-care service provision and drug supply. , plans and models of hiv/aids interventions that are appropriate to local communities are being developed. accessibility and coverage of testing, interventions, treatment, pmtct, care and support and other services are being enhanced. community-based models with multisectoral accountability are being established. sustainable hiv/aids services are being promoted. developing evidence-based decision making processes and policies and strategies is vital to the success of china's future hiv response. as the epidemic shifts towards being caused increased sexual transmission, china will continue to develop and improve its information-driven policy response to hiv/aids. empirically based scientific information will dictate which policies will be effective and sufficient to turn the tide of the hiv epidemic. greater emphasis may need to be placed on communitybased and multisectoral involvement as a comprehensive response to the hiv/aids epidemic. sound policy decisions will be enacted as china works to ensure universal access to hiv/aids prevention, treatment, care and support services. conflicts of interest: none declared. landmark national-level aids policies, e.g., 'four frees and one care', have facilitated massive scaling up of prevention, treatment and care services over the past decade in china. china's current national policies are increasingly information driven and responsive to changes in the epidemic. gaps remain in policy implementation, and new policies are needed to meet emerging challenges. rules for implementation of the law of the people's republic of china on control of the entry and exit of aliens. beijing: the state council of china rules for implementation of the law of the people's republic of china on control of the entry and exit of aliens three ones'-principles for the coordination of national aids responses report on strengthening surveillance to prevent imported cases of hiv/aids. beijing: ministry of health of china ministry of health of china. notice on banning import of blood products such as factor viii. beijing: ministry of health of china ministry of health of china. notice on strengthening hiv/ aids management. beijing: ministry of health of china identification of hiv infection among drug users in china cohort study of hiv infection among drug users in ruili, longchuan and luxi of yunnan province, china ministry of health of china, ministry of public security of china. notice on providing compulsory testing and treatment of sexual transmitted diseases for sex workers and their clients. beijing: ministry of health of china the hiv/aids epidemic in china: history, current strategies and future challenges hiv- infection in commercial plasma donors in china prevalence of hiv infection among former commercial plasma donors in rural eastern china epidemiological research cases in china. beijing: people's medical publishing house state development planning commission, ministry of science and technology, ministry of finance. china's medium and long-term plan on prevention and control of hiv/aids. beijing: chinese ministry of health working duty in hiv/aids prevention and control for related ministries, committees, administrations and social groups china's action plan for reducing and preventing the spread of hiv/aids ( - ). beijing: state council office state council of the people's republic china. notice on strengthening aids prevention, treatment and care programs the evolution of china's response to hiv/ aids regulations on aids prevention and treatment. beijing: state council office action plan on hiv/aids prevention and containment ministry of health of china, ministry of public security of china, ministry of justice of china. notice on hiv screening of inmates of prisons and detoxification centers. beijing: ministry of health of china beijing: ministry of health of china annual report of hiv/aids/std prevention, treatment and care in china in state education commission of china, ministry of health of china. notice on performing hiv test for foreign students. beijing: state education commission of china, ministry of health of china ministry of health of china, ministry of public security of china. provisions concerning the provision of health certificate by foreigners seeking entry. beijing: ministry of health of china ministry of health of china, ministry of foreign affairs of china, ministry of public security of china, et al. several provisions concerning hiv surveillance and management. beijing: ministry of health development of a unified web-based national hiv/aids information system in china doctor did not know blood donation law causing patients infected with hiv in bei-an, heilongjiang rapid scale up of harm reduction in china effectiveness of first eight methadone maintenance treatment clinics in china scaling up the national methadone maintenance treatment program in china: achievements and challenges ministry of health of the people's republic of china public health. hiv testing in china five-year outcomes of the china national free antiretroviral treatment program china cipra project team. understanding hiv-related stigma and discrimination in a 'blameless' population announcement on establishing high risk behavioral intervention team among all level of centers for disease control and prevention in china scaling up prevention programs to reduce the sexual transmission of hiv in china the first law suit to aids discrimination in china ii international journal of epidemiology ministry of health of china, unaids, who. the estimation of hiv/aids in china in annual report of hiv/aids/std prevention, treatment and care in china in annual report of hiv/aids/std prevention, treatment and care in china in state council aids working committee office, un theme group on aids in china. a joint assessment of hiv/aids prevention, treatment and care in china key: cord- -t l zii authors: mayer, j.d. title: emerging diseases: overview date: - - journal: international encyclopedia of public health doi: . /b - - . - sha: doc_id: cord_uid: t l zii emerging infectious diseases are diseases that are either new, are newly recognized, or are increasing in prevalence in new areas. resurgent diseases are also usually grouped in this category, as is antimicrobial resistance. these diseases have been given formal recognition in the past two decades, although a historical outlook demonstrates that the phenomenon has probably been persistent, although largely undetected, through recorded history. emergence has accelerated recently, driven by factors such as demographic change, land use change, increased rapidity and frequency of intercontinental transportation, and other mostly social trends. continued infectious disease emergence poses, and will continue to pose, significant challenges for public health and for basic science. emerging and re-emerging infectious diseases have been major features of contemporary societies. indeed, there is evidence that history has been characterized by the constant interplay of humans and pathogens (mcneill, ) . however, it is impossible to say when the terms 'emerging infection' or 'emerging infectious diseases' were first used to describe new infectious diseases, or diseases that meet the criteria that are described in this article. the belief in the s that the threat of infectious diseases had been eliminated in developed countries was unfounded. a broader view of history would have demonstrated this. one possible reason for the optimism is that the s was a decade of optimism in general. in the united states, social programs were instituted to address inequities; humankind had not only orbited the earth, but landed on the moon; the gains of science and technology were impressive; economic expansion was equally impressive; poliomyelitis had been all but eliminated in the united states; and the sense of 'control' was widespread. beyond the borders of the united states, however, in africa, asia, latin america, and elsewhere, malaria proved to be a huge challenge to life, although its prevalence was decreasing, and diarrheal diseases continued to take their toll, particularly among the young. transportation links created the potential for transmission of infection between tropical regions and developed countries such as the united states. the potential for new diseases to emerge in the united states was there, and it took just a few years until this happened, catching the medical and public health communities by surprise. in discussions of emergence, both 'emerging infections' and 'emerging infectious diseases' are commonly found. while the two are closely related, they are not synonymous. an infection does not necessarily represent a state of disease. 'infection' suggests that an agent (usually a microbe) has become resident in the host. usually that agent is replicating in the host. however, the host need not show any sign of disease, in the sense that it can conduct its normal activities without hindrance. 'disease' is a state in which the normal functioning of the host is impaired, and both signs and symptoms are present -indeed, they are what limit normal function. an infectious disease is therefore a disease that is due to a pathogen. appeared de novo, or are being experienced in a region with greater intensity, or for the first time. some authors have used a more specific definition of emerging to diseases and have specified five types of emerging diseases: ( ) diseases that arise de novo, ( ) diseases that are newly recognized, ( ) diseases that have not previously existed in a specific area, ( ) diseases that had not yet made a species jump to humans until the present, and ( ) diseases that are increasing in prevalence. there are other definitions as well. the simplest definitions are frequently the most useful, and thus morse's definition will be used in this article. re-emerging infectious diseases are frequently thought of as being closely related phenomena to emerging infectious diseases. whereas emerging diseases denote diseases that are being experienced for the first time in a given location, re-emerging diseases are diseases that are reappearing in regions from which they have disappeared. usually eradication is due to deliberate efforts on the parts of government and public health agencies. for example, malaria control programs following the end of world war ii were instrumental in the elimination of malaria from some areas of the world, such as italy and spain. sometimes, malaria eradication was eliminated as part of multisector development programs. for example, the tennessee valley authority, created during the s primarily for flood control, hydroelectric power, and economic development, also had an explicit aim of malaria control. this resulted in the drainage of most swamps, and the elimination of malaria from this part of the united states. just as malaria was disappearing from many regions in the s, the next decade saw the resurgence of malaria, and the global prevalence of malaria has been increasing ever since. there are multiple reasons for this. these include anopheline spp. resistance to ddt, banning of ddt because of suspected environmental effects, and the development of resistance to chloroquine. malaria, then, is a re-emerging disease. another is tuberculosis. in many societies, tb had been nearly eliminated, but with the appearance of hiv/aids, immunocompromised individuals were much more susceptible to tb reactivation. tb, therefore, is also considered to be a re-emerging disease. the public and the medical and public health communities gradually came to realize that their complacency over the potential threat of infectious diseases was misplaced, and that new and emerging diseases constituted one foci of concern over health threats to the public. this change in attitude came gradually, and can be thought of as a series of historical 'moments,' each of which refocused attention on infectious diseases. while it is impossible to be exhaustive here, this section takes a roughly chronological approach in describing the events that led the public and professional communities to realize that infectious diseases had not been 'conquered.' the bicentennial of the united states was celebrated in , and there were many gala events around the nation in july. one was the meeting of the pennsylvania chapter of the american legion. the events surrounding this meeting were the first to bring the attention of both the population and the broad scientific and medical communities to the argument that infectious diseases in the united states had been 'conquered,' and both alarmed the public and aroused the curiosity of the scientific and medical communities because this appeared to be a new disease. indeed, before legionellosis was identified and antimicrobial treatment identified, legionellosis was called a 'monster disease. ' over members of the american legion who had attended the meeting developed an unusual respiratory illness, and it became clear that it was of bacterial etiology, although it was initially thought to be viral, due to its close clinical resemblance to influenza. approximately people died as a result of this outbreak. however, two things remained unclear. first, the pathogen could not be identified with conventional methods, and second, no common source of exposure could be identified initially, although the fact that the number of incident cases followed a typical epidemic curve suggested very strongly that there was some sort of common exposure to the pathogen. the news media seized upon this medical 'mystery,' and the public knew that they were dealing with an unknown infectious disease. this constituted a historical moment in contemporary american history, because it had been decades since something like this had happened. six months later, the bacterium was finally identified. legionella was not a new bacterium. stored samples from outbreaks as early as tested positive for legionella spp. however, the bacterium had not been identified in these outbreaks because it had not yet been described and characterized. in retrospect, most renowned is an outbreak that occurred in pontiac, michigan in , although the symptoms were milder than in the legionella outbreak in philadelphia. in fact, mild legionellosis with a nonpneumonic form is often called 'pontiac fever.' this is not the place to review the epidemiology, pathophysiology, and clinical aspects of legionellosis in depth. briefly, though, it usually has an acute onset, and is usually caused by legionella pneumophila, although other species are also pathogenic. in fact, there are species of the genus, and numerous serotypes. epidemiologically, l. pneumophila is by far the dominant species in human disease. the major reservoirs are bodies of freshwater, and the main mode of transmission is through small droplets that are inhaled from the environment. in the philadelphia outbreak, the source was finally traced to the air conditioning system in the hotel in which most attendees were lodged; the attendees were inhaling small particles in certain parts of the building. dozens of subsequent outbreaks have been traced to similar mechanisms. these have been not only air conditioners but also shower heads, aerosolizers in sinks, and whirlpools. virtually anything that aerosolizes fresh water is a potential mechanism by which legionellosis may be transmitted. symptoms of classic legionnaires disease are nonspecific and include fever, malaise, headaches, and myalgias. frequently, rigors will develop, as will a productive cough (in about half the cases). dyspnea (shortness of breath) is almost invariably present, and chest pain is common, as is a relative bradycardia for the elevated temperature. there are a number of abnormalities in laboratory tests, and chest films are markedly abnormal. a urine antigen test is available for one serotype, so laboratory diagnosis must frequently rely on more complex and time-consuming laboratory methods such as dfa. sputum cultures or cultures from bronchoalveolar lavage have been the mainstay of laboratory diagnosis. since laboratory methods do not show a definitive diagnosis until a minimum of days following onset, diagnosis is usually made on clinical grounds, and treatment is initiated based upon index of suspicion. erythromycin proved to be effective in , and other macrolides (azithromycin, clarithromycin) are highly effective. tetracycline and doxycycline are frequently used, as are the fluoroquinolones, such as levofloxacin. in hosts who are not immunocompromised, the prognosis is generally positive. there is no doubt that legionellosis was an emerging disease when it was first identified. its particular significance lies in its historical context -in the fact that this was the first occurrence that began shaking the optimism of the s and early s that infectious diseases had been conquered, and also in the fact that the etiology of an obviously infectious syndrome with a reasonably high case fatality ratio remained unknown for a number of months. chronologically, the next event to bring infectious disease to the attention of the public was another emerging infectious syndrome. in late and , a number of women in the united states became seriously ill with a syndrome characterized by high fever, shock, rash, hypotension, and capillary leak. this syndrome had been first described as such years earlier, although in retrospect it had been noted in the medical literature in the s. the paper identified toxic shock syndrome in males, females, and children -and the females were both menstruating and not menstruating. the outbreak was associated with menstruating women, many of whom were using superabsorbent tampons. although this was a major risk factor in the - outbreak, much of the public and many physicians were under the erroneous impression that toxic shock syndrome (tss) was necessarily associated with menstruating women who were using superabsorbent tampons. although tss is not necessarily associated with menstruating women, this does remain a risk factor in the epidemiology of tss. as with legionnaires disease, tss was a rare disease, yet the public's perception of it was out of proportion to its true prevalence -the risk was exaggerated. this is something that social scientists have called the 'social amplification of risk' in the context of new events that are potentially dangerous, but that nonetheless carry with them a low risk. amplification takes place as a result of media coverage, and as a result of intrapsychic processes that tend to amplify the threat of novel threats when the locus of control over the event is external to the individual. during the outbreak of toxic shock syndrome, newspapers were full of stories about tss and the sometimes deadly consequences of developing the syndrome. these were frequently on 'page above the fold' and necessarily caught the attention of the public. the same was true of television news. once this outbreak of tss appeared to be concentrated in one single group -menstruating women using superabsorbent tampons -the general public's fear of tss began to diminish, and the federal government mandated the withdrawal of those tampons from the market. the number of incident cases began a rapid decline, and was back to baseline of about cases per year by . some reports demonstrated that there was a decrease in the use of all tampons -not just superabsorbent tampons. it was already known in that toxic shock syndrome was caused by staphylococci (specifically, s. aureus). in these cases, treatment is threefold: removal of the tampon, indwelling tampon, or other hypothesized environmental cause; aggressive fluid resuscitation; and rapid use of antistaphylococcal antibiotics. other bacterial species can cause toxic shock syndrome. in rare cases, other staphylococcus species have been associated with toxic shock syndrome, and because they are coagulase-negative, they are difficult to treat. at this time, coagulase-negative staphylococci constitute the most common cause of hospital-acquired bacteremia. this sometimes results in endocarditis, and usually the only effective treatment is surgical valve replacement, particularly in the case of those who have had earlier valve replacement. aggressive antibiotic therapy is occasionally effective. should toxic shock syndrome be considered to be an emerging disease? it certainly was in , when the public was so concerned with its appearance. now, in , years after it was first described, this label is more questionable. what was most significant about toxic shock syndrome, however, was its historical significance. it followed the outbreak of legionnaires disease so closely that it turned the public's attention, once again, to infectious diseases, and to infectious diseases that had been unknown. it also reminded the biomedical community that infectious diseases had not been conquered. the issue at the time was whether legionnaires disease and toxic shock syndrome were anomalies, whether the assumption of the conquest of infectious diseases had clearly been erroneous, or whether these two outbreaks were harbingers of a new stage in 'epidemiologic history'a historical period during which emerging infections would become common and would catch the attention of the public, the public health community, the medical community, and government agencies. the public health and medical communities were divided on this. it would soon become clear, however, that the latter would hold true -that emerging infectious diseases would come to the forefront of public health, epidemiology, and the medical community. in the cases of legionnaires disease and tss, the social amplification of risk exaggerated perceived threats. nonetheless, the public became more attentive to infection. two other phenomena would solidify this attention. one was the appearance of hiv/aids in the united states, and the other was public attention that was drawn to hemorrhagic fevers, mostly in africa. the details of hiv/aids are covered elsewhere in this encyclopedia, and there will be no attempt here to duplicate this material. rather, this discussion concentrates on the significance of hiv/aids. when hiv/aids first appeared in several urban areas in the united states in , it appeared to be an anomalous syndrome. it was not called 'aids' until , when the centers for disease control (cdc) gave the syndrome that label. in the same year, researchers at cdc also linked one of the pathways of transmission to blood and blood products, causing a great deal of public concernif it was possible to contract aids through a frequently used medical practice, it had the potential of affecting millions of people. until then, aids was thought to be restricted to the gay community. in , blood banks were warned by the cdc that blood and blood products could definitely transmit aids, and surgeons and other medical personnel began rethinking the criteria necessary for transfusion. by , it was clear that the exponential increase in the number of incident cases was a definite trend. in and , two teams discovered that the pathogen causing aids was viral, and although it had a different nomenclature at first, there was a great deal of relief that the causal agent had been discovered. it is an interesting study in the sociology of science to analyze the competing claims by luc montagnier at the institut pasteur and robert gallo in the united states concerning their respective claims that they discovered hiv. it is now clear that montagnier discovered the virus. shortly after the virus was discovered and characterized, an antibody test was developed to detect hiv in vivo. this was quickly used to screen blood products as well as to detect hiv in individuals. whereas some people decried the slowness of the u.s. government's response to hiv, the time from the first presentation of a group of males with kaposi's sarcoma or oral thrush until the antibody test for a recently identified virus was only years. granted, the president of the united states, ronald reagan, had not even mentioned aids, and funding was less impressive than it could have been, but the time was quite short. the real challenge with hiv has been to find an effective vaccine, or to find a 'cure,' although antivirals have been effective in suppressing viral load in the majority of cases since - . the prevalence and mortality data are well-known. the best estimates are that globally, over million people are living with hiv/aids, and approximately million have died of hiv/aids. currently, about - million of those living with hiv/aids are women, and in developing countries, particularly in sub-saharan africa, hiv/aids is becoming, increasingly, a disease of women. currently, approximately two-thirds of those living with hiv/aids are in sub-saharan africa, but the increasing prevalence and incidence of hiv/aids in asia -and particularly, in india and china -are making east asia and south asia regions of tremendous concern. this is because each country has over billion people, and the prevalence rates do not have to be high to result in large numbers of infected people. the global significance of hiv/aids is that it, by itself, has altered demographic trends, and the political economy of nations and regions, not to mention the human suffering that this disease has exacted. in botswana and swaziland, for example, the gains in life expectancy during the th century have not only been completely reversed, but the life expectancy at birth is lower now than it was at the beginning of the th century. in the context of this article, hiv/aids is an emerging infectious disease par excellence. a generation ago, it was literally unheard of. now in all developed countries and in many developing countries, hiv/aids shapes many behaviors, is responsible for significant stigma, is feared, and causes a significant percentage of deaths. globally, hiv/aids is the fourth leading cause of death, although in many parts of africa, it is the leading cause of death. hiv/aids is an emerging infectious disease because of the historical rapidity with which it moved from an unknown localized zoonotic complex in west and central africa to the most prevalent infectious disease in the world. while the scientific evidence suggests that there were a number of species jumps of both hiv- and hiv- that occurred in africa, these were so localized and the societies isolated enough from the rest of the world that hiv went unnoticed. thus, it appeared as though the disease went from nonexistence to a major pandemic in a matter of a few years. and there is another major significant dimension. since hiv/aids appears to have originated in africa -'out there,' away from northern europe and north america -some have argued that hiv/aids acquired a certain nefariousness -a disease emerging from the dark, foreign, isolated jungle -the stereotypical cauldron of new diseases. viral hemorrhagic fevers have been in the public eye since , when there was a major outbreak of a hemorrhagic fever in the jos plain of nigeria. the disease came to be called lassa fever, caused by an arenavirus (lassa) that seemed particularly undesirable to the public. the virus is named after the town in which this outbreak occurred. like all hemorrhagic fevers, including dengue in some cases, one of the characteristics of lassa fever is that it can disturb the clotting/coagulation mechanism, resulting in disseminated intravascular coagulation (dic) and diffuse hemorrhage. the outbreak was publicized in the united states through the news media, perhaps because it was an 'exotic' or newsworthy event, and once again, the social amplification of risk was responsible for exaggerated fears of 'what if it spreads here?' that this outbreak occurred in sub-saharan africa, which, in the eyes of the north american public, may have been thought to be all 'jungle' (the jos plain is not rain forest) probably also contributed to the amplification of risk. serologic tests demonstrate that exposure to lassa virus is common in west africa. for example, in parts of nigeria, seroprevalence is positive in % of those tested; in sierra leone, the figure varies from - % depending on the region (richmond and baglole, ) . it is now known that humans are dead-end hosts, and that the rat species mastomys natalensi is the natural host. these rats are extremely common throughout sub-saharan africa. people become infected by inhaling aerosols from rat excreta, and risk is increased by eating them, which is a very common practice in west africa. modern modes of travel have allowed infected individuals who are either symptomatic or asymptomatic at time of entry to travel to other continents, where they require treatment for lassa fever. these cases have not been numerous, but cases have appeared in the united states and japan, as well as in several european countries. this has caught some clinicians unprepared, since they were not trained in tropical medicine and were unaware of how to diagnose or manage a viral hemorrhagic fever. the prevalence rate of lassa fever is much higher than was initially thought. in one series, lassa fever accounted for % of adult deaths in sierra leone, and as many as % of hospital admissions (richmond and baglole, ) . following the outbreak in , it took some time to investigate adequate treatment protocols, but now, aggressive fluid replacement and the use of antiviralsparticularly ribavarin -are the treatments of choice. ebola hemorrhagic fever and closely related marburg virus are both single-stranded rna viruses, as are other viruses that cause hemorrhagic fevers. ebola and marburg are filoviruses; ebola virus is actually a genus and there are four species. it was first described in the sudan in , and estimates are that mortality from this virus has now exceeded people. the case fatality ratio exceeds %, and may be as high as % in some cases. transmission is different than lassa fever. it is usually through direct contact with blood and bodily secretions from individuals who are ill with ebola fever, or from nonhuman primates who are also infected. evidence points to bats as the natural reservoir of ebola virus, but this is not certain. in several studies, however, bats have been shown to be infected by the virus (leroy et al., ) . this is highly suggestive, but it is not conclusive proof. like so many other viral hemorrhagic fevers, the symptomatology of ebola is very nonspecific and typical of viral syndromes in general. the clinician needs to have a high index of suspicion. at this point, the only certain treatment is supportive, and from a public health point of view, quarantine is of the utmost importance, since ebola fever is so contagious. this was well-documented by the news media in the outbreak in kikwit, democratic republic of the congo (drc, then zaire) in . this was so well-documented that once again it led to exaggerated perceptions of risk, with overtones of the 'exotic disease' from sub-saharan africa and its possible spread to the united states. recent advances in understanding the pathogenesis of ebola and the role of proinflammatory cytokines has led to the use of some recombinant products that block the progression of the inflammatory cascade to dic in some animal models. nonetheless, this approach has not been used in humans as of . there are three notable points that need to be mentioned concerning ebola. first is that it appears to be increasing in prevalence in africa. this may be because detection is better and the disease has been better described, both epidemiologically and pathophysiologically. second is that there is significant concern that ebola virus could be used as a biological weapon. it has thus been placed on the highest level (category a) of potential biological weapons by the cdc. finally, ebola, more than any other emerging infectious disease, typifies in the mind of the public the sort of dangerous, threatening disease risk that is associated with tropical areas, the 'jungle,' and the threats that are associated with a more interconnected world. bovine spongiform encephalopathy (bse), or 'mad cow disease' in nontechnical terms, is another infectious disease that focused public awareness on emerging infections. the pathogen in this case was unusual not only in the sense that it had not been described elsewhere, but also because the whole class of pathogens -prionshave been very rare. like another neurologic disease, kuru, bse turned out to be due to a prion. essentially, prions are very simple since they are just unusually folded and self-replicating proteins. they cannot even be described as organisms. the source of the prion is not known, although many speculate that it is somehow derived from sheep infected with scrapie. in , an unusual disease seemed to be affecting cattle in the united kingdom, and by the end of the year, over cattle had died because of spongiform encephalopathy. since it was apparent that the disease was contagious, over million cattle were intentionally slaughtered to limit contagion and ensuing effects on the cattle industry. by the mid- s, there was a clear epidemiologic association between bse and a variant of a neurodegenerative disease in humans that had been described in the middle of the th century: creutzfeldt-jakob disease (cjd). however, there were some notable differences between cjd and the disease that was affecting humans in the s. the median age of this new syndrome was much younger than in classical cjd; the median duration of survival from onset of symptoms was longer than in classical cjd; and pathological differences and differences on mri were apparent with this new variant. accordingly, the cjd associated with bse first was named 'new variant creutzfeldt-jakob disease' or 'nvcjd;' as time progressed, nvcjd was renamed 'variant cjd' or 'vcjd.' although there were very few cases of vcjd in the uk human population, the threat of this disease was great according to public perception. according to the world health organization (who), as of november , there had been cases of vcjd in the united kingdom, six in france, and one each in several other countries (who, ) . nearly all of those with vcjd died or would die within years. because of the realistic fear of contagion, several steps have been taken to limit the spread of vcjd. feeding practices for cattle have changed so that it is no longer legal to feed animal protein that might contain any tissues proximal to the central nervous system to other cattle. in the united kingdom, there was a ban on cattle over months old from entering the commercial food supply. in the united states, individuals who have lived in the united kingdom or who have spent more than months in the united kingdom are banned from being blood donors on the assumption that they might have consumed infected beef during their stay(s) in the united kingdom. a ban was instituted on importing cattle and cattle feed from the united kingdom, and, occasionally, from canada, in an attempt to prevent bse from spreading to the united states (kuzma and ahl, ) . while the number of incident cases of vcjd and bse have decreased in a typical epidemic curve pattern, the effects of the bse 'scare' have been tremendous. the very credibility of the uk government was threatened. the whole cattle and meat industries were severely hurt. on the other hand, surveillance techniques and understanding of cattle food chains were vastly improved. severe acute respiratory syndrome (sars) proved to be of great import in both the public awareness of emerging infectious diseases and in the testing and real-time construction of both domestic and international systems of public health surveillance and response. it was particularly important in terms of public awareness because it spread very rapidly on the international and intercontinental scales. sars apparently began as a few cases of a viral pneumonia in guangdong province in southeastern china in late . however, this was not immediately apparent to the global public health communities because it was not publicized by the chinese government. what catapulted sars to international attention in the media and in the public health community was the appearance and rapid increase of incident cases in guangdong in february (zhao, ) . sars spread rapidly to hong kong, where contact tracing eventually identified one night in a specific hotel where the index case stayed as being the epidemic focus. the index case infected at least others who were in the hotel at one time or another during that night. sars spread from hong kong to other areas of hong kong and to singapore, vietnam, and canada (toronto, ontario). the spread of all these cases has been traced to airplane travel, followed by localized spread by an index case. a case definition was developed based upon clinical presentation, which typically consisted of fever, initially, followed by lower respiratory signs and symptoms, sometimes resulting in acute respiratory distress syndrome and respiratory distress typical of acute lung injury as a response to the inflammatory cascade. just over cases were identified worldwide, and died, for a case fatality ratio just < %. a disproportionate degree of contagion occurred in intensive care units and areas of hospitals in which hospital personnel were exposed to respiratory excretions; close proximity -within m -to an infected patient who was undergoing endotracheal intubation was the single greatest risk factor for contracting sars. local measures to control the spread of sars consisted largely of quarantine and containment. in china, for example, separate quarters for sars patients were constructed very rapidly. in singapore, arriving and departing passengers were required to pass through automated temperature detectors, and anybody with a fever was required to undergo further medical evaluation. the same was true at most points of entry in most developed countries. since most cases were contracted in hospitals and health facilities, rigorous contact control procedures were instituted, and in some cases, hospitals were closed to visitors and new admissions. the identification of the pathogen causing sars constitutes a textbook example of how international cooperation in science and public health may occur when the willpower is there and the scientific capability exists. by mid-march , many leading laboratories with advanced virologic capabilities had agreed to cooperate in a network that was coordinated by the world health organization. within weeks, a pathogen was identified as a novel coronavirus, using a combination of methods: molecular polymerase chain reaction, culture, and electron microscopy, and shortly thereafter, the criteria of koch's postulates were met. thus, the evidence was quite clear that the new coronavirus was the pathogen. the virus was named the sars coronavirus, or, almost always, sars cov. the ecology of sars was not understood as quickly as the pathogen was identified. some features were identified within a number of months. first was the phenomenon of superspreaders, which is a concept that previously had received scant attention. in this case, it became apparent that a small number of individuals spread sars to a disproportionately large number of people. it is not clear whether this is because of behavioral factors, host-pathogen interaction, or environmental factors. what is fairly clear is that were it not for superspreaders, the epidemic would not have affected nearly as many people as it did. this is because the r , or number of people who one individual could infect, was inflated by superspreaders. thus there was a domino effect of contagion. in , bats were identified as the reservoir of sars cov. there had previously been some speculation about bats being the reservoir, but there was no solid evidence, and the reservoir had been a mystery. some had suggested that proximity of people to avian species could possibly be a factor in the pathogenesis of sars, because of the importance of this process in avian influenza. however, this turned out not to be the case with sars. sars is a prototype of an emerging infectious disease (berger et al., ) . there is no evidence that sars cov existed in the human population prior to the outbreak of late - . the specific syndrome surprised the public health and medical communities, yet its general features did not, and the emergence of new diseases had been a familiar concept since the u.s. institute of medicine report of . at the same time, the rapidity of the appearance of sars and its very rapid spread at every scale fueled public apprehension, and even hysteria in some cases. evidence exists that history has been punctuated by relatively regular influenza epidemics and pandemics. the rapidity of epidemic spread, leading to pandemics, is largely determined by the velocity of the prevailing transportation modes. severe epidemics and pandemics are caused by genetic shift, whereby the viral genome expressing surface antigens (hemagglutinin and neuraminidase) undergoes relatively major change. relatively minor epidemics occur because of genetic shift, in which the surface antigens undergo minimal yet detectable changes in their configuration. following genetic shift, people have minimal immunity to the virus, and are susceptible. in one sense, each year influenza constitutes an emerging infection, because the precise genome of the influenza viruses and the surface antigens undergo change. similarly, whenever a pandemic occurs, influenza represents a more significant emerging infection. on the other hand, influenza represents a disease entity that is not new to the population. thus, it is a matter of semantics whether to consider influenza to be an emerging infection. avian influenza may constitute the next serious pandemic threat. it has been known for decades that genetic reassortment occurs in southeastern china because of the proximity of humans, avian species, and swine. an unusual number of influenza epidemics appear to arise there. however, the concern over avian influenza arises from a slightly different situation. it has been known for some time that no less than influenza subtypes -different configurations of surface antigens -can infect aquatic bird species. it has been wellestablished that several of these subtypes can infect humans, although recent experience suggests that all subtypes that circulate in avian species may have the potential to infect humans. this is one of the reasons that has given rise to concern over the possibility of an avian influenza pandemic. this theoretical concern moved closer to reality in hong kong in , when one influenza strain (h n ) was transmitted directly from poultry to humans. this took place in 'wet markets' -markets in which live poultry are densely packed, and where people co-mingle with their intended purchases. the transmission in appears to have been limited: only cases were confirmed. however, the case fatality ratio was high. six of the people died. transmission also occurred with another strain - h n -in , and in and there was widespread transmission and mortality among chickens in hong kong. because of a concern over possible transmission to humans, and because of the devastating economic potential in the poultry industry, containment of this epidemic in poultry was partly obtained by the slaughter of millions of chickens and other poultry. avian influenza viruses have shown some propensity, since , for transmission to humans. so far, human cases of influenza that have been identified as avian strains have been limited to approximately , and these have all been in asia. human-to-human transmission has been implicated in only a few cases. if this is the case, what is the concern over avian influenza? because of the tendency for influenza viruses to mutate, many virologists and epidemiologists predict that there is a high likelihood that a mutation could occur that would facilitate human-to-human transmission of h n and other avian subtypes that have been transmitted to humans. if this occurs, then there is little doubt that this strain would spread rapidly among the human population, and would spread locally, nationally, and between continents in a manner similar to sars. other epidemiologists and virologists are more circumspect in their predictions, and argue that the probability of a mutation that would increase the propensity of avian influenza to spread from human to human is unknown. a minority of authorities argue that the probability is low. thus, in assessing the overall threat of avian influenza, the crucial question is whether the virus will spread readily from human to human. at this point (mid- ) , it is unknown whether this will occur. however, it is prudent public health policy to bolster surveillance systems, and governments are stockpiling neuraminidase inhibitors, which are medications that can moderate the course of influenza if taken early in the course of clinical disease, or sometimes prevent the onset of symptoms if taken prophylactically. similarly, there has been great emphasis on vaccine development and stockpiling. in response to growing public concern over emerging infectious diseases, both domestically and internationally, as well as to both interest and concern in the medical and public health communities, a major conference on emerging viruses was held at rockefeller university in . the conference was cosponsored by several government agencies. the conference participants reached many conclusions, but two of them were that emerging infections had become a major focus for scientific research and that emerging infectious diseases had become and would remain a major public health challenge for the united states. accordingly, the institute of medicine of the national research council of the united states took a proactive role and sought funding for a major study of emerging infections. the study was funded by a number of government units, and in early , a high-powered committee met in washington for the first time to: identify significant emergent infectious diseases, determine what might be done to deal with them, and recommend how similar future threats might be confronted to lessen their impact on public health. (institute of medicine, : vi) the committee issued a report in that quickly became a standard scientific and policy reference on emerging infectious disease. emerging infections: microbial threats to health was the first major comprehensive discussion of how emerging infections arise, and how they might be addressed by the public health community. the committee also identified the six 'factors' or causes of emergence. briefly, the factors that this committee identified were the following: human demographics and behavior; technology and industry; economic development and land use; international travel and commerce; microbial adaptation and change; and the breakdown of public health measures. it is notable that five of these six factors are social factors that are consequences of changes in society. even microbial adaptation and change, such as the development of antimicrobial resistance as a response to selective pressure, has a large behavioral dimension. this is partly a response to a technical innovation -the development of antimicrobials -and partly a response to a behaviorthe prescribing of those antimicrobials. of course, one dimension of this factor is the nonselective and improper prescribing of antimicrobials. this has several dimensions: the prescription of antibiotics when none are needed, the prescription of broad-spectrum antibiotics when narrowspectrum antibiotics are sufficient, the free availability of antibiotics in many developing countries on the street and in pharmacies where no prescription is needed, and the free use of late-generation antibiotics in the food industry to promote the growth of cattle, chickens, and other animals intended for human consumption. so, in fact, all of the six factors of emergence are social and behavioral in nature. it is ironic that despite the fact that both institute of medicine reports concluded that the major causes of emergence have been social, there have been very few social analyses of emerging infections. for example, emerging infectious diseases, a new journal founded in in response to the growing importance of emerging infections, has an explicit aim of including a social understanding of emerging infections in its contents, yet there have been very few articles written by social scientists in this journal, and very few articles with any social content have been published. the main point is that the overwhelming understanding of emerging infections has been 'biomedical.' this is not a criticism of either the journal or of any field in public health or medicine. in large part, this is the result of the sociology of knowledge and science. for whatever reason, few social scientists have become involved in research on emerging infections, whereas the same cannot be said about chronic diseases. some researchers have asked the question of why emerging infectious diseases are emerging now and in the societies where they are emerging, and have sought a more contextual understanding of emerging infections. david bradley asks a very penetrating question: [a]ttaching a microbiological label to an outbreak. . .does not answer either the micro-scale questions such as ''why is there an outbreak here, now, of this size, affecting these people?'' nor does it answer the macro-questions such as ''why are there more (or fewer) outbreaks this decade than last?'' nor does it answer the question ''what drives the overall worldwide trends in such problems?'' (bradley, : ) for example, a number of individuals have argued that emerging infections may represent another stage in the epidemiologic transition. our understanding of emerging infections has not been totally devoid of social analysis. inequality and poverty have become a major focus for the social analysis of health and disease. the argument is that through a complicated series of pathways that are yet to be fully understood, both poverty and inequality result in poor health status. this has not been applied extensively to emerging infectious diseases, although paul farmer's ( ) insightful work has been applied to emerging infections. in his critical analysis of emerging infection, farmer asks, ''emerging for whom?'' in other words, the diseases that westerners might label as emerging may have been present or endemic in poorer societies for a long time: if certain populations have long been afflicted by these disorders, why are the diseases considered ''new'' or ''emerging''? is it simply because they have come to afflict more visible -read more ''valuable'' persons? this would seem to be an obvious question from the perspective of the haitian or african poor. (farmer, : ) in other words, farmer argues, the concept of emerging infectious diseases is one of epistemology -the theory of knowledge. how do emerging diseases come to be categorized as 'emerging'? by implication, many of these diseases have been present in poorer societies for a long time. the evidence affirms this. hiv was probably present in small foci in central africa for decades to centuries; ebola was similarly endemic in west africa for an unknown period, as was lassa fever. what is novel about the past few decades is greater interconnection between places, allowing diseases, and news of diseases, to spread; better methods of detection; and changing settlement geographies that have brought people into different forms of contact with animal reservoirs. the root cause of the infectious disease emergence is human action, both intentional and unintentional. most of this action is the result of cumulative individual acts on a mass scale. for example, the mass urbanization of society in poorer countries is the sum of millions of individuals who move from rural to urban areas. this is largely the result of the perceived economic opportunities in urban areas, and the 'push' factor of lack of opportunity in rural areas. yet, taken together, millions of individual moves result in urbanization, and this urbanization facilitates the spread of diseases by the respiratory route, the fecal-oral route, and many other modes of transmission. the institute of medicine committee also developed a set of policy recommendations. these concentrated in two areas: the need for vastly increased resources for interdisciplinary training in infectious diseases because of the depleted workforce resources in this area; and the need to develop new surveillance and public health response systems, since the committee had determined that emerging infections did, indeed, constitute a major public health threat to the united states. this report was issued with a great deal of publicity. the u.s. public's attention was already focused on emerging infectious diseases as a result of legionnaires disease, viral hemorrhagic fevers, and toxic shock syndrome. now there was a major quasi-governmental report by a group of the nation's leading scientists who issued the sobering conclusion that: even with unlimited funds, no guarantee can be offered that an emerging microbe will not spread disease and cause devastation. (institute of medicine, : ) part of the institute's report identified specific microbes and diseases that could possibly threaten public health in the future. three of these were e. coli :h , cryptosporidiosis, and hantavirus. the report was prescient, because within a few years there were serious outbreaks of all of these. in , which was the year after the iom report was issued, there was a major outbreak of cryptosporidiosis on the south side of milwaukee, wisconsin. it caused diarrhea, ranging from mild to severe, in over people. cryptosporidium parvum is a protozoan parasite; evidence in animal models is that ingestion of even one oocyst can result in severe gastrointestinal symptoms. in humans, as few as oocysts can produce these effects (king and monis, ) . it is impervious to usual methods of water treatment, and only recently has an effective medication become available. the milwaukee outbreak was probably due to groundwater absorption of cattle feces, subsequent runoff due to both heavy rains and snow melting, transport of the oocysts to river tributaries, and movement of the oocysts into lake michigan, which serves as the water supply for the south side of milwaukee. the filtration plant for that water was ineffective in eliminating the oocysts. many of these events are putative, but together they constitute a logical chain. meanwhile, research is still proceeding on the ecology of cryptosporidiosis. understanding is progressing, but it is still incomplete. e. coli :h was also mentioned in the iom report as being an emerging disease. in january , the washington state department of health ascertained that an outbreak of :h was occurring in the state, and this outbreak was associated with having eaten at jack in the box fast-food restaurants. subsequently, it became apparent that the epidemic was not limited to washington, but also included idaho and nevada. the epidemiologic investigation of this outbreak was intricate, and implicated a chain of events. first, because meat inspection in the united states was inadequate, one theory is that e. coli :h from the bowels of cattle had gotten into meat that was sent to market when cattle were slaughtered, and the bowel was probably nicked or severed. another is that under stress, cattle defecate over one another, and fecal matter from one cow can contaminate the hides of other cattle. second, when this meat was ground into hamburger, it increased the surface area of the meat by several orders of magnitude, thereby allowing the pathogen a great deal of exposure. third, once this hamburger meat was shipped to jack in the box restaurants, it appears that hamburgers were being systematically undercooked, below industry standards. this allowed the e. coli to survive and enter the hosts' systems. the consequences of such infection can be severe, and were in , with those who were symptomatic frequently suffering from bloody diarrhea, fever, cramps, and, in the worst case, hemolytic uremic syndrome. the pathogenesis of this disease was only partially understood in , but understanding is more complete in . the third disease that was mentioned in the iom report that occurred shortly after its publication was hantavirus. in may , in the four corners area of arizona, new mexico, california, and utah, several males who were otherwise in good health developed a sudden serious respiratory disease that was thought to be a rapidly progressing acute respiratory distress syndrome, since this was the immediate cause of death. however, it was noted that these cases had formed a cluster, and investigators tried to find some sort of common source to explain a possible environmental exposure to explain this serious and sometimes fatal syndrome. though hantavirus had never been described in the united states, serologic tests in patients showed a surprising seropositivity to hantavirus. it was apparent that this was the pathogen that had caused the dozen deaths associated with the outbreak. the chain of events that led up to the outbreak is now fairly clear. winter was unusually warm in the four corners area as a result of el nino, and the spring was also unusually rainy. these two conditions led to the rapid and plentiful growth of pinon trees, which provided food for a number of rodents. there is consensus that the deer mouse (peromyscus maniculatus) population increased by an order of magnitude. testing demonstrated that about % of the mice that were trapped after this epidemic were infected with hantavirus, and studies demonstrate that households from which infected individuals came were far more likely to have heavy rodent infestations than were households of controls. more rigorous studies eventually showed that transmission occurred from rats to humans, and that many of the cases, in this instance, were associated with crawling under houses and other places in which rodent exposure was likely to occur. by , many of the predictions of the first institute of medicine report ( ) had been realized, and understanding of emerging infectious diseases had improved. there was greater focus on globalization as a process of disease spread, and the attacks on the world trade center and pentagon on september , focused attention on terrorism. a new institute of medicine committee was formed to consider the nature of microbial threats and emerging diseases, and the report of this committee was issued in (institute of medicine, ) . this report represented a rethinking of the factors of emergence, and presented a more nuanced understanding of the causes of emerging diseases, most of which were still social at one level or another. bioterrorism ('intent to harm') was specifically mentioned as a factor of emergence, as was lack of political will. policy recommendations for surveillance, response, and training were more detailed than in the report, and there was a more urgent tone to the need to respond to emerging threats. in this report, the emphasis on biological and social interaction was strong: genetic and biological factors allow microbes to adapt and change, and can make humans more or less susceptible to infections. changes in the physical environment can impact on the ecology of vectors and animal reservoirs, the transmissibility of microbes, and the activities of humans that expose them to certain threats. human behavior, both individual and collective, is perhaps the most complex factor in the emergence of disease. emergence is especially complicated by social, political, and economic factors. . .which ensure that infectious diseases will continue to plague us. (institute of medicine, : ) increasing resistance to antibacterials, antivirals, and other antimicrobials is frequently grouped under the heading of 'emerging infections.' resistance is certainly a constantly growing and very major public health problem, but this is of importance to emerging infections only in the sense that diseases that were once highly treatable with first-and second-generation antimicrobials are no longer treatable by them. the selective pressures exerted by antimicrobials have made numerous pathogens resistant to even the newest antimicrobials due to mechanisms that are now understood. for example, many respiratory pathogens are no longer treatable by b-lactam antibiotics since their b-lactam rings are cleaved by b-lactamases. there are fluoroquinolone-resistant strains of neisseria gonorrhoeae, resistant strains of staphylococcus aureus, and so on. the problem is most severe in hospitals, where severe infections once responsive to vancomycin are now resistant to this glycopeptide. several new antimicrobials have been developed, in part to address vancomycin resistance, but resistance to these medications developed within a few years of their introduction. thus, antimicrobial resistance is both a community problem and a hospital problem. there is great concern over multiple drug-resistant tuberculosis, which is defined as tuberculosis that is resistant to two first-line medications, and extensively resistant tuberculosis, which has a more complex definition specifying several medications. there is not space in this article to explore antimicrobial resistance in greater depth. the relationship between people and pathogens has been an integral part of history, and will continue to be. the progress in the diagnosis, detection, and clinical management of infectious diseases has been substantial. indeed, fauci ( ) has gone so far as to argue that: the successful diagnosis, prevention, and treatment of a wide array of infectious diseases has altered the very fabric of society, providing important social, economic, and political benefits. nonetheless, infectious diseases, aggregated together, constitute the second leading cause of death worldwide, and in many regions, they account for the dominant cause. moreover, emerging diseases will continue to emerge, because of constantly changing social and demographic conditions, as well as selective pressures. the prototypical emerging infectious disease, hiv/aids, has an uncertain future in the long run. perhaps a vaccine will be developed that will be inexpensive, and perhaps distribution systems will be developed that will transport the vaccine to points of demand. perhaps antiretrovirals will become extremely inexpensive, and perhaps the failure rate for antimicrobials of % will be overcome. however, it is unlikely under present conditions that all of these improvements will occur. thus, the future of hiv/aids is more sobering. the same is true of antimicrobial resistance. in an age of optimism when antimicrobials were developed and used successfully -perhaps the first years of antimicrobial use -concern over resistance was minimal. however, the fact that organisms adapt to changing environmental conditions and threats is something that has not been realized only recently. the inevitability of adaptation is undeniable, and the only way to meet the challenges of resistance is through a combination of appropriate antimicrobial use (including the use of narrow-spectrum antibiotics as soon as possible in the clinical course of an individual) and the development of new antimicrobials, as well as new understanding in the physiology and genetics of microorganisms, which might lead to the development of new technologies in addressing the pathogenic basis of disease. see also: aids, epidemiology and surveillance; antimicrobial resistance; severe acute respiratory syndrome (sars); transmissible spongiform encephalopathies; tuberculosis: overview; west nile disease. acromegaly a condition produced by overproduction of growth hormone, leading to excessive growth of the hands, feet, and jaw in postpubertal individuals and giantism in prepubertal children. adrenal glands two endocrine organs situated above the kidneys that make a series of hormones: cortisol (stress hormone), aldosterone (salt-retaining hormone), and catecholamines (stress hormones). autoimmunity a situation in which part of the body, often an endocrine organ, is recognized as 'foreign,' triggering an immune response that tends to lead to destruction of the endocrine gland. cushing syndrome excessive production of cortisol with loss of the normal circadian variation leading to weight gain, hypertension, and type diabetes mellitus. g protein proteins within the cell that transfer the hormone message from the receptor to specific parts of the cell. graves disease a combination of thyroid overactivity due to an autoimmune disorder and eye problems. hypothalamus part of the brain containing control centers for appetite, thirst, and pituitary hormone secretion. pituitary major regulator of hormone production. secretion of hormones regulated by the hypothalamus. severe acute respiratory syndrome (sars): paradigm of an emerging viral infection new and resurgent infectious: prediction, detection, and management of tomorrow's epidemics infections and inequalities: the modern plagues infectious diseases: considerations for the st century emerging infections: microbial threats to health in the united states microbial threats to health critical processes affecting cryptosporidium oocyst survival in the environment living with bse fruit bats as reservoirs of ebola virus plagues and peoples factors in the emergence of infectious diseases lassa fever: epidemiology, clinical features, and social consequences variant creutzfeldt-jakob disease sars molecular epidemiology: a chinese fairy tale of controlling an emerging zoonotic disease in the genomics era the coming plague: newly emerging diseases in a world out of balance new and resurgent infections: prediction, detection, and management of tomorrow's epidemics the changing face of disease: implications for society the challenge of emerging and re-emerging infectious diseases an emptying quiver: antimicrobial drugs and resistance the politics of emerging and resurgent infectious diseases disease in evolution: global changes and emergence of infectious diseases endocrine diseases: overview p c hindmarsh key: cord- -ynqxgyw authors: epstein, jay s.; jaffe, harold w.; alter, harvey j.; klein, harvey g. title: blood system changes since recognition of transfusion‐associated aids date: - - journal: transfusion doi: . /trf. sha: doc_id: cord_uid: ynqxgyw nan the fact that transfusions could transmit infectious diseases, namely, bacterial infections, syphilis, and hepatitis, was recognized before taa with progressive interventions dating back to the dawn of blood banking. donor testing for antibodies to syphilis began in . bacterial infections, a major threat at the time of world war ii, were later decreased by cold storage of whole blood and red blood cells (rbcs) in plastic containers. , in the s, transfusion-associated hepatitis (tah) was largely prevented by near elimination of paid donation through product labeling to identify paid collections, concurrent with testing for hepatitis b virus (hbv) infections. however, the medical importance of the residual hepatitis risk, mostly attributed to non-a, non-b hepatitis (nanbh), was recognized slowly. with the acute threat of bacterial infections largely controlled, syphilis effectively prevented, and the full consequences of nanbh transmission unappreciated, the blood community in the late s was more focused on systemic issues of economic competition and supply instabilities than on transmissible disease. then came aids! aids was first reported as a "gay-related immune deficiency" in , but soon was identified in other risk groups including sex workers, haitian entrants to the united states, and injection drug users. , evidence for transfusion transmission emerged in when a few cases of aids were reported in hemophilia patients and later in transfusion recipients. however, despite a number of high-level federal meetings, actions by the national government to contain the aids risk from transfusion were not undertaken until . although transfusion transmission of hiv undoubtedly took place at least years before the recognition of taa due to the very long asymptomatic period of the disease, the delay in a response to taa subsequent to these initial reports of disease in persons with hemophilia and transfusion recipients also contributed to the aids tragedy. rage within the hemophilia community, due both to the fact of transmission of a fatal infection and to the failure of authorities to provide adequate warnings and preventions, was expressed in a demand for a congressional investigation. members of congress instead directed the department of health and human services (hhs) to look into the matter. this was accomplished through a contract with the institute of medicine (iom) to study the evolving hiv-related events impacting blood safety and the decision-making process in this crisis period. in its report, entitled "hiv and the blood supply: an analysis of crisis decision making ( )," the iom found no wrongdoing by organizations or officials, but identified failed opportunities to better protect public health. these failures to act more rapidly and aggressively in the face of taa were seen to unmask an underlying weakness in the ability of federal agencies to address a new threat in the face of substantial scientific uncertainty. this weakness was attributed to systemic deficiencies, primarily of leadership and coordination. in particular, the iom criticized the federal agencies for lack of top-level leadership needed to overcome inherent bureaucratic inertia; absence of a systematic approach within advisory committees sufficient to maintain their focus; over dependency on the regulated industry as a source of data given the inherent conflict of interest; and failure to engage in forward thinking both with respect to new technologies and emerging safety threats. as a consequence, the risk of taa was severely underestimated; patients and care providers were not suitably warned of the risk; and resistance to a change in the status quo caused delayed intervention. in a set of recommendations directed primarily at federal agencies, the iom called for a more responsive and integrated decision-making process including establishment of a blood safety council reporting to a designated blood safety director within hhs and a standing "expert panel" to assure communication of blood product risks and alternatives to their use both to care providers and to the public. specifically to the food and drug administration (fda), the iom recommended that, "where uncertainties or countervailing public health concerns preclude eliminating potential risks, the fda should encourage, and where necessary require, the blood industry to implement partial solutions that have little risk of causing harm." while not itself a mandate, the iom's admonition that the fda should institute measured precautions in the face of uncertainty has become a dominant factor in blood safety decision making. a more vigilant and proactive fda approach to blood safety unfortunately has had the unintended consequence of dramatically increasing the manufacturing costs and therefore the price of blood. the hhs response to the iom report established a new landscape for federal oversight of the blood system, which continues to the present day. the present structure includes the assistant secretary for health (ash) as the blood safety director; heads of public health service and related agencies as members of a blood, organ and tissue safety executive council (botsec); and an hhs secretary's advisory committee for blood and tissue safety and availability (formerly the advisory committee for blood safety and availability). the ash is the acknowledged national blood safety director with final responsibility and authority for decisions regarding blood safety and availability. an interagency blood, organ and tissue safety working group meets monthly by teleconference, more often when necessary, and the botsec meets approximately quarterly face to face with the ash to provide information and guidance regarding current and emerging issues involving the nation's blood supply. unlike fda's blood products advisory committee, whose function is to provide external scientific advice relevant to regulation, the secretary's advisory committee is empowered to discuss broad legal, ethical, social, and economic issues affecting the blood system. to give voice to patient concerns, both advisory committees seat voting representatives of communities that have been particularly affected by taa. additionally, in response to a series of congressional hearings, reports from the government accountability office, and the iom study, the fda developed and hhs subsequently adopted a comprehensive "blood action plan" designed to address the identified shortcomings, to ensure greater coordination among the department's public health agencies, and to increase the effectiveness of the fda's scientific and regulatory activities. notably, the post-taa era has witnessed an aggressive effort by the fda to improve blood safety through enforcement of cgmp in blood product collection and processing aligned with the model of pharmaceutical manufacturing and a more formal relationship than blood establishments experienced in the past. the fda initiative also involved promotion of automation to reduce human errors, including use of validated blood bank software. an intensive program of field inspections designed to assure universal regulatory compliance of blood collection establishments resulted in a number of court-enforced voluntary injunctions (consent decrees). known and emerging infectious threats to blood safety have continued to demand attention in the post-taa era, repeatedly testing whether the lessons of taa were learned. are we prepared to deal with potential threats from bioterrorism agents? how much effort should be expended to prepare for an outbreak of chikungunya virus that might never happen? what should we do about pandemic influenza and middle east respiratory syndrome coronavirus in the absence of studies to establish the presence or absence of viremia in the course of the infections? does it make sense to screen all blood donations when risks of babesiosis and dengue are seasonal and geographical? what changes to the current paradigm of donor screening and testing can be considered when pathogen reduction becomes available for all blood components? more generally, as we become increasingly proactive in addressing infectious risks, are we misdirecting resources that could be better spent to improve blood safety in other ways? readers of this commentary are encouraged to ask themselves whether the lessons of taa have been optimally incorporated during the decades of challenge and response that followed. a sentinel event in the history of blood safety was the recognition and response to taa. although the etiology remained unknown, the report of aids in three persons with hemophilia a in july suggested a blood-borne pathogen as the causative agent. these three individuals were reported to be heterosexual, had no other known aids risk factors, and had all received frequent administration of factor viii concentrate. the evidence for transmission of the "aids agent" through blood was further strengthened in december by the report of a -month-old infant in san francisco who had developed unexplained immunodeficiency after transfusion of multiple blood products to treat erythroblastosis fetalis. one of the blood donors was a man who was healthy at the time of donation, but subsequently died of aids. to address the possibility that aids was associated with the receipt of blood and blood products, the centers for disease control and prevention (cdc) convened a meeting on january , , with participation by the fda, the national hemophilia foundation, blood banking officials, and patient advocacy groups. from the cdc perspective, the purpose of the meeting was to discuss how to reduce the risk of aids in transfusion recipients and persons with hemophilia in the absence of a test for the etiologic agent. several possible strategies were presented, including deferral of blood donations by persons known to be at increased risk for aids and the use of surrogate tests to identify persons at increased risk of transmission, such as those with detectable antibody to hepatitis b core antigen (anti-hbc) or low cd /cd t-cell ratios. however, the meeting turned into a contentious debate about the existence of aids in transfusion recipients and persons with hemophilia, and no agreement was reached on a risk reduction strategy. on march , , the us public health service published the first recommendations for prevention of aids. among the recommendations was a statement that, "as a temporary measure, members of groups at increased risk for aids should refrain from donating plasma and/or blood." in addition to persons with clinical evidence of aids and their sexual partners, those considered to be at increased risk included "sexually active homosexual or bisexual men with multiple partners; haitian entrants to the united states; present or past abusers of iv drugs; patients with hemophilia; and sexual partners of individuals at increased risk for aids." at the time, these recommendations were controversial. in particular, restricting blood donation by homosexual men was seen as a civil rights issue, and deferring donations by haitian entrants undoubtedly led to discrimination against haitian americans. from a public health perspective, however, these measures were needed to increase blood safety. with the identification of hiv, screening of donated blood and plasma became possible. bulk preparations of the virus, known at the time as htlv-iii, were provided by the national cancer institute to diagnostics companies for the development of antibody detection tests. the first such screening test, developed by abbott laboratories, was approved by the fda in march . because of concerns that persons would donate blood for the purpose of learning their hiv infection status, the cdc funded the first alternative hiv test sites, where individuals could obtain free and confidential testing. blood banks also established the option of confidential unit exclusion to allow persons who had donated blood to confidentially indicate that the blood should not be used for transfusion. a watershed event in blood safety was the statement by the fda commissioner at a september workshop that nucleic acid technology should be implemented to close the window period for hiv detection by serology. this technology had been considered too costly and cumbersome for practical application in blood banking. the introduction of direct testing for hiv in donor blood, first by p antigen assays, which proved largely unproductive, and then by nucleic acid tests (nats) for viral rna, which proved beneficial, put to rest a decade of concern about residual hiv risk from donations in the -to -week infectious "window period" before seroconversion dependent on the sensitivity of different screening tests. the successful adaptation of nat to donor screening, including testing of specimens in small pools of to , established a new era in risk reduction from transfusiontransmitted viral diseases. in addition to increasing the safety of transfused blood, hiv antibody screening of donors led to "lookback" programs in which recipients of previous unscreened donations from infected donors were identified. these recipients were found to be at substantial risk for infection. , although no effective treatment was available at the time, infected recipients could be counseled to reduce the risk of hiv transmission to others. another retrovirus, htlv-i, was also found to cause disease, including adult t-cell leukemia or lymphoma and htlv- associated myelopathy or tropical spastic paraparesis. the virus can be transmitted by transfusion of cellular blood products, but not plasma fraction or plasma derivatives. in november , the fda issued guidance recommending antibody testing of donated whole blood and cellular components for htlv-i. because of a high degree of sequence homology, the currently approved htlv-i screening assay also detects antibodies to htlv-ii, a virus with transmission routes similar to htlv-i but with less clear disease associations. although not fda approved, western blot and pcr tests can be used to distinguish between the two viruses. world war ii led to recognition of the frequent occurrence of hepatitis among military personnel through the confluence of contaminated water, massive immunizations, and for the first time, blood transfusion. it was during this time that food-and water-borne "infectious hepatitis" was distinguished from parenterally transmitted "serum hepatitis" and these entities were later termed hepatitis a and b, respectively. in , beeson reported seven cases of jaundice occurring to months after transfusion of blood or plasma. a dramatic outbreak of hepatitis involving , us soldiers was traced to serum-contaminated preparations of yellow fever vaccine, which conclusively documented parenteral transmission. decades later, this outbreak was shown by seeff and colleagues to be due to the hepatitis b virus. the us army extensively studied serum hepatitis during and after the war and characterized both the epidemiology and the resultant disease, but could not identify the causative agent. the etiologic breakthrough began in the early s with the discovery of the australia antigen by blumberg and coworkers at the national institutes of health (nih). this single finding changed the course of hepatitis history when in , the australia antigen was shown by the blumberg group to be associated with viral hepatitis and then by prince and colleagues to be specifically associated with hepatitis b. in england, dane and coworkers showed by immune electron microscopy that the australia antigen represented the envelope protein of hbv and it was renamed the hepatitis b surface antigen (hbsag). the serologic distinctions between hepatitis a and b were further solidified by the controversial, but definitive prospective studies by krugman and colleagues at the willowbrook state school. the us government played a pivotal role in these momentous events, first through the initial discovery of the australia antigen in the intramural program at nih and then through extensive grant support of the blumberg laboratory at the institute for cancer research in philadelphia. in the late s and early s, prospective studies at the nih clinical center revealed several critical elements of tah, including: . that the primary risk factor for tah was the use of paid donor blood confirming earlier studies; in , this led to an fda mandate requiring the labeling of paid donor blood, which effectively resulted in the near-universal adoption of blood collection only from unpaid volunteers, one of the most important transfusion-transmitted infectious disease interventions ever implemented. . that hbsag testing of blood donors was effective even when using insensitive techniques such as agar gel diffusion and counterelectropherseis; nationwide testing for hbsag was delayed until more practical and confirmable assays were introduced in . volunteerism and first-generation hbsag screening reduced the incidence of tah from % to approximately % and that this massive reduction was more dependent on the donor source than on blood screening because hbv was shown to account for less than % of total tah. feinstone and coworkers at nih, it became evident that hav was not responsible for the residual cases of tah, giving rise to the cumbersome, but nonpresumptive designation nanbh. while intensive efforts to isolate the nanbh agent in the decade from to were unsuccessful, studies at the nih and cdc revealed that the agent was small, lipid-enveloped and most similar to the small rna alpha and flaviviruses. [ ] [ ] [ ] despite the absence of a specific test for detecting the nanbh agent, tah incidence declined because of the more judicious use of blood fostered by the recognition that nanbh could result in cirrhosis and death and by the devastating consequences of transfusion-transmitted hiv. further, in the absence of specific nanbh assays, surrogate assays were advocated. the transfusion transmitted virus study, supported by the national heart, lung and blood institute, published a retrospective analysis of a prospective study that showed that alanine aminotransferase (alt) testing of donors might effect a % reduction in tah incidence. this was confirmed by a similar analysis of the nih prospective tah study, but implementation of alt donor screening at the nih failed to demonstrate the predicted benefit. similar retrospective testing of the transfusion transmitted virus study and the nih prospective studies suggested that anti-hbc testing might result in a % to % reduction in tah, and this fostered the voluntary introduction of alt and anti-hbc donor testing in to ; the fda recommended routine donor testing for anti-hbc in . although anti-hbc screening was introduced specifically to detect hbv carriers who were hbsag negative (now termed occult hepatitis b), it also served as a surrogate for nanb carriers and for seronegative hiv carriers because of overlapping transmission routes. had anti-hbc surrogate testing been introduced in the early s it presumably would have prevented some cases of transfusion-transmitted aids and nanbh. this delayed implementation was the basis for extensive litigation, but also served as the driver for the iom recommendation of invoking the "precautionary principle" when weighing new donor screening interventions and this precautionary approach has significantly improved transfusion safety. industry has played a major role in hepatitis prevention, first by developing increasingly sensitive assays for hbsag, by developing nucleic acid detection assays for all the major viruses, and particularly by cloning the nanb agent. the latter was a monumental achievement by chiron corporation in collaboration with dan bradley at the cdc. using the then-novel technique of expression cloning, these investigators identified a single clone among millions tested that reacted with serum from patients with nanbh. houghton and associates at chiron then "walked" the genome, characterized an antigen derived from the nonstructural region of the viral genome, and developed an antibody assay to detect this viral protein. studies at the nih confirmed that the cloned agent, designated hepatitis c virus (hcv), was detected in virtually all nanbh cases and identified an implicated donor in near % of these cases. first-generation anti-hcv testing was introduced in and secondgeneration assays in . prospective studies at the nih clinical center documented the virtual eradication of tah by ; mathematical modeling after the introduction of nat screening in predicts that the current risk of transfusion-related hepatitis c is approximately one case in every million transfusions, approximately the same risk as being hit by lightning. west nile virus (wnv) was first identified in the united states in after an outbreak of encephalitis in newyork. four cases of unexplained fever and encephalitis in recipients of organ transplants from a common donor proved to be caused by wnv and raised the possibility of transmission through blood transfusion. initial efforts to screen blood donors using signs and symptoms of wnv infection proved ineffective. in , a total of cases of human illness were reported, and at least people contracted wnv through transfusion, six of whom died. the rapid expansion of wnv across the united states and reported to botsec by the cdc lent urgency to developing a screening test before the next epidemic season. the fda requested that industry develop such a test; the national heart, lung and blood institute provided $ . million in research support; the american red cross provided , archived specimens; and the fda facilitated rapid national test implementation and ultimate approval. although development of blood screening tests usually takes years, the nat assay for wnv was available for the epidemic season, building on technology platforms already developed for hiv and hcv. west nile virus was the first acute infection with a short asymptomatic viremia and an epidemic spread to warrant routine donor testing and demonstrated a successful collaboration of government, blood collectors, and the diagnostics industry. , a footnote to the wnv screening success was the recognition that testing of pooled samples was insufficiently sensitive to detect low-titer viremia in blood donations, including in the infectious preseroconversion donations commonly encountered during epidemic spread. however, universal testing of individual units in nonepidemic areas nationwide was inefficient and costly. this problem was solved through a novel strategy of triggering individual testing based on the yield of pool testing. this approach effectively detected and interdicted approximately potentially infectious blood donations during to . the emergence of variant creutzfeldt-jakob disease (vcjd) in the united kingdom and france first reported in posed what has been arguably the most challenging blood safety problem for decision makers since the beginning of the aids epidemic. like aids, vcjd presented a new disease with unknown transmission dynamics, the potential for transmission through blood transfusion, the recognition of a novel infectious agent (prions), and near invariable fatality. vcjd was linked to bovine spongiform encephalopathy, a disease recognized in the united kingdom since , so the incubation period of the disease was assumed to be lengthy. the scope of the epidemic was and remains unknown. , for prions, unlike for bacteria and viruses, no technology for developing diagnostic or screening assays was available. the fda established a transmissible spongiform encephalopathies advisory committee to assure focused, objective, and transparent input to its decision making. based on the available epidemiologic data in , the fda recommended that blood components collected from donors diagnosed with vcjd be withdrawn and developed a mathematical model for indefinite donor deferral based on geographic exposure (donors who resided in the united kingdom for a total of months or more, between and ) that eliminated an estimated % of donor exposuredays to bovine spongiform encephalopathy in the united kingdom with a projected loss of approximately % of donors, which was considered a difficult balance of safety and supply, necessitating close monitoring of the blood supply. based on continuing surveillance of vcjd, the geographic exclusion was expanded in , providing approximately a % reduction in total risk-weighted person-days of donor exposure to bovine spongiform encephalopathy in western europe including the united kingdom with an estimated total donor loss of approximately %. the question of blood transmission was answered when the united kingdom reported four cases of vcjd infections associated with blood transfusion that occurred between and . all four recipients had received transfusions of nonleukoreduced rbcs between and , which confirmed the long incubation. only time will tell whether the steps taken in the united states will prove both warranted and sufficient, but the policy reflects adoption of a "partial solution" when it appears to reduce risk and an attempt to act expeditiously and responsibly with a benefit-to-risk model to address risk in the face of scientific uncertainty. chagas disease, caused by the protozoa trypanosoma cruzi, affects an estimated million people globally; an estimated , people in the united states and canada are infected. most infections are found in immigrants from latin america. whereas most new infections are vector borne, transmission by blood transfusion is well recognized. six transmissions had been reported in the united states before the ability to screen blood donors. as early as , the fda blood products advisory committee recognized that while only % to % of those infected with t. cruzi develop symptomatic disease, the infection is lifelong in the absence of early treatment and can be fatal. in view of increasing immigration to the united states from endemic regions, the blood products advisory committee recommended testing donors when a suitable test became available. donor history screening proved insufficiently sensitive and specific. not until was a test found suitable for licensure. shortly thereafter, the major blood collectors undertook universal donor screening for antibodies to t. cruzi. in retrospect, an earlier study in los angeles and miami suggested that seropositivity did not equate with infectivity; none of recipients of blood from a subsequently identified seropositive donor had evidence of infection. two years of screening in the united states established that whereas the seroprevalence may be as high as in , donors in some regions, infections confirmed by lookback studies are rare. , reexamination by the fda of its decision to recommend universal donor screening led to a novel policy of once-in-a-lifetime donor testing based on the demonstrated rarity of acute or incident t. cruzi infections in us donors. anthrax: bioterrorism, public concern, and the blood supply anthrax is caused by infection with a spore-forming gram-positive bacterium bacillus anthracis found globally in temperate zones, but uncommon in the united states. only seven cases of cutaneous anthrax had been reported to the cdc between and when in an outbreak of bioterrorism-related anthrax resulted in confirmed or suspected cases including five fatalities. this episode raised public concern about the blood supply during a period of high anxiety regarding threats of bioterrorism. bacteremia is present during fulminant cutaneous and respiratory anthrax; however, bacteremia in asymptomatic individuals has not been described. the period between exposure to b. anthracis and development of clinical anthrax is reported as to days but may be as long as days. little information exists regarding transmission via blood transfusion from an asymptomatic individual who has been exposed to b. anthracis. no such cases have been reported and no licensed diagnostic or blood donor screening test exists. the fda received several inquiries regarding the risk to the blood supply from donors in direct contact with material contaminated with b. anthracis. after consulting with experts at the cdc, the nih, and the us army medical research institute for infectious diseases, the fda issued guidance regarding measures to reduce possible risk for transmission of anthrax from blood. the guidance did not recommend any changes to standard donor screening and blood collection procedures, but emphasized that standard blood collection procedures already in place include deferral of any donor who is not in good health at the time of donation. nevertheless, to address public concerns as well as the dearth of scientific information regarding blood transmission, the fda provided prudent but specific recommendations concerning donors with a confirmed medical diagnosis of anthrax or proven colonization with b. anthracis and provided criteria for product quarantine and retrieval related to reports of postdonation illness. in , the journal science reported that a gamma retrovirus, xenotropic murine leukemia virus-related virus (xmrv) was isolated from blood in two-thirds of patients diagnosed with chronic fatigue syndrome (cfs) and, most alarmingly, in . % of healthy subjects. a second article reported a related retrovirus (pmlv) with an even higher prevalence of . % among blood donors. these reports generated enormous public interest and concern. given the possibility that xmrv could be transmitted by transfusion, immediate calls arose to screen blood donors for signs and symptoms of cfs and to test donations for xmrv. at the same time, intensive efforts were being undertaken worldwide to resolve this potential safety concern. a federal interagency working group met repeatedly by teleconference and electronic communication, and laboratories within the cdc, nih, and fda invested resources into investigating discrepant laboratory results. additionally, representatives of the cdc, the fda, and the intra-and extramural programs at the nih participated in a public-private interorganizational task force assembled within days by the aabb (formerly american association of blood banks). the result was voluntary implementation of an interim aabb recommendation that blood collectors should "actively discourage potential donors who have been diagnosed by a physician with cfs, chronic fatigue and immune dysfunction syndrome, or myalgic encephalomyelitis from donating blood" and ultimately definitive laboratory evidence that xmrv or pmlv bore no association with cfs and posed no threat to the blood supply. , ongoing threats and challenges several infectious threats are currently challenging federal decision makers. bacterial contamination of platelets is a clearly identified risk that is being addressed with "partial solutions," culture, and point-of-issue serologic testing. hepatitis e virus is known to be transfusion transmitted, but potential disease burden has not been defined. the geographic and travel exclusions to limit the risk of malaria transmission continue to be refined pending development of screening assays or pathogen reduction technology. surveillance for the coronaviruses responsible for severe acute respiratory syndrome and middle east respiratory syndrome is active and the possibility that these agents as well as pandemic influenza and monkey pox might be transfusion transmitted or disrupt blood donation is unresolved. the possibility of seasonal and geographic-based donor screening with validated tests for dengue and babesiosis has been modeled even as pilot studies of screening assays are ongoing. , pathogen reduction technology offers an alternative approach to risk mitigation. such technology would change the riskbenefit paradigm both for the known infectious agents and for those likely to threaten the blood supply in the future. federal decision makers are involved in deter-mining when and how this technology should be applied to the nation's blood and blood components. the federal response to transfusion-transmitted infections has evolved dramatically since the emergence of hiv as a transfusion-transmitted infection. the philosophy of risk management has become more precautionary and patient focused, yet still data driven. regulation of notfor-profit blood collectors has become more formal and stringent. manufacturers of blood components are now held accountable for meeting cgmp standards similar to those that apply to the manufacture of medical devices and pharmaceutical-type drugs. a new and arguably more responsive federal structure for addressing issues of blood safety and availability has been adopted. the decisionmaking structure places a premium on clear lines of authority, internal and public communication, flexibility, and coordination among the federal agencies with major roles in blood safety. federal agencies have encouraged public discourse through workshops, joint initiatives with industry, and participation in public-private partnerships with professional societies and blood collectors. these adjustments have allowed federal agencies to respond with appropriate urgency to the differing situations posed by emerging infectious agents in the era since recognition of taa years ago. hiv's leading men years after hiv discovery: prospects for cure and vaccine epidemiologic notes and reports pneumocystis carinii pneumonia among persons with hemophilia a possible transfusion-associated acquired immune deficiency syndrome (aids)-california the hazards of blood transfusion in historical perspective transfusion-associated infections: years of relentless challenges and remarkable progress syphilis: a disease of direct transfusion hiv and the blood supply: an analysis of crisis decision making. washington dc: institute of medicine national academy press staff costs associated with the implementation of a comprehensive compliance program in a community blood center risk-based decision-making for blood safety: preliminary report of consensus conference us department of health and human services. improving blood safety and supply in the u.s the efficiency of hiv p antigen screening of us blood donors: projections versus reality risk of human immunodeficiency virus infection from blood donors who later developed the acquired immunodeficiency syndrome risk of human immunodeficiency virus (hiv) transmission by blood transfusions before the implementation of hiv- antibody screening guidelines for counseling persons with human t-lymphotropic virus type i (htlv-i) and type ii (htlv-ii) jaundice occurring one to four months after transfusion of blood or plasma: report of seven cases a serologic follow-up of the epidemic of post-vaccination hepatitis in the united states army a "new" antigen in leukemia sera australia antigen and acute viral hepatitis immunologic distinction between infectious and serum hepatitis virus-like particles in serum of patients with australia-antigen-associated hepatitis infectious hepatitis: evidence for two distinctive clinical, epidemiological, and immunological types of infection posttransfusion hepatitis after open-heart operations serum hepatitis from transfusions of blood posttransfusion hepatitis after exclusion of the commercial and hepatitis b antigen positive donor hepatitis a: detection by immune electron microscopy of a virus-like antigen associated with acute illness transfusion-associated hepatitis not due to viral hepatitis type a or b posttransfusion non-a, non-b hepatitis: physiochemical properties of two distinct agents inactivation of hepatitis b virus and non-a, non-b virus by chloroform determining the size of non-a, non-b hepatitis virus by filtration the chronic sequelae of non-a, non-b hepatitis serum alanine aminotransferase of donors in relation to the risk of non-a, non-b hepatitis in recipients: the transfusion-transmitted virus study the relationship of donor transaminase (alt) to recipient hepatitis: impact on blood transfusion services hepatitis c virus and eliminating post-transfusion hepatitis hepatitis b virus antibody in blood donors and the occurrence of non-a, non-b hepatitis in transfusion recipients: an analysis of the transfusion-transmitted virus study antibody to hepatitis b core antigen as a paradoxical marker for non-a, non-b hepatitis agents in donated blood isolation of a cdna clone derived from a blood-borne non-a, non-b viral hepatitis genome an assay for circulating antibodies to a major etiologic virus of non-a, non-b hepatitis detection of antibody to hepatitis c virus in prospectively followed transfusion recipients with acute and chronic non-a, non-b hepatitis and update on west nile virus infections in recipients of blood transfusions west nile virus transmission investigation team. transmission of west nile virus through blood transfusion in the united states in as west nile virus season heats up, blood safety testing lags behind west nile virus among blood donors in the united states screening the blood supply for west nile virus rna by nucleic acid amplification testing triggers for switching from minipool testing by nucleic acid technology to individual-donation nucleic acid testing for west nile virus: analysis of data to inform decision making transmissible spongiform encephalopathies estimation of epidemic size and incubation time based on age characteristics of vcjd in the united kingdom uncertainty due to model choice in variant creutzfeldt-jakob disease projections guidance for industry: revised preventive measures to reduce the possible risk of transmission of creutzfeldt-jakob disease (cjd) and variant creutzfeldt-jakob disease (vcjd) by blood and blood products transfusion transmission of human prion diseases transfusion-associated chagas disease (american trypanosomiasis) in mexico: implications for transfusion medicine in the united states guidance for industry: use of serological tests to reduce the risk of transmission of trypanosoma cruzi infection in whole blood and blood components intended for transfusion trypanosoma cruzi in los angeles and miami blood donors: impact of evolving donor demographics on seroprevalence and implications for transfusion transmission epidemiological and laboratory findings from years of testing united states blood donors for trypanosoma cruzi the united states trypanosoma cruzi infection study: evidence for vector-borne transmission of the parasite that causes chagas disease among united states blood donors anthrax as a biological weapon: medical and public health management. working group on civilian biodefense summary of notifiable diseases-united states detection of an infectious retrovirus, xmrv, in blood cells of patients with chronic fatigue syndrome detection of mlv-related gag gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors absence of evidence of xenotropic murine leukemia virus-related virus infection in persons with chronic fatigue syndrome and healthy controls in the united states xenotropic murine leukemia virus-related virus (xmrv) and blood transfusion: report of the aabb interorganizational xmrv task force failure to confirm xmrv/mlvs in the blood of patients with chronic fatigue syndrome: a multi-laboratory study a multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus aabb bacterial contamination task force. survey of methods used to detect bacterial contamination of platelet products in the united states in seroprevalence and incidence of hepatitis e virus infection in german blood donors dengue viremia in blood donors identified by rna and detection of dengue transfusion transmission during the dengue outbreak in puerto rico babesia microti real-time polymerase chain reaction testing of connecticut blood donors: potential implications for screening algorithms protecting the blood supply from emerging pathogens: the role of pathogen inactivation emerging infectious agents and the nation's blood supply: responding to potential threats in the st century none. key: cord- -v k yxg authors: mockiene, vida; suominen, tarja; välimäki, maritta; razbadauskas, arturas; caplinskas, saulius; martinkenas, arvydas title: nurses' willingness to take care of people living with human immunodeficiency virus/acquired immunodeficiency syndrome (hiv/aids) — does a teaching intervention make a difference? date: - - journal: nurse education today doi: . /j.nedt. . . sha: doc_id: cord_uid: v k yxg summary the aim of this study is to describe the impact of an education intervention programme on nurses' willingness to care for hiv-positive people in lithuania. methods the study utilizes a randomized controlled trial design (rct). the total sample comprises nurses working in medical, surgical and gynaecological units, and primary health care centres from the same hospital areas in three lithuanian hospitals. the data were analyzed using spss . and descriptive statistics. findings our educational intervention did not have an impact on the nurses' willingness to take care of people living with hiv (plhiv), as their level of willingness was high already before the education intervention. conclusions further research on this issue is needed to try to understand the forces acting on our nursing staff in order to ensure appropriate care for plhiv. diseases such as acquired immune deficiency syndrome (aids), severe acute respiratory syndrome (sars) and the avian influenza seem to raise new challenges for society as well as for nursing research. these new diseases certainly indicate that diseases nowadays are global phenomena and that new problems may be transported around the world rapidly (hallberg, ) . since the first cases were recorded in , aids and its causative agent, hiv (human immunodeficiency virus), have taken an enormous toll around the world. according to the world health organization ( ) every day more than people become infected with hiv and more than die, mostly because they have no access to hiv prevention, treatment and care services. despite progress made in scaling up the response over the last decade, the hiv pandemic remains the most serious infectious disease challenge to global public health. at the front line of the war against hiv, health service providers are positioned to respond with needed services and care (li et al., ) . it is acknowledged that personal factors, health care systems and cultures may have an impact upon the willingness of nurses to work with hiv-positive people (ives et al., ) . while general societal attitudes towards plhiv may be less favourable, these negative attitudes may also be seen among health care personnel (tyer-viola, ) . in lithuania, the aids centre conducted an anonymous survey in to clarify the attitude of medical staff towards those living with hiv. the results showed that up to % of the medical staff were not willing to care for patients with hiv. although the situation changed over the years (from to ) and the proportion of staff unwilling to care for patients with hiv was reduced to . %, doctors and nurses, in particular those not working in major cities, still feel a certain fear and tend to separate people living with hiv (lithuanian country report, ). for example, % of lithuanian health care workers would not allow their child to a kindergarten group, which is visited by a hiv-positive child (lithuania national aids program evaluation, ) . these examples show that broad-scale education and extensive information to reduce these barriers are still required. however, little research has focused on adapting the education interventions to target new behaviours associated with hiv, such as increasing nurses' engagement in hiv health care and supportive services. the medline, cochrane library, eric databases, and lithuanian aids centre were searched for relevant english-language citations between and using the following search terms: education intervention, hiv, lithuania, nurse, and willingness to take care. the keywords were used both alone and interchangeably. willingness to care is defined as the caregiver's attitude towards providing emotional, physical and instrumental support for plhiv. when willingness to care is assessed in the context of an existing relationship, the primary concerns are whether the relationship can be sustained over time and what issues or perceptions may need to be addressed to make it mutually functional for caregiver and care recipient (abell, ) . it has been debated whether it is ethically permissible to refuse to treat those with hiv. ehrenstein et al. ( ) found that % of german healthcare workers may abandon work in favour of protecting themselves and family. another study (qureshi et al., ) found that the most significant barrier to us healthcare workers' willingness to work with plhiv was fear for their own and their family's health. most recent studies (gurung and sangchart, ; williams et al., ) reported that the majority of nurses are willing to care for and treat plhiv, but some other studies (oyeyemi et al., ; cai et al., ) showed that nurses are reluctant to deal with these patients. different background factors have been found to have an impact on whether nurses are willing to provide care or not: cultural values (oyeyemi et al., ) , age (välimäki et al., ) , gender (oyeyemi et al., ; cai et al., ) , whether nurses have met (tyer-viola, ) , taken care of (oyeyemi et al., ; pisal et al., ; williams et al., ; peate et al., ) plhiv or worked with colleagues with hiv (kiragu et al., ) . the number of working years has been shown to be negatively associated with willingness to treat plhiv (e.g. worthington et al., ) . furthermore, nurses' willingness to take care of plhiv has been found to be related to whether the hiv-positive people were homosexuals, intravenous drug users or prostitutes (tyer-viola, ) . nurses' continuing education may be a way to support nurses' willingness to care for plhiv. slaten et al. ( ) , for example, reported after seven training workshop sessions during a five-month period a positive impact on nurses' willingness to take care of plhiv. buskin et al. ( ) found after two lectures that additional education could help eliminate a substantial amount of unwillingness to be in proximity of a person with hiv. it is not clear, however, what educational methods would be best to make an impact. in most intervention studies educational programmes have included workshops (williams et al., ; ezedinachi et al., ; slaten et al., ) or lectures (buskin et al., ) . it has been assumed that the educational programmes related to hiv should consist of various different teaching methods to allow debating and discussion about willingness to take care of plhiv (wu et al., ; uwakwe, ) . models of education that show most promise are those that use experiential styles of learning. it has been shown that it is possible to increase nurses' empathic ability (e.g. brunero et al., ) . furthermore, uwakwe ( ) found that an indicator of the degree of success of the programme is the increased willingness of the participating nurses subsequently to work with and treat plhiv. the aim of the study is to explore the impact of an intervention programme on nurses' willingness to take care of hiv-positive people in lithuania. in lithuania, aids is a late arrival (caplinskas, ) . while the first hiv-positive case was reported in , today there are positive cases in the country (population about . million). (lithuania aids centre, ). the study population was made up of registered nurses in lithuania who work in the surgical, medical, or gynaecological wards of the hospital and in primary health care centres attached to the hospitals. these nurses were selected because they worked in both hospitals and primary health care areas, and were thus at the front line of hiv prevention, care and advocacy. all nurses in the selected wards of three lithuania hospitals (approximately from each) and primary health care centres attached to the hospital areas constituted the selected population. firstly, nine biggest lithuanian hospitals were chosen for the study. three hospital areas were randomly selected from these. a total of randomly selected nurses from these hospital areas were invited to participate in the study. the recruitment occurred at the same time for all groups. the study utilized a randomized controlled trial design with pre-test evaluation and a three-month repeated follow-up evaluation. randomisation was made by a statistician together with the researchers. to determine the number of participants needed in the study, we performed a power analysis for a one-way anova. the minimum required number of participants was per group. however, we decided to increase the sample size because of possible dropouts. a total sample of participants was recruited: the first educational intervention (two-day workshop and written material) group consisted of participants (eg ), the second educational intervention (written material) group consisted of participants (eg ), as did the control group (cg). the participants were selected by the cluster random sampling method using the spss . statistical analysis software. nurses from one hospital were selected for the first intervention group, nurses from the second hospital were chosen for another intervention group and nurses from the third randomly selected hospital were used as a control group. the data collection was conducted between december and march . the first data collection sample included participants. the response rate was . % (n = ) in eg , . % (n = ) in eg and . % (n = ) in cg in december . the follow-up data collection consisted of participants. the response rate after one reminder letter (in march ) was for the first group % (n = ), for the second group % (n = ) and for the control group % (n = ). there were two different educational interventions in this study. the first intervention included a two-day workshop ( h) and the distribution of written material ( pages). the content areas covered were: hiv and aids related epidemiology and history, prevention, transmission, hiv treatment, and counselling hiv-positive patients and ethical considerations. the intervention included lectures, group discussions, conversations with a hiv-infected person, watching a film about hiv and the distribution of written materials. the lectures were delivered by a physician-nurse pair. also an hiv-positive person participated in the group discussions. in addition to the lecture handouts, the participants were asked to review lithuanian academic journal articles ( pages) of the content areas mentioned above. the second intervention consisted of the articles ( pages) that were provided to the eg nurses and two pages about new statistics of the hiv situation in lithuania and in the world from eg were provided to eg . in total, eg participants received pages of written materials. cg nurses received no lectures or written materials. additionally, the participants from both intervention groups received continuing education credits as participation incentive from the continuing educational centre. the pre-test was done at the beginning of the first day of the twoday workshop among the members of the first education intervention group (eg ) in december . the other groups (eg and cg) received the questionnaires at the same time by post. reminder letters (both pre-test and post-test) were sent to all participants one week later. the post-test was repeated for all groups after three months by post. the questionnaire used consisted of two parts: the background questions and the nursing willingness questionnaire (nwq). the background questions asked for demographic information (i.e. age, gender, mother tongue, marital status, number of children, education, and work experience) while the general questions were related to taking care of hiv positive (i.e. if they were willing to care for plhiv). additionally, the respondents were asked to answer dichotomous questions (yes/no answers). they were also asked about their general willingness to take care of plhiv. the nurses' willingness to care for plhiv was evaluated using the nwq scale developed by dubbert et al. ( ) . previous studies suggest that the nwq is a reliable and valid instrument for evaluating a construct of current concern to nursing administrators and educators (dubbert et al., ) . the original self-report instrument used a -word vignette, whereas the present modified version was reduced to a vignette of english words to describe a person who has progressed to aids (called henes), whose health was deteriorating. the patient's symptoms were: diarrhoea, high temperature, double incontinence, vomiting and mental confusion. using these items, the nurses' willingness to carry out certain nursing activities was explored by items ( = strongly agree, = agree, = undecided, = disagree, and = strongly disagree). the translation into lithuanian was achieved by using the backtranslation technique (burns & grove, ) . the modified version has previously been used and found to be valid and reliable in finland, estonia and lithuania; for the whole data set among the three countries the cronbach's alpha value was . and in lithuania . (välimäki et al., ). in the current study, the cronbach's alpha values for the total data set were . (in the three groups before the intervention) and . (in the three groups after the intervention) which varied before and after the intervention among the groups as follows: for the first group . / . , second group . / . and control group . / . . permission to conduct the study was obtained from institution authorities and approved by the ethics committees of the hospitals and one university. each participant was given a unique identification (id) code which was used during the research and evaluation process to ensure nurses' confidentiality. individual consent was sought from the study participants before starting the study. the consent forms and the letters informing about the study were mailed to the possible participants. the letter contained relevant information on the study and a statement of voluntary participation, as well as assurances of confidentiality and honesty in the reporting of the results. the nurses (eg and cg) were provided with information on respondent anonymity, and all nurses were free to withdraw without prejudice at any stage of the research. additionally, the researchers were working at universities, and study participants in hospitals or public health care centres. statistical analysis of the data was performed by using the spss . software package. nurses' demographic variables and items concerning their perceptions related to their willingness to care for plhiv were examined using descriptive analysis. after testing for normality, we used parametric and nonparametric criteria, the student's t, anova, and mann-whitney and kruskal-wallis tests to compare two or more groups. cronbach's alpha was used to evaluate the internal consistency of the scales. p-values less than . were interpreted as statistically significant. in the following text only statistically significant results are reported. all participating nurses were female (n= , %). the nurses ranged in age from to years, their mean age being . (sd = . ). the nurses in the first group were the youngest, with the difference between the groups being statistically significant (p= . ). nurses in the first group had less children (p= . ), and more university-level qualifications (p = . ). also the length of the nurses' work experience at the present workplace varied in the different groups as follows: eg . - (mean . , sd . ); eg . - (mean . , sd . ) and cg . - (mean . , sd . ). the nurses from the first group had the least work experience (p= . ). other demographic differences are presented in table . our educational interventions, meaning the workshop and the written materials distributed to the nurses (eg ), or the written materials distributed alone (eg ), did not have an impact on the nurses' willingness to take care of plhiv. however, the nurses from all groups were willing to care for plhiv even before the education intervention (nwq scores: . - . ), meaning the most positive and the most negative score. changes in willingness were found only in eg , among those who had received the workshop and the written materials (mean score . , sd . ), but the result was not statistically significant (table ) . when comparing the nurses' willingness in the specific nursing activities, it was found that, because of the intervention, nurses in eg were more willing to take an hiv-patient's vital signs, clean supplies, complete catheter care, shave, empty the urinary draining bags, start intravenous fluids and administer a blood transfusion, that is, do more "dirty" nursing activities than before the intervention (table ) . before the intervention, nurses from eg were the most willing to care for plhiv (mean score . , sd . ) while those from the cg were the least willing to provide care (mean score . , sd . ). there were no statistically significant changes in the nurses' willingness to take care of plhiv in eg nor in cg after the intervention. in eg , participants were asked to answer just one general background question on whether they were willing to take care of plhiv or not. after the intervention, the nurses tended to be more willing to take care of plhiv (mean score . , sd . versus mean . , sd . , p = . ). as a background factor, all participants were asked to answer one general question concerning their willingness to take care of a patient with hiv. we found that after the intervention, nurses from all three groups: eg %, n = ; eg %, n = ; cg %, n = , reported unwillingness to take care of a patient with hiv. no adverse events occurred during the intervention study. we should point out that there could be some limitations in using the three intervention arms because of the demanding practical arrangements and/or scenario used in this teaching programme. however, at the same time it was valuable to see the impact of two different programmes in a country with limited funding possibilities. the mean difference is significant at the . level (mann-whitney test). eg intervention group ( -day workshop and written material); eg intervention group (written material); and cgcontrol group. the aim of this study was to ascertain what kind of impact the intervention has on nurses' willingness to take care of hiv-positive people or those with aids in lithuania. the ultimate goal was to create a realistic teaching programme with limited funding in order to establish an ongoing continuing education programme for lithuanian nurses. our study revealed that, in general, nurses from all three groups (eg , eg and cg) were willing to perform required nursing activities for a fictional person who has progressed to aids (see dubbert et al., ) . as health professionals become part of the social space of people living with these infections, they become part of the patient's social surroundings as empathic figures, people who know "how it feels" (worthington et al., ) . hiv-related stigma is reduced if plhiv are not seen as "different". however, when using just one general background question on whether nurses were willing to take care of plhiv, up to % of the control group nurses reported unwillingness to care for plhiv. keeping in mind that drug use is the main route of transmission in lithuania, this may be a potential cause of the lack of willingness to provide care. drug use generally is a stigmatised activity, which is why people may be unwilling to care for drug users. although our first teaching intervention showed a positive impact on nurses' knowledge level (mockiene et al., ) only minor changes could be observed in the willingness to care. after the educational intervention, nurses in eg were more willing, for example, to carry out daily nursing activities such as to clean up faeces or vomit only using gloves and feed dinner. similar results were obtained by wu et al. ( ) and williams et al. ( ) . however, the fact that nurses in the first intervention group were younger, had more university-level qualifications and less work experience at the present ward than in the other groups, may have had have a positive impact on the results (see also välimäki et al., , worthington et al., . the distribution of written materials only (eg ) did not have a positive impact on increasing nurses' willingness to take care of plhiv. uwakwe ( ) indicated that the mere production of hiv information materials and dissemination with minimal personalized contact does not always yield optimum results in health behaviour modification and written materials, no matter how good they are, may not always be read by the target group. our study showed that the nurses who had more work experience were more willing to care for plhiv than nurses whose work history was short. this result differed from the results of another study which showed that the number of years in professional practice was negatively associated with willingness to treat plhiv (worthington et al., ) . it is likely that the preparation of nurses to take care of hiv-positive patients is influenced by different educational backgrounds, whereas the limitations of the education systems in lithuania, for example, can be problematic in themselves. according to williams et al. ( ) , nurses need to have the knowledge and confidence to protect themselves from performing the mean difference is significant at the . level (mann-whitney test). eg intervention group ( -day workshop and written material); eg intervention group (written material); and cgcontrol group. this work effectively, and must be well-informed about the clinical course of hiv and about effective strategies for its prevention and treatment. besides, they must be prepared to care for patients from a variety of cultural and social backgrounds whose experiences and values may differ from their own, and recognize that patients with hiv should be given the same care as hiv-negative patients. the present study was the first attempt to conduct a rct in the field of nursing research in lithuania. we emphasize the importance of such studies in all east-european countries in order to develop evidence-based nursing. even though it is problematic to carry out research on interventions (also internationally), and usually the conclusions cannot explain causality, such studies are needed to advance nursing knowledge (hallberg, ) . this is also true for research on implementing evidence for education. several variables may affect empathy education that need to be accounted for in future studies such as gender, cultural values and clinical speciality experience. models of education that show most promise are those that use experiential styles of learning. studies have demonstrated that it is possible to increase nurses' empathic ability (brunero et al., ) . the fact that lithuania was attributed to the low-prevalence countries after the first hiv cases, had a negative impact of hiv awareness. this might have been influenced by the attitude towards continuing studies of nurses. however, having reviewed the plans of the institutions providing services in lithuania, it was noted that the training in this area is the thing that nurses miss most. it is therefore important to focus on improving nurse education, and basic educational support should be a priority for those working with plhiv. a more organized educational structure, targeted at all health care professionals in the form of health talks/ seminars, in-service training, continuing medical education and nursing curricula, would improve the knowledge level related to hiv for health care providers most efficiently and effectively. consequently, educational programmes based on research evidence must play a leading role in educational strategies to help nurses understand hiv-positive people and change their attitudes towards taking care of them. in the future, we need more outcome research and intervention studies to assess their effects systematically as stated by hallberg ( ) . assessing willingness to care for persons with aids: validation of a new measure a review of empathy education in nursing the practice of nursing research: conduct, critique and utilization hiv/aids knowledge and attitudes in chinese medical professionals and students before and after an informational lecture on hiv/aids inequality and unwillingness to care for people living with hiv/aids: a survey of medical professionals in southeast china epidemiology of hiv/aids in lithuania in - : review of present situation and prognosis of hiv transmission trends development of a measure of willingness to provide nursing care to aids patients influenza pandemic and professional duty: family or patient's first? a qualitative survey of hospital employees the impact of an intervention to change health workers' hiv/aids attitudes and knowledge in nigeria: a controlled trial nurses knowledge, attitude and willingness to take care for hiv/aids patients in bhutan challenges for future research: providing evidence for health-care education moving nursing research forward towards a stronger impact on health care practice? healthcare workers' attitudes to working during pandemic influenza: a qualitative study colleagues with hiv/ aids: perspectives from health workers in zambia using case vignettes to measure hiv-related stigma among health professionals in china the impact of an intervention to change nurses' knowledge and hiv/aids related attitudes in lithuania: a randomized controlled trial caring for patients living with aids: knowledge, attitude and global level of comfort knowledge, attitude and willingness of nigerian physiotherapists to provide care for patients living with acquired immunodeficiency syndrome hiv/aids and its impact on student nurses nurses health education program in india increases hiv knowledge and reduces fear healthcare workers' ability and willingness to report to duty during catastrophic disasters training mental health professionals on ethical issues and hiv obstetric nurses' attitudes and nursing care intentions regarding care of hiv-positive pregnant women systematized hiv/aids education for student nurses at the university of ibadan, nigeria: impact on knowledge, attitudes and compliance with universal precautions willingness to care for patients with hiv/aids effectiveness of an hiv/ aids educational programme for chinese nurses priority interventions hiv/aids: prevention, treatment and care in the health sector. world health organization, hiv/aids department rehabilitation professionals and human immunodeficiency virus care: results of a national canadian survey diffusion of hiv/aids knowledge, positive attitudes, and behaviours through training of health professionals in china the researchers would like to thank the finnish nursing education foundation for financial support.we would also like to thank the nurses in lithuania for their contribution in this study. key: cord- - of ertf authors: lo, catherine yuk-ping title: securitizing hiv/aids: a game changer in state-societal relations in china? date: - - journal: global health doi: . /s - - - sha: doc_id: cord_uid: of ertf background: china has experienced unprecedented economic growth since the s. despite this impressive economic development, this growth exists side by side with the human immunodeficiency virus/acquired immune deficiency syndrome (hiv/aids) and severe acute respiratory syndrome (sars) crises and the persisting deficiencies in public health provision in china. acknowledging the prevailing health problems, the chinese government has encouraged the development of health non-governmental organizations (ngos) to respond to the health challenges and address the gaps in public health provision of the government. hiv/aids-focused ngos have been perceived as the most outstanding civil society group developed in china. considering the low priority of health policies since the economic reform, the limitation of the “third sector” activity permitted in authoritarian china, together with the political sensitivity of the hiv/aids problem in the country, this article aims to explain the proliferation of hiv/aids-focused ngos in china with the usage of the securitization framework in the field of international relations (ir). methods: the research that underpins this article is based on a desk-based literature review as well as in-depth field interviews with individuals working in hiv/aids-focused ngos in china. face-to-face interviews for this research were conducted between january and may in , and between december and january , in china. discourse analysis was in particular employed in the study of the security-threat framing process (securitization) of hiv/aids in china. results: this article argues that the proliferation of hiv/aids-related ngos in china is largely attributed to the normative and technical effects of hiv/aids securitization ushered in by the united nations security council (unsc) and supported by the global fund to fight aids, tuberculosis, and malaria (hereinafter global fund) observed in china. despite depicting a positive scenario, the development of hiv/aids-focused ngos in china generated by the international securitization efforts is largely limited. an internal and external factor was identified to verify the argument, namely ( ) the reduction of international financial commitments, as well as ( ) the fragmentation of hiv/aids-focused ngo community in china. conclusions: this article shows that international securitization weakened with the rise of chinese commitment on hiv/aids interventions. in other words, hiv/aids-related responses delivered by the national government are no longer checked by the global mechanism of hiv/aids; thus it is unclear whether these ngos would remain of interest as partners for the government. the fragmentation of the hiv/aids community would further hinder the development, preventing from ngos with the same interest forming alliances to call for changes in current political environment. such restriction on the concerted efforts of hiv/aids-related ngos in china would make achievement of the sustainable development goals (sdgs) to foster stronger partnerships between the government and civil society difficult, which in turn hindering the realization of ending hiv/aids in the world by . china has experienced remarkable economic growth since the initiation of the economic reform in the s. the average gdp growth in china was . % annually during the first two decades of the economic reform [ ] . the rising nation became the world's leading manufacturing power in , and it surpassed the united states as the world's largest trading country [ ] . jakovljievic further predicted that the economic growth in china would continue at least up to the middle of the st century [ ] . despite such impressive economic performance, the provision of public health and the control of infectious diseases have been marginalized. between the late s and , the chinese national government public health spending as a proportion of total health spending plunged from % to just over % [ ] , despite the fact that china has outperformed other developing countries, such as other brics members, regarding the public health spending in nominal terms [ ] . as argued by yip and mahal, chinese political leaders in the abovementioned period of time simply perceived health as "a consumption activity rather than a productive good and therefore was given lower priority in government funding" [ ] . in this regard, the chinese authorities deliberately curtailed the level of public health expenditures so that economic development could be pursued and the legitimacy of the one-party authoritarian regime bolstered. acknowledging the economic success in the past decades, hiv/aids nevertheless emerged as one of the "negative externalities" of public health threats brought about by the s economic reform. hiv/aids was first discovered in china during the mid- s, the same period when the economic reform was just beginning. the epidemic was exacerbated in china in the s mainly because of government-supported blood plasma selling, which did not follow adequate sterilization procedures. this lack of regulation resulted in the emergence of so-called aids villages (aizibing cun) in henan and its outlying provinces, where a large percentage of rural residents were infected with hiv/aids [ ] . having little benefit from the economic reform in ways that coastal provinces did during the s, many residents in the central plains had little choice but to engage in the blood-plasma industry to improve their standard of living. since , hiv/aids has become a politically sensitive issue in china because of the international condemnation of the henan blood scandal. according to the latest figures released by the joint united nations program on hiv/aids (unaids), , people were estimated to have hiv/aids in china in [ ] . the country has the second largest hiv/aids population in asia after india. the chinese government started addressing the hiv/ aids problem after years of denial and underestimation of the hiv/aids prevalence in the country, especially among the most-at-risk populations (marps) including injecting drug users (idus), female sex workers (fsw), and men who have sex with men (msm) [ ] . however, national hiv/aids policies in the early years were very much driven in a top-down manner with government institutions (i.e. mainly the chinese centers for disease control and prevention [china cdc hereinafter] ) playing a leading role and with limited engagement of the "third sector" [ , ] . given the association of the disease with behaviors that are legally or socially unacceptable in the country (i.e., commercial sex work, injecting drug use, and men having sex with men), hiv/aids high-risk individuals refrain from using the related services provided by the government agencies because they wish to avoid being seized or humiliated by public security officials or by thugs hired by local officials [ ] . in this regard, gåsemyr claimed that the emergence of hiv/aids-focused non-governmental organizations (ngos) in china during the early s could fill the capacity gap of the government by implementing national hiv/aids policies and providing the related services for those marps that are hard to reach by the authorities [ ] . considering the low priority of health policies since the economic reform, the limitation of the "third sector" activity permitted in authoritarian china, together with the political sensitivity of the hiv/aids problem in the country, it is believed that the involvement of hiv/aids-related ngos in china would be largely limited. this is however not the case. over the last years there has been a dramatic increase in the number of hiv/aids-focused ngos operating in china. while gåsemyr argued that the growth of hiv/ aids-related ngos is mainly attributed to the devastating health crisis of sars in china and the new chinese leadership in [ ] , the previous work cannot explain why a high degree of political recognition was observed in solely hiv/aids ngos, instead of other health ngos, such as tb or cancer ngos in china. this article aims to fill this research gap with regard to the proliferation of hiv/aids-focused ngos in china with the use of the securitization framework in the field of ir. the research that underpins this article is based on desk-based literature review as well as in-depth field interviews with individuals working in hiv/aids-focused ngos in china. discourse analysis was in particular employed to study the securitization of hiv/aids in china. potter argued that "discourse analysis has an analytic commitment to studying discourses as texts and talks in social practice…the focus is…on language as… the medium for interaction…one theme that is particularly emphasized here is the rhetorical or augmentative organization of talk and texts" [ ] . silverman pointed out that the intellectual ancestor of discourse analysis is john langshaw austin, the original inventor of the idea of speech acts that later became the core element in securitization theory [ ] . concerning discourse analysis and speech acts share the austinian concern with the rhetorical structure of talk and texts, the founding scholars of securitization theory, buzan, waever and wilde explicitly stated, "the obvious method [to study securitization] is discourse analysis, since we are interested in when and how something is established by whom as a security threat" [ ] . the authors also noted that the technique of employing discourse analysis to securitization studies is to "read[ing], looking for arguments that take the rhetorical and logical form defined here as security" [ ] . the meaning of security is constructed when the political leaders (securitizing actors) frames an issue as an existential threat to the referent objects, claiming the issue as having an absolute priority on the government agenda, thereby invoking a right to handle such an issue with extraordinary/emergency measures to ensure the survival of the referent objects [ ] . in this research, public speeches (in written form) related to hiv/aids problems, which were delivered by the top-level political leaders, were examined. a specific rhetorical structure had to be located in their discourses, consisting of either one or all of the following elements: ( ) the existence of an existential threat; and/or ( ) the perceived threat is challenging the survival of the states or people in the states (referent objects), and/or which it requires to ( ) be urgently dealt with by new political measures of the respective country. an array of documents ranging from official documents, reports, newspaper articles was initially identified via the search engines of google scholar and proquest with the keywords of "hiv/aids", "security threat", and "china". nine key articles were consequently singled out to identify the textual discourses related to hiv/aids threat/ security nexus in china, published or released between and (table ) . a total of semi-structured interviews were conducted along with the discourse analysis. apart from the background information of the respective ngos, the interview questions used in this study are categorized into three main dimensions: ( ) the priority of hiv/aids on the government agenda; ( ) the perceptions on the changing international and national financial commitment on hiv/aids interventions; and ( ) civil society involvement and coordination in national hiv/aids policies. the first dimension aimed to ensure that the ngos respondents were knowledgeable about the changing national government perceptions and policy priority towards hiv/aids in china, therefore, the researcher could rule out those comments given by unknowledgeable respondents so as to enhance the internal validity of the data collected. the second dimension was included to study their perceptions on the level of hiv/aids funding and effect (if any) on the service provision. the third dimension aimed to discover the actual level of involvement of ngos in national hiv/aids interventions as well as the level of coordination and cooperation between different ngos working on hiv/aids. two types of non-probability sampling-purposive sampling, including "theoretical sampling" and snowball sampling-were employed in the selection process of key informants. for purposive sampling method, samples were selected based on the "logic" or "commonsense" of the researcher in terms of the target population, its elements, and the purpose of the study. in this study, the target population consisted of the individuals working in hiv/aids-related ngos at global, national, and grassroots levels. in the course of the data collection, "theoretical sampling" was also applied to understand the subjects from a theoretical perspective. hence, academic scholars who have conducted research on hiv/aids policies in china were also included in the interviewee list. interviewees were also recruited via snowball sampling. the researcher collected data on the few members, and each respondent was asked to suggest people whom the respondent believed to be the most influential for interviewing. interviews for this research were undertaken between january and may in , and between december and january with leaders or senior officers working on hiv/aids in china, including international ngos, nine self-help groups, four gongos, five advocacy groups, two national ngo, one independent consultant, two academia, and two networks (see table ). twenty-six respondents were pinpointed based on the civil society (minjian shehui) was not considered as part of the political system in the pre-modern era; the emergence of a relatively independent civil society is a product of modern china. the changing socio-economic relations brought about by "open door policy" resulted in the recognition and growth of civil society for the first time in the chinese history [ ] . despite the early emergence of civil society, the falung gong incident showcased the destructive power of civil society in the eyes of the chinese government, worrying a robust, well-organized, and out-of-control civil society could overthrow and replace the ccp ruling position. meanwhile, the authorities realized the supplementary role ngos could perform in policy implementation. the chinese government has thus resolved such dilemma by adopting a "state-led" approach to manage civil society in china. based on frolic's concept of "state-led civil society", civil society is created by and belong to the state, thus the independence and autonomy of civil society are at all time bounded by the state [ ] . the state has the role of legitimating social organizations, demanding a disciplined partnership. accordingly, antagonism inherited in the western concept of civil society is not allowed to exist in the state-society relations in chinese authoritarian regime; any alternative force to the state is considered as an attempt to curtail or overturn its political legitimacy and power. accordingly, the state apparatus has managed the numbers and restricted the growth of both international and grassroots ngos via various legislative means, thereby allowing ngos to operate openly but at the same time keep the organization growth in check [ , ] despite these regulations, the chinese authorities had relatively given more autonomy to ingos than grassroots ngos operating in its territory, since the government could access international expertise and tap foreign money to tackle with the emerging social problems in china [ ] . such degree of autonomy is nevertheless problematic after the promulgation of foreign ngos management law (jingwai fei zhengfu zuzhi guanli fa) in april . the law stipulates that ingos operating in china must register with public security officials, and must not engage in political or religious activities that damage "china's national interests" or "ethnic unity". international community and western governments perceived the new law as a reinforcement of restriction of the numbers and scopes of foreign entities operating in the authoritarian regime. grassroots ngos are regulated by the regulation on registration and administration of social organizations (shehui tuanti dengji guanli tiaoli). according to the regulation (amended in february ), a ngo must possess a minimum asset of , yuan and have a "professional management unit" (zhuguan danwei) that acts as a supervisory body to the organization in order to register under the ministry of civic affairs (moca). fulfilling these two requirements is very formidable for grassroots ngos. the financial situation is problematic in many grassroots ngos because of the limited source of funding. on the one hand, most grassroots ngos receive limited financial support from the government, as they usually do not have political ties with the government. grassroots ngos also seldom receive donations from local communities because ( ) newly developed ngos do not have good track records that enable them to win the trust of the locals, and ( ) donors cannot receive tax breaks for their donation to unregistered ngos [ , ] . in addition, most government departments simply reject their applications due to fear of consequences of taking responsibilities for grassroots ngos. many grassroots ngos are hence often unregistered or registered as business entities with the ministry of industry and commerce (moic) [ ] . in addition to the abovementioned restrictions, the regulation also bans "similar organizations" coexisting at the various administrative levels [ ] , facilitating the management and even control the legal status of grassroots ngos in china. having official registration, to certain extent, is sine qua non to the survival of organizations as the legal status entitles ngos as official recognized entities to receive legal and financial supports from the government; unregistered ngos are officially perceived as illegal that would be subjected to prosecution and coercion by the state apparatus. considering a restrictive engagement of grassroots ngos in china, instead of grassroots ngos, early hiv/ aids-related responses at societal level were largely conducted by gongos [ ] , [ ] . considering the low priority of health policies since the economic reform, the limitation of the "third sector" activity permitted in authoritarian china, together with the political sensitivity of the hiv/aids problem in the country, it is intriguing to uncover the reasons for the growth of hiv/aids-focused ngos in china since . gåsemyr argued that the growth of hiv/aids-related ngos is mainly attributed to the devastating health crisis of sars in china and the new chinese leadership in [ ] . having said that the chinese government realized the impacts health problems or infectious diseases could have on its economic and social development, the previous work cannot explain why a high degree of political recognition was observed solely in hiv/ aids ngos, instead of other health ngos, such as tb or cancer ngos in china. considering the regime type of the government, allowing the growth of local ngos would in turn potentially attenuate the supremacy of the chinese communist party (ccp) in ruling the country or erode the autonomy of the state, why the chinese government tolerated, allowed, or even encouraged the growth of ngos in fixing hiv/aids problems, especially the epidemic has been viewed as a politically sensitive issue in china? how can one account for and understand the phenomenon? answering the key question with an ir perspective, this article argues that the rapid development of hiv/ aids-related ngos in china is attributed to the effects of hiv/aids securitization at the international level since . considering one of the most influential theories developed in the field of ir, securitization describes the process of defining an issue as a security threat (speech acts) and the corresponding political responses to block the adverse development of the perceived threat (emergency measures). this article particularly pinpoints the unsc and the global fund, which provide normative and technical supports, to study this endeavor. normative influences in this article refer to the effects of security-threat discourses, primarily resolution of the unsc, on the national government's perception on hiv/aids problems, whereas technical influences refer to the effects of global emergency measures, in particular the global fund, on the funding and management of hiv/aids-related policies at the state level [ ] . this article aims to demonstrate the ways in which international hiv/aids securitization has served as a game changer in altering state-society relations in china. drawing on literature reviews and fieldwork materials, this article further argues that the proliferation of hiv/aids-focused ngos in china generated by the international securitization efforts is nevertheless largely limited owing to the reduction of international financial commitments. the fragmentation of hiv/aids-focused ngo community is another factor hindering the development of a full-fledged third sector in the country. securitization in the ir discipline is a model outlining the process of framing an issue as a security threat and the corresponding political reactions to block the adverse development of the perceived threat. employing the theory, one is required to look for three criteria to determine whether an issue is a threat to the country and its people, including ) discourses uttered by toplevel political leader (securitizing actor) declaring a particular referent objects as an existential threat to security; ) acceptance by the targeted audience convinced of its potential to be an existential threat (audience acceptance); and also ) redirections of existing financial resources, new policies, or practices (emergency measures) are implemented to address the issue following the security-threat claim [ ] . in other words, the resolution of the "existential threat" posed by "x" takes precedence over other problems [ ] . numbers of security studies scholars believed that hiv/aids is the first infectious disease being securitized by the international institutions and national governments as the abovementioned criteria were all fulfilled in the case of hiv/aids [ , [ ] [ ] [ ] . speech acts concerning hiv/aids as a security threat were first identified in a unsc meeting in january . in july of the same year, the unsc passed resolution , acknowledging the urgent need to address hiv/aids, which threatens the stability and security if left unchecked [ ] . it is perceived that the particular security framing of hiv/aids gained acceptance by the national governments (audience of the hiv/aids security-threat claim) since countries unanimously adopted and signed the declaration of commitment on hiv/aids in . the urgency of addressing hiv/aids problems was reinforced in the special united nations general assembly special session (ungass) devoted to hiv/aids that has taken place every years since [ ] [ ] [ ] [ ] . the abovementioned events are significant because they represented the first time that the unsc general assembly devoted an entire session to a single disease, and the first time that the international political authorities framed hiv/ aids as a global health threat to national and international security instead of solely as a developmental or public health problem [ ] . the rhetorical act was backed by operational emergency responses in terms of the augmentation of the global hiv/aids spending since . the amount was exponentially surged from about us$ million in to us$ billion by ; and to an estimated us$ billion in [ ] . several hiv/aids-related funding agencies and health programs formulated after , also referred to global health initiatives (ghis), brought in additional monetary resources for hiv/aids [ ] . perceiving as the most prominent ghis, the global fund pledges to accelerate the end of the three epidemics, [hiv/]aids, tuberculosis, and malaria by providing financial support (us$ billion annually) for low-income countries to respond to the three diseases [ ] . undoubtedly, the introduction of the abovementioned ghis has brought about unprecedented levels of funding for diseases, in particular hiv/aids, in countries that have insufficient resources, whether because of poor socio-economic development or lack of political will, to orchestrate appropriate responses to the intractable disease. acknowledging international securitizing efforts on hiv/aids, this article illustrates the normative effects of resolution of the unsc and the technical influences of the global fund on national-level hiv/aids responses. china is selected as a case study to investigate this endeavor. china's response to the hiv/aids problem changed from an ignorance of "global evidencebased policy recommendations and international advice" into "one of our success stories [in global hiv/aids fight] during this past years," as claimed by michel sidibe, executive director of the unaids [ , ] . the subsequent sections demonstrate the ways in which the securitization effort in the international level acted as a game changer for hiv/aids-focused ngos in participating in national hiv/aids undertakings in china. chinese case study discourse analysis: normative influences and the role of the unsc in china, many of the first cases of hiv/aids since occurred among foreigners and homosexuals. therefore, the official discourses at that time promoted the idea that hiv/aids only affected non-local chinese people and foreigners, asserting "drug taking, alcoholism, robbery, homicide, suicide, divorce, prostitution, homosexuality, syphilis, aids…these kinds of western social ills come from their ideology", and also claiming "china had no sources of hiv/aids" [ , ] . the rhetorical acknowledgement of hiv/aids as a health security threat to the chinese population was largely absent during the early period of time. ramiah also pinpointed that the chinese leadership was extremely reluctant to acknowledge hiv/aids as a problem and securitize hiv/aids in china prior to the s [ ]. one probable reason for the resistance to hiv/aids securitization is economic: the period of early hiv/aids outbreak coincided with the initial years of open door policy and economic reform (gaige kaifang) of china to the outside world. the thirst for economic growth and performance preceded the urgency of disease management: local authorities feared their respected jurisdictions would lose external or foreign investment if the full extent of the problem were known, or that they would be punished by superiors for failing to prevent the hiv/aids spread. the "cover-up" practice also oc- in response to the designated targets, the securitythreat framing of hiv/aids has been fully adopted in the official discourses of chinese leaders and in official documents since . previously viewing hiv/aids as a "western disease" or "non-chinese disease", executive vice minister of health gao qiang stated in the hiv/ aids high-level meeting of the un general assembly that "hiv/aids is a common enemy of the whole mankind as it seriously threatens public health and safety. the chinese government has attached great importance to hiv/aids prevention and treatment and has treated it as a strategic issue for social stability, economic development, national prosperity and security, making it a first priority of the government work" [emphasis added] [ ] . the chinese president hu jintao once claimed in a public speech that "hiv/aids prevention, care and treatment is a major issue pertinent to the quality and prosperity of the chinese nation"; whereas premier wen likewise asserted that "dealing with hiv/aids as an urgent and major issue is related to the fundamental interests of the whole chinese nation" [emphasis added] [ ] . the ideas in the speeches were restated in the official document entitled state council notice on strengthening hiv/aids prevention and control (guowuyuan guanyu qieshi jiangqiang aizibing fangzhi gongzuo de tongzi). this document explicitly demonstrated the determination of the chinese authorities in grappling with the disease and stated that "hiv/aids prevention and control is linked to economic development, social stability, and national security and prosperity. long-term commitment to respond to hiv/aids is hence necessary" [emphasis added] [ ] . china's hiv/ aids prevention and control policies were further strengthened in the state council notice on further strengthening hiv/aids prevention and control (guowuyuan guanyu jinyibu jiangqiang aizibing fangzhi gongzuo de tongzi) in late , claiming that "the prevention and control of hiv/aids is related to the people's physical health and social and economic development, as well as to national security and the rise and fall of the nation. the party central committee and the state council have always attached great importance to the prevention and treatment of hiv/aids" [emphasis added] [ ] . based on the discourse analysis of the official documents and newspaper articles, it is argued that chinese national leaders followed suit the international move (i.e. unsc resolution ) to securitize hiv/aids in the country, framing hiv/ aids as a threat with social, political, economic, and security implications. such an alteration in perception toward the epidemic brought about the political recognition of the hiv/ aids-focused ngos, which has also been highlighted by multiple statements delivered by various top-level government officials since . in , vice premier wu yi stated, "we should mobilize all the partners in society to participate in the fight against hiv/aids. we need to improve our policies and strategies to build a better environment for the society to participate in the response, and try our best to facilitate the involvement of all sectors" [ ] . in , vice minister of health yin li publicly proclaimed "civil societies play an indispensable role in effective hiv/aids interventions led by the government" [ ] . premier li keqiang even promoted tax break for ngos specializing in hiv/aids prevention, claiming the role of ngos in hiv/aids prevention "is an irreplaceable and unique force" [ ] . to a certain extent, these aforementioned statements demonstrate the state's recognition of ngos' works and its willingness to engage with ngos in national hiv/aids interventions, although the political space of involvement is by and large bounded by the state [ ] . the previous section illustrates the change in the perception of the chinese government toward the hiv/ aids problems: from denial to the acceptance of the threats that could be posed by the disease on the country and its people. such threat recognition also brought about the acknowledgement that the government alone could not resolve the hiv/aids problems because of the complicated nature of the epidemic; the involvement of civil society groups was a globally recognized recommendation leading to the successful containment of the epidemic. nevertheless, verbal recognition is not sufficient to enhance the engagement and development of hiv/aids-focused ngos, especially in the preexisting authoritarian government structure; the governance and funding mechanism for hiv/aids responses requires alternation in china. as illustrated in the following section, this was the mechanism of the global fund that enhanced the funding for hiv/aids-focused ngos, facilitating the involvement of civil society groups in translating the rhetorical acts into emergency responses of hiv/aids in china. among the international funding agencies emerging after the hiv/aids securitization launched by the unsc, the global fund was the most renowned major contributor to the hiv/aids interventions in china. the global fund finally accepted the first proposal submitted by the chinese government on hiv/aids interventions in late , after the previous proposals being turned down twice in [ ] . between and , the chinese government has received over us$ billion in grants from the global fund; approximately us$ million were disbursed to hiv/aids intervention programs [ ] . further information regarding the global fund on hiv/aids in china is illustrated in table . intervention of the global fund's funding mechanism was deemed to transform the primary hiv/aids governance in china [ ] . the global fund required the governments to set up a country-level country coordination mechanism (ccm) to construct the grant proposals in line with the national hiv/aids-related strategies, manage the use and distribution of grants, and also oversee the implementation of successful applications. as per the requirement of the global fund, ccm should consist of a broad representation from the government, ngos, multilateral and bilateral agencies, and private sector [ ] . in the existing government structure in china, grassroots ngos have limited channels to participate in policymaking and implementation processes. thus, the multi-sectoral structure of ccm contributed to enhancing the government's commitment to involve ngos in national hiv/aids prevention and control measures [ ] . two among the seats in chinese ccm were reserved for the representatives of hiv/ aids-related grassroots ngos and people living with hiv/aids are a case in point [ ] . considering the existing government structure does not allow the full involvement of ngos in china, the ccm provided valuable opportunities for civil society groups to engage in hiv/aids-related policymaking. the involvement of ngos in national hiv/aids programs was notably highlighted in round of the global fund in china, since the theme of the grant proposal submitted by the ccm was directly linked to the development of civil society groups (refer to table ). in the course of the interview, a director of a hong kongbased ngo commented on the profound influence of the round on the ngo development: "round of the global fund acts as a pushing force for the government to involve more grassroots ngos in hiv/aids interventions" (national ngo- ). in line with the respondent's opinion, kaufman argued the round in particular "was seen by many as a further mechanism to institutionalize hiv/[aids] ngos roles in china's [hiv]/aids response [ ] ." in addition to the increase in participation, financial support for ngos working on hiv/aids-related programs surged through the global fund. as the principal recipient (pr) of the country, the chinese government (i.e., china cdc or the nhfpc) was required to disburse a designated portion of the grants to hiv/aids-related ngos (in the form of sub-recipients) operating in the country [ ] . following the instruction, % of the total grant was allocated to support ngos in round and , whereas % of its grant was distributed to ngos in round of the global fund [ ] . in line with the theme of round entitled "mobilizing civil society to scale up hiv/aids control efforts in china" proposed by the chinese ccm, the proportion granted to hv/aids-related ngos reached % [ ] . owing to the constructive political atmosphere and promising financial resources in the country, a burgeoning number of individual-organized hiv/aids-focused ngos was established in china; over % of the number of grassroots ngos increased in china between and [ ] . the suspension of the global fund in demonstrated that the funding mechanism to some extent held the chinese government accountable for the financial supports of hiv/aids-focused ngos. the global fund once suspended its funding to chinese hiv/aids programs in early because the chinese ccm failed to allocate % of the us$ million hiv/aids grant to grassroots ngos as pledged; less than % was distributed to hiv/aids-focused ngos [ ] . a program officer of a ngo mentioned the failure of ccm to allocate the right portion of the global fund grant to grassroots ngos: "government officials and representatives from gongos dominate the ccm. only a few representatives are from grassroots ngos and civil society" (advocacy group- ). the improper management and use of the global fund was even admitted by a senior government official in the shanghai cdc in times of the interview: first, the global fund required at least percent to percent of the grant should be given to grassroots ngos. however, the government failed to achieve this requirement. second, the management fee in some provinces was too high. third, one of the elements in the rcc program was related to budget aggregation (i.e., monetary contribution by both the national government and the global fund). however, the chinese government did not allocate enough money for the aggregated budget (ccdc/nhfpc- ). the determination of the chinese government to resolve the suspension of the global fund was observed in the course of fieldwork research. during a face-to-face interview inside the office building of the ministry of health (renamed national health and family planning commission in ) in may , the respondent told the investigator "the representatives of the chinese government and the global fund representatives are meeting upstairs to negotiate for the resumption of the grants" (ccdc/nhfpc- ). the dispute was eventually resolved; the chinese government promised to allocate at least % of the global fund grant to ngo work [ ] . in this regard, the global fund mechanism contributed to the political and financial supports of ngos, thereby resulting in the proliferation of hiv/aids-specific grassroots ngos in china, and also the proactive involvement of ngos in national hiv/aids undertakings. in other words, international securitization altered the hiv/aids policy in china, allowing numerous grassroots-level ngos working on hiv/aids to grow in a prevailing political system with "bounded autonomy". an injecting drug use self-help group leader believed the upsurge in the involvement of civil society also resulted in the improvement of state-societal relations, stating, "in the past, the relationship with the government was not good, but it becomes much better now. the government sent officials to visit our center to learn the management strategy of our organization" (self-help group- ). another ngo interviewee in beijing also claimed that "an increase in the acceptance of the government, especially the ministry of health, on grassroots ngos, [is observed in china] . the ministry of health does open the opportunity for ngos to cooperate with the government" (advocacy group- ). having said that the improvement of state-societal relations, it is noted that the chinese state is not a monolithic actor, but a conglomeration of departments and officials with competing and sometimes conflicting agendas in the national and sub-national levels [ ] . a beijing ngo leader pinpointed this phenomenon, stating, "the ministry of health is fine to cooperate with those ngos that can help, regardless of whom. however, state security bureau usually holds a relatively hostile view on the existence of grassroots ngos since the bureau is concerned about social stability" (advocacy group- ). considering hiv/aids as a health threat to the country and its people, the recognition and involvement by the central government and the nhfpc and other related government agencies is of particular vital to the proliferation of hiv/aids-focused ngos in a statedominated society in the current political regime. despite depicting a positive scenario, this article further illustrates that the development of hiv/aids-focused ngos in china generated by the international securitization efforts is largely limited. in other words, the growth of the number of ngos working on hiv/ aids in china would be ceased or even decreased in long term, and also the political space for grassroots to involve in hiv/aids policy making and implementation would be further restricted. an internal and external factor was identified to verify the argument, namely ( ) the reduction of international financial commitment, as well as ( ) the fragmentation of hiv/aids-focused ngo community in china. external factor: the reduction of international financial commitment china resembles some developing countries in that it has faced the problem of decreasing international hiv/ aids financial commitments in supporting its national hiv/aids responses [ ] . given the global financial crisis and the continuous economic boom in china, international and bilateral funding agencies argue that china should be the donor instead of the recipient of international hiv/aids-specific grants and loans [ ] . owing to a lack of international and national hiv/ aids funding, the number of ngos working on hiv/ aids was drastically reduced; many ngos and cbos were simply closed down, only a few of them could barely survive with the support by other funding sources (national ngo- ). the retreat of the global fund has subsequently created a policy vacuum for the chinese government in taking the lead in managing the development of hiv/ aids-related ngos in china. mimicking the funding mechanism of the global fund, the state council launched the china aids fund for non-governmental organizations (cafngo) (shehui zuzhi canyu aizibing fangzhi jijin), providing financial resources for hiv/ aids-related ngos via the submission of grant proposal starting from [ ] . the reduction of the chinese government's reliance on the global fund implies that the hiv/aids-related responses delivered by the national government are no longer checked by the external mechanism. the authoritarian regime is probably the only agency defining/restricting the political space that ngos could work in. explaining the interaction between the chinese authorities and ngos, a university professor in beijing suggested: "in normal circumstances, local cdc staff hand over treatment delivery work to grassroots ngos. nonetheless, cdc officials intend to keep these ngos small, giving them just enough money to run the programs, so that they will not grow too strong to pose potential threats to the government" (academic- ). along with the weakening of international securitization efforts and the rise of chinese government's involvement in managing ngos in the post-global fund era, the continuous proliferation of ngos is further complicated by the fragmented nature of hiv/aids-focused civil society groups in china. it is argued that the existing ngo registration system, as previously mentioned, has brought about a fragmented ngo community in china. apparently, governmentorganized non-government organization (gongo) and registered ngos working on hiv/aids are included in hiv/aids national policy implementation processes, whereas excluding unregistered grassroots ngos that are perceived as illegal or "anti-government" organizations. based on the nature of services that individual hiv/ aids-focused ngos provided, service providers are preferred by the state, whereas ngos serving as advocates of human rights and agencies providing legal services for hiv/aids-infected people would be subjected to prosecution and coercion. a hiv/aids specialist working in an international ngo in beijing stated, "during a hiv/aids ngo meeting, the chinese government clearly claimed that the authorities would like to work with ngos/cbos conducting service delivery, but not with those working on hiv/aids-related human rights or gender issues" (ingo- ). to further illustrate this point, the chinese political leaders publicly praised a guangxi-based ngo named aids care china, recognizing the work the organization had been done in hiv/aids prevention, meanwhile stifling numbers of hiv/aids activists through imprisonment, house arrest, or assault. dr. wang yanhai and dr. gao yaojie were two of the prominent chinese hiv/aids activists that fled to the united states in and , respectively, due to the recurrent pressure and disturbance exerted by chinese authorities owing to their advocacy work. in june , a hiv/aids-related legal aid ngo, beijing yirenping, was raided, and two of its activists were detained. in this regard, the continuous inclusion/exclusion selection process would weaken unregistered or advocacy groups that conceived as threats to the legitimacy of the authoritarian regime [ ] , while preserving ngos that are willing to under control by the state apparatus and prepared to accept the regime's policy measures. for the sake of reaching a modus vivendi, these ngos usually display self-limiting behaviors, avoiding actions that would be interpreted as threats to the regime [ ] , such as having close relationship or cooperation with ngos being "excluded" by the state apparatus. while a formal local network for hiv/aids-related ngos or civil society groups has been established in many countries in asia, such coordination mechanism between non-state actors is largely absent in china. the fragmentation of hiv/aids ngo community is likewise observed in the course of interview sessions. amongst the interviewees, the majority of the ngo respondents believed that cooperation dramatically increased between the government and ngos working on hiv/aids, especially in the areas of treatment, care, and prevention. only a few of them nevertheless stated that communication and coordination occurred amongst ngos in policy implementation. a national-wide ngo respondent claimed that "we seldom cooperate with other ngos or ingos; we have our own teams to do the work" (national ngo- ). some grassroots ngo respondents in shanghai and kunming expressed their unwillingness to cooperate with so-called "unauthentic" ngos or ngos having so-called "government background": few ngos have cooperative relationship. there are lots of "fake" ngos in china. the cdc found some patients to set up grassroots ngos and then through the name of such ngo to apply for the global fund. after they received the money, cdc would become the one who controlled the funding (self-help group- ). eighty-five percent of the hiv/aids-focused ngos in yunnan have government background…for those ngos that are funded by the global fund or china-bill gates projects, these are organizations with the government background…or if you read their introduction saying "with the help and support of government", you will know these are ngos with the government background (self-help group- ). a "we-they" distinction has apparently prevailed amongst the hiv/aids ngos community in china, reinforcing the atomization of hiv/aids-focused ngos, discouraging the proliferation of civil society in china. horizontal relationship amongst ngos working on hiv/aids is relatively weak and ill-organized, thereby avoiding these organizations joining hand to call for favorable political environment or monetary supports to continue their operation in china. owing to the reduction of international financial commitments, as well as the fragmentation of hiv/aids-focused ngo community in china, the proliferation of hiv/aids-focused ngos in china generated by the international securitization efforts is nevertheless largely limited in long run. such restriction on the concerted efforts of hiv/aids-related ngos will inevitably pose challenges to china to fulfill the pledge of the agenda to end hiv/aids as one of the targets of the sustainable development goals (sdgs) [ ] . hiv/aids was officially announced as a security issue in by the unsc resolution , which claimed that the pandemic could pose security threats if left unchecked. the rhetorical security-threat claim resulted in the burgeoning number of ghis organized by the international and bilateral organizations operating at the state level. this article illustrates the ways in which the unsc resolution and the global fund influencing the hiv/aids governance in china. rhetorically acknowledged the hiv/aids problems and the irreplaceable role of hiv/aids-focused ngos in combating the disease by the chinese government, the monetary and technical supports by the global fund enabled hiv/aids-focused ngos to participate in the national policymaking process, facilitating the proliferation and development of civil society in china. this success nevertheless does come with concerns regarding sustainability. this article shows that international securitization weakened with the rise of chinese commitment on hiv/aids interventions. in other words, hiv/aids-related responses delivered by the national government are no longer checked by the global mechanism of hiv/aids; thus it is unclear whether these ngos would remain of interest as partners for the government [ ] . the fragmentation of the hiv/aids community would further hinder the development, preventing from ngos with the same interest forming alliances to call for changes in current political environment. such restriction on the concerted efforts of hiv/ aids-related ngos in china would make achievement of the sdgs to foster stronger partnerships between the government and civil society (goal ) difficult, which in turn hindering the realization of ending hiv/aids in the world by (goal ). this research has several limitations. firstly, there is a lack of available information regarding the operation of local or grassroots hiv/aids-specific ngos that are in particular helping marps in china, owing to the political sensitivity of hiv/aids, the unregistered status of ngos working on hiv/aids, the increasing restrictive environment for ngos operating in china especially under the xi administration, together with the social stigma attached to their service objects as well as the ngos themselves as the service providers. secondly, it is difficult to conduct longitudinal study on the development of hiv/aids-specific ngos in china. the researcher realized that many of the ngos that had been interviewed in were no longer under operation in the follow-up fieldwork in , either because these ngos could not secure sustainable funding, or they were cracked down by local authorities for advocating hiv/aids-related human rights or gender equality, or having very close links to foreign (western) organizations. further research therefore needs to be conducted to remedy these technical weaknesses. it is suggested that comparative research could be conducted on the effects (if any) of the regime types, such as china and thailand, and the level of socio-economic development of the country, such as china and singapore, on the effects of international hiv/aids securitization in the national levels. endnotes here ngos does not include government-organized non-governmental organizations (gongos). referent objects refer to "things that are seen to be existentially threatened and that have a legitimate claim to survival." see buzan b et al., security: a new framework for analysis, p. . "civil society" is often translated as "minjian shehui", "shiming shehui" and "gongming shehui" in chinese. in fact, the three different chinese terms do not have the same meaning. many scholars actually use these different chinese terms of civil society simultaneously. "minjian shehui" is used in this article because the term is widely used in the academic research in china's modern civil organizations. "civil society" in this article refers to a sphere that is conceptually separable from the state and government. at the same time the state council abolished the jijin guanli banfa stipulated in . the chinese and english versions of the revised regulation ( ) can be found in chinalawinfo. "regulation on registration and administration of social organizations ( ) (shehui tuanti dengji guanli tiaoli). nevertheless, grassroots ngos registered under the moic also encounter problems with regard to the amount and source of funding. as registered commercial entities, grassroots ngos are required to pay a % tax on any revenue, even for funding received for non-profit purposes. in recent years, the abovementioned legislative hurdle in ngo registration has been relaxed in some parts of china, first in shenzhen and then in beijing. the local government in these two cities relaxed its ngo registration rule, and allowed ngos in the fields of business, charity, welfare, and social services to register directly with the moca. such a move can also be observed at the national level. in early , the national government started planning to revise the regulations on ngo registration and management. if the revised version is passed by the state council, the individual-organized or grassroots ngos can directly register with the moca without seeking a supervisory body prior to the registration. it is noted that the author is fully aware of the arguments put forward by timothy hildebrandt, stating chinese ngos could be favored or cracked down by the state apparatus irrespective of registration status. the author is argued that unregistered ngos are comparatively easier to be targeted and cracked down by the government officials in the name of "unlawful organizations". for hildebrandt's argument, see hildebrandt, t. the political economy of social organization registration in china. the china quarterly. ; : - . gongos are composed of three types of organizations existed in the s and s: ( ) private organizations from the "old china"; ( ) friendship associations for the promotion of trade, and cultural exchange agencies; and ( ) people's organizations and mass organizations. in the course of the meeting, us vice president al gore claimed that hiv/aids was a security threat because "it threatens not just individual citizens, but the very institutions that define and defend the character of a society. the disease weakens workforces and saps economic strength. hiv/aids strikes at teachers, and denies education to their students. it strikes at the military, and subverts the forces of order and peacekeeping". mcinnes and rushton ( ) argued that the hiv/ aids securitization in was not a successful or complete securitization. however, this article does not intend to examine whether the international hiv/aids securitization has been fully accepted by the target audience. it intends to examine the influences of the hiv/ aids international securitization on the national and sub-national levels in china. in , the bush administration launched the president's plan for emergency aids relief (pepfar), pledging us$ billion from to to "turn the tide against hiv/aids." the who launched the " × " campaign that targets getting million people on antiretroviral treatment by , while the multi-country hiv/aids program of the world bank provided more than us$ . billion for grants and concessional loans to help governments respond to hiv/aids issues. examples included the indian network of people living with hiv/aids, thai network of people living with hiv/aids, asia pacific council of aids service organization in malaysia, and also action for aids singapore, economic reform and growth in china routledge handbook of chinese security. london: routledge bric's growing share of global health spending and their diverging pathways the health care systems of china and india: performance and future challenges evolving health expenditure landscape of the brics nations and projections to rural china, a steep price of poverty: dying of aids: new york times unaids data china's pragmatic approach to aids hiv/aids in china and india: governing health security geopolitics in health: confronting obesity, aids, tuberculosis in the emerging brics economies unleash civil society in china to save lives. human rights watch twenty years of mobilizing around aids in china: the main actors and influences behind organizational growth discourse analysis as a way of analyzing naturally-occurring talk interpreting qualitative data: methods for analyzing talk, text and interaction security: a new framework for analysis. usa: lynne rienner publishers security, insecurity and asecurity in the west european non-war community civil society, corporatism and capitalism in china the civil society in china social organizations and the authoritarian state in china ngos in china: an overview. international community foundation is china's new overseas ngo management law sounding the death knell for civil society? maybe not china's evolving civil society: from environment to health china's rapidly growing non-governmental organizations. eai background brief no. from spectators to implementers: civil society organizations involved in aids programs in china defining chinese nongovernmental organizations. volunt int j volunt nonprofit org globalization and its methodological discontents: contextualizing globalization through the study of hiv how is health a security issue? politics, responses and issues securitizing infectious disease should hiv/aids be securitized? the ethical dilemmas of linking hiv/ aids and security where are the links? council on foreign relations on the responsibility of the security council in the maintenance of international peace and security: hiv/aids and international peace-keeping operations. united nation security council united nations general assembly united nations general assembly political declaration on hiv/aids: intensifying our efforts to eliminate hiv/ aids. united nations general assembly united nations general assembly aids and security: where are we now? hiv/aids and securitization theory the global fund to fight aids, tuberculosis, and malaria china's evolving aids policy: the influence of global norms and transnational non-governmental organizations china among success stories in global hiv/aids fight: unaids chief. xinhua. peking daily cautions against western threats of aids, drugs: the associated press leexisnexis newspapers . ramiah i. securitizing the aids issue in asia gao qiang, at the hiv/aids high-level meeting of the un general assembly. permanent mission of the people's republic of china to the un state council notice on strengthening hiv/aids prevention and control. ncaids, china cdc 国务院关于进一步加强艾滋病防治工作的通知 [state council notice on further strengthening hiv/aids prevention and control.] 国发 号 [state council document no red ribbon forum redoubles aids fighting bid. china daily keqiang wants tax break for ngos specializing aids/hiv work. south china morning post china after the global fund investment in hiv/ aids programs: does it help strengthen health systems in developing countries? glob health the global fund: managing great expectations china country coordinating mechanism secretariats. the global fund to fight aids, tuberculosis, and malaria people's republic of china: national center for aids/std control and prevention aids funds frozen for china in grant dispute global fund lifts china grant freeze. the body china aids fund for non-governmental organizations making turkey's transformation possible: claiming "securityspeak"-not desecuritization! southeast european and black sea studies estimates of global, regional, and national incidence, prevalence, and mortality of hiv, - : the global burden of disease study the political economy of social organization registration in china this work is supported by a hong kong university research council general research fund grant # . the author would like to thank anonymous reviewers for their useful suggestions. the author would also like to express the appreciation to dr. nicholas thomas for his comments on an earlier version of the manuscript. all errors and omissions are the author's responsibility alone. the author declares that she has no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. the author read and approved the final manuscript. key: cord- -l db gll authors: kino, tomoshige; chrousos, george p. title: virus-mediated modulation of the host endocrine signaling systems: clinical implications date: - - journal: trends in endocrinology & metabolism doi: . /j.tem. . . sha: doc_id: cord_uid: l db gll viruses, which are among the simplest infective pathogens, can produce characteristic endocrine manifestations in infected patients. in addition to the classic modification of the host endocrine system by either direct or indirect destruction of the endocrine organs and/or effects exerted by systemic production of inflammatory and/or stress mediators, recent progress in molecular virology and endocrinology has revealed that virus-encoded molecules might alter the host endocrine-signaling systems by affecting extracellular and/or intracellular signal transduction and hormone sensitivity of host target tissues. here, we provide a brief overview of such viral-mediated modulation of host endocrine signaling systems. we propose that virus-encoded molecules and the signaling systems they influence are potential therapeutic targets for the treatment of disorders that are associated with some viral infections. viruses are among the simplest infective pathogens on earth. viruses cause a variety of pathological conditions of occasionally pandemic proportions, and constitute potential major threats to the human population [ ] . even after the development of vaccines, which have been tremendously effective in controlling many viral infections, viruses are still among the most common human pathogens, sometimes causing life-threatening diseases [ ] . the latter is evident from recent epidemics, such as acquired immunodeficiency syndrome (aids), caused by the human immunodeficiency virus type- (hiv- ), and severe acute respiratory syndrome (sars), caused by the sars corona virus [ , ] . replication and survival of viruses inside host cells are dependent on the cellular machinery of the host. viruses might usurp the regulation of and change host-cell functions for their benefit. indeed, through molecules encoded by viral genetic material, whose expression is synchronized with specific phases of the viral life cycle, viruses increase the chance of their own replication and survival. virusinduced alterations of host-cell functions cause a broad spectrum of cellular damage, from a transient, mild change of function to neoplastic transformation, apoptosis and necrosis. recent research has revealed that viruses, through the molecules they encode, modulate endocrine signaling systems in the host to cause characteristic changes in both endocrine organs and hormone target tissues. here, we provide a brief overview of recent progress in understanding virus-induced modifications of endocrine signaling systems and of the resultant pathological states in the host. on the basis of this understanding, potential new therapeutic targets for the development of anti-viral disease agents are envisioned. virus-induced modifications of host endocrine systems: the classic view generally, entry of viruses into and infection of host tissues evokes several levels of host reactions that might be associated with pathological manifestations. thus, infection of host tissues might damage infected organs and tissues directly. by contrast, viruses themselves and tissues that are infected with viruses might activate the host immune reaction, leading to the development of inflammatory lesions and/or the destruction of infected tissues [ ] . in addition, host immune responses induced against viruses and infected tissues might damage uninfected tissues, partly because of the similarity between viral antigens and those of host cells (molecular mimicry), and because of a systemic, generalized inflammatory reaction that results in dysfunction of multiple organs [ ] . viral-induced inflammation and viremia also activate the systemic stress response, in which the hypothalamicpituitary-adrenal (hpa) axis has a major role. secreted glucocorticoids, the end-effectors of the hpa axis, protect peripheral organs from inflammation-induced tissue damage by suppressing an overshoot of the host immune reaction and by rendering tissues resistant to toxic inflammatory agents [ ] [ ] [ ] . thus, viral infections classically induce the host reactions shown in box and figure . examples of classic host responses to viral infections are also described in table . both host-and virus-encoded molecules in the regulation of gene expression and function. numerous cell-surface molecules and nuclear hormone receptors (nrs) that transduce the signals of circulating hormones in the cytoplasm and/or the nucleus have been identified and their biological functions have been elucidated. in parallel, it has become evident that some viruses cause pathological changes because they encode molecules that affect host signaling pathways directly [ , ] and these actions sometimes cause serious clinical problems (table ) [ , ] . indeed, viruses have developed some of their unique, highly sophisticated molecules through the mutational selection of protein isoforms that increase the chance of their replication and/or survival inside infected cells, and their propagation from cell-to-cell and host-to-host. these viral molecules regularly influence crucial steps in host signaling systems and, thus, dramatically change cellular functions towards conditions that are beneficial to the replication, survival and/or propagation of the viruses that encode them. sometimes, these viral molecules mimic functions of host proteins. for example, hiv- -encoded gp molecules, which are located on the surface of the viral particle and have a major role in the entry of viruses into target cells, demonstrate amino acid sequence similarity to the growth hormone-releasing hormone (ghrh) receptor of the host and suppress the activation of this receptor by ghrh. this phenomenon might contribute to growth retardation of hiv- -infected children [ ] . this viral molecule is also similar to vasoactive intestinal peptide, which interacts with cd , a receptor for hiv- , to facilitate its entry into t cells [ , ] . the amino acid sequence of the hiv- nef protein resembles a portion of the thyroid-stimulating hormone receptor, and this crossreactivity might contribute to the development of grave's disease in hiv- -infected patients [ ] . in addition to their extracellular actions, many viral molecules act inside infected cells to modulate intracellular host signaling systems, including transcriptional regulation of target genes by hormones. these molecules are intended primarily to benefit viral replication, but, frequently, they alter the intracellular milieu, disturbing cellular functions as a 'side-effect' and causing specific, recognizable, pathological conditions [ , ] . in the following sections, examples of extracellular and intracellular modifications of host endocrine signaling systems caused by viral molecules are discussed. human t-cell leukemia (lymphotrophic) virus type (htlv- ), the single-stranded rna virus of the retroviridae family that specifically infects cd -positive t cells, is a causative agent of adult t-cell leukemia (atl) and htlv-associated myelopathy [ ] . atl patients infected with htlv- may also develop hypercalcemia because of aberrant expression of parathyroid hormone (pth)-related protein (pthrp) [ ] . pthrp is a amino acid protein that shares significant n-terminal sequence homology box . virus-induced alterations of the host endocrine system activation of the hpa axis/stress system indirectly, as a result of a general inflammatory response to the systemic viral infection and secretion of mediators of inflammation with stress systemstimulating activity. damage of virus-infected endocrine cells by viral replication, proliferation and assembly. damage of virus-infected endocrine organs by activation of the immune reaction against these organs. damage against uninfected endocrine organs through an autoimmune mechanism. alteration of hormonal activity and/or hormone secretion by viral gene products. with pth [ ] . in humans, pthrp is present in many normal and neoplastic tissues, whereas pth is present only in the parathyroid gland [ ] . leukemic cells from atl patients, as well as lymphocytes from asymptomatic htlv- -positive carriers, contain high levels of pthrp; the secreted protein exerts biological effects that are similar to those of pth because pthrp binds to the pth receptor and stimulates downstream cellular events [ ] . hence, pthrp, like pth, increases serum ca + concentrations by stimulating bone turnover and enhancing ca + absorption from the kidney and the gut [ ] . accumulating evidence indicates that the htlv- -encoded tax protein stimulates pthrp synthesis in htlv- -infected lymphocytes by activating the pthrp promoter [ ] . tax is a nuclear phosphoprotein of either or kda that is required for transactivation of the htlv- ltr and the transformation of t cells [ ] . tax does not bind dna directly but transactivates numerous cellular genes by interacting physically with host transcription factors [ ] . tax appears to stimulate the promoter activity of the gene that encodes pthrp by communicating with multiple transcription factors, including activator protein (ap ), ap , est and sp [ ] . tax forms a ternary complex with est and sp , and their binding to the pthrp promoter strongly stimulates its transcriptional activity [ ] . aggravated hypercalcemia, however, is observed most often in end-stage atl when tax expression is relatively low [ ] . mice infected experimentally with tax-defective htlv- have high levels of pthrp and develop hypercalcemia [ ] . thus, as yet unknown viral factors appear to contribute to the development of htlv- -associated hypercalcemia in addition to tax. alteration of glucocorticoid and insulin sensitivity in hiv- -infection: implications for aids-related lipodystrophy and insulin-resistance syndrome hiv- infection is associated with profound immunosuppression, muscle wasting and, occasionally, the aids-related lipodystrophy and insulin-resistance syndrome. the latter is characterized by a sometimes striking phenotype and marked metabolic disturbances, especially after addition of potent anti-hiv- treatment regimens, which have significantly improved patients' life expectancy and allowed sufficient time for the syndrome to develop [ ] . patients with this syndrome have a combination of regional lipodystrophy and characteristic redistribution of adipose tissue with accumulation of visceral, breast and nuchal fat and loss of subcutaneous fat [ , ] . the aids-related lipodystrophy and insulin-resistance syndrome is accompanied by profound dyslipidemia and either carbohydrate intolerance or overt diabetes mellitus [ ] . as the phenotypic and metabolic manifestations of the aids-related lipodystrophy and insulin-resistance syndrome are reminiscent of the typical phenotype of chronic glucocorticoid excess or cushing syndrome, this syndrome was referred to initially as a pseudo-cushing state [ ] . anti-hiv- drugs, such as nucleotide reverse transcriptase and protease inhibitors, appear to contribute to the development of this syndrome, based on the evidence that the majority of aids patients develop this syndrome after taking such compounds [ , ] . however, some patients develop the characteristic features of the syndrome before treatment, which indicates that either hiv- infection itself induces these pathological changes or that it increases the vulnerability of patients to the facilitation of expression of this syndrome by anti-viral drugs [ , ] . in this context, anti-hiv- drugs might exacerbate already present, smoldering or subclinical lipodystrophy and insulin-resistance that is masked by illness-associated wasting, in agreement with the evidence that the drug effects listed above do not explain the complete clinical picture of aids-related lipodystrophy and insulin resistance [ , ] . because the clinical picture of aids-related lipodystrophy and insulin-resistance syndrome overlaps with that of cushing syndrome, the adrenal function of patients with these syndromes has been examined, however, their hpa axis is normal [ ] . moreover, glucocorticoid receptors (grs) are present at normal concentrations on peripheral leukocytes and the affinity of these receptors for dexamethasone is similar to that of controls. therefore, biochemical hypercortisolism is not likely to be a major cause of immunosuppression, muscle wasting and aids-related lipodystrophy and insulin resistance. rather, either localized or tissue-specific hypersensitivity to glucocorticoids might be involved in these phenomena [ ] . furthermore, hypersensitivity to glucocorticoids might explain the increased vulnerability of aids patients to hhv- infections and the development of kaposi sarcoma [ ] . in agreement with these findings, one of the hiv- proteins, vpr, which is a -amino acid virion-associated accessory protein that has multiple functions (including influencing transcriptional activity and arresting the cell cycle), increases the effects of gr stimulation by several fold, functioning as a nuclear receptor coactivator in cooperation with a host cell coactivator complex containing p or its homolog creb-binding protein (cbp) [ ] [ ] [ ] [ ] . these proteins regulate many signal transduction cascades mediated by transcription factors, including nrs, crebinding protein (creb), ap- , nuclear factor-kb (nf--b) and the signal transducers and activators of transcription [ ] . p and cbp have intrinsic histone acetyltransferase activity and attract other histone acetyltransferase coactivators, such as the p /cbp-interacting factor (p/caf) and p -type nuclear receptor coactivator proteins to the transcription initiation site [ ] . thus, p /cbp act as regulatory 'platforms' for the transcription of numerous host genes, regulating transcriptional activity of many trans-acting factors and nrs (figure ). vpr contains a nr coactivator box. this is similar to those on p and p /cbp nr coactivators, potentiating the effect of ligandbound gr and p . vpr penetrates the cell membrane easily to exert its biological effects even when added in the media surrounding the cells [ ] , thus, its effects might extend to tissues that are not infected with hiv- . another hiv- accessory protein, tat, the most potent transactivator of the hiv- -ltr, also potentiates gr-induced transcriptional activity moderately, possibly through accumulation of the positive-acting transcription elongation factor b (ptefb) complex, which is comprised of the cyclin-dependent kinase and its partner molecule cyclin t, on glucocorticoid-responsive promoters [ ] . because tat, like vpr, circulates in blood and exerts its actions as either an auto/paracrine or an endocrine factor by penetrating the cell membrane [ ] , it is possible that tat modulates tissue sensitivity to glucocorticoids irrespective of whether a cell is infected with hiv- . concomitantly with vpr, tat might induce tissue hypersensitivity to glucocorticoids that might contribute to viral proliferation indirectly, by suppressing activity of the host immune system and altering the host metabolic balance, both functions governed by glucocorticoids [ ] . vpr reduces tissue sensitivity to insulin by potentiating the actions of glucocorticoids as well as by modulating the transcriptional activity of insulin ( figure ) [ , ] . insulin uses the forkhead transcription factors (foxos) to control gene induction. baseline, unphosphorylated foxos are active, reside in the nucleus and bind to their responsive sequences in the promoter region of insulin-responsive genes. by contrast, insulin activates akt kinase, which phosphorylates specific serine and threonine residues in foxos to render them inactive [ ] . indeed, once foxos are phosphorylated at specific residues, they lose their figure . linearized diagrams of (i) p , (ii) ctbp , (iii) vpr, (iv) tat, and (v) e a and their mutual-interaction domains. numerous transcription factors, transcriptional regulators and viral molecules bind the transcriptional coactivator p or its homolog cbp. binding sites of p nr coactivators and vpr overlap, and both bind nrs and p or cbp. thus, vpr mimics the host p nr coactivators and enhances nr transcriptional activity. p /cbp facilitates attraction of transcription factors, cofactors and general transcription complexes by loosening the histone-dna interaction through acetylation of histone tails by its hat domain. the n-terminal portion of ctbp interacts physically with hdac and rb, which repress transcription. ctbp regulates interaction with its binding partners by sensing nadh levels through its nad + -binding domain. e a binds to the c-terminal portion of p and associates physically with the n-terminal portion of ctbp through its c-terminal end. the hat domain of p and the nad + -binding domain of ctbp are indicated in red. this figure is based on refs [ , , ] . abbreviations: creb, cre-binding protein; hat, histone acetyltransferase; hdac , histone deacetylases ; nf-kb, nuclear factor-kb; nad, nicotinamide adenine dinucleotide; nr, nuclear hormone receptor; p/caf, p /cbp-associating factor; ptefb, positive-acting transcription elongation factor b; rb, retinoblastoma protein; sf- , steroidogenic factor- ; stat , signal transducer and activator of transcription ; tfiib, transcription factor iib. transcriptional activity, by binding to and translocating into the cytoplasm with proteins of the - - family [ ] . we have found that vpr moderately inhibits insulininduced translocation of foxo a into the cytoplasm through inhibiting its association with - - [ ] . based on these in vitro findings, vpr might be a key viral factor that induces lipodystrophy, insulin resistance and hyperlipidemia by interfering with and/or modulating cellular activities, such as transactivation of nrs and insulin [ ] . unpublished information indicates that induction of insulin resistance by vpr might be compounded by the ability of the viral protein to interfere with signal transduction by another nr, peroxisome proliferation receptor g. * paget's disease of bone and the measles virus paget's disease of bone is a chronic, focal, skeletal disorder that causes bone deformities and fractures as a result of uncoupled bone remodeling [ ] . the primary abnormality of this disease resides in the osteoclasts, which demonstrate increased capacity for bone resorption and hypersensitivity to vitamin d [ ] . immunocytochemical studies have shown that osteoclasts from patients with paget's disease of bone contain paramyxoviral-like nuclear inclusions that cross-react with antibodies to measles virus, respiratory syncytial virus and canine distemper virus nucleocapsid antigen [ ] . nucleocapsid transcripts of measles virus (mvnp), the negative single-strand rna virus of the paramyxoviridae family, have also been detected in osteoclasts from patients with paget's disease of bone [ ] . indeed, forced expression of mvnp in normal osteoclast precursor cells enhances formation of mature osteoclasts that possess many characteristics of those in patients with paget's disease, including increased sensitivity to vitamin d [ ] . transgenic expression of mvnp induces bone lesions similar to those found in paget's disease [ ] . osteoclasts that express mvnp demonstrate increased levels of tafii- , which is one of the components of the general transcriptional complexes that are attracted to the ligand-activated vitamin d receptor [ ] . thus, it is possible that paget's disease of bone might be caused, in part, by the measles virus, through its encoded molecule mvnp increasing the sensitivity of osteoclasts to vitamin d. possible alteration of endocrine system by adenovirus e a protein adenoviruses are the double strand dna viruses of the adenoviridae family. this group of viruses causes illness of the respiratory system, such as common cold syndrome, pneumonia, croup and bronchitis, as well as illnesses of other organs, such as gastroenteritis, conjunctivitis and cystitis [ ] . adenoviruses encode the e a protein, which is expressed just after infection and is necessary for the transcriptional regulation of adenovirus-encoded genes [ ] . in addition to viral genes, e a regulates the transcriptional activity of several host genes through interaction with the host transcriptional integrator p and its homologous molecule cbp ( figure ) [ , ] . in an in vitro system, e a, in contrast to vpr, blocks the actions of glucocorticoids on the transcriptional activity of genes, producing resistance to glucocorticoids [ ] . e a also interacts with the c-terminal tail-binding protein (ctbp), which functions as a transcriptional repressor of numerous transcription factors by communicating with class ii histone deacetylases and other inhibitory molecules, such as the retinoblastoma protein (rb) (figure ) [ ] . e a suppresses the activity of p /cbp and ctbp by binding to functionally crucial domains [ , ] . although there is no supportive clinical evidence, it is possible that adenovirus changes the peripheral action of circulating hormones, such as glucocorticoids and other bioactive molecules that activate nrs and directly regulate the transcriptional activity of their target genes, ultimately contributing to the pathological states observed in adenoviral infection. in , the virus that caused a newly identified illness called sars spread rapidly worldwide, causing almost deaths [ , ] . sars starts with flu-like symptoms, such as fever, myalgia, somnolence, gastrointestinal symptoms, cough and sore throat, and eventually develops into pneumonia with severe respiratory failure [ , ] . mechanical ventilation is required in $ - % of cases and the death rate is almost % [ , ] . the causative virus of this severe respiratory syndrome is the sars coronavirus (sars-cov), a positive single-strand rna virus of the coronaviridae family [ ] . subsequently, the angiotensin-converting enzyme (ace ) was identified as a cellular receptor for the entry of this virus [ ] . ace was first cloned as a homolog of ace in [ , ] . although it functions as a carboxypeptidase similar to ace, it has different substrate specificity: ace cleaves a single residue from angiotensin i (ang i) and ang ii to generate the inactive forms angiotensin ( - ) and angiotensin ( - ), respectively, whereas ace removes dipeptides from the c-terminus of ang i to produce potent, bioactive ang ii (figure ) [ ] . from mouse knockout studies, ace is a negative regulator of the rennin-angiotensin system that counterbalances the function of ace [ ] . ang ii is a potent stimulator of vascular constriction, na + uptake in the renal tubules, aldosterone secretion from the adrenal glands and vasopressin secretion from the pituitary gland [ ] . ang ii also has important roles in lung physiology and pathophysiology [ ] . indeed, ace and ang ii function as promoting factors for acute lung injury, whereas ace protects against lung injury [ ] . as sars-cov infection downregulates ace expression markedly in the lung and reduces circulating concentrations of ang ii [ ] , it is likely that sars-cov contributes to severe lung disease and other systemic complications through dysregulation of the reninÀangiotensin system. this is in contrast to other coronaviruses that infect the lung epithelium like sars-cov but cause much milder diseases [ ] . conclusions: virus-induced modulation of host signaling systems as a new therapeutic target vaccines, which stimulate the host-immune reaction to protect the organism from the entry of viruses, are the most effective, first-line therapeutics against viral infection. this approach has been extremely useful in controlling epidemics, such as those caused by smallpox, poliomyelitis, measles, influenza, varicella and rubella viruses [ ] . however, some viruses are resistant to vaccine development by conventional approaches. for example, so far, anti-hiv- vaccines have not been sufficiently effective to protect from infection by this virus, despite the tremendous efforts of the scientific community. this is possibly because of the high genetic instability of hiv- , which changes the immunogenicity [ , ] . anti-viral agents are used because vaccines are either not available or have failed to protect us. expansion of our understanding of virus-induced modifications of the host signaling systems, such as those discussed above, might prove highly beneficial for the development of new vaccines and novel anti-viral agents, based on knowledge of the potential indispensability of specific viral molecules for the entry, replication, and intracellular and extracellular survival and propagation of these viruses. indeed, this approach has been followed successfully in the development of nucleoside analogs, such as acyclovir for the herpes simplex virus and ganciclovir for cytomegalovirus, which specifically block transcription promoted by virus-encoded and virus-specific dna polymerases [ ] . oseltamivir, a neuraminidase inhibitor that blocks the influenza virusencoded neuraminidase, is effective in controlling infection by blocking the release of newly replicated viruses from the infected cells, a step in which this enzyme has a major role [ ] . thus, either vaccines or chemical compounds, including nucleotides (e.g. antisense dna and sirna) that inhibit the expression and/or function of specific viral molecules, are promising approaches for the treatment of viral illnesses. indeed, vaccines against hiv- tat are under development with promising effects [ ] . we envision that future research to further elucidate the effects of viral molecules on the host endocrine signaling systems will improve our ability to intercept viral infection and prevent virus infection-associated diseases that affect endocrine systems. and endocrine target organs. a different view of smallpox and vaccination hiv/aids epidemiology, pathogenesis, prevention, and treatment ace : from vasopeptidase to sars virus receptor immunology of viral infections molecular mimicry and immune-mediated diseases the hypothalamic-pituitary-adrenal axis and immune-mediated inflammation effectiveness of prolonged glucocorticoid treatment in acute respiratory distress syndrome: the right drug, the right way? immune modulation of the hypothalamicpituitary-adrenal (hpa) axis during viral infection adenovirus e a: remodelling the host cell, a life or death experience aids-related lipodystrophy/insulin resistance syndrome hypercalcemia, parathyroid hormone-related protein expression and human t-cell leukemia virus infection hiv gp inhibits the somatotropic axis: a possible gh-releasing hormone receptor mechanism for the pathogenesis of aids wasting perturbation of in vitro hiv pathogenic effects by peptides showing sequence similarities with the c conserved domain of gp vasoactive intestinal peptide - : a ligand for the cd (t )/human immunodeficiency virus receptor nucleotide and amino acid homology between the human thyrotropin receptor and the hiv- nef protein: identification and functional analysis glucocorticoid and mineralocorticoid resistance/hypersensitivity syndromes constitutive expression of parathyroid hormone-related protein gene in human t cell leukemia virus type (htlv- ) carriers and adult t cell leukemia patients that can be transactivated by htlv- tax gene parathyroid hormone and parathyroid hormone-related peptide, and their receptors molecular mechanisms of cellular transformation by htlv- tax interaction of human t-cell lymphotropic virus type i tax, ets , and sp in transactivation of the pthrp p promoter humoral hypercalcemia of malignancy: severe combined immunodeficient/beige mouse model of adult t-cell ace converts angiotensin i (ang i) into ang ii, which acts as a vasopressor and a mitogen for smooth muscle cells and fibroblasts through the angiotensin (at ) receptor. by contrast, ace [ ] converts ang i and ang ii into angiotensin ( - ) and angiotensin ( - ), respectively lymphoma independent of human t-cell lymphotropic virus type- tax expression metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy metabolic complications associated with antiretroviral therapy metabolic disorders among hiv-infected patients treated with protease inhibitors: a review hiv-associated lipodystrophy syndrome human immunodeficiency virus type- accessory protein vpr: a causative agent of the aids-related insulin resistance/lipodystrophy syndrome? endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy aids-related kaposi's sarcoma: evidence for direct stimulatory effect of glucocorticoid on cell proliferation partner molecules of accessory protein vpr of the human immunodeficiency virus type human immunodeficiency virus type (hiv- ) accessory protein vpr induces transcription of the hiv- and glucocorticoid-responsive promoters by binding directly to p /cbp coactivators the hiv- virion-associated protein vpr is a coactivator of the human glucocorticoid receptor hiv- protein vpr suppresses il- production from human monocytes by enhancing glucocorticoid action: potential implications of vpr coactivator activity for the innate and cellular immunity deficits observed in hiv- infection cbp/p in cell growth, transformation, and development hiv- vpr displays natural proteintransducing properties: implications for viral pathogenesis nuclear receptor coactivator p proteins enhance the hiv- long terminal repeat promoter by bridging promoter-bound factors and the tat-p-tefb complex tat-mediated delivery of heterologous proteins into cells hiv- accessory protein vpr inhibits the effect of insulin on the foxo subfamily of forkhead transcription factors by interfering with their binding to - - proteins: potential clinical implications regarding the insulin resistance of hiv- -infected patients vpr protein of human immunodeficiency virus type binds to - - proteins and facilitates complex formation with cdc c: implications for cell cycle arrest foxo proteins in insulin action and metabolism paget disease of bone measles virus rna detected in paget's disease bone tissue by in situ hybridization expression of measles virus nucleocapsid protein in osteoclasts induces paget's disease-like bone lesions in mice textbook of human virology the multifunctional role of e a in the transcriptional regulation of creb/cbp-dependent target genes ctbp, an unconventional transcriptional corepressor in development and oncogenesis severe acute respiratory syndrome (sars): development of diagnostics and antivirals a novel coronavirus associated with severe acute respiratory syndrome angiotensin-converting enzyme is a functional receptor for the sars coronavirus a novel angiotensin-converting enzymerelated carboxypeptidase (ace ) converts angiotensin i to angiotensin - a human homolog of angiotensin-converting enzyme. cloning and functional expression as a captopril-insensitive carboxypeptidase angiotensin-converting enzyme in lung diseases angiotensin-converting enzyme is an essential regulator of heart function pleiotropic at receptor signaling pathways mediating physiological and pathogenic actions of angiotensin ii a crucial role of angiotensin converting enzyme (ace ) in sars coronavirus-induced lung injury hiv pathogenesis: knowledge gained after two decades of research hiv vaccines antivirals for the treatment of herpesvirus infections neuraminidase inhibitors for influenza hiv- tat-based vaccines: from basic science to clinical trials pituitary-testicular interrelationships in mumps orchitis and other viral infections hypopituitarism as a late complication of hemorrhagic fever herpes simplex virus infections in neonates and early childhood aids/hpa axis therapeutic management of extrahepatic manifestations in patients with chronic hepatitis c virus infection autoimmunity in congenital rubella syndrome molecular mimicry, microbial infection, and autoimmune disease: evolution of the concept infection, thyroid disease, and autoimmunity viral persistence: parameters, mechanisms and future predictions selective inhibition of nuclear steroid receptor function by a protein from a human tumorigenic poxvirus this article was funded by the intramural research program of the national institute of child health and human development, national institutes of health. key: cord- -wawui fd authors: tulchinsky, theodore h.; varavikova, elena a. title: communicable diseases date: - - journal: the new public health doi: . /b - - / - sha: doc_id: cord_uid: wawui fd publisher summary in a world of rapid international transport and contact between populations, systems are needed to monitor the potential explosive spread of pathogens that may be transferred from their normal habitat. the potential for the international spread of new or reinvigorated infectious diseases constitute threat to mankind akin to ecological and other man-made disasters. public health has addressed the issues of communicable disease as one of its key issues in protecting individual and population health. methods of intervention include classic public health through sanitation, immunization, and well beyond that into nutrition, education, case finding, and treatment, and changing human behavior. the knowledge, attitudes, beliefs, and practices of policy makers, health care providers, and parents is as important in the success of communicable disease control as are the technology available and methods of financing health systems. together, these encompass the broad programmatic approach of the new public health to control of communicable diseases. important for all health providers and public health personnel so as to be able to cope with the scale of these problems and to absorb new technologies as they emerge from scientific advances and experience, and their successful application. lived. it was to be observed, indeed, that it did not come straight on toward us; for the city, that is to say within the walls, was indifferently healthy still; nor was it got over the water into southwark; for though there died that week , of all distempers, whereof it might be supposed above died of the plague, yet there was but in southwark, lambeth parish included; whereas in the parishes of st. giles the agent-host-environment triad, discussed in chapter , is fundamental to the success of understanding transmission of infectious diseases and their control, including those well known, those changing their patterns, and those newly emerging or escaping current methods of control. infection occurs when the organism successfully invades the host body, where it multiplies and produces an illness. a host is a person or other living animal, including birds and arthropods, who provides a place for growth and sustenance to an infectious agent under natural, as opposed to experimental, conditions. some organisms, such as protozoa or helminths, may pass successive stages of their life cycle in different hosts, but the primary or definitive host is the one in which the organism passes its sexual stage. the secondary or intermediate host is where the parasite passes the larval or asexual stage. a transport host is a carrier in which the organism remains alive, but does not develop. an agent of an infectious disease is necessary, but not always sufficient to cause a disease or disorder. the infective dose is the quantity of the organism needed to cause clinical disease. a disease may have a single agent as a cause, or it may occur as a result of the agent in company with contributory factors, whose presence is also essential for the development of the disease. a disease may be present in an infected person in a dormant form such as tuberculosis, or a subclinical form, such as poliomyelitis or hiv. the virulence or pathogenicity of an infective agent is the capacity of an infectious agent to enter the host, replicate, damage tissue, and cause disease in an exposed and susceptible host. virulence is indicated by the severity of clinical disease and case fatality rates. the environment provides a reservoir for the organism, and the mode of transmission, by which the organism reaches a new host. the reservoir is the natural habitat where an infectious agent lives and multiplies, from which it can be transmitted directly or indirectly to a new host. the reservoir refers to the natural habitat of the organism, which may be in people, animals, arthropods, plants, soil, or substances in which an organism normally lives and multiplies, and on which it depends for survival or in which it survives in a dormant form. contacts are persons or animals who have been in association with an infected person, animal, or contaminated inanimate object, or environment that might provide an opportunity for acquiring the infective agent. persons or animals that harbor a specific infectious agent, often in the absence of discernible clinical disease, and who serve as a source of infection or contamination of food, water, or other materials, are carriers. a carrier may have an inapparent infection (a healthy cartier) or may be in the incubation or convalescent stage of the infection. communicable diseases may be classified by a variety of methods: by organism, by mode of transmission, by methods of prevention (e.g., vaccine preventable, vector controllable), or by major organism classification, that is, viral, bacterial, and parasitic disease. a virus is a nucleic acid molecule (rna or dna) encapsulated in a protein coat or capsid. the virus is not a complete cell and can only replicate inside a complete cell. the capsid may have a protective envelope of a lipid containing membrane. the capsid and membrane facilitate attachment and penetration of a host cell. inside the host cell, the nucleic molecule may cause the cell's chromosomes to be changed in its own genetic material or so that there is cellular manufacture and virus replication. viroids are smaller rna structures without capsids which can cause plant disease. prions are recently discovered (stanley prusiner, nobel prize, ) variants of viruses or viroids which are the infective agents cause of scrapie in sheep, and similar degenerative central nervous system diseases in cattle and in man (mad cow disease or creutzfeld-jakob disease in humans). bacteria are unicellular organisms that reproduce sexually or asexually, grow on cell-free media, and can exist in an environment with oxygen (aerobic) or in one lacking oxygen (anaerobic). some may enter a dormant state and form spores where they are protected from the environment and may remain viable for years. bacteria include a nucleus of chromosomal dna material within a membrane surrounded by cytoplasm, itself enclosed by the cellular membrane. bacteria are often characterized by their coloration under gram's stain, as gram-negative or gram-positive, as well as by their microscopic morphology, colony patterns on growth media, by the diseases they may cause, as well as by antibody and molecular (dna) marking techniques. bacteria include both indigenous flora (normal resident) bacteria and pathogenic (disease causing) bacteria. pathogenic bacteria cause disease by invading, overcoming natural or acquired resistance, and multiplying in the body. bacteria may produce a toxin or poison that can affect a body site distant from where the bacterial replication occurs, such as in tetanus. bacteria may also initiate an excessive immune response, producing damage to other body tissues away from the site of infection, e.g;, acute rheumatic fever and glomerulonephritis. parasitology studies protozoa, helminths, and arthropods that live within, on, or at the expense of a host. these include oxygen-producing, flagellate, unicellular organisms such as giardia and trichomonas, and amoebas such as entamoeba important in enteric and gynecologic disorders. sporozoa are parasites with complex life cycles in different hosts, such as cryptosporidium or malarial parasites. parasitic disease usually refers to infestation, with fungi, molds, and yeasts that can affect humans. helminths are worms that infest humans especially in poor sanitation and tropical areas. transmission of diseases is by the spread of an infectious agent from a source or reservoir to a person (table . ). direct transmission from one host to another occurs during touching, biting, kissing, sexual intercourse, and projection via droplets, as in sneezing, coughing, or spitting, or by entry through the skin. indirect transmission includes via aerosols of long-lasting suspended particles in air, fecal-oral transmission such as food and waterborne as well as by poor hygenic conditions with inanimate materials, such as soiled clothes, handkerchiefs, toys, or other objects. vector-borne diseases are transmitted via crawling or flying insects, in some cases with multiplication, and development of the organism in the vector, as in malaria. the subsequent transmission to humans is by injection of salivary gland fluid during biting, e.g., congenital syphilis, or by deposition of feces, urine or other material capable of penetrating the skin through a bite wound or other trauma. transmission may occur with insects as a transport mechanism, as in salmonella on the legs of a housefly. airborne transmission occurs inderectly via infective organisms in small aerosols that may remain suspended for long periods of time and which easily enter the respiratory tract. small particles of dust may spread organisms from soil, clothing, or bedding. vertical transmission occurs from one generation to another, or from one stage of the insect life cycle to another stage. maternal-infant transmission occurs during pregnancy (transplacental), delivery, as in gonorrhoea, breast-feeding, e.g., hiv, with transfer of infectious agents from mother to fetus or newborn. resistance to infectious diseases is related to many host and environmental factors, including age, sex, pregnancy, nutrition, trauma, fatigue, living and socioeconomic conditions, and emotional status. good nutritional status has a protective effect against the results of an infection. vitamin a supplements reduce complication rates of measles and enteric infections. tuberculosis may be present in an individual whose resistance is sufficient to prevent clinical disease, but the infected person is a cartier of an organism which can be transmitted to another or cause clinical disease if the person's susceptibility is reduced. immunity is resistance to infection resulting from presence of antibodies or cells that specifically act on the microorganism associated with a specific disease or toxin. immunity to a specific organism can be acquired by having the disease, that is, natural immunity, or by immunization, active or passive, or by protection box . vaccines and prevention "the greeks had two gods of health, aesculapius and hygeia, therapy and prevention, respectively. medicine in the twentieth century retains those two concepts, and vaccination is a powerful means of prevention. what follows is information on the vaccines that together with sanitation, make modem society possible, and that if wisely used will continue to bestow on mankind the gift of prevention, which according to proverb is worth far more than cure." source: plotkin, s. a., mortimer, e. a. . vaccines. second edition. philadelphia: wb saunders (with permission). infectious agent: a pathogenic organism (e.g., virus, bacteria, rickettsia, fungus, protozoa, or helminth) capable of producing infection or an infectious disease. infection: the process of entry, development, and proliferation of an infectious agent in the body tissue of a living organism (human, animal, or plant) overcoming body defense mechanisms, resulting in an inapparent or clinically manifest disease. antigen: a substance (e.g., protein, polysaccharide) capable of inducing specific response mechanisms in the body. an antigen may be introduced into the body by invasion of an infectious agent, by immunization, inhalation, ingestion, or through the skin, wounds, or via transplantation. antibody: a protein molecule formed by the body in response to a foreign substance (an antigen) or acquired by passive transfer. antibodies bind to the specific antigen that elicits its production, causing the infective agent to be susceptible to immune defense mechanisms against infections e.g., humoral and cellular. immunoglobulins: antibodies that meet different types of antigenic challenges. they are present in blood or other body fluids, and can cross from a mother to fetus in utero, providing protection during part of the first year of life. there are five major classes (igg, igm, iga, igd, and ige) and subclasses based on molecular weight. anfisera or antitoxin: materials prepared in animals for use in passive immunization against infection or toxins. source: jawetz, melrick, and adelberg, medical microbiology, . through elimination of circulation of the organism in the community. immunity may be by antibodies produced by the host body or transferred from externally produced antibodies. the body also reacts to infective antigens by cellular responses, including those that directly defend against invading organisms and other cells which produce antibodies. the immune response is the resistance of a body to specific infectious organisms or their toxins provided by a complex interaction of antibodies and cells including a. b cells (bone marrow and spleen) produce antibodies which circulate in the blood, i.e., humoral immunity; b. t cell-mediated immunity is provided by sensitization of lymphocytes of thymus origin to mature into cytotoxic cells capable of destroying virusinfected or foreign cells; c. complement, a humoral response which causes lysis of foreign cells; d. phagocytosis, a cellular mechanism which ingests foreign microorganisms (macrophages and leukocytes). surveillance of disease is the continuous scrutiny of all aspects of occurrence and spread of disease pertinent to effective control of that disease. maintaining ongoing surveillance is one of the basic duties of a public health system, and is vital to the control of communicable disease, providing the essential data for tracking of disease, planning interventions, and responding to future disease challenges. surveillance of infectious disease incidence relies on reports of notifiable diseases by physicians, supplemented by individual and summary reports of public health laboratories. such a system must concern itself with the completeness and quality of reporting and potential errors and artifacts. quality is maintained by seeking clinical and laboratory support to confirm first reports. completeness, rapidity, and quality of reporting by physicians and laboratories should be emphasized in undergraduate and postgraduate medical education. enforcement of legal sanctions may be needed where standards are not met. surveillance of infectious diseases includes the following: . morbidity reports from clinics to public health offices; . mortality reports from attending doctors to vital records; . reports from selected sentinel centers; . special field investigations of epidemics or individual cases; . laboratory monitoring of infectious agents in population samples; . data on supply, use, and side effects of vaccines, toxoids, immune globulins; . data on vector control activities such as insecticides use; . immunity levels in samples of the population at risk; . review of current literature on the disease; . epidemiologic and clinical reports from other jurisdictions. epidemiologic monitoring based on individual and aggregated reports of infectious diseases provide data vital to planning interventions at the community level or for the individually exposed patient and his contacts, along with other information sources such as hospital discharge data and monitoring of sentinel centers. these may be specific medical or community sites that are representative of the population and are able to provide good levels of reporting to monitor an area or population group. a sentinel center can be a pediatric practice site, a hospital emergency room, or other location which will provide a "finger on the pulse" to assess the degree and kind of morbidity occurring in the community. it can also include monitoring in a location previously known for disease transmission, such as hong kong in relation to influenza. epidemiologic analysis provided by government public health agencies should be published weekly, monthly, and annually and distributed to a wide audience of public health and health-related professionals throughout the country. feedback to those in the field on whose initial reports the data are based is vital in order to promote involvement and improved quality of data, as well as to allow evaluation of the local situation in comparison to other areas. in a federal system of government, national agencies report regularly on all state or provincial health patterns. state or provincial health authorities provide data to the counties and cities in their jurisdictions. such data should also be readily available to researchers in other government agencies, universities, and other academic settings for further research and analysis both on internet and hard-copy publications. notifiable diseases are those which a physician is legally required to report to state or local public health officials, by reason of their contagiousness, severity, frequency, or other public health importance (table . ). public health laboratory services provide validation of clinical and epidemiologic reports. they also pro- vide day-to-day supervision of public health conditions, and can monitor communicable disease and vaccine efficacy and coverage. in addition, they support standards of clinical laboratories in biochemistry, microbiology, and genetic screening. nosocomial or hospital-acquired infections constitute a major health hazard associated with care in institutions. in the united states, they occur in - % of hospital admissions and are the cause of lengthening of hospital stay and an estimated , deaths per year. in developing countries, nosocomial infection rates may occur in up to % of hospitalizations. this category of infectious disease most commonly includes infections of the urinary tract, surgical wounds, lower respiratory tract (pneumonias), and blood poisoning or septicemias. in the united states, up to % of hospital-acquired infections are caused by multidrug resistant organisms. staphylococcus infections resistant to many current antibiotics, for example, methicillin and vancomycin, are a notable cause of prolongation of hospitalization or even death. the increasing number of immunodeficient patients has increased the importance of prevention of nosocomial infections. where standards of infection control are lacking, in both developed and developing countries, hospital staff are vulnerable to serious infection. in developing countries, deadly new viruses, such as ebola and marburg viruses mainly affect nursing, medical, and other staff as secondary cases. surveillance and control measures are important elements of hospital management. hospital epidemiologists and infection control staff are part of modem hospital staffing. the cost to the health system of nosocomial infections is a major consideration in planning health budgets. reducing the risk of acquiring such infections in hospital justifies substantial expenditures for hospital epidemiology and infection control activities. with diagnostic related group payment for hospital care (by diagnosis rather than by days of stay) the good manager has a major incentive to ensure that the risk of nosocomial infections is minimized, since they can greatly prolong hospital stays, raising patient dissatisfaction and health care costs. an endemic disease is the constant usual presence of a disease or infectious agent in a given geographic area or population group. hyperendemic is a state of persistence of high levels of incidence of the disease. holoendemic means that the disease appears early in life and affects most of the population, as in malaria or hepatitis a and b in some regions. an epidemic is the occurrence in a community or region of a number of cases of an illness in excess of the usual or expected number of cases. the number of cases constituting an epidemic varies with the disease, and factors such as previous epidemiological patterns of the disease, time and place of the occurrence, and the population involved must be taken into account. a single case of a disease long absent from an area, such as polio, constitutes an epidemic, and therefore a public health emergency because a clinical case may represent a hundred carriers with nonparalytic or subclinical poliomyelitis. in the s, two to three or more cases of measles linked in time and place may be considered sufficient evidence of transmission and presumed to be an epidemic. a pandemic is occurrence of a disease over a very wide area, crossing international boundaries, affecting a large proportion of the population. each epidemic should be regarded as a unique natural experiment. the investigation of an epidemic requires preparation and field investigation in conjunction with local health and other relevant authorities. verification of cases and the scope of the epidemic will require case definition and laboratory confirmation. tabulation of known cases according to time, place, and person are important for immediate control measures and formulation of the hypothesis as to the nature of the epidemic. an epidemic curve is a graphic plotting of the distribution of cases by the time of onset or reporting, which gives a picture of the timing, spread, and extent of the disease from the time of the initial index cases and the secondary spread. epidemic investigation requires a series of steps. this starts with confirmation of the initial report and preliminary investigation, defining who is affected, determining the nature of the illness and confirming the clinical diagnosis, and recording when and where the first (index) and follow-up (secondary) cases occurred, and how the disease was transmitted. samples are taken from index case patients (e.g., blood, feces, throat swabs) as well as from possible vectors (e.g., food, water, sewage, environment). a working hypothesis is established based on the first findings, taking into account all plausible explanations. the epidemic pattern is studied, establishing common source or risk factors, such as food, water, contact, environment, and drawing a time line of cases to define the epidemic curve. how many are ill (the numerator) and what is the population at risk (the denominator) establish the attack rate, namely, the percentage of sick among those exposed to the common factor. what is a reasonable explanation of the occurrence; is there a previous pattern, with the present episode a recurrence or new event? consultation with colleagues and the literature helps to establish both a biological and epidemiologic plausibility. what steps are needed to prevent spread and recurrence of the disease? coordination with relevant health and other officials and providers is required to establish surveillance and control systems, document and distribute reports, and respond to the public's fight to know. the first reports of excess cases may come from a medical clinic or hospital. the initial (sentinel or index) cases provide the first clues that may point to a common source. investigation of an epidemic is designed to quickly elucidate the cause and points of potential intervention to stop its continuation. this requires skilled investigation and interpretation. epidemiologic investigations have defined many public health problems. rubella syndrome, legionnaire's disease, aids, and lyme and hantavirus diseases were first identified clinically when unusually large numbers of cases appeared with common features. the suspicions that were raised led to a search for causes and the identification of control methods. a working hypothesis of the nature of an epidemic is developed based on the initial assessment, the type of presentation, the condition involved, and previous local, regional, national, and international experience. the hypothesis provides the basis for further investigation, control measures, and planning additional clinical and laboratory studies. surveillance will then monitor the effectiveness of control measures. communication of findings to local, regional, national, and international health reporting systems is important for sharing the knowledge with other potential support groups or other areas where similar epidemics may occur. the centers for disease control and prevention (cdc), originally organized in as the office for malaria control in war areas, is part of the u.s. public health service. as of , the cdc had a budget of $ . billion, and employees include epidemiologists, microbiologists, and many other professionals. the cdc includes national centers for environmental health and injury control, chronic disease prevention and health promotion, infectious diseases, prevention services, health statistics, occupational safety and health, and international health. the epidemic intelligence service (eis) of the cdc in the united states is an excellent model for the organization of the national control of communicable diseases. young clinicians are trained to carry out epidemiologic investigations as part of training to become public health professionals. eis officers are assigned to state health departments, other public health units, and research centers as part of their training, carrying out epidemic investigation and special tasks in disease control. the cdc, in cooperation with the who, has developed and offers free of charge, a personal computer program to support field epidemiology, including epidemic investigations (epi-info), which can be accessed and down-loaded from the worldwide web. this program should be adopted widely in order to improve field investigations, to encourage reporting in real time, and to develop high standards in this discipline. cdc's morbidity and mortality weekly report (mmwr) is a weekly publication of the cdc's epidemiologic data, also available free on the internet. it includes special summaries of reportable infectious diseases as well as noncom- although an infectious disease is an event affecting an individual, it is communicable to others, and therefore its control requires both individual and community measures of protection. control of the disease is a reduction in its incidence, prevalence, morbidity, and mortality. elimination of a disease in a specified geographic area may be achieved as a result of intervention programs such as individual protection against tetanus; elimination of infections such as measles requires stoppage of circulation of the organism. eradication is success in reduction to zero of incidence of the disease and presence in nature of the organism, such as with smallpox. extinction means that a specific organism no longer exists in nature or in laboratories. public health applies a wide variety of tools for the prevention of infectious diseases and their transmission. it includes activities ranging from filtration and disinfection of community drinking water to environmental vector control, pasteurization of milk, and immunization programs (see table . ). no less important are organized programs to promote self protection, case finding, and effective treatment of infections to stop their spread to other susceptible persons (e.g., hiv, sexually transmitted diseases, tuberculosis, malaria). planning measures to control and eradicate specific communicable diseases is one of the principal activities of public health and remains so for the twenty-first century. treating an infection once it has occurred is vital to the control of a communicable disease. each person infected may become a vector and continue the chain of transmission. successful treatment of the infected person reduces the potential for an uninfected contact person to acquire the infection. bacteriostatic agents or drugs such as sulfonamides inhibit growth or stop replication of the organism, allowing normal body defenses to overcome the organism. bacteriocidal drugs such as penicillin act to kill pathogenic organisms. traditional medical emphasis on single antibiotics has changed to use of multiple drug combinations for tuberculosis and more recently for hospital-acquired infections. antibiotics have made enormous contributions to clinical medicine and public health. however, pathogenic organisms are able to adapt or mutate and develop resistance to antibiotics, resulting in drug resistance. wide-scale use of antibiotics has led to increasing incidence of resistant organisms. multidrug resistance constitutes one of the major public health challenges at the end of the twentieth century. antiviral agents (e.g., ribovarin) are important additions to medical treatment potential, as are "cocktails" of antiviral agents for management of hiv infection. antibiotic use is a health problem requiting attention of clinicians and their teachers as well as the public health community and health care managers, representing the interaction of health issues across the entire spectrum of services. organized public health services are responsible for advocating legislation and for regulating and monitoring programs to prevent infectious disease occurrence and/or spread. they function to educate the population in measures to reduce or prevent the spread of disease. health promotion is one of the most essential instruments of infectious disease control. it promotes compliance and community support of preventive measures. these include personal hygiene and safe handling of water, milk, and food supplies. in sexually transmitted diseases, health education is the major method of prevention. each of the infectious diseases or groups of infectious diseases have one or more preventive or control approaches (table . ). these may involve the coordinated intervention of different disciplines and modalities, including epidemiologic monitoring, laboratory confirmation, environmental measures, immunization, and health education. this requires teamwork and organized collaboration. very great progress has been made in infectious disease control by clinical, public health, and societal means since in the industrialized countries and since the s in the developing world. this is attributable to a variety of factors, including organized public health services; the rapid development and wide use of new and improved vaccines and antibiotics; better access to health care; and improved sanitation, living conditions, and nutrition. triumphs have been achieved in the eradication of smallpox and in the increasing control of other vaccine-preventable diseases. however, there remain serious problems with tb, stds, malaria, and new infections such as hiv, and an increase in multiple drug-resistant organisms. vaccines are one of the most important tools of public health in the control of infectious diseases, especially for child health. vaccine-preventable diseases ta b l e . annual incidence of selected vaccine-preventable infectious diseases in rates per , population selected years, united states, - disease the body responds to invasion of disease-causing organisms by antigenantibody reactions and cellular responses. together, these act to restrain or destroy the disease-causing potential. strengthening this defense mechanism through im-box . definitions of immunizing agents and processes vaccines: a suspension of live or killed microorganisms or antigenic portion of those agents presented to a potential host to induce immunity to prevent the specific disease caused by that organism. preparation of vaccines may be from: a. live attenuated organisms which have been passed repeatedly in tissue culture or chick embryos so that they have lost their capacity to cause disease but retain an ability to induce antibody response, such as polio-sabin, measles, rubella, mumps, yellow fever, bcg, typhoid, and plague. b. inactivated or killed organisms which have been killed by heat or chemicals but retain an ability to induce antibody response; they are generally safe but less efficacious than live vaccines and require multiple doses, such as polio-salk, influenza, rabies, and japanese encephalitis. c. cellular fractions usually of a polysaccharide fraction of the cell wall of a disease-causing organisms, such as pneumococcal pneumonia or meningococcal meningitis. d. recombinant vaccines produced by recombinant dna methods in which specific dna sequences are inserted by molecular engineering techniques, such as dna sequences spliced to vaccinia virus grown in cell culture to produce influenza and hepatitis b vaccines. toxoids or antisera: modified toxins are made nontoxic to stimulate formation of an antitoxin, such as tetanus, diphtheria, botulism, gas gangrene, and snake and scorpion venom. immune globulin: an antibody-containing solution derived from immunized animals or human blood plasma, used primarily for short-term passive immunization, e.g., rabies, for immunocompromised persons. antitoxin: an antibody derived from serum of animals after stimulation with specific antigens and used to provide passive immunity, e.g., tetanus. munization is one of the outstanding achievements of public health, as treatment of infectious diseases by antimicrobials is a major element of clinical medicine. immunization (vaccination) is a process used to increase host resistance to specific microorganisms to prevent them from causing disease. it induces primary and secondary responses in the human or animal body: a. primary response occurs on first exposure to an antigen. after a lag or latent period of - days (depending on the antigen) specific antibodies appear in the blood. antibody production ceases after several weeks but memory cells that can recognize the antigen and respond to it remain ready to respond to a further challenge by the same antigen. b. secondary (booster) response is the response to a second and subsequent exposure to an antigen. the lag period is shorter than the primary response, the peak is higher and lasts longer. the antibodies produced have a higher affinity for the antigen, and a much smaller dose of the antigen is required to initiate a response. c. immunologic memory exists even when circulating antibodies are insufficient to protect against the antigen. when the body is exposed to the same antigen again, it responds by rapidly producing high levels of antibody to destroy the antigen before it can replicate and cause disease. immunization protects susceptible individuals from communicable disease by administration of a living modified agent, or subunit of the agent, a suspension of killed organisms or an inactivated toxin (see table . ) to stimulate development of antibodies to that agent. in disease control, individual immunity may also protect another individual. herd immunity occurs when sufficient persons are protected (naturally or by immunization) against a specific infectious disease reducing circulation of the organism, thereby lowering the chance of an unprotected person to become infected. each pathogen has different characteristics of infectivity, and therefore different levels of herd immunity are required to protect the nonimmune individual. the critical proportion of a population that must be immunized in order to interrupt local circulation of the organism varies from disease to disease. eradication of smallpox was achieved with approximately % world coverage, followed by concentration on new case findings and immunization of contacts and surrounding communities. for highly infectious diseases, such as measles, immunization coverage of over % is needed to achieve local eradication. immunization coverage in a community must be monitored in order to gauge the extent of protection and need for program modification to achieve targets of disease control. immunization coverage is expressed as a proportion in which the numerator is the number of persons in the target group immunized at a specific age, and the denominator is the number of persons in the target cohort who should have been immunized according to the accepted standard: vaccine coverage = no. persons immunized in specific age group • no. persons in the age group during that year immunization coverage in the united states is regularly monitered by the national immunization survey by a household survey in all states, as well as selected urban areas considered to be at high risk for undervaccination. an initial telephone survey is followed by confirmation, where possible, from documentation from the parents or health care providers. the survey for july -june examined children born between august and november (i.e., aged - months, median age months). the results show improving coverage, with % having received three or more doses of dpt (diphtheria, pertussis, and tetanus), % with three or more doses of opv (oral polio vaccine), % with three or more doses of haemophilus influenzae, type b (hib), but only % with three or more doses of hepatitis b. however, only % had received all recommended vaccines at the recommended ages. eases that still cause millions of deaths globally each year. other important infectious diseases are still not subject to vaccine control because of difficulties in their development. in some cases, a microorganism can mutate with changes. viruses can undergo antigenic shifts in the molecular structure in the organism, producing completely new subtypes of the organism. hosts previously exposed to other strains may have little or no immunity to the new strains. antigenic drift refers to relatively minor antigenic changes which occur in viruses. this is responsible for frequent epidemics. antigenic shift is believed to explain the occurrence of new strains of influenza virus necessitating, for example, annual reformulation of the influenza vaccine associated with large scale epidemics and pandemics. new variants of poliovirus strains are similar enough to the three main types so that immunity to one strain is carded over to the new strain. molecular epidemiology is a powerful new technique used to specify the geographic origin of organisms such as poliomyelitis and measles viruses, permiting tracking of the source of the virus and epidemic. combinations of more than one vaccine is now common practice with a trend to enlarging the cocktail of vaccines in order to minimize the number of injections, and visits required. this reduces the number of visits to carry out routine immunization saving staff time and costs, as well as increasing compliance. there are virtually no contraindications to use of multiple antigens simultaneously. examples of vaccine cocktails include dpt (diphtheria, pertussis, and tetanus) in combination with haemophilus influenzae b, poliomyelitis, and varicella, or mmr (measles, mumps, and rubella) vaccines. interventions in the form of effective vaccines save millions of lives each year and contribute to improved health of countless children and adults throughout the world. vaccination is now accepted as one of the most cost-effective health interventions currently available. continuous policy review is needed regarding allocation of adequate resources, logistical organization, and continued scientific effort to seek effective, safe, and inexpensive vaccines for other important diseases such as malaria and hiv. new technology of recombinant vaccines, such as that of hepatitis b, holds promise for important vaccine breakthroughs in the decades ahead. internationally, much progress was made in the s in the control of vaccinepreventable diseases. at the end of the s, fewer than % of the world's children were being immunized. who, unicef, and other international organizations mobilized to promote an expanded programme on immunization (epi) with a target of reaching % coverage by . immunization coverage increased in the developing countries, preventing some million child deaths annually. bacillus calmette-gu rin (bcg) coverage rose from to %; poliomyelitis with opv (three doses) from to %, and tetanus toxoid for pregnant women from to %. since , there has been a decline in coverage in some parts of the world, mainly in sub-saharan africa. the challenge remains to achieve control or eradication of vaccine-preventable diseases, thus saving millions of more lives. part of the hfa stresses the epi approach, which includes immunization against diphtheria, pertussis, tetanus, po-liomyelitis, measles, and tuberculosis. an extended form of this is the epi plus program which combines epi with immunization against hepatitis b and yellow fever and, where appropriate, supplementation with vitamin a and iodine. the success in international eradication of smallpox is now being followed by a campaign to eradicate poliomyelitis and other important infectious diseases. diphtheria. diphtheria is an acute bacterial disease of the tonsils, nasopharynx, and larynx caused by the organism corynebacterium diphtheriae. it occurs in colder months in temperate climates where the organism is present in human hosts and is spread by contact with patients or carriers. it has an incubation period of - days. in the past, this was primarily an infection of children and was a major contributor to child mortality in the prevaccine and preantibiotic eras. diphtheria has been virtually eliminated in countries with well-established immunization programs. in the s, an outbreak of diphtheria occurred in the countries of the former soviet union among people over age . it reached epidemic proportions in the s, with , cases ( - ) with deaths in in russia alone. this indicates a failure of the vaccination program in several respects: it used only three doses of dpt in infancy; no boosters were given at school age or subsequently; the efficacy of diphtheria vaccine may have been low, and coverage was below %. efforts to control the present epidemic include mass vaccination campaigns for persons over years of age with a single dose of dt (diphtheria and tetanus) and increasing coverage of routine dpt vaccines to four doses by age years. the epidemic and its control measures have led to improved coverage with dt for those over years, and % coverage among children aged - months. who recommends three doses of dpt in the first year of life and a booster at school entry. this is considered by many to be insufficient to produce long-lasting immunity. the united states and other industrialized countries use a four-dose schedule and recommend periodic boosters for adults with dt. pertussis. pertussis is an acute bacterial disease of the respiratory tract caused by the bacillus bordetella pertussis. after an initial coldlike (catarrhal) stage, the patient develops a severe cough which comes in spasms (paroxysms). the disease can last - months. the paroxysms can become violent and may be followed by a characteristic crowing or high pitched inspiratory whooping sound, followed by expulsion of a tenacious clear sputum, often followed by vomiting. in poorly immunized populations and those with malnutrition, pneumonia often follows and death is common. pertussis declined dramatically in the industrialized countries as a result of widespread coverage with dpt. however, because the pertussis component of the vaccine caused some reactions, many physicians avoided its use, using dt alone. during the s in the united kingdom, many physicians recommended against vaccination with dpt. as a result, pertussis incidence increased with substantial mortality rates. this led to a reappraisal of the immunization program, with insti-tution of incentive payments to general practitioners for completion of vaccination schedules. as a result of these measures, vaccination coverage, with resulting pertussis control, improved dramatically in the united kingdom. pertussis continues to be a public health threat and recurs wherever there is inadequate immunization in infancy. a new acellular vaccine is ready for widespread use and will be safer with fewer and less severe reactions in infants, increasing the potential for improved confidence and support for routine vaccination. use of the new vaccine is spreading in the united states and forms part of the u.s. recommended vaccination schedule. tetanus. tetanus is an acute disease caused by an exotoxin of the tetanus bacillus (clostridium tetani) which grows anaerobically at the site of an injury. the bacillus is universally present in the environment and enters the human body via penetrating injuries. following an incubation period of - days, it causes an acute condition of painful muscular contractions. unless there is modem medical care available, patients are at risk of high case fatality rates of - % (highest in infants and the elderly). antitetanus serum (ats) was discovered in and during world war i, ats contributed to saving the lives of many thousands of wounded soldiers. tetanus toxoid was developed in . the organism, because of its universal presence in the environment, cannot be eradicated. however, the disease can be controlled by effective immunization of every child during infancy and school age. adults should receive routine boosters of tetanus toxoid once very decade. newborns are infected by tetanus spores (tetanus neonatorum) where unsanitary conditions or practices are present. it can occur when traditional birth attendants at home deliveries use unclean instruments to sever the umbilical cord, or dress the severed cord with contaminated material. tetanus neonatorum remains a serious public health problem in developing countries. immunization of pregnant women and women of childbearing age is reducing the problem by conferring passive immunity to the newborn. the training of traditional birth attendants in hygienic practice and the use of medically supervised birth centers for delivery also decreases the incidence of tetanus neonastorum. elimination of tetanus neonatorum by the year was made a health target by the world summit of children in . in that year, the number of deaths from neonatal tetanus was reported by unicef as , infants worldwide, declining to , in . immunization of pregnant women increased from under % in to % in - . despite progress, coverage is still too low to achieve the target of elimination. poliomyelitis. polio virus infection may be asymptomatic or cause an acute nonspecific febrile illness. it may reach more severe forms of aseptic meningitis and acute flaccid paralysis with long-term residual paralysis or death during the acute phase. poliomyelitis is transmitted mainly by direct person-to-person contact, but also via sewage contamination. large-scale epidemics of disease, with attendant paralysis and death, occurred in industrialized countries in the s and s, engendering widespread fear and panic and thousands of clinical cases of "infantile paralysis". growth of the poliovirus by john enders and colleagues in tissue culture in led to development of the first inactivated polio vaccine by jonas salk in the mid- s and gave hope and considerable success in the control of the disease. the development of the live attenuated oral poliomyelitis vaccine by albert sabin, licensed in , added a new dimension to its control because of the effectiveness, low cost, and ease of administration of the vaccine. the two vaccines in their more modern forms, enhanced strength inactivated polio vaccine (eipv), and triple oral polio vaccine (topv), have been used in different settings with great success. oral polio vaccine (opv) induces both humoral and cellular, including intestinal, immunity. the presence of opv in the environment by contact with immunized infants and via excreta of immunized persons in the sewage gives a booster effect in the community. immunization using opv, in both routine and national immunization days (nids) has proven effective in dramatically reducing poliomyelitis and circulation of the wild virus in many parts of the world. use of the enhanced strength ipv (eipv) produces early and high levels of circulating antibodies, as well as protecting against the vaccine-associated disease. in rare cases opv can cause vaccine-associated paralytic poliomyelitis (vapp), with a risk of case per , with initial doses, and case per over million with subsequent doses. approximately eight to ten cases of vapp occur annually in the united states, with clinical, ethical, and legal implications. use of ipv as initial protection eliminates this problem. experience in gaza and the west bank in the s and s, and later in israel, showed that a combination of ipv and opv is effective in overcoming endemic and imported poliovirus. opv requires multiple doses to achieve protective antibody levels. where there are many enteroviruses in the environment, as is the case in most developing countries, interference in the uptake of opv may result in cases of paralytic poliomeylitis among persons who have received or even doses of adequate opv. controversy as to the relative advantages of each vaccine continues. the opv program of mass repeated vaccination in control of poliomyelitis in the americas established the primacy of opv in practical public health, and the momentum to eradicate poliomyelitis is building. a combined schedule of ipv and opv would eliminate the wild virus and protect against vaccine-associated disease. the sequential use of ipv and opv was adopted as part of the routine infant immunization program in the united states in , but ipv alone was adopted in . there are concerns that exclusive use of either vaccine alone will not lead to the desired goal of eradication of polyomyelitis. progress in global eradication of polio has been impressive. global coverage of infants with three doses of opv reached % in as compared to % in . the african region of who had an increase in opv coverage from % in to % in . national immunization days (nids) were conducted in countries in and in , covering million children in . mopping up operations to reinforce coverage of children in still endemic areas is proceeding along with increased emphasis on acute flaccid paralysis (afp) monitoring. confirmed polio cases reported continued at - , per year in - . with continued national and international emphasis, and support of who, rotary international, unicef, donor countries, and others, there is a real prospect of a world without polio, if not by the year , then or shortly thereafter. measles is an acute disease caused by a virus of the paramyxovirus family. it is highly infectious with a very high ratio of clinical to subclinical case ratio ( / ). measles has a characteristic clinical presentation with fever, white spots (koplik spots) on the membranes of the mouth, and a red blotchy rash appearing on the rd- th day lasting - days. mortality rates are high in young children with compromised nutritional status, especially vitamin a deficiency. the measles virus evolved from a virus disease of cattle (rinderpest) some - years ago, becoming an important disease of humans with high mortality rates in debilitated, poorly nourished children, and significant mortality and morbidity even in industrialized countries. in the prevaccine era, measles was endemic worldwide, and even in the late s it remains one of the major childhood infectious diseases. it is one of the commonest causes of death for school age children worldwide. despite earlier predictions that measles deaths would be halved to , by , who reported . million measles deaths in that year and over million in . eradication in the first decade of the next century is a feasible goal, provided that there is an adequate international effort. measles immunization increased from under % worldwide in to % in - , but % in sub-saharan africa. single-dose immunization failed to meet control or eradication requirements even in the most developed parts of the world. a live vaccine, licensed in , was later replace by a more effective and heat stable vaccine, but still with a primary vaccination failure rate (i.e., fails to produce protective antibodies) of - %, and secondary failure rate (i.e., produces antibodies but protection is lost over time) of %. a two-dose policy incorporates a booster dose, usually at school-age, in addition to maximum feasible infant coverage of children in the - month period (timing varies in different countries). catch-up campaigns among schoolage children should be carried out until the routine two-dose policy has time to take full effect. nearly universal primary education in developing countries, offers an opportunity for mass coverage of school age children with a second dose of measles and a resulting increase of herd immunity to reduce the transmission of the virus. the two-dose policy adopted in many countries, should be supplemented with catch-up campaigns in schools to provide the booster effect for those previously immunized and to cover those previously unimmunized, especially in developing countries. the cdc considers that domestic transmission in the united states has been interrupted and that most localized outbreaks were traceable to imported cases. south america and the caribbean countries are now considered free of indigenous measles, based on their successful use of nids, although a large epidemic occurred in in brazil. it now appears that eradication has become a feasible target during the early part of the next century, with a strategy of levels of coverage in in-fancy with a two-dose policy, supplemented by catch-up campaigns to older children and young adults, and outbreak control. mumps. mumps is an acute viral disease characterized by fever, swelling, and tenderness usually of the parotid glands, but also other glands. the incubation period ranges between and days. orchitis, or inflammation of the testicles, occurs in - % of postpubertal males and oophoritis, or inflammation of the ovaries, in % of postpubertal females. sterility is an extremely rare result of mumps. central nervous system involvement can occur in the form of aseptic meningitis, almost always without sequelae. encephalitis is reported in - per , cases with an overall case fatality rate of . %. pancreatitis, neuritis, nerve deafness, mastiffs, nephritis, thyroiditis, and pericarditis, although rare, may occur. most persons born before are immune to the disease, because of the nearly universal exposure to the disease before that time. the live attenuated vaccine introduced in the united states in is available as a single vaccine or in combination with measles and rubella as the measlesmumps-rubella (mmr) vaccine. it provides long-lasting immunity in % of cases. mumps vaccine is now recommended in a two-dose policy with the first dose of mmr given between and months of age and a second dose given either at school entry or in early adolescence. mmr in two doses is now standard policy in the united sates, sweden, canada, israel, the united kingdom, and other countries. the incidence of mumps has consequently declined rapidly. local eradication of this disease is worthwhile and should be part of a basic international immunization program. rubella. rubella (german measles) is generally a mild viral disease with lymphadenopathy and a diffuse, raised red rash. low grade fever, malaise, coryza, and lymphadenopathy characterize the prodromal period. the incubation period is usually - days. differentiation from scarlet fever, measles, or other febrile diseases with rash may require laboratory testing and recovery of the virus from nasopharyngeal, blood, stool, and urine specimens. in , norman gregg, an australian ophthalmologist, noted an epidemic of cases of congenital cataract in newborns associated with a history of rubella in the mother during the first trimester. subsequent investigation demonstrated that intrauterine death, spontaneous abortion, and congenital anomalies occur commonly when rubella occurs early in pregnancy. congenital rubella syndrome (crs) occurs with single or multiple congenital anomalies including deafness, cataracts, microophthalmia, congenital glaucoma, microcephaly, meningoencephalitis, congenital heart defects, and others. moderate and severe cases are recognizable at birth, but mild cases may not be detected for months or years after birth. insulin-dependent diabetes is suspected as a late sequela of congenital rubella. each case of crs is estimated to cost some $ , in health care costs during the patient's lifetime. prior to availability of the attenuated live rubella vaccine in , the disease was universally endemic, with epidemics or peak incidence every - years. in unvaccinated populations, rubella is primarily a disease of childhood. in areas where children are well vaccinated, adolescent and young adult infection is more apparent, with epidemics in institutions, colleges, and among military personnel. a sharp reduction of rubella cases was seen in the united states following introduction of the vaccine in , but increased in , following rubella epidemics in - . a further reduction in cases was followed by a sharp upswing of rubella and crs in [ ] [ ] [ ] . an outbreak of rubella among the amish in the united states, who refuse immunization on religious grounds, resulted in cases of crs in . it is now thought that vaccination of sufficient numbers in the united states reduced circulation of the virus and protected most vulnerable groups in the population. in the past, immunization policy in some countries was to vaccinate school girls aged to protect them for the period of fertility. the current approach is to give a routine dose of mmr in early childhood, followed by a second dose in early school age to reduce the pool of susceptible persons. women of reproductive age should be tested to confirm immunity before pregnancy and immunized if not already immune. should a woman become infected during pregnancy, termination of pregnancy previously recommended is now managed with hyperimmune globulin. the infection of pregnant women during their first trimester of pregnancy is the primary public health implication of rubella. the emotional and financial burden of crs, including the cost of treatment of its congenital defects, makes this vaccination program cost-effective. its inclusion in a modem immunization program is fully justified. elimination of crs syndrome should be one of the primary goals of a program for prevention of vaccine-preventable disease in developed and developing countries. adoption of mmr and the two-dose policy will gradually lead to eradication of rubella and rubella syndrome. viral hepatitis. viral hepatitis is a group of diseases of increasing public health importance due to their large scale worldwide prevalence, their serious consequences, and our increasing ability to take preventive action. viral hepatic infectious diseases each have specific etiologic, clinical, epidemiologic, serologic, and pathologic characteristics. they have important short-and long-term sequelae. vaccine development is of high priority for control and ultimate eradication. hepatitis a. hepatitis a (hav) was previously known as infectious hepatitis or epidemic jaundice. hav is mainly transmitted by the fecal-oral route. clinical severity varies from a mild illness of - weeks to a debilitating illness lasting several months. the norm is complete recovery within weeks, but a fulminating or even fatal hepatitis can occur. severity of the disease worsens with increasing age. hav is sporadic/endemic worldwide. improving sanitation raises the age of exposure, with accompanying complications. it now occurs particularly in persons from industrialized countries when exposed to situations of poor hygiene, or among young adults when traveling to areas where the disease is en-demic. common source outbreaks occur in school-aged children and young adults from case contact, or from food contaminated by infected handlers. hepatitis a may be a serious public health problem in a disaster situation. prevention involves improving personal and community hygiene, with safe chlorinated water and proper food handling. hepatitis a vaccine has been recently licensed for use in the united states, and will probably soon be recommended for routine vaccination programs, as well as for persons traveling to endemic areas. hepatitis b. hepatitis b (hbv) once called serum jaundice, was thought to be transmitted only by injections of blood or blood products. it is now known to be present in all body fluids and easily transmissible by household and sexual contact, perinatal spread from mother to newborn, and between toddlers. however, it is not spread by the oral-fecal route. hepatitis b virus is endemic worldwide and is especially prevalent in developing countries. carrier status with persistent viremia varies from < % of adults in north america to % in some parts of the world. carders have detectable levels of hbsag, the surface antigen (i.e., australian antigen), in their blood. high risk groups in developed countries include intravenous drug users, homosexual men, persons with high numbers of sexual partners, those receiving tattoos, body piercing or acupuncture treatments, and residents or staff of institutions such as group homes and prisons. immunocompromised and hemodialysis patients are commonly carders of hbv. hbv may also be spread in a health system by use of inadequately sterilized reusable syringes, as in china and the former soviet union. transmission is reduced by screening blood and blood products for hbsag and strict technique for handling blood and body fluids in health settings. hbv is clinically recognizable in less than % of infected children but is apparent in - % of infected adults. clinically hbv has an insidious onset with anorexia, abdominal discomfort, nausea, vomiting, and jaundice. the disease can vary in severity from subclinical, very mild to fulminating liver necrosis, and death. it is a major cause of primary liver cancer, chronic liver disease, and liver failure, all devastating to health and expensive to treat. hepatitis b virus is considered to be the cause of % of primary cancer of the liver in the world and the most common carcinogen after cigarette smoking. the who estimates that more than billion people alive today have been infected with hbv. it is also estimated that million persons are chronic carriers of hbv, with an estimated - . million deaths per year from cirrhosis or primary liver cancer. this makes hepatitis b control a vital issue in the revision of health priorities in many countries. strict discipline in blood banks and testing of all blood donations for hbv, as well as hiv, and hepatitis c, is mandatory, with destruction of those with positive tests. contacts should be immunized following exposure with hbv immunoglobulin and hbv vaccine. the inexpensive recombinant hbv vaccine should be adopted by all countries and included in routine vaccination of infants. catch-up immunization for older children is also desirable. immunization programs should include those exposed at work, such as health, prison, or sex workers and adults in group settings. hbv immunization has been included in who's epi-plus expanded program of immunization. hepatitis c. first identified in , and previously known as non-a, non-b hepatitis, hepatitis c (hcv) has an insidious onset with jaundice, fatigue, abdominal pain, nausea, and vomiting. it may cause mild to moderate illness, but chronicity is common going on to cirrhosis and liver failure. the cdc estimates that million americans are chronically infected with hcv, with - , resulting deaths per annum, and the main cause of liver transplants. hcv is transmitted most commonly in blood products, but also among injecting drug users ( % of intravenous drug users were hcv positive in a vancouver study in ), and is also a risk for health workers. the disease may also occur in dialysis centers and other medical situations. person-to-person spread is unclear. prevention of transmission includes routine testing of blood donations, antiviral treatment of blood products, needle exchange programs, and hygiene. the who in has declared hepatitis prevention as a major public health crisis, with an estimated million persons infected worldwide ( ) , stressing that this "silent epidemic" is being neglected and that screening of blood products is vital to reduce transmission of this disease as for hiu hcv is a major cause of chronic cirrhosis and liver cancer. no vaccine is available at present, but an experimental vaccine is undergoing field trials. interferon and ribavirin treatment is reportedly effective in % of cases. hepatitis d. hepatitis d virus (hdv) also known as delta hepatitis, may be self-limiting or progress to chronic hepatitis. it is caused by a viruslike particle which infects cells along with hbv as a coinfection or in chronic carriers of hbv. hdv occurs worldwide in the same groups at risk for hbv. it also occurs in epidemics and is endemic in south america, africa, and among drug users. prevention is by measures similar to those for hbv. management for hdv is by passive immunity with immunoglobulin for contacts and high risk groups, and should include hbv vaccination as the diseases often coincide. there is currently no vaccine for hdv. hepatitis e. hepatitis e virus has an epidemiological and clinical course similar to that of hav. there is no evidence of a chronic form of hev. one striking characteristic of hev is its high mortality rate among pregnant women. the disease is caused by a viruslike particle with an incubation period of - days and is most common in young adults. sporadic cases as well as epidemics have been identified in india, pakistan, burma, china, russia, mexico, and north africa. hev results from waterborne epidemics or as sporadic cases in areas with poor hygiene, spread via the oral-fecal route. it is a hazard in disaster situations with crowding and poor sanitary conditions. prevention is by safe management of water supplies and sanitation. disease management is supportive care; passive immunization is not helpful and no vaccine is currently available. teria which causes meningitis and other serious infections in children under months of age. before the introduction of effective vaccines, as many as in children developed invasive hib infection. two-thirds of these had hib meningitis, with a case fatality rate of - %. long-term sequelae such as hearing impairment and neurological deficits occurred in - % of survivors. the first hib vaccine was licensed in , based on capsular material from the bacteria. extensive clinical trials in finland demonstrated a high degree of efficacy, but less impressive results were in seen in postmarketing efficacy studies. by , a conjugate vaccine based on an additional protein cell capsular factor capable of enhancing the immunologic response was introduced. several conjugate vaccines are now available. the conjugate vaccines are now combined with dpt as their schedule is simultaneous with that of the dpt. although the hib vaccine has been found to be cost-effective, despite initially being as costly as all the basic vaccines combined (i.e., dpt, opv, mmr, and hbv). for this reason, its use thus far has been limited to industrialized countries. the vaccine is a valuable addition to the immunologic armamentarium. it showed dramatic results in local eradication of this serious early childhood infection in a number of european countries and a sharp reduction in the united states. impressive field trials in the gambia showed a sharp reduction in mortality from invasive streptococcal diseases. the price of the vaccine has also fallen dramatically since the mid s. as a result, in , the world health organization recommended inclusion of hib vaccine in routine immunization programs in developing countries. influenza. influenza is an acute viral respiratory illness characterized by fever, headache, myalgia, prostration, and cough. transmission is rapid by close contact with infected individuals and by airborne particles with an incubation period of - days. it is generally mild and self-limited with recovery in - days. however, in certain population groups, such as the elderly and chronically ill, infection can lead to severe sequelae. gastrointestinal symptoms commonly occur in children. during epidemics, mortality rates from respiratory diseases increase because of the large numbers of persons affected, although the case fatality rates are generally low. over the past century, influenza pandemics have occurred in , , , and , while epidemics are annual events. the influenza pandemic of caused millions of deaths among young adults, by some estimates killing more than had died in world war i. it was the fear of recurrence of this pandemic which led the cdc to launch a massive immunization program in the united states in to prevent swine flu (the virus was a strain antigenically similar to that of the pandemic influenza) from spreading from an isolated outbreak in an army camp. the effort was stopped after millions of persons were immunized with an urgently produced vaccine when serious reactions occurred (guillain-barre syndrome, (i.e., a type of paralysis), and when no further cases of swine flu were seen. this demonstrated the difficulty of extrapolating scenarios from a historical experience. each year, epidemiologic services of the who and collaborating centers such as the cdc recommend which strains should be used in vaccine preparation for use among susceptible population groups. these vaccines are prepared with the current anticipated epidemic strains. the three main types of influenza (a, b, and c) have different epidemiological characteristics. type a and its subtypes, which are subject to antigenic shift, are associated with widespread epidemics and pandemics. type b undergoes antigenic drift and is associated with less widespread epidemics. influenza type c is even more localized. active immunization against the prevailing wild strain of influenza virus produces a - % level of protection in high risk groups. the benefits of annual immunization outweigh the costs, and it has proven to be effective in reducing cases of influenza and its secondary complications such as pneumonia and death from respiratory complications in high-risk groups. pneumococcal disease. pneumococcal diseases, which are caused by streptococcus pneumoniae, include pneumonia, meningitis, and otitis media. the capsular types of pneumococci selected out of known types of the organism for the vaccine are those responsible for % of pneumococcal pneumonia cases and - % of all pneumonia cases in the united states, and are responsible for some , deaths per year. this vaccine has been found to be cost-effective for high risk groups, including persons with chronic disease, hiv carriers, patients whose spleens were removed, the elderly, and those with immunosuppressive conditions. it should be included in preventive-oriented health programs, especially for long-term care of the chronically ill. because pneumococci cause bacterial meningitis, pneumococcal vaccine may be a future candidate for use in routine immunization programs for children (over age ). varicella is an acute, generalized virus disease caused by the varicella zoster virus (vzv). despite its reputation as an innocuous disease of childhood, varicella patients can be quite ill. a mild fever and characteristic generalized red rash lasts for a few hours, followed by vesicles occurring in successive crops over various areas of the body. affected areas may include the membranes of the eyes, mouth, and respiratory tract. the disease may be so mild as to escape observation or may be quite severe, especially in adults. death can occur from viral pneumonia in adults and sepsis or encephalitis in children. neonates whose mothers develop the disease within days of delivery are at increased risk with a case fatality rate of up to %. long-term sequelae include herpes zoster or shingles with a severely painful, vesicular rash along the distribution of sensory nerves, which can last for months. its occurrence increases with age and it is primarily seen in the elderly. it can, however, occur in immunocompromised children (especially those on cancer chemotherapy), aids patients, and others. some % of a population will experience herpes zoster during their lifetimes. reye's syndrome is an increasingly rare but serious complication from varicella or influenza b. it occurs in children and affects the liver and central nervous system. congenital varicella syndrome with birth defects similar to congenital rubella syndrome has been identified recently. varicella vaccine is now recommended for routine immunization at age - months in the united states, with catch-up for children up to age years and for occupationally exposed persons in health or child care settings. varicella vaccine is also recommended for nonpregnant women of child bearing years. cost-benefit studies indicate a : ratio if both direct and indirect costs are included (see chapter ). varicella vaccine is likely to be added to a "cocktail vaccine" containing dpt, polio (ipv), and hib. meningococcal meningitis. meningococcal meningitis, caused by the bacterium neisseria meningitides, is characterized by headache, fever, neck stiffness, delirium, coma, and/or convulsions. the incubation period is - days. it has a case fatality rate of - % if treated early and adequately, but rises up to % in the absence of treatment. there are several important strains (a, b, c, x, y, and z). serogroups a and c are the main causes of epidemics, with b causing sporadic cases and local outbreaks. transmission is by direct contact and droplet spread. meningitis (group a) is common in sub-saharan african countries, but epidemics have occurred worldwide. during epidemics, children, teenagers, and young adults are the most severely affected. in developed countries, outbreaks occur most frequently in military and student populations. in , meningococcal meningitis spread widely in the "meningitis belt" in central africa. epidemic control is achieved by mass chemoprophylaxis with antibiotics (e.g., rifampin or sulfa drugs) among case contacts, although the emergence of resistant strains is a concern. vaccines against serotypes a and c (bivalent) or a, c, w, and y are available. their use is effective in epidemic control and prevention institutions and military recruits, especially for a and c serogroups. vaccination is one of the key modalities of primary prevention. immunization is cost-effective and prevents wide-scale disease and death, with high levels of safety. despite the general consensus in public health regarding the central role of vaccination, there are many areas of controversy and unfulfilled expectations. a vaccination program should aim at % coverage at appropriate times, including infants, school children, and adults. immunization policy should be adapted from current international standards applying the best available program to national circumstances and financial capacities (table . ). public health personnel with expertise in vaccine-preventable disease control are needed to advise ministries of health and the practicing pediatric community on current issues in vaccination and to monitor implementation and evolution of control programs. controversies and changing views are common to immunization policy, so that discussions must be conducted on a continuing basis. policy should be under continuing review by a ministerially appointed national immunization advisory committee, including professionals from public health, academia, immunology, laboratory sciences, economics, and relevant clinical fields. bduring , the recommendation for polio virus was changed to doses of ipv in infancy. vaccine supply should be adequate and continuous. supplies should be ordered from known manufacturers meeting international standards of good manufacturing practice. all batches should be tested for safety and efficacy prior to release for use. there should be an adequate and continuously monitored cold chain to protect against high temperatures for heat labile vaccines, sera, and other active biological preparations. the cold chain should include all stages of storage, transport, and maintenance at the site of usage. only disposable syringes should be used in vaccination programs to prevent any possible transmission of blood-borne infection. a vaccination program depends on a readily available service with no barriers or unnecessary prerequisites, free to parents or with a minimum fee, to administer vaccines in disposable syringes by properly trained individuals using patientoriented and community-oriented approaches. ongoing education and training on current immunization practices are needed. incentive payments by insuring agency or managed care systems promote complete, on-time coverage. all clinical encounters should be used to screen, immunize, and educate parents/guardians. contraindications to vaccination are very few; vaccines may be given even during mild illness with or without fever, during antibiotic therapy, during convalescence from illness, following recent exposure to an infectious disease, and to persons having a history of mild/moderate local reactions, convulsions, or family history of sudden infant death syndrome (sids). simultaneous administration of vaccines and vaccine "cocktails" reduces the number of visits and thereby improves coverage; there are no known interferences between vaccine antigens. accurate and complete recording with computerization of records with automatic reminders helps promote compliance, as does co-scheduling of immunization appointments with other services. adverse events should be reported promptly, accurately, and completely. a tracking system should operate with reminders of upcoming or overdue immunizations; use mail, telephone, and home visits, especially for high risk families, with semiannual audits to assess coverage and review patient records in the population served to determine the percentage of children covered by second birthday. tracking should identify children needing completion of the immunization schedule and assess the quality of documentation. it is important to maintain up-to-date, easily retrievable medical protocols where vaccines are administered, noting vaccine dosage, contraindications, and management of adverse events. all health care providers and managers should be trained in education, promotion, and management of immunization policy. health education should target parents as well as the general public. monitoring of vaccines used and children immunized, individually and by category of vaccination can be facilitated by computerization of immunization records, or regular manual review of child care records. where immunization is done by physicians in private practice, as in the united states, determination of coverage is by periodic surveys. inspection of vaccines for safety, purity, potency, and standards is part of the regulatory function. vaccines are defined as biological products and are therefore subject to regulation by national health authorities. in the united states, this comes under the legislative authority of the public health service act, as well as the food, drug and cosmetics act, with applicable regulations in the code of federal regulations. the federal agency empowered to carry out this regulatory function is the center for drugs and biologics of the federal food and drug administration. litigation regarding adverse effects of vaccines led to inflation of legal costs and efforts to limit court settlements. the u.s. federal government enacted the child vaccine injury act of . this legislation requires providers to document vaccines given and to report on complications or reactions. it was intended to pay benefits to persons injured by vaccines faster and by means of a less expensive procedure than a civil suit for resolving claims. using this no-fault system, petitioners do not need to prove that manufacturers or vaccine givers were at fault. they must only prove that the vaccine is related to the injury in order to receive compensation. the vaccines covered by this legislation include dtp, mmr, opv, and ipv. development of vaccines from jenner in eighteenth century to the advent of recombinant hepatitis b vaccine in , and of vaccines for acellular pertussis, varicella, hepatitis a, and rotavirus in the s, has provided one of the pillars of public health and led to enormous savings of human life. vaccines for viral in-fections in humans for hiv, respiratory syncytial virus, papilloma, epstein-barr virus, dengue fever, and hantavirus are under intense research with genetic approaches using recombinant techniques. the potential for the future of vaccines will be greatly influenced by scientific advances in genetic engineering, with potential for development of vaccines attached to bacteria or protein in plants, which may be given in combination for an increasing range of organisms or their harmful products. recombinant dna technology has revolutionized basic and biomedical research since the s. the industry of biotechnology has produced important diagnostic tests, such as for hiv, with great potential for vaccine development. traditional whole organism vaccines, alive or killed, may contain toxic products that may cause mild to severe reactions. subunit vaccines are prepared from components of a whole organism. this avoids the use of live organisms that can cause the disease or create toxic products which cause reactions. subunit vaccines traditionally prepared by inactivation of partially purified toxins are costly, difficult to prepare, and weakly immunogenic. recombinant techniques are an important development for production of new whole cell or subunit vaccines that are safe, inexpensive, and more productive of antibodies than other approaches. their potential contribution to the future of immunology is enormous. molecular biology and genetic engineering have made it feasible to create new, improved, and less costly vaccines. new vaccines should be inexpensive, easily administered, capable of being stored and transported without refrigeration, and given orally. the search for inexpensive and effective vaccines for groups of viruses causing diarrheal diseases led to development of the rotavirus vaccine. some "edible" research focuses on the genetic programming of plants to produce vaccines and dna. vaccine manufacturers, who spend huge sums of money and years of research on new products, tend to work on those which will bring great financial rewards for the company and are critical to the local health care community. this has led to less effort being made in developing vaccines for diseases such as malaria. yet industry plays a crucial role for continued progress in the field. since the eradication of smallpox, much attention has focused on the possibility of similarly eradicating other diseases, and a list of potential candidates has emerged. some of these have been abandoned because of practical difficulties with current technology. diseases that have been under discussion for eradication have included measles, tb, and some tropical diseases, such as malaria and dracunculiasis. eradication is defined as the achievement of a situation whereby no further cases of a disease occur anywhere and continued control measures are unnecessary. reducing epidemics of infectious diseases, through control and eradication in selected areas or target groups, can in certain instances achieve eradication of the disease. local eradication can be achieved where domestic circulation of an organism is interrupted with cases occurring from importation only. this requires a strong, sustained immunization program with adaptation to meet needs of importation of carriers and changing epidemiologic patterns. smallpox was one of the major pandemic diseases of the middle ages and its recorded history goes back to antiquity. prevention of smallpox was discussed in ancient china by ho kung (circe ao ), and inoculation against the disease was practiced there from the eleventh century ad. prevention was carried out by nasal inhalation of powdered dried smallpox scabs. exposure of children to smallpox when the mortality rate was lowest assumed a weakened form of the disease, and it was observed that a person could only have smallpox once in a lifetime. isolation and quarantine were widely practiced in europe during the sixteenth and seventeenth centuries. variolation was the practice of inoculating youngsters with material from scabs of pustules from mild cases of smallpox in the hope that they would develop a mild form of the disease. although this practice was associated with substantial mortality, it was widely adopted because mortality from variolation was well below that of smallpox acquired during epidemics. introduced into england in (see chapter ) it was commonly practiced as a lucrative medical specialty during the eighteenth century. in the s, variolation was also introduced into the american colonies, russia, and subsequently into sweden and denmark. despite all efforts, in the early eighteenth century smallpox was a leading cause of death in all age groups. toward the end of the eighteenth century an estimated , persons died annually from smallpox in europe. vaccination, or the use of cowpox vaccinia virus to protect against smallpox, was initiated late in the eighteenth century. in , a cattle breeder in yorkshire, england, inoculated his wife and two children with cowpox to protect them during a smallpox epidemic. in , edward jenner, an english country general practitioner, experimented with inoculation from a milkmaid's cowpox pustule to a healthy youngster, who subsequently proved resistant to smallpox by variolation (see chapter ). vaccination, the deliberate inoculation of cowpox material, was slow to be adopted universally, but by , over , persons in england were vaccinated. vaccination gathered support in the nineteenth century in military establishments, and in some countries which adopted it universally. opposition to vaccination remained strong for nearly a century based on religious grounds, observed failures of vaccination to give lifelong immunity, and because it was seen as an infringement of the state on the rights of the individual. often the protest was led by medical variolationists whose medical practice and large incomes were threatened by the mass movement to vaccination. resistance was also offered by "sanitarians" who opposed the germ theory and thought cleanliness was the best method of prevention. universal vaccination was increasingly adopted in europe and america in the early nineteenth century and eradication of smallpox in developed countries was achieved by the mid twentieth century. in , the soviet union proposed to the world health assembly a program to eradicate smallpox internationally and subsequently donated million doses of vaccine per year as part of the million needed to promote vaccination of at least % of the world population. in , who adopted a target for the eradication of smallpox. a program was developed which included a massive increase in coverage to reduce the circulation of the virus through person-to-person contact. where smallpox was endemic, with a substantial number of unvaccinated persons, the aim of the mass vaccination phase was % coverage. increasing vaccination coverage in developing countries reduced the disease to periodic and increasingly localized outbreaks. in , countries were considered endemic for smallpox, and another experienced importation of cases. by , the number of endemic countries was down to , and by only countries were still endemic, including india, pakistan, bangladesh, and nepal. in these countries, a new strategy was needed, based on a search for cases and vaccination of all contacts, working with a case incidence below per , . the program then moved into the consolidation phase, with emphasis on vaccination of newborns and new arrivals. surveillance and case detection were improved with case contact or risk group vaccination. the maintenance phase began when surveillance and reporting were switched to the national or regional health service with intensive follow-up of any suspect case. the mass epidemic era had been controlled by mass vaccination, reducing the total burden of the disease, but eradication required the isolation of individual cases with vaccination of potential contacts. technical innovations greatly eased the problems associated with mass vaccination worldwide. during the s, there was wide variation in sources of smallpox vaccine. in the s, efforts to standardize and further attenuate the strains used reduced complication rates from vaccinations. the development of lyophilization (freeze-drying) of the vaccine in england in the s made a heat-stable vaccine that could be effective in tropical field conditions in developing countries. the invention of the bifurcated needle (bernard rubin ) allowed for easier and more widespread vaccination by lesser trained personnel in remote areas. the net result of these innovations was increased world coverage and a reduction in the spread of the disease. smallpox became more and more confined by increasing herd immunity, thus allowing transition to the phase of monitoring and isolation of individual cases. in the last case of smallpox was identified in somalia, and in the who declared the disease eradicated. no subsequent cases have been found except for several associated with a laboratory accident in the united kingdom in . the who recommends that the last stores of smallpox virus should be destroyed in . the cost of the eradication program was $ million or $ million per year. worldwide savings are estimated at $ billion annually. this monumental public health achievement set the precedent for eradication of other infectious diseases. the world health assembly decided to destroy the last two remaining stocks of the smallpox virus in atlanta and moscow in . destruction of the remaining stock was delayed in to because of concern that illegal stocks may be held by some states or potential bioterrorists for potential use in weapons of mass destruction, concern regarding the appearance of monkeypox and a wish to use the virus for further research. in , the who established a target of eradication of poliomyelitis by the year . global immunization coverage with three doses of opv increased from some % in to over % in , with a slight decline in the period - . support from member countries and international agencies such as unicef and rotary international has led to widescale increases in immunization coverage throughout many parts of the world. the world health organization promotes use of opv only as part of routine infant immunization or national immunization days (nids). this strategy has been successful in the americas and in china, but india and the middle east remain problematic. eradication of wild poliomyelitis by the year will require flexibility in vaccination strategies and may require the combined approach, using opv and ipv, as adopted in the united states in to prevent vaccine-associated clinical cases. the combination of opv and ipv may be needed where enteric disease is common and leads to interference in opv uptake, especially in tropical areas where endemic poliovirus and diarrheal diseases are still found. the world bank estimated that achievement of global eradication would save $ million annually in the united states alone. since the eradication of smallpox, discussion has focused on the possibility of similarly eradicating other diseases, and a list of potential candidates has emerged. some of these have been abandoned because of practical difficulties with current technology. diseases that have been under discussion for eradication have included measles, tb, and tropical diseases such as malaria and dracunculiasis. eradication of malaria was thought to be possible in the s when major gains were seen in malaria control by aggressive case environmental control, case finding, and management. however, lack of sustained vector control and an effective vaccine has prevented global eradication. malaria control suffered serious setbacks because of failure in political resolve and capacity to continue support needed for necessary programs. in the s and s, control efforts were not sustained in many countries, and a dreadful comeback of the disease occurred in africa and asia in the s. the emergence of mosquitoes resistant to insecticides, and malarial strains resistant to antimalarial drugs, have made malaria control even more difficult and expensive. renewed effort in malaria control may require new approaches. use of community health workers (chws) in small villages in highly endemic regions of colombia resulted in a major drop in malaria mortality during the s. the chws investigate suspect cases by taking clinical histories and blood smears. . scientific feasibility a. epidemiologic vulnerability; lack of nonhuman reservoir, ease of spread, no natural immunity, relapse potential; b. effective practical intervention available; vaccine or other primary preventive or curative treatment, or vectoricide that is safe, inexpensive, long lasting, and easily used in the field; c. demonstrated feasibility of elimination in specific locations, such as an island or other geographic unit. . political will/popular support a. they examine smears for malaria parasites and a diagnosis is made. therapy is instituted and the patient is followed. quality control monitoring shows high levels of accuracy in reading of slides compared to professional laboratories. in the late s, there was widespread discussion in the literature of the potential for eradication of measles and tb. measles eradication was set back as breakthrough epidemics occurred in the united states, canada, and many other countries during the s and early s, but regional eradication was achieved combining the two-dose policy with catch-up campaigns for older children or in national immunization days, as in the caribbean countries. tuberculosis has also increased in the united states and several european countries for the first time in many decades. unrealistic expectations can lead to inappropriate assessments and policy when confounding factors alter the epidemiologic course of events. such is the case with tb, where control and eradication have receded from the picture. this deadly disease has returned to developed countries, partly in association with the hiv infection and multiple-drug-resistant strains, as well as homelessness, rising prison populations, poverty, and other deleterious social conditions. directly observed therapy is an important recent breakthrough, more effective in use of available technology and will play a major role in tb control in the twenty-first century. a decade after the eradication of smallpox was achieved, the international task force for disease eradication (itfde) was established to systematically evaluate the potential for global eradicability of candidate diseases. its goals were to identify specific barriers to the eradication of these diseases that might be surmountable and to promote eradication efforts. the subject of eradication versus control of infectious diseases if of central public health importance as technology expands the armamentarium of immunization and vector control into the twenty-first century. the control of epidemics, followed by interruption of transmission and ultimately eradication, will save countless lives and prevent serious damage to children throughout the world. the smallpox achievement, momentous in itself, points to the potential for the eradication of other deadly diseases. the skillful use of existing and new technology is an important priority in the new public health. flexibility and adaptability are as vital as resources and personnel. selecting diseases for eradication is not purely a professional issue of resources such as vaccines and manpower, organization and financing. it is also a matter of political will and perception of the burden of disease. there will be many controversies. the selection of polio for eradication while deferring measles when polio kills few and measles kills many may be questioned. the cdc published criteria for selection of disease for eradication are shown in box . . the who, in a review of health targets in the field of infectious disease control for the twenty-first century, selected the following targets: eradication of chagas' disease by ; eradication of neonatal tetanus by ; eradication of leprosy by ; eradication of measles by ; eradication of trachoma by ; reversing the current trend of increasing tuberculosis and hiv/aids. in , a conference in atlanta, georgia, reviewed the subject, which is still very much in a state of flux. table . summarizes the selection of diseases which are presently seen as controllable and those considered to be potentially eradicable. the subject will be under review in the years ahead. mycobacterium tuberculosis in humans and m. bovis in cattle. the disease is primarily found in humans, but it is also a disease of cattle and occasionally other primates in certain regions of the world. it is transmitted via airborne droplet nuclei from persons with pulmonary or laryngeal tb during coughing, sneezing, talking, or singing. the initial infection may go unnoticed, but tuberculin sensitivity appears within a few weeks. about % of those infected enter a latent phase with a lifelong risk of reactivation. approximately % go from initial infection to pulmonary tb. less commonly, the infection develops as extrapulmonary tb, involving meninges, lymph nodes, pleura, pericardium, bones, kidneys, or other organs. untreated, about half of the patients with active tb will die of the disease within years, but modern chemotherapy almost always results in a cure. pulmonary tb symptoms include cough and weight loss, with clinical findings on chest examination and confirmation by findings of tubercle bacilli in stained smears of sputum and, if possible, growth of the organism on culture media, and changes in the chest x-ray. tuberculosis affects people in their adult working years, with - % of cases in persons between the ages of and . its devastating effects on the work force and economic development contribute to a high cost-effectiveness for tb control. the tubercle bacillus infects approximately . billion people in the world today, causing over million cases and nearly million deaths in . during , new cases of tb included . million ( %) in southeast asia and the western pacific regions of who, with . million cases in india, and . million in indonesia. by , the incidence of tb may increase to . million new cases per year, a % increase over . between and , who estimates there were million new cases of tb, of which million cases were in association with hiv infection. during the s, an estimated million persons died of tb, including . million with hiv infection. a new and dangerous period for tb resurgence has resulted from parallel epidemiologic events: first, the advent of hiv infection and second, the occurrence of multiple drug resistant tb (mdrtb), that is, organisms resistant at least to both isoniazid (inh) and rifampicin, two mainstays of tb treatment. mdrtb can have a case fatality rate as high as %. hiv reduces cellular immunity so that people with latent tb have a high risk of activation of the disease. it is estimated that hiv negative persons have a - % lifetime risk of tb; hiv positive people have a risk of % per year of developing clinical tuberculosis. drug resistance, the long period of treatment, and the socioeconomic profile of most tb patients combine to require a new approach to therapy. directly observed treatment, short-course (dots), has shown itself to be highly effective with patients in poor self-care settings, such as the homeless, drug users, and those with aids. the strategy of dots uses community health workers to visit the patient and observes him or her taking the various medications, providing both incentive, support, and moral coercion to complete the needed to month therapy. dots has been shown to cure up to % of cases, at a cost of as little as $ per patient. it is one of the few hopes of containing the tb pandemic. in , who released a new strategy for control of tuberculosis over the next decade. the plan calls for new guidelines for control, new aid funds for developing countries, and enlistment of ngos to assist in the fight. the new guidelines stress short-term chemotherapy in well-managed programs of dots, stressing strict compliance with therapy for infectious cases with a goal of an % cure rate. even under adverse conditions, dots produces excellent results. it is one of the most cost-effective health interventions combining public health and clinical medical approaches. tuberculosis incidence in the united states decreased steadily until , increased in , and has declined again since. from to , there was an excess of , cases over the expected rate if the previous decline in case incidence had continued. this rise was largely due to the hiv/aids epidemic and the emergence of mdrtb, but also greater incidence among immigrants from areas of higher tb incidence, drug abusers, the homeless, and those with limited access to health care. this is particularly true in new york city, where mdrtb has appeared in outbreaks among prison inmates and hospital staff. from to , tb incidence in the united states declined by % and in some states, including new york, by % or more. this turnaround was due to stronger tb control programs that promptly identified persons with tb and initiated and ensured completion of appropriate therapy. aggressive staff training, outreach, and case management approaches were vital to this success. concern over rising rates among recent immigrants and the continued challenge of hiv/aids and coincidental transmission of hepatitis a, b, and c among drug users and marginal population groups show that continued support for tb control is needed. bacillus calmette-gurrin (bcg) is an attenuated strain of the tubercle bacillus used widely as a vaccination to prevent tb, especially in high incidence areas. it induces tuberculin sensitivity or an antigen-antibody reaction in which antibodies produced may be somewhat protective against the tubercle bacillus in % of vaccinees. although the support for its general use is contradictory, there is evidence from case-control and contact studies of positive protection against tb meningitis and disseminated tb in children under the age of . in some developed, low-incidence countries, it is not used routinely but selectively. it may also be used in asymptomatic hiv-positive persons or other high risk groups. the bcg vaccine for tuberculosis remains controversial. while used widely internationally, in the united states and other industrialized countries, it is thought to hinder rather than help in the fight against tb. this concern is based on the usefulness of tuberculin testing for diagnosis of the disease. where bcg has been administered, the diagnostic value of tuberculin testing is reduced, especially in the period soon after the bcg is used. studies showing equivocal benefit of bcg in preventing tuberculosis have added to the controversy. while those in the field in the united states continue to oppose the use of bcg, internationally it is still felt to be of benefit in preventing tb, primarily in children. a metaanalysis of the literature of bcg carried out by the technology assessment group at harvard school of public health concluded: on average, bcg vaccine significantly reduces the risk of tb by %. protection is observed across many populations, study designs, and forms of tb. age at vaccination did not enhance predictiveness of bcg efficacy. protection against tuberculous death, meningitis, and disseminated disease is higher than for total tb cases, although this result may reflect reduced error in disease classification rather than greater bcg efficacy. [colditz et al., jama, .] box . control of tuberculosis . identifying persons with clinically active tb; . diagnostic methods--clinical suspicion, sputum smear for bacteriologic examination, tuberculin skin testing, chest radiograph; . case finding and investigation programs in high risk groups; . contact investigation; . isolation techniques during initial therapy; . treatment, mainly ambulatory, of persons with clinically active tb; . treatment of contacts; . directly observed treatment, short-course (dots), where compliance suspect; . environmental control in treatment settings to reduce droplet infection; . educate health care providers on suspicion of tb and investigation of suspects. currently, the who recommends use of bcg as close to birth as possible as part of the expanded programme of immunization (epi). tuberculosis control remains feasible with current medical and public health methods. deterioration in its control should not lead to despair and passivity. the recent trend to successful control by dots despite the growing problem of mdrtb suggest that control and gradual reduction can be achieved by an activist, community outreach approach. the who in made tb control one of its major priorities, expressing grave concern that the mdr organism, now widely spread in countries of asia, eastern europe, and the former soviet union, may spread the disease much more widely. the disease constitutes one of the great challenges to public health at the start of the new century. acute infectious diseases caused by group a streptococci include streptococcal sore throat, scarlet fever, puerperal fever, septicemia, ersypelas, cellulitis, mastoiditis, otitis media, pneumonia, peritonsillitis (quinsy), wound infections, toxic shock syndrome, and fasciitis, the "flesh eating bacteria." streptococcus pyogenes group a include some serologically distinct types which vary in geographic location and clinical significance. transmission is by droplet, person-to-person direct contact, or by food infected by carriers. important complications from a public health point of view include acute rheumatic fever and acute glomerulonephritis, but also skin infections and pneumonia. acute rheumatic fever is a complication of strep a infection that has virtually disappeared from industrialized countries as a result of improved standards of living and antibiotic therapy. however, outbreaks were recorded in the united states in , and an increasing number of cases have been seen since . in developing countries, rheumatic fever remains a serious public health problem affecting school age children, particularly those in crowded living arrangements. longterm sequelae include disease of the mitral and aortic heart valves, which require cardiac care and surgery for repair or replacement with artificial valves. acute glomerulonephritis is a reaction to toxins of the streptococcal infection in the kidney tissue. this can result in long-term kidney failure and the need for dialysis or kidney transplantation. this disease has become far less common in the industrialized countries, but remains a public health problem in developing countries. the streptococcal diseases are controllable by early diagnosis and treatment with antibiotics. this is a major function of primary care systems. recent increases in rheumatic fever may herald a return of the problem, perhaps due to inadequate access to primary care in the united states for large sectors of the population, along with increased social hygiene problems. where access to primary care services is limited, infections with streptococci can result in a heavy burden of chronic heart and kidney disease with substantial health, emotional, and financial tolls. measures to improve access to care and pub-lic information are needed to assure rapid and effective care to prevent chronic and costly conditions. zoonoses are infectious diseases transmissible from vetebrate animals to humans. common examples of zoonoses of public health importance in nonindustrialized countries include brucellosis and rabies. in industrialized countries, salmonellosis, "mad cow disease" and influenza have reinforced the importance of relationships of animal and human health. strong cooperation between public health and veterinary public health authorities are required to monitor and to prevent such diseases. brucellosis is a disease occurring in cattle (brucella abortus), in dogs (br. cahis), in goats and sheep (br. melitensis), and in pigs (br. suis). humans are affected mainly through ingestion of contaminated milk products, by contact, or inhalation. brucellosis (also known as relapsing, undulant, malta, or mediterranean fever) is a systemic bacterial disease of acute or insidious onset characterized by fever, headache, weakness, sweating, chills, arthralgia, depression, weight loss, and generalized malaise. spread is by contact with tissues, blood, urine, vaginal discharges, but mainly by ingestion of raw milk and dairy products from infected animals. the disease may last from a few days to a year or more. complications include osteoarthritis and relapses. case fatality is under %, but disability is common and can be pronounced. the disease is primarily seen in mediterranean countries, the middle east, india, central asia, and in central and south america. brucellosis occurs primarily as an occupational disease of persons working with and in contact with tissues, blood, and urine of infected animals, especially goats and sheep. it is an occupational hazard for veterinarians, packinghouse workers, butchers, tanners, and laboratory workers. it is also transmitted to consumers of unpasteurized milk from infected animals. animal vectors include wild animals, so that eradication is virtually impossible. diagnosis is confirmed by laboratory findings of the organism in blood or other tissue samples, or with rising antibody titers in the blood, with confirmation by blood cultures. clinical cases are treated with antibiotics. epidemiologic investigation may help track down contaminated animal flocks. routine immunization of animals, monitoring of animals in high risk areas, quarantining sick animals, destroying infected animals, and pasteurizing milk and milk products prevents spread of the disease. control measures include educating farmers and the public not to use unpasteurized milk. individuals who work with animals (cattle, swine, goats, sheep, dogs, coyotes) should take special precautions when handling animal carcasses and materials. testing animals, destroying carriers, and enforcing mandatory pasteurization will restrict the spread of the disease. this is an economic as well as public health problem, requiring full cooperation between ministries of health and of agriculture. rabies is primarily a disease of animals, with a variety of wild animals serving as a reservoir for this disease, including foxes, wolves, bats, skunks, and raccoons, who may infect domestic animals such as dogs, cats, and farm animals. animal bites break the skin or mucous membrane, allowing entry of the virus from the infected saliva into the bloodstream. the incubation period of the virus is - weeks; it can be as long as several years or as short as days, so that postexposure preventive treatment is a public health emergency. the clinical disease often begins with a feeling of apprehension, headache, pyrexia, followed by muscle spasms, acute encephalitis, and death. fear of water ("hydrophobia") or fear of swallowing is a characteristic of the disease. rabies is almost always fatal within a week of onset of symptoms. the disease is estimated to cause , deaths annually, primarily in developing countries. it is uncommon in developed countries. rabies control focuses on prevention in humans, domestic animals, and wildlife. prevention in humans is based on preexposure prophylaxis for groups at risk (e.g., veterinarians, zoo workers) and postexposure immunization for persons bitten by potentially rabid animals. because reducing exposure of pets to wild animals is difficult, immunization of domestic animals is one of the most important preventive measures. prevention in domestic animals is by mandatory immunization of household pets. all domestic animals should be immunized at age months and revaccinated according to veterinary instructions. prevention in wild animals to reduce the reservoir is successful in achieving local eradication in settings where reentry from neighboring settings is limited. since , the use of oral rabies immunization has been successful in reducing the population of wild animals infected by the rabies virus. rabies eradication efforts, using aerial distribution of baits containing fox rabies vaccine in affected areas of belgium, france, germany, italy, and luxembourg, have been underway since . the number of rabies cases in these affected areas has declined by some %. switzerland is now virtually rabies-free because of this vaccination program. the potential exists for focal eradication, especially on islands or in partially restricted areas with limited possibilities of wild animal entry. livestock need not be routinely immunized against rabies, except in high risk areas. where bats are major reservoirs of the disease, as in the united states, eradication is not presently feasible. salmonella, discussed later in this chapter under diarrheal diseases, is one of the commonest of all infectious diseases among animals and is easily spread to humans via poultry, meat, eggs, and dairy products. specific antigenic types are associated with food-borne transmission to humans, causing generalized illness and gastroenteritis. severity of the disease varies widely, but the diseases can be devastating among vulnerable population groups, such as young children, the elderly, and the immunocompromised. epidemiologic investigation of common food source outbreaks may uncover hazardous food handling practices. laboratory confirmation or serotypes helps in monitoring the disease. prevention is by maintaining high standards of food hygiene in processing, inspection and regulation, food handling practices, and hygiene education. bacillus anthracis causes a bacterial infection in herbivore animals. its spores contaminate soil, worldwide. it affects humans exposed in occupational settings. transmission is cutaneous by contact, gastrointestinal by ingestion, or respiratory by inhalation. it has gained recent attention (iraq, ) as a highly potent agent for germ warfare or terrorism. limited supplies of vaccine are available. creutzfeld-jakob disease is a degenerative disease of the central nervous system linked to consumption of beef from cattle infected with bovine spongiform encephalopathy. it is transmitted by prions in animal feed prepared from contaminated animal material and in transplanted organs. this disease was identified in the united kingdom linked to infected cattle leading to a ban on british beef in many parts of the world and slaughter of large numbers of potentially contaminated animals. the tapeworm causing diphyllobothriasis (diphyllobothrium latum) is widespread in north american freshwater fish, passing from crustacean to fish to humans by eating raw freshwater fish. it is especially common among inuit peoples and may be asymptomatic or cause severe general and abdominal disorder. food hygiene (freezing and cooking of meat) is recommended; treatment is by anthelminthics. leptospiroses are a group of zoonotic bacterial diseases found worldwide in rats, raccoons, and domestic animals. it affects farmers, sewer workers, dairy and abattoir workers, veterinarians, military personnel, and miners with transmission by exposure to or ingestion of urine-contaminated water or tissues of infected animals. it is often asymptomatic or mild, but may cause generalized illness like influenza, meningitis, or encephalitis. prevention requires education of the public in self protection and immunization of workers in hazardous occupations, along with immunization and segregation of domestic animals and control of wild animals. vector-borne diseases are a group of diseases in which the infectious agent is transmitted to humans by crawling or flying insects. the vector is the intermediary between the reservoir and the host. both the vector and the host may be affected by climatic condition; mosquitoes thrive in warm, wet weather and are suppressed by cold weather; humans may wear less protective clothing in warm weather. the only important reservoir of malaria is humans. its mode of transmission is from person to person via the bite of an infected female anopheles mosquito (ronald ross, nobel prize, ) . the causative organism is a single cell parasite with four species: plasmodium vivax, p malariae, p falciparum, and p ovale. clinical symptoms are produced by the parasite invading and destroying red blood cells. the incubation period of approximately - days, depending on the specific plasmodium involved. some strains of p vivax may have a protracted incubation period of - months and even longer for p ovale. the disease can also be transmitted through infected blood transfusions. confirmation of diagnosis is by demonstrating malaria parasites on blood smears. falciparum malaria, the most serious form, presents with fever, chills, sweats, and headache. it may progress to jaundice, bleeding disorders, shock, renal or liver failure, encephalopathy, coma, and death. prompt treatment is essential. case fatality rates in untreated children and adults are above %. an untreated attack may last months. other forms of malaria may present as a nonspecific fever. relapse of the p ovale may occur up to years after initial infection; malaria may persist in chronic form for up to years. malaria control advanced during the s- s through improved chlovaquine treatment and use of ddt for vector control with optimism for eradication of the disease. however, control regressed in many developing countries as allocations for environmental control and case findings/treatment were reduced. there has also been an increase in drug resistance, so that this disease is now an extremely serious public health problem in many parts of the world. the need for a vaccine for malaria control is now more apparent than ever. the world health organization estimated that, in , sub-saharan africa (ssa) had million new malaria cases, with % of children up to age . over million deaths occur annually from malaria more than two-thirds of them in ssa. large areas, particularly in forest or savannah regions with high rainfall, are holoendemic. in higher altitudes, endemicity is lower, but epidemics do occur. chloroquine-resistant p. falciparum has spread throughout africa, accompanied by an increasing incidence of severe clinical forms of the disease. the world bank estimates that % of all disability-adjusted life years (dalys) lost per year in ssa are from malaria, which places a heavy economic burden on the health systems. in the americas, the number of cases detected has risen every year since , and the who estimates there to have been . - . million cases in . the nine most endemic countries in the americas achieved a % reduction in malaria mortality between and . southeast asian region reports some . million cases of malaria in and deaths from tb. this accounts for more than one-third of all non-african malaria cases. there is an increase in resistant strains to the major available drugs and of the mosquitoes to insecticides in use. vector control, case finding, and treatment remain the mainstay of control. use of insecticide-impregnated bed nets and curtains, and residual house spraying, and strengthened vector control activities are important, as are early diagnosis and carefully monitored treatment with monitoring for resistance. control of malaria will ultimately depend on a safe, effective, and inexpensive vaccine. attempts to develop a malaria vaccine have been unsuccessful to date due to the large number of genetic types of p. falciparum even in localized areas. a colombian-developed vaccine is being field-tested with partial effectiveness. research in vaccines for malaria has also been hampered by the fact that it is a relatively low priority for vaccine manufacturers because of the minimal potential for financial benefit. research on malaria concentrates on the pharmacological aspects of the disease because of increasing drug resistance. in , who has initiated a new campaign to "roll back malaria" and maintain the dream of eradication in the future. effective low technology interventions include community-based case finding, early treatment of good quality, insecticide use, and vector control. the use of community health workers in endemic areas, has shown promising results. local control and even eradication can be achieved with currently available technology. this requires an integration of public health and clinical approaches with strong political commitment. the rickettsia are obligate parasites, i.e., they can only replicate in living cells, but otherwise they have characteristics of bacteria. this is a group of clinically similar diseases, usually characterized by severe headache, fever, myalgia, rash, and capillary bleeding causing damage to brain, lungs, kidneys, and heart. identification is by serological testing for antibodies, but the organisms can also be cultured in laboratory animals, embryonic eggs, or in cell cultures. the organisms are transmitted by arthropod vectors such as lice, fleas, ticks, and mites. the diseases caused millions of deaths during war and famine periods prior to the advent of antibiotics. these diseases appear in nature in ways that make them impossible to eradicate, but clinical diagnosis, host protection, and vector control can help reduce the burden of disease and deal with outbreaks that may occur. public education regarding self-protection, appropriate clothing, tick removal, and localized control measures such as spraying and habitat modification are useful. epidemic typhus, first identified in , is due to rickettsia prowazekii. spread primarily by the body louse, typhus was the cause of an estimated million deaths, i.e., during war and famine, in poland and the soviet union from - . untreated, the fatality rate is - %. typhus responds well to antibiotics. it is currently largely confined to endemic foci in central africa, central asia, eastern europe, and south america. it is preventable by hygiene and pediculicides such as ddt and lindane. a vaccine is available for exposed laboratory personnel. murine typhus is a mild form of typhus due to rickettsia typhi, which is found worldwide and spread in rodent reservoirs. scrub typhus, also known as tsutsugamushi or japanese river fever, is located throughout the far east and the pacific islands, and was a serious health problem for u.s. armed forces in the pacific during world war ii. it is spread by the rickettsia tsutsugamushi and has a wide variation in case fatality according to region, organism, and age of patient. rocky mountain spotted fever is a well-known and severe form of tick-borne typhus due to rickettsia rickettsii, occurring in western north america, europe, and asia. q. fever is a tick-borne disease caused by coxiella burnetii and is worldwide in distribution, usually associated with farm workers, in both acute and chronic forms. regular anti-tick spraying of sheep, cows, and goats helps protect exposed workers. protective clothing and regular removal of body ticks help protect exposed persons. arthropod-borne viral diseases are caused by a diverse group of viruses which are transmitted between vertebrate animals (often farm animals or small rodents) and people by the bite of blood-feeding vectors such as mosquitoes, ticks, and sandflies and by direct contact with infected animal carcasses. usually the viruses have the capacity to multiply in the salivary glands of the vector, but some are carried mechanically in their mouthparts. these viruses cause acute central nervous system infections (meningoencephalitis), myocarditis, or undifferentiated viral illnesses with polyarthritis and rashes, or severe hemorrhagic febrile illnesses. arbovirus diseases are often asymptomatic in vertebrates but may be severe in humans. over antigenetically distinct arboviruses are associated with disease in humans, varying from benign fevers of short duration to severe hemmorhagic fevers. each has a specific geographic location, vector, clinical, and virologic characteristics. they are of international public health importance because of the potential for spread via natural phenomena and modem rapid transportation of vectors and persons incubating the disease or ill with it, with potential for further spreading at the point of destination. arboviruses are responsible for a large number of encephalitic diseases characterized by mode of transmission and geographic area. mosquito-borne arboviruses causing encephalitis include eastern and western equine, venezuelan, japanese, and murray hill encephalitides. japanese encephalitis is caused by a mosquito-borne arbovirus found in asia and is associated with rice-growing areas. it is characterized by headache, fever, convulsions, and paralysis, with fatality rates in severe cases as high as %. a currently available vaccine is used routinely in endemic areas (japan, korea, thailand, india, and taiwan) and for persons traveling to infected areas. tick-borne arboviruses causing encephalitis include the powassan virus, which occurs sporadically in the united states and canada. tickborne encephalitis is endemic in eastern europe, scandinavia, and the former soviet union. an epidemic of mosquito-borne encephalitis in new york city in included cases and deaths, due to the west nile fever virus, never before found in the united states. other insect vectors. it affects animals and humans who are in direct contact with the meat or blood of affected animals. the virus causes a generalized illness in humans with encephalitis, hemorrhages, retinitis and retinal hemorrhage leading to partial or total blindness, and death ( - %). it also causes universal abortion in ewes and a high percentage of death in lambs. the normal habitat is in the rift valley of eastern africa (the great syrian-african rift), often spreading to southern africa, depending on climactic conditions. the primary reservoir and vector is the aedes mosquito, and affected animals serve to multiply the virus which is transmitted by other vectors and direct contact with animal fluids to humans. an unusual spread of rvf northward to the sudan and along the aswan dam reservoir to egypt in - caused hundreds of thousands of animal deaths, with , human cases and deaths. rvf appeared again in egypt in . this disease is suspected to be one of the ten plagues of egypt leading to the exodus of the children of israel from egypt during pharaonic-biblical times. in , an outbreak of rvf in kenya, initially thought to be anthrax, with hundreds of cases and dozens of deaths, was related to abnormal rainy season and vector conditions. satellite monitoring of rainfall and vegetation is being used to predict epidemics in kenya and surrounding countries. animal immunization, monitoring, vector control, and reduced contact with infected animals can limit the spread of this disease. arboviruses can also cause hemorrhagic fevers. these are acute febrile illnesses, with extensive hemorrhagic phenomena (internal and external), liver damage, shock, and often high mortality rates. the potential for international transmission is high. yellow fever. yellow fever is an acute viral disease of short duration and varying severity with jaundice. it can progress to liver disease and severe intestinal bleeding. the case fatality rate is < % in endemic areas, but may be as high as % in nonendemic areas and in epidemics. it caused major epidemics in the americas in the past, but was controlled by elimination of the vector, aedes aegypti. a live attenuated vaccine is used in routine immunization endemic areas and recommended for travelers to infected areas. determining the mode of transmission and vector control of yellow fever played a major role in the development of public health (see chapter ). in , the who reported , cases and , deaths from yellow fever globally. dengue hemorrhagic fever. dengue hemorrhagic fever is an acute sudden onset viral disease, with - days of fever, intense headache, myalgia, arthralgia, box . dengue fever and dengue hemorrhagic fever, dengue fever, a severe influenza-like illness, and dengue hemorrhagic fever are closely related conditions caused by four distinct viruses transmitted by aedes aegypti mosquitos. dengue is the world's most important mosquito-borne virus disease. a total of , million people worldwide are at risk of infection. an estimated million cases occur each year, of whom , need to be hospitalized. this is a spreading problem, especially in cities in tropical and subtropical areas. major outbreaks were reported in colombia, cuba, and many other locations in . source: world health organization. . world health report gastrointestinal disturbance, and rash. hemorrhagic phenomena can cause case fatality rates of up to %. epidemics can be explosive, but adequate treatment can greatly reduce the number of deaths. dengue occurs in southeast asia, the pacific islands, australia, west africa, the caribbean, and central and south america. an epidemic in cuba in included more than , cases, and deaths. vector control of the a. aegypti mosquito resulted in control of the disease during the s- s, but reinfestation of mosquitoes led to incresased transmission and epidemics in the pacific islands, caribbean, central and south america in the s and s. outbreaks in vietnam included , cases in , another , cases in , and a similar sized outbreak in . indonesia had over , cases in with deaths, and in over , cases (january-may) with at least deaths. in , epidemics of dengue were reported in fiji, the cook islands, new caledonia, and northern australia. the who estimates , deaths and . million cases worldwide in . monkeys are the main reservoir, and the vector is the a. aegypti mosquito. no vaccine is currently available, and management is by vector control. lassa fever. lassa fever was first isolated in lassa, nigeria, in and is widely distributed in west africa, with , - , cases and deaths annually. it is spread by direct contact with blood, urine, or secretions of infected rodents and by direct person-to-person contact in hospital settings. the disease is characterized by a persistent or spiking fever for - weeks, and may include severe hypotension, shock, and hemorrhaging. the case fatality rate is %. marburg disease. marburg disease is a viral disease with sudden onset of generalized illness, malaise, fever, myalgia, headache, diarrhea, vomiting, rash, and hemorrhages. it was first seen in marburg, germany, in , following ex-posure to green monkeys. person-to-person spread occurs via blood, secretions, organs, and semen. case fatality rates can be over %. ebola fever. ebola fever is a viral disease with sudden onset of generalized illness, malaise, fever, myalgia, headache, diarrhea, vomiting, rash, and hemorrhages. it was first found in zaire and sudan in in outbreaks which killed more than persons. it is spread from person to person by the blood, vomitus, urine, stools, and other secretions of sick patients, with a short incubation period. the disease has case fatality rates of up to %. an outbreak of ebola among laboratory monkeys in a medical laboratory near washington, d.c., was contained with no human cases. the reservoir for the virus is thought to be rodents. an outbreak of ebola in may in the town of kikwit, zaire, killed persons out of cases ( % case fatality rate). this outbreak caused international concern that the disease could spread, but it remained localized. another outbreak of ebola virus occurred in gabon in early , with cases, of whom had direct exposure to an infected monkey, the remainder by human-to-human contact, or not established; of the cases died ( %). this disease is considered highly dangerous unless outbreaks are effectively controlled. in zaire, lack of basic sanitary supplies, such as surgical gloves for hospitals, almost ensures that this disease will spread when it recurs. lyme disease is characterized by the presence of a rash, musculoskeletal, neurologic, and cardiovascular symptoms. confirmation is by laboratory investigation. it is the most common vector-borne disease in the united states, with , cases reported between and . it primarily affects children in the - age group and adults aged - . lyme disease is preventable by avoiding contact with ticks, by applying insect repellant, wearing long pants and long sleeves in infected areas, and by the early removal of attached ticks. several u.s. manufacturers produced vaccines which are approved for animal and human use. in the mid s, a mother of two young boys who were recently diagnosed with arthritis in the town of lyme, connecticut, conducted a private investigation among other town residents. she mapped each of the six arthritis cases in the town, cases which had occurred in a short time span among boys living in close proximity. this suggested that this syndrome of "juvenile rheumatoid arthritis" was perhaps connected with the boys playing in the woods. she presented her data to the head of rheumatology at yale medical school in new haven, who investigated this "cluster of a new disease entity." some parents reported that their sons had experienced tick bites and a rash before onset of the arthritis. a tick-borne, spiral shaped bacterium, a spirochete, borrelia burgdorferi, was identified as the organism, and ticks shown to be the vector. cases repond well to antibiotic therapy. in over , cases ( . per , ) were reported from states, an increase from , in and , in . cases were mainly located in the northeast, north central, and mid-atlantic regions. the disease accounts for over % of vector-borne disease in the united states and was the ninth leading reported infection in . lyme disease has been identified in many parts of north america, europe, the former soviet union, china, and japan. a newly licensed vaccine is effective for people exposed to ticks but not general usage. personal hygiene for protection from ticks and environmental modification are important to limit spread of the disease. source: cdc, , mmwr, : - ; and cdc, , mmwr, , no. . lyme disease website http://www.cdc.gov/ncidad/disease/lyme/lyme.htm medically important parasites are animals that live, take nourishment, and thrive in the body of a host, which may or may not harm the host, but never brings benefit. they include those caused by unicellular organisms such as protozoa, which include amoebas (malaria, schistosomiasis, amebiasis, and cryptosporidium), and helminths (worms), which are categorized as nematodes, cestodes, and trematodes. public health continues to face the problems of parasitic diseases in the developing world. increasingly, parasitic diseases are being recognized in industrialized countries. giardiasis and cryptosporidium infections in waterborne and other outbreaks have occurred in the united states. parasitic diseases are among the most common causes of illness and death in the world, e.g., malaria. milder illnesses such as giardiasis and trichomoniasis cause widespread morbidity. intestinal infestations with worms may cause of severe complications, although they commonly cause chronic low-grade symptomatology and iron deficiency anemia. echinococcosis (hydatid cyst disease) is infection with echinococcus granulosus, a small dog tapeworm. the tapeworm forms unilocular (single, noncompartmental) cysts in the host, primarily in the liver and lungs, but they can also grow in the kidney, spleen, central nervous system, or in bones. cysts, which may grow up to cm in size, may be asymptomatic or, if untreated, may cause severe symptoms and even death. this parasite is common where dogs are used with herd grazing animals and also have intimate contact with humans. the middle east, greece, sardinia, north africa, and south america are endemic areas, as are a few areas in the united states and canada. the human dis-ease has been eliminated in cyprus and australia. while the dog is the major host, intermediate hosts include sheep, cattle, pigs, horses, moose, and wolves. preventive measures include education in food and animal contact hygiene, destroying wild and stray dogs, and keeping dogs from the viscera of slaughtered animals. a similar, but multilocular, cystic hydatid disease is widely found in wild animal hosts in areas of the northern hemisphere, including central europe, the former soviet union, japan, alaska, canada, and the north-central united states. another echinococcal disease (echinococcus vogeli) is found in south america, where its natural host is the bush dog and its intermediate host is the rat. the domestic dog also serves as a source of human infection. surgical resection is not always successful, and long-term medical treatment may be required. control is through awareness and hygiene as well as the control of wild animals that come in contact with humans and domestic animals. control may require cooperation between neighboring countries. tapeworm infestation (taeniasis) is common in tropical countries where hygienic standards are low. beef (taenia saginata) and pork (t. solium) tapeworms are common where animals are fed with water or food exposed to human feces. freezing or cooking meat will destroy the tapeworm. fish tapeworm (diphyllobothrium latum) is common in populations living primarily on uncooked fish, such as inuit people. these tapeworms are usually associated with northern climates. toddlers are especially susceptible to dog tapeworm (dipylidium caninum), which is present worldwide, and domestic pets are often the source of oral-fecal transmission of the eggs. the disease is usually asymptomatic. similarly, dwarf tapeworm (hymenolepis nana) is transmitted through oral-fecal contamination from person to person, or via contaminated food or water. rat tapeworm (hymenolepis diminuta) also mostly affects young children. onchocerciasis (fiver blindness) is a disease caused by a parasitic worm, which produces millions of larvae that move through the body causing intense itching, debilitation, and eventually blindness. the disease is spread by a blackfly that transmits the larva from infected to uninfected people. it is primarily located in sub-saharan africa and in latin america, with over million persons at risk. control is by a combination of activities including environmental control by larvicidal sprays to reduce the vector population, protection of potential hosts by protective clothing and insect repellents, and case treatment. a who-initiated program for onchocerciasis control started in is sponsored by four international agencies: the food and agriculture organization (fao), the united nations development program (undp), the world bank, and who. it covers countries in sub-saharan africa, focusing on control of the blackfly by destoying its larvae, mainly via insecticides sprayed from the air. prevalence in was reported by who as over million persons. the program has been successful in protecting some million persons and helping . million infected persons to recover from this disease. who estimates that the program will have prevented , cases of blindness by the year and has freed million hectares of land for resettlement and cultivation. the program cost $ million. this investment is considered by the world bank to have a return of - % in terms of large scale land reuse and improved output of the population. a who program, the african program for onchocerciasis control (apoc), started in , uses a new drug (ivermectin) and selective vector control efforts by spraying. this involves countries in africa, and in a similar program in south america. see website http://www/who.int/ocp and is financed by many donor countries, internation organizations, merck & company, and ngos. dracunculiasis (guinea worm disease) is a parasitic disease of great public health importance in india, pakistan, and central and west africa. it is an infection of the subcutaneous and deeper tissues caused by a large ( cm) nematode, usually affecting the lower extremities and causing pain and disability. the nematode causes a burning blister on the skin when it is ready to release its eggs. after the blister ruptures, the worm discharges larvae whenever the extremity is in water. the eggs are ingested in contaminated water and the larva released migrate through the viscera to locate as adults in the subcutaneous tissue of the leg. incubation is about months. the larva released in water are ingested by minute crustaceans and remain infective for as long as a month. prevention is based on improving the safety of water supplies and by preventing contamination by infected persons. education of persons in endemic areas to stay out of water sources and to filter drinking water reduces transmission. insecticides remove the crustaceans. chlorine also kills the larvae and the crustaceans which prologue larval infectivity. there is no vaccine. treatment is helpful, but not definitive. dracunculiasis was traditionally endemic in a belt from west africa through the middle east to india and central asia. it was successfully eliminated from central asia and iran and has disappeared from the middle east and from some african countries (gambia and guinea). the world health organization has promoted the eradication of dracunculiasis. major progress has been made in this direction. worldwide prevalence is reported to have been reduced from million cases in to million in , , in , and , cases in . eradication was anticipated for the year , and in the who established a commission to monitor and certify eradication in formerly endemic areas. india's reported cases fell from , in to in , and the country was free of transmission in . in , formerly high prevalence countries such as kenya reported no cases in , while chad, senegal, cameroons, yemen, and the central african republic less than cases each. eradication of this disease appears to be imminent. the who eradication program was developed successfully as an independent program with its own direction and field staff, but further progress will require the integration of this program with other basic primary care programs in order to be self-sustaining as an integral part of community health. community-based surveillance systems for this disease are being converted to work for monitoring of other health conditions in the community. schistosomiasis (snail fever or bilharziasis) is a parasitic infection caused by the trematode (blood fluke) and transmitted from person to person via an intermediate host, the snail. it is endemic in countries in africa, south america, the caribbean, and asia. there are an estimated million persons infected worldwide and more than million at risk for the disease. the clinical symptoms include fever, nausea, vomiting, abdominal pain, diarrhea, and hematuria. the organisms schistosoma mansoni and s. japonicum cause intestinal and hepatic symptoms, including diarrhea and abdominal pain. schistosoma haematobium affects the genitourinary tract, causing chronic cystitis, pyelonephritis, with high risk for bladder cancer the ninth most common cause of cancer deaths globally. infection is acquired by skin contact with freshwater containing contaminated snails. the cercariae of the organism penetrate the skin, and in the human host it matures into an adult worm that mates and produces eggs. the eggs are disseminated to other parts of the body from the worm's location in the veins surrounding the bladder or the intestines, and may result in neurological symptoms. eggs may be detected under microscopic examination of urine and stools. sensitive serologic tests are also available. treatment is effective against all three major species of schistosomiasis. eradication of the disease can be achieved with the use of irrigation canals, prevention of contamination of water sources by urine and feces of infected persons, treatment of infected persons, destruction of snails, and health education in affected areas. persons exposed to freshwater lakes, streams, and rivers in endemic areas should be warned of the danger of infection. mass chemotherapy in communities at risk and improved water and sanitation facilities are resulting in improved control of this disease. leishmaniasis causes both cutaneous and visceral disease. the cutaneous form is a chronic ulcer of the skin, called by various names, e.g., rose of jericho, oriental sore, and aleppo boil. it is caused by leishmania tropica, l. brasiliensis, l. mexicana, or the l. donovani complex. this chronic ulcer may last from weeks to more than a year. diagnosis is by biopsy, culture, and serologic tests. the organism multiplies in the gut of sandflies (phlebotomus and lutzomi) and is transmitted to humans, dogs, and rodents through bites. the parasites may remain in the untreated lesion for - months, and the lesion does not heal until the parasites are eliminated. prevention is through limiting exposure to the phlebotomines and reducing the sandfly population by environmental control measures. insecticide use near breeding places and homes has been successful in destroying the vector sandflies in their breeding places. case detection and treatment reduce the incidence of new cases. there is no vaccine, and treatment is with specific antimonials and antibiotics. visceral leishmaniasis (kala azar) is a chronic systemic disease in which the parasite multiplies in the cells of the host's visceral organs. the disease is characterized by fever, the enlargement of the liver and spleen, lymphadenopathy, anemia, leukopenia, and progressive weakness and emaciation. diagnosis is by culture of the organism from biopsy or aspirated material, or by demonstration of intracellular (leishman-donovan) bodies in stained smears from bone marrow, spleen, liver, or blood. kala azar is a rural disease occurring in the indian subcontinent, china, the southern republics of the former u.s.s.r., the middle east, latin america, and sub-saharan africa. it usually occurs as scattered cases among infants, children, and adolescents. transmission is by the bite of the infected sandfly with an incubation period of - months. there is no vaccine, but specific treatment is effective and environmental control measures reduce the disease prevalence. this includes the use of antimalarial insecticides. in localities where the dog population has been reduced, the disease is less prevalent. sleeping sickness. sleeping sickness a disease caused by trypanosoma brucei, transmitted but the tsetse fly, primarily in the african savannahs, affecting cattle and humans. some million persons are at risk in sub-saharan africa. who reported , new cases, a total prevalence of , cases, and , deaths from this disease in . prevention depends on vector control, and effective treatment of human cases. chagas disease is a chronic and incurable vector and blood transfusion borne parasitic disease (trypanosoma cruzi) which causes disability and death. it affects some million persons mainly in latin america, with some , new cases and , deaths occurring annually. about % of affected persons develop severe heart disease. brazil, which accounts for % of the cases prevalent in latin america, achieved elimination of transmission in , after uruguay ( ) and venezuela ( ) and followed by argentina ( ) . elimination of transmission is projected by who by the year . control is difficult, but control measures include reducing the animal host and vector insect population in its habitat by ecological and insectiside measures, education of the population in prevention by clothing, bednets, and repellents, and with chemotherapy for case management. amebiasis. amebiasis is an infection with a protozoan parasite (entamoeba histolytica) which exists as an infective cyst. infestation may be asymptomatic or cause acute, severe diarrhea with blood and mucus, alternating with constipation. amebic colitis can be confused with ulcerative colitis. diagnosis is by microscopic examination of fresh fecal specimens showing trophozoites or cysts. transmission is generally via ingestion of fecal-contaminated food or water containing cysts, or by oral-anal sexual practices. amebiasis is found worldwide. sand filtration of community water supplies removes nearly all cysts. suspect water should be boiled. education regarding hygienic practices with safe food and water handling and disposal of human feces are the basis for control. ascariasis. ascariasis is infestation of the small intestine with the roundworm ascaris lumbricoides, which may appear in the stool, occasionally the nose or mouth, or may be coughed up from lung infestation. the roundworm is very common in tropical countries, where infestation may reach or exceed % of the population. children aged - years are especially susceptible. infestation can cause pulmonary symptoms and frequently contributes to malnutrition, especially iron deficiency anemia. transmission is by ingestion of infective eggs, common among children playing in contaminated areas, or via the ingestion of uncooked products of infected soil. eggs may remain viable in the soil for years. vermox and other treatments are effective. prevention is through education, adequate sanitary facilities for excretion, and improved hygienic practices, especially with food. use of human feces for fertilizer, even after partial treatment, may spread the infestation. mass treatment is indicated in high prevalence communities. pinworm disease or enterobiasis. pinworm disease (oxyuriasis) is common worldwide in all socioeconomic classes; however, it is more widespread when crowded and unsanitary living conditions exist. the enterobius vermicularis infestation of the intestine may be symptomless or may cause severe perianal itching or vulvovaginitis. it primarily affects schoolchildren and preschoolers. more severe complications may occur. adult worms may be seen visually or identified by microscopic examination of stool specimens or perianal swabs. transmission is by the oral-fecal ingestion of eggs. the larvae grow in the small intestine and upper colon. prevention is by educating the public regarding hygiene and adequate sanitary facilities, as well as by treating cases and investigating contacts. treatment is the same as for ascariasis. mass treatment is indicated in high prevalence communities. ectoparasites. ectoparasites include scabies (sarcoptes scabiei), the common bed bug (cimex lectularius), fleas, and lice, including the body louse (pediculus humanis), pubic louse (phthirius pubis), and the head louse (pediculus humanus capitis). their severity ranges from nuisance value to serious public health hazard. head lice are common in schoolchildren worldwide and are mainly a distressing nuisance. the body louse serves as a vector for epidemic typhus, trench fever, and louse-borne relapsing fever. in disaster situations, disinfection and hygienic practices may be essential to prevent epidemic typhus. the flea plays an important role in the spread of the plague by transmitting the organism from the rat to humans. control of rats has reduced the flea population, but during war and disasters, rat and flea populations may thrive. scabies, which is caused by a mite, is common worldwide and is transmitted from person to person. the mite burrows under the skin and causes intense itching. all of these ectoparasites are preventable by proper hygiene and the treatment of cases. the spread of these diseases is rapid and therefore warrants attention in school health and public health policy. legionnelae, a gram-negative group of bacilli, with species and many serogroups. the first documented case was reported in the united states in , and the first disease outbreak was reported in the united states in among participants of a war veterans convention. general malaise, anorexia, myalgia, and headache are followed by fever, cough, abdominal pain, and diarrhea. pneumonia followed by respiratory failure may follow. the case fatality rate can be as high as % of hospitalized cases. a milder, nonpneumonic form of the disease (pontiac fever) is associated with virtually no mortality. the organism is found in water reservoirs and is transmitted through heating, cooling, and air conditioning systems, as well as from tap water, showers, saunas, and jaccuzzi baths. the disease has been reported in australia, canada, south america, europe, israel, and on cruise ships. prevention requires the cleaning of water towers and cooling systems, including whirlpool spas. hyperchlorination of water systems and the replacement of filters is required where cases and/or organisms have been identified. antibiotic treatment with erythromycin is effective. leprosy (hansen's disease) was widely prevalent in europe and mediterranean countries for many centuries, with some , leprosaria in the year . leprosy was largely wiped out during the black death in the fourteenth century, but continued in endemic form until the twentieth century. leprosy is a chronic bacterial infection of the skin, peripheral nerves, and upper airway. in the lepromatous form, there is diffuse infiltration of the skin nodules and macules, usually bilateral and extensive. the tuberculoid form of the disease is characterized by clearly demarcated skin lesions with peripheral nerve involvement. diagnosis is based on clinical examination of the skin and signs of peripheral nerve damage, skin scrapings, and skin biopsy. transmission of the mycobacterium leprae organism is by close contact from person to person, with incubation periods of between months and years (average of - years). rifampicin and other medications make the patient noninfectious in a short time, so that ambulatory treatment is possible. multidrug therapy (mdt) has been shown to be highly effective in combating the disease, with a very low relapse rate. treatment with mdt ensures that the bacillus does not develop drug resistance. mdt is covering % of known cases in , according to who reports, as compared to only % in . the increase has been associated with improved case finding. bcg may be useful in reducing tuberculoid leprosy among contacts. investigation of contacts over years is recommended. the disease is still highly endemic primarily in five countries, india, brazil, indonesia, myanmar, and bangladesh, and is still present in some countries in southeast asia, including the philippines and burma, sub-saharan africa, the middle east (sudan, egypt, iran), and in some parts of latin america (mexico, colombia) with isolated cases in the united states. world prevalence has declined from . million cases in , . million in , to less than million cases in . the world health organization expects to eliminate leprosy as a public health problem by the year , defined as prevalence of less than per , population, or less than , cases. trachoma is currently responsible for million blind persons or % of total blindness in the world. the causative organism, chlamydia trachomatis, is a bacteria which can survive only within a cell. it is spread through contact with eye discharges, usually by flies, or household items (e.g., handkerchiefs, washcloths). trachoma is common in poor rural areas of central america, brazil, africa, parts of asia, and some countries in the eastern mediterranean. the resulting infection leads to conjuncfival scarring and if untreated, to blindness. who estimates there are million cases of active disease in endemic countries. hygiene, vector control, and treatment with antibiotic eye ointments or simple surgery for scarring of eyelids and inturned eyelashes prevent the blindness. a new drug, azithromycin, is effective in curing the disease. the who is promoting a program for the global elimination of trachoma using azithromycin and hygiene education in endemic areas. chlamydia (chlamydia pneumonia) is suspected of playing a role in coronary artery disease by intraarterial infection, with plaque formation and occlusion of the artery by thrombi consisting mainly of platelets. if borne out, this will provide potential for low cost intervention to reduce the burden of the leading worldwide cause of death. sexually transmitted diseases (stds) are widespread internationally with an estimated million new cases per year, with . million new cases, over million total cases, and . million deaths ( ), aids has captured world attention over the past decade. the global burden of stds is enormous (table . ), and the public health and social consequences are devastating in many countries. sexually transmitted diseases, especially in women, may be asymptomatic, so that severe sequelae may occur before patients seek care. infection by one std increases risk of infection by other diseases in this group. syphilis is caused by the spirochete treponema pallidum. after an incubation period of - days (mean - ), primary syphilis develops as a painless ulcer or chancre on the penis, cervix, nose, mouth, or anus, lasting - weeks. the patient may first present with secondary syphilis - weeks (up to weeks) after infection with a general rash and malaise, fever, hair loss, arthritis, and jaundice. these symptoms spontaneously disappear within weeks or up to months later. tertiary syphilis may appear - years after initial infection. complications of tertiary syphilis include catastrophic cardiovascular and central nervous system conditions. early antibiotic treatment is highly effective when given in a large initial dose, but longer term therapy may be needed if treatment is delayed. gonorrhea (gc) is caused by the bacterium neisseria gonorrhoeae. the incubation period is - days. gonorrhea is often associated with concurrent chlamydia infection. in women, gc may be asymptomatic or it may cause vaginal discharge, pain on urination, bleeding on intercourse, or lower abdominal pain. untreated, it can lead to sterility. in men, gc causes urethral discharge and painful urination. treatment with antibiotics ends infectivity, but untreated cases can be infectious for months. drug resistance to penicillin and tetracycline has increased in many countries so that more expensive and often unavailable drugs are necessary for treatment. prevention of gonococcal eye infection in newborns is based on routine use of antibiotic ointments in the eyes of newborns. chancroid. chancroid is caused by haemophilus ducreyi. in women chancroids may cause a painful, irregular ulcer near the vagina, resulting in pain on in-tercourse, urination, and defection, but it may be asymptomatic. in men it causes a painful, irregular ulcer on the penis. the incubation period is usually - days, but may be up to days. an individual is infectious as long as there are ulcers, usually - months. treatment is by erythromycin or azithromycin. herpes simplex. herpes simplex is caused by herpes simplex virus types and and has an incubation period of - days. genital herpes causes painful blisters around the mouth, vagina, penis, or anus. the genital lesions are infectious for - days. herpes may lead to central nervous system meningoencephalitis infection. it can be transmitted to newborns during vaginal delivery, causing infection, encephalitis, and death. cesarian delivery is therefore necessary when a mother is infected. anti-viral drugs are used in treatment, orally, topically, or intravenously. chlamydia. chlamydia is caused by chlamydia trachomatis. in women, it is usually asymptomatic but may cause vaginal discharge, spotting, pain on urination, lower abdominal pain, and pelvic inflammatory disease (pid). in newborns, chlamydia may cause eye and respiratory infections. in men, chlamydia causes urethral discharge and pain on urination. the incubation period is - days and the infectious period is unknown. treatment for chlamydia is doxycycline, azithromycin, or erythromycin. chlamydia infection, not necessarily venereal in transmission, may be transmitted to newborns of infected mothers. chlamydia pneumoniae, presently under investigation as a possible cause or contributor to coronary heart disease, and is widespread in poor hygenic conditions. trichomoniasis. trichomoniasis is caused by trichomonas vaginalis. the incubation period is - days (mean = ). in women, trichomoniasis may be asymptomatic or may cause a frothy vaginal discharge with foul odor, and painful urination and intercourse. in men, the disease is usually mild, causing pain on urination. treatment is by metronidazole taken orally. without treatment, the disease may persist and remain infectious for years. (hpv). it is a sporadic disease which may be associated with cervical neoplasia and cancer of the cervix. hpv includes many types associated with a variety of conditons. the search for a hpv vaccine to prevent cancer of the cervix looks promising. in areas where a full range of diagnostic services is lacking, a "syndromic approach" is recommended for the control of stds. the diagnosis is based on a group of symptoms and treatment on a protocol addressing all the diseases that could possibly cause those symptoms, without expensive laboratory tests and repeated visits. early treatment without laboratory confirmation helps to cure persons who might not return for follow-up, or may place them in a noninfective stage so that even without follow-up they will not transmit the disease. std incidence between and is shown in table . , with decline overall except around , with subsequent further fall in incidence. screening in prenatal and family planning clinics, prison medical services, and selected years - disease syphilis ( [ ] [ ] [ ] [ ] [ ] [ ] and subsequent decline by more than % in reported cases includes all three stages of the disease as well as congential syphilis. rates are cases per , population, rounded. in clinics serving prostitutes, homosexuals, or other potential risk groups will detect subclinical cases of various stds. treatment can be carried out cheaply and immediately. for instance, the screening test for syphilis costs $ . and the treatment with benzathine penicillin injection costs about $ . in . partner notification is a controversial issue, but may be needed to identify contacts who may be the source of transmission to others. control of stds through a syndrome approaach based on primary care providers is being promoted by who. health education directed at high risk target groups is essential. providing easy and cost-free access to acceptable, nonthreatening treatment is vital in promoting the early treatment of cases and thereby reducing the risk of transmission. promoting prevention through the use of condoms and/or monogamy requires long-term educational efforts that are now fostered by the hiv/aids pandemic. increased use of condoms for hiv prevention is associated with reduced risk of other stds. training medical care providers in std awareness should be stressed in undergraduate and continuing educational efforts including personal protection as care givers. human immunodeficiency virus (hiv) is a retrovirus that infects various cells of the immune system, and also affects the central nervous system. two types have been identified: hiv , worldwide in distribution, and the less pathogenic hiv , found mainly in west africa. hiv is transmitted by sexual contact, exposure to blood and blood products, perinatally, and via breast milk. the period of communicability is unknown, but studies indicate that infectiousness is high, both during the initial period after infection and later in the disease. antibodies to hiv usually appear within - months. within several weeks to months of the infection, many persons develop an acute self-limited flulike syndrome. they may then be free of any signs or symptoms for months to more than years. onset of illness is usually insidious with nonspecific symptoms, including sweats, diarrhea, weight loss, and fatigue. aids represents the later clinical stage of hiv infection. according to the revised cdc case definition ( ), aids involves any one or more of the following: low cd count, severe systematic symptoms, opportunistic infections such as pneumocystis pneumonia or tb, aggressive cancers such as kaposi's sarcoma or lymphoma, and/or neurological manifestations, including dementia and neuropathy. the who case definition is more clinically oriented, relying less on often unavailable laboratory diagnoses for indicator diseases. aids was first recognized clinically in in los angeles and new york. by mid- it was considered an epidemic in those and other u.s. cities. it was primarily seen among homosexual men and recipients of blood products. after initial errors, testing of blood and blood products became standard and has subsequently closed off this method of transmission. transmission has changed markedly since the initial onslaught of the disease, with needle sharing among intravenous drug users, heterosexual, and maternal-fetal transmission becoming major factors. comorbidity with other stds apparently increases hiv infectivity and may have helped to convert the epidemiology to a greater degree of heterosexual transmission. the disease grew exponentially in the united states (table . ), but incidence of new cases nas declined since . aids has become a major public health problem in most developed and developing countries, reaching catastrophic proportions in some sub-saharan african countries affecting up to % of the population. hiv-related deaths were the eighth leading cause of all deaths in in the u.s., the leading cause among men aged - years of age, and the fourth leading cause for women in this age group. by , aids had been diagnosed in , persons and , had died. it is estimated that up to million persons are hiv infected in the united states. globally, deaths from aids totalled . million in , with an estimated . million person having died from this pandemic up to . in , an estimated . million person were hiv infected with . million new infection in . the declining incidence of new cases in the industrialized countries may be the result of greater awareness of the disease and methods of prevention of transmission. improving early diagnosis and access to care, especially the combined therapy programs that are very effective in delaying onset of symptoms, are important parts of public health management of the aids crisis. until an effective vaccine is available, preventive reliance will continue to be on behavior risk-reduction and other prevention strategies such as needle and condom distribution among high risk population groups. throughout the world, hiv continues to spread rapidly, especially in poor countries in africa, asia, and south and central america. the united nations reports that million persons are living with hiv/aids, % of them in developing countries, where transmission is % by heterosexual contact. every day, more than persons are infected, including children. in thailand, person in is now infected. in sub-saharan africa person in is infected, and in some cities as many as person in carries the virus. estimations of new infections per year in sub-saharan africa range from to million persons, while in asia the range is from . to . million new infected persons per year. lessons are still being learned from the aids pandemic. the explosive spread of this infection, from an estimated , people in to an anticipated million persons hiv infected, shows that the world is still vulnerable to pandemics of "new" infectious diseases. enormous movements of tourists, business people, truck drivers, migrants, soldiers, and refugees promote the spread of such diseases. widespread sexual exchange, traffic in blood products, and illicit drug use all promote the international potential for pandemics. war and massive refugee situations promote rape and prostitution, worsening the aids situation in some settings in africa. hiv has arrived in almost every country. however, there is the somewhat hopeful indication that the rate of increase, has slowed in the united states. this may be an indication either of higher levels of self-protective behavior, or that the most susceptible population groups have already been affected and the spread into the general population is at a slower rate. it is also possible that this may yet prove to be only a lull in the storm, as heterosexual contact becomes a more important mode of transmission. the eleventh international conference on aids, held in vancouver, canada, in july , reported signs that combinations of several drugs from among a number of antiretroviral medications are showing promise to suppress the aids virus in infected people. at a current annual price of $ , - , per patient, these sums well beyond the capacity of most developing countries. development of methods of measuring the hiv viral load have allowed for better evaluation of potential therapies and monitoring of patients receiving therapy. in developed countries, transmission by blood products has been largely controlled by screening tests; transmission among homosexuals has been reduced by safe sex practices; transmission to newborns has been reduced by recent therapeutic advances. safe sex practices and condom use may have helped in reducing heterosexual transmission. further advances in therapy and prevention with a vaccine are expected over the next decade. the hiv/aids pandemic is one of the great challenges to public health for the st century due to its complexity, its international spread, its sexual and other modes of transmission, its devastating and costly clinical effects, and its impact on parallel diseases such as tuberculosis, respiratory infections, and cancer. the cost of care for the aids patient can be very high. needed programs include home care and community health workers to improve nutrition and self-care, and mutual help among hiv carriers and aids patients. the ethical issues associated with aids are also complex regarding screening of pregnant women, newborns, partner notification, reporting, and contact tracing, as well as financing the cost of care. diarrheal diseases are caused by a wide variety of bacteria, parasites, and viruses (table . ) infecting the intestinal tract and causing secretion of fluids and dis- solved salts into the gut with mild to severe or fatal complications. in developing countries, diarrheal diseases account for half of all morbidity and a quarter of all mortality. diarrhea itself does not cause death, but the dehydration resulting from fluid and electrolyte loss is one of the most common causes of death in children worldwide. deaths from dehydration can be prevented by use of oral rehydration therapy (ort), an inexpensive and simple method of intervention easily used by a nonmedical primary care worker and by the mother of the child as a home intervention. in , diarrheal diseases were the cause of almost million child deaths, but by this had declined to . million, largely under the impact of increased use of ort. diarrheal diseases are transmitted by water, food, and directly from person to person via oral-fecal contamination. diarrheal diseases occur in epidemics in situations of food poisoning or contaminated water sources, but can also be present at high levels when common source contamination is not found. contamination of drinking water by sewage and poor management of water supplies are also major causes of diarrheal disease. the use of sewage for the irrigation of vegetables is a common cause of diarrheal disease in many areas. salmonella are a group of bacterial organisms causing acute gastroenteritis, associated with generalized illness including headache, fever, abdominal pains, and dehydration. there are over serotypes of salmonella, many of which are pathogenic in humans, the most common of which are salmonella typhimurium, s. enteritidis, and s. typhi. transmission is by ingestion of the organisms in food, derived from fecal material from animal or human contamination. common sources include raw or uncooked eggs, raw milk, meat, poultry and its products, as well as pet turtles or chicks. fecal-oral transmission from person to person is common. prevention is in safe animal and food handling, refrigeration, sanitary preparation and storage, protection against rodent and insect contamination, and the use of sterile techniques during patient care. antibiotics may not eliminate the carrier state and may produce resistant strains. shigella are a group of bacteria that are pathogenic in man, with four groups: type a = shigella dysenteriae, type b = s. flexneri, type c = s. boydii, and type d = s. sonnei. types a, b, and c are each further divided into a total of serotypes. shigella are transmitted by direct or indirect fecal-oral methods from a patient or carrier, and illness follows ingestion of even a few organisms. water and milk transmission occurs as a result of contamination. flies can transmit the organism, and in nonrefrigerated foods the organism may multiply to an infectious dose. control is in hygienic practices and in the safe handling of water and food. escheria eoli e. coli are common fecal contaminants of inadequately prepared and cooked food. particularly virulent strains such as o :h can cause explosive outbreaks of severe (enterohemmorhagic) diarrhoeal disease with a hemolytic-uremic syndrome and death, as occurred in japan in with cases and deaths due to a foodborne epidemic. other milder strains cause travellers diarrhoea and nursery infections. inadequately cooked hamburger, unpasturized milk, and other food vectors are discussed under food safety in chapter . cholera is an acute bacterial enteric disease caused by vibrio cholerae, with sudden onset, profuse painless watery stools, occasional vomiting, and, if untreated, rapid dehydration, and circulatory collapse, and death. asymptomatic infection or carrier status, and mild cases are common. in severe, untreated cases, mortality is over %, but with adequate treatment, mortality is under %. diagnosis is based on clinical signs, epidemiologic, serologic and bacteriologic confirmation by culture. the two types of cholera are the classic and el tor (with inaba and ogawa serotypes). in , a large scale epidemic of cholera spread through much of south america. it was imported via a chinese freighter, whose sewage contaminated shellfish in lima harbor in peru (box . ). the south american cholera epidemic has caused hundreds of thousands of cases and thousands of deaths since . prevention requires sanitation, particularly the chlorination of drinking water, prohibiting the use of raw sewage for the irrigation of vegetable crops, and high standards of community, food, and personal hygiene. treatment is prompt fluid therapy with electrolytes in large volume to replace all fluid loss. oral rehydration should be accomplished using standard ort. tetracycline shortens the duration of the disease, and chemoprophylaxis for contacts following stool samples may help in reducing its spread. a vaccine is available but is of no value in the prevention of outbreaks. viral gastroenteritis can occur in sporadic or epidemic forms, in infants, children, or adults. some viruses, such as the rotaviruses and enteric adenoviruses, af- in the s, peruvian officials stopped the chlorination of community water supplies because of concern over possible carcinogenic effects of trihalomethanes, a view encouraged by officials of the u.s. environmental protection agency (epa) and the u.s. public health service. in january , a chinese freighter arrived in lima, peru, and dumped bilge (sewage) in the harbor, apparently contaminating local shellfish. consumption of raw shellfish is a popular local delicacy (ceviche) and associated with cases of cholera seen in local hospitals. contamination of local water supplies from sewage resulted in the geometric increase in cases, and by the end of the pan american health organization (paho) reported an epidemic of , cases and deaths. the epidemic spread to countries, and in there were a further , cases and deaths spreading over much of south america, continuing in . in the united states, cases of cholera were reported in ; of these, cases and death were among passengers of an airplane flying from south america to los angeles in which contaminated seafood was served. in , cases of cholera were reported in the united states which were unrelated to international travel. these occurred mostly among persons consuming shellfish from the gulf coast with a strain of cholera similar to the south american strain, also possibly introduced in ship ballast. cholera organisms are reported in harbor waters in other parts of the united states (promed, , promed, . fect mainly infants and young children, and may be severe enough to cause hospitalization for dehydration. others such as norwalk and norwalk-like viruses affect older children and adults in self-limited acute gastroenteritis in family, institution, or community outbreaks. rotaviruses cause acute gastroenteritis in infants and young children, with fever and vomiting, followed by watery diarrhea and occasionally severe dehydration and death if not adequately treated. diagnosis is by examination of stool or rectal swabs with commercial immunologic kits. in both developed and developing countries, rotavirus is the cause of about one-third of all hospitalized cases for diarrheal diseases in infants and children up to age . most children in developing countries experience this disease by the age of years, with the majority of cases between and months. in developing countries, rotaviruses are estimated to cause over , deaths per year. the virus is found in temperate climates in the cooler months and in tropical countries throughout the year. breastfeeding does not prevent the disease but may reduce its severity. oral rehydration therapy is the key treatment. a live attenuated vaccine was approved by the fda in and adopted in the u.s. recommended routine vaccination programs for infants. adenoviruses. adenoviruses, norwalk, and a variety of other viruses (including astrovirus, calcivirus, and other groups) cause sporadic acute gastroenteritis worldwide, mostly in outbreaks. spread is by the oral-fecal route, often in hospital or other communal settings, with secondary spread among family contacts. food-borne and waterborne transmission are both likely. these can be a serious problem in disaster situations. no vaccines are available. management is with fluid replacement and hygienic measures to prevent secondary spread. giardiasis. giardiasis (caused by giardia lamblia) is a protozoan parasitic infection of the upper small intestine, usually asymptomatic, but sometimes associated with chronic diarrhea, abdominal cramps, bloating, frequent loose greasy stools, fatigue, and weight loss. malabsorption of fats and vitamins may lead to malnutrition. diagnosis is by the presence of cysts or other forms of the organism in stools, duodenal fluid, or in intestinal mucosa from a biopsy. this disease is prevalent worldwide and affects mostly children. it is spread in areas of poor sanitation and in preschool settings and swimming pools, and is of increasing importance as a secondary infection among immunocompromised patients, especially those with aids. waterborne giardia was recognized as a serious problem in the united states in the s and s, since the protozoa is not readily inactivated by chlorine, but requires adequate filtration before chlorination. person-to-person transmission in day-care centers is common, as is transmission by unfiltered stream or lake water where contamination by human or animal feces is to be expected. an asymptomatic carrier state is common. prevention relies on careful hygiene in settings such as day-care centers, filtration of public water supplies and the boiling of water in emergency situations. cryptosporidium. cryptosporidium parvum is a parasitic infection of the gastrointestinal tract in man, small and large mammals and vertebrates. infection may be asymptomatic or cause a profuse, watery diarrhea, abdominal cramps, general malaise, fever, anorexia, nausea, and vomiting. in immunosuppressed patients, such as persons with aids, it can be a serious problem. the disease is most common in children under years of age and those in close contact with them, as well as in homosexual men. diagnosis is by identification of the cryptosporidium or-ganism cysts in stools. the disease is present worldwide. in europe and the united states, the organism has been found in < to . % of individuals sampled. spread is common by person-to-person contact by fecal-oral contamination, especially in such settings as day-care centers. raw milk and waterborne outbreaks have also been identified in recent years. a large waterborne disease outbreak due to cryptosporidium occurred in milwaukee in described in chapter . management is by rehydration and prevention is by careful hygiene in food and water safety. helicobacter pylori. helicobacter pylori, first identified in , is a bacterium causally linked to duodenal ulcers and gastritis, contributing to high rates of gastric cancer (chapter ). it is an important example of the link between infection and chronic disease. this has enormous implications for prevention of cancer of the stomach, chronic peptic ulcers and large-scale use of hospitals and other medical resources (see chapter ). the control of diarrheal diseases requires a comprehensive program involving a wide range of activities, including good management of food and water supplies, education in hygiene, and, particularly where morbidity and mortality are high, education in the use of oral rehydration therapy (ort). oral rehydration therapy (ort) is considered by unicef and who to have resulted in the saving of million lives each year in the s. proper management of an episode of diarrhea by ort (table . ), along with continued feeding, not only saves the child from dehydration and immediate death, but also contributes to early restoration of nutritional adequacy, sparing the child the prolonged effects of malnutrition. the world summit for children (wsc) in called for a reduction in child deaths from diarrheal diseases by one-third and malnutrition by one-half, with em- phasis on the widest possible availability, education for, and use of ort. this requires a programmatic approach. public health leadership must train primary care doctors, pediatricians, pharmacists, drug manufacturers, and primary care health workers of all kinds in ort principles and usage. they must be backed by the widest possible publicity to raise awareness among parents. oral rehydration therapy is an important public health modality in developed countries as well as in developing countries. diarrhoeal disease may not cause death as frequently in developed countries, but it is still a significant factor in infant and child health and, even under the most optimal conditions, can cause setbacks in the nutritional state and physical development of a child. use of ort does not prevent the disease (i.e., it is not a primary prevention), but it is excellent in secondary prevention, by preventing complications from diarrhoea, and should be available in every home for symptomatic treatment of diarrheal diseases. an adaptation of ort has found its place in popular culture in the united states. a form of ort, marketed as "sports drinks," is used in sports where athletes lose large quantifies of water and salts in sweat and insensible loss from the respiratory tract. the wider application of the principles of ort for use in adults in dry hot climates and in adults under severe physical exertion with inadequate fluid/salt intake situations requires further exploration. management of diarrheal diseases should be part of a wider approach to child nutrition. the child who goes through an episode of diarrheal disease may have a faltering in growth and development. supportive measures may be needed following the episode as well as during it. this involves providing primary care services that are attuned to monitoring individual infant and child growth. growth monitoring surveillance is important to assess the health status of the individual child and the child population. supplementation of infant feeding with vitamins a and d, and iron to prevent anemia are important for routine infant and child care, and more so for conditions affecting total nutrition such as a diarrheal disease. in the developing world, respiratory infections account for over one-quarter of all deaths and illnesses in children. as diarrheal disease deaths are reduced, the major cause of death among infants in developing countries is becoming acute respiratory infections (aris). in industrialized countries, aris are important for their potentially devastating effects on the elderly and chronically ill. they are also the major cause of morbidity in infants in developed countries, causing much anxiety to parents even in areas with good living conditions. cigarette smoking, chronic bronchitis, poorly controlled diabetes or congestive heart failure, and chronic liver and kidney disease increase susceptibility to aris. aris place a heavy burden on health care systems and individual families. improved methods of management of such chronic diseases are needed to reduce the associated toll of morbidity, mortality, and the considerable expenses of health care. acute respiratory infections are due to a broad range of viral and, to a lesser extent, bacterial infections. it is the latter which can progress to pneumonia with mortality rates of - %. acute viral respiratory diseases include those affecting the upper respiratory tract, such as acute viral rhinitis, pharyngitis, and laryngitis, as well as those affecting the lower respiratory tract, tracheobronchitis, bronchitis, bronchiolitis, and pneumonia. aris are frequently associated with vaccine-preventable diseases, including measles, varicella, and influenza. they are caused by a large number of viruses, producing a wide spectrum of acute respiratory illness. some organisms affect any part of the respiratory tract, while others affect specific parts and all predispose to bacterial secondary infection. while children and the elderly are especially susceptible to morbidity and mortality from acute respiratory disease, the vast numbers of respiratory illnesses among adults cause large-scale economic loss from work absence. bacterial agents causing upper respiratory tract infection include group a streptococcus, mycoplasma pneumonia, pertussis, and parapertussis. pneumonia or acute bacterial infection of the lower respiratory tract and lung tissue may be due to pneumococcal infection with streptococcus pneumoniae. there are known types of this organism, distinguished by capsule characteristics; account for % of pneumococcal infections in the united states. an excellent polyvalent vaccine based on these types is available for high risk groups such as the elderly, immunodeficient patients, and persons with chronic heart, lung, liver, blood disorders, or diabetes. opportunistic infections attack the chronically ill, especially those with compromised immune suystems, often with life-threatening aris. mycoplasma (primary atypical pneumonia) is a lower respiratory tract infection which sometimes progresses to pneumonia. tb and pneumonocytis carynia are especially problematic for aids patients. other organisms causing pneumonias include chlamydia pneumoniae, h. influenza, klebsiella pneumonia, escherichia coli, staphylococcus, rickettsia (q fever), and legionella. parasitic infestation of lungs may occur with nematodes (e.g., ascariasis). fungal infections of the lung may be caused by aspergillosis, histoplasmosis, and coccidiomycosis, often as a complication of antibiotic therapy. access to primary care and early institution of treatment are vital to control excess mortality from aris. in developed countries, aris as contributors to infant deaths are largely a problem in minority and deprived population groups. because these groups contribute disproportionately to childhood mortality, infant mortality reduction has been slower in countries such as the united states and russia than in other industrialized countries. the continuing gap in mortality rates between white and black children in the united states can, to a large extent, be attributed to aris and less access to organized primary care. children are brought to emergency rooms for care when the disease process is already advanced and more dangerous than had it been attended to professionally earlier in the process. many field trials of ari prevention programs have been proved successful involving parent education and training of primary care workers in early assessment and, if necessary, initiation of treatment. this needs field testing in multiple settings. reliance on vaccines to prevent respiratory infectious diseases is not currently feasible. aris are caused by a very wide spectrum of viruses, and the development of vaccines in this field has been slow and limited. the vaccine for pneumococcal pneumonia has been an important breakthrough, but it is still inadequately utilized by the chronically ill because of its limitations, costs, and lack of sufficient awareness, and it is too expensive for developing countries. improvements in bacterial and viral vaccine development will potentially help to reduce the burden of aris. a programmatic approach with clinical guidelines and education of family and care givers is currently the only feasible way to reduce the still enormous morbidity and mortality from aris on the young and the elderly. the success of sanitation vaccines and antibiotics led many to assume that all infectious diseases would sooner or later succumb to public health and medical technology. unfortunately, this is a premature and even dangerous assumption. despite the longstanding availability of an effective and inexpensive vaccine, the persistence of measles as a major killer of million children per year represents a failure in effective use of both the vaccine and the health system. the resurgence of tb and malaria have led to new strategies, such as managed or directly observed care, with community health workers to assure compliance needed to render the patient noninfectious to others and to reduce the pool of carriers of the disease. current successes in reducing poliomyelitis, dracunculiasis, onchocerciasis, and other diseases to the point of eradication has raised hopes for similar success in other fields. but there are many infectious diseases of importance in developed and developing countries where existing technologies are not fully utilized. oral rehydration therapy (ort) is one of the most cost-effective methods of preventing excess mortality from ordinary diarrheal diseases, and yet is not used on sufficient scale. biases in the financing and management of medical insurance programs can result in underutilization of available effective vaccines. hospital-based infections cause large-scale increases in lengths of stay and expenditures, although application of epidemiologic investigation and improved quality in hospital practices could reduce this burden. control of the spread of aids using combined medical therapies is not financially or logistically possible in many countries, but education for "safe sex" is effective. community health worker programs can greatly enhance tuberculosis, malaria, and std control, or in aids care, promote prevention and appropriate treatment. in the industrialized and mid-level developing countries, epidemiologic and demographic shifts have created new challenges in infectious disease control. prevention and early treatment of infectious disease among the chronically ill and the elderly is not only a medical issue, it is also an economic one. patients with chronic obstructive lung disease (copd), chronic liver or kidney disease, or congestive heart failure are at high risk of developing an infectious disease followed by prolonged hospitalization. public health has addressed, and will continue to stress the issues of communicable disease as one of its key issues in protecting individual and population health. methods of intervention include classic public health through sanitation, immunization, and well beyond that into nutrition, education, case finding, and treatment, and changing human behavior. the knowledge, attitudes, beliefs, and practices of policy makers, health care providers, and parents is as important in the success of communicable disease control as are the technology available and methods of financing health systems. together, these encompass the broad programmatic approach of the new public health to control of communicable diseases. in a world of rapid international transport and contact between populations, systems are needed to monitor the potential explosive spread of pathogens that may be transferred from their normal habitat. the potential for the international spread of new or reinvigorated infectious diseases constitute threat to mankind akin to ecological and other man-made disasters. the eradication of smallpox paved the way for the eradication of poliomyelitis, and perhaps measles, in the foreseeable future. new vaccines are showing the capacity to reduce important morbidity from rubella syndrome, mumps, meningitis, and hepatitis. other new vaccines on the horizon will continue the immunologic revolution into the twenty-first century. as the triumphs of control or elimination of infectious diseases of children continue, the scourge of hiv infection continues with distressingly slow progess an effective vaccine or cure for the disease it engenders. partly as a result of the hiv/ aids, tb staged a comeback in many countries where it was thought to be merely a residual problem. at the same time an old/new method of intervention using directly observed short-term therapy has shown great success in controlling the tb epidemic. the resurgence of tb is more dangerous in that mdrtb has become a widespread problem. this issue highlights the difficulty of keeping ahead of drug resistance in the search for new generations of antibiotics, posing a difficult challenge for the pharmaceutical industry, basic scientists as well as public health workers. the burden of infectious diseases has receded as the predominant public health problem in the developed countries but remains large in the developing countries. with increases in longevity and increased importance of chronic disease in the health status of the industrial and mid-level developing nations, the effects of infectious disease on the care of the elderly and chronically ill is of great importance in the new public health. long-term management of chronic disease needs to address the care of vulnerable groups, promoting the use of existing vaccines and antibiotics. most important is the development of health systems that provide close monitoring of groups at special risk for infectious disease, especially patients with chronic diseases, the immunocompromised, and the elderly. the combination of traditional public health with direct medical care needed for effective control and eradication of communicable diseases is an essential element of the new public health. the challenge is to apply a comprehensive approach and management of resources to define and reach achievable targets in communicable disease control. access to e-mail and the internet are vital to current practice of public health and nowhere is this more important than in communicable diseases. there are many such information sites and these will undoubtedly expand in the coming years. several sites are given as examples. the internet has great practical implications for keeping up to date with rapidly occurring events in this field. outstanding encyclopedia database on infectious diseases (available via mdcassoc@ix.netcom.com at reduced price for promed users, and free to sub-saharan african sites) promed is an excellent, free report on current events in communicable diseases internationally; join via owner-promed @usa recommended readings centers for disease control. . update: international task force for disease eradication addressing emerging infectious disease threats: a prevention strategy for the united states. executive summary update: trends in aids incidence--united states one thousand days until the target date for global poliomyelitis eradication tuberculosis morbidity--united states measles--united states, . morbidity and mortality weekly report national adult immunization awareness week--october - , recommended readings ; and influenza and pneumococcal vaccination levels among adults aged --- years impact of the sequential ipv/opv schedule on vaccination cover-agemunited states advances in global measles control and elimination: summary of the international meeting recommended childhood immunization schedulemunited states impact of vaccines universally recommended for childrenmunited states progress toward global poliomyelitis eradication global disease elimination and eradication as public health strategies childhood immunizations rotavirus vaccines: who position paper. weekly epidemiologic record infectious diseases of humans: dynamic and control vaccines and world health: science, policy, and practice control of communicable diseases manual jawetz, melnick and adelberg's medical microbiology, twenty-first edition preventive medicine and public health, second edition efficacy of bcg vaccine in the prevention of tuberculosis. meta-analysis of the published literature manson's tropical diseases vaccination and world health principles and practice oflnfectious diseases immunization of adolescents: recommendations of the advisory committee on immunization practices, the american academy of pediatrics, the american academy of family physicians and the combination vaccines for childhood immunization: recommendations of the advisory committee on immunization practices, the american academy of pediatrics, the american academy of family physicians and the poliomyelitis prevention: revised recommendations for use of inactivated and live oral poliovirus vaccines diphtheria outbreakmrussian federation rubella and congenital rubella syndrome~united states compendium of animal rabies control, : national association of state public health veterinarians progress toward elimination of haemophilus influenzae type b disease among infants and children in the united states tetanus surveillance~united states, - recommendations and reports--vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of measles: recommendations of the advisory committee on immunization practices national, state and urban area vaccination coverage levels among children aged - months~united sates varicella related deaths among children--united states progress toward global poliomyelitis eradication ten great public health achievements--united states a ten-year experience in control of poliomyelitis through a combination of live and killed vaccines in two developing areas measles control in developing and developed countries: the case for a two-dose policy integration of vitamin a supplementation with immunization. weekly epidemiological record update cholera--western hemisphere, . morbidity and mortality weekly report isolation of vibrio cholerae o from oystersmmobile bay, - estimates of future global tuberculosis morbidity and mortality arbovirus disease--united states ~:~ other communicable diseases update: outbreak of legionnaire's disease associated with a cruise ship rift valley fever--egypt the role of bcg vaccine in the prevention and control of tuberculosis in the united states: a joint statement by the advisory council for the elimination of tuberculosis and the advisory committee on immunization practices update: trends in aids incidence--united states case definition for infectious conditions under public health surveillance guidelines for treatment of sexually transmitted diseases primary and secondary syphilis--united states global tuberculosis incidence and mortality during the th century pandemic: need for surveillance and research escherichia coli o :h diarrhoea in the united states: clinical and epidemiologic features the state of the world's children the rational use of drugs in the management of acute diarrhoea in children world health organization. . the malaria situation in aids: images of the epidemic. geneva: who. world health organization progress toward the elimination of leprosy as a public health problem the world health report : fighting disease, fostering development the world health report health for all in the twenty-first century. eb / . geneva: who. world health organization. . the world health report : life in the twenty-first century: a vision for all world health organization. . the world health report : making a difference key: cord- -wg sa u authors: quah, stella r. title: public image and governance of epidemics: comparing hiv/aids and sars date: - - journal: health policy doi: . /j.healthpol. . . sha: doc_id: cord_uid: wg sa u abstract a comparative analysis of the – infectious disease outbreak, severe acute respiratory syndrome (sars), and the hiv/aids epidemic that has affected the world over the past two decades reveals the significant role of socio-cultural beliefs and attitudes in the shaping of people's lifestyles and approaches to the control and prevention of epidemics. the main research question is: what can we learn from the sars experience about effective prevention of hiv/aids? the sources of data include population figures on the development of these epidemics and findings from two sociological studies of representative samples of singapore's multi-ethnic population. the comparative study illustrates the impact of cultural beliefs and attitudes in shaping the public image of these two different infectious diseases; the relevance of public image of the disease for effective prevention and control of epidemics. traditionally, the human suffering inflicted by longterm epidemics have tended to find expression in literature and the fine arts thus becoming a visible part of the collective memory and shaping the public image of the disease. for example, the impact of the bubonic and pneumonic plague or "black death" had a major influence on painters of the gothic period [ ] ; tuberculosis is featured in eugene g. o'neill's long day's journey into night; franz kafka's diaries; thomas mann's the magic mountain [ ] ; victor hugo's les misérables; dickens' nicholas nickleby, brontë's wuthering heights; verdi's la traviata [ ] . among e-mail address: socquahs@nus.edu.sg. epidemics in the past three decades (hiv/aids, sars, mad cow disease, and avian flu among others), only hiv/aids has lasted long enough to inspire artistic expressions in literature [ ] [ ] [ ] [ ] , theatre [ ] , dance [ ] , and film [ ] mostly used as vehicles for hiv/aids preventive education programs particularly in africa [ ] [ ] [ ] [ ] [ ] . one of the pioneer studies in prevention was published in by zinsser [ ] . ever since, a community of experts worldwide has been dedicated to prevention [ ] [ ] [ ] [ ] [ ] [ ] [ ] . however, despite the struggle to convey a more accurate and humane public image of aids in the past decade, the stigma attached to hiv/aids still persists as a formidable obstacle to prevention efforts [ ] [ ] [ ] . figures on the spread of the disease suggest we are losing the battle against hiv/aids especially in developing countries [ , [ ] [ ] [ ] [ ] . in china alone, the estimated number of deaths due to aids as of december (latest figures available), ranged from , to , and , persons infected with hiv/aids. the figures for thailand, the second most affected east asian country, are , - , deaths, and , persons infected with hiv (appendix a, table a . ). in contrast to the dismal hiv/aids situation, the - outbreak of severe asymptomatic respiratory syndrome or sars, offers a completely different picture for the analysis of preventive efforts. although sars, like hiv/aids, was unknown in the medical world and hit unexpectedly, there are some significant differences, particularly in their etiology, epidemiology, natural history and clinical outcomes of the two diseases. hiv/aids is asymptomatic for - years after infection so that hiv-positive persons may continue to spread the disease unknowingly. the main mode of hiv/aids transmission is through direct contact with infected body fluids or blood (sexual intercourse, use of infected needles by drug users and receiving contaminated blood transfusions). sars is caused by the sars coronavirus and characterized by airborne transmission. sars develops very rapidly, with an average incubation period of days or a range of - days after contact. within week of the illness patients show typical influenza-like symptoms such as fever, malaise, and headache with cough and diarrhoea getting worst in the second week of infection. it has been determined that "transmission occurs mainly during the second week of illness". these external signs facilitate prompt action: exposed patients may be placed under fever surveillance twice a day "in an isolation facility or ward for at least days after the last exposure to the source case(s)" [ ] . in the span of months sars infected persons, caused deaths (appendix a, table a . ) and became a widespread visible threat through the serious disruption of normal daily activities of individuals and major sectors of the economy such as transportation, commerce, industrial production, and tourism [ ] [ ] [ ] . the first probable sars case was reported in china on november and the infection spread to other countries around the world but the largest number of locally transmitted infections and deaths were reported in china, hong kong, taiwan, canada, and singapore (appendix a, table a . ). despite the fact that sars caught the world unprepared, hit at great speed, and it is very difficult to eradicate [ ] , the outbreak was contained within months, a relatively brief period of time (appendix a, table a . ). despite the medical differences (in etiology, epidemiology, natural development and clinical outcomes) between these two epidemics, i argue and attempt to demonstrate in this study that we may advance our knowledge on preventive strategies by conducting a systematic comparison of important social aspects of hiv/aids and sars. what can we learn from the sars experience about effective prevention of hiv/aids? more specifically, why were the efforts to contain and prevent the spread of a new epidemic like sars successful while it has taken years so far to contain the spread of hiv/aids and no effective solution is yet in sight? social science research has identified over the past decades a complex array of factors and conditions associated with disease prevention in individuals (micro-level analysis) as well as collectivities (macro-level analysis) but the factors and conditions vary for different diseases and there may be many other factors yet to be identified. still, contrasting the two epidemics in terms of social attitudes and beliefs at the micro-and macro-levels, will help us to elucidate some of the major obstacles to hiv/aids prevention. therefore, this paper focuses on only three possible factors: the impact of perceived severity and susceptibility to infection and the public image of the epidemic (micro-level factors); and the governance of epidemics (macro-level factor). sociology and social psychology offer some interesting explanations of the sluggishness of preventive health behavior in individuals [ , ] . among ten theories identified as the "most often used" today [ ] , the top two explanatory models are the social cognitive theory (sct) and the health belief model (hbm) [ , ] . both social theories are useful in the analysis of preventive action: they focus on the individual's capacity to make his/her own decisions, and the recognition that there are multiple and varied factors involved in a person's health-related actions. the sct explains people's health-related actions primarily in terms of their expectations of the outcome, their confidence in the success of their actions, and their ability to perform the action; but perhaps the most relevant aspect of the sct is its consideration of the individual's environment as one of the important determinants of his/her behavior [ ] . the hbm proposes that the likelihood of a person taking preventive action increases if he/she believes in his/her personal susceptibility to the illness and in the severity of the illness; perceives the preventive action as beneficial; believes that there are no barriers to action or that barriers can be overcome; believes in the net gain -benefits exceed barriers or costs-of taking preventive action [ , , ] . a comprehensive review of studies applying the hbm [ ] found the variables perceived susceptibility and perceived severity to be closely correlated and to have significant influence upon a variety of preventive behaviors. the combination of both perceived severity and perceived susceptibility labeled "perceived threat" has been found to be a more significant explanatory variable than severity and susceptibility used separately [ ] . the hbm variable influencing the perception of effective prevention of hiv/aids in three ethnic communities is perceived severity or seriousness of the disease, together with the perception of personal responsibility for contracting the disease [ ] . i ascertained perceived severity of hiv/aids in terms of the respondents' subjective perception of the likelihood of death using the close-ended question "when you think about aids, how serious do you feel it is? this approach is basically the same as that of janz et al. [ ] who define perceived severity as "one's belief of how serious a condition and its sequelae are". strecher et al. had offered earlier [ ] a wider definition of perceived severity: "personal evaluations of the probable biomedical, financial and social consequences of contracting hiv and having aids". although there are slight variations in the wording of the question asked in interviews and in the definition of perceived severity, the general consensus in the literature is that this conceptual construct, often together with perceived susceptibility, is essential in the analysis of people's motivation to take preventive action. nevertheless, as preventive health behavior is influenced by a multiplicity of factors, the hbm, sct and all the other top eight theories [ ] are limited as they offer only partial explanations of health-related behavior, but they are complementary. i include social constructs from the hbm and the sct and some relevant contextual social factors, to explore the research question "what can we learn from the sars experience about effective prevention of hiv/aids"? combining the analysis of individuals' responses with their collective implications, i attempt to demonstrate that perceived severity together with perceived susceptibility and the public image of the two epidemics help to explain some of the difference in prevention effectiveness. i test two related assumptions: ( ) a higher perception of disease severity and personal susceptibility to sars as compared to hiv/aids, contributed to the higher effectiveness of sars prevention efforts; ( ) the second assumption is two-fold: (a) in contrast to sars, the overall negative social 'image' of hiv/aids as a disease associated with particular types of individuals tends to weaken people's perception of susceptibility; (b) correspondingly, low perceived susceptibility tends to discourage public support for robust preventive efforts at the community level. these assumptions require elaboration. following the hbm, the first assumption to be tested is that a person's perception of the severity of the disease and his/her perceived susceptibility to that disease are likely to motivate him/her towards taking preventive action. all things being equal, such a commitment to prevention would weaken or be altogether absent when perceived severity and/or susceptibility are low or nil. the perceived severity of hiv/aids was ascertained through the question "when you think about aids, how serious do you feel it is? four alternative response categories were provided (see tables and a. ) . for the logistic analysis, the responses were dichotomized into high perceived severity (( ) "very serious, causes death"), and low perceived severity (( ) "not very serious" or "not serious at all" and "don't know"). perceived susceptibility to hiv/aids was ascertained by the level of agreement to the statement "aids doesn't happen to people like me" (tables and a. ). in the study of sars, perceived susceptibility was ascertained through the question "how likely do you think it is for you to contract sars"? respondents expressed their belief in their personal susceptibility by indicating whether they saw the likelihood of contracting sars as "very likely", "likely", "not very likely", "not likely at all", or did not know ( table ). the perception of severity of sars was measured by the question "if you have contracted sars, what is the likelihood of survival"? the four response categories were "very likely", "likely", "not very likely" and "not likely at all" ( table ) . the second assumption is that in contrast to sars, the overall negative public 'image' of hiv/aids as a disease associated with particular types of individuals tends to weaken people's perception of susceptibility and, correspondingly, tends to discourage public support for robust preventive efforts at the community level. the individual's 'image' of the disease shapes his/her perception of seriousness and susceptibility and thus contributes to his/her motivation to take preventive action. that 'image' of the disease and of persons affected, however, is shaped to a large extent by prevailing values and normative beliefs in the community and it is subject to change over time. this process is suggested by many sociological theories including social networks and social support theory [ ] , rational choice theory [ ] , and the sct. the sct offers the concept "reciprocal determinism" [ ] that proposes a dynamic interplay of "the person, behavior, and the environment". a eight preventive measures were considered as part of the respondents' "activities during the past days": covering the mouth with paper tissue or handkerchief when sneezing or coughing; covering the mouth with bare hand when sneezing or coughing; washing hands after sneezing or coughing; using soap or liquid hand-wash when washing hands; wearing a mask over the mouth; using serving utensils (chopsticks or spoons) for shared food when joining others for meals; when touching objects that may possible carry the sars virus (e.g., door handles, buttons in lifts), taking preventive measures (e.g., pressing lift buttons with tissue paper); washing hands as soon as possible after touching objects that may possibly carry the sars virus (e.g., door handles, buttons in lifts). b the original response categories for perceived susceptibility (that is, the perceived likelihood of contracting sars) were: "very likely", "likely", "not very likely", "not likely at all" and "don't know". for the logistic regression analysis the latter group, . % of respondents who had no idea on their susceptibility to sars, were contrasted with all other respondents who did have an assessment of their likelihood of getting infected. c the original response categories for perceived severity (that is, the likelihood of survival) were "very likely", "likely", "not very likely" and "not likely at all". for the logistic regression analysis, these responses were dichotomized into low perceived severity (survival "very likely/likely") and high perceived severity (survival "not very likely"/"not likely at all"). d the respondents' appraisal of the health authorities' crisis management was ascertained by their assessment of the distribution of information in terms of accuracy, clearness, sufficiency, timeliness, and trustworthiness in a scale from very negative (score ) to very positive (score ). the scale had high reliability (α = . ) and the mean score was . (s.d. = . ). in my view, the dynamic interaction of the individual's health-related behavior and the environment is better explained by the individual's subjective perception of the situation (for example a crisis or stressor) and the social context of the situation, as proposed by symbolic interaction and family stress theory [ ] . thus, my assumption that a person's motivation to take preventive action may also be manifested in his or her cooperation with community-based preventive measures is explained clearly by the application of the conceptual premises on community responses to stressor events formulated by reiss and oliveri [ ] . the public's perception of the scope of the problem was highlighted by these authors as part of their concept "community's punctuation of an event". they defined the community's punctuation of an event or perceived scope as "when the problem begins and when it ends and who is involved". they proposed that the community and its leaders would be more inclined to invest concerted efforts to solve a problem if three conditions are met: accountability, duty, and competence [ ] . that is, the community and its policy-makers would be most inclined to mobilize assistance and preventive efforts when these three conditions are met: the persons affected are perceived as not being accountable for the problem; they are regarded as having the duty to request outside help; they are considered as lacking the competence to solve by themselves the problem affecting them. i suggest that these three conditions shape the public image of sars and hiv/aids and add to our understanding of the disparity in prevention effectiveness of these two epidemics at the community level. the public image of hiv/aids was ascertained through one open-ended question about persons living with hiv/aids: "what kind of people do you think are most likely to get aids"? the analysis of responses revealed three types of stereotypes or 'images': 'risktakers', 'deviants', and 'victims'. only a small group of respondents had not particular image of people living with hiv/aids ( table ). the public image of sars may be ascertained indirectly through the respondents' perception of a sense of social responsibility and willingness to make some personal sacrifices in combating the disease. those perceptions reflect people's collective sense of accountability and duty and their recognition of the need for expertise to handle the crisis. referring the respondents to the measures implemented to prevent the spread of sars, they were asked their level of agreement (strongly agree to strongly disagree) with these statements: "people should be willing to make some personal sacrifices"; "people have mostly been socially responsible"; "if you did not develop symptoms of sars after having close contact with someone diagnosed with sars, would you agree to be quarantined for days?"; "if you did not develop symptoms of sars after having non-close contact with someone diagnosed with sars, would you agree to be quarantined for days"? ( table ). the condition of "competence" identified by reiss and oliveri [ ] as discussed above, has to do with expertise in handling the crisis, and thus brings in a final concept of relevance to this discussion: governance. governance is another socially significant aspect of hiv/aids and sars as a strong political will at the national level is needed to invest state resources, and to utilize knowledge and technology creatively for their detection and prevention. but these epidemics are also global problems that challenge national boundaries and the conventional idea of state sovereignty and governance, and test international cooperation, because of their mode of transmission and the increasing movement of people across countries for leisure, trade, and study among other activities. given the easiness and speed of their international transmission, these epidemics have unwittingly pushed forth a new phenomenon that fidler [ ] calls "global health governance" that is, "the proposition that governance of public health issues must include not only state actors but also non-state actors". examining the international impact of sars, this international law expert concluded that "to govern an increasingly borderless world, requires, in essence, increasingly borderless governance" [ ] . the analysis of the sars crisis management in singapore suggests that effective containment and prevention of infectious disease outbreaks requires dedicated and transparent governance at both levels, national and global. and to be successful, global governance requires timely and effective response and collaboration from sovereign nations. but as i shall discuss later, the governance approach to sars differs substantially from that applied to hiv/aids. first, a word of caution: i reiterate that this study is by necessity limited and exploratory because the two epidemics, hiv/aids and sars, are very different microbiologically and epidemiologically as indicated in the introduction; and there is a -year gap between the two surveys. the sars study was conducted as the outbreak progressed in may , years after the hiv/aids study. nonetheless, despite these methodological difficulties, i believe it is important to scrutinize available information on both epidemics in the hope of increasing our understanding of the dynamics of preventive action against hiv/aids. while the two epidemics are different in many respects, they are both serious public health threats that require a collective response [ , ] as indicated earlier. two general types of data are discussed here: population figures and data from personal interviews. the international population figures on the impact and spread of hiv/aids and sars are taken from who's published reports [ , , , [ ] [ ] [ ] . the analysis of behavior and attitudes of individuals is based on data from two separate studies i conducted in singapore as principal investigator. the data on hiv/aids are from a study of attitudes and preventive behavior regarding hiv/aids based on a survey of personal interviews with a representative stratified random sample of adults aged and older following a structured questionnaire. respondents were from the chinese, malay, and indian communities, the three largest ethnic groups in singapore. the sample characteristics and the details on measurement of the variables included in this analysis are described in tables and a. . the data discussed in this paper are part of a larger study on preventive health behavior regarding cancer, heart disease, and hiv/aids supported by a research grant from the national university of singapore. further methodological details are provided elsewhere [ ] . the new findings discussed in this paper were obtained through logistic regression analysis. the data on behavior and attitudes on sars are from a study based on telephone interviews with a representative stratified random sample of adults aged and older, following a structured questionnaire. the three main ethnic groups in singapore (chinese, malays, and indians) were proportionally represented. the interviews were conducted within the span of days, from to may, while the country was facing the sars epidemic. telephone interviews were the only data collection option because it was imperative at the time to follow the public health advice to restrict personal contact to home and the workplace, whenever possible. the main characteristics of the sample and the attitudinal measurements applied are presented in table . further methodological details of this study are described elsewhere [ ] . the new findings presented in this paper were obtained through logistic regression analysis. while the data refer to three ethnic communities in singapore the findings illustrate the impact of social attitudes upon the governance of epidemics in a high density global city. acknowledging the multiplicity of factors that may play a role in shaping the success or failure of illness prevention and containment of epidemics, this study deals only with a small number of variables. the analysis of data in both studies comprised two stages: an initial scrutiny of the main assumed correlations and attitudinal scales using partial correlation and factor analysis; logistic regression to explore the likelihood of occurrence of stereotypical images of people living with hiv/aids, the dependent variable in the hiv/aids study; and likelihood of public support of the sars crisis management, the dependent variable in the sars study. logistic regression is a very useful tool to explore the probability of occurrence of the dependent variable over the probability of it not occurring and the outcome is provided as odds ratios. the odds ratio is the odds of one variable occurring to the odds of another [ , ] . the logistic regression analysis of the public image of hiv/aids comprised three sets of variables: sociodemographic variables (gender, age, ethnicity, marital status and religion); social class factors (occupation, personal monthly income, and educational level); attitudinal factors proposed by the hbm and the sct (tendency to worry about falling ill; future orientation; sense of personal control of one's life; life satisfaction; perceived severity of hiv/aids; perceived susceptibility to hiv/aids; belief in effective prevention of hiv/aids) and perception of hiv/aids. a description of these variables is provided in table a. . five sets of variables were included in the logistic regression analysis of the public support of the sars crisis management: socio-demographic variables (gen- der; age; ethnicity; place of birth; marital status); social class (educational level and personal monthly income); health behavior variables (smoking, exercising regularly, and preventive measures against sars taken over the days preceding the interview); attitudes suggested by the hbm including perceived susceptibility and perceived severity; and attitudes on sars crisis management. to meet requirements of the logistic regression analysis the response categories of the question on perceived susceptibility were dichotomized contrasting the respondents who expressed an estimation of their likelihood of infection on the one hand, with respon-dents who have no awareness of their susceptibility to sars, on the other hand. the response categories for perceived severity were dichotomized into "high" severity (survival not very likely or not likely at all) versus "low" severity (all other responses including "don't know"). the complete list and explanation of all the variables are presented in table . the discussion follows the two related assumptions presented earlier. the first assumption to be tested is that a higher perception of disease severity and personal susceptibility to sars as compared to hiv/aids, contributed to the higher effectiveness of sars prevention efforts. show that the sars outbreak was contained within months of its onset while the hiv/aids epidemic continues undefeated after nearly three decades. would people's sense of susceptibility to these diseases and their severity contribute to that difference? the survey data from singapore on the two epidemics provide a tentative yet useful indication of the differential perception of severity and susceptibility. only . % of the respondents expressed high susceptibility to hiv/aids (table ) compared to . % of respondents in the case of sars ( table ). the corresponding figures on the expression of high perceived severity are . % of the respondents in the case of hiv/aids (table ) and only . % of the respondents in the case of sars ( table ) . the findings from the analysis of the belief in effective hiv/aids prevention in the total sample (appendix a, table a. ) indicate that people who believe that hiv/aids is very serious and fatal (high perceived severity) are significantly more inclined than those with low perceived severity to believe there are effective ways of preventing the disease. this belief in effective prevention of hiv/aids is also found among people with high future orientation, those who are inclined to worry about falling ill; it is expressed by men more than women. the nagelkerke r coefficient of . suggests that . % of the overall variation in the belief in effective prevention of hiv/aids is predicted by the variables in the model. the model predicted correctly the belief in effective hiv/aids prevention . % of the time. in the case of sars, preventive measures were being implemented as the outbreak progressed. the interviews took place in the midst of the crisis as the country and the region were coping with this completely new threat. no clear indication of effective prevention was in sight but through a steep learning process several effective preventive measures were being identified and the information transmitted from the experts to the public daily through various mass media including radio, newspapers, the internet, regular television, and a dedicated television channel set up specifically for that purpose. this special situation may explain the respondents' very low perceived severity of sars and their very high sense of susceptibility to it as ways of transmission encroached into people's daily life, for example: droplets from the sneezing or coughing of an infected person, and the touching of infected commonly used objects such as eating utensils, buttons in elevators, and door handles [ , ] . the second assumption to be explored here is that in contrast to sars, the overall negative social 'image' of hiv/aids as a disease associated with particular types of individuals tends to weaken people's perception of susceptibility and, correspondingly, tends to discourage public support for robust preventive efforts at the community level. as suggested earlier, this assumption may be examined using reiss and oliveri's [ ] concept "community's punctuation of an event" and the three conditions -accountability, duty, and competence -these authors identified as requirements for the community's positive response. in the case of hiv/aids and sars the focus is the community's endorsement of disease prevention and containment plans and their active collaboration in prevention efforts. when does the problem begin and when does it end and who is involved? the answers to these questions mark the community's punctuation of crises and show that the punctuation of the sars outbreak was rather different from that of hiv/aids. the punctuation of the sars outbreak as a crisis was very clear. sars was imported into singapore at the end of february, , when an infected vacationer returned home from hong kong where she caught the infection while staying at the same hong kong hotel where a doctor from guangzhou, china who had treated sars patients there, was residing [ ] . the unknown cause and nature of the disease deterred the assignment of blame or accountability. sars patients were not held accountable for their illness. nor were they assumed to have the expertise to solve the problem on their own although it soon became a duty for people with the publicized symptoms to seek immediate expert medical help [ , ] . the findings from the sars study in table show that . % of the respondents made a positive appraisal of the health authorities' management and control of the sars crisis; . % had the chance to express their opinions to the authorities; . % were prepared to be quarantined for days after close contact with an infected person and . % would agree to be quarantined even if there was non-close contact. further indications of the public's willingness to collaborate in preventive efforts against sars were the very positive attitudes of the majority of respondents: although about one of every two agreed that preventive measures taken against sars "have affected my personal choice and freedom in life", most respondents ( . %) agreed that "people should be willing to make some personal sacrifices" to contain the epidemic and % felt that "people have mostly been socially responsible". the findings from the logistic regression analysis of the sars study data confirm that this sense of social responsibility was a fundamental manifestation of the community's positive and compassionate 'image' of sars patients and it was significantly associated with their endorsement of the health authorities' management of the crisis in the total sample as well as among people with lower education, and ethnic minorities such as the singaporean malays (table ) . among the respondents, the endorsement of the health authorities' crisis management was particularly supported by people who perceived the community as being socially responsible; those who believed that the crisis justified making some personal sacrifices (especially with regard to movement outside their homes, restricting or changing their travel patterns, and abiding by quarantine regulations); those felt that they had the chance to be part of the effort and express their personal opinions; people who had formed an opinion on their personal susceptibility to the infection (in contrast to those who had no or very little information on sars). the nagelkerke r coefficient of . suggests the factors in the model explain . % of the variation in endorsement of the crisis management in the total population. the analysis of the same factors was repeated among three specific subgroups that have shown less positive appraisal of crisis management: the senior cohort (respondents aged and older), the lower educated (people with only primary or lower education), and malays. as illustrated in table , even among the lower educated and the malay, the sense of social responsibility was significantly associated with their endorsement of preventive efforts (dependent variable). however, perceived susceptibility to sars did not influence significantly the appraisal of crisis management by the seniors and the less educated but it did among malays in the expected direction: persons who have no idea of their susceptibility (no awareness of it) were most likely to give a negative appraisal of crisis management. no significant impact of perceived severity upon people's appraisal of crisis management was detected in the total sample or any of the three subgroups. overall, the nagelkerke r coefficients indicate that, compared to the total sample, variables in the model helped explain a larger proportion of the variance in the dependent variable among subgroups such as seniors ( . %), the less educated ( . %) and the malay community ( . %) about % of the time. these figures point to the importance of variations the perception of and responses to crises among different segments of the population given their differences in life experiences, in knowledge and level of information on the problem, and in cultural values and beliefs, among other factors. as indicated earlier, from the contextual perspective proposed by reiss and oliveri [ ] the public image of a crisis or stressor (e.g., an infectious disease epidemic) refers to the public's perception of its scope and its social acceptability. in terms of the scope of the problem -when it begins and when it ends -the quiet and prolonged way in which the hiv virus enters and destroys the immune system represents a major challenge for the mobilization of public interest and support of testing. visible signs of the disease tend to appear only in the late stages. the opposite occurred with respect to sars. two separate studies of the awareness of health threats in the united kingdom confirm these findings on impact of the public image of the problem and punctuation or scope of the event: british lay respondents and journalists were inclined to see aids as a "far-flung" risk of no immediate relevance to their lives [ , ] . regarding social acceptability, if the stressor is seen by the community as the consequence of socially unacceptable behavior, one would expect collective apathy or reluctance or opposition to the investment of public funds and efforts to contain and solve the problem. the findings in tables , and a. suggest that this appears to be the case with hiv/aids. the public image of hiv/aids tends to be shaped by normative expectations or stereotypes in the community. the large majority of the respondents ( . %) associated a particular lifestyle with the contracting of the disease thus forming negative images of people living with hiv/aids. as shown in table , over half of the respondents ( %) saw them as "risk-takers": people who engage in activities that put them at risk of infection such as having multiple sexual partners or procuring the services of commercial sex workers. another % of the respondents associated them with people who engage in 'deviant' activities such as commercial sex workers and injecting drug users who exchange infected needles. a small group ( . %) considered them as "victims" of "fate" or "bad luck" or accidental infection. only . % of the respondents did not have an opinion or image of people living with hiv/aids. practically all in this group had no information on hiv/aids. table presents some of the factors that contribute to the formation of a particular 'image' of people living with hiv/aids. the odds of seeing them as 'victims' (column b) were significantly higher among older people, those who do not think hiv/aids is a serious and deadly disease; and those who do not believe there is an effective way of preventing the illness. interestingly, the same features are exhibited by the small group who did not put a label on people living with hiv/aids (column a): they tend to be older, unaware of the severity of the disease, and unaware of any effective preventive measures. the odds of perceiving hiv/aids sufferers as 'risk-takers' that is, associating a 'risk-taking' life style with hiv/aids infection (column c), decreased by % among men; increased significantly among people who worry about falling ill and those who believe that there are effective ways of preventing the disease. the most negative 'image' or lifestyle associated with hiv/aids infection is that labeled 'deviants' (column d). the odds of having this image of hiv/aids sufferers increase significantly among women in contrast to men; among younger people in contrast to people who are or older; among those believe the disease is very severe, and among people who do not worry much about falling ill. the nagelkerke r coefficients indicate that the variables in the model explain . % of the overall variation in emphasis on the 'victim' image; . % of the emphasis on the 'risk-takers' image; . % of the emphasis on the 'deviant' image, and . % of the variance on the absence of a stereotypical image of hiv/aids sufferers. this variable is explained correctly by the variables in the model . % of the time (table ). these findings fit the international pattern: the presence of stereotypical images of people who get infected with hiv/aids is not restricted to a particular country [ , ] . state regulations on infectious diseases such as notification and surveillance systems have been in place for more than a century in many countries [ , ] and today they are followed by all state members of the united nations including singapore [ ] . but the official approach to the control and prevention of hiv/aids differs widely from that of sars and the difference has to do with the public image of the disease discussed in the preceding sections. the experience of sars in singapore provides an interesting illustration of the positive synergy between national governance and global health governance. the main features of the state's crisis management approach illustrate the situation well. those features were: (a) transparency; (b) public education; (c) multi-pronged approach; (d) legislation. in contrast to the situation in china and some other affected countries at the onset of the epidemic [ , ] , the sars situation in singapore was characterized throughout by transparency on the part of the health authorities in their reporting and distribution of a continuous flow of information to the public on new infections and deaths, locations, and contact tracing efforts and approaches. it was believed that an informed public can collaborate better and participate more effectively in containing the spread of the disease than a public kept ignorant of the seriousness of the situation. news reports on the progress of the epidemic were transmit- notes: total sample size, . * statistically significant at p = . - . . ** statistically significant at p = . - . . *** statistically significant at p = . - . . **** statistically significant at p = . or lower. ted to the public through all printed media, radio and television in all the four official languages (mandarin, malay, tamil and english). exceptional measures were taken to reach as many people as possible throughout singapore: broadcasting was resumed temporarily in some of the chinese dialects that had not been used in tv for nearly two decades; a new dedicated tv channel was set up, sarstv. singapore was the only country affected by sars to set up this public service [ ] . informing the public on the development of the epidemic went hand-in-hand with public health education whereby public information on the current state of knowledge on the disease was constantly updated at various levels of sophistication, from medical and epidemiological data in specialized publications [ , ] to newspaper articles explaining how the coronavirus attacks a healthy cell, to cartoons illustrating the proper use of masks, of serving utensils, and to take one's temperature correctly with a thermometer, and how to wash hands thoroughly, among other things. it was evident to the authorities and the population that the sars epidemic affected the daily life activities of every citizen and demanded drastic changes in lifestyle. this realization led to the implementation of a multi-pronged approach to deal with the crisis. all relevant ministries, statutory boards and other organs of the state were mobilized and non-governmental organizations and the private sector joined the effort. this approach was in fact a typical response in singapore as "ministries and government agencies had honed emergency preparedness to a fine art" [ ] . part of that preparedness was the use of legislation including quarantine laws and other preventive measures. for example, section of the infectious diseases act was amended with effect from april requiring "medical or dental practitioners to obtain information from their patients and transmit such information to the director [of medical services] to investigate the outbreak or prevent the spread of an infectious disease such as sars"; a new "patient declaration form" was used for this purpose during the outbreak [ ] . while transparency, public education, the implementation of a multi-pronged approach, and the use of legislation were characteristics of the national government's response internally, there was also transparency and close collaboration of singapore with the who and other international organizations. in his global analysis of the epidemic, fidler highlights this feature: "singapore was initially scheduled to be removed from the [who's] list of sars-affected areas on may; but, on that date, singapore reported a new case of sars to who, an indication of singapore's commitment to open reporting and cooperation with who" [ ] . a sovereign state's abiding to international guidelines, even at the expense of its own economic interests, illustrates the importance of "global health governance" to deal with infectious disease epidemics and similar health threats in the st century. the control and prevention of hiv/aids has followed a different approach. fidler [ ] correctly highlights "the conceptual and policy shifts" from standard procedures applied to infectious diseases by the who and public health experts. the international health regulations (ihr) "are the only set of international legal rules binding on who member states concerning the control of infectious diseases" [ ] . yet, in fidler's view, one distinguishing feature of the official international approach to deal with the hiv/aids epidemic was that public health experts and the who did not follow the ihr's classical "westphalian" model -that emphasizes state sovereignty and non-intervention -to deal with infectious diseases "but rather turned to international human rights law to provide governance norms for the fight against this new plague" [ ] . this conceptual shift was unique. the approach to hiv/aids was "the first time in history [that] preventing discrimination towards those affected by an epidemic became an integral part of a global strategy to prevent and control an epidemic of infectious disease" [ , ] . danziger [ ] suggests that this conceptual shift was promoted and supported by the "neoliberal democratic ideology" prevalent in western countries by the end of the th century and enthusiastic enough to lead some countries to abandon the compulsory surveillance methods and "placing protection of individual rights on a par with (or even above) the protection of the public health". apart from the ideological angle, the who's concern with human rights and particularly with the matter of discrimination of people living with hiv/aids has its roots in actual manifestations of social stigma associated with the presumed lifestyle of the first persons affected by the disease. in june and july, , five young homosexual men were diagnosed with pneumocystis carinii pneumonia and young homosexual men with kaposi's sarcoma "a rare form of cancer which had until then been associated with elderly americans"; added to the spectrum of aids features in the early s was the confirmation that one of the main forms of transmission is sexual intercourse [ ] . the spread of the epidemic has been so extensive geographically as well as socially, that people living with hiv/aids today come from all walks of life. but as the figures in appendix a, table a . indicate, the highest prevalence of hiv are still found among some distinct lifestyle groups including commercial sex workers and injecting drug users. the survey data discussed in the preceding sections suggest that the public image of hiv/aids reflects the prevalence figures among some specific groups; a large majority of respondents saw hiv/aids sufferers as following their lifestyle by personal choice. thus, their image remains negative despite public education efforts by the who, non-state organizations and non-governmental organizations. an additional aspect is the slow pace of development of the disease: people may be infected for many years without developing any symptoms and may thus continue unwittingly to infect others [ ] . the global governance approach to protect people with hiv/aids from discrimination involves avoidance of disclosure of one's health condition and of routinely or compulsory name-linked testing and other features of standard infectious disease surveillance. danziger [ ] sees this position as "possessive individualism" that demands testing to be done only if the person has consented freely and has received full information on the consequences through the process of informed consent. moreover, danziger points out that with the current stage of knowledge on hiv/aids, "there is little or no gain for a hiv-infected person to be tested and identified as hiv-positive" [ ] . this reasoning creates a dilemma because experts agree that standard infectious disease surveillance is indispensable for the effective prevention and control of infectious diseases [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] , ] that is, the beneficiaries of effective control and prevention are the rest of the community. according to danziger [ ] the dilemma has been sorted out internationally by an apparent consensus of stakeholders to consider hiv/aids as "a crisis of human rights" and not as a "public health crisis". however, with the epidemic proceeding unrelentingly, there are signs of concern. a recent development in singapore is illustrative of the range of opinions on this matter: the ministry of health announced on july that "spouses of patients with hiv will be informed of their partner's illness, regardless of whether the infected person agrees" [ ] . the newspaper report cited the case of four women who discovered they had hiv when they did their blood test during their pregnancies. the husband of one of them had been diagnosed with hiv since . previously, patients were counseled and informed consent was required. now the doctor needs only to keep the patient "appropriately informed". the spouses will be informed "in a sensitive manner" by trained personnel of a new hiv prevention unit. the infectious diseases act will be invoked as is the case with all other infectious diseases [ ] . the singapore shift towards a version closer to standard surveillance of hiv/aids is indicative of its concern for the rights of the infected person as well as the rights of the patient's partner, and of all other persons involved. the global governance of hiv/aids prevention needs to address the public image of the disease and the impact that such an image has upon efforts to mobilize the community in prevention efforts. for as long as hiv/aids is seen as a problem of particular lifestyles (that is, of specific types of people), prevention efforts such as condom use and testing are bound to have limited impact. the analysis was based on data from two separate studies of singapore residents' attitudes and behavior. given the differences in questions asked during the respective interviews, the -year difference between studies and the significant differences in the etiology, nature, and development of the two infectious diseases, the findings must be treated with caution. that said, the availability of data from the two studies offered a good opportunity for this exploratory comparison of attitudes towards and the public image of hiv/aids and sars in search of a better understanding of the social obstacles to effective prevention against hiv/aids. this exploratory comparison was guided by two main assumptions. the first assumption was that a higher perception of disease severity and personal susceptibility to sars as compared to the level of perceived susceptibility to and severity of hiv/aids, contributed to the difference in effectiveness of prevention efforts. the data from the singapore study support that assumption partially and revealed a new aspect of the problem. perceived susceptibility was high for sars but relatively low for hiv/aids. the opposite was found for perceived severity. the findings suggest that among the complex set of factors that motivate people to take preventive measures, perceived susceptibility to the disease (your subjective assessment of the likelihood of becoming infected) is more relevant than perceived severity of the disease. the data show a strong tendency for people to consider hiv/aids as peculiar to certain types of people different from themselves. thus their belief that their chances of being infected with the hiv virus are remote is not surprising. these findings on low perceived susceptibility and high perceived severity are also meaningful in the context of the second assumption tested. the second assumption explored in this study was two-fold: (a) that in contrast to sars, the overall negative social 'image' of hiv/aids as a disease associated with particular types of individuals tends to weaken people's perception of susceptibility; (b) that correspondingly, low perceived susceptibility tends to discourage public support for robust preventive efforts at the community level. the findings verify and clarify these assumptions. only out of every respondents expressed high perceived susceptibility to hiv/aids compared to out of every in the case of sars. but, as mentioned above, it was also found that the perceived severity of hiv/aids was significantly higher than the perceived severity of sars. more importantly, the labeling of people living with hiv/aids as 'risktakers' or 'deviants', was expressed by nine out of every of the respondents who believed hiv/aids was a incurable disease (high perceived severity) and believed that the disease is mostly linked to one's lifestyle choice. the challenge for health authorities is to enhance the population's perceived susceptibility to hiv/aids. the first step in this direction is the widespread distribution of accurate, clear and consis-tent information on the 'silent' nature of the disease in its early stages. the second part of this assumption was on the mobilization of the community's endorsement and active participation in the control and prevention of the epidemics. i have discussed the elements involved including the community's punctuation of the crisis and the aspects of accountability, duty, and competence. in the case of epidemics, competence is typically found at the community level and this brings us to the question of governance: how does a government deal with the health crisis represented by an infectious disease epidemic? much has been learned over the centuries around the world but each new epidemic brings new dangers. the sars outbreak tested the state's level of emergency preparedness and commitment to transparency particularly in asian countries, but it also highlighted the need for global governance of health threats that cut across national boundaries. in contrast, the hiv/aids epidemic still represents a challenge in terms of public health, political ideology, human rights, and social discrimination. the lack of success in the control and prevention of the epidemic highlights the fact that after nearly three decades the global governance of hiv/aids is still a work-in-progress. the urgency of the problem is well recognized by most world leaders and specialists with some experts warning that "new threats to [world] stability and secu-rity may emerge as the pandemic escalates" because, among other reasons, large numbers among police and armed forces in many countries and un peacekeeping forces are getting infected [ ] . the current global governance of hiv/aids requires critical scrutiny, as well as active exploration of solutions -among all types of stakeholders with differing ideological and social perspectives -to the slackness of preventive efforts against the two main behaviors that are sustaining the epidemic: "high-risk sexual activity and drug use" [ ] . one aspect of that critical scrutiny is the systematic and comparative analysis of hiv/aids global governance with the global governance of other infectious disease epidemics that have been successful. in sum, the findings on the sars and hiv/aids experiences suggest that health authorities need to navigate effectively the local and global obstacles to prevention by: (a) enhancing the public's understanding of the etiology of hiv/aids, its modes of transmission and effective preventive measures; and (b) correcting the lay public's inaccurate perception of personal susceptibility and 'the punctuation of the event'. tables a. -a. . very serious because it can cause death and has no cure serious but has some partial cure only mildly serious because does not cause death not serious at all scores range from (very serious) to (not serious at all). for the logistic regression analysis these response categories were dichotomized: ( ) "very serious" vs. ( ) all other responses perceived susceptibility to hiv/aids "aids doesn't happen to people like me" mean, . ; s.d., . ; sample size, this statement is part of a series involving cancer, heart disease and aids. respondents were asked to tell the interviewer if they strongly agree (sa), agree (a), disagree (d) or strongly disagree (sd) with each statement scores range from (sa) to (sd), with higher scores indicating higher perceived susceptibility for the logistic regression analysis these response categories were dichotomized: ( ) "sa/a" vs. ( ) all other responses belief in effective hiv/aids prevention "is there an effective way of protecting yourself from aids"? mean, . ; s.d., . ; sample size, the responses were scored as "yes" ( ) vs. "no" ( ) dependent variable: perception of people living with hiv/aids "what kind of people do you think are most likely to get hiv/aids?" during the personal interviews this open-ended question was preceded by identical questions for cancer and heart disease. factor analysis of the responses revealed three categories or 'images': (a) "victims" of "fate" or "bad luck" or accidental infection; (b) "risk-takers": people who engage in activities that put them at risk of infection such as having multiple sexual partners or procuring the services of commercial sex workers; (c) people who engage in 'deviant' activities such as commercial sex workers and injecting drug users who exchange infected needles. a fourth category comprises a small group of respondents who did not label people living with hiv/aids. each of the four categories is examined using separate logistic regression analyses (see table ) ( ) . **** personal control: high ( ) . life satisfaction: high ( ) . perceived severity: high ( ) . **** perceived susceptibility: high ( ) . nagelkerke r . variance predicted correct (%) . a see table a . for the description of measurement of belief in effective prevention. total sample size: . ** statistically significant at p = . - . . *** statistically significant at p = . - . . **** statistically significant at p = . or lower. dk publishing and national gallery of art illness as a metaphor and aids and its metaphors disease and the modern world. to the present day hiv stories: the archaeology of aids writing in france narrative in the time of aids: postcolonial kenyan women's literature the evil of the th century: poetry and aids on finding in a book of poems by norman dubie, a -year-old letter from the bookbinder to my cousin now dead of aids playing for life: performance in africa in the age of aids choreographer mark sieczkarek's 'living with aids' with the dance-factory in ghana nationalizing the gay body: aids and sentimental pedagogy in 'philadelphia'. american literary history narrative in times of crisis: aids stories in ghana playing for life: performance in africa in the age of rats, lice and history emerging issues in infectious disease epidemiology mapping the world of epidemiology. . the disease detectives disease detectives are turning to molecular techniques to uncover emerging microbes epidemiology: a science of patterns st century detectives-the laboratory professional in the prevention of infectious disease the making of a germ panic, then and now disease detectives celebrate years of successful sleuthing a critical analysis of the brazilian response to hiv/aids: lessons learned for controlling and mitigating the epidemic in developing countries measuring stigma in older and younger adults with hiv/aids: an analysis of an hiv stigma scale and initial exploration of subscales aids-related discrimination in asia treat three million people living with hiv/aids by . in: plenary address by director of hiv/aids, who at the seventh international congress on aids in asia and the pacific world health organization [who] position statement on condoms and hiv prevention the politics of emerging and resurgent infectious diseases. london: macmillan the lessons of hiv/aids world health organization. who guidelines for the global surveillance of severe acute respiratory syndrome (sars) crisis prevention and management during the sars outbreak sars, governance and the globalization of disease world health organization. who global conference on severe acute respiratory syndrome (sars)-where do we go from here? geneva: who health behavior. emerging research perspectives handbook of health behavior research health behavior and health education. theory, research and practice promoting health: intervention strategies from social and behavioral research how individuals, environments, and health behavior interact. social cognitive theory the health belief model and health behavior the health belief model hiv/aids prevention and public health education social networks and social support rational choice theory: advocacy and critique family stress management. a contextual approach family stress as community frame global atlas of infections -epidemiological fact sheet - update world health organization. summary of probable sars cases with onset of illness from summary table of areas that experienced local transmission of sars during the outbreak period from ordinary least squares and logistic regression analysis medical statistics a defining moment. how singapore beat sars at the epicentre. hong kong and the sars outbreak infectious diseases law & sars. singapore: times editions the politics of emerging and resurging infectious diseases hiv in singapore-past, present and future the sars epidemic under china's media policy online news media as interactive community bulletin boards. coverage of sars in the greater china regions the sars channel in singapore severe acute respiratory syndrome (sars) human rights and aids: the future of the pandemic new rule overrides patient confidentiality in order to protect the vulnerable aids as a social problem. the creation of social pariahs in the management of an epidemic. in: ritzer g, editor. handbook of social problems. a comparative international perspective representations of far-flung illnesses: the case of ebola in britain representations of sars in the british newspapers