key: cord- - qo krxv authors: wilcox, bruce a.; gubler, duane j. title: disease ecology and the global emergence of zoonotic pathogens date: - - journal: environ health prev med doi: . /bf sha: doc_id: cord_uid: qo krxv the incidence and frequency of epidemic transmission of zoonotic diseases, both known and newly recognized, has increased dramatically in the past years. it is thought that this dramatic disease emergence is primarily the result of the social, demographic, and environmental transformation that has occurred globally since world war ii. however, the causal linkages have not been elucidated. investigating emerging zoonotic pathogens as an ecological phenomenon can provide significant insights as to why some of these pathogens have jumped species and caused major epidemics in humans. a review of concepts and theory from biological ecology and of causal factors in disease emergence previously described suggests a general model of global zoonotic disease emergence. the model links demographic and societal factors to land use and land cover change whose associated ecological factors help explain disease emergence. the scale and magnitude of these changes are more significant than those associated with climate change, the effects of which are largely not yet understood. unfortunately, the complex character and non-linear behavior of the human-natural systems in which host-pathogen systems are embedded makes specific incidences of disease emergence or epidemics inherently difficult to predict. employing a complex systems analytical approach, however, may show how a few key ecological variables and system properties, including the adaptive capacity of institutions, explains the emergence of infectious diseases and how an integrated, multi-level approach to zoonotic disease control can reduce risk. the growing problem of globally emerging infectious diseases (eids) has prompted a substantial effort by the biomedical research establishment to identify the causes and recommend action. as reported in the most recent of a series of volumes ( ), a main finding is that the current episode of global infectious disease emergence is the result of a convergence of factors involving complex interactions among numerous variables. this includes genetic, biological, social, economic, political, ecological, and physical environmental factors, and calls for an interdisciplinary research agenda. it is also concluded that "human development and large scale social phenomena are closely associated to infectious disease threats at a global level," which points to the need for research focused on "social and ecological factors affecting infectious disease emergence" ( ) . the phenomenon of globally emerging infectious diseases requires understanding biological systems in the broadest sense and dealing with their extraordinary complexity. this includes processes operating at the level of transmission and evolution of a pathogen within and among host species and humans. it extends to and includes processes involving ecosystems and regional environmental change occurring on a global scale ( ) . in fact the scale and magnitude of anthropogenic activity has reached a point of virtual co-dominance with natural processes of energy and material flows globally ( ) . understanding these kinds of processes traditionally has been the domain of classical ecology, or natural history, plus systems ecology ( , ) . adding to this are recent ecological perspectives and models applied at the molecular, cellular level, and organismal levels ( ) , and others addressing the complexity, multiple variables, cross-scale influences, and dynamic behavior at the level of natural ecosystems ( ) , and social-ecological systems ( ) . along with the research at the organismal level and below, that aimed at the level of social-ecological (coupled humannatural systems) is critical to the development of the comprehensive scientific framework necessary for understanding zoonotic infectious disease emergence in particular. not only does this new area address the dynamic behavior of complex, large scale systems, but also bridges theory from the traditionally separate biological and social science disciplines, thus contributing to the interdisciplinary research agenda also called for in the above reports. the purpose of this paper is to consider how regional and global zoonotic disease emergence trends might be explained on the basis of current thought in biological ecology including the very recent developments new to the field of infectious disease ecology. here we draw on ecological science as broadly defined as a basis for identifying causal mechanisms of zoonotic disease emergence, the ultimate goal being to enhance disease prevention and control programs. several authors have categorized causal factors of infectious disease emergence, including explicitly citing 'ecological' ones involving land use change ( ) ( ) ( ) ( ) or 'land use drivers' ( ) , human movement ( , ) , encroachment and wildlife translocation ( , ) , rapid transport ( , ) and climate change ( , ) . most recently, the institute of medicine ( ) described these along with others ( categories of factors in all) and a model stating the major categories of factors have historically converged to bring about the current global emerging infectious disease crisis. ecological factors are described as one of four major categories of factors that have converged with social, political, and economic factors; genetic and biological factors; and physical environmental factors. we take a different approach to understanding the interaction of the above factors and their causal relationships by focusing on disease emergence as an ecological-evolutionary phenomenon influenced by human factors. our interest is in how human factors interact with natural processes and, in particular, how mechanisms operating at levels meaningful to understanding pathogen transmission and evolution can result in regional and ultimately global phenomena (i.e., regional endemism, epidemics, or global pandemics). as a first step we distinguish between the two broad categories of human factors, 'demographic and societal' and 'disease intervention and policy' suggested previously by gubler ( ) ( table ) . this categorization differentiates between factors associated with specific kinds of environments or ecosystems and those involving biological and policy factors not so associated. however, both can be described as part of a single ecological framework involving interaction of systems of essentially natural versus human design, respectively. our focus is on the first category from the standpoint of how disease emergence is explained by ecological concepts and principles. this includes some relatively new models and theory not previously used to explain the current trend in increasing emerging infectious diseases. we present a general model of zoonotic disease emergence on this basis. we also discuss recent explanations based on complexity theory for how human behavior and ecosystems interact to contribute to disease emergence. classical ecology, or natural history, has been the basis and mainstay of infectious disease research since its origins with 'koch's postulates' and subsequent development of microbiology and zoonotic disease epidemiology during the th and th centuries ( , ) . throughout much of its early history, zoonotic disease research involved this descriptive, empiricallybased ecology: identifying the life cycle, transmission, incidental and natural hosts of pathogens, along with demographic, life history, dispersal, and habitat attributes of reservoirs and vectors. a substantial theoretical dimension has developed, beginning with ross's mathematical analysis of malaria transmission ( ) and extending to anderson and may's ( ) recent synthesis infectious diseases of humans. although essential to designing effective prevention and control programs, empirical field based, disease ecology has been neglected in recent years ( ) . fortunately, theoretical disease ecology, stimulated largely by the work of anderson, may and others has flourished and led to a significant syntheses involving application of ecological-evolutionary biology to the study of infectious diseases ( , ) . parallel to this, systems ecology has begun to extend its domain by applying complexity theory to emerging infections with at least initial suggestions of its implications ( ) . this development in particular, along with observations from several decades of applications of systems ecology to natural resources and economic development ( , ( ) ( ) ( ) , have resulted in important insights of significant potential in understanding zoonotic disease emergence as a cross-scale process. this area uses complex systems theory applied to coupled, human-natural systems to explain how processes such as local phenomena can result in a cascade of effects ultimately reaching global proportions. the finding suggests this crossscale behavior is controlled by relatively few variables, and is mitigated by social and ecological resilience. the loss of this resilience in ecological systems is observed to lead inevitably to unpredictable events or the 'surprise' characteristic of complex systems generally. this combination of socialecological systems and resilience theory helps explain the unpredictability of disease emergence events. it represents another potentially useful area of application to understanding emerging infectious diseases along with those areas generally considered within the domain of ecology mentioned above: population ecology and genetics, community ecology, and systems ecology. population ecology, genetics and disease emergence of particular relevance to disease emergence is the explanation provided by theoretical population biology, already mentioned, of how host (including human) population size determines whether or not a pathogen can persist in a population. the accumulated findings demonstrate thresholds exist, depending on the type of pathogen and host population, below which a pathogen cannot be sustained. considered in light of the exponentially increasing size of human and domestic host and vector populations in the world, the breaching of thresholds of pathogen persistence can explain much of the increase in emerging infectious diseases. this can be explained as follows. although zoonotic disease emergence is not entirely a tropical phenomenon, it is mostly associated with tropical developing regions undergoing the most rapid population growth and ecological changes. prior to the post-wwii economic era, most regional ecosystems in the tropics consisted of relatively scattered human settlements, and only a few large cities (> , ) ( ) . these were separated by large expanses of cropland and pastureland and relatively undisturbed forest. since then, in what has been the most rapid period of large scale ecological transformation in human history, the pattern has essentially reversed ( ) . the once scattered settlements and few large cities have coalesced into expansive megacities and surrounding periurban settlements with only remnant patches of undisturbed forest remaining in a sea of cropland, scrub, and ecologically degraded lands. dacca, bangladesh, which grew from a population size of , to million from to , is one of many examples. thus the existence of population density-dependent thresholds for disease emergence is particularly relevant ( , ) . this explains the abrupt transitions of urban diseases between non-persistence to endemic and endemic to epidemic behavior as population densities of susceptible humans, hosts, and vectors reach critical densities. the classic illustration is that of measles which, given its particular transmission rate, requires human settlements with population sizes in excess (> , ) of what historically existed in most pre-industrial states and geographically isolated populations even today ( ). thus, for example, many infectious diseases endemic on continents have not become established on islands despite their occasional introduction and the occurrence of local outbreaks. the same mathematical ecology that explains why measles and virtually all diseases have threshold densities, explains the much lower thresholds existing for vector-borne diseases such as arboviruses ( ) . particularly noteworthy is the theoretical demonstration that the pathogen 'reproductive rate' increases with the square of vector population density. this indicates threshold densities can fast be breached as domestic and peridomestic hosts and vectors expand (or re-expand) their geographic ranges (once they are introduced or re-introduced) and increase their densities. this helps explain the explosive re-emergence of dengue and dengue hemorrhagic fever in the american tropics as vector populations responded to relaxed controls and new breeding habitats associated with urbanization ( ) . this phenomenon can be likened to the gradual build-up of 'dead and down' wood across a forested landscape with a history of fire suppression. the build-up of fuel, like that of host or vector populations, becomes an 'accident waiting to happen' when a single ignition event in one locality, similar to a single infection event, spreads to the entire region. another consequence of the dramatically increased densities of humans, host reservoirs, and vectors is the increased number of pathogen genomes. the resulting increased levels of genetic variability can accelerate microbial adaptation, including evolution of pathogenesis, and antimicrobial resistance. genetic variability increases with population size and density through a variety mechanisms including mutation. the probability of producing more virulent variants not only increases with host population size but also with crowding and co-mingling of different host species ( ) . in general, parasite (pathogen)-host relations naturally constitute a co-adaptive/ evolutionary 'dance' along the pathogenicity threshold, which is likely to be crossed with greater frequency due to unnatural anthropogenic disturbances ( ) independent of increasing population sizes and pathogen genetic diversity. the study of ecological communities and the 'community ecology' theory it has yielded includes a number of principles and mechanisms that describe how human disturbances as well as natural environmental variation can contribute to any of the above population level factors ( ) . there are a number of implications to zoonotic disease emergence, although most have not yet been described in terms of disease emergence or in the medical, public health, or zoonotic disease literature. of critical significance from this area of ecology is the general principle of community assembly. research has demonstrated that communities of arranged predicably in terms of 'assembly rules' ( ) . this order, in terms of the spatial distribution, composition and the abundance of each species in an ecological community, is affected by interspecific interactions (predation, competition, and parasitism). density independent factors (e.g., weather, natural catastrophes) play an important, but a more ephemeral role in most ecosystems. the process of community assembly (and disassembly) has been particularly well demonstrated through studies of insular ecosystems, the so-called 'species area relationship,' and the phenomenon of faunal collapse ( ) ( ) ( ) . a principal outcome and the ecological significance of this body of research first described in terms of the process of 'habitat fragmentation', has been identified as the principal mechanism by which human land and resource use contributes to species extinction ( ) . although initially debated, a significant amount of evidence has since accumulated resulting in its general acceptance and applicability, particularly to tropical forest ecosystems ( , , ) . the critical significance of habitat fragmentation and related human disturbances to disease emergence stems from it contribution to the disassembly of orderly natural communities. for example, human activities such deforestation, use of pesticides, and various forms of pollution often result in the loss of predators. in fact, carnivorous mammals typically are the first species to disappear following forest fragmentation. their local extinction represents the loss of 'top down' natural control in ecological communities. this can in turn result is an increase in abundance, even 'hyper-abundance' ( ) , of species such as rodents and biting insects. community disassembly and the resulting loss of natural population control mechanisms for such species generally is associated with the conversion of natural landscapes to urban and agriculture landscapes. broad spectrum pesticide use and habitat simplification, along with habitat fragmentation, are important contributing factors. the reduction in species diversity can contribute to the phenomenon of 'ecological release' in remaining species, whose predators, competitor and parasites are reduced in numbers or eliminated. some of these may be already serving as zoonotic reservoirs or vectors. if so, ecological release may result in their proliferation. this helps explain why many emerging zoonotic diseases occur in areas where settlement and agricultural expansion recently have encroached into tropical forests. a similar phenomenon, associated with the regrowth of forests in developed regions, can lead to zoonotic disease emergence. the pattern of reforestation in eastern north america during the past half-century resulted in increased habitat favored by forest edge adapted species such as whitetail deer and white-footed mice. white-tailed deer, the principle host of the adult tick ixodes scapulari, reinvaded the area and with few predators and competitors the population exploded. this pattern of ecological change arguably has been a major factor in the emergence of lyme disease in this region. an extension of the concept of 'ecological release' has been suggested to explain the invasive species phenomenon in which super-successful introduced (alien) species have escaped from their natural complement of parasites ( ) , as well as predators and competitors. this may explain in large part our most successful invasive domestic species, rattus and aedes species, which are hosts and vectors of some of our current and historically most problematic urban zoonotic diseases. in sum, zoonotic infectious disease emergence can be explained in part as a consequence of the disruption of natural ecological communities, and the breakdown of naturally existing predator-prey, competitive, and host-parasite relationships that tend regulate and stabilize species' abundance. this can occur through the use of non-selective pesticides through changes in land use and land cover that affect the distribution and abundance of species. it should be noted that the disassembly of natural ecological communities that results from habitat fragmentation is a protracted process compared to exponential decay. depending on the extent of habitat loss and other factors such as the sizes, shapes and spatial relationships of remaining fragments, the process may require decades, centuries or longer as communities 'relax' toward a new equilibrium ( , , ) . it follows that the frequency of disease emergence can be expected to follow a similar path: highest rates at first, followed by gradual decline as an ecosystem 'stabilizes'. the application of systems thinking to ecological communities centers on the ecosystem concept and has been the basis of significant research activity in ecological science since the 's ( ) . much of the focus has been on describing and understanding energy and nutrient fluxes across different kinds of ecosystems, and more recently emphasizing the human dimensions of global environmental change ( ) . although global scale ecosystem change has been considered in reference to human and infectious diseases ( , ) , no systematic framework has yet been presented in this regard. the evidence presented has been anecdotal. however, the development and application of systems theory independently of and largely outside the realm of mainstream systems ecology ( ) shows significant promise in providing a basis for more systematic interpretation of the role of ecosystem change in disease emergence. recent thinking draws in particular on the application of the theory of 'complex adaptive systems' to ecological systems in which ecosystems are represented as scaled, self-organizing, far from equilibrium, evolutionary, and non-linear ( ) . organization, diversity, and resilience are important 'emerging' properties of complex systems-often equated with a 'healthy' state. 'surprise', or qualitative disagreements of system behavior with a priori expectations, is another property ( ) . their association with loss of system resilience and increased vulnerability applies both to increasing inflexible social systems 'managing' and attempting to 'control' natural variables (i.e., vectors, pathogens) and that of the ecosystems whose component variables (e.g., vector and pathogen populations) are targeted for management or control. alteration of natural disturbance regimes (via control of natural variation via flood control projects for example) reduces resilience, while secondary disturbance events (wildfires, storms, floods, and earthquakes) precipitate events caused by crossscale influences (e.g., a thunderstorm igniting a fire locally that spreads regionally as a result of fuel build-up from years of artificial fire suppression). regional environmental change such as that associated with population growth development often does not accommodate the need to maintain resilience ( ) . such ecosystems have been described as 'over-connected' or 'brittle' and, as stated above, 'accidents waiting to happen' ( , ) . floods, often associated with waterborne disease outbreaks, occur more frequently and with greater severity as a result of lost resilience in natural systems due to attempts to 'control' (in contrast to manage) natural variation. conversion of upland forests to plantations or cropping systems for more 'efficient' natural resource production is another, as is agriculture generally. both result in a reduction of heterogeneity in ecosystems that tend to 'buffer' against disease outbreaks, which can spread more readily across the more uniform landscape including immunologically vulnerable domesticated species. gunderson et al. ( , ) describe this as general pattern of institutional behavior. it begins with the targeting of a natural variable for control, followed by increasing institutional efficiency and inflexibility in the control methods used. as the target variable and ecosystem changes and initial signs of failure are ignored, the ultimate result is a crisis. this 'pathology of regional resource and ecosystem management' and is apparently applicable to infectious disease management as well. the above body of ecological theory and observations involving specific emerging infectious disease cases suggests a causal schema that links ecological phenomena on the scale of pathogen transmission and evolution to regional and global transformations. this is represented by figure , focusing on the role of demographic and societal factors in disease emergence (shown in table ). this schema is constructed using the generally adopted view of human-environment interaction in which the impact of human population and technology is taken as the driving force, or ultimate cause. clark et al. ( ) elaborate on this in their seminal treatment on global and regional change. here, the combination of population, technological capacity, and sociocultural organization act as the system drivers of regional environmental change. these and 'mitigating' forces are in turn influenced by 'human behavior', referring to patterns of actions and the rationales giving rise to them. broadly speaking, these forces and their affects on ecosystems represent the 'ecological factors' in social-ecological systems, while human behavior represents the 'social factors' for the purposes of discussion. this schema represents zoonotic disease emergence from the perspective of the ecosystems within a regional environment, the large scale processes involved, and the associated ecological effects and processes involved in disease emergence. thus, referring to table , the factors under 'demographic and societal changes' can be identified in reference to particular ecosystems and processes (i.e., urban and urbanization, agriculture and agricultural intensification, forest and forest alteration), and associated factors operating on regional and global scales. these are unprecedented population growth, unplanned and uncontrolled urbanization, non-biodegradable packaging of consumer goods, and modern transportation, all contributing to conditions that promote pathogen transmission and persistence. for zoonotic diseases, which by definition involve the jumping of a pathogen from its natural host to humans, and in some instances extension of its host cycle to include humans, conditions can be described for this simple schema as follows. the likelihood or frequency of transmission events change when the natural host or pathogen changes, humans change, or the ecosystem supporting both changes. thus, fundamentally the processes influencing transmission of zoonotic pathogens can be described as a consequence of one or a combination of three possible kinds of change: expansion of the habitat or geographic range of a host, of a pathogen or both; expansion of human's habitat or geographic range; or change in the habitat or ecosystem occupied by both humans and the natural host. evolutionary adaptation of pathogens is omitted from the figure. however, it can be assumed any factor contributing to increased likelihood of transmission, as well as increased population size of hosts and pathogens will contribute to the potential that new, increasingly pathogenic, infectious, antimicrobial resistant variants will emerge. anthropogenic climate change, while not incorporated in the diagram, can be considered to potentially contribute to disease emergence through its contribution to habitat alteration. our review of ecological theory and the resulting complex model described here demonstrates the limitation of classical disease ecology and natural history. for example, without incorporation of population genetic theory in ecology as 'evolutionary ecology', along with the concepts of pathogen spillover and cross-scale ecosystem dynamics, classical disease ecology cannot explain recent emergence events like those involving hiv/aids, sars, avian influenza, e. coli : , dengue, malaria, west nile virus, and nipah virus, among others. the resurgence of vector populations, having acquired pesticide resistance and lost predators and competitors as natural controls after a regimen of inappropriate pesticide use, similarly is explained by modern ecology and evolutionary biology. this has direct application to control and intervention policies and practices. for example, it points to the need to adopt control strategies that integrate landscape and habitat management with careful rotation of targeted chemical and biological agents ( ) . developing such strategies requires detailed field studies, built on traditional natural history and classical disease ecology, but supplemented with advanced molecular techniques, as well as ecological research that takes into account the community and systems level dimensions of a particular pathogen-host complex. the continual expansion of human populations since prehistoric times, and particularly since the advent of settled agriculture with its associated domesticated animals exposing humans to their pathogens as well as those spilling over from wild animal populations, has incrementally added to the pathogen load through successive invasions by different organisms over time ( , ) . well established principles of population ecology, applied via mathematical epidemiology as anderson and may and others so aptly have done, readily explain why, ceteris paribus, infectious disease incidence should generally be increasing with human population size, as it has in the world's poorest and most populous regions. yet in spite of what are in general commonly understood principles, and warning signs that went unheeded in the 's and 's ( , ), biomedical and public health institutions were unprepared for the recent surge in emerging infectious diseases ( , , , ) . not until the 's, prompted in part by the hiv/aids pandemic and the failure of 'quick-fix' solutions based on drugs, vaccines, and pesticides ( ) , did the biomedical science and public health communities begin to launch a significant response. in light of the complexity of the factors involved, this lack of preparedness should perhaps not be surprising. as explained by the infectious disease ecology described here, zoonotic disease emergence involves biological processes operating on the scale of molecules and cells to that of coupled, regional scale human-natural systems. the latter involve political economic factors and policies driving regional environmental change, spreading geographically across the globe. it is this process of globalization-its ecological underpinnings and consequences-to which the current eid global trend of zoonotic disease emergance can be largely attributed. lack of awareness of the ecological implications of fig. diagram depicting infectious disease ecology causal schema. the aggregate variable at the top of the diagram, representing population and consumption, along with mitigating socio-cultural attributes, is the driver or 'forcing function' responsible for land use and land cover change characteristic of a particular region. the result is varying degrees (and types) of urbanization, agricultural intensification (including food production and distribution), and alteration of natural habitat. these changes at the level of landscapes and habitat produce conditions influencing the ecological and evolutionary dynamics of vector and host species and vector/host-pathogen dynamics. in turn, these conditions facilitate the geographic expansion, novel appearance, or increased epidemic activity of a disease. regional environmental transformations, and of their synergy with the ecological and evolutionary consequences of inadequate or inappropriate policies or methods of vector control and disease prevention, have unwittingly promoted disease emergence. the 'ecological' changes taking place as a result of public health agencies' actions (or inaction) involve pathogen biology and are small scale in time and space: selection for vector pesticide and antimicrobial resistance. however, the cumulative effect of micro-scale processes involving pathogen adaptation and host range expansion (or re-expanding) can ultimately produce regional and even global consequences. however, policy action and inaction outside the domain of biomedical or public health agencies has produced ecological changes at a historically unprecedented rate and scale. urbanization, agricultural and food production intensification, alteration of natural habitat, along with concomitant loss of ecosystem functions, have transformed entire regional ecosystems during the past years. the role of urbanization cannot be underestimated. the direct land use changes associated with urbanization effectively concentrate human, animal reservoir and vector populations at unprecedented densities. but urbanization also is strongly tied to socio-economic and cultural factors, along with human migration dynamics, affecting agricultural and food production intensification, as well as rural and natural ecosystems. in the case of food production and distribution, dramatically increased contact with and transport of wildlife (e.g., bush meat trade in africa), and increased ruralurban transport and concentration of wild species for the exotic food market (e.g., civet cats in guangdong, china), is another contributor to increasing disease emergence. it can be assumed these impacts on wildlife populations also contribute to changes in the composition of ecological communities on a regional scale ( ) , and often result in a hyper-abundance of small mammal species low in the food chain, which are likely to serve as human disease reservoirs. similar effects of ecological disruption appear to generally apply to invertebrate commu- whether a disease 'jumps' to the regional population and the global human population scale is determined by quite different processes. these depend on demographic and transport patterns related to processes, like urbanization, influencing pathogen transmission and behavior operating on the regional and global scales. physical environmental processes such as climate variability (on the right side of the figure), which are episodic by nature, include short term and small scale variations in the form of seasonal storms (e.g., monsoons), for example, as well as larger time and space scale variations. these include, for example, decadal and regional scale changes in weather patterns such as el niño. these climate changes and weather events can precipitate floods and droughts. these act as cross-scale mediators that directly affect disease reservoir and vector populations, or pathogens (e.g, dispersal via flood waters). they cause the disease to jump from a smaller demographic unit to a larger one (e.g., from a single village to a district). human factors such as land use and land cover changes (table and fig. ) produce ecosystem changes contributing or magnifying the cross-scale processes. for example, urbanization and deforestation increase the magnitude of floods and droughts resulting from natural or anthropogenic climate variation. nities ( ) , the kinds of organisms most commonly serving as human disease vectors. the estimated acceleration of natural species extinction rates by orders of magnitude over nonanthropogenic extinction rates ( ) gives an indication of the scale and magnitude of change in natural communities, particularly in the tropics. in these regional ecosystems, the original extent of tropical forest has declined to a fraction of its original area with concomitant affects on biodiversity ( ) . large scale agricultural expansion (a common proximate cause of tropical deforestation) has decelerated and all but ended in many regions. this suggests that further contributions from what historically has been a main factor in natural habitat alteration, ecosystem disturbance and biodiversity loss, will decline. yet agricultural intensification has replaced expansion with technologies that further impact native biodiversity ( ) . the reduction in plant species richness that accompanies agricultural intensification leads to changes in the community composition of the pest complex-herbivorous insects, their natural enemies (predators and parasites), and the microbial community attacking crops ( ) . the schema described here demonstrates how regional environmental change, involving ecological dynamics such as demographic or landscape transformations on the scale of decades, interact with change on the scale of host-parasite/ pathogen dynamics. how these cross-scale mechanisms produce regional or global scale disease emergence patterns is beyond the realm of conventional epidemiology, or analytical approaches generally. this may explain why such changes either are not apparent or their implications in terms of disease emergence are a low priority to biomedical and public health agencies. such cross-scale processes are however characteristic of ecosystems, whose dynamics involve interaction of variables and operate on vastly different time and space scales, involving natural processes that are discontinuously distributed as shown in figure . change in such systems is difficult to understand employing conventional analytic approaches alone, but require new thinking and analytical methods drawn from complex systems theory. the discontinuous character of the processes or variables makes their interaction intuitively improbable except for the mediating effect of 'cross-scale influences' as illustrated in figure . examples include the eruption of hantavirus in the american southwest, thought be associated with weather events precipitated by el nino southern oscillation. storms events are similarly episodic, and represent a discontinuous form of variation transporting pathogens via flood waters in domestic and natural environments. on the other hand, massive environmental events, like the recent southeast asian tsunami, are potentially capable of producing epidemics across an entire region, and may episodically extinguish some zoonotic diseases by temporarily destroying reservoir and vector populations and habitat. the roles of resilience and vulnerability in determining the severity of such events, both in terms of social systems and ecological systems is another critical aspect of social-ecological systems behavior ( ) . the recent worldwide upsurge of zoonotic infectious diseases, involving the resurgence of a growing number of diseases previously believed under control or the emergence of newly recognized diseases, has been attributed to a list of global factors characterized in terms ranging from microbial adaptation and land use to changing ecosystems, breakdown of public health, and poverty ( , ) . the categorization provided by gubler ( ) , elaborated here based on an expanded view of infectious disease ecology, provides the basis for a schema describing the causal relations involving factors previously identified, along with hypothesized mechanisms. the complicated nature of this problem, which obviously entails numerous interacting variables operating on different time and space scales pose a significant challenge to biomedical science and epidemiological research as well as public health intervention. however, the current trend of increasing global emerging infectious diseases is linked with another issue of 'global governance', sustainable development, with which disease control and prevent strategies must be integrated. here too, the problems of politically stability, population growth, unplanned urbanization and economic development, income disparity, and environmental degradation, are all integral to the solution. this interdisciplinary imperative challenges what historically has been an increasing disciplinarily focus in infectious disease research. greater investment in research has succeeded in revealing more detail about diseases within specific disciplines. yet this arguably has been at the cost of greater disintegration rather than integration among disciplines. the division is widest between the genetic and biological aspects of disease and health on the one hand and the social, economic, political, and physical environmental factors on the other. the disciplinary distinctions within infectious disease research of course belie the true transdisciplinary nature of this and most problems in the global heath and environment arena ( ). the above disciplinary divisions largely reflect the gap between disciplines focusing on systems at or below and above the level of the organism or species. the former involve disciplines addressing the genetics, pathogenesis, or immune response within particular organisms (humans, vectors of pathogens), for example, or disease as a statistical phenomena at the species population level (the mainstay of epidemiology). the latter deal with social or ecological phenomena, essentially representing higher levels of biological organization, within which the organism-level processes operate but that also involve many other variables or processes operating on a wide range of biological scales (from genes to the biosphere) characterized by cross-scale influences, and interactions at multiple societal and ecological levels. it follows that for intervention to be globally effective, in addition to rebuilding public health infrastructure based on the comprehensive view of infectious disease ecology presented here, at least three elements are required: . a multilevel ecosystem approach, involving cross-scale integration. . incorporated ecological theory and data for the specific disease system, . local scale intervention using a participatory approach that matches pathogen management with sustainable 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change: research pathways for the next decade ecosystem change and public health: a global perspective systems thinking, systems practice adaptive dancing: interactions between social resilience and ecological crises plagues and peoples human frontiers, environments and disease emerging infectious diseases: a cdc perspective a global perspective on habitat disturbance and tropical rainforest mammals species richness-decomposition relationships depend on species dominance extinction rates agricultural intensification and ecosystem properties biodiversity and ecosystem processes in tropical forests emerging infections: microbial threats to health in the united states transdisciplinarity: recreating integrated knowledge. mcgill-queen's university press we thank shannon bennett, kristin duin, mayee wong, and yuko chiba for assisting with the research for this paper and its critical review. 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- -qy tg ow authors: christopeit, maximilian; schmidt-hieber, martin; sprute, rosanne; buchheidt, dieter; hentrich, marcus; karthaus, meinolf; penack, olaf; ruhnke, markus; weissinger, florian; cornely, oliver a.; maschmeyer, georg title: prophylaxis, diagnosis and therapy of infections in patients undergoing high-dose chemotherapy and autologous haematopoietic stem cell transplantation. update of the recommendations of the infectious diseases working party (agiho) of the german society of hematology and medical oncology (dgho) date: - - journal: ann hematol doi: . /s - - - sha: doc_id: cord_uid: qy tg ow to ensure the safety of high-dose chemotherapy and autologous stem cell transplantation (hdc/asct), evidence-based recommendations on infectious complications after hdc/asct are given. this guideline not only focuses on patients with haematological malignancies but also addresses the specifics of hdc/asct patients with solid tumours or autoimmune disorders. in addition to hbv and hcv, hev screening is nowadays mandatory prior to asct. for patients with hbs antigen and/or anti-hbc antibody positivity, hbv nucleic acid testing is strongly recommended for months after hdc/asct or for the duration of a respective maintenance therapy. prevention of vzv reactivation by vaccination is strongly recommended. cotrimoxazole for the prevention of pneumocystis jirovecii is supported. invasive fungal diseases are less frequent after hdc/asct, therefore, primary systemic antifungal prophylaxis is not recommended. data do not support a benefit of protective room ventilation e.g. hepa filtration. thus, agiho only supports this technique with marginal strength. fluoroquinolone prophylaxis is recommended to prevent bacterial infections, although a survival advantage has not been demonstrated. high-dose chemotherapy (hdc) and autologous stem cell transplantation (asct) constitute a standard of care in the treatment of heamatologic malignancies, in particular, multiple myeloma [ ] , malignant lymphoma [ , ] and acute myeloid leukaemia [ ] . hdc and asct are also used in solid tumours such as neuroblastoma, sarcoma, germinal tumours [ ] and autoimmune diseases e.g. multiple sclerosis [ ], systemic sclerosis [ ] and crohn's disease [ ] . in total, the number of asct reported to the european society for blood and marrow transplantation in exceeds , , including more than for non-malignant disorders, mostly autoimmune diseases, and for solid tumours [ ] . after hdc and asct, up to % of patients will experience infections, mostly presenting as fever of unknown origin (fuo) [ ] . due to indwelling venous catheters and toxicities of conditioning regimens, in particular, mucositis and gastrointestinal barrier impairment, both gram-positive and gramnegative bacteria may cause fever and infection after hdc/ asct [ ] . bacterial pneumonia, colitis and bloodstream infection (bsi), including catheter-related bsi, are the prevailing documented infections in patients after hdc/asct [ , ] . invasive fungal disease and viral infections, ranging from herpes to hepatitis viruses, may occur as well, extending into the period after transplantation [ , ] . these recommendations on prophylaxis, diagnosis and treatment of infectious complications after hdc/asct by the infectious diseases working party (agiho) of the german society of haematology and medical oncology (dgho) are the fourth edition after , and [ ] [ ] [ ] . the expert panel assessed the recommendations in a stepwise consensus process, consisting of telephone and video conferences. all members of the agiho were invited to the consensus meetings. the guideline was approved by the agiho assembly on may , . this guidance document is embedded into other agiho recommendations on infection management in patients with haematological and oncological diseases [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . it provides an evaluation of current evidence and the consensus interpretation of the authors. recommendations are not mandatory and intend to assist physicians in decisions on individual patients. we regard correct dosing to be a responsibility of the prescribing physicians and do not mention this in this guideline. strength of recommendation and quality of evidence were graded according to the criteria applied by the european society for clinical microbiology and infectious diseases (escmid) and the european confederation of medical mycology (ecmm ; table ) [ , ] . both depth and duration of neutropenia have been associated with the risk of cancer patients to develop an infection that will take a more severe and complicated course [ ] . agiho regards patients with expected neutropenia < /μl for at least days to be at high risk and those with an expected duration of neutropenia of up to days at standard risk for the development of an infection with a complicated course [ ] . while it is generally presumed that patients after hdc/asct are amongst those with neutropenia lasting for days or longer, thus are at high risk for complicated infection, data from prospective clinical trials show that the duration of neutropenia may often be in the standard risk range after hdc/ asct [ ] . however, profound, and sometimes longlasting defects of components of the adaptive immune system are observed besides neutropenia after hdc/ asct. causes may lie in the nature of the underlying disease, timing and type of previous treatments, history of previous infection and specifics of the conditioning regimen e.g. nucleoside analogues or antilymphocyte globulins [ , [ ] [ ] [ ] [ ] [ ] . in conclusion, agiho considers patients after hdc/asct at high risk for developing infections with a complicated course. hereby, conditioning with carmustine, etoposide, cytarabine and melphalan (beam) prior to asct is associated with an increased risk for infections compared to conditioning with highdose melphalan [ ] . diagnostic procedures before the onset of fever or infection surveillance blood cultures in the absence of fever or other signs of infection are discouraged [ , ] . likewise, routine screening for invasive aspergillosis by serial determination of galactomannan antigen or , -β-d-glucan is not recommended in these patients [ ] . in individual patients at increased risk for invasive aspergillus spp. infection, e.g. patients with previous aspergillosis who are without current systemic mould-active prophylaxis, twice-weekly galactomannan and/ or , -β-d-glucan surveillance may be considered. for more detailed information, refer to the separate guideline on diagnosis of fungal infection [ ] . screening for hepatitis b virus (hbv; anti-hbc antibodies, hbsag, nucleic acid testing), hepatitis c virus (hcv; anti-hcv, nucleic acid testing), hepatitis e virus (hev; nucleic acid testing) and human immunodeficiency virus (hiv; hiv / antibodies, nucleic acid testing) is requested in all patients prior to release of the autologous graft [ , ] . these screening tests should be repeated at least days before hdc/asct. monitoring of hbv viral load is strongly recommended in hbsag and/or anti-hbc antibody positive patients for months after hdc/asct, as immunosuppression can lead to viral reactivation and disease [ ] [ ] [ ] [ ] [ ] . if maintenance therapy using rituximab, lenalidomide or bortezomib is administered, monitoring should be continued for months following cessation of the respective maintenance therapy. in patients with respiratory symptoms, screening for respiratory tract pathogens should include severe acute respiratory syndrome coronavirus (sars-cov- ). hdc/asct may be deferred until the patient is asymptomatic [ , ] . diagnostic procedures recommended before onset of fever or infection are given in table . thorough physical examination of a febrile neutropenic patient is mandatory. we strongly recommend two separate pairs of venous blood cultures in case of fever or other signs or symptoms of infection. in the presence of a central venous catheter (cvc), one of the two pairs should be obtained from the catheter. to increase the diagnostic yield of blood cultures, it is recommended with moderate strength to draw blood from each individual cvc lumen, or to obtain a third pair of blood cultures [ ] [ ] [ ] . determination of the differential time to positivity (dttp) between blood cultures drawn from the cvc and a peripheral vein might be useful to identify the source of bsi [ ] . dttp of h or more is suggestive of catheter-related bsi [ ] . dttp may be a useful tool to diagnose candida spp. bsi, with a cut-off value of h for candida glabrata bsi and h for other candida spp. [ ] . in contrast, dttp has not proven useful in the diagnosis of staphylococcus aureus bsi [ , ] . in s. aureus or candida spp. bsi cvc should be removed whenever possible, independent of the exact source of infection [ ] . chest x-rays are commonly discouraged to diagnose lung infection in tumour patients, since infiltrates are frequently invisible [ , ] . high-resolution/multislice thoracic ct scan without contrast enhancement has a significantly higher sensitivity than chest x-ray and should be performed in patients with respiratory symptoms or persisting fever despite antimicrobial treatment over - h [ , ] . diagnostic bronchoscopy, bronchial or bronchoalveolar lavage for patients with pulmonary infiltrates (histology, cytology, culture, antigen testing, nucleic acid testing) should be applied whenever possible. further diagnostics (e.g. abdominal or central nervous system imaging) might also be required, depending on symptoms, clinical signs and laboratory parameters. signs of sepsis in the absence of fever as well as hypothermia should prompt diagnostic procedures as for a first fever, and empiric antibiotic treatment. diagnostic procedures recommended at onset of fever or infection are summarized in table . [ ] antimicrobial prophylaxis for patients during and after hdc/asct prophylactic antimicrobial use can be considered in asct recipients during pre-engraftment when the duration of profound neutropenia (absolute neutrophil count < /μl) is expected to be at least days. one placebo-controlled randomized trial has shown a reduction in the number of infections in patients, including those after hdc/asct, when using levofloxacin prophylaxis [ ] . moreover, a retrospective study with asct recipients has shown significant reduction of febrile neutropenia and bsi under prophylaxis with [ ] levofloxacin [ ] . of note, levofloxacin is not approved for antibacterial prophylaxis in germany. an increasingly critical view of fluoroquinolone prophylaxis is explained by the absence of a survival benefit of fluoroquinolone prophylaxis in randomized clinical trials as well as by toxicities associated with fluoroquinolone use [ , ] . fluoroquinolone-resistant enterobacteriaceae have been linked to community fluoroquinolone consumption. prophylactic efficacy is reduced in neutropenic patients when the prevalence of fluoroquinolone resistance exceeds % in gram-negative bacteria [ ] . in summary, agiho recommends to critically weigh expected benefits of fluoroquinolone prophylaxis against the risks and consider local bacterial epidemiology and individual patient risk factors for fatal outcome of infections. agiho strongly recommends fluoroquinolone prophylaxis if the intention is to prevent bacterial infection. it cannot be expected to reduce risk of death with such prophylaxis [ ] . clostridioides difficile enteritis occurred in % vs. % after hdc/asct in a randomized comparison of fidaxomicin versus placebo [ ] . since the incidence of c. difficile-associated diarrhoea was low in both the placebo and in the fidaxomicin arm, agiho does not recommend prophylaxis of c. difficile enteritis after hdc/asct in the clinical routine. available data do not support the prophylactic use of antifungals to prevent invasive fungal disease (ifd). those are rare events after hdc/asct and no reduction in mortality has been found in patients after hdc/asct [ , ] . this is particularly true for mould-active antifungal agents. yet, antifungal prophylaxis might be considered on a case-by-case basis if severe and long-lasting immunosuppression is expected. the value of protective room ventilation such as highefficiency particulate air (hepa) filtration, positive pressure-directed airflow or laminar airflow is not well established for hdc/asct patients. during the last two decades, the use of air-filtered rooms has decreased as the incidence of filamentous fungal infections is extremely low in patients undergoing hdc/asct [ ] . in a prospective clinical trial with hdc/asct patients from nine transplant centres, no significant impact of hepa filtration on the incidence of pneumonia, including ifd, or mortality rate was observed [ ] . thus, there are no data to mandate air-filtered rooms and agiho supports a recommendation of air-filtered rooms with marginal strength. prophylaxis against pneumocystis jirovecii pneumonia (pjp) is efficacious with trimethoprim/sulfamethoxazole (tmp/smx). a meta-analysis calculated an rr of . ( % ci . - . ) for an hiv-negative immunosuppressed individual to experience pjp when receiving prophylaxis with tmp/smx, with a reduction of p. jirovecii-related mortality but no effect on all-cause mortality [ ] . reflecting mostly low quality of evidence due to bias and imprecision, agiho moderately supports a recommendation of tmp/ smx to prevent pjp after hdc/asct. if the administration of tmp/smx is not feasible, alternatives are atovaquone, or pentamidine administered by inhalation or intravenously. these alternatives have not been studied in the hdc/asct setting and recommendations are transferred from other populations. the duration of p. jirovecii-directed prophylaxis should last for at least months, preferably until the cd + t cell count stably exceeds /μl. there are no large randomized controlled trials that evaluate antiviral drugs to prevent herpes simplex virus (hsv) and varicella zoster virus (vzv) disease after hdc/asct. newer studies-including recently published placebocontrolled vaccination trials-showed that hsv infection, in particular, gingivostomatitis, and herpes zoster are still of concern in these patients [ ] [ ] [ ] . noteworthy, herpes zoster also frequently occurred beyond months post-transplant, particularly in unvaccinated patients [ ] . antiviral drug use was reported in~ % in this trial, with a duration of > months iñ % [ ] . several studies, including placebo-controlled studies and meta-analyses (but not focused on asct patients) showed that acyclovir is useful to prevent and treat hsv and vzv diseases [ , ] . thus, we strongly recommend acyclovir prophylaxis for at least months, in particular, if cd selected grafts are used [ , ] . inactivated vzv vaccine is strongly recommended for all seropositive hdc/asct patients [ ] . cytomegalovirus (cmv) infection (reactivation) has been reported in some patients of mainly retrospective analyses focused to patients with fever after hdc/asct [ , ] . however, cmv disease, i.e. organ involvement, is very rare in this setting [ ] . in summary, cmv is no major concern in patients after hdc/asct. agiho supports a recommendation against the use of cmv prophylaxis. human herpes virus (hhv- ) and epstein-barr virus (ebv) infections are infrequent after hdc/asct and routine prophylaxis is not recommended [ , ] . however, ebv reactivation has been reported at a high frequency in patients with multiple sclerosis undergoing asct [ ] . thus, nucleic acid-based screening for ebv viremia at follow-up presentations and preemptive treatment with rituximab in the case of ebv infection should be considered in these patients. reactivation of viral hepatitis in patients after hdc/asct with previous or ongoing chronic hbv infection i.e. hbsag and/or anti-hbc positivity is associated with considerable morbidity and mortality. reactivation has long been prevented using lamivudine. lamivudine resistance can reach more than % in primary treatment of viral hepatitis b after long-time therapy [ ] . here, viral clearance and hbeag status, amongst others, are important risk factors for the development of resistance. today, tenofovir and entecavir are antiviral substances with resistance rates of - %. their prophylactic administration is safe even in combination with most of the conditioning regimens [ , ] . agiho strongly recommends the use of either tenofovir or entecavir in patients with hbsag-and/or anti-hbc positivity. patients should regularly be monitored for reactivation despite antiviral prophylaxis by hbv dna measurements. in addition to patients after hdc/ asct, patients under steroid medication and patients after the use of anti-cd -antibodies, e.g. during maintenance therapy after hdc/asct, are at high risk for hbv reactivation [ ] . notably, the presence of anti-hbc igm indicates acute infection and should trigger hbv dna pcr. in acute hbv infection, clinical priority will frequently be to treat hepatitis before continuing antineoplastic treatment. for negative hbv dna pcr, a combination of hbsag negativity, anti-hbc positivity, anti-hbs negativity most frequently is a sign of resolved infection. as it can also mirror low-level chronic infection or resolving acute infection, agiho recommends repeating such test to rule out a false-positive result for anti-hbc. likewise, virustatic prophylaxis as outlined before and close monitoring of hbv dna load is recommended if this specific constellation is repeatedly documented. agiho as well as the german standing committee on vaccination recently published separate guidelines on antiinfective vaccination measures against vaccine-preventable diseases with an own section on the situation after hdc/ asct [ , ] . recommendations on antimicrobial prophylaxis are summarized in table . [ ] empiric antimicrobial therapy of fever of unknown origin empiric treatment of fuo during neutropenia after hdc/ asct should follow recently published guidelines on the management of high-risk febrile neutropenia [ ] . in summary, agiho strongly recommends to use single-agent broadspectrum pseudomonas-active antibiotics such as piperacillin/ tazobactam, ceftazidime, cefepime, meropenem or imipenem/ cilastatin as first line antibiotic therapy [ , ] . as there is no systematic data on the empiric use of doripenem [ ] , ceftazidime-avibactam [ ] , ceftolozane-tazobactam [ ] or cefozopran [ ] in this setting, they are not discussed here. the upfront routine addition of tigecycline to first-line betalactam with anti-pseudomonal activity did not reduce the mortality rate and is therefore not recommended outside settings of high-level multidrug resistance [ ] . upfront addition of antibiotics with activity against gram-positive bacteria such as glycopeptides (e.g. vancomycin, teicoplanin) [ ] , oxazolidinones (e.g. linezolid) or cyclic lipopeptides (e.g. daptomycin) has either shown no benefit or has not been studied properly, thus, we do not recommend their use. in patients with known colonization by vre, addition of linezolid was not beneficial [ , ] . the administration of antimicrobial agents active against mrsa or esbl-producing gram-negative bacteria is recommended with marginal strength in case of colonization with these pathogens. the addition of an aminoglycoside in clinically stable patients in first-line therapy is not recommended [ ] [ ] [ ] . however, in case of clinical instability, their addition is moderately recommended as might the addition of glycopeptides. changing the first-line antibiotic regimen in a clinically stable patient who is still febrile after > h is not generally recommended [ , , ] . empiric use of antifungals during first-line therapy in a clinically stable patient with fuo after hdc/asct is not recommended [ ] [ ] [ ] . however, second-line addition of a mould-active antifungal is recommended with marginal strength for patients with persisting fever for at least h receiving a broad-spectrum first-line antibacterial therapy who had not received prior antifungal prophylaxis and [ ] who are expected to experience neutropenia for more than days [ ] [ ] [ ] . this is not recommended if a mouldactive antifungal prophylaxis had been administered prior to signs of infection or fever. for second-line empiric a n t i f u n g a l t h e r a p y , c a s p o f u n g i n o r l i p o s o m a l amphotericin b are preferred, while conventional amphotericin b deoxycholate is not recommended due to an unfavourable toxicity profile. recommendations on empiric antimicrobial therapy are summarized in table . recommendations on management of pulmonary infiltrates [ ] , gastrointestinal and perineal infections [ ] , central nervous system infection [ ] , central venous catheter-related infection [ ] and invasive fungal infections [ ] can be found in the respective guidelines of the infectious diseases working party (agiho) of the german society of haematology and medical oncology (dgho). georg maschmeyer reports personal fees from gilead, merck-serono, astra zeneca and amgen and personal fees and non-financial support from janssen cilag, outside the submitted work. ethical approval this article does not contain any studies with human participants or animals performed by any of the authors. open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if 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institutional affiliations key: cord- -mrpovgf authors: miyazaki, m.; une, h. title: infectious waste management in japan: a revised regulation and a management process in medical institutions date: - - journal: waste manag doi: . /j.wasman. . . sha: doc_id: cord_uid: mrpovgf in japan, the waste management practice is carried out in accordance with the waste disposal law of . the first rule of infectious waste management was regulated in , and infectious wastes are defined as the waste materials generated in medical institutions as a result of medical care or research which contain pathogens that have the potential to transmit infectious diseases. revised criteria for infectious waste management were promulgated by the ministry of environment in . infectious waste materials are divided into three categories: the form of waste; the place of waste generation; the kind of infectious diseases. a reduction of infectious waste is expected. we introduce a summary of the revised regulation of infectious waste management in this article. the waste management practice in japan is performed in accordance with the waste disposal and public cleansing law (the waste disposal law) of . medicines, equipment, instruments and food are used while treating in-patients and out-patients at hospitals and clinics, producing a variety of waste materials. waste materials generated at hospitals and clinics (medical institutions) are divided into infectious and noninfectious. the waste generated from the treatment of patients suffering from infectious diseases may spread infection either through direct contact or indirectly through the environment. transmission of infectious diseases is a serious matter. therefore, an appropriate waste management system is essential. the world health organization ( ) , us environmental protection agency ( , ) , us centers for disease con-trol and prevention ( ) , germany (muhlich et al., ; the ministry of environment, ) , and many other countries have already established strict guidelines for the management of infectious waste materials disposed of from medical institutions. in japan, the first regulation focusing on all medical facilities, such as, hospitals, clinics, laboratories and animal clinics, was promulgated in . the management of infectious waste materials was regulated in under the amended waste disposal law of . however, troublesome problems on management practices of infectious waste materials in medical institutions have been recognized by the agencies concerned (miyazaki, (miyazaki, , miyazaki and une, a) . in fact, medical institutions have faced difficult problems at many places regarding the treatment and disposal of infectious waste in practice. furthermore, many articles reported technologies of disinfection methods in medical institutions (haishima, ; matsumoto, ; takatsuki, ; murata et al., ) and reports about a management system of infectious waste are rare (hayashi and shigematsu, ; miyazaki, miyazaki, , the waste disposal law was amended in and the revised regulation including new criteria for the infectious waste management was provided in by the ministry of environment. the purpose of this study was to introduce the new criteria and a summary of the revised regulation about the management of infectious waste materials for medical institutions in japan. the management of hazardous waste is one of the most important problems in medical institutions (naito, ) and infectious waste is one category of hazardous waste. infectious waste materials need to be handled with careful consideration to prevent the spread of pathogens and to protect environmental health, in addition to being segregated from other waste materials. in the amended waste disposal law of , infectious wastes are defined as the infectious waste materials generated in medical institutions as a result of medical care or research which contain pathogens that have the potential to transmit infectious diseases. infectious waste materials disposed from medical institutions have been regulated since . infectious waste materials become non-infectious after they have lost infectivity by an intermediate treatment, such as incineration, melting or sterilization, and they are buried in a landfill. waste disposed of from medical institutions is divided into infectious and non-infectious. characteristics of infectious waste materials are classified into the form of waste, the place of waste generation, and the kind of infectious diseases. infectious waste is defined as follows in the revised guideline ( fig. ): . form of waste. the following waste materials are defined as infectious waste: ( ) blood and body fluids. ( ) tissues, organs and body parts. ( ) sharp objects contaminated with blood and body fluids. ( ) test equipment and cultures of infectious agents. infectious waste materials include cultures of infectious agents from laboratory work. these waste materials include human tissues, organs, body parts, and other items, like cotton battings contaminated with blood and body fluids. waste materials disposed of from veterinary clinics are also included in infectious waste. . place of waste generationwaste materials disposed of from a room mentioned below are defined as infectious waste: a ward for infectious diseases; an opera-tion theater; an emergency room for out-patients; an intensive care unit; an inspection room such as a pathological and a biological laboratory and an autopsy room.infectious waste is all materials used for the treatment and examination of patients in these rooms. . kind of infectious disease. waste materials relating to infectious diseases which are enumerated below are defined as infectious waste: ( ) infectious diseases of group - determined in the law concerning prevention on infectious diseases and health care for patients of infectious diseases (the infectious diseases law) ( table ) ; infectious waste is all materials used for the treatment and examination of patients with infectious diseases in table . ( ) tuberculosis.infectious waste is all materials used for the treatment and examination of patients with tuberculosis. ( ) infectious diseases of group and determined in the infectious diseases law (tables and ) . tables and . materials are cotton battings, cotton dressings and gauzes (sanitary materials), and disposable equipment contaminated with bloods and body fluids. in a case in which the persons concerned cannot readily determine whether the was is infectious, the decision is made by a physician. not only waste materials with sharp-edges, like injection needles, but also those that become sharp objects when broken, such as ampoules, handled as infectious waste from the viewpoint of mechanical hazard, even though the waste materials may be non-infectious. waste management is carried out in japan in accordance with the waste disposal law of . waste materials are classified as industrial and general-household (municipal wastes): industrial waste materials generated as a result of industrial activities and general-household waste materials, referred to as waste materials other than industrial waste. infectious waste materials disposed from hospitals and clinics are defined as industrial waste, and infectious waste materials are also categorized as one type of hazardous waste material (naito, ) . the management of hazardous waste is one of the most important problems in medical institutions (abatemarco et al., ; ostry et al., ; almuneef and memish, ) . a revised regulation was needed with a clear and precise definition of infectious waste is essential, because criteria in the former regulation were only a form of waste (the ministry of health and welfare, ) and infectious waste needs to be handled carefully and strictly to prevent the spread of pathogens and to protect environmental health. the waste generated from the treatment of patients suffering from infectious diseases may spread infection either through direct contact or indirectly through the environment. the management of these infectious waste materials was regulated in under the waste disposal law of . all wastes including infectious waste disposed off from medical institutions are termed medical waste in japan. medical waste is, however, not defined in the waste disposal law of . in addition, radioactive medical waste is regulated in the radioactive prevention law of by the science technology agency. therefore, the new regulation focuses on an appropriate management system of infectious waste, and radioactive medical waste is not addressed in this one. furthermore, infectious waste materials are not recyclable (miyazaki and une, ) . in accordance with this new regulation, waste materials with sharp-edges are collected and segregated from other wastes to prevent injury. sharp objects also include both unused sharp objects and disinfected sharp ones, such as a scalpel. sharp objects need to be put in a tight container, such as a can, with a lid so as not to injure the persons concerned. needle-prick accidents have been reported by approximately % of municipal governments (miyazaki and une, b) . therefore, such segregation is based on the treatment of infectious waste materials requiring special care. a container including sharp objects is never opened and it is transported to a waste incinerator which is authorized by a prefectural government. with respect to storage, all infectious waste materials are segregated from other wastes in special storage areas to prevent the spread of infection in medical institutions. a hermetically tight container is used and a notice indicating the type of infectious waste materials is attached to the container. each label is colored based on the type of waste: labels for blood and body fluids are red, solid materials are orange, and sharp objects are yellow. a regular cart is used for transportation of a container to reduce a risk of direct contact and contamination in medical institutions. a container including infectious waste materials is kept in the special storage areas for the shortest period of time possible and no one except the persons concerned is permitted to enter the storage areas. a sign stating ''infectious waste'' is posted to be easily visible in each storage area. as regards the disposal practice from medical institutions, a medical institution contracts with specified businesses that are authorized by a prefectural government for collecting, transporting and incinerating infectious waste materials. all infectious waste materials have to be segregated from other wastes. waste workers of a medical institution collect all infectious waste materials from special storage spots and transport them to a restricted place where a special infectious waste business (contractor) collects them. waste workers wear gloves and a mask while at work. a contractor directly transports infectious waste materials to an incinerator which is authorized by a prefectural government, and these wastes materials are burnt by more than °c soon after collection. in japan, because infectious waste materials disposed of from medical institutions are not collected and transported by the municipal governments, a medical institution is responsible for the associated expense. each medical institution, therefore, must contract a specified business authorized by a prefectural government for the treatment of infectious waste, and disposal cost is becoming a serious matter. the collection and transportation price is determined by the quantity of waste, transportation distance and frequency, a container price, and an incineration price. a contractor specifies a container which a medical institution must use. the standard of containers was regulated in under the waste disposal law of . it is estimated that yen - (us$ = yen ) / l container or yen - /kg of infectious waste is a typical cost (miyazaki, ) . however, not all medical institutions have obtained accurate information on each infectious waste handling business including their qualities (such as the number of years dealing in infectious waste and the existence of violations) and a treatment price. a contract with a dishonest business induces a cost for handling of infectious waste for as little as yen or less (miyazaki, ) . in such a case, illegal dumping often occurs. to prevent the illegal dumping of infectious waste materials; an information network needs to be established by the cooperative harmony of the stakeholders including the ministry of environment. the manager of a medical institution is obligated to educate the persons concerned, such as medical, health care and hospital waste workers, about the treatment of infectious waste. a control manager handling infectious waste should institute an education program and prepare a plan for the reduction and disposal methods of infectious waste materials, because cost-effective management is needed (byeong-kyu et al., ) . the most important outcome of the infectious waste management plan is to convince medical care workers that the plan is safe and has a significant benefit for the medical institution. in addition, the support of the administration division is also indispensable for ensuring the success of the management plan. to reduce infectious waste materials, the segregation of waste in a medical institution must be strictly per-formed and non-infectious waste materials must not be disposed of as infectious waste, because a reduction of infectious waste results in a reduction of disposal costs. intensive education on proper infectious waste procedures should be provided through lectures, posters, and handouts. in addition, various reusable items, such as linens, should be positively utilized to reduce infectious waste materials. both the education of personnel concerned (including medical staffs and waste workers) and accurate information on special infectious waste businesses are indispensable to appropriately treat and dispose of infectious waste. moreover, monitoring workersÕ compliance and direct feedback of information, such as a disposal cost and a quantity of infectious waste, are also considered essential for the continued success in reducing infectious waste materials. the potential for causing infection varies greatly depending on the sharpness and quality of waste. strict adherence to the revised regulation by medical institutions can thus protect waste workers from being infected. this paper is a summary of the revised regulation for infectious waste management in japan. infectious waste must be managed in accordance with the waste disposal law of and the rules promulgated in by the ministry of environment. infectious waste materials are to be collected and segregated from other wastes, and transported to incinerators where they are combusted by a special waste handling business with which a medical institution contracts. disposal costs are, however, becoming expensive. therefore, medical institutions should make every effort to reduce infectious waste generated in their facilities. due to the increase in the quantity and to the diversified quality of waste materials disposed of from medical institutions, the management of such materials has become increasingly important in order to protect waste workers from infection. the revised regulation is expected to encourage the reduction of infectious waste and to protect waste workers from being infected. medical surveillance practices of blue collar and white collar hazardous waste workers effective medical waste management: it can be done alternative technologies on infectious waste treatment, and guidelines for evaluation on safety and efficacy of the alternative technologies proper disposal (management) of medical wastes infection prevention and waste management (clean hospital project) at hiroshima city, asa hospital alternative for treatment and disposal cost reduction of regulated medical wastes proper disposal (management) of medical wastes; 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murray, virginia title: examining the relationship between infectious diseases and flooding in europe: a systematic literature review and summary of possible public health interventions date: - - journal: disaster health doi: . /dish. sha: doc_id: cord_uid: qhumjas introduction many infectious diseases are sensitive to climatic changes; specifically, flooding. this systematic literature review aimed to strengthen the quality and completeness of evidence on infectious diseases following flooding, relevant to europe. methods a systematic literature review from – was performed. focused searches of the following databases were conducted: medline, scopus, pubmed, cochrane library, and evidence aid. personal communications with key informants were also reviewed. results thirty-eight studies met the inclusion criteria. evidence suggested that water-borne, rodent-borne, and vector-borne diseases have been associated with flooding in europe, although at a lower incidence than developing countries. conclusion disease surveillance and early warning systems, coupled with effective prevention and response capabilities, can reduce current and future vulnerability to infectious diseases following flooding. defining what constitutes a flood can be quite complex as floods can take many forms; therefore, no universal definition exists. generally and in the context of this review, a flood is defined as the overflow of areas that are not normally submerged with water or a stream that has broken its normal confines or has accumulated due to lack of drainage. overall, different flood characteristics affect the severity of the flood event; specifically, regularity, speed of onset, velocity of flow, and depth of water. quantifying the level of flooding has proven to be difficult; however, the emergency events database (em-dat) provides information about flood events and the impact of floods. for a flood to be classified as a disaster or flood event by em-dat one of the criteria must be fulfilled: either ten or more people killed; or more people affected; declaration of a state emergency; and/or call for international assistance. em-dat defines a flood as a significant rise in water level in a stream, lake, reservoir, or coastal region and includes general river floods, flash floods, and storm surges or coastal flooding. flood disasters hit some european regions very frequently, and in some circumstances every year. in europe from - , flash floods and general floods were reported by em-dat. in terms of the number of people affected, out of the most important floods ever recorded in europe occurred during the - decade. a study concluded a rising number in flood disasters from - in the european union (eu). according to frei et al. there has been a significant trend toward increased intense winter rainfall events in europe. other studies do not find a rising incidence of flooding. for example mudelsee et al. examined river flood patterns in central europe, and despite the occurrence of two flood events exceeding the -year flood level in and , found no increased trend in extreme flood frequency over recent decades. analyzing the more frequent, small-magnitude flood events as well as high-magnitude floods can make it easier to detect shifting trends in flood frequency. flood trend analysis is essential to understand future flood risk and vulnerability. • what evidence-based public health interventions are used to minimize infectious disease incidence following flooding. • knowledge gaps and issues for further research. the initial search generated , relevant articles. after reviewing the abstracts, full-text articles were examined in more detail for eligibility. of these articles, peer-reviewed articles were found to fit the inclusion criteria. increased infectious disease transmission and outbreaks following global flood events have been documented ( table ). the study design and main results of all papers found meeting the inclusion criteria are listed in detail in appendices a-d. some articles and gray literature not meeting the specific inclusion criteria were incorporated into the conceptual framework to give a better contextual outline. water-borne outbreaks are an acute aftermath of flood disasters, mainly as a result of contaminated drinking water supply. intense precipitation can mobilize pathogens in the environment and transport them into the aquatic environment, increasing the microbiological agents on surface water. [ ] [ ] [ ] [ ] chen et al. found extreme torrential rain (> mm) was a significant risk factor for enteroviruses (rr = . ; % ci . - . ) and bacillary dysentery (rr = . ; % ci . - . ). globally, water-borne epidemics have shown an increasing trend from - which coincides with the increasing number of flood events. according to a global systematic literature review performed by cann et al. the most common water-borne pathogens to be identified following flooding were vibrio spp. the most common water-borne pathogens associated with heavy rainfall were campylobacter, followed by vibrio spp. appendices a, b list published studies which have reported post-flood increases in cholera, cryptosporidiosis, non-specific diarrhea, rotavirus, and typhoid and paratyphoid. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] several studies have implicated excess rainfall in water-borne disease outbreaks because of the transportation of bacteria, parasites, and viruses into water systems. marcheggiani et al. showed a potential association between flood events and a range of water-borne infectious diseases in italy; including, legionellosis, salmonellosis, hepatitis a, and infectious diarrhea. reacher et al. performed a historical cohort study following a severe flood in in lewes, both climatic and non-climatic impacts, such as land-use dynamics, are expected to influence future flooding in europe. although considerable limitations remain in the ability to make robust projections of changes in flood size and frequency due to climate change, common projections appear to be emerging. according to the latest intergovernmental panel on climate change's (ipcc) srex report there is a - % probability that the intensity of heavy precipitation and the proportion of total rainfall will increase particularly in northern mid-latitudes and high latitudes of europe. the highest total precipitation increases are projected to occur during the winter months. although the ipcc states a general decrease in mean precipitation in the southern european region, rainfall may become more irregular and intense. however there remains low confidence in projections of changes in riverine floods. climate change is likely to increase the frequency of storm surges and coastal flooding due to rise in sea levels, and threaten an additional . million people per year in europe by the s. overall, changes in the climate that may affect the transmission of infectious diseases include temperature, humidity, altered rainfall, and sea-level rise. flooding can have a range of health impacts but this review focused solely on infectious diseases. the diseases most likely to be affected by flooding are those that require a vehicle for transfer from host to host (water-borne) or a host/vector as part of its life cycle (vector-borne). flood-affected areas serve as ideal breeding grounds for pathogens and may alter vector breeding grounds and zoonotic reservoirs. , where infectious disease transmission is endemic, it can present a major public health concern following flooding. the risk of infectious diseases following flooding is exacerbated by the fact many factors work together to increase incidence. the significance of the association between precipitation and disease is potentially amplified when considering the effects of global climate change and land use changes. flooding can alter the equilibrium of the environment and may affect the incidence and geographic range of climate-sensitive infectious diseases. a better understanding of the associations and underlying mechanisms of infectious disease outbreaks following flooding will help support evidence-based flood policies and mitigation strategies. this systematic literature review aimed to identify and examine the relationship between infectious disease incidence and flooding in order to gain a better understanding of: outcome (combined with or) amoebiasis, bacillary dysentery, burul*, campylo*, chikungunya, cholera, communicable disease*, contamination, crypto*, dengue, dengue virus, dermatitis, diarrhea*, diarrhea*, disease*, disease vector*, disease outbreak*, epidemic*, enteric fever, escherichia coli, gastrointestinal, giardia*, hanta virus infections, health, health effect*, health impact*, hemorrhagic fever, hepatitis a, hepatitis e, illness, infectio*, infectious disease*, japanese encephalitis, legionellosis, leptospirosis, lyme disease, lymphatic filariasis, malaria, morbidity, mosquito*, norovirus, naeg*, outbreak*, onchocerciasis, physical health, plague, pollut*, public health, q fever, risk factor*, rodent*, rodentborne, rodent-borne, rodent related, rodent-related, salmonellosis, sars virus, severe acute respiratory syndrome, shigellosis, schistosomiasis, tick*, tick-borne encephalitis, tularaemia, tularemia, typhoid, water, waterborne, water-borne, water related, water-related, west nile fever, vector*, vectorborne, vector-borne, vector related, vector-related, yellow fever, yersini* risk, rising temperatures, overcrowding, poor sanitation, poor health care, poverty, and an abundance of rats and other animal reservoirs. rodent-borne pathogens can be indirectly affected by ecological determinants of food sources which have an effect on the size of rodent populations. for example, lack of garbage management and collection following flooding where rubbish is left on the streets contributes to an increased rodent population. appendices a, c summarize the key studies assessing the relationship between flooding and rodent-borne diseases. outbreaks of leptospirosis were observed in the czech republic following floods in and . , the rate of serologically confirmed cases of leptospirosis was three times higher than usual at . cases/ , inhabitants (average incidence rate was . cases/ , inhabitants). the first leptospirosis outbreak in austria in july , involved four athletes who swam in recreational waters during a triathlon. heavy rains had preceded the triathlon ( mm). this outbreak demonstrates a risk of contracting leptospirosis in recreational waters, especially after heavy rainfall. in marseilles, france the incidence of leptospirosis identified in the laboratory increased significantly between january and july (p < . ). between and , the rate of leptospirosis incidence in southern france was very low, . cases/ , inhabitants. in , this incidence increased to england. the risk of gastroenteritis was significantly associated with depth of flooding in people whose households were flooded (rr = . ; % ci . - . ; p for trend by flood depth = . ). additionally, an outbreak of norovirus in american tourists was linked to direct exposure to floodwater contaminated with raw sewage in germany. earlier research has shown an association between waterborne diseases and flooding in high-income countries. from - , more than half of the water-borne disease outbreaks in the united states were preceded by heavy rainfall (p = . ). research from finland found that water-borne disease outbreaks from - were associated with un-disinfected groundwater contaminated by floodwaters and surface runoff. surveys in high-income countries where individuals reported their own symptoms have indicated an increase in water-borne diseases following flooding. , [ ] [ ] [ ] rodent-borne rodent-borne diseases are climate sensitive and may increase during heavy rainfall and flooding because of altered patterns of human-pathogen-rodent contact. flooding and heavy rainfall have been associated with numerous outbreaks of leptospirosis from a wide-range of countries around the world. , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] areas at the highest risk for leptospirosis outbreaks are those where multiple risk factors are likely to coexist; such as, increased flooding ahern et al. reviewed earlier studies addressing flood-associated outbreaks of leptospirosis from a wide-range of countries: argentina, brazil, cuba, india, korea, mexico, nicaragua, portugal, and puerto rico. in in the krasnodar territory in russia, a severe outbreak of leptospirosis took place in connection with a high flood. sanders et al. stated that flooding after heavy rain favors leptospires. it prevents animal urine from being absorbed into the soil or evaporating; therefore leptospires may pass directly into the surface water or persist in mud. the evidence of this review, supported by several other reviews, suggests the association between leptospirosis and flooding is fairly robust even in high-income countries. vector-borne precipitation changes are known to effect the reproduction, development, behavior, and population dynamics of arthropod vectors, their pathogens, and non-human vertebrate reservoirs. mosquito-borne infections tend to increase with warming and certain changes in rainfall patterns. vector-borne diseases are unlikely to be a problem during the onset phase of the flood, as many vector breeding habitats are expected to . cases/ , inhabitants. the first three autochthonous cases identified in marseilles (october ) were preceded by heavy rainfall. the study showed the first autochthonous case was identified after a period of flooding preceded by heavy rainfall over several days ( . mm/day; . mm/day; mm/ day with an episode of mm/ hr). similarly, the other two autochthonous cases occurred during a period of high rainfall ( . - . mm). pellizzer et al. performed a sero-epidemiological study to evaluate the risk of leptospirosis in a population in northeast italy exposed to a severe flood event. this area is endemic for leptospirosis and exhibits and average of cases/ , inhabitants. seven out of subjects exposed to floodwaters exhibited anti-leptospira specific igm antibodies and five were confirmed positive by micro-agglutination test. re-testing a few months later found significant antibody titers greater than against serovar copenhangeni in three cases ( . % seroconversion rate). overall, the rate for seroconversion for leptospirosis appeared to be low, and while flooding appeared to be the sole risk factor, confirmation was not possible due to a lack of a control group. ahmed et al. pakistan, cross-sectional study- , flood affected individuals interviewed to determine frequency of infectious diseases. gastrointestinal ( %), skin and soft tissue infection ( %), conjunctivitis ( %), ear, nose and throat infection ( %), respiratory tract infection ( %), suspected malaria ( %). no comparative data before flooding. bich et al. vietnam, cross-sectional study-rural and urban districts interviewed within mo after flood about social, economic, and health impacts. in each district, a flooded commune and a less affected commune (control commune) were selected. no statistically significant differences in proportion of dengue cases in flood affected and less affected communes. higher proportions of pink eye and dermatitis in severely flood affected communes. in flood affected communes, / urban cases (p < . ) and / rural cases (p < . ) contracted pink eye after flood. in flood affected communes, / urban cases and / (p < . ) rural cases contracted dermatitis after flood. chen et al. taiwan, - routine data-analysis of a database integrating daily precipitation and temperature and an infectious disease case registry. heavy precipitation ( - mm) a significant risk factor for enteroviruses (rr = . ; % ci . - . ) and dengue fever (rr = . ; % ci . - . ). extreme torrential rain (> mm) a significant risk factor for enteroviruses (rr = . ; % ci . - . ) and bacillary dysentery (rr = . ; % ci . - . ). associations between precipitation levels and enterovirus infections, japanese encephalitis (p < . ), and stronger linear relationships between precipitation and bacillary dysentery, dengue fever, leptospirosis (p < . ). marcheggiani et al. italy, - routine data-national statistics collected by italian ministry of health. association between hepatitis a, salmonellosis, infectious diarrhea, leptospirosis, cutaneous and visceral leishmaniasis, legionellosis and flood events from - seemed to exist. milojevic et al. bangladesh, controlled interrupted time series-diarrheal incidence of a cohort of , residents classified as flooded or non-flooded in . after fully controlling pre-flood rate differences and seasonality, no clear evidence of excesses mortality or diarrhea risk during/ after flooding. no evidence of excess risk from acute respiratory illnesses during flood but moderate increase in risk mo after flood (rr = . ; % ci . - . ). su et al. taiwan, routine data-to clarify association between leptospirosis and melioidosis epidemics and flooding. positive correlation for leptospirosis (r = . ; p < . ) and for melioidosis (r = . ; p < . ) with cumulative rainfall. increase in melioidosis cases significantly associated with > mm/day (p < . ). number of leptospirosis cases positively correlated with -h cumulative rainfall (r = . ; p = . ). appendix b. studies assessing the relationship between infectious diseases and flooding: water-borne apisarnthanarak et al. thailand, case report- melioidosis patients located through active case surveillance. cases reported excess flooding of homes and had traditional risk factors for melioidosis. all cases survived. auld et al. canada, outbreak investigation-e. coli o :h and campylobacter outbreak. outbreak occurred several days after heavy rainfall ( -d accumulation - mm). heavy rainfall hypothesized as a causative factor of the outbreak. carrel et al. bangladesh , - longitudinal study- -y data cluster analysis of health surveillance and geographic information system to investigate temporal and spatial distribution of cholera following flood protection interventions. , confirmed cholera cases. two clusters of lower than expected cases, clusters of higher than expected cases found (p < . ). following flood protection interventions, overall decrease in cholera incidence, differences in the geography of high vs. low spatial clusters of cholera, and shifts in location of unusually high spatio-temporal cholera clusters. harris et al. bangladesh hashizume et al. bangladesh, routine data-number of observed cases of cholera and non-cholera diarrhea per week during flood and post-flood periods compared with expected numbers. during flooding, cholera cases . times higher ( % ci - ) and non-cholera cases . times higher ( % ci . - . ) than expected. post-flood period, cholera cases . times higher ( % ci . - . ) and non-cholera cases . times higher ( % ci . - . ). ko et al. taiwan, routine data-melioidosis outbreak. melioidosis cases identified following flooding. onset within d. qadri et al. bangladesh, routine data-diarrheal stools collected from patients during flooding. of stool specimens tested, positive for v. cholerae o ( . %), for shigella spp ( . %), for salmonella spp ( . %). reacher et al. england, historical cohort study-post-flooding survey interview. flooding associated with significant increase in risk of gastroenteritis with depth of flooding (rr = . ; % ci . - . p = . , p for trend by flood depth = . ). schwartz et al. bangladesh , , , routine data-diarrheal patients during the , , and floods compared with non-flood periods. cross-sectional study- , individuals provided flood survey health data. house/yard flooding signficantly associated with gastrointestinal illness (incidence rate ratio = . ; % ci . - . ). volume issue appendix c. studies assessing the relationship between infectious diseases and flooding: rodent-borne amilasan et al. the philippines, hospital-based investigation-investigating risk factors for leptospirosis mortality following flooding. prospective surveillance and retrospective data collection. outbreak of leptospirosis cases, cases died. patients predominately young and male. delayed initiation of treatment, older age, jaundice, anuria, hemoptysis increased risk for death. bhardwaj et al. india, case-control study-identifying risk factors for leptospirosis during flooding. confirmed cases and age and sex matched fever and healthy controls given a questionnaire. chiu et al. taiwan, - routine data-analyze characteristics of patients with laboratory-diagnosed leptospirosis and correlate onset of symptoms with exposure to floodwater. patients identified with history of contact with contaminated soil/water. / patients ( %) suffered from leptospirosis after typhoon. dechet et al. guyana, routine data-laboratory testing on suspected leptospirosis hospitalizations and deaths. confirmed outbreak of leptospirosis after severe flooding. sero-epidemiogical study-evaluated leptospirosis risk in flood-exposed population. / patients exposed to floodwaters exhibited anti-leptospira specific igm antibodies and confirmed positive. re-testing months later found significant antibody titers > against serovar copenhangeni in cases ( . % seroconversion rate). flooding appeared to be sole risk factor, verification not possible due to lack of control group. radl et al. austria, outbreak investigation-leptospirosis. st documented outbreak of leptospirosis in austria. four serologically confirmed cases, all triathlon athletes. triathlon preceded by heavy rainfall ( mm (appendices a, d) older studies have shown associations. in romania, flooded basements were a significant risk factor for wnv in apartment dwellers (p = . ). in , heavy rains in moravia, czech republic resulted in flooding, and mosquito populations in the area amplified immediately. wnv activity was reported in the area. hubálek and halouzka stated environmental factors such as flooding can facilitate the re-emergence of wnv. be overwhelmed by the flood waters. while flooding may initially wash out vector populations, they return when the waters recede. receding flood water can provide ideal breeding habitats. therefore, vector-borne diseases are likely to have mid-term to long-term impacts on health following flooding (fig. ) . vector-borne virus outbreaks are strictly determined by the presence of the pathogen and particular competent disease vectors. the current and future establishment of exotic mosquito species in europe is a cause for serious concern, as the newly introduced species may already be disease vectors or could potentially become vectors. west nile virus (wnv) emerged in europe after heavy rains and flooding, with outbreaks in romania in - , the czech republic in , and italy in . the flood in the czech republic resulted in mass mosquito breeding with a biting frequency peaking at bites per person per minute. specimens from flood-affected residents were examined serologically for mosquito-borne viruses. paired serum samples showed one tahyna virus infection among residents. jiménez-sastré et al. sampled dwellings in tabasco, mexico, post-flood for dengue fever cases and found the geographical distribution of dengue fever cases was associated with the proximity of two permanent bodies of water. chen et al. found heavy precipitation was a significant risk factor for dengue fever (rr = . ; %; ci . - . ). additionally, more non-european appendix d. studies assessing the relationship between infectious diseases and flooding: vector-borne hassan et al. sudan, outbreak investigation-rift valley fever. confirmed human cases including deaths. outbreak followed heavy rainfall with severe flooding. hubalek et al. czech republic, routine data-specimens from residents in flooded area examined serologically for mosquito-borne viruses. antibodies detected after flood for tahyna, sindbis, and batai viruses, with only activity found for tahyna virus among residents. jiménez-sastré et al. mexico, cross-sectional study-convenience sampling of dengue fever in flooded colonies. cases with positive serology of igg ( . %) and cases of positive igm ( . %). geographical distribution associated with proximity to permanent water bodies. tong et al. australia , - routine data-assessment of variability in environmental and vector factors on ross river virus transmission. wu et al. china, - longitudinal study-review of retrospective data to determine intermediate host snail dispersal patterns and acute and chronic infections of schistosomiasis after floods. average number of acute schistosomiasis cases recorded in flood years . times higher than in years with little to no flooding. re-emerging and new snail infested areas in flood years on average . and . times larger than in years with normal water levels. flooding of marshlands identified as main driver for vector dispersal. responsible for local disease transmission, the factors that influence transmission, location of breeding ground, and which measures of control should be implemented. local destruction of breeding sites after flooding has receded is extremely effective, so individuals should remove unused vessels and stagnant water when possible. water storage containers need to be covered to protect from disease vectors, such as egg-laying female mosquitoes. individuals can protect themselves against mosquito bites by using repellents during biting hours, mosquito nets, and screens in doors and windows. individual and community awareness and participation is essential for successfully reducing the risk of infectious diseases following flooding. understanding the social and cultural influences on response behavior in the time of a flood emergency is crucial to inform the design and targeting of warnings and health education messages. some studies showed the frequency of infectious diseases can increase in the weeks to months after flooding, and figure illustrates when infectious disease outbreaks following flood events are likely to occur. however, there remains scientific uncertainty about the strength of association between infectious disease incidence and flooding. floods can cause population displacement and changes in population density, raise concern about waste management and the availability of clean water, as well as affect the availability and access to healthcare services. all of these are risk factors for an infectious disease outbreak. kouadio et al. and watson et al. suggested that unless there is a substantial population displacement, there is minimal risk of infectious disease transmission and outbreaks following flooding. overall, the risk of infectious disease following flooding is context-specific, differs between countries, and is dependent upon a number of synergistic factors. outbreaks of leptospirosis and diarrheal diseases following flooding have been documented in europe , , , , , , , [ ] [ ] [ ] but the evidence of increased incidence of vector-borne diseases following flooding is lacking because the time lag before onset can be several months. past studies have indicated possible associations between vector-borne diseases and flooding in europe. , [ ] [ ] [ ] european residents may be exposed to these risks while traveling. foreign relief workers can potentially introduce infectious diseases into an area affected by flooding and these workers may be susceptible to endemic diseases that are more prevalent because of the flood. surveillance in flood-affected areas is fundamental to understanding the impact of flooding on infectious disease incidence. surveillance and early warning systems may reduce current and future vulnerability. a comprehensive risk assessment could help determine priority diseases for inclusion in the enhanced surveillance system and prioritize prevention and control measures. in addition to surveillance and early warning systems to detect epidemic-prone diseases, assuring access to clean water, proper sanitation, adequate shelter, and primary healthcare services is essential. despite a considerable amount of research on the relationship between infectious diseases and flooding, globally and in summary of possible public health interventions public health interventions include those made before, during, and after flooding to reduce vulnerability to infectious diseases. interventions need to take place at a variety of levels: individual, household, community, regional, national, and international. the public health measures cited in the literature to reduce the risk of infectious diseases as a result of flooding focus on: risk assessments, enhanced surveillance systems, and specific prevention and control measures depending upon the type of infectious disease risk. , a rapid disease risk assessment should be conducted by a representative multi-agency group within the first week of the flood including: data on the flooded region and displaced persons, the main disease threats for the enhanced surveillance system, baseline data collection, and identification of priority interventions. , during a flood event, hand-held devices that allow workers to enter and analyze data in the field can assist the rapid risk assessment. existing disease surveillance systems can be enhanced to target specific diseases or syndromes and to support timely response actions to reduce disease impact and risk of transmission. , public health teams need to establish adequate disease surveillance systems which take into account the inherent disruption of the public health infrastructure that may occur during flooding. an enhanced surveillance system should be adaptable and context-specific, monitor key epidemiological data and compare with baseline data, monitor vulnerable groups, identify any emerging outbreaks, and result in timely public health action. in high-income countries, risk assessments and surveillance systems need to be very refined to detect small differences from baseline incidence data. prevention of infectious diseases following flooding involves maintenance of health services, provision of shelter, clean water supplies, proper sanitation, regular and adequate food supply, and in some cases mass vaccination campaigns and control of disease vectors. , water and sanitation are vital elements in the transmission of water-borne diseases; hence, providing clean drinking water is a priority in the initial days following flooding. clasen et al. found that household interventions were more effective in preventing diarrhea than interventions at the water-source. interventions at the household level reviewed included: chlorination, filtration, solar disinfection, and combined flocculation and disinfection. ejemot-nwadiaro et al. found hand-washing interventions can reduce diarrhea episodes by one-third. rodent control is another prevention measure that needs to be considered during flooding. the local rodent species and their behaviors should be identified, water and food storage containers should be rodent-proofed, and solid waste should be properly stored, collected, and disposed. , according to bhardwaj et al. prompt and vigilant fever surveillance activities in pre-flooding preparedness plans, rodent control programs, and improvement of environmental sanitary conditions may help greatly reduce leptospirosis incidence. vector control can reduce disease transmission by rendering the environment unfavorable for the survival, development, and reproduction of the vector. , establishing surveillance for the introduction of new vector species could contribute substantially to vector-control. an expert should identify vectors • papers on unrelated subject areas; such as, biochemistry, molecular biology, and genetics. personal communications between key informants were conducted in conjunction with the literature review. the context of the questions included the current state of knowledge of the association between flooding and infectious diseases and potential solutions to mitigate the risks. because flooding is a natural disaster and cannot be induced experimentally, the research evidence was unlikely to be the considered 'gold standard' of a systematic literature review or a randomized controlled trial. most of the data were observational, and because of the insufficient numbers of similar studies and variations in outcome reporting, no studies were excluded on the basis of study quality. a formal assessment of bias was not possible for each individual study. it is important for health officials and the public to understand that exacerbation of disease risk factors contribute to infectious disease outbreaks following flooding. population and individual vulnerability and resilience factors can worsen or mitigate infectious diseases following flooding. the community needs to be aware of actions that can facilitate or prevent infectious disease. to mitigate infectious disease risk following flooding, those involved in flood planning, response, and recovery should be aware of the results of this systematic literature review. if climate change causes more floods, then the future health burden of infectious diseases from floods could increase. in europe, maintenance and continuous adaptation and improvement of public health measures is important to sustain the low risk of infectious disease outbreaks following floods. presently, there are clear research needs to improve the understanding of the association between infectious diseases and flooding: • more robust epidemiological studies on infectious diseases covering the pre-, mid-, and post-flood periods. • further research assessing the effectiveness of public health interventions minimizing risk from infectious diseases following flooding. • investigation of infectious disease incidence following smaller flood events. • analysis of the differences between summer and winter flooding on infectious disease incidence. • analysis of the differences between flash and riverine flooding on infectious disease incidence. no potential conflicts of interest were disclosed. this work was carried out within public health england's department of extreme events and health protection, funded partly by the eu project "public health adaptation strategies europe, the body of information still remains fragmentary. many studies attempted to collect data retrospectively, had methodological shortcomings, lacked longitudinal data/baseline health data, control groups for comparison, and measures of clear disease outcomes. the studies included in this review were mainly observational studies with widely varying quality levels and study designs. because it is unethical to conduct experimental studies on this topic, rigorous observational studies must be continue to be undertaken. observational studies can present particular challenges because of the unpredictability of the timing and location of floods. reporting and recall bias was very likely in many studies. additionally, many studies relied on data from disease surveillance systems. obtaining relevant disease surveillance data pre-, mid-, and post-flooding is frequently challenging. population displacement can distort the rates of comparison for infectious disease incidence. the quality and robustness of disease surveillance systems can vary from country to country, and a country with a weak disease surveillance system will probably lack pre-flood baseline data. flood damage to pre-existing public health infrastructure can exacerbate weaknesses in a disease surveillance system. furthermore, it is difficult to attribute an increase in infectious disease incidence solely to a flood event, and therefore this issue may be under-investigated and under-reported. finally, this systematic review is not entirely exhaustive, and there may be many other reports in gray literature, but the quality is likely to be lower than the peer-reviewed published reports identified. the search strategy used was adapted from two studies ( table ) . , all papers with the specified search terms in their titles, abstracts, or keywords were searched for. focused searches of the following databases were conducted: medline, scopus, and pubmed. the cochrane database of systematic reviews was searched for further existing epidemiological reviews, as well as evidence aid. further relevant articles were identified manually from cited references from each selected full-text paper. data from gray literature were not systematically searched, but sources and advice from key experts were discussed in the accompanying text. inclusion criteria • papers published from january to september . ahern et al. included studies associated with infectious disease incidence following flooding up to . • epidemiological studies. • studies conducted in any country, because europe experiences a wide range of climate and geographical variation. • papers in all languages with english abstracts. • all papers where an explicit link is studied between flooding as an exposure and an infectious disease as an outcome. exclusion criteria • papers concerned primarily with mental health effects, flood-related injuries, population displacement, economic costs, and disruption of food supplies. a role of high impact weather events in waterborne disease outbreaks in canada risk factors for typhoid and paratyphoid fever in jakarta, indonesia health impacts of flooding in lewes: a comparison of reported gastrointestinal and other illness and mental health in flooded and non-flooded households outbreak of norovirus infection associated with contaminated flood water extreme precipitation linked to waterborne disease outbreaks. sciencedaily did a severe flood in the midwest cause an increase in the incidence of gastrointestinal symptoms? waterborne epidemics in finland in - a case control study to explore the risk factors for acquisition of leptospirosis in surat city, after flood resurgence of field fever in a temperate country: an epidemic of leptospirosis among seasonal strawberry harvesters in germany in leptospirosis on oahu: an outbreak associated with flooding of a university campus leptospirosis following a flood in the veneto area later leptospirosis after flood in tabasco, mexico strikes, flooding, rats, and leptospirosis in marseille, france climate change, flooding, urbanisation and leptospirosis: fuelling the fire? infectious diseases following natural disasters: prevention and control measures infectious diseases that pose specific challenges after natural disasters: a review global health impacts of floods: epidemiologic evidence climate change and infectious diseases in europe extreme water-related weather events and waterborne disease risks of water-borne disease outbreaks after extreme events influence of environmental factors and human activity on the presence of salmonella serovars in a marine environment systematic review of waterborne disease outbreaks following extreme water events effects of extreme precipitation to the distribution of infectious diseases in taiwan heavy rainfall and waterborne disease outbreaks: the walkerton example factors determining vulnerability to diarrhoea during and after severe floods in bangladesh medicaid outpatient utilization for waterborne pathogenic illness following hurricane floyd flood hazards and health: responding to present and future risks. tyndall centre for climate change research global trends in waterrelated disasters: an insight for policy-makers. the united nations world water assessment program. international center for water hazard and risk management building human resilience: the role of public health preparedness and response as an adaptation to climate change health impacts of floods in europe: data gaps and needs from a spatial perspective major flood disasters in europe future change of precipitation extremes in europe: intercomparison of scenarios from regional climate models no upward trends in the occurrence of extreme floods in central europe summary for policymakers: managing the risks of 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nadal, david title: pediatric infectious diseases — quo vadis ? date: journal: pediatric infectious diseases revisited doi: . / - - - - _ sha: doc_id: cord_uid: cus sqka in modern medicine the discipline pediatric infectious diseases is an essential medical specialty. the challenging and complex tasks in the next years include meticulous consolidation and careful extension of existing activities aiming at conducting high level research, offering high standard teaching, and providing high quality patient management. this can only be accomplished by exquisitely dedicated individuals with extraordinary communication and integrative skills following painstaking continued training and formation. potential careers in the discipline can be envisioned not only in academics, but also in government, public health, and industry, whilst less likely in private practice. the discipline pediatric infectious diseases has evolved to an essential medical specialty and faces major challenges in the years to come. one of the most important tasks of pediatricians has always been the management of patients with communicable diseases. the main reason for this is the higher frequency of infectious diseases in infants and young children compared to older children and adults due to the limited adaptive immunity repertoire and thus increased susceptibility to common pathogens. therefore, pediatricians are considerably involved in the diagnosis, treatment and prevention of infectious diseases. in consequence, every pediatrician must be considered also an infectious disease specialist. this, in turn, has been a downside for the development of pediatric infectious diseases as a medical discipline recognized on its own in many countries. nevertheless, the multiple technical advances in the recent years have led to substantially improved prevention and treatment success rates in many pediatric disciplines, and a plethora of these success rates are linked to the integral role of pediatric infectious disease specialists providing profound knowledge, expertise and quality assurance. accordingly, pediatric infectious disease specialists nowadays play a pivotal role both for community pediatrics and for clinical pediatrics in highly specialized medical centers. this chapter attempts to summarize the current different activities of pediatric infectious disease specialists, to delineate their interactions with other medical disciplines and to speculate on the near future goals and development of this specialty with the widest scope compared to all the specialties in medicine. pediatric infectious disease specialists are based mainly in hospital settings and have very similar activities in clinics, teaching and research compared to their counterparts in adult medicine. the four disciplines microbiology, epidemiology, immunology, and pharmacology build up the essential basis for both pediatric and adult infectious disease specialists. nevertheless, despite several overlaps that are beneficial for constructive professional interactions, the position of the pediatric infectious disease specialists differ from those of specialists for adult infectious diseases. these differ not only in relation to the basic training in pediatrics and internal medicine, respectively, but also in relation to distinct focuses in the clinics obviously mandated by many age-related uniqueness of patients in the pediatric age (tab. ). etiology, epidemiology, pathogenesis, management and prevention of infectious diseases in children may substantially differ from those in adults. one important example of the uniqueness of pediatric infectious diseases is the need to deal with infections in newborns. newborns have distinct pathophysiological characteristics, which mainly relate to the immature immune system. another example of uniqueness comes from the age-related and more frequent contacts to potential infectious sources or index cases in nurseries, day-care centers or schools. these contacts lead to increased risks to preferentially acquire respiratory or gastrointestinal infections. similar reasons account for higher frequency of outbreaks of infectious diseases in children compared to adults. infants and toddlers are often the source of infections within a household, for health care workers or medical personnel as well as for nursery employees and teachers. infections represent the reason for up to % of the hospitalization of children. etiological diagnosis of these infections may be hampered by the limited volumes of biological samples including blood or cerebrospinal fluid available from young children, often affording rather judicious, and to this-age-group-adapted, diagnostic approaches. moreover, most of the hospitalized children are prescribed one or more antibiotics [ ] . in this context it needs to be underscored that the pharmacokinetics and pharmacodynamics of antimicrobial substances are rather different in children compared to adults. this may afford the use of distinct preparations or dosages in children. in addition, pharmacology and toxicology of antimicrobial drugs in newborns and specifically in preterm or small-for-date babies are rather special. accordingly, in pediatrics special knowledge in the distinct uniqueness of newborns and other age groups, other disciplines and on nosocomial infections in neonatal and pediatric nurseries and intensive care units is warranted. finally, vaccinations make up a larger proportion of the preventive measures in pediatrics than in adult medicine, and this is mirrored by the extraordinary success of general immunization campaigns in children [ ] . pediatricians in private practice and, in some countries or regions, also general practitioners, are in charge of the management of children with common and frequent infectious diseases [ ] . the quality of this management benefits highly from the continued access to and availability of a pediatric infectious disease specialist during the medical formation and training as well as throughout private practice activities. pediatric infectious disease specialists provide important recommendations on the use of microbiological and other diagnostic tests, application of antimicrobial drugs, and measures for infection control, which may substantially differ in children compared to in adults. furthermore, infectious disease specialists possess the required expertise for the establishment of standards of care for frequent communicable diseases and relevant guidelines for the community. pediatric infectious disease specialists are involved in the care of both outpatients and inpatients [ ] . the impact of the pediatric infectious disease specialist within a hospital can easily be deduced from the number of consultations related to infectious disease or infection control issues requested by both experienced table . specific clinical tasks of the pediatric infectious disease specialist [ ] -integrative discipline -provision of primary care and consultative services to patients from all pediatric disciplines -implementation of quality assurance programs in hospitals and other health care settings, e.g., infection control, hospital epidemiology, antimicrobial management programs -engagement in preventive efforts through implementation of vaccine strategies and other means; play a significant role in public health programs at all political levels -conduction of research seeking cures for new diseases as well as preventive measures, such as new vaccines -teaching and leadership in academic health institutions and non-experienced physicians within or outside the hospital. bedside consultations and phone consultations both play an important role [ ] . the multiple interactions result, e.g., in a more considerate selection of diagnostic measures and assays, more judicious and less costly use of antimicrobials, and reduction of formal consultations and hospitalizations [ ] ( fig. ) . much of the shared knowledge originates from pediatric infectious diseases research programs, as they substantially contribute to the development of improved diagnostic, treatment and prevention means as well as to the understanding of pathogenesis and epidemiology of infectious diseases. the multifaceted roles of the pediatric infectious disease specialist clearly improve the quality of patient care and teach physicians who are involved in primary health care [ ] . specialty in pediatric infectious diseases is the paradigm of an integral and integrative discipline providing paramount professional help, advice and support to other pediatric disciplines and to disciplines from adult medicine. obvious examples are consultations for patients with underlying conditions including congenital heart disease, cystic fibrosis, primary or secondary immunodeficiencies such as due to hiv infection or iatrogenic immunosuppression following allograft transplantation, or tumors. many of these patients nowadays survive beyond the pediatric age and need to undergo the difficult process of transition to medical care for adults [ ] . thus, close interactions with colleagues from adult medicine taking over the care of these patients before, during and after the transition process are indispensable to ensure satisfaction and compliance of the patients with often heavy burdens in addition to the burdens of adolescence. infectious disease specialists have a considerable number of skills at their disposal [ ] . experienced infectious disease specialists, for example, often reduce the use of expensive diagnostic measures even in the most complex patient situations, apply intravenous antimicrobial treatment also to outpatients and switch from intravenous to apt oral medication on time. hence, infectious disease specialists increase the satisfaction of patients while ensuring management quality at lowest possible expenses. an outlook into the future cannot be undertaken without careful consideration of the past and the current situation. thus, recent changes in the spectrum of infectious diseases, progress in the field of vaccinology, advances in microbiology, and quantum leap in communication technology are likely to determine new developments and areas of activity for the pediatric infectious disease specialist. the variety of topics covered in the chapters of this book nicely mirrors the wide spectrum of pediatric infectious diseases and the most recent novel developments in the field. several achievements including clean water, improved sanitation, vaccination and antimicrobial therapies have brought many important infectious diseases under control. nevertheless, we have had to face the emergence of pathogens that are resistant to antimicrobials and of new pathogens that have not been previously detected in humans. the principal diseases of the last decade can be segregated into three major groups: (i) infections against which significant progresses have been achieved; (ii) newly emerged infections; and (iii) infections on which we had no impact [ ] . in industrialized countries, infections with hiv or hepatitis c virus (hcv) have been transformed from diseases with no cure to manageable chronic infections due to newly available treatment or prevention modalities. most importantly, mother-to-child transmission rates in these countries have fallen from around - % to below %, and where preventive measures are strictly applied, vertical transmission of hiv has virtually vanished [ ] . this success story, however, evolved at the expense of intrauterine and neonatal exposure to drugs with a considerable toxic potential [ ] . thus, pediatric infectious disease specialists need to conduct long-term surveys on the evolution of these children following exposure to antiretrovi-ral drugs in a life period with highest vulnerability, especially of the central nervous system. testing of blood products has not only virtually abolished transfusion-related hiv infections but also hcv transmission [ ] . poliomyelitis vaccination campaigns have been extremely effective both in industrialized and in non-industrialized countries. globally, the number of poliomyelitis cases has been reduced by % from cases in to less than cases in [ ] . the goal to eradicate poliomyelitis, however, seems to be hurdled by unprecedented reemergence of poliomyelitis due to "escape" variants [ ] or due to outbreaks in communities reluctant to vaccination, mainly for religious reasons and in countries where there are governmental obstacles to vaccination campaigns [ ] . the tasks waiting the pediatric infectious disease specialists are to promote vaccination at the individual, at the community and at the country levels. this will demand persuasion activities focusing on individuals and on politicians. similarly, measles, rubella and mumps are three viruses against which we possess excellent vaccines, and thus could be eliminated given that the only host for these viruses is humans. we will eventually defeat theses viruses only if pediatric infectious disease specialists succeed in convincing parents of the necessity of vaccination. many parents are no longer familiar with the disastrous consequences of these viruses simply because of the decreased circulation of these viruses in the populations due to the fact that a large proportion has been previously vaccinated. but convincing just the parents will not be sufficient, physicians and politicians will need to be convinced too [ ] . the general introduction of the conjugate vaccine against haemophilus influenzae type b for infants and young children early in the s has resulted in a dramatic reduction of h. influenzae type b invasive infections including meningitis, epiglottitis, arthritis, and osteomyelitis [ ] . more recently, conjugate vaccines against streptococcus pneumoniae or neisseria meningitidis type c have also been introduced in general vaccination programs, and it appears that we will again witness a success. nevertheless, not all s. pneumoniae serotypes are represented in the vaccine and the serotypes against which the vaccine elicits immunity may be replaced by other serotypes. furthermore, a universal vaccine against n. meningitidis type b is still lacking. thus, the reduction of s. pneumoniae or n. meningitidis-induced disease will not be as impressive as for h. influenzae type b. in consequence, pediatric infectious disease specialists will have to explore modalities to improve surveillance and treatment of these prominent and potentially deadly bacterial infections. it goes without saying that more research on the elucidation of bacterial and host-related pathogenetic mechanisms is needed to cut the imminent danger from these pathogens [ ] [ ] [ ] . we have also witnessed the emergence of an unprecedented number of infections. most of these infections are of animal origin: avian influenza, severe acute respiratory syndrome (sars), west nile, ebola, and variant creutzfeldt-jacob disease. another unprecedented observation was the increase in the prevalence of antibiotic-resistant bacteria and the reemergence of previously eradicated pathogens as agents of bioterror. among the most feared and serious antibiotic-resistant bacteria are methicillin-resistant staphylococcus aureus. multiple antibiotic resistances are a problem also with s. pneumoniae, enterococcus faecalis, pseudomonas aeruginosa and mycobacterium tuberculosis [ ] . a main challenge for pediatric infectious disease specialists in addition to the challenge faced by their adult counterparts in this context will be the availability of apt antimicrobials in apt formulations. this in turn will demand that pharmacokinetic, efficacy and safety clinical trials for new drugs are conducted in parallel for adults and different age groups of children, to acquire the needed antimicrobial armamentarium on time. unfortunately, during the last decade we had no impact on tuberculosis, malaria and worldwide hiv, the three leading killer infectious diseases which contribute to half of the global burden of mortality from infectious diseases. in fact, the absolute number of the epidemics has steadily increased. this may cause repercussions in industrialized countries. thus, we pediatric infectious disease specialists who are in a privileged situation cannot neglect these unsolved medical problems, but rather need to increase our efforts to share our time, knowledge and expertise for the benefit of those who need it most. vaccines against these three pathogens are, without a doubt, of paramount priority. finally, another important issue has come up recently: pediatric infectious disease specialists have to deal with aspects of biological terrorism against children (see the chapter by kwang sik kim). the development of several vaccines has been hampered by technical difficulties. vaccines can be developed following the principles of pasteur, i.e., isolating, inactivating and injecting causative microorganisms. such development, however, is not apt for all pathogens, especially for those which cannot be grown in cultures, including hcv, papillomaviruses and and mycobacterium leprae or for antigenically hypervariable microorganisms such as n. meningitidis type b, n. gonorrhoea, malaria and hiv [ ] . in recent years, many obstacles in the engineering of vaccines have been overcome. using "reverse vaccinology" [ ] , a process in which computer analysis, microarrays, proteomics and other genome-based systematic approaches are used to select genomic sequences of microorganisms, antigens likely to confer protective immunity can be identified. candidate antigens can be expressed by recombinant dna and be tested in animal models. reverse vaccinology has enabled the production of vaccines against hcv, human papillomaviruses, and meningococci type b. these examples will be followed for other pathogens representing a threat to infants and children. the pediatric infectious disease specialist will have to define priorities, and will have to conceive plans to test the safety and efficacy of these future vaccines, as well as the surveillance of the epidemiology of the targeted pathogens following the introduction of the vaccines on a larger scale. a change in paradigm in vaccinology has come from the recognition that conquering the most difficult infections such as hiv and malaria may require the t cell arm of the immune system. most vaccines available today work by inducing antibodies, and quantification of these antibodies is often used as a parameter for immunogenicity of and protection by a given vaccine. unfortunately, protective antibody levels are not clearly defined for every available vaccine. moreover, as in the example of hbv vaccine, the levels of specific antibodies may not be indicative for the status of protection. the level of specific antibodies may be below the limit of detection but vaccinated individuals may be still protected against hbv infection by the cellular immune responses. the effective stimulation of cytotoxic t cells can be obtained using engineered non-replicating viral vectors, such as modified vaccinia virus, replication-incompetent adenoviruses and dna vaccines [ ] . another recent quantum jump has been that we -as other living organisms -possess a conserved "innate" immune defense against pathogens. the innate immune defense senses invading microorganisms or their components, and determines the type of adaptive immune response that will eventually result in protection. toll-like receptors and nod proteins are involved in this process. an improved knowledge of the pathways of innate immunity, their selectivity and their interactions is likely to improve the efficacy of vaccines, since certain compounds triggering innate immune defenses, e.g., unmethylated cpg, which mimics microbial dna or lipopolysaccharide as a bacterial cell wall component, could be used as novel vaccine adjuvants to enhance immunity. the field of innate immunity is certainly one of the most promising fields for laboratory and clinic-based research in pediatric infectious diseases [ ] . among the most important developments resulting in unprecedented insights into pathogenesis, susceptibility and diagnosis of infectious diseases are advances in microbiology, immunology and genetics. important changes, with introduction of molecular biology techniques and laboratory automation, have increased the accuracy and velocity of microbiological diagnosis (fig. ) , and new tools are still being developed [ ] . the pediatric infectious disease specialist will considerably benefit from close collaborations with microbiologists both at the research and at the routine level. an equally symbiotic relationship between pediatric immunologists and geneticists will help establish the reasons for increased susceptibility to distinct patho-gens as, for example, mycobacteria or salmonella [ ] and novel treatment modalities for immunocompromised children [ ] . the sick child has the right to receive the best possible medical attention. this includes the caring physicians calling in specialists for consultations, and interdisciplinary consultations can be predicted to become a pivotal component of standard care for patients in the future. who would dare to prevent a sick child from getting optimal remedial management? given the growing medical knowledge and the increasing complexity of modern medical care, pediatric infectious disease specialists can be anticipated to become highly solicited. thus, intra-and interdisciplinary interactions will be more than ever crucial for pediatric infectious disease specialists in the years to come. continued extensive communication, and close collaboration and partnership with other pediatric infectious disease specialists as well as with experts from pediatric immunology, clinical microbiology, pharmacy, epidemiology and all other pediatric subspecialties will build up the key for pediatric infectious disease specialists to ensure the indispensable optimal patient care, efficient teaching, and prosperous research. the most demanding challenge for pediatric infectious disease specialists will therefore be to comprehensively compile expertise, knowledge and cutting edge research for the ultimate benefit of the patient. whereas improved communication within the own hospital setting will help to cope with unqualified management of the sick child as much as pos- sible, installment of a regular and frequent dialog with other centers will not only provide helpful suggestions from peers for the management of patients, but also facilitate and improve continuous education in the field and ensure exchange of ideas for independent and collaborative patient-related or laboratory-based research. the rapidly evolving communication technology has established excellent and affordable tools to allow for quick and reliable data and digital picture transfer as well as for audiovisual conferences at the national, international and intercontinental levels. indeed, digital picture documentation of clinical and laboratory findings is advancing and will evolve. the improved communication at the national and international level should pave the way towards standardized training curricula and the development of training quality evaluation programs. in countries where medical specialty units specifically devoted to pediatric infectious diseases await establishment, support from national and international professional societies will be required to promote the specialty, and communication networks will certainly contribute to expediting this process. the goal to install a pediatric infectious disease service at least in every large medical center is justified. networking will become more and more important to conduct multicenter studies devoted to the pathogenesis, diagnosis or management of less common infectious diseases to enable inclusion of sufficient patients in an appropriate time frame or to adequately respond to emerging infectious diseases [ ] . further, networking that also included experts other than pediatric infectious disease specialists will become increasingly essential to collect and exchange data pertinent to interdisciplinary managed patients as, for example, neonates, cystic fibrosis patients or transplant recipients, to optimize clinical research and management as well as issuing guidelines. such guidelines will gain importance, e.g. in preventing misuse of highly expensive biologicals or drugs (http://www.swiss-paediatrics.org/paediatrica/vol /n /palivizumab -ge.htm). the pediatric infectious disease specialist faces many challenging and complex tasks in the next few years. these tasks will include meticulous consolidation and careful extension of existing activities aiming at conducting high-level research, offering high-standard teaching, and providing highquality patient management. these contributions to modern health care and medicine in general and pediatrics in particular can only be accomplished by dedicated individuals with extraordinary communication and integrative skills following painstaking continued training and formation. potential careers in the discipline can be envisioned not only in academics, but also in government, public health, and industry, although less likely in private practice. the diversity of issues and questions to be confronted makes the specialty of pediatric infectious diseases the specialty with the widest scope compared to all the specialties in medicine. accordingly, commitment to pediatric infectious diseases will be extremely demanding. since not all imposed tasks can be successfully completed by one person only, it will be of paramount importance to focus the activities and to carefully define priorities. nevertheless, such demanding commitment will be fully compensated by manifold societal and personal rewards. prospective survey of antibiotic utilization in pediatric hospitalized patients to identify targets for improvement of prescription the japanese experience with vaccinating schoolchildren against influenza trends in doctor consultations, antibiotic prescription, and specialist referrals for otitis media in children the pediatric infectious disease physician: current roles and importance of the specialty in the care of children. strategic development and long-range planning committee prospective study of telephone consultation and communication in pediatric infectious diseases medical errors detected and corrected by a pediatric infectious diseases consultation service strategies for improving transition to adult cystic fibrosis care, based on patient and parent views withdrawal of pneumocystis jirovecii prophylaxis in hiv-infected children under highly active antiretroviral therapy from pasteur to genomics: progress and challenges in infectious diseases prevention of vertical hiv transmission: additive protective effect of elective cesarean section and zidovudine prophylaxis persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues current and emerging infectious risks of blood transfusions polio endgame. polio: the final assault? poliomyelitis eradication -a dangerous endgame is the cultural context of mmr rejection a key to an effective public health discourse? worldwide haemophilus influenzae type b disease at the beginning of the st century: global analysis of the disease burden years after the use of the polysaccharide vaccine and a decade after the advent of conjugates invasive pneumococcal disease among infants before and after introduction of pneumococcal conjugate vaccine effect of introduction of the pneumococcal conjugate vaccine on drug-resistant streptococcus pneumoniae reverse vaccinology, a genome-based approach to vaccine development reverse vaccinology -in search of a genome-derived meningococcal vaccine therapeutic potential of toll-like receptor activation what does the future hold for clinical microbiology? human genetics of infectious diseases: fundamental insights from clinical studies treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the european experience i thank horst schroten, christoph berger, christian kahlert, and erika schläpfer for their most valuable comments on this manuscript. key: cord- -m nb kf authors: vignier, nicolas; bouchaud, olivier title: travel, migration and emerging infectious diseases date: - - journal: ejifcc doi: nan sha: doc_id: cord_uid: m nb kf emerging infectious diseases (eid) threaten public health and are sustained by increasing global commerce, travel and disruption of ecological systems. travelers could play a role in importing eids and could be a sentinel of major epidemics. in connection with the extension of poverty, urbanization, extensive livestock rearing and globalization, we could be exposed to a third epidemiological transition characterized by zoonotic diseases and infections with multidrug-resistant bacteria. the risk appears low for emerging infectious diseases, or very low for high-risk emerging infectious diseases, but higher for multidrug-resistant enterobacteriaceae carriage with possibly limited consequences. the role played by migrants is weaker than imagined. immigrants don’t play the role of sentinel epidemic so far. they could play a role in importing multidrug-resistant enterobacteriaceae, but it is poorly evaluated. emerging infectious diseases (eid) threaten public health and are sustained by increasing global commerce, travel and disruption of ecological systems. travelers could play a role in importing eids and could be a sentinel of major epidemics. in connection with the extension of poverty, urbanization, extensive livestock rearing and globalization, we could be exposed to a third epidemiological transition characterized by zoonotic diseases and infections with multidrugresistant bacteria. the risk appears low for emerging infectious diseases, or very low for high-risk emerging infectious diseases, but higher for multidrug-resistant enterobacteriaceae carriage with possibly limited consequences. the role played by migrants is weaker than imagined. immigrants don't play the role of sentinel epidemic so far. they could play a role in importing multidrug-resistant enterobacteriaceae, but it is poorly evaluated. emerging infectious diseases (eids) have led to cooperation between countries, the first international epidemic response conference in and the establishment of who in . eids are diseases that have appeared recently or that have recently increased in frequency, geographical distribution or both ( ) . since the end of the th century, there has been a constant stream of newly identified pathogens and an increasing occurrence of pandemic threats to global health ( ) . eids threaten public health and are sustained by increasing global commerce, travel and disruption of ecological systems and in particular urbanization. urbanization is characterized by rapid intensification of agriculture, socioeconomic change, and ecological fragmentation, which can have profound impacts on the epidemiology of infectious disease ( ). however, their interactions with travel and migrations are less well known. travelers could play a role in importing eids and could be a sentinel of major epidemics. in france, there are more than million travelers every year, . million of which are destined for areas at high risk for health. there are several modes of travel: tourist, business or visiting friends and relatives. trips can be very short or extended in time. infectious diseases are rare health events, with the exception of common infectious diseases such as traveler's diarrhea and are a single cause of death, far behind accidents and cardiovascular disease ( ) . the risk of emerging infections such as dengue in a risk zone was estimated at % for one month of travel ( ). we have seen (re-)emergence of diseases imported by travellers in europe, such as chikungunya and dengue in france and itay, and malaria in greece ( ) ( ) ( ) . apart from these examples, these are rare situations. however, with global travel growth, the risk could become more tangible ( ) . a particular concern is that of multidrug resistant enterobacteriaceae (mre) carriage. mre acquisition is very frequent among travellers to tropical regions ( ) . the acquisition was higher in asia ( %) than in sub-saharan africa ( %) or latin america ( %). however, the same study showed that mre carriage was limited in time and disappeared after a few months. migration is a global phenomenon that influences the health of individuals and populations over the course of their lives ( ) . migrants are special travellers who, in most case, do not migrate by choice. migrants are considered at higher risk for a range of health problems including infectious diseases as hiv, hepatitis b, tuberculosis, schistosomiasis and malaria ( , ) . this higher risk is partly due to poor socioeconomic conditions and, in some countries, is due to the lack of rights to health coverage for undocumented migrants ( ) ( ) ( ) ( ) . existing evidence from different european countries highlights the difficulties to access health services that migrants are facing ( ) ( ) ( ) ( ) . these infectious diseases unequally expose the majority nicolas vignier, olivier bouchaud travel, migration and emerging infectious diseases population, from none at all (e.g., malaria) to a little (e.g., tuberculosis). one can take the examples of epidemics of middle east respiratory syndrome coronavirus -merscov-and ebola, for which no secondary case has been reported in france. among the published studies on migrants and infectious diseases, the majority were non-emergent diseases with the exception of mdr tuberculosis and multidrug-resistant bacteria ( , ) . in connection with the increased use of antibiotics in low-resource countries, there is a worrying increase in the prevalence of multidrug-resistant bacteria ( , ) . this increase could lead to an increased risk for migrants and their relatives, but there are few data on this point ( ) . the risk seems particularly increased when they return home to visit friends and relatives ( ) . while antimicrobial resistance is of concern, the prospects for pandemic spread of a bacterial or fungal emerging pathogen by migrants seem less likely ( ) . endemic disease, as tuberculosis, impose a far higher public health burden than epidemic disease ( ) . denmark experienced an increase in the incidence of tuberculosis in the s in relation to the increase in the number of cases among migrants ( ) . the rate of tuberculosis in france is times higher among immigrants than in the majority population. refugees and asylum seekers may have a heightened risk of mdr-tb infection and worse outcomes but the data remains poor ( ) . thus, there is little evidence to support the theories by which migrants would expose the host population to significant infectious risk. however, human diseases acquire a social status based on their perceived risk that determines their acceptability ( ) . in a study that we conducted with a number of doctors in france (infectious diseases and general practitioners), they were asked if firsttime migrant people represent a vector of infectious diseases different from the majority population: % answered no, % yes but weakly, % yes but moderately, % yes significantly and % did not know. thereby, apart from infections such as tuberculosis and multidrug-resistant bacteria, the introduction of eids into human populations seems to be more often a consequence of economic development that brings zoonotic reservoirs in closer proximity to people. indeed, most pandemic threats are caused by viruses from either zoonotic sources or vectorborne sources ( ) . there is a need for rapid diagnosis of eids. systems biology approaches can lead to a greater understanding of eids pathogenesis and facilitate the evaluation of newly developed vaccine-induced immunity in a timely manner ( , ) . close collaboration is therefore needed between specialists in tropical medicine, in public health, immunologists and biologists to anticipate the risk of eids in order to achieve the sustainable development goals established by the united nations in ( ). the who established a department of pandemic and epidemic diseases in to better prepare for and respond to eids. in conclusion, in connection with the extension of poverty, urbanization, extensive livestock rearing and globalization, we could be exposed to a third epidemiological transition characterized by zoonotic diseases and infections with multidrugresistant bacteria ( ) . the risk appears low for eids, or very low for high-risk eids, but higher for mre carriage with possibly limited consequences. the role played by migrants is weaker than imagined (except for tuberculosis). immigrants don't play 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multiresistant bacteria-a crosssectional study emerging viral diseases from a vaccinology perspective: preparing for the next pandemic when an emerging disease becomes endemic migration, refugees, and health risks multidrug-resistant tuberculosis and migration to europe systems biology-based platforms to accelerate research of emerging infectious diseases the evolution of disease: anthropological perspectives on epidemiologic transitions key: cord- -afgvztwo authors: nan title: engineering a global response to infectious diseases: this paper presents a more robust, adaptable, and scalable engineering infrastructure to improve the capability to respond to infectious diseases.contributed paper date: - - journal: proc ieee inst electr electron eng doi: . /jproc. . sha: doc_id: cord_uid: afgvztwo infectious diseases are a major cause of death and economic impact worldwide. a more robust, adaptable, and scalable infrastructure would improve the capability to respond to epidemics. because engineers contribute to the design and implementation of infrastructure, there are opportunities for innovative solutions to infectious disease response within existing systems that have utility, and therefore resources, before a public health emergency. examples of innovative leveraging of infrastructure, technologies to enhance existing disease management strategies, engineering approaches to accelerate the rate of discovery and application of scientific, clinical, and public health information, and ethical issues that need to be addressed for implementation are presented. powerful antibiotics and vaccines helped mitigate the threat from infectious diseases for several generations. in , most human deaths were associated with infectious diseases like tuberculosis and influenza. as recently as , the worldwide mortality associated with infectious diseases was . percent of deaths from all causes. in , this had continued to decline to . percent. unfortunately, this means there were still over million deaths associated with infectious diseases [ ] . a recent review examined antimicrobial resistance and predicted that by , the impact would include a reduction of the world's potential gross domestic product by % to . % and cause an additional million premature deaths a year [ ] . although beyond the scope of this paper, it is worth noting that microorganisms have also been implicated as contributing to or causing many chronic diseases, including some forms of cancer, arthritis, and neurological disease [ ] . it is tempting to approach the infectious disease challenge as doing battle with a pathogen enemy where brigades of combatant bacteria or viruses are held back or even defeated by increasingly sophisticated pharmaceutical weapons. there is certainly a place for improved pharmaceuticals; however, a sustainable approach will need to be much more sophisticated. microbes and their hosts form a complex and dynamic ecosystem, and a long-term strategy for infectious disease control must take into account the fact that diseases can result from changes in the microbe, the host, or the environment. it is time to move beyond the simple war metaphor [ ] . to compound the challenge, microbes are notoriously fast in adapting to new environments. this can include bacteria developing antibiotic resistance or acquiring metabolic traits that allow them to thrive in a new environmental niche, and viruses evolving to reduce the effectiveness of antivirals and vaccines. in addition to the evolution of existing pathogens, like the seasonal influenza virus, there are emerging pathogens that are often the result of changing or encroachment upon new ecosystems and the ''leap'' from a conventional host to a new host species. an example from recent headlines is the middle east respiratory syndrome coronavirus. mers-cov appears to have reached humans by direct contact and potentially airborne transmission through animal hosts including camels [ ] . the mers-cov is related to the coronavirus that caused severe acute respiratory syndrome (sars). the sars outbreak began in and likely spread to humans via bats [ ] . although the viruses are similar, this does not guarantee that utilization of the same medical and public health intervention techniques will be effective. there are many examples of emerging infectious disease outbreaks, including the on-going hiv/aids pandemic that has already caused million deaths [ ] . each pathogen involved in an infectious disease outbreak provides an opportunity to identify what scientific data are needed to support effective interventions. quoted in the global health security agenda [ ] , u.s. president obama said in ''. . . we must come together to prevent, and detect, and fight every kind of biological dangervwhether it's a pandemic like h n , or a terrorist threat, or a treatable disease.'' the agenda complements and supports existing international health regulations of the world health organization [ ], u.s. public health [ ] , [ ] , and biodefense objectives [ ] - [ ] . the framework for data requirements and response priorities used in this paper integrates across these initiatives and regulations. specifically, in order to manage infectious diseases, capabilities are required for: preparedness, detection, characterization, response, and support for the return to normal, see fig. . this framework is analogous to homeostasis in living organisms. these capabilities are relevant for addressing health interests from the global to the individual organism, e.g., human, animal, plant, or bacterium. the global perspective is studied and implemented by public health, ecological, industrial, and other communities with the principal foci of public benefit, humanitarian needs, scaling, and statistical measures. for an individual human, the perspectives are from medical, economic, relationship, and other personal priorities with the foci of individual health, quality of life, and gaining access to effective care. integrating frameworks are needed to support optimization of technical, economic, medical, and ethical components of this complex system. infectious diseases are a major cause of death and economic impact worldwide. a more robust, adaptable and scalable infrastructure would improve the capability to respond to epidemics. because engineers contribute to the design and implementation of infrastructure, there are opportunities for innovative solutions to infectious disease response within existing systems that have utility, and therefore resources, before a public health emergency. examples of innovative leveraging of engineered infrastructure are provided throughout the paper. the next section of this paper discusses opportunities for technology to improve on current approaches to infectious disease management and the following section discusses engineering challenges to accelerate the application of science to infectious disease planning and response at the global scale. i conclude with a brief discussion of the importance and opportunity for engineers to address the ethical issues needed to leverage traditional infrastructure for infectious disease response and help nurture a global culture of responsibility in both healthcare and technical applications. leveraging their significant investment in planning and response experience, i adopted from the u.s. pandemic influenza plan [ , p. g- ], infectious disease management goals to provide: public health policy-makers with data to guide response, and clinicians with scientific data to justify recommended treatments, vaccines, or other interventions. i have integrated priorities from the influenza plan with a more pathogen-centric approach from the food industry [ ] in table to provide descriptions of priority data to support infectious disease outbreak response. health have parallels shown in the inner and outer rings, respectively. because traditional diagnostics and treatments have long lead development, regulatory approval, and manufacturing lead times, it is challenging to provide timely and effective interventions at a public health scale for an outbreak caused by an emerging or novel pathogen. approaches to achieving robust, economically viable scaling include improved leveraging of existing infrastructure, establishment of an integrating framework like the digital immune system for optimization, and spiral development processes similar to homeostasis. these data can be provided with currently available technologies. however, there are several recurring issues that inhibit global utilization. the issues that can be addressed, even if only partially, by technology are discussed. the key recurring issue is availability. limited availability is driven by many factors including cost, appropriate sharing of data and materials, and timely manufacture and distribution. on a more basic level, one of the key factors in sustainable preparedness is infrastructure, and availability is a challenge here as well. malnutrition due to starvation, unsafe water, and insufficient sanitation all impact infectious disease mortality. in , over half of the deaths of children under five years old were associated with infectious diseases and the significant contributing factor for many of these deaths was under nutrition [ ] . building the infrastructure to eliminate these hazards has historically been the domain of civil and agricultural engineers. electrical and computer engineers are now providing valuable low-cost information linkages across systems so that weather satellite data can be utilized to help increase local crop yields and prepare water treatment and sanitation plants for adverse weather. the computational algorithms and information networks can be applied worldwide for irrigation and weather prediction for storm and drought management [ ] . remote sensing has been utilized to indirectly detect vibrio cholera [ ] and predict a rift valley fever (rvf) outbreak [ ] . in both of these examples, the disease and environmental biology were shown to correlate with changes that could be measured by air and space borne sensors. for v. cholerae, sea-surface temperature and sea height were linked to the inland incursion of water with commensal plankton. satellite measurements of seasurface temperature, rainfall, and vegetation changes were used to predict the areas where outbreaks of rvf in humans and animals occurred in africa. the techniques and data used for rvf may be more broadly applicable to other vector-borne diseases. in regions with limited infrastructure, it is often difficult or impossible to provide the refrigeration required to maintain the ''cold chain'' for life-saving vaccines and other medicines. an inspirational consortium of industry, churches, and nonprofits in zimbabwe, africa, leveraged the reliable power requirements of cellphone towers to help address the refrigeration storage needs for many vaccines [ ] . the initiative has included innovative contributions by wireless providers, refrigerator manufacturers, and others in order to help provide immunizations against polio, measles, and diphtheria. another area in which technology is poised to impact infectious disease management is in gaining timely situational awareness of outbreaks. global and regional travel often make this a difficult task, and data collection and sharing for epidemiologists, care providers, patients, and the public is also limited by other factors such as privacy concerns for individual patients' medical data, governmental goals to protect tourism and other local-to-national interests, the lack of recognized standards for sharing protected data, and an accepted international norm for transfer of public and commercial material during and in response to an infectious disease. improved network, encryption and access information technologies are also necessary to support managed care organizations and telemedicine applications. a global system addressing these issues and capable of operating on time scales relevant to controlling an epidemic is needed. a comparison of five outbreak detection algorithms was conducted using a surveillance case study of the seasonal ross river virus disease [ ] . challenges were identified for making quantitative comparisons of the algorithms as well as in evaluating the performance of each algorithm. a network model has been proposed that has the potential to address algorithm shortcomings for outbreak localization and performance under changing baselines [ ] . this is accomplished through modeling the relationships among different data streams rather than only the time series of one data stream compared to its historical baseline. using measured and simulated data, this approach showed promise for addressing shifts in health data that occur due to special events, worried well, and other population shifts that happen during significant events like pandemics. another study compared animal and public health surveillance systems, finding challenges due to a limited number of common attributes, unclear surveillance objectives of the design, no common [ ] . privacy issues pose challenges that are difficult to address with technology, but they have been addressed in some applications through voluntary enrollment. for example, the geographic location capability in many cell phones allows applications to push public health and animal disease outbreak information to users based on location. the u.s. centers for disease control and prevention (cdc) has the fluview application that provides geographic information on influenza-like illness activity [ ] . obviously, the pervasiveness of cell phones improves timely reporting from the field for both the public and the public health profession. moving forward, addressing privacy issues will be critical so that geographic tracking of a phone's location could be used to help inform an individual of potential contact with infected persons or animals and support automated, anonymous, electronic integration of those data to accelerate the epidemiological detective work of identifying and surveying those same individuals for public health benefit. electronic health information systems have made significant progress. however, even as recently as , it was noted: ''despite progress in establishing standards and services to support health information exchange and interoperability, practice patterns have not changed to the point that health care providers share patient health information electronically across organizational, vendor, and geographic boundaries. electronic health information is not yet sufficiently standardized to allow seamless interoperability'' [ ] . the u.s. has taken a risk-based approach to health information technology (it) regulation [ ] . safety in health it has been recognized as part of a larger system that needs to consider not just specific software, but how it interacts with the it system and how it will be used by clinicians [ ] . continued development of quality management, human factors, and other standards to support usability and regulatory review are needed. as the large-scale systems that require computer algorithms to scan and integrate data into summary reports continue to progress, significant benefit is being derived from systems with fairly simple technology. in , promed was started as the first e-mail reporting system with curation. it has grown to over , subscribers in over countries and has roles in outbreak detection including sars in [ ] . there are many health alert networks (han) that utilize websites and electronic communications [ ] , [ ] . a study in new york city showed that most physicians ( %) received health department communications, but less than half of those ( %) received the information through the han [ ] . an important trend is that % prefer e-mail distribution of communications and this preference trends with younger respondents. looking to the future, achieving the benefits of distributed diagnostics and electronic reporting will depend on both technical and clinical integration. this would improve individual care as well as reduce or eliminate separate data entry and reporting for public health surveillance. in order to realize the benefits of personalized medicine with treatment customized to the individual, the costs, scalability, and compatibility across all data sources must be addressed. personalized infectious disease medicine might include customization of antimicrobials to an individual patient to improve care and help reduce overuse and misuse of antibiotics. similarly at the global health scale, timely identification of appropriate virus strains coupled with rapid manufacturing for seasonal influenza vaccination would reduce the disease burden of thousands. in personalized and global applications, the approaches will need to move from diagnostics, characterizations, and interventions aimed at a single specific disease causing pathogen to robust methods that can be adapted for safe and effective use in a timely manner for broad classes of disease. fully realizing these goals will require improved scientific understanding and new engineering and computational approaches. there are significant challenges in utilizing traditional engineering approaches in the life sciences. living organisms are complex by most machine standards. individual organisms are also typically influenced by peer organisms forming a community, by other living organisms that may be beneficial, neutral or detrimental, and by the environment. there are opportunities for engineers to develop improved measurement, analysis, and model systems to better characterize, predict and manage infectious diseases. given the complexity of these interacting systems, there are significant challenges to the reductionist approaches familiar to design-based engineering. fortunately, as the history of vaccination demonstrates, a comprehensive knowledge of the biology is not always required in order to provide healthcare benefits. with the advent of deoxyribonucleic acid (dna) sequencing and the efficient detection and laboratory replication of dna through polymerase chain reaction (pcr) amplification, there are opportunities to organize scientific and medical data using dna-based indices. the field that has grown up around these technologies, genomics, is an excellent example of how engineering can enable profound advances in biological research. a significant contributor to the organizing principles and demonstrator of this dnabased approach, carl woese, summarized in the impact as providing ''a new and powerful perspective, an image that unifies all life through its shared histories and common origin, at the same time emphasizing life's incredible diversity and the overwhelming importance of the microbial world,'' [ ] . here, i build on this insight as well as our previous assessment in of the engineering contributions and opportunities related to dna sequence fitch: engineering a global response to infectious diseases data that describe an organism's genome, transcriptome and proteome [ ] . as depicted in fig. , nucleic acid sequence provides a common framework to organize data related to infectious diseases. today's dna sequencing instruments can produce terabases of data in a few days with per-base costs a million-fold lower than a decade ago. recent studies have demonstrated the power of personalized approaches to major human diseases like cancer. it appears likely that the next few years will bring the personalized human genome and the miniaturized sequencing instrument, each for less than one thousand dollars. now is the time to innovate and apply the engineering approaches needed to utilize these and other data. dna sequencing and the associated bioinformatics tools for analysis provide a powerful methods-based approach to monitoring living systems. dna and ribonucleic acid (rna) provide data that help characterize an individual's health status as well as the status of the surrounding environment. because sequencing converts biological information to digital data, computer networks, data management, integrity, scaling, analysis, privacy, and affordability are keys to expanding access. the ''digital immune system'' is a powerful concept that generalizes the method to population dynamics and public health [ ] . basing the system on dna allows correlation techniques to identify patterns in the sequence datavrecurring and deviate patterns. these patterns can be indicative of healthy or pathologic host status as well as the absence or presence of pathogens in clinical and environmental samples. the growth of sequence databases with appropriate clinical and environmental metadata will improve the potential quality of the analyses and the impact on individual and public health. growing databases will also need to address the scaling and privacy issues. one of the most powerful features of the digital immune system approach is the potential to detect a novel pathogen, i.e., one that is not already in the database. the flexibility inherent in this methodbased approach is a huge strength and distinguishes it from many of the traditional methods which are not able to detect or characterize a new or emerging pathogen. seasonal influenza provides an example of a system of method-based opportunities. the influenza virus changes genetically as it uses an error-prone enzyme to replicate its genome, and mutates further as it migrates from host-tohost, across speciesve.g., waterfowl to humans, and across ecosystems of the environment. this mutation process gives rise to a different population of viruses in circulation each year, and poses a challenge to vaccine manufacturers, as one year's vaccine will typically have little value when confronted with the next year's viral strains. each year's vaccine is constructed specifically to protect against the strains that are projected to be dominant in the upcoming flu season. the current process uses egg-based techniques for manufacturing influenza vaccine and has been successfully utilized for decades as have the techniques for isolating and identifying emerging strains of the virus. unfortunately, the combined pipeline is relatively slow and does not typically allow for vaccine manufacturing to be based on strains that have been detected at the start of the flu seasonvvaccine production must be started earlier, and so relies heavily on imperfect predictions as to which strains of influenza will dominate. rna sequence data provide a method-based framework for managing influenza response at the global scale. in addition to the detection and identification of the virus, sequence data can be utilized to compare and predict the performance of egg and other manufacturing approaches. as the sequence, clinical, animal, and environmental data are accumulated, there is also the potential to support computational safety and efficacy screening. shortening the current timeline from detection through vaccination would have significant positive health benefits. there are method-based approaches to vaccine manufacturing with significant potential to improve upon the egg-based approach. even though the influenza virus has only eight genes and an ominous history of multimillion death pandemics, the scientific understanding is not yet sufficient to avoid the thousands of deaths annually from seasonal influenza nor to mitigate the potential from a pandemic strain. complex samples to be converted to nucleic acid sequence data that are easily represented in a digital computer. these data can be used as a framework or index for health and disease related metadata supporting correlative studies across species and providing insight into infectious diseases. because genetic material is traded among organisms and is often part of complex nonlinear networks within an organism and beyond, increased collection and interpretation of the associations across dna sequence and metadata are needed. a digital immune system for individuals and populations is envisioned that identifies causation and intervention options to support patient-specific and public health interventions. biocontainment laboratories are needed to safely conduct the research needed to understand pathogens as well as analyze clinical samples. characterization of existing pathogens increases understanding of current diseases and also helps to prepare for emerging diseases. laboratories that work with infectious agents are categorized by biosafety level (bsl) ranging from a basic biomedical laboratory (bsl- ) to bsl- laboratories (fig. ) that can safely handle untreatable disease agents [ ] . the engineering systems for automatically controlling airflow and other facility safety components are critical for supporting clinical and research laboratories. infectious disease research is benefiting from ''omic'' methods for characterizing proteins (proteomics), metabolites (metabolomics), messenger rna (transcriptomics), etc. in order to safely produce genomic data more quickly, dna sequencing instruments have been moved into our biocontainment laboratories. these methods produce large volumes of data, requiring research and clinical labs to have access to traditional engineering disciplines in data management and analysis. data management is not the only challenge. so far, our descriptions have implied a single host interacting with a single invading pathogenvthe war metaphor. it is not that the metaphor does not work in many cases. for instance, the eradication of smallpox was accomplished through an aggressive worldwide campaign as was the animal and livestock disease rinderpest [ ] . it is that the war metaphor is an oversimplification with an often unrealizable aspiration for victory. consider that most hosts, including bacteria, have associated pathogens and symbiotic microbes. for example, a tropical grass, fungus, and virus have been found to have a three-way symbiosis that confers heat tolerance [ ] . when the virus is removed from the fungus, thermal tolerance is lost by the grass. if the virus is reintroduced to the fungus, thermal tolerance is conferred to the grass. viruses can also integrate their genes into animal genomes as part of the animal's nuclear dna affecting inherited traits [ ] . virus infection is one of several naturally occurring changes in the nucleic acid of a genome. even simple nucleic acid transfers among different biological entities often have difficult to predict results. the complexity compounds as the number of entities increases and community behaviors emerge. for each of the approximately one trillion human cells in our bodies, there are about ten microbes. the microbes are distributed in different, highly specialized, communities in the gut, mouth, skin, etc. collectively referred to as the microbiota [ ] , [ ] . given a global population over billion, there are approximately cells/microbes associated with people on the planet. for comparison, it has fig. . engineering, process, and other controls allow important infectious disease experiments to be conducted safely. representative biosafety level (bsl) labs are shown. bsl- is for agents not known to cause disease in normal, healthy humans. bsl- is for moderate-risk agents that may cause disease of varying severity through ingestion or percutaneous or mucous membrane exposure. bsl- is for agents with a known potential for aerosol transmission and that may cause serious and potentially lethal infections. bsl- is for agents that pose a high individual risk of life-threatening disease resulting from exposure to infectious aerosols, or for agents where the risk of aerosol transmission is unknown. agents appropriate for this level have no vaccine available, and infection resulting from exposure has no treatment other than supportive care. fig. . the global ecosystem is a highly interconnected network of hosts and environments each with its own associated microbiome. nucleic acids, chemicals, and energy are shared within each environment as well as across the global network. new approaches are needed to visualize and understand the relationships among these environments to improve infectious disease management. fitch: engineering a global response to infectious diseases been estimated that there are cells of prochlorococcus bacteria in the ocean [ ] . equally impressive, there are viruses in the ocean causing roughly viral infections every second [ ] . as represented in fig. , whether, grass, animals, or humans, the microbes, the communities, and their host community are sharing chemicals, energy, and nucleic acids. it is no surprise that clinical, animal, environmental, and other samples often have significant genetic complexity. information visualization tools like krona (fig. ) , support analysis of complex metagenomic data [ ] . these types of data can be used to support many applications including investigating food borne disease outbreaks [ ] . genomics helped explain the initiation of the ebola outbreak in sierra leone in [ ] . genomes from virus samples from patients provided evidence that the index case and associated thirteen initial cases in sierra leone had attended the funeral of a traditional healer that had been seeing ebola patients from nearby guinea. the sequence data also showed mutations in parts of the genome that might impact diagnostics, vaccines and therapies. even though the west africa ebola virus disease (evd) epidemic is by far the largest to date, fortunately ''the clinical course of infection and the transmissibility of the virus are similar to those in previous evd outbreaks'' [ ] . the goal is to be able to make these clinically relevant assessments from the virus genome prospectivelyvi.e., before the epidemic provides the observations. computational algorithms and tools are available to find signatures of existing pathogens as well as recognize patterns that help identify previously unidentified pathogens. moving forward, computational models for the interactions among the different genes are needed that provide a context for the correlations in data as well as improve predictive capabilities. for instance, going beyond detecting disease outbreaks to being able to assess and predict disease risks is desired. these much more complicated models offer the potential to accelerate disease understanding and the development and safe utilization of medical interventions at both the individual and the global scales. there are multiple initiatives underway that will lay the foundation and strengthen the underlying science. the foundation will enable new engineering approaches that will achieve the greater goals for infectious disease management. using an approach that parallels the evolution of electrical circuit design and fabrication, the biobricks approach is having increasing impact [ ] . perhaps most famous for its student genetic engineering competition , the biobricks approach of utilizing a library of well-characterized, interconnectable parts is powerful. just as early circuit designers benefited from standards for circuit fabrication, design, interfaces and modules, aspects of biology are amenable to these approaches. not only does the approach provide validation of reductionist concepts of each ''brick,'' but the innovative integration of parts also contributes to the characterization and future sharing of more complicated parts. just as circuit designers can incorporate existing designs or entire functional units like memory or analog to digital conversion, biologists are increasingly able to import others' designs and achieve significantly more functionality. for instance, a rewritable digital memory system has been demonstrated that writes and rewrites nucleic acid bases in a chromosome [ ] . just as dna sequencing brought a methods-based structure to pathogen detection, approaches like biobricks bring structure to biological circuits. the electronic circuit analogy continues with the opportunity for software to facilitate design and accelerate testing and evaluation. just as in our early example for influenza vaccine development, the components of the biobricks approach are amenable to spiral engineering for both performance and cost. building computer architectures and software that can implement ab initio test and evaluation calculations for infectious disease trials would require significant advances in algorithms, capabilities, and fundamental biochemical data. while exciting progress is being made in these areas, an alternative approach is to consider the network of interactions among fundamental building blocks and identify correlations with disease and health. this is the domain of systems biology and the building blocks can include dna, rna, and peptides. progress in systems biology is often paced by access to appropriately curated and calibrated datavnot just the underlying nucleic acid content but the associated metadata that describe the host and the relevant associated microbial communities. one of the multiple approaches to address data needed is the hundred person wellness project of the institute for systems biology. this project is measuring multiple indicators of health over a nine month period and will include lifestyle coaching as part of the study [ ] . if successful, the project already has plans to scale to a thousand and then thousand participants. there are similar concepts underway at organizations as diverse as google x and human longevity. even though these studies do not focus on infectious diseases, they are of significant value in helping to define the baselines for ''normal'' at different ages, genders, and many other variations that may affect health. infectious disease is a global issue that remains a significant cause of death and economic impact. engineers and engineering have many opportunities to help mitigate these diseases ranging from using cell tower power to help deliver vaccines to providing new network analysis software to identify novel viruses in an outbreak. the joint evolution of engineering and life sciences brings expanded availability and opportunity to understand and design living systems. these are attributes that will be needed to address the medical and infrastructure needs for effective global infectious disease management. however, the zeal to innovate needs to be mediated by a culture of responsibility [ ] where the benefits and the risks are considered. the ieee code of conduct [ ] is consistent with this ethos and addresses quality of life and privacy topics that have been discussed in this paper. engineers have an opportunity to provide innovative application of existing infrastructure to infectious disease management and to help nurture a global culture of responsibility in both healthcare and technical 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and burden of disease attributable to selected major risks global agricultural report: sustainable pathways to sufficient nutritious and affordable food climate and infectious disease: use of remote sensing for detection of vibrio cholerae by indirect measurement prediction of a rift valley fever outbreak power from cellphone towers keeps vaccines cool outbreak detection algorithms for seasonal disease data: a case study using ross river virus disease. bmc medical informatics and decision making an epidemiological network model for disease outbreak detection evaluation of animal and public health surveillance systems: a systematic review. epidemiology infection report to congress: update on the adoption of health information technology and related efforts to facilitate the electronic use and exchange of health information the office of the national coordinator for health information technology, food and drug administration and federal communications commission building safer systems for better care global infectious disease surveillance and health intelligence: the development of effective, interconnected systems of infectious disease surveillance is essential to our survival nyc health alert network putting public health into practice: a model for assessing the relationship between local health departments and practicing physicians ( s ), pp. s -s interpreting the universal phylogenetic tree genomic engineering: moving beyond dna sequence to function the rise of a digital immune system. gigascience department of health and human services oie world organization for animal health a virus in a fungus in a plant: three-way symbiosis required for thermal tolerance endogenous viral elements in animal genomes human microbiota human microbiome project present and future global distributions of the marine cyanobacteria prochlorococcus and synechococcus marine virusesvmajor players in the global ecosystem interactive metagenomic visualization in a web browser whole-genome sequencing expected to revolutionize outbreak investigations. food safety news genomic surveillance elucidates ebola virus origin and transmission during the outbreak the who ebola response teamonline. ebola virus disease in west africavthe first months of the epidemic and forward projections rewrittable digital data storage in live cells via engineered control of recombination directionality medicine gets up close and personal guidance for enhancing personnel reliability and strengthening the culture of responsibility the author thanks dr. k. bernard for his suggestion to consider the broader utility of pandemic influenza plans to other diseases, dr. n. bergman for his valuable suggestions and comments, and ms. c. conrad for her expert assistance preparing the manuscript. key: cord- -uvozcpmh authors: siddiquee, shafiquzzaman title: the basic concept of microbiology date: - - journal: practical handbook of the biology and molecular diversity of trichoderma species from tropical regions doi: . / - - - - _ sha: doc_id: cord_uid: uvozcpmh aseptic technique is a method that involves target-specific practices and procedures under suitably controlled conditions to reduce the contamination from microbes. it is a compulsory laboratory skill to conduct research related in the field of microbiology. mycologist/microbiologists must follow aseptic techniques for multiplicity procedures such as screening of isolates/strains, pure cultures, slant cultures, single spore cultures, microbes transferring cultures, inoculating media, and conducting several microbiological experiments. proper aseptic technique has prevented the cultures contamination from inborn and outborn microbes in the environment. as example, airborne microbes (e.g., fungi) handpicked from the surveyor’s health, the lab benchtop, unsterilized glassware and equipment, dust, and other areas, thus interfering to get proper experiment results. using the proper aseptic technique can significantly reduce/minimize the risk of contamination. that are properly handled and kept in the laboratory. personnel working with transferable agents are acquainted with hazards that require the proper training and skillful practices for handling such materials. all laboratories are required to develop a biosafety or operations manual that categorizes the hazards that may be met, and that specifies the proper practices and techniques to reduce/or minimize the hazard exposures. a microbiologist/scientist, and knowledgeable laboratory techniques, safety procedures, and hazards associated with handling transferrable agents will accountable for the comportment of research with infectious agents or materials. the proper design and work structures, safety equipment, and controlling practices should enhance the laboratory personnel and safety practices. cliffe ( ) has mentioned that many biosafety levels (bsls) have been developed for laboratories to enhance the protection levels of environment and staff. bsls have standard guidelines that described the proper containment equipment, services, and procedures for apply by laboratory researchers/scientists/technicians/ students. the bsls are categorized into bsl to bsl , and the risk associated with every bsl increases with the infectious microbes encountered. bsl practices are mostly followed by clinical microbiology laboratories. when conducting works with high transmissible agents, the risk of aerosol transmission is so high, so microbiology laboratories must follow bsl practices. in biosafety level (bsl- ) denotes a fundamental level of containment that be contingent on standard microbiology practices with never requiring any special primary or secondary barriers recommendation, other than washing hand. bsl- practices are appropriate to teaching, diagnostic, clinical, and other laboratories in which work has conducted wide-range of indigenous moderate-risk agents that are available in the community and allied with human disease. the objective of this chapter is to provide the proper hand-on practices in microbiology laboratory to teachers, students, researchers, scientists, and technicians and also ensure the studies proceed safely and succeed the successfully of educational standard. good microbiological laboratory practices (e.g., aseptic technique) when handling microorganisms have prevented contamination of the workplace from other microorganisms or nontarget microorganisms. they supplement the containment facilities, procedures and processes to reduce the spread of microorganism contamination and prevent the exposure of people and the environment to the microorganisms that are being deliberately manipulated either by accident or once work has finished. the principles of gmlp summarized below should be adopted when working with microorganisms, so it should be declaim in conjunction with the guidance on containment. principles of good microbiological practices (chosewood and wilson ) . never uses any pipette substance by mouth. in laboratory always avoid contact hand to mouth or hand to eye. in the laboratory, never drink, eat, apply cosmetics, lip balm, handle contact lenses and taken medication. . aseptic techniques properly use. right way wash your hand after removing gloves, other personnel protective equipment (ppe), handling potentially infectious agents or materials and exiting of laboratory. . centers for disease control and prevention (cdc)/national institutes of health (nih) biosafety in microbiological and biomedical laboratories (bmbl) have recommends that laboratory personnel must be protected their streetwear clothing from contamination by wearing appropriate attire (e.g., gloves, lab shoes or use shoe covers) when conducting works in bsl- laboratory. streetwear clothing and street shoes are not permitted for use in bsl- laboratory; in the lab always preferred to change of streetwear clothes and shoe covers or shoes keen for uses. in bsl- is mandatory changed from streetwear clothes/ shoes to use the permitted laboratory attires and footwear. . once removing the hazardous material in the laboratory, personnel must be followed occupational safety and health act (osha). when infectious agents are handled in laboratories; syringes, and needles or other sharp instru- ments should be restricted. a used needle never repetited. dispose of syringeneedle assemblies in properly labeled, lesion resistant, autoclavable sharps containers. . knob infectious materials as determined by a risk assessment. airborne infectious agents should be controlled by a certified biosafety cabinet (bsc) appropriate to the bsls and risks for the agent. . make sure that engineering controls (e.g., eyewash, bscs, safety showers, and sinks) are properly maintained and inspected. . the contaminated lab ware or materials never leave open to the outside of bsc. all biohazardous materials steadily stored with proper labeled, and sealed containers. . must be displayed all laboratories doors with the recognized biohazard symbol, a list of the infectious agents, access requirements (e.g., ppe) and emergency contact information. . avoid the use of aerosol-producing techniques when working with infectious materials. pipette mixing, needle clipping, centrifugation, and sonication can generate considerable aerosols. . antiseptic traps and inline filters on vacuum lines are used to defend vacuum lines from contamination. . follow the laboratory biosafety design for the infectious materials that are conducting with the accurate decontamination methods to decontaminate the infectious materials. always keep spill kits available in the lab for managing an accidental spill of pathogenic materials. . clean the worktable area with an appropriate disinfectant after conducting work with infectious materials in the laboratory. must not be cluttered the laboratory containment in order to authorize suitable floor and disinfect work area. . without decontaminated or sterilized or autoclaved (temperature ( °c), pressure ( psi), and time ( - min)), never allow to leave unwanted infectious materials or contaminated agents in the laboratory or to be put in the sanitary sewer. . when transferring or shipping infectious materials to other laboratory, always use postal or department of transportation (dot) approved, leak-proof sealed and properly packed containers (primary and secondary containers). be sure the lid is on tight and avoiding the container contamination from the outside. before transporting infectious materials, make sure that the outside of container is decontaminated. ship infectious materials in accordance with federal and local necessities. . all accidents, occurrences, and unexplained illnesses must be reported to lab technician/supervisor and the occupational health physician. . always think safety first priority during laboratory operations. evoke, if you are not clearly apprehend the proper handling and safety procedures or how properly use safety equipment; avoid conducting work with the infectious materials until you get proper instruction or consult the cdc/nih bmbl for further information. (note: remember, the abovesaid principles of good microbiological practices will help and protect you, your fellow worker and the public from the infectious agents you use.) teachers, researchers, scientists, and lab technicians may make practical amendments to the risk assessments model according to their professional judgment based on their proficiencies. the legislation governing hazardous substances and dangerous goods entails that entire procedures and experiments involving hazardous materials must have documentation and minimize exposure. the risk management approach always apply for safety in the laboratory before starting any new research projects or experiments work. conducting risk assessment it should detect potential hazards and control the actions to reduce any risks of personnel health. the spillages cultures are immediately reported to the teacher/researchers or lab technicians for dealt with quickly. spilled cultures and adjacent debris (glass, cotton wool plugs, etc.) must not be touched with unprotected hands/open-handed. must wear disposable gloves and cover the disinfect spill area with several layers of cloth/ towel drenched in a proper disinfectant and leave for at least - min. immediately spill debris cleaned into a container/dustpan using towels. transferring all disposable materials (e.g., roasting bag) into suitable container for autoclaving and disposal. a container must be sterilized or decontaminated by autoclaving or by soaking (at least h) in hypochlorite (sodium chlorate i). the broken glass must be cleaned prudently into proper container, autoclaved and disposed of in a lesion-proof container. the contaminant clothes should be waterlogged in disinfectant. splashes on the skin should be cured as quickly; hot water and soap may be sufficient for washing; if necessary the skin can be disinfected. (continued) clean laboratory coat/apron: protection of clothing, containment of dust on clothing; safety spectacles: not considered essential when dealing with suitable cultures and observing gmlp but may be required by local regulations and for dealing with chemicals. use culture media ingredients stock wide range of culture media in dehydrated form (powder/ tablets) disinfectants decontaminant the surface of workbenches before and after use and spillages; always disposal of the used pipettes and slides. in soap use for hand washing ethanol ( % industrial methylated spirit) autoclave indicator tape changes color in response to heat to distinguish those items that have received heat treatment (although it is not effective sterilization) steriliser control tube/ strip changes color when accurate temperature applied and held for the obligatory length of time to effect sterilization non absorbent cotton wool plugs for test tubes, flasks, and pipettes dealing with spilled cultures . for sterilization of needle/loop, first hold the needle/loop in the flame of the bunsen burner to kill all infecting substances/organisms. . the needle/loop can be made red-hot for a few seconds ( fig. . ). . after flaming, make sure that the needle/loop is slightly cool before taking sample from the inoculum culture (for transferring culture). the neck of bottle/tube is passed through the flame of bunsen burner to create a convection current which forces air out of the bottle/tube. avoid the airborne contaminations from the bottle/tube. heat of the bunsen burner causes the air near by work area to increase, reducing the accidental airborne microbes contaminating cultures. . loosen the cover/cap of the bottles/tubes so it can be removed easily ( fig. . ). . hold the bottle/test tube with left hand. . take out the cover/cap of the bottle/cotton wool plug with little finger of the right hand. . don't put down the cover/cap or cotton wool plug. . flame the bottle/test tube neck (forward and back) through a hot bunsen flame. . the mandatory procedures are always followed, e.g., removing culture, replace the cover/cap on the bottle/cotton wool plug using the little finger (turn the bottle, not the cap). the prepareation of agar media is followed according to manufacturer's instructions. before sterilization, make sure all elements are entirely melted by using microwave oven heat if further required. avoid wastage by preparing only sufficient for either immediately use or use in the near future. usually authorize about • label the tubes/bottles in a place that cannot clean off in handling. use marker pens or self-adhesive labels. • cotton wool plugs may accidentally catch fire. if so, immediate cover with lid or dry cloth, avoid blowing or soaking in water. - cm medium/petri dish. agar slopes are prepared with universal bottles allowing sterile molten media to solidify in a sloped position. . sterile molten agar bottle is used from the incubator at °c. . hold the bottle in the left hand and remove the lid using the right hand little finger. . flame the bottle neck by passing through back and forward of neck. . remove the lid/cover of the petri dish using the right hand and pour around ml of the sterile molten agar into petri dish and replace the lid/cover of the petri dish ( fig. . ). . after that, flame the bottle neck and cover with the lid. . smoothly rotate the petri dish to make sure that the whole media is equally dispersed in the plate. . keep the petri dish for few minutes for solidification. . properly seal the petri dish using parafilm, and incubate in an inverted position. the growth of fungal colonies are transferred into agar slants, in addition, uncertainty found any excess broth in the bottle/tube and agar plates, it should be removed. univerial bottle/tube containing agar should be solid formed that call a agar slant. a needle/loop can be used to inoculate an agar slant by stabbing the needle containing inoculum into the agar (fig. . ) . blue screw-capped bottles of agar and broth should be kept at temperatures of -l °c for months. when reuse the kept agar media, it should be remelt again using hot water or streaming bath or microwave oven or pressure cooker. after completely melted, the molten agar can be kept in incubator at least °c for ready to use or further uses. all stored media should be kept away from light. after pouring agar in the plates, the plate should be sealed with parafilm and put in well-sealed plastic bags, then kept at - °c for further reuse. freshly prepared media are always better than stored media. it is very important to avoid prolong storage times. labile beta-lactam selective agents have very short active lives and the media containing some elements that needed within a few days of preparation. a good laboratory practice always supports the shelf-lives of all media preparations and also postmarks the containers or boxes accordingly. otherwise poor fungal growth results from loss of moisture from agar plates. make sure that all agar plates are incubated in a moist environment. look through the contamination symptom, color changes, irregular filling or bubbles on surface of agar, hemolysis, and symbols of dryness such as cracking, shrinking, and loss of volume. any defective plates or tubes should be removed. specific disinfectants are used for the specific purposes of working strengths. disinfection is defined as the destruction, inhibition, or removal of microorganisms that may cause disease or other difficulties, e.g., spoilage. the use of chemicals also disinfectants occurred. • when making the strength of working solutions from stock with dealing powder form, wear eye protection and gloves to avoid irritant or harmful effects. • the uses of disinfectants at working strength newly made from powder form or stock strength. • the activity of virkon solution may obtain until week or less, e.g., day, after use. the working strength of hypochlorite is prepared on the day. the lid and agar plate can be taped together with - short strips of parafilm as protection from accidently (or unauthorized) opening during incubation agar plates should be seeded with uppermost if not the molten agar can be dripped on the lid and the culture. fungal colonies may cause and spread to each other and the risk of spillage of the contaminated liquid incubators are set up at the specific temperatures and avoid the cultures being interfered with or accidentally discarded. many fungal cultures grow optimally at room temperature ± °c incubators should be locked to prevent breakage disconnected computer and electronic equipment are covered with plastic and transferred to one room topics in safety. the association for science education: promoting excellence in science teaching and learnin biosafety in microbiological and biomedical laboratories th edn. u.s. department of health and human services safety norms and regulations in handling fungal specimens basic practical microbiology: a manual aseptic technique and the transfer of microorganisms . researchers/scientists/technicians must evacuate from the contamined work area, e.g., breakage of culture tubes, etc., the workplace area should be completely decontaminated. . you should follow several steps if a culture tube/plate is broken.(a) all staffs should immediately evacuate the workplace.. (b) proper ppe must be worn from the decontaminated room. (c) the room and cover spill is removed using paper towels properly soaking with % amphyl solution (as disinfectant). before cleaning up the spill, the towels should be left for at least h; after that keep the wet area with amphyl to protect dried particles becoming airborne. emergencies such as explores, hurricanes, and other disasters, its happen normal working environment. the realistic disruptions are commonly occurred as exposures, injuries, spills, equipment failure, electricity power, fire, water loss, or flooding. handling each of these emergencies and disturptions can follow each institutional guidelines. however, keep a written emergency and evacuation guilde line in workplace and talk to all personnel for such circumstances to avoid worker injury or contamination via infectious agents.the microbiology laboratory should take the following steps for emergency: . all doors should be made of wood. . all hitech equipment, refrigerators, and freezers should be provided with emergency electrical outlets or red sockets. key: cord- -i jh bcn authors: zanetti, a. r.; zappa, a. title: emerging and re‐emerging infections at the turn of the millennium date: - - journal: haemophilia doi: . /j. - . . .x sha: doc_id: cord_uid: i jh bcn summary. after world war ii, mankind believed that infectious diseases were on the way to being defeated. unfortunately, they still are the second worldwide cause of death. globalization changes promote the emergence of new infections and pandemics; international deliveries and travelling facilitate the dissemination of infectious agents; man‐induced environmental changes create new opportunities for contacts between species, leading to infections in aberrant hosts, including man; global warming enables insects, a major vector of pathogens, to thrive in more countries. the main pandemics have been caused by viruses, such as hiv and novel subtypes of influenza viruses. in addition, prion proteins are a threat. the transmission of the creutzfeld jakob disease variant through blood transfusion and the recent discovery of prion protein in the spleen of a haemophilia patient are a matter of further concern. the end of the war against infectious diseases is not in sight. mankind’s battle with pathogens has lasted millennia and is destined to continue. throughout history man has periodically been the victim of epidemics: we have historical reports that vividly report these calamities, such as 'the plague of justininan' [ ] dating back to the roman empire, 'the black death' in the middle ages [ ] , the 'spanish flu' in [ ] , the emergence of acquired immunodeficiency syndrome (aids) in the early s and the more recent severe acute respiratory syndrome (sars) at the beginning of the xxi century [ ] . after world war ii, the extensive knowledge on infectious agents and their hosts, environmental factors involved in their transmission, improvements in hygiene, healthcare and socioeconomic status and, last but not least, the discovery of effective antimicrobial therapy and the availability of vaccines, lulled man into believing that 'the war against infectious diseases had been won' and that epidemics were a phenomenon of the past [ , ] . nothing could have been further from the truth. at the beginning of the third millennium, infectious diseases still are the second cause of death in the world (the first in developing countries). fifteen million humans die every year of infectious diseases, the five 'big killers' being aids, tuberculosis, malaria, respiratory infections and infantile diarrhoea [ , ] . in the last decades, a number of new pathogens responsible for emerging infectious diseases, such as avian and swine flu, aids, sars, west nile, ebola and variant of creutzfeldt-jacob disease (vcjd) have been identified and other infectious diseases are re-emerging after a period of quiescence, such as malaria and tuberculosis caused by multidrug resistant strains [ , , , , ] . the picture is compounded by the so-called 'deliberately emerging' pathogens, such as anthrax and smallpox -biological weapons that humans might plan to spread deliberately as an act of bioterrorism [ , , ] . in the world of globalization, regular exchanges of enormous amounts of goods throughout the world and low-cost frequent travelling, whereby hundred thousands of people move from one side of the earth to the other within a matter of hours, facilitate the dissemination of infectious agents (microbial traffic). infectious diseases that once upon a time would have remained confined to their ecological niche can now potentially spread rapidly to every corner of the earth before preventive measures can be implemented [ , ] . what is more, a number of other factors promote not only the dissemination but also the emergence of new infectious diseases: intensive farming and breeding associated with crowding promote the development of foci of infection; global warming has modified the climate, making insects, a major vector of pathogens, able to thrive in countries where the climate was previously hostile; the exploitation of natural resources has produced environmental changes that create opportunities for new contacts between species leading to emergence of infections in new hosts. the ability of an infectious agent to mutate and to jump the barrier species from animals to humans contributes to the emergence of zoonotic diseases. indeed, most of the outbreaks in the last years have been caused by infectious agents normally hosted by wild animals (reservoir hosts). following the loss of their normal habitat (e.g., climate changes, ecological changes in land use), these animals can move closer to farms where they infect livestock (spillover hosts). in parts of the world characterized by crowding and low hygiene standards, the livestock then infect man. in some cases, man results to be a 'dead-end' host (aberrant host), who does not transmit the infection any further. for instance, in the s, an unexplained epidemic of acute cardiopulmonary syndrome occurred unexpectedly in a navajo tribe living on the border of the four corners region (new mexico, arizona, colorado, utah) of the southern-western united states [ ] . this potentially deadly disease caused by an unknown virus (sin nombre virus or 'nameless virus') subsequently identified as a member of the hantavirus genus (bunyaviridae family) is transmitted from mice to humans by inhalation of aerosolized virus-contaminated rodent excreta (saliva, urine, droppings). during the navajo outbreaks, the wet and mild conditions as a result of changes in climate caused by el niñ o favoured an abundance of mice food allowing a significant increase in the deer mouse population (peromyscus mariculatus), the natural reservoir of this virus [ ] . the migration of infected rodents near human settlements created the ideal conditions for the outbreak onset. the deforestation that occurred in australia and malaysia in the late s forced fruit bats (flying foxes), the reservoir of nipah and hendra viruses (henipavirus genus, paramyxoviridae family), to move closer to human dwellings creating the conditions for the emergence of focal outbreaks of encephalitis with high fatality rate in humans [ ] . in this case, viruses were transmitted from bats to livestock animals (pigs and horses) and from these to humans. in other cases, however, zoonotic transmission is followed by viral adaptation to the new host that makes human-to-human transmission feasible. this is the case of several mutated viruses [ , , ] . most of the emerging infections are caused by viruses, which, according to nobel prize winner peter medawar, are 'bad news inside a protein envelope'. the 'bad' news consists of strands of dna or rna that are able to penetrate mammalian cells, obliging them to reproduce the viral components instead of their own. the bad news can get even worse as viruses adapt continually to the environment by mutation, recombination or gene reassortment [ , ] . the two key features of intracellular replication and genetic evolution make viral infections particularly difficult to combat: currently available anti-viral agents block viral replication by various mechanisms, but hardly remove dormant viruses that have already penetrated inside host cells and the protection conferred by vaccination can be made fruitless by genetic evolution of the pathogen, which may enable it to escape previously induced immunity. an example that shows why zoonotic transmission must be avoided is the infection by hiv. its natural reservoir is a non-human primate, called pan troglodytes troglodytes, in which it is fairly harmless. man became probably infected through contacts with infected blood during hunting and slaughtering processes ('bush meat', hunter's cut) about - years ago [ ] . the infection remained confined to areas of africa up to about years ago when international travelling and exchanges became more widespread. infected subjects moved from africa to haiti; from there, the infection then spread, as a result of sex tourism, first to gay communities in cities of north america (los angeles, san francisco, new york) and then to europe. at first, it spread in high-risk groups, such as male homosexuals, intravenous drug abusers and recipients of multiple transfusions; then, it extended to the general population. the outcome is the current pandemic: in , who estimated that million adults and children were living with hiv infection/aids worldwide, that more than million people have died of the disease so far and that the number of deaths in the last year amounted to million [ ] . another well known example of recent worldwide pandemic is the sars. this emerging airborne viral disease had a great impact on account of its rapid international spread under favourable conditions created by our highly mobile, closely interconnected world. the origin of sars was in areas of dense population in southern china, where humans and animals are packed side by side providing ideal conditions for a new virus to emerge by jumping across species. the natural reservoir of sars virus (sars-cov) is the horseshoe bat, the spillover host is the masked palm civet or raccoon dog; man is an aberrant host [ ] . the pandemic originated in guangdong, in southern china, where families often cohabit with the animals they rear. the promiscuity enabled the sars-cov to skip across species and find a new host -man. it has been documented how the first identified infected human (index case) unintentionally infected another humans in the metropole hotel in hong kong, who then travelled to five different countries (germany, canada, thailand, vietnam and singapore), giving rise to new foci of infection. this ultimately led to a worldwide epidemic affecting more than people, with a death rate of . % [ ] . this event showed how modern transport systems can enable an emerging infection in one part of the earth to spread rapidly throughout the globe. however, it also showed how international healthcare co-operation can achieve control of a rising pandemic within less than a year. however, not all viruses behave this way. some viruses adopt the so called 'hit and run' strategy as they cause recurrent, geographically confined, usually self-limiting outbreaks. this is the case of ebola and marburg viruses, both members of the family filoviridae, causing severe and often fatal haemorrhagic fevers in humans and non-human primates. in , transmission of ebola virus from its natural reservoir, which is still unknown, to man resulted in two simultaneous but separate, explosive outbreaks of human disease caused by two distinct virus subtypes in zaire and sudan with a case-fatality rate of approximately % and % respectively. the disease was self-limited both in space and time: it remained confined to well-defined geographical areas and mysteriously resolved [ ] . since then, recurrent outbreaks have been reported in african countries including sudan, gabon, the democratic republic of congo, republic of congo and uganda. a variant of the african ebola virus, the reston virus, was first identified in in reston, virginia, usa and in in italy (siena) in colonies of cynomolgus macaques imported from the philippines [ ] . despite its high pathogenicity in non-human primates, this virus does not seem to cause disease in humans. the infection by the marburg virus followed a similar course: in , german laboratory workers were infected by african green monkeys belonging to the cercopithecus aethiops species imported from uganda and developed fatal haemorrhagic fever [ , ] . west-nile, dengue and chikungunya viruses: vector-borne throughout the world arthropod-borne viruses are very common (more than ) and more than cause diseases in humans in more than countries world-wide, with a disease burden as high as a hundred million cases every year. ecological factors, such as new routings of long-distance bird migrations and the increased long-distance air travel facilitate the movement of infected persons, livestock and exotic arthropod vectors around the world contributing to the spread of vector-borne diseases from the original niches to new geographical areas. changing in public health policy, insecticide and drug resistance are additional factors which can contribute to the emergence or resurgence of vector-borne infectious diseases [ ] . an example is the west nile virus (wnv) infection, originally confined to africa (along the nile), southern europe, parts of the middle east and india, which has recently modified its epidemiological picture. in , wnv was firstly imported into the new york area and, thanks to the presence of specific vectors (culex mosquito) and natural susceptible hosts (crows, jays), the infection rapidly spread coast to coast. man is a dead-end incidental host: it has now been estimated that - million people have been infected by wnv in north america. west nile (wn) is a potentially serious illness whose symptoms may range from mild to severe. in about % of cases, infection is asymptomatic and asymptomatic carriers may be infectious via blood transfusion or through organ and tissues donations [ ] . in , there were documented cases of wnv transfusion-transmitted infections, which induced the usa blood collection agencies (bcas) to implement blood screening for this virus [ ] . from june to september , several hundred potentially infectious components were identified by the tests. in the last years, outbreaks of wnv have been reported in some european countries both in horses and humans. in september-october , the first two cases of wnv neuroinvasive disease have been reported in northern italy [ ] . to prevent infection through blood donations by infected donors during the viremic peak, screening programmes have been introduced during the seasonal mosquito activity in the affected area. other examples of vector-borne diseases that have extended elsewhere in view of the climate changes and global warming is the re-emergence of dengue virus (dv) infection transmitted by aedes aegypti mosquito in tropical and subtropical countries. the susceptibility of aedes albopictus also known as 'tiger' mosquito (a mosquito of asian origin currently widespread in countries with a temperate climate) to serve as a new vector of dv gives new opportunities to the virus to extend its area of spread. the tiger mosquito which is the vector of chikungunya virus (chikv), a virus that caused several epidemics in africa, southeast asia, the western pacific and india, was first introduced in italy in the early s by importing used tyres. in , the chikv transmitted by this mosquito caused the first autochthonous epidemic outbreak in europe, in the north-east of italy (emilia romagna region) which involved more than cases [ , ] . this prompted the national blood centre and regional health authorities to take specific precautionary measures to ensure the safety of blood supply. influenza a is an airborne virus that repeatedly produces epidemics every year during the cold season. its hosts include birds (natural reservoir) and a number of mammals, including whales, seals, horses, pigs and man. it is particularly able to adapt to new hosts, thanks to its unique capacity for genetic variation: its surface proteins are able to mutate up to % of their amino acid sequence without losing their capacity to infect mammalian cells and its genome is made of eight rna segments that are genetically independent and that can therefore randomly reassort, forming antigenically novel subtypes [ ] . such novel strains have caused a number of dangerous pandemics in the past, such as the spanish flu in , asian flu in and hong-kong flu in . currently, avian flu is a real threat caused by mutated strain h n , which continues to spread in humans. the cumulative number of human cases of avian influenza h n reported by who by august amounted to cases and deaths [ ] . the issue is whether this virus or other avian viruses (h n , h n ) will cause a novel pandemic or not [ ] . to cause a pandemic, three characteristics are required: (i) the ability of the virus to replicate in a human host, (ii) the population has to be susceptible to it, and (iii) human-to-human transmission has to be possible. at present, for h n , the first two features are satisfied, but not the third. however, it cannot be excluded that it will develop the third feature in the future. on the contrary, human-to-human transmission has been proven for the novel swine flu caused by the influenza a (h n ) virus (s-oiv) isolated for the first time in march-april in mexico [ ] . this novel strain is a cause for concern as it has resulted from the unique reassortment of genetic elements of influenza viruses that normally infect three different kinds of host -swine, birds and human beings. the study of its structure has revealed that it differs considerably from its predecessors, isolated in human beings: its h antigen, which enables it to bind and infect cells of different species, has changed in terms of amino acid sequence alignment by approximately % and its n antigen, which enables it to digest sialic acids (neuraminidase activity), ensuring better access and spread in the organism, has changed by about %. this means that exposure to its predecessors may not provide any immunity to this unique strain and the whole population on earth is theoretically at risk [ ] . indeed, in april , who declared a phase- alert indicating that a pandemic was imminent and that it was urgent to finalize the organization, communication and implementation of the pandemic preparedness plans. on june , who then announced the beginning of a flu pandemic with a total of cases worldwide and deaths. only one month later, on july , , who reported that the number of infections had increased up to nearly with deaths. laboratory-confirmed cases as officially reported to who as of august amount to with deaths. given that countries are no longer to test and report individuals, we can estimate that the number of cases reported actually understates the true number of cases. at the time of writing (mid-august ), who considers the pandemic to be moderate. the speed at which the infection is spreading is such that infection of millions of people worldwide is considered to be inevitable. however, symptoms are mild and most people recover from the infection without the need for hospitalization or medical care. the rate of severe infections is currently similar to what is generally seen during local seasonal influenza. however, monitoring is essential as it is not possible to predict how the pandemic will evolve. h n might disappear spontaneously, cause a mild pandemic or a severe pandemic after virus mutation/re-assortment. concerning blood transfusions, the risk of direct transmission of influenza via blood or blood products is extremely low. the major issue will be a temporary loss of blood donors during the pandemic peak, with impact on blood supply, as donors may not attend blood collection services on account of illness. an atypical infectious agent is the prion protein, a conformational variant of a naturally occurring protein that cannot be removed by normal degradation processes and accumulates forming fibrous aggregates that are believed to be involved in the pathogenesis of the disease [ ] . the new prion disease that emerged in man in the uk in was a food-borne infection caused by modern intensive meat production based on 'industrial cannibalization': a prion disease that has been known to affect sheep and goats for more than years (scrapies) had been transmitted to cattle via inadequately sterilized fodder of animal origin, giving rise to an epidemic of bovine spongiform encephalopathy (bse), also called 'mad cow disease', which in turn was then transmitted to man via meat consumption. prion-infected humans develop a variant of classic sporadic creutzfeld-jakob disease (vcjd), an invariably fatal neurodegenerative disease. it is not known what proportion of prion-infected humans develop symptomatic disease. also, the mean latency period from prion infection to the development of overt disease remains unknown. over the period - , a total of cases were reported, nearly all in the uk and attributed to dietary exposure. possible transmission of vcjd by blood transfusion has been documented in the uk [ ] . the emergence of prion disease has led to a reduction in the number of donors as people with a history of visiting the uk during the cattle bse epidemic are excluded. recently, the prion protein has been found in the spleen during the postmortem examination of a year-old patient suffering from haemophilia who died of causes unrelated to vcjd. indeed, this patient did not have any neurological symptoms before death [ ] . of some concern is the fact that in , this patient received a batch of factor viii manufactured using plasma from a donor who developed symptoms of vcjv months after donation. although the mode of transmission has not been confirmed, the uk health protection agency together with the haemophilia centre doctor's organization alerted haemophiliacs about this finding. a related alert had been made a few years earlier: in patients with bleeding disorders who had been treated with plasma-derivatives made with blood collected in uk between and were told that they were potentially at risk of vcjd and excluded from donating organs. however, although patients exposed to contaminated products in the past may be at risk for vcjd, this does not mean that currently available plasma-derived products (manufactured with uk free plasma) still carry such risk. [ ] . an important treatment option for patients with bleeding disorder is the administration of recombinant factors viii, which is not derived from plasma and undergoes several processing steps to remove any contaminating viruses and prions [ ] . the development of new antimicrobial drugs and antibiotics together with the availability of safe and effective vaccines led to a spirit of optimism towards the definitive control and prevention of several infectious diseases. man may have won some battles against infectious diseases, but the war is still raging and the end is not in sight. in general, there is no way to predict when or where the next pathogens will emerge. emerging and resurging diseases are common in areas rich in wild animals and where natural and social environmental factors, including man's activities, increase the opportunities for the pathogens to extend their ecological niches and to be transferred to and from humans and other animals. the continual emerging of new infectious agents and re-emerging of drug resistant strains of old ones are issues with far reaching consequences. infectious diseases have always been present in society and are destined to remain part of human life in the future. emerging and re-emerging infections plague: the dreadful visitation occupying the human mind for centuries the challenge of emerging and re-emerging infectious diseases the influenza pandemic world health organization. severe acute respiratory syndrome (sars) changing patterns of infectious disease infectious diseases: considerations for the st century report: the global burden of disease: update social and environmental risk factors in the emergence of infectious diseases from pasteur to genomics: progress and challenges in infectious diseases geography, ecology and emerging infectious diseases infectious diseases update: outbreak, hantavirus infection -southwestern united states hantavirus cardiopulmonary syndrome hendra and nipah viruses: different and dangerous global trends in emerging infectious diseases molecular constraints to interspecies transmission of viral pathogens the origins of acquired immune deficiency syndrome viruses: where and when a review of studies on animai reservoirs of the sars coronavirus world health organization. cumulative number of reported probable cases of severe acute respiratory syndrome (sars) viral haemorrhagic fever in southern sudan and northern zaire: preliminary studies on the aetiological agent world health organization. ebola haemorrhagic fever in imported monkeys marburg virus ecology of marburg and ebola viruses: speculations and directions for future research response to imported case of marburg hemorrhagic fever, the netherlands resurgent vector-borne diseases as a global health problem transmission of wet nile virus through blood transfusion-united states update: 'detection of west nile virus in blood donations -united states west nile virus in italy: a further threat to blood safety, a further challenge to blood system infection with chikungunya virus in italy: an outbreak in a temperate region the chikungunya epidemic in italy and its repercussion on the blood system influenza virus: a master of metamorphosis world health organization. cumulative number of confirmed human cases of avian influenza a/(h n ) reported to who avian influenza virus (h n ): a threat to human health outbreak of swine-origin influenza a (hinl) virus infection -mexico towards a sane and rational approach to management of influenza h n transmissible spongiform encephalopathies: the story of a pathogenic protein possible transmission of variant creutzfeldt-jacob disease by blood transfusion preclinical vcjd after blood transfusion in a prnp codon heterozygous patient signs of variant creutzfeldt-jakob disease in a patient with hemophilia: fviii concentrates most likely cause pathogen safety of manufacturing processes for biological products: special emphasis on kogenate bayer the authors stated that they had no interests which might be perceived as posing a conflict or bias. key: cord- -uazc lyg authors: hedrick, stephen m. title: the imperative to vaccinate date: - - journal: the journal of pediatrics doi: . /j.jpeds. . . sha: doc_id: cord_uid: uazc lyg nan stephen m. hedrick, phd the disease legacy of civilization h uman beings are almost certainly the most diseased species on earth. by one accounting, there are at least human pathogens, including bacteria, fungi, prions, protozoa, viruses, and worms, and of these, - appear capable of causing human epidemics. , even this is likely to be an underestimate, as new and sensitive sequencing techniques continue to uncover new viruses at a steady rate. we human beings are remarkable in many ways, but why are we remarkable for playing host to so many infectious agents? why is it that we must maintain high levels of vaccine coverage to prevent infectious agents from sickening or even killing large swaths of the population? the answers lie in the story of human disease epidemics, and it begins with human cultural and technological ascendance and what we now understand to be its inevitable consequences for pestilence and death. it is about our ingenuity, which has caused the retreat of many infectious diseases, but highlights a central tension in human existence-immediate self-interest vs long-term collective welfare. the concept is not just academic; there are realworld implications that we can resolve with an understanding of human disease ecology. the notion is that we are not only culturally connected or genetically connected through a common ancestry. rather, there is another fundamental concept that is, perhaps, not widely accepted or even understood. we are biologically connected, in the present, through our exchange of infectious agents and our common susceptibility to disease. to understand modern human disease prevalence, we have only to look to the most basic principles of epidemiology. a simplified version is that diffuse or small host populations cannot sustain an acutely infectious agent, meaning one in which infection is followed by clearance and long-term immunity. as the number of people with immunity increases, the density of susceptible hosts decreases, and with the corresponding decline in transmission, the infectious agent is not maintained in the population. this principle described our preagricultural ancestors-a few thousand individuals congregated in groups but spread out over an enormous area. small or low-density populations can only sustain a certain type of infectious agent, one that persists, usually for the life of the host. , once infected with herpes viruses, such as herpes simplex virus, cytomegalovirus, or epstein-barr virus, we are infected for life, and such viruses have infected us since even before we became human beings. [ ] [ ] [ ] [ ] to some extent, this was the primordial state of disease in diffuse bands of preagricultural hunter-gathers: persistent viruses, bacteria (eg, mycobacterium tuberculosis), intestinal protozoa, worms, and fleas. our paleolithic ancestors were not disease-free, but they almost certainly did not experience periodic and devastating epidemics. , conversely, large populations that live at high density, such as modern human beings, can sustain a much greater diversity of infectious agents, including those that the immune system is able to clear. transmission from person to person is rapid enough and continuous, such that there is little selective pressure for persistence. large and dense urban populations can maintain acutely infectious agents indefinitely due to a constant source of newly susceptible hosts in the form of immigration or births. these agents often share an ability to be transmitted by casual contact such as respiratory droplets produced by a cough or a sneeze, and as evidence of the success of this pathogen strategy, there are more than different viruses from at least different virus families (adenovirus, coronaviruses, influenza virus, parainfluenza virus, respiratory syncytial virus, and rhinovirus) that cause "cold" symptoms: sneezing, coughing, and runny nose. the dawn of agriculture and the domestication of animals, especially herd animals, allowed the emergence of permanent human settlements and the growth of large situated communities. the world's population increased approximately -fold from the beginning of the agricultural revolution to the end of the th century, and most importantly, settlements eventually grew into a huge massing of humanity. simultaneously, we domesticated animals and ourselves, and we sampled all of the viruses and bacteria existing in cows, horses, pigs, sheep, goats, and birds. those that could replicate in human beings and spread from person to person by respiratory propulsion (or other means, such as fecal-oral) became established evermore in the human population. this is the answer to why we are the most diseased species on earth. we are the only species to so profoundly and rapidly change the way in which we interact with each other and other animals; in other words, we invented for ourselves an entirely new ecosystem. so, in addition to the endless parade of cold viruses that circulate among us, we acquired a great many deadly infectious agents, such as those that cause diphtheria, influenza, measles, meningitis, mumps, plague, rubella, smallpox, typhus, whooping cough, and others. each disease has its own history and severity, but all rely on large, high-density populations for continued propagation. these newly acquired infectious agents not only caused severe or deadly disease, they shaped the population. many are known as childhood diseases because they infect susceptible children who either recover from the disease and retain immunity or die. in a population in which a disease like measles existed, everyone contracted the virus exactly once, such that almost all surviving adults were immune. what does the world look like in the face of measles? from to , before the availability of a vaccine, an average of cases of measles were reported each year in the us, along with an average of measles-related deaths, encephalitis cases (often with permanent brain damage), and respiratory complications. the measles vaccine was licensed in and the measles, mumps, rubella (mmr) vaccine was licensed in . for the years between and , the number dropped to cases of measles in children younger than years of age; died, contracted encephalitis, and contracted pneumonia. since , there has been less than case per million population in the us. the global burden of measles in was an estimated deaths that were reduced through a world-wide vaccination campaign to an estimated deaths in . those who survive measles without lasting effects still have worries. one is that measles infection depresses the immune system for up to years, making children more susceptible to other infections, and a second is the possibility of developing subacute sclerosing panencephalitis, a usually fatal neurologic degenerative disease caused by reactivation of latent measles virus. the assessed risk is on the order of in measles cases and as much as -fold greater for children who contract measles before the age of months. for children who are immunocompromised, such as those being treated for leukemia, an actual measles infection is severe, extended, and often fatal. although measles is possibly the world's most infectious human virus, it was not the most devastating of the childhood infectious diseases. the smallpox death toll for just the th century has been estimated at upwards of million people, similar to the entire population of the present-day us. smallpox caused more deaths than all the wars in history. for centuries before vaccination, most urban families could count on losing multiple children to smallpox, diphtheria, scarlet fever, or whooping cough. with widespread vaccination, combined with targeted vaccination to insulate the last few cases, smallpox was eliminated as an infectious disease on earth. smallpox eradication was our first and thus far only complete victory over a human disease-causing agent, made possible by universal, global vaccination, and intensive surveillance. after tortuous millennia of epidemic disease and hundreds of millions dead, who would argue that this was not a most wonderful gift given by humankind to itself? but that gift was not without cost, and the cost was a tincture of personal independence and the acknowledgement that each of us is inextricably tied to the entire human community. it took the idea of community out of the realm of philosophy and placed it as a fundamental property of life. smallpox eradication itself was a physical enactment of the tension between personal freedom and the authority of society. in on liberty, in chapter iv, john stuart mill asks, "what then is the rightful limit to the sovereignty of the individual over himself? where does the authority of society begin? how much of human life should be assigned to individuality, and how much to society?" mill's inquiries can be answered by biology, but first consider the concept of community protection (often referred to as "herd immunity"). as the density of susceptible (unvaccinated or disease naïve) hosts declines, so does the incidence of disease. below a certain threshold, the incidence of disease (frequency of new infections), even in unimmunized people, approaches zero. this is community protection, and it follows directly from basic epidemiology. vaccination effectively reduces the number and density of the disease-susceptible people, making acutely infectious agents unsustainable in the population. conversely, because vaccine protection is sometimes imperfect, a vaccinated individual living within a diseasesusceptible population is at substantial risk. the risk of disease for any individual is thus most importantly dependent on the collective immunity of the population, especially those most susceptible to infection, usually the youngest children and oldest adults. in this regard, disease ecology does not equivocate; in the world as it exists today, our health and our very being depend on the immune status of the rest of humanity. the rightful limit to the sovereignty of the individual over him or herself stops at the boundary of disease immunity. as long as one case of smallpox could be found on earth, billions were at risk. even without considering the imperative of contagious disease, mill came to the same conclusion, "as soon as any part of a person's conduct affects prejudicially the interests of others, society has jurisdiction over it. . .." two centuries before on liberty and before the enlightenment, this was expressed after a fashion in john donne's meditation xvii, "now this bell tolling softly for another, says to me, thou must die," written while he was convalescing from a near-fatal disease, possibly typhus. although this meditation was ostensibly concerned with god as the author of every person and every death, we might equally apply it in a way that donne could not-we are each of a network, a medium for disease that transcends us as individuals. the death of one of us portends many more. we can rage against this injustice, but it is literally a fact of life. in this context, the famous line from meditation is relevant, "no man is an island, entire of itself." community protection is a fundamental concept with no strict definition. the threshold is sharp but varies with each infectious agent. it protects vaccinated and unvaccinated people alike. it is the most powerful force in disease prevention but exists only in the immunity status of the entire population network. considering the difficulty of this concept, it is no wonder that as a society and as a people we do not have a consensus the journal of pediatrics • www.jpeds.com volume • october concerning the responsibility of individuals to vaccinate their children. one way to understand vaccination decisions is as an exercise in game theory played out over the entire human population of the earth. in this case, each individual is defined narrowly in economic terms, acting as if he or she balances costs against benefits to maximize personal advantage. if most everyone cooperates (vaccinates), then everyone enjoys the benefits of being disease free. in contrast, the decision to cooperate may be perceived to have a cost, and individuals looking to maximize personal advantage will choose noncooperation at a certain probability. when no one is vaccinated and everyone is in danger, that probability is close to zero-everyone is incentivized to vaccinate or risk the possibility of deadly disease. this must have been the dominant sentiment in the time of smallpox. as universal vaccination is approached, danger diminishes with or without vaccination, and the probability of noncooperation increases. for measles, the threshold for community protection is calculated to be . %, that is, when . % of the population has received doses of mmr vaccine, the community is protected from disease. under such conditions, some parents may decide not to vaccinate and thus avoid even very rare adverse effects. the consequence of this is that the rate of vaccination drops below the threshold, and the community is no longer protected. in other words, as we proceed toward elimination of a disease by vaccination, as we are for poliomyelitis, the invisible hand of the market pulls defeat from the jaws of victory. from this reasoning, elimination of a disease on a purely voluntary basis has been proposed to be unlikely, and the thought is that compliance to protect the population or eradicate a disease can only be achieved by a mandatory vaccination policy. in the western hemisphere, we have all but eliminated measles and rubella, in one sense moving us backward in time to the pre-columbian rarity of acutely infectious diseases. however, should we lapse in our vaccination vigilance, within one generation we could replay the disease devastation of the th century that included death of more than one-half of the native inhabitants of the western hemisphere. we are part of, what watts and strogatz called, a small-world network -with no more than degrees of separation connecting the entire + billion human beings on earth. like the spread of middle east respiratory syndrome from the middle east to korea, we can consummate those connections, wherever they may be, with a day's travel. a glimpse of a future with poor vaccine adherence occurred not too long ago, with an outbreak of measles originating in anaheim, california. the infecting person (patient zero) almost certainly arrived from abroad, but most of the infected individuals were unvaccinated us residents. the decline in mmr vaccination compliance began with a medical report in the journal lancet. andrew wakefield and colleagues published an analysis of children claiming to show a connection between mmr vaccination and the onset of a newly described "pervasive developmental disorder" that they summarized as a "chronic enterocolitis in children that may be related to neuropsychiatric disorder." at face value, this is a tiny sample size with no controls. it linked common conditions with mmr vaccination based on parent's recollections. multiple large studies subsequently showed no such association, and the paper was retracted by of the authors and by the journal after a prolonged study by the general medical council in the united kingdom; however, it was not just a case of flawed science, it turned out to be fraud driven by avarice. in articles published by the british medical journal, the investigative journalist brian deer revealed how wakefield had been hired to attack the mmr vaccine by a lawyer, richard barr. wakefield and colleagues were paid to contrive the existence of a syndrome, he initially called, "autistic enterocolitis" for the express purpose of bringing a class action lawsuit against vaccine manufacturers; this occurred before initiation of the disgraced study. another apparent moneymaking scheme was ironically to market vaccines. in a press conference given after the publication of his lancet paper, wakefield said he could not support the triple mmr vaccination and called for vaccination to each disease separately. he had previously patented a single measles vaccine. the british general medical council revoked his license to practice medicine, and he was asked to leave the royal free hospital in london. the wakefield study has no basis in reality, but its publication corresponded to a substantial drop in mmr coverage in the united kingdom, europe, and the us. in response, some countries or states within the us have made vaccination a mandatory condition for entrance into schools. for example, california senate bill no. , signed into law june , requires vaccination for all children attending any public or private elementary or secondary school, childcare center, day nursery, nursery school, family daycare home, or development center. exemptions for described medical conditions are permitted, but those based on personal or religious beliefs were to be phased out. because california requires vaccination records for all schools, the effects of the bill could be tracked-and the effects were dramatic. in , more than % of school children lived in california counties with vaccination rates less than %, and % of children lived in counties with less than a % vaccination rate. interestingly, the counties with the lowest rates of vaccination were of types, rural counties largely located in the most northern part of the state and counties that include the tony urban communities surrounding san francisco and los angeles. by , more than % of children were from counties with greater than % vaccination. nonetheless, the law only requires vaccination records for students as they enter each grade span (kindergarten, seventh grade, etc), and it recognizes personal exemptions previously on file. as such, there are still schools in which a single case of measles could spark a local epidemic. contrast the vaccination rate in california, where comprehensive vaccination is required to attend school, with that of oregon, where exclusions based on personal beliefs are allowed with only a requirement for completing an informational module online. the proportion of the population in oregon counties with kindergarten vaccination rates greater than % has gone from almost % in to just % as of . in addition to community health, the notion of not vaccinating seems to deny short-term self-interest. even with a low disease incidence brought about by community protection, pertussis vaccination is a small price to pay for the prevention of whooping cough. beyond that, universal vaccination protects children with immunodeficiencies that arise either from congenital or acquired conditions and their treatments. it can eliminate a disease from the world for all time, saving all future generations, but at what cost? what is the safety of vaccination? each vaccine from each manufacturer is reviewed by the food and drug administration for safety before licensing, and after licensing, the centers for disease control and prevention and food and drug administration maintain a nationwide monitoring system, the vaccine adverse event reporting system, a signal detection system to identify rare events not found in prelicensing reviews. the program allows anyone to report an adverse reaction online, by fax, or by mail. the centers for disease control and prevention also operates the vaccine safety datalink in conjunction with us care organizations that track data from more than million people. these data provide the means to monitor the safety of current and recently introduced vaccines nearly in real-time as they are administered to people across the country. the data from the vaccine safety datalink are used to devise the vaccine regime for children and assess the frequency of complications as they arise. there also exists a national vaccine injury compensation program (vicp), run by the health resources and services administration. this program receives reports of adverse vaccine reactions, studies each claim, and makes of determinations: ( ) an adverse reaction occurred "more likely than not"; ( ) the individual is compensated, although the panel does not concede that there occurred a vaccine-related adverse reaction; and ( ) the case is adjudicated by a court within the us court of federal claims. because the vicp is the only avenue for vaccine-related compensation in this country, the number of filed cases is one measure of the number of adverse reactions severe enough to incite a claim. for the years of through , there were approximately . billion vaccine doses distributed in the us. the total number of cases brought before the vicp was , and the number ultimately compensated was . that is, about in a million vaccine doses was associated with some sort of adverse reaction severe enough to bring a patient to the vicp. importantly, this is but an average for all vaccines and all groups of people, but it highlights the overall rarity of vaccine-associated, severe adverse events. considering the benefit to the individual and to society, this would seem to be a reasonable risk. aside from sober risk assessment, sticking an infant with a needle to induce an immune reaction might feel unnatural. but it isn't so. the immune system is naturally engaged and constantly fighting many potential infections on a continuous basis. for example, in people with an acquired immunodeficiency, such as those low numbers of t lymphocytes, previously benign bacteria, fungi, and viruses become deadly: cytomegalovirus, candida, pneumocystis carinii (now pneumocystis jirovecii), toxoplasma, and other environmental agents can cause sickness or death. regardless of the presence of actual disease-causing agents, without the constant activity of our immune system, we perish. another concern is that multiple vaccinations might "overload" the immune system, causing children to be more susceptible to unvaccinated diseases. however, in a study of nonvaccine-targeted infections recorded from emergency department visits, there was no significant correlation with the number of vaccines given to children - months of age. medical studies are difficult to evaluate, even for professionals. the wisdom of one moment is often replaced in the next. a reasonable course of action with respect to new clinical findings is to wait and act conservatively. however, we now have a century's worth of experience in vaccinating billions of people. we have witnessed the regression or elimination of many infectious diseases in the face of vaccination. and we have studied the short-and long-term effects of vaccination. this is now established science. we can work to make vaccines even safer and more effective, but we cannot as a society regress to some past era in which we count hundreds of thousands of measles or polio cases per year. infectious diseases are a major, and almost certainly permanent, part of human existence. the growth of civilization with the addition of animal domestication made the appearance of epidemic diseases inevitable, but human inventiveness has allowed us to find countermeasures that relieve at least some of our collective misery. furthermore, the experience of humankind over the past several millennia has shown that we have no choice; our place in the network of hosts susceptible to human pathogens gives lie to our notions of complete personal independence. even the most atavistic society would not choose for their children a path of immune naiveté (at least not for long). perhaps this is an instructive irony. it takes deadly infectious diseases to see that we are all of a one species, biologically connected, and isolated on earth. ■ submitted for publication jan , ; last revision received jun , ; accepted jun , risk factors for human disease emergence ecological origins of novel human pathogens search strategy has influenced the discovery rate of human viruses the meaning of human existence network structure and the biology of populations measles endemicity in insular populations: critical community size and its evolutionary implication epidemiology meets evolutionary ecology molecular phylogeny and evolutionary timescale for the family of mammalian herpesviruses epstein-barr virus infection review of cytomegalovirus seroprevalence and demographic characteristics associated with infection evolutionary origins of human herpes simplex viruses and infectious diseases in primitive societies genomics, the origins of agriculture, and our changing microbe-scape: time to revisit some old tales and tell some new ones the common cold plagues and peoples historical comparisons of morbidity and mortality for vaccine-preventable diseases in the united states vaccines. long-term measles-induced immunomodulation increases overall childhood infectious disease mortality subacute sclerosing panencephalitis: the devastating measles complication that might be more common than previously estimated human immunology of measles virus infection smallpox and its eradication. geneva: world health organization vaccination and herd immunity to infectious diseases why does measles persist in europe vaccination and the theory of games : new revelations of the americas before collective dynamics of 'small-world' networks measles outbreak linked to disney theme parks reaches five states and mexico wakefield's "autistic enterocolitis" under the microscope how the case against the mmr vaccine was fixed after a debacle, how california became a role model on measles vaccination rate jumps in california after tougher inoculation law safety monitoring in the vaccine adverse event reporting system (vaers) the vaccine safety datalink: successes and challenges monitoring vaccine safety opportunistic infections in patients with and patients without acquired immunodeficiency syndrome association between estimated cumulative vaccine antigen exposure through the first months of life and non-vaccine-targeted infections from through months of age key: cord- -zhmnfd w authors: straif-bourgeois, susanne; ratard, raoult title: infectious disease epidemiology date: journal: handbook of epidemiology doi: . / - - - - _ sha: doc_id: cord_uid: zhmnfd w the following chapter intends to give the reader an overview of the current field of applied infectious disease epidemiology. prevention of disease by breaking the chain of transmission has traditionally been the main purpose of infectious disease epidemiology. while this goal remains the same, the picture of infectious diseases is changing. new pathogens are identified and already known disease agents are changing their behavior. the world population is aging; more people develop underlying disease conditions and are therefore more susceptible to certain infectious diseases or have long term sequelae after being infected. the following chapter intends to give the reader an overview of the current field of applied infectious disease epidemiology. prevention of disease by breaking the chain of transmission has traditionally been the main purpose of infectious disease epidemiology. while this goal remains the same, the picture of infectious diseases is changing. new pathogens are identified and already known disease agents are changing their behavior. the world population is aging; more people develop underlying disease conditions and are therefore more susceptible to certain infectious diseases or have long term sequelae after being infected. infectious diseases are not restricted to certain geographic areas anymore because of the increasing numbers of world travelers and a worldwide food distribution. the fear of a bioterrorist attack adds a new dimension in infectious disease epidemiology, and health departments enhance their surveillance systems for early detection of suspicious disease clusters and for agents used as weapons of mass destruction. improvements in laboratory techniques and mapping tools help to expand the knowledge of transmission of disease agents and enhanced surveillance techniques are feasible as a result of software progress and reporting of diseases via secure internet sites. surveillance and outbreak investigations remain the major responsibilities in public health departments. epidemiologic methods and principles are still the basis for these tasks but surveillance techniques and outbreak investigation are changing and adapting to improvements and the expanded knowledge. conducting surveys is a useful way to gather information on diseases where surveillance data or other data sources are not available, especially when dealing with emerging or re-emerging pathogens. program evaluation is an important tool to systematically evaluate the effectiveness of intervention or prevention programs for infectious diseases. infectious diseases are a major cause of human suffering in terms of both morbidity and mortality. in , out of an estimated total of million deaths, million were due to infectious diseases (who a,b) . the most common cause of infectious disease deaths were pneumonia ( million), diarrhea ( million) followed by tuberculosis, malaria, aids and hepatitis b. not surprisingly, there is a large imbalance in diseases between developing and industrialized countries (see table . ). morbidity due to infectious diseases is very common in spite of the progress accomplished in recent decades. even in industrialized countries, the prevalence of infection is very high for some infectious agents. serologic surveys found that by young adulthood the prevalence of antibodies was % against herpes simplex virus type , - % against type , % against human herpes virus, % against hepatitis a, % against hepatitis c, - % against hepatitis b, and % against chlamydia pneumoniae (american academy of pediatrics ; mandell et al. ) . annually, approximately , , episodes of diarrhea leading to , hospitalizations and deaths occur among adults in the united states (mounts et al. ). the center for disease control and prevention (cdc) estimates that each year million people in the us get sick, more than , are hospitalized and die as a result of foodborne illnesses (cdc ) . every year influenza circulates widely, infecting from % to % of the world population. the importance of infectious disease epidemiology for prevention it is often said that epidemiology is the basic science of preventive medicine. to prevent diseases it is important to understand the causative agents, risk factors and circumstances that lead to a specific disease. this is even more important for infectious disease prevention, since simple interventions may break the chain of transmission. preventing cardiovascular diseases or cancer is much more difficult because it usually requires multiple long term interventions requiring lifestyle changes and behavior modification, which are difficult to achieve. in , the american commission of yellow fever, headed by walter reed, was sent to cuba. the commission showed that the infective agent was transmitted by the mosquito aedes aegypti. this information was used by the then surgeon general of the us army william gorgas, to clean up the year old focus of yellow fever in havana by using mosquito proofing or oiling of the larval habitat, dusting houses with pyrethrum powder and isolating suspects under a mosquito net. this rapidly reduced the number of cases in havana from in to in (goodwin ) . a complete understanding of the causative agent and transmission is always useful but not absolutely necessary. the most famous example is that of john snow who was able to link cholera transmission to water contamination during the london cholera epidemic of by comparing the deaths from those households served by the southwark & vauxhall company versus those served by another water company. john snow further confirmed his hypothesis by the experiment of removing the broad street pump handle (wills a ). over the past three decades, more than new pathogens have been identified, some of them with global importance: bartonella henselae, borrelia burgdorferi, campylobacter, cryptosporidium, cyclospora, ebola virus, escherichia coli :h , ehrlichia, hantaan virus, helicobacter, hendra virus, hepatitis c and e, hiv, human herpesvirus and , human metapneumovirus, legionella, new variant creutzfeldt-jakob disease agent, nipah virus, parvovirus b , rotavirus, severe acute respiratory syndrome (sars) etc.. while there are specific causative agents for infectious diseases, these agents may undergo some changes over time. the last major outbreak of pneumonic plague in the world occurred in manchuria in . this scourge, which had decimated humans for centuries, is no longer a major threat. the plague bacillus cannot survive long outside its animal host (humans, rodents, fleas) because it lost the ability to complete the krebs cycle on its own. while it can only survive in its hosts, the plague bacillus also destroys its hosts rapidly. as long as susceptible hosts were abundant, plague did prosper. when environmental conditions became less favorable (lesser opportunities to sustain the host to host cycles), less virulent strains had a selective advantage (wills b) . the influenza virus is the best example of an agent able to undergo changes leading to renewed ability to infect populations that had been already infected and immune. the influenza virus is a single stranded rna virus with a lipophilic envelope. two important glycoproteins from the envelope are the hemagglutinin (ha) and neuraminidase (na). the ha protein is able to agglutinate red blood cells (hence its name). this protein is important as it is a major antigen for eliciting neutralizing antibodies. antigenic drift is a minor change in surface antigens that result from point mutations in a gene segment. antigenic drift may result in epidemics, since incomplete protection remains from past exposures to similar viruses. antigenic shift is a major change in one or both surface antigens (h and|or n) that occurs at varying intervals. antigenic shifts are probably due to genetic recombination (an exchange of a gene segment) between influenza a viruses, usually those that affect humans and birds. an antigenic shift may result in a worldwide pandemic if the virus can be efficiently transmitted from person to person. in the past three decades throughout the world, there has been a shift towards an increase in the population of individuals at high risk for infectious diseases. in industrialized nations, the increase in longevity leads to higher proportion of the elderly population who are more prone to acquiring infectious diseases and developing life threatening complications. for example, a west nile virus (wnv) infection is usually asymptomatic or causes a mild illness (west nile fever); rarely does it cause a severe neuro-invasive disease. in the epidemic of west nile in louisiana, the incidence of neuro-invasive disease increased progressively from . per , in the to age group to per , in the to year old age group and jumped to per , in the age group and older. mortality rates showed the same pattern, a gradual increase to . per , in the to age group with a sudden jump to per , for the oldest age group of and older. improvement in health care in industrialized nations has caused an increase in the number of immune-deficient individuals, be it cancer survivors, transplant patients or people on immuno-suppressive drugs for long term auto-immune diseases. some of the conditions that may increase susceptibility to infectious diseases are: cancers, particularly patients on chemo or radiotherapy, leukemia, lymphoma, hodgkin's disease, immune suppression (hiv infection), long term steroid use, liver disease, hemochromatosis, diabetes, alcoholism, chronic kidney disease and dialysis patients. for example persons with liver disease are times more likely to develop vibrio vulnificus infections than are persons without liver disease. some of these infections may be severe, leading to death. in developing countries a major shift in population susceptibility is associated with the high prevalence of immune deficiencies due to hiv infections and aids. in botswana which has a high prevalence of hiv (sentinel surveillance revealed hiv seroprevalence rates of % among women presenting for routine antenatal care), tuberculosis rates increased from per , in to per , in (lockman et al. ) while before the hiv|aids epidemics, rates above were very rare. changes in lifestyles have increased opportunities for the transmission of infectious disease agents in populations previously at low risk. intravascular drug injections have increased the transmission of agents present in blood and body fluids (e.g. hiv, hepatitis b and c). consumption of raw fish, shell fish and ethnic food expanded the area of distribution of some parasitic diseases. air travel allows people to be infected in a country and be half-way around the globe before becoming contagious. by the same token, insects and other vectors have become opportunistic global travelers. aedes albopictus, the asian tiger mosquito, was thus imported in to houston, texas inside japanese tires. subsequently, it has invaded us states. with the advent of nucleic acid tests, it has become possible to detect the presence of infectious disease agents in the air and environmental surfaces. for example, the use of air samplers and polymerase chain reaction analysis has shown that bordetella pertussis dna can be found in the air surrounding patients with b. pertussis infection, providing further evidence of airborne spread (aintablian et al. ) and thus leading to re-evaluate the precautions to be taken. however the presence of nucleic acids in an environmental medium does not automatically mean that transmission will occur. further studies are necessary to determine the significance of such findings. infectious disease agents, when used in bioterrorism events, have often been reengineered to have different physical properties and are used in quantities not usually experienced in natural events. there is little experience and knowledge about the human body's response to large doses of an infectious agent inhaled in aerosol particles that are able to be inhaled deep into lung alveolae. during the anthrax letter event, there was considerable discussion about incubation period, recommended duration of prophylaxis, and minimum infectious dose. this lack of knowledge base has led to confusion in recommendations being made. although the basics of infectious disease epidemiology have not changed and the discipline remains strongly anchored on some basic principles, technological developments such as improved laboratory methods and enhanced use of informatics (such as advanced mapping tools, web based reporting systems and statistical analytical software) have greatly expanded the field of infectious disease epidemiology. molecular techniques are being used more and more as a means to analyze epidemiological relationships between microorganisms. hence the term molecular epidemiology refers to epidemiologic research studies made at the molecular level. the main microbial techniques used, target plasmids and chromosomes. more specifically, plasmid fingerprinting and plasmid restriction endonuclease (rea) digestion, chromosomal analysis including pulse field gel electrophoresis (pfge), restriction fragment length polymorphism (rflp), multi-locus sequence type (mlst) and spa typing to name a few of these techniques. polymerase chain reaction (pcr) is used to amplify the quantity of genomic material present in the specimen. real-time pcr detection of infectious agents is now possible in a few hours. these techniques are becoming more widely used, even in public health laboratories for routine investigations. it is beyond the scope of this text to describe these methods in more detail. applications of molecular epidemiology methods have completely changed the knowledge about infectious disease transmission for many microorganisms. the main application is within outbreak investigations. being able to characterize the nucleic acid of the microorganisms permits an understanding of how the different cases relate to each other. molecular epidemiology methods have clarified the controversy about the origin of tuberculosis cases: is it an endogenous (reactivation) or exogenous (reinfection) origin? endogenous origin postulates that mycobacterium tuberculosis can remain alive in the human host for a lifetime and can start multiplying and producing lesions. on the other hand exogenous origin theory postulates that reinfection plays a role in the development of tuberculosis. the immunity provided by the initial infection is not strong enough to prevent another exposure to mycobacterium tuberculosis and a new infection leads to disease. in countries with low tuberculosis transmission, for example the netherlands, most strains have unique rflp fingerprints. each infection is unique and there are hardly any clusters of infections resulting from a common source. most cases are the result of reactivation. this is in contrast with areas of high endemicity where long chains of transmission can be identified with few rflp fingerprinting patterns (alland et al. ) . in some areas, up to % of tuberculosis cases are the result of reinfection. numerous new immunoassays have been developed. they depend on an antigenantibody reaction, either using a test antibody to detect an antigen in the patient's specimen or using a test antigen to detect an antibody in the patient's specimen. an indicator system is used to show that the reaction has taken place and to quantify the amount of patient antigen or antibody. the indicator can be a radioactive molecule (radioimmunoassay [ria]), a fluorescent molecule (fluorescent immunoassay [fia]), a molecule with an attached enzyme that catalyzes a color reaction (enzyme-linked immunoassay [elisa or eia]), or a particle coated with antigen or antibody that produces an agglutination (latex particle agglutination [la] ). the reaction can be a simple antigen|antibody reaction or a "sandwich" immunoassay where the antigen is "captured" and a second "read out" antibody attaches to the captured antigen. the antibody used may be polyclonal (i.e. a mixture of immunoglobulin molecules secreted against a specific antigen, each recognizing a different epitope) or monoclonal (i.e. immunoglobulin molecules of single-epitope specificity that are secreted by a clone of b cells). it may be directed against an antigen on an epitope (i.e. a particular site within a macromolecule to which a specific antibody binds). plotting diseases on a map is one of the very basic methods epidemiologists do routinely. as early as john snow, suspecting water as a cause of cholera, plotted the cases of cholera in the districts of golden square, st. james and berwick, in london. the cases seemed to be centered around the broad street pump and less dense around other pumps. the map supplemented by other observations led to the experiment of removing the handle on the broad street pump and subsequent confirmation of his hypothesis (snow ) . geographical information systems (gis) have been a very useful tool in infectious disease research. gis are software programs allowing for integration of a data bank with spatial information. the mapping component includes physical layout of the land, towns, buildings, roads, administrative boundaries, zip codes etc. data may be linked to specific locations in the physical maps or to specific aggregates. a gis system includes tools for spatial analysis. climate, vegetation and other data may be obtained through remote sensing and combined with epidemiologic data to predict vector occurrence. however, these tools should be used with caution. they can be useful to generate hypotheses and identify possible associations between risk of disease and environmental exposures. because of potential bias, mapping should never be considered as more than an initial step in the investigation of an association. "the bright color palettes tend to silence a statistical conscience about fortuitous differences in the raw data" (boelaert et al. ) . for statistical methods in geographical epidemiology see chap. ii. of this handbook. web based reporting, use of computer programs and developments of sophisticated reporting and analytical software have revolutionized epidemiologic data collection and analysis. these tools have provided the ability to collect large amounts of data and handle large databases. however this has not been without risks. it remains crucial to understand the intricacies of data collected to avoid misinterpretation. for example, one should be aware that diseases and syndromes are initially coded by a person who may not be very software proficient, using shortcuts and otherwise could enter data of poor quality. what are the questions to be answered? too often one sees epidemiologists and statisticians preparing questionnaires, carrying out surveys, gathering surveillance information, processing data and producing reports, tables, charts and graphs in a routine fashion. epidemiology describes the distribution of health outcomes and determinants for a purpose. it is important to question the goals and objectives of all epidemiologic activities and tailor these activities to meet these objectives. the description of disease patterns includes analysis of demographic, geographical, social, seasonal and other risk factors. age groups to be used differ depending on the disease e.g. diseases affecting young children should have numerous age groups among children; sexually transmitted diseases require detailed age groups in late adolescence and early adulthood. younger age groups may be lumped together for diseases affecting mainly the elderly. gender categorization, while important for sexually transmitted diseases and other diseases with a large gender gap (such as tuberculosis), may not be important for numerous other diseases. geographical distribution is important to describe diseases linked to environmental conditions but may not be so useful for other diseases. surveillance, both active and passive, is the systematic collection of data pertaining to the occurrence of specific diseases, the analysis and interpretation of these data, and the dissemination of consolidated and processed information to contributors to the program and other interested persons (cdc b). in a passive surveillance system the surveillance agency has devised and put a system in place. after the placement, the recipient waits for the provider of care to report. passive case detection has been used for mortality and morbidity data for decades. it is almost universal. most countries have an epidemiology section in the health department that is charged with centralizing the data in a national disease surveillance system collecting mortality and morbidity data. in theory, a passive surveillance system provides a thorough coverage through space and time and gives a thorough representation of the situation. practically, compliance with reporting is often irregular and incomplete. in fact, the main flaws in passive case detection are incomplete reporting and inconsistencies in case definitions. the main advantages are the low cost of such a program and the sustained collection of data over decades. the purpose is to produce routine descriptive data on communicable diseases, generate hypotheses and prompt more elaborate epidemiologic studies designed to evaluate prevention activities. some conditions must be met to maximize compliance with reporting: . make reporting easy: provide easy to consult lists of reportable diseases, provide pre-stamped cards for reporting, provide telephone or fax reporting facilities. . do not require extensive information: name, age, sex, residence, diagnosis. some diseases may include data on exposure, symptoms, method of diagnosis etc. . maintain confidentiality and assure reporters that confidentiality will be respected. . convince reporters that reporting is essential: provide feedback; show how the data are used for better prevention. confidentiality of data is essential, particularly for those reporting health care providers who are subject to very strict confidentiality laws. any suspicion of failure of maintaining secure data would rapidly ruin a passive surveillance program. in an active surveillance system, the recipient will actually take some action to identify the cases. in an active surveillance program, the public health agency organizes a system by searching for cases or maintaining a periodic contact with providers. regular contacting boosts the compliance of the providers. providers are health agencies but also as in passive case detection, there may be day care centers, schools, long term care facilities, summer camps, resorts, and even public involvement. the agency takes the step to contact the health providers (all of them or a carefully selected sample) and requests reports from them at regular intervals. thus no reports are missing. active surveillance has several advantages: it allows the collection of more information. a provider sees that the recipient agency is more committed to surveillance and is therefore more willing to invest more time her|himself. it allows direct communication and opportunities to clarify definitions or any other problems that may have arisen. active surveillance provides much better, more uniform data than passive case detection but active case detection is much more expensive (see tables . and . ). active surveillance systems are usually designed when a passive system is deemed insufficient to accomplish the goals of disease monitoring. this type of surveillance is reserved for special programs, usually when it is important to identify every single case of a disease. active surveillance is implemented in the final phases of an eradication program: smallpox eradication, poliomyelitis eradication, guinea worm eradication and malaria eradication in some countries. active surveillance is also the best approach in epidemic or outbreak investigations to elicit all cases. in the smallpox eradication program, survey agents visited providers, asking about suspected cases and actually investigating each suspected case. in polio eradication programs, all cases of acute flaccid paralysis are investigated. in malaria eradication programs and some malaria control programs, malaria control agents go from house to house asking who has fever or had fever recently (in the past week or month for example). a blood smear is collected from those with fever. a case register is a complete list of all the cases of a particular disease in a definite area over a certain time period. registers are used to collect data on infections over long periods of time. registers should be population based, detailed and complete. a register will show an unduplicated count of cases. they are especially useful for long term diseases, diseases that may relapse or recur and diseases for which the same cases will consult several providers and therefore would be reported on more than one occasion. case registers contain identifiers, locating information, disease, treatment, outcome and follow-up information as well as contact management information. they are an excellent source of information for epidemiologic studies. in disease control, case registers are indispensable tools for follow up of chronic infections disease such as tuberculosis and leprosy. the contents and quality of a case register determine its usefulness. it should contain patient identifiers with names (all names), age, sex, place and date of birth, complete address with directions on how to reach the patient, name and address of a "stable" relative that knows the patient's whereabouts, diagnosis information with disease classification, brief clinical description (short categories are better than detailed descriptions), degree of infectiousness (bacteriological, serological results), circumstances of detection, initial treatment and response with specific dose, notes on compliance, side effects, clinical response, follow-up information with clinical response, treatment regimen, compliance, side effects, locating information; for some diseases contact information is also useful. updating a register is a difficult task. it requires cooperation from numerous persons. care must be taken to maintain the quality of data. it is important to only request pertinent information for program evaluation or information that would remind users to collect data or to perform an exam. for example, if compliance is often a neglected issue, include a question on compliance. further details concerning the use of registries in general are given in chap. i. of this handbook. sentinel disease surveillance for sentinel disease surveillance, only a sample of health providers is used. the sample is selected according to the objectives of the surveillance program. providers most likely to serve the population affected by the infection are selected, for example child health clinics and pediatricians should be selected for surveillance of childhood diseases. a sentinel system allows cost reduction and is combined with active surveillance. a typical surveillance program for influenza infections includes a selected numbers of general practitioners who are called every week to obtain the number of cases presented to them. this program may include the collection of samples for viral cultures or other diagnostic techniques. such a level of surveillance would be impossible to maintain on the national level. surveillance systems are evaluated on the following considerations (cdc b): usefulness: some surveillance systems are routine programs that collect data and publish results; however it appears that they have no useful purpose -no conclusions are reached, no recommendations are made. a successful surveillance system would provide information used for preventive purposes. sensitivity or the ability to identify every single case of disease is particularly important for outbreak investigations and eradication programs. predictive value positive (pvp) is the proportion of reported cases that actually have the health-related event under surveillance. low pvp values mean that non-cases might be investigated, outbreaks may be exaggerated or pseudo outbreaks may even be investigated. misclassification of cases may corrupt the etiologic investigations and lead to erroneous conclusions. unnecessary interventions and undue concern in the population under surveillance may result. representativeness ensures that the occurrence and distribution of cases accurately represent the real situation in the population. simplicity is essential to gain acceptance, particularly when relying on outside sources for reporting. flexibility is necessary to adapt to changes in epidemiologic patterns, laboratory methodology, operating conditions, funding or reporting sources. data quality is evaluated by the data completeness (blank or unknown variable values) and validity of data recorded (cf. chap. i. of this handbook). acceptability is shown in the participation of providers in the system. timeliness is more important in surveillance of epidemics. stability refers to the reliability (i.e., the ability to collect, manage and provide data properly without failure) and availability (the ability to be operational when it is needed) of the public health surveillance system. the major elements of a surveillance system as summarized by who are: mortality registration, morbidity reporting, epidemic reporting, laboratory investigations, individual case investigations, epidemic field investigations, surveys, animal reservoir and vector distribution studies, biologics and drug utilization, knowledge of the population and the environment. traditional surveillance methods rely on counting deaths and cases of diseases. however, these data represent only a small part of the global picture of infectious disease problems. mortality registration was one of the first elements of surveillance implemented. the earliest quantitative data available on infectious disease is about mortality. the evolution of tuberculosis in the us for example, can only be traced through its mortality. mortality data are influenced by the occurrence of disease but also by the availability and efficacy of treatment. thus mortality cannot always be used to evaluate the trend of disease occurrence. reporting of infectious diseases is one of the most common requirements around the world. a list of notifiable diseases is established on a national or regional level. the numbers of conditions vary; it ranges usually from to conditions. in general, a law requires that health facility staff, particularly physicians and laboratories, report these conditions with guaranteed confidentiality. it is also useful to have other non-health related entities report suspected communicable diseases such as day care centers, schools, restaurants, long term care facilities, summer camps and resorts. regulations on mandatory reporting are often difficult to enforce. voluntary compliance by the institution's personnel is necessary. reporting may be done in writing, by phone or electronically in the most advanced system. since most infectious diseases are confirmed by a laboratory test, reporting by the laboratory may be more reliable. the advantage of laboratory reporting is the ability to computerize the reporting system. computer programs may be set up to automatically report a defined set of tests and results. for some infectious diseases, only clinical diagnoses are made. these syndromes may be the consequences of a large number of different microorganisms for which laboratory confirmation is impractical. when public or physician attention is directed at a specific disease, reporting may be biased. when there is an epidemic or when the press focuses on a particular disease, patients are more prone to look for medical care and physicians are more likely to report. reporting rates were evaluated in several studies. in the us, studies show report rates of % for viral hepatitis, hemophilus influenzae %, meningococcal meningitis % and shigellosis %. it is important to have a standardized set of definitions available to providers. without standardized definitions, a surveillance system may be counting different entities from one provider to another. the variability may be such that the epidemiologic information obtained is meaningless. most case definitions in infectious disease epidemiology are based on laboratory tests, however some clinical syndromes such as toxic shock syndrome do not have confirmatory laboratory tests. most case definitions include a brief clinical description useful to differentiate active disease from colonization or asymptomatic infection. some diseases are diagnosed based on epidemiologic data. as a result many case definitions for childhood vaccine preventable diseases and foodborne diseases include epidemiologic criteria (e.g., exposure to probable or confirmed cases of disease or to a point source of infection). in some instances, the anatomic site of infection may be important; for example, respiratory diphtheria is notifiable, whereas cutaneous diphtheria is not (cdc ) . cases are classified as a confirmed case, a probable or a suspected case. an epidemiologically linked case is a case in which ) the patient has had contact with one or more persons who either have|had the disease or have been exposed to a point source of infection (including confirmed cases) and ) transmission of the agent by the usual modes is plausible. a case may be considered epidemiologically linked to a laboratory-confirmed case if at least one case in the chain of transmission is laboratory confirmed. probable cases have specified laboratory results that are consistent with the diagnosis yet do not meet the criteria for laboratory confirmation. suspected cases are usually cases missing some important information in order to be classified as a probable or confirmed case. case definitions are not diagnoses. the usefulness of public health surveillance data depends on its uniformity, simplicity and timeliness. case definitions establish uniform criteria for disease reporting and should not be used as the sole criteria for establishing clinical diagnoses, determining the standard of care necessary for a particular patient, setting guidelines for quality assurance, or providing standards for reimbursement. use of additional clinical, epidemiological and laboratory data may enable a physician to diagnose a disease even though the formal surveillance case definition may not be met. surveillance programs collect data on the overt cases diagnosed by the health care system. however these cases may not be the most important links in the chain of transmission. cases reported are only the tip of the iceberg. they may not at all be representative of the true endemicity of an infectious disease. there is a continuous process leading to an infectious disease: exposed, colonized, incubating, sick, clinical form, convalescing, cured. even among those who have overt disease there are several disease stages that may not be included in a surveillance system: some have symptoms but do not seek medical attention some do get medical attention but do not get diagnosed or get misdiagnosed some get diagnosed but do not get reported cases reported cases diagnosed but not reported cases who seek medical attention but were not diagnosed cases who were symptomatic but did not seek medical attention cases who were not symptomatic infectious disease cases play different roles in the epidemiology of an infectious disease; some individuals are the indicators (most symptomatic), some are the reservoir of microorganisms (usually asymptomatic, not very sick), some are amplifiers (responsible for most of the transmission), some are the victims (those who develop severe long term complications). depending on the specific disease and the purpose of the surveillance program, different disease stages should be reported. for example in a program to prevent rabies in humans exposure to a suspect rabid animal (usually a bite) needs to be reported. at the stage where the case is a suspect, prevention will no longer be effective. for bioterrorism events, reporting of suspects is of paramount importance to minimize consequences. waiting for confirmation causes too long of a delay. in the time necessary to confirm cases, opportunities to prevent co-infections may be lost and secondary cases may already be incubating, depending on the transmissibility of the disease. surveillance for west nile viral infections best rests on the reporting of neuroinvasive disease. case reports of neuro invasive diseases are a better indicator than west nile infection or west nile fever cases that are often benign, go undiagnosed and are reported haphazardly. for gonorrhea, young males are the indicators because of the intensity of symptoms. young females are the main reservoir because of the high proportion of asymptomatic infections. females of reproductive age are the victims because of pelvic invasive disease (pid) and sterility. a surveillance program for hepatitis b that only would include symptomatic cases of hepatitis b could be misleading. a country with high transmission of hepatitis b from mother to children would have a large proportion of infected newborn becoming asymptomatic carriers and a major source of infection during their lifetime. typically in countries with poor reporting of symptomatic hepatitis, the reporting of acute cases of hepatitis b would be extremely low in spite of high endemicity which would result in high rates of chronic hepatitis and hepatic carcinoma. most morbidity reporting collects data about individual cases. reporting of individual cases includes demographic and risk factor data which are analyzed for descriptive epidemiology and for implementation of preventive actions. for example, any investigation leading to contact identification and prophylaxis requires a start from individual cases. however, identification of individuals may be unnecessary and aggregate data sufficient for some specific epidemiologic purposes. monitoring an influenza epidemic for example, can be done with aggregate data. obtaining individual case information would be impractical since it would be too time consuming to collect detailed demographics on such a large number of cases. aggregate data from sentinel sites consists of a number of influenza-like illnesses by age group and the total number of consultants or the total number of 'participants' to be used as denominators. such data is useful to identify trends and determine the extent of the epidemic and geographic distribution. collection of aggregate data of the proportion of school children by age group and sex is a useful predictive tool to identify urinary schistosomiasis endemic areas (lengeler et al. ) without having to collect data on individual school children. epidemics of severe diseases are almost always reported. this is not the case for epidemics of milder diseases such as rashes or diarrheal diseases. many countries do not want to report an outbreak of disease that would cast a negative light on the countries. for example, many countries that are tourism dependent do not report cholera or plague cases. some countries did not report aids cases for a long time. case investigations are usually not undertaken for individual cases unless the disease is of major importance such as hemorrhagic fever, polio, rabies, yellow fever, any disease that has been eradicated and any disease that is usually not endemic in the area. outbreaks or changes in the distribution pattern of infectious diseases should be investigated and these investigations should be compiled in a comprehensive system to detect trends. while the total number of infectious diseases may remain the same, changes may occur in the distribution of cases from sporadic to focal outbreaks. for example the distribution of wnv cases in louisiana shifted from mostly focal outbreaks the first year the west nile virus arrived in the state in , to mostly sporadic cases the following year in (see fig. . ) . surveys are a very commonly used tool in public health, particularly in developing countries where routine surveillance is often inadequate (cf. chap. iv. of this handbook). survey data needs to be part of a comprehensive surveillance database. one will acquire a better picture from one or a series of well constructed surveys than from poorly collected surveillance data. surveys are used in control programs designed to control major endemic diseases: spleen and parasite surveys for malaria, parasite in urine and stools for schistosomiasis, clinical surveys for leprosy or guinea-worm disease and skin test surveys for tuberculosis. surveillance of microbial strains is designed to monitor, through active laboratory based surveillance, the bacterial and viral strains isolated. examples of these systems are: in the us, the pulsenet program is a network of public health laboratories that performs dna fingerprinting of bacteria causing foodborne illnesses (swaminathan et al. ). molecular sub-typing methods must be standardized to allow comparisons of strains and the building of a meaningful data bank. the method used in pulsenet is pulse field gel electrophoresis (pfge). the use of standardized subtyping methods has allowed isolates to be compared from different parts of the country, enabling recognition of nationwide outbreaks attributable to a common source of infection, particularly those in which cases are geographically separated. the us national antimicrobial resistance monitoring system (narms) for enteric bacteria is a collaboration between cdc, participating state and local health departments and the us food and drug administration (fda) to monitor antimicrobial resistance among foodborne enteric bacteria isolated from humans. narms data are also used to provide platforms for additional studies including field investigations and molecular characterization of resistance determinants and to guide efforts to mitigate antimicrobial resistance (cdc ) . monitoring of antimicrobial resistance is routinely done by requiring laboratories to either submit all, or a sample of their bacterial isolates. surveillance for zoonotic diseases should start at the animal level, thus providing early warning for impending increases of diseases in the animal population. rabies surveillance aims at identifying the main species of animals infected in an area, the incidence of disease in the wild animals and the prevalence of infection in the asymptomatic reservoir (bats). this information will guide preventive decisions made when human exposures do occur. malaria control entomologic activities must be guided by surveillance of anopheles population, biting activities, plasmodium infection to biting acivities and plasmodium infection rates in the anopheles population. surveillance for dead birds, infection rates in wild birds, infection in sentinel chickens and horse encephalitis are all part of west nile encephalitis surveillance. these methods provide an early warning system for human infections. the worldwide surveillance for influenza is the best example of the usefulness of monitoring animals prior to spread of infection in the human population. influenza surveillance programs aim to rapidly obtain new circulating strains to make timely recommendations about the composition of the next vaccine. the worldwide surveillance priority is given to the establishment of regular surveillance and investigation of outbreaks of influenza in the most densely populated cities in key locations, particularly in tropical or other regions where urban markets provide opportunities for contacts between humans and live animals (snacken et al. ). the rationale for selecting infectious diseases and an appropriate surveillance method is based on the goal of the preventive program. outbreaks of acute infectious diseases are common and investigations of these outbreaks are an important task for public health professionals, especially epidemiol-ogists. in , a total of foodborne outbreaks with , cases involved were reported in the us (cdc ) with norovirus being the most common confirmed etiologic agent associated with these outbreaks (see table . ). outbreaks or epidemics are defined as the number of disease cases above what is normally expected in the area for a given time period. depending on the disease, it is not always known if the case numbers are really higher than expected and some outbreak investigations can reveal that the reported case numbers did not actually increase. the nature of a disease outbreak depends on a variety of circumstances, most importantly the suspected etiologic agent involved, the disease severity or case fatality rate, population groups affected, media pressure, political inference and investigative progress. there are certain common steps for outbreak investiga-tions as shown in table . . however, the chronology and priorities assigned to each phase of the investigation have to be decided individually, based on the circumstances of the suspected outbreak and information available at the time. another way to detect an increase of cases is if the surveillance system of reportable infectious diseases reveals an unusually high number of people with the same diagnosis over a certain time period at different health care facilities. outbreaks of benign diseases like self-limited diarrhea are often not detected because people are not seeking medical attention and therefore medical services are not aware of them. furthermore, early stages of a disease outbreak are often undetected because single cases are diagnosed sporadically. it is not until a certain threshold is passed, that it becomes clear that these cases are related to each other through a common exposure or secondary transmission. depending on the infectious disease agent, there can be a sharp or a gradual increase of number of cases. it is sometimes difficult to differentiate between sporadic cases and the early phase of an outbreak. in the st. louis encephalitis (sle) outbreak in louisiana, the number of sle cases increased from to between week one and two and then the numbers gradually decreased over the next weeks to a total of cases (jones et al. ) . . after the initial report is received, it is important to collect and document basic information: contact information of persons affected, a good and thorough event description, names and diagnosis of hospitalized persons (and depending on the presumptive diagnosis their underlying conditions and travel history), laboratory test results and other useful information to get a complete picture and to confirm the initial story of the suspected outbreak. it also might be necessary to collect more biological specimens such as food items and stool samples for further laboratory testing. . based on the collected information the decision to investigate must be made. it may not be worthwhile to start an investigation if there are only a few people who fully recovered after a couple of episodes of a self-limited, benign diarrhea. other reasons not to investigate might be that this type of outbreak occurs regularly every summer or that it is only an increase in number of reported cases which are not related to each other. on the other hand, however, there should be no time delay in starting an investigation if there is an opportunity to prevent more cases or the potential to identify a system failure which can be caused, for example, by poor food preparation in a restaurant or poor infection control practices in a hospital or to prevent future outbreaks by acquiring more knowledge of the epidemiology of the agent involved. additional reasons to investigate include the interest of the media, politicians and the public in the disease cluster and the pressure to provide media updates on a regularly basis. another fact to consider is that outbreak investigations are good training opportunities for newly hired epidemiologists. sometimes lack of data and lack of sufficient background information make it difficult to decide early on if there is an outbreak or not. the best approach then is to assume that it is an outbreak until proven otherwise. . prevention of more cases is the most important goal in outbreak investigations and therefore a rapid evaluation of the situation is necessary. if there are precautionary measures to be recommended to minimize the impact of the outbreak and the spread to more persons, they should be implemented before a thorough investigation is completed. most likely control measures implemented by public health professionals in foodborne outbreaks are: recall or destruction of contaminated food items, restriction of infected food handlers from food preparation, correction of any deficiency in food preparation or conservation. . after taking immediate control measures, the next step is to know more about the epidemiology of the suspected agent. the most popular books for public health professionals include the "red book" (american academy of pediatrics ), the "control of communicable diseases manual" from the american public health association (apha ) or other infectious disease epidemiology books as well as the cdc website (www.cdc.gov). if the disease of interest is a reportable disease or a disease where surveillance data are available, baseline incidence rates can be calculated. then a comparison is made to determine if the reported numbers constitute a real increase or not. furthermore, the seasonal and geographical distribution of the disease is important as well as the knowledge of risk factors. many infectious diseases show a seasonal pattern such as rotavirus or neisseria meningitides. for example in suspected outbreaks where cases are associated with raw oyster consumption, the investigator should know that in the us gulf states vibrio cases increase in the summer months because the water conditions are optimal for the growth of the bacteria in water and in seafood. this kind of information will help to determine if the case numbers show a true increase and if it seems likely to be a real outbreak. . for certain diseases, numbers are not important. depending on the severity of the disease, its transmissibility and its natural occurrence, certain diseases should raise a red flag for every health care professional and even a single case should warrant a thorough public health investigation. for example a single confirmed case of a rabid dog in a city (potential dog to dog transmission within a highly populated area), a case of dengue hemorrhagic fever or a presumptive case of smallpox would immediately trigger an outbreak investigation. . sometimes an increase of case numbers is artificial and not due to a real outbreak. in order to differentiate between an artificial and a natural increase in numbers, the following changes have to be taken into consideration: alterations in the surveillance system, a new physician who is interested in the disease and therefore more likely to diagnose or report the disease, a new health officer strengthening the importance of reporting, new procedures in reporting (from paper to web based reporting), enhanced awareness or publicity of a certain disease that might lead to increased laboratory testing, new diagnostic tests, a new laboratory, an increase in susceptible population such as a new summer camp. . it is important to be sure that reported cases of a disease actually have the correct diagnosis and are not misdiagnosed. is there assurance that all the cases have the same diagnosis? is the diagnosis verified and were other differential diagnoses excluded? in order to be correct, epidemiologists have to know the basis for the diagnosis. are laboratory samples sufficient? if not, what kind of specimens should be collected to ascertain the diagnosis? what are the clinical signs and symptoms of the patient? in an outbreak of restaurant associated botulism in canada only the th case was correctly diagnosed. the slow progression of symptoms and misdiagnosis of the dispersed cases made it very difficult to link these cases and identify the source of the outbreak (cdc (cdc , . . the purpose of a case definition is to standardize the identification and counting of the number of cases. the case definition is a standard set of criteria and is not a clinical diagnosis. in most outbreaks the case definition has components of person, place and time, such as the following: persons with symptoms of x and y after eating at the restaurant z between date and date . the case definition should be broad enough to get most of the true cases but not too narrow so that true cases will not be misclassified as controls. a good method is to analyze the data, identify the frequency of symptoms and include symptoms that are more reliable than others. for example, diarrhea and vomiting are more specific than nausea and headache in the case definition of a food related illness. . what kind of information is necessary to be collected? it is sufficient to have a simple database with basic demographic information such as name, age, sex and information for contacting the patient. more often, date of reporting and date of onset of symptoms are also important. depending on the outbreak and the potential exposure or transmission of the agent involved further variables such as school, grade of student or occupation in adults might be interesting and valuable. . during an outbreak investigation it is important to identify additional cases that may not have been known or were not reported. there are several approaches: interview known cases and ask them if they know of any other friends or family members with the same signs or symptoms, obtain a mailing list of frequent customers in an event where a restaurant is involved, set up an active surveillance with physicians or emergency departments, call laboratories and ask for reports of suspected and confirmed cases. another possibility is to review surveillance databases or to establish enhanced surveillance for prospective cases. occasionally it might be worthwhile to include the media for finding additional cases through press releases. however the utility of that technique depends on the outbreak and the etiologic agent; the investigator should always do a benefit risk analysis before involving the media. . after finding additional cases, entering them in the database and organizing them, the investigator should try to get a better understanding of the situation by performing some basic descriptive epidemiology techniques such as sorting the data by time, place and person. for a better visualization of the data, an epidemic or "epi" curve should be graphed. the curve shows the number of cases by date or time of onset of symptoms. this helps to understand the nature and dynamic of the outbreak as well as to get a better understanding of the incubation period if the time of exposure is known. it also helps to determine whether the outbreak had a single exposure and no secondary transmission (single peak) or if there is a continuous source and ongoing transmission. figures . and . show "epi" curves of two different outbreaks: a foodborne outbreak in a school in louisiana, and the number of wnv human cases in louisiana in the outbreak, respectively. sometimes it is useful to plot the cases on a map to get a better idea of the nature and the source of an outbreak. mapping may be useful to track the spread by water (see john snow's cholera map) or by air or even a person to person transmission. if a contaminated food item was the culprit, food distribution routes with new cases identified may be helpful. maps, however, should be taken with caution and carefully interpreted. for example, wnv cases are normally mapped by residency but do not take into account that people might have been exposed or bitten by an infective mosquito far away from where they live. for outbreak investigations, spot maps are usually more useful than rate maps or maps of aggregate data. depending on the outbreak it might be useful to characterize the outbreak by persons' demographics such as age, sex, address and occupation or health status. are the cases at increased susceptibility or at high risk of infection? these kinds of variables might give the investigator a good idea if the exposure is not yet known. for typical foodborne outbreaks however, demographic information is not very useful because the attack rates will be independent of age and sex. more details on methods used in descriptive epidemiology are given in chap. i. of this handbook. . based on the results of basic descriptive epidemiology and the preliminary investigation, some hypotheses should be formulated in order to identify the cause of the outbreak. a hypothesis will be most likely formulated such as "those who attended the luncheon and ate the chicken salad are at greater risk than those who attended and did not eat the chicken salad". it is always easier to find something after knowing what to look for and therefore a hypothesis should be used as a tool. however, the epidemiologist should be flexible enough to change the hypothesis if the data do not support it. if data clues are leading in another direction, the hypothesis should be reformulated such as "those who attended the luncheon and ate the baked chicken are at greater risk than those who attended and did not eat the baked chicken". to verify or deny hypotheses, measures of risk association such as the relative risk (rr) or the odds ratio (or) have to be calculated (as described in chaps. i. , i. , and i. of this handbook). the cdc has developed the software program 'epiinfo' which is easy to use in outbreak investigations, and, even more importantly, free of charge. it can be downloaded from the cdc website (http:||www.cdc.gov|epiinfo|). measures of association, however, should be carefully interpreted; even a highly significant measure of association can not give enough evidence of the real culprit or the contaminated food item. the measure of association is only as good and valid as the data. most people have recall problems when asked what they ate, when they ate and when their symptoms started. even more biases or misclassifications of cases and controls can hide an association. a more confident answer comes usually from the laboratory samples from both human samples and food items served at time of exposure. agents isolated from both food and human samples that are identified as the same subtype, in addition to data results supporting the laboratory findings, are the best evidence beyond reasonable doubt. . as the last step in an outbreak investigation, the epidemiologist writes a final report on the outbreak and communicates the results and recommendations to the public health agency and facilities involved. in the us, public health departments also report foodborne outbreaks electronically to cdc via a secure web based reporting system, the electronic foodborne outbreak reporting system (efors). the "traditional" foodborne outbreak the "traditional" foodborne outbreak is usually a small local event such as family picnic, wedding reception, or other social event and occurs often in a local restaurant or school cafeteria. this type of outbreak is highly local with a high attack rate in the group exposed to the source. because it is immediately apparent to those in the local group such as the group of friends who ate at the restaurant or the students' parents, public health authorities are normally notified early in the outbreak while most of the cases are still symptomatic. epidemiologists can start early on with their investigation and therefore have a much better chance to collect food eaten and stool samples of cases with gastroenteritis for testing and also to detect the etiologic agent in both of them. in a school outbreak in louisiana, eighty-seven persons (sixty-seven students and twenty faculty members) experienced abdominal cramps after eating at the school's annual "turkey day" the day before. stool specimens and the turkey with the gravy were both positive for clostridium perfringens with the same pulse field gel electrophoresis (pfge) pattern (merlos ) . the inspection of the school cafeteria revealed several food handling violations such as storing, cooling and reheating of the food items served. other than illnesses among food handlers, these types of improper food handling or storage are the most common causes of foodborne outbreaks. a different type of outbreak is emerging as the world is getting smaller. in other words persons and food can travel more easily and faster from continent to continent and so do infectious diseases with them. foodborne outbreaks related to imported contaminated food items are normally widespread, involving many states and countries and therefore are frequently identified. in , a large outbreak of cyclospora cayetanensis occurred in us states and ontario, canada and was linked to contaminated raspberries imported from south america. several hundred laboratory confirmed cases were reported, most of them in immunocompetent persons (cdc ) . a very useful molecular tool to identify same isolates from different geographic areas is sub-typing enteric bacteria with pfge. in the us, the pulsenet database allows state health department to compare their isolates with other states and therefore increase the recognition of nationwide outbreaks linked to the same food item (swaminathan et al. ) . in a different scenario, a widely distributed food item with low-level contamination might result in an increase of cases within a large geographic area and therefore might be not get detected on a local level. this kind of outbreak might only be detected by chance if the number of cases increased in one location and the local health department alerts other states to be on the lookout for a certain isolate. another type of outbreak is the introduction of a new pathogen into a new geographic area as it happened in when vibrio cholerae was inadvertently introduced in the waters off the gulf coast of the united states. in the u.s., however, most cases are usually traced back to people who traveled to areas with a high cholera risk or to people who ate food imported from cholera-risk countries and only sporadic vibrio cholerae cases are associated with the consumption of raw or undercooked shellfish from the gulf of mexico (cdc b). food can not only be contaminated by the end of the food handling process i.e. by infected food handlers but also can be contaminated by any event earlier in the chain of food production. in , an ice cream outbreak of salmonella enteritidis in a national brand of ice cream resulted in , illnesses. the outbreak was detected by routine surveillance because of a dramatic increase of salmonella enteritidis in south minnesota. the cause of the outbreak was a basic failure on an industrial scale to separate raw products from cooked products. the ice cream premix was pasteurized and then transported to the ice cream factory in tanker trucks which had been used to haul raw eggs. this resulted in the contamination of the ice cream and subsequent salmonella cases (hennessey et al. ) . surveys are useful to provide information for which there is no data source or no reliable data source. surveys are time consuming and are often seen as a last choice to obtain information. however, too often unreliable information is used because it is easily available. for example, any assessment of the legionella problem using passive case detection will be unreliable due to under-diagnosis and under-reporting. most cases of legionellosis are treated empirically as community acquired pneumonias and are never formally diagnosed. in developing countries, surveys are often necessary to evaluate health problems since data collected routinely (disease surveillance, hospital records, case registers) are often incomplete and of poor quality. in industrialized nations, although many sources of data are available, there are some circumstances where surveys may be necessary. prior to carrying out surveys involving human subjects, special procedures need to be followed. in industrialized countries, a human subject investigation review board has to evaluate the project's value and ethics. in developing countries, however, such boards may not be formalized but it is important to obtain permission from medical, national and local political authorities before proceeding. surveys of human subjects are carried out by mail, telephone, personal interviews, and behavioral observations. in infectious diseases, the collection of biological specimens in humans (i.e. blood for serologic surveys) or the collection of environmental samples (food, water, environmental surfaces) is very common. personal interviews and specimen collection require face to face interaction with the individual surveyed. these are carried out in offices or by house to house surveys. non-respondents are an important problem for infectious disease surveys. those with an infection may be absent from school, may not answer the door or may be unwilling to donate blood for a serologic survey, thus introducing a systematic bias into the survey results. since surveys are expensive, they cannot be easily repeated. all field procedures, questionnaires, biological sample collection methods and laboratory tests should be tested prior to launching the survey itself. feasibility, acceptability and reliability can be tested in a small scale pilot study. more details on survey methods are to be found in chap. i. of this handbook. sampling . . since surveys are labor intensive, they are rarely carried out on an entire population but rather on a sample. to do a correct sampling, it is necessary to have a sampling base (data elements for the entire population) from which to draw the sample. examples of sampling bases are population census, telephone directory (for the phone subscriber population), school roster or a school list. in developing countries such lists are not often available and may have to be prepared before sampling can start. more information on sampling designs can be found in chap. iv. of this handbook. community surveys (house to house surveys) . . most community surveys are carried out in developing countries because reliable data sources are rare. the sampling base often ends up to the physical layout of the population. a trip and geographical reconnaissance of the area are necessary. the most common types of surveys undertaken in developing countries are done at the village level; they are based on maps and a census of the village. in small communities, it is important to obtain the participation of the population. villagers are often wary of government officials counting people and going from door to door. to avoid misinterpretations and rumors, influential people in the community should be told about the survey. their agreement is indispensable and their help is needed to explain the objectives of the survey and particularly its potential benefits. increasing the knowledge about disease, disease prevention and advancing science are abstract notions that are usually poorly understood or valued by villagers who are, in general, very practical people. if a more immediate benefit can be built into the survey, there will be an increase in cooperation of the population. incentives such as offering to diagnose and treat an infection or drugs for the treatment of common ailments such as headaches or malaria enhance the acceptance of the survey. in practically all societies the household is a primary economic and social unit. it can be defined as the smallest social unit of people who have the same residency and maintain a collective organization. the usual method for collecting data is to visit each household and collect samples or administer a questionnaire. medical staff may feel left out or even threatened whenever a medical intervention (such as a survey) is done in their area. a common concern is that people will go to their medical care provider and ask questions about the survey or about specimen collection and results. it is therefore important to involve and inform local medical providers as much as practical. a rare example of a house to house survey in an industrialized nation was carried out in slidell, louisiana for the primary purpose of determining the prevalence of west nile infection in a southern us focus. since the goal was to obtain a random sample of serum from humans living in the focus, the only method was a survey of this type. a cluster sampling design was used to obtain a representative number of households. the area was not stratified because of its homogeneity. census blocks were grouped so that each cluster contained a minimum of households. the probability of including an individual cluster was determined by the proportion of houses selected in that cluster and the number of persons participating given the number of adults in the household. a quota sampling technique was used, with a goal of enlisting participating households in each cluster. inclusion criteria included age (at least years of age) and length of residence (at least years). the household would be included only if an adult household resident was present. a standardized questionnaire was used to interview each participant. information was collected on demographics, any recent febrile illness, knowledge, attitudes, and behaviors to prevent wnv infection and potential exposures to mosquitoes. a serum sample for wnv antibody testing was drawn. in addition, a second questionnaire regarding selected household characteristics and peridomestic mosquito reduction measures was completed. informed consent was obtained from each participant, and all participants were advised that they could receive notification of their blood test results if they wished. institutional review board approvals were obtained. logistics for specimen collection, preservation and transportation to the laboratory were arranged. interpretation of serologic tests and necessary follow up were determined prior to the survey and incorporated in the methods submitted to the ethics committee. sampling weights, consisting of components for block selection, householdwithin-block selection, and individual-within-household participation, were used to estimate population parameters and % confidence intervals (ci). statistical tests were performed incorporating these weights and the stratified cluster sampling design. in this survey, households were surveyed (a % response rate), including participants. there were igm seropositive persons, for a weighted seroprevalence of . % (with a % confidence interval of . %- . %) (vicari et al. ). program evaluation is a systematic way to determine if prevention or intervention programs for the infectious disease of interest are effective and to see how they can be improved. it is beyond the scope of this chapter to explain program evaluation in detail however there is abundant information available i.e. the cdc's framework for program evaluation in public health (cdc a) as well as text books on program evaluation (fink ) . most importantly, evaluators have to understand the program such as the epidemiology of the disease of interest, the program's target population and their risk factors, program activities and resources. they have to identify the main objectives of the control actions and determine the most important steps. indicators define the program attributes and translate general concepts into measurable variables. data are then collected and analyzed so that conclusions and recommendations for the program are evidence based. evaluating an infectious disease control program requires a clear understanding of the microorganism, its mode of transmission, the susceptible population and the risk factors. the following example of evaluation of tuberculosis control shows the need to clearly understand the priorities. most of tuberculosis transmission comes from active pulmonary tuberculosis cases who have positive sputum smear (confirmed as tuberculosis mycobacteria on culture). to a lesser extent, smear negative culture positive pulmonary cases are also transmitting the infection. therefore priority must be given to find sputum positive pulmonary cases. the incidence of smear positive tuberculosis cases is the most important incidence indicator. incidences of active pulmonary cases and of all active cases (pulmonary and extra-pulmonary) are also calculated but are of lesser interest. the following proportions are used to detect anomalies in case finding or case ascertainment: all tuberculosis cases who are pulmonary versus extra-pulmonary, smear positive, culture positive, pulmonary cases versus smear negative, culture positive, pulmonary cases, culture positive, pulmonary cases versus culture negative, pulmonary cases. poor laboratory techniques or low interest in obtaining sputa for smears or cultures may result in underestimating bacteriological confirmed cases. excessive diagnosis of tuberculosis with reliance on chest x-rays on the other hand may overestimate unconfirmed tuberculosis cases. once identified, tuberculosis cases are placed under treatment. treatment of infectious cases is an important preventive measure. treatment efficacy is evaluated by sputum conversion (both on smear and culture) of the active pulmonary cases. after months of an effective regimen, % of active pulmonary cases should have converted their sputum from positive to negative. therefore the rate of sputum conversion at months becomes an important indicator of program effectiveness. this indicator must be calculated for those who are smear positive and with a lesser importance for the other active pulmonary cases. to ensure adequate treatment and prevent the development of acquired resistance, tuberculosis cases are placed under directly observed therapy (dot). this measure is quite labor intensive. priority must therefore be given to those at highest risk of relapse. these are the smear positive culture proven active pulmonary cases. dot on extra-pulmonary cases is much less important from a public health standpoint. the same considerations apply to contact investigation and preventive treatment in countries that can afford a tuberculosis contact program. a recently infected contact is at the highest risk of developing tuberculosis the first year after infection; hence the best preventive return is to identify contacts of infectious cases. those contacts are likely to have been recently infected. systematic screening of large population groups would also identify infected individuals but most would be 'old' infections at lower risk of developing disease. individuals infected with tuberculosis and hiv are at extremely high risk of developing active tuberculosis. therefore the tuberculosis control program should focus on the population at high risk of hiv infection. often, program evaluation is performed by epidemiologists who have not taken the time to understand the dynamics of a disease in the community. rates or proportions are calculated, no priorities are established and precious resources are wasted on activities with little preventive value. for example, attempting to treat all tuberculosis cases, whether pulmonary or not with dot, investigating all contacts regardless of the bacteriologic status of the index case, would be wasteful. today the world is smaller than ever before, international travel and a worldwide food market make us all potentially vulnerable to infectious diseases no matter where we live. new pathogens are emerging such as the sars or spreading through new territories such as wnv. wnv introduced in the us in , became endemic in the us over the next years. hospital-associated and community-associated methicillin resistant staphylococcus aureus (mrsa) and resistant tuberculosis cases and outbreaks are on the rise. public health professionals are concerned that a novel recombinant strain of influenza will cause a new pandemic. but not only the world and the etiologic agents are changing, the world population is changing as well. in industrialized countries, the life expectancy is increasing and the elderly are more likely to acquire a chronic disease, cancer or diabetes in their lifetime. because of underlying conditions or the treatment of these diseases, older populations also have an increased susceptibility for infectious diseases and are more likely to develop life-threatening complications. knowledge in the field of infectious disease epidemiology is expanding. while basic epidemiological methods and principles still apply today, improved laboratory diagnoses and techniques help to confirm cases faster, see how cases are related to each other and therefore can support the prevention of spread of the specific disease. better computers can improve the data analysis and internet allows access to in depth disease specific information. computer connectivity improves disease reporting for surveillance purposes and the epidemiologist can implement faster preventive measures if necessary and is also able to identify disease clusters and outbreaks on a timelier basis. the global threat of bioterrorism adds a new dimension. the intentional release of anthrax spores, and the infection and death of persons who contracted the disease created a scare of contaminated letters in the us population. with all these changes, there is renewed emphasis on infectious disease epidemiology and makes it a challenging field to work in. detection of bordetella pertussis and respiratory syncytial virus in air samples from hospital rooms transmission of tuberculosis in new york city. an analysis by dna fingerprinting and conventional epidemiologic methods report of the committee on infectious diseases in: chin j (ed) control of communicable diseases manual, th edn geographical information system (gis), gimmick or tool for health district management update: international outbreak of restaurant-associated botulism -vancouver epidemiologic notes and reports restaurant associated botulism from mushrooms bottled in-house -vancouver outbreaks of cyclospora cayetanensis infection -united states case definitions for infectious conditions under public health surveillance cdc ( a) framework for program evaluation in public health summary of infections reported to vibrio surveillance system (http:||www.cdc.gov|ncidod|dbmd|diseaseinfo|files|vibcste web.pdf) accessed norowalk-like viruses": public health consequences and outbreak management updated guidelines for evaluating public health surveillance systems: recommendations from the guidelines working group outbreaks of gastroenteritis associated with noroviruses on cruise ships -united states diagnosis and management of foodborne illnesses: a primer for physicians and other health care professionals epiinfo (http:||www.cdc.gov|epiinfo|) accessed evaluation fundamentals: guiding health programs, research and policy yellow fever. in: cox cr (ed) the wellcome trust illustrated history of tropical diseases a national outbreak of salmonella enteritidis infections from ice cream encephalitis outbreak in louisiana in simple school questionnaires can map both schistosoma mansoni and schistosoma haematobium in the democratic republic of congo molecular and conventional epidemiology of mycobacterium tuberculosis in botswana: a population-based prospective study of pulmonary tuberculosis patients dolin r (eds) ( ) mandell, douglas, and bennett's principles and practice of infectious diseases epidemiology, principles and methods. little, brown and company an uninvited guest at "turkey day trends in hospitalizations associated with gastroenteritis among adults in the united states the next influenza pandemic: lessons from hong kong on the mode of communication of cholera pulsenet: the molecular subtyping network for foodborne bacterial disease surveillance, united states late-breaker report presented at the cdc "annual epidemic intelligence service conference http:||www.who.int|whr | | archives|index.htm) accessed statistical annex. (http:||www.who.int| whr | |archives| |en|pdf|statisticalannex.pdf) accessed cholera, the black one. in: yellow fever black goddess, the coevolution of people and plagues four tales from the new decameron. in: yellow fever black goddess, the coevolution of people and plagues key: cord- -c o b j authors: matibag, gino c.; igarashi, manabu; la porte, ron e.; tamashiro, hiko title: advocacy, promotion and e-learning: supercourse for zoonosis date: - - journal: environmental health and preventive medicine doi: . /bf sha: doc_id: cord_uid: c o b j this paper discusses the history of emerging infectious diseases, risk communication and perception, and the supercourse lectures as means to strengthen the concepts and definition of risk management and global governance of zoonosis. the paper begins by outlining some of the key themes and issues in infectious diseases, highlighting the way which historical analysis challenges ideas of the ‘newness’ of some of these developments. it then discusses the role of risk communication to public accountability. the bulk of the paper presents an overview of developments of the internet-based learning system through the supercourse lectures that may prove to be a strong arm for the promotion of the latest medical information particularly to developing countries. we live in a dangerous world. yet it is also a world far safer in many ways than it has ever been. diseases that only recently were mass killers have been all but eradicated. advances in public health, medicine, environmental regulation, food safety, and worker protection have dramatically reduced many of the major risks we faced just a few decades ago. governance refers to how societies structure responses to the challenges they face. analyses of emerging and re-emerging infectious diseases (eids) have made it clear that national and international societies are confronting increased microbial threats ( ) ( ) ( ) . whether the focus is bioterrorism, hiv/aids, severe acute respiratory syndrome (sars), or avian influenza, germs increasingly pose dangers to human societies. germ governance concerns how societies, both within and beyond national borders, structure their responses to pathogenic challenges ( ) . the global nature of the microbial threat requires that governance address the borderless challenges presented by infectious diseases. the emergence of sars is a major global public health threat that requires a coordinated global response in terms of continued and improved surveillance and of research into a number of important public health issues. while much has been learnt about sars since it was brought to international attention in march , there remain many unanswered questions about where it came from, how it spreads, and the effectiveness of public health and other measures employed to control the disease. the overall goal of the "supercourse for zoonosis" is to show the most recent development in the knowledge of sars and other zoonotic diseases such as avian influenza and bovine spongiform encephalopathy (bse), inter alia, which have significant global impact not only on health but also on the economy. the specific objectives of "supercourse for zoonosis" are to develop a set of educational materials for the control of zoonotic diseases, to disseminate them effectively via the internet, to facilitate their use in the prevention and control of the diseases, and to promote human health while minimizing their economic impact. in the light of all these advances, it is most appropriate that all countries remain vigilant, not only with sars, but also to all zoonotic diseases that may toll the productivity of human, animal, ecological, and economical sectors of our daily lives. emerging 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 ( ) . 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 ( ) . 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. about million (more than %) 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 ( ) . 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 diarrheal diseases alone ( )). in developed nations, infectious disease mortality disproportionately affects indigenous and disadvantaged minorities ( ) . bacteria and viruses existed long before humans evolved, and bacterial diseases probably co-evolved with each species. many bacterial diseases that we see today have been around for as long as we have, others may have developed later. 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 ( ) . importation of smallpox into mexico caused - million deaths in - , effectively ending aztec civilization ( , ) . with the beginning of microbiology, pathogens became apparent. 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 in the development of vaccines and ultimately of antimicrobials ( ) . by the s, which had 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 skeptical, aware of the current 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. 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 the re-emergence of historically important diseases such as cholera, diphtheria, trench fever and plague. many re-emergences have been catalyzed by wars, loss of 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 ( ) ( ) ( ) ( ) ( ) ( ) ( ) . these infections are those that have not previously been recognized in man. many diverse factors contribute to their emergences (table ) . 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. at the end of , an estimated . million (range . - . million) people around the world were living with hiv, including the . million (range . - . million) people who acquired hiv in . the epidemic claimed an estimated . million (range . - . million) lives in . sub-saharan africa remains the most affected region and is home to about % of the total number of people living with hiv worldwide ( ) . before jumping to humans an estimated - years ago ( ) , perhaps through consumption of 'bush meat' from nonhuman 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 may never have emerged had it not been for disruptions in the economic and social infrastructure in postcolonial sub-saharan africa. increased travel, the movement of rural populations to large cities, urban poverty and a weakening of family structure, all these promoted sexual practices such as promiscuity and prostitution that facilitate hiv 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 ( , ) . 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 behavioral factors. farming, the keeping of domestic pets, hunting and camping, deforestation and other types of habitat destruction all create new opportunities for such infectious agents to invade human hosts ( ) ( ) ( ) ( ) ( ) ( ) ( ) . examples include the arenavirus hemorrhagic fevers (argentine, bolivian, venezuelan and lassa hemorrhagic fevers) and hantavirus pulmonary syndrome (hps). variant creutzfeldt-jakob disease (vcjd) is another example of a zoonotic disease emerging in humans. it is caused by the human-adapted form of the prion associated with the emerging epizootic (large-scale animal outbreak) of bovine spongiform encephalopathy (bse), commonly known as mad cow disease. 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 ( ) . infectious agents indirectly transmitted to or between humans by way of human-modified environments account for other emerging zoonoses. legionnaire's disease, first identified in , is caused by legionella pneumophilia, 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 escherichia coli infect agricultural animals, gaining access to humans through food, milk, water or direct animal contact. other enteric pathogens, such as the vibrios which cause classic 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 'fecal-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 ( ) . scarlet fever, then the leading cause of death in children, is now rare, but has largely been supplemented by other streptococcal complications such as streptococcal toxic shock syndrome, necrotizing fasciitis and re-emergent rheumatic fever ( ) . streptococcus pyogenes has been studied more extensively, but the basis of severe disease emergence seems to be more complex. 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 helicobacter pylori with gastric ulcers and gastric cancer ( ) ( ) ( ) . some data even suggest infectious etiologies 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-emergence is caused by some of the factors that allow for newly emerging infectious diseases, factors such as microbial evolutionary vigor, 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 ( ) . travel has an important role in bringing people into contact with infectious agents ( ) . an increase in travelassociated 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 hemorrhagic conjunctivitis in ( ), 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 ( ) . plasmodium falciparum malaria was neglected for several decades, but is now among the most important re-emerging diseases worldwide. years of effective use of dichlorodiphenyltrichloroethane (ddt) had led to the abandonment of other mosquito-control programs, 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 ( ) . the remarkable re-emergence of tuberculosis was fuelled by the immune deficiencies of people with hiv infection, 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 extensive 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. drug resistance, another factor causing microbial and viral re-emergence, may result from mutation or from bacterial acquisition of extraneous genes through transformation or infection with plasmids. sequential emergences of staphylococcus aureus that are resistant to sulpha drugs ( s), penicillin ( s), methicillin ( s) and to vancomycin in ( )-a last line of antibiotic defense for some multiply drug-resistant bacteria-are troubling. nosocomial enterococcus faecalis became fully resistant to vancomycin by , and then apparently transferred vana resistance genes to co-infecting staphylococci ( ) . methicillin-resistant staphylococci are now being isolated from livestock that have been fed with growthpromoting antibiotics ( ) , possibly contributing to resistance problems in humans. immune deficiency associated with hiv infection, 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 herpesvirus ( ) . the simultaneous emergences of encephalitis due to west nile virus (wnv) in the united states and russia ( , ) reflect abundances of eclectic vector mosquitoes and avian hosts in these locations. both were probably connected to endemic sites by virus carriage in migratory birds and travelers. the remarkable geographical spread of wnv in the five years since its introduction into the western hemisphere reflects an unfortunate confluence of viral promiscuity and ecological diversity ( ) . although humans are dead-end hosts for wnv, the risk of infection is greatly increased by marked zoonotic viral amplification and persistence in the environment. although wnv is now a major epidemiological concern in the developed world, dengue remains the most significant and widespread flavivirus disease to have emerged globally ( ) . usually transmitted by aedes aegypti mosquitoes, dengue has recently been transmitted by aedes albopticus-a vector switch of potential significance with respect to dengue reemergence ( ) . dengue re-emergence is further complicated by disturbing increases in a serious and formerly rare form of the disease, dengue hemorrhagic 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 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 and to undergo gene transfer events that lead to new strains containing further virulence gene combinations ( ) . thus, although 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 ( , ) . 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 hemagglutinin site that attaches to human cells. deliberately emerging microbes are those that have been developed by humans, usually for nefarious use. they include microorganisms or toxins produced in a form that would cause maximal harm because of ease of dissemination, enhanced infectivity or heightened pathogenicity ( ) . 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-sporefilled letters to prominent figures, including two us senators, resulted in illness in at least people and the death of five of these individuals. the united states, the united kingdom, the russian federation and other nations once had sophisticated offensive bioweapons programs that included the production of weaponized anthrax spores ( ) . in japan, the doomsday sect, aum supreme truth, carried out a nerve-gas attack on the tokyo subway in , and made a trial run on an anthrax weapon, using harmless vaccine bacteria as a test ( ) . bioterror agents have been grouped into three categories (a, b and c) according to risk ( ) . the six category a agents (anthrax, smallpox, plague, tularaemia, viral hemorrhagic 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. risk is the probability that exposure to a hazard will lead to a negative consequence ( ) . risk communication is an interactive exchange of information and opinion on risk among risk assessors, risk managers, and other interested parties ( ) . humans tend to fear similar things, for similar reasons. scientists studying human behavior have discovered psychological patterns in the subconscious ways we "decide" what to be afraid of and how afraid we should be. any given risk has a set of identifiable characteristics that help predict what emotional responses that risk will trigger. people's perceptions of the magnitude of risk are influenced by factors other than numerical data ( ) . the factors influencing risk perception are summarized in table . merely disseminating information without regard for communicating the complexities and uncertainties of risk does not necessarily ensure effective risk communication. wellmanaged efforts will help ensure that messages are constructively formulated, transmitted, and received and that they result in meaningful actions. the seven cardinal rules of risk communication are demonstrated in table . the fundamental goal of risk communication is to provide meaningful, relevant and accurate information, in clear and understandable terms, targeted to a specific audience ( ) . the goals of risk communication are summarized in table . it may not resolve all differences between interested parties, but may working in earthquake-prone areas hormone replacement therapy . risks perceived to be fairly distributed are more accepted than risks to be unfairly distributed. gun shots (in japan) traffic accidents . risks perceived to be natural are more accepted than risks perceived to be manmade. radiation from mobile phones radiation from the sun . risks perceived to be statistical are more accepted than risks perceived to be catastrophic. eaten by a shark (catastrophe) heart disease (statistics) . risks perceived to be generated by a well-known source are more accepted than risks perceived to be generated by a less known source. private industry government . risks perceived to be familiar are more accepted than risks perceived to be exotic. . risks perceived to affect adults are more accepted than risks perceived to affect children. asbestos exposure for children asbestos exposure in workplace . risks perceived with less uncertainty are more accepted than risks with high uncertainty. new technology conventional technology . risks perceived that could directly affect others are more accepted than risks that could affect oneself. table seven cardinal rules of risk communication* . accept and involve the public as a partner. the goal is to produce an informed public, not to defuse public concerns or replace actions. different goals, audiences, and media require different actions. . listen to the public's specific concerns. people often care more about trust, credibility, competence, fairness, and empathy than about statistics and details. . be honest, frank, and open. trust and credibility are difficult to obtain; once lost, they are almost impossible to regain. . work with other credible sources. conflicts and disagreements among organizations make communication with the public much more difficult. . meet the needs of the media. the media are usually more interested in politics than risk, simplicity than complexity, danger than safety. . speak clearly and with compassion. never let efforts prevent acknowledging the tragedy of an illness, injury, or death. people can understand risk information, but they may still not agree; some people will not be satisfied. * from: covello v and allen f. . (reference no. ) lead to a better understanding of those differences. it may also lead to more widely understood and accepted risk management decisions. effective risk communication should have goals that build and maintain trust and confidence. it should facilitate a higher degree of consensus and support by all interested parties for the risk management options being proposed. many considerations for effective risk communication, especially those involving the public, can be grouped in a sequence following the systematic approach of the risk communication process. this starts with gathering background and needed information, followed by the preparation and assembly of the message and its dissemination and distribution, with a follow-up review and evaluation of its impact ( ) . the general considerations for effective risk communication are demonstrated in table . risk communication efforts and programs need to be evaluated both regularly and systematically to determine their effectiveness and to provide for change when needed. communication aims and objectives need to be clearly stated if an evaluation is to be effective. this could include the proportion of at-risk population to be reached, adoption of appropriate risk reduction practices, and the extent of resolution of the crisis. it is important to learn from both positive and negative risk communication experiences, in order to adjust and improve ongoing communication activities. only through systematic evaluations, which are performed throughout the communication process, can that process be strengthened ( ) . globalization of disease prevention lectures, through the supercourse prevention project, is funded by the us national institutes of health (nih). the supercourse is an internet library of lectures on prevention, shared for free by , table goals of risk communication* . promote awareness and understanding of these specific issues under consideration during the risk analysis process, by all participants; . promote consistency and transparency in arriving at and implementing risk management decisions; . provide a sound basis for understanding the risk management decisions proposed or implemented; . improve the overall effectiveness and efficiency of the risk analysis process; . contribute to the development and delivery of effective information and education programs, when they are selected as risk management options; . foster public trust and confidence in the safety of the food supply; . strengthen the working relationships and mutual respect among all participants; . promote the appropriate involvement of all interested parties in the risk communication process; and, . exchange information on the knowledge, attitudes, values, practices and perceptions of interested parties concerning risks associated with food and related topics. table . japan has associated with the global health network through supercourse japan ( ) where a series of lectures in health, environment and sustainable development, epidemiology for decision-making, and zoonosis have so far been developed. the supercourse on health, environment and sustainable development was designed to provide an overview on health and environment in the context of sustainable development for public health students around the world, as well as decision makers, community leaders, scientists and professionals in government and non-governmental organizations, who are interested in health and environmental linkages in sustainable development ( ) . the supercourse on epidemiology for decision-making provides a learning resource for students of environmental and occupational epidemiology, and its main purpose is to promote the understanding and application of epidemiology in the prevention of environmental and occupational disease and the promotion of health ( ) . the supercourse on zoonosis aims to disseminate rapidly the latest information on animal diseases transmittable to humans. severe acute respiratory syndrome (sars) and bovine spongiform encephalopathy (bse) are some of the lectures discussed which will help in information sharing to developing countries ( ) . a joint action plan through the 'the pacific islands forum' was created in . its five priority policy targets are: ) enhancement of security in the pacific region, ) creation of a safer and more sustainable environment, ) improvement in education and human resources development, ) improvement in health, and ) promotion of more vigorous and continued trade and economic growth. the countries in the pacific region face a contradictory dilemma: some of the poorest countries have the most expensive telecommunications, yet information and telecommunication technology (ict) need to be extensively utilized. in these circumstances telemedicine, such as for remote clinical and pathological diagnosis, is too expensive and technically demanding to be widely used. since information in the future will be technology-and network-based, it is imperative for "supercourse asia" to fully exploit the potential of ict for health education and health service development in the region. the advantages of this approach are to use the most appropriate, inexpensive, opensource, and low-band ict, and to operate it through active national networking. the supercourse asia network (scan) is an offshoot of this initiative and aims that all children and adults will have equal access to health and education of sufficient quality to empower them to break the poverty cycle, to improve their quality of life (qol), and to participate effectively in national development. the mission is to alleviate poverty and improve health and qol of developing countries in the pacific region through advances in a cost-effective ict-based health educational system. the internet is the most inexpensive and speed efficient means to penetrate the remote places such as the pacific islands. japan, a leader of modern technology in the region, is in the best position to provide these technological and educational tools to contribute to the well-being of people in the region. the scan is a group of primarily academics, united by a common belief: the internet is the best way to disseminate knowledge, especially knowledge about health promotion and prevention. they are working towards facilitating the dissemination of health-related information over the internet and improving teaching in the field of education, social/preventive medicine, public health and epidemiology. the members are voluntary professionals in academia, healthcare, telecommunications, the government, ngos, and other public and private sector organizations who will work together towards developing "supercourse asia." they are not only active members of the scan but also the main contributors of "supercourse asia" lectures, reviewers, translators, and its major user group. the challenges for the scan are ) how to effectively utilize the national networks among the participating countries and within each participating country that may be geographically remote, ) how to evaluate the effects of the scan on the advancement of health and qol, and the alleviation of poverty though "supercourse asia" in the region, and ) how to sustain the network activities for many years to come. currently, the public has become concerned with information and safety, however, gaps between the understanding of safety and assurance are widening. health advocacy and promotion through e-learning are becoming more important in the framework of risk communication for the community. the supercourse lectures will serve as an international platform for sharing information, lectures, and ideas. understand the public perception of the risk through such means as risk surveys, interviews and focus groups expect different people to see the risk differently. preparation/assembly . avoid comparisons between familiar risks and new risks, as they may seem flippant and insincere unless presented properly. . recognize and respond to the emotional aspects of risk perceptions. speak with sympathy and never use logic alone to convince an audience characterized by emotion express risk in several different ways, making sure not to evade the risk question explain the uncertainty factors which are used in risk assessment and standard setting maintain an openness, flexibility, and recognition of public responsibilities in all communication activities accept and involve the public as a legitimate partner by describing risk/benefit information and control measures in an understandable way. . share the public's concern rather than deny it as not legitimate or as unimportant. be prepared to give people's concerns as much emphasis as the risk statistics be honest, frank, and open in discussing all issues if explaining statistics derived from risk assessment, explain the risk assessment process before presenting the numbers coordinate and collaborate with other credible sources evaluate the effectiveness of risk messages and communication channels. . emphasize action to monitor, manage, and reduce risk plan carefully and evaluate efforts it is based on the open source model, which allows free redistribution, shows the source code, and allows modifications and derived works this is especially useful for developing countries and minority populations with limited access to resources it aims to overcome the digital divide by improving access in places with low bandwidth internet connection it is a teaching support system -differing from a traditional distance education system it provides timely information for action -one of the greatest advantages of having a regional faculty base with varied areas of expertise which are very important in the field of public health (e.g., lectures on sars from the members in china and singapore, where it is most rampant) it is a "hyper-text comic book format hypertext links from text, images, tables, and pictures take the reader to other relevant supercourse lectures, images, or other websites on the internet oaks sc editors. emerging infections; microbial threats in the united states world health organization. removing obstacles to healthy development global defence against the infectious disease threat. world health organization globalisation of prevention education: a golden lecture factors in the emergence of infectious diseases threats to global health and survival; the growing crises of tropical infectious diseasesan unfinished agenda emerging infectious diseases among indigenous peoples epidemiology of the plague of athens the columbian exchange: biological and cultural consequences of . greenwood, westport: connecticut princes and peasants. smallpox in history. chicago: univ untersuchungen über bacterien. v. die aetiologie der milzbrand-krankheit, begründet auf die entwicklungsgeschichte des bacillus anthracis spreading germs: diseases, theories, and medical practice in britain the greatest benefit to 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for deciding what's really safe and what's really dangerous in the world around you world health organization. the application of risk communication to food standards and safety matters, a joint fao/ who expert consultation supercourse: epidemiology, the internet, and global health seven cardinal rules of risk communication key: cord- -qau gvw authors: willermain, françois; van laethem, yves; caspers, laure title: global variations and changes in patterns of infectious uveitis date: - - journal: emerging infectious uveitis doi: . / - - - - _ sha: doc_id: cord_uid: qau gvw before , most uveitis cases were supposed to be due to infectious agents, mainly syphilis or tuberculosis [ ]. progress in the understanding of intraocular inflammation led to the discovery that uveitis can be of infectious and noninfectious origin and that many pathogens can cause infectious uveitis. theoretically, koch postulates must be fulfilled, in order to formerly demonstrate that a disease is due to an infectious agent. however, in infectious uveitis, most often, serological evidence, molecular or histological demonstration, and treatment response are usually the only available elements to suggest the infectious origin of the uveitis. using those evidences, a large number of infectious organisms have been demonstrated to cause infectious uveitis. some have a global importance around the world, while others have more limited niches. many of them have been considered as emerging pathogens. before , most uveitis cases were supposed to be due to infectious agents, mainly syphilis or tuberculosis [ ] . progress in the understanding of intraocular inflammation led to the discovery that uveitis can be of infectious and noninfectious origin and that many pathogens can cause infectious uveitis. theoretically, koch postulates must be fulfilled, in order to formerly demonstrate that a disease is due to an infectious agent. however, in infectious uveitis, most often, serological evidence, molecular or histological demonstration, and treatment response are usually the only available elements to suggest the infectious origin of the uveitis. using these evidence a large number of infectious organisms have been demonstrated to cause infectious uveitis. some have a global importance around the world, while others have more limited niches. many of them have been considered as emerging pathogens. according to woolhouse, an emerging pathogen can be defined as an infectious agent whose incidence is increasing following its introduction into a new host population. a pathogen will be reemerging when its incidence increases in an existing host population [ ] . however, in practice, both expressions are likely used by many authors regardless of those biological and epidemiological criteria. the term emerging disease will thus also be used in situation of increase awareness or discovery of pathogen in previously supposed non-infectious diseases [ ] . as far as we know, most emerging infectious uveitis agents fall into the two last categories. emerging disease by definition, the question of emerging infectious disease addresses how a microbe becomes a pathogen in the human species. emerging infectious disease thus resumes the origin of human infectious disease. most of the emerging infections discovered during the last decades are zoonosis. major modifications in human behavior have facilitated their jump from animals to humans. the global population has increased from million humans around to . to . billion in , billion in , and more than billion in . more than % of those people reside in urban areas (from % in africa to % in the americas), in contrast with only % in . environmental modifications were mandatory to build those cities, with deforestation or other forms of land use than in the past. therefore, and also linked to widespread international trade of goods and animals, microbes have received a new and rapid access to an ever larger human population. in addition, the population is globally more mobile also; international travel rose above one billion people in , further increasing pathogen dissemination around the globe. in the past decades, most new pathogens were acute respiratory viruses. for instance, human metapneumovirus (first reported in in the netherlands but demonstrated thereafter in specimens stored since the s at least) is a paramyxovirus leading to very frequent and sometimes very severe respiratory tract infections in small children [ ] . a new betacoronavirus is the agent of sars (severe acute respiratory syndrome), discovered in after a physician infected a dozen patients in hong kong, with subsequent more than , cases in countries and deaths [ ] . another new coronavirus (mers-cov, middle east respiratory syndrome coronavirus) has been demonstrated as the causative agent of a deadly respiratory tract infection in the middle east since , with more than , cases and deaths [ ] . but of all these emerging pathogens, the flu viruses, are the most widespread and deadly. influenza a is a zoonose, with viruses mutating and mixing in swine and birds. if the spanish flu (new h n influenza a virus) killed more than million people in - , several pandemics (h n in , h n in , and new h n in ) appeared in the more recent decades, with a lower but consequent mortality. in more restricted areas, non-pandemic strains of influenza a as h n (asia and egypt) or h n (china) are still potential deadly sword of damocles [ ] . one of the most severe emerging infections of the last centuries is obviously aids (acquired immu-nodeficiency syndrome) linked to the hiv (and rarely hiv ) [ ] . if it was first recognized in in the united states, its emergence in the human world is older and faraway from our western world. indeed, the oldest known case (a posteriori) is a man in the present democratic republic of congo, in . analysis of the virus in his frozen serum as well as others suggests that hiv and hiv were separately acquired from monkeys in the s, in the western part of central africa. in more than siv (simian immunodeficiency viruses) presently known, only hiv and hiv were able to infect humans and to establish persistent human to human transmission. here again, urbanization and increasing local/regional trade, with all the sociologic modifications that it implicated, have largely contributed to the dissemination of the disease in sub-saharan africa. in a second time, international travel, sexual behaviors, and iv drug abuse have been keystone factors in the worldwide propagation of aids [ ] . if emerging disease brings us to the origin of infectious disease, re-emerging disease deals with the evolution of infectious disease and the impact of the human society on it. most of those reemerging infections are also zoonoses, often linked to a vector. climatic changes (global warming) have allowed ticks to reach higher latitudes as well as altitudes, with transmission of lyme disease or tick-borne encephalitis more in the north of scandinavia or at higher altitude in central europe [ ] [ ] [ ] . similarly, mosquitos as aedes albopictus are now found in the south of europe (as france and italy), with several local transmissions during the summer of dengue or chikungunya from imported cases. chikungunya virus was discovered years ago in tanzania and since that time has spread to several parts of africa and in all indian ocean/western pacific countries [ , ] . due to the introduction by an international traveler of an asian strain in the caribbean in , chikungunya is now an important public health problem not only in those islands but already also in central and south america [ ] . west nile virus infection was unknown in the americas until . due to migration from the old world of birds wearing infected ticks, the infection was introduced in the northeast of the united states, and in a few years, it spread to all the states [ ] . few studies, and mainly from the occidental world, address the incidence and prevalence of uveitis [ ] . it is therefore difficult to raise conclusions on global variations or evolution of this epidemiological aspect of intraocular inflammation. this contrasts with the important literature describing the causes of uveitis in different center and location in world which clearly shows important variations of the distribution of different etiologies around the globe. those differences are mainly due to genetic and environmental factors and often grouped between the so-called developed and developing worlds. accordingly, the distribution of both specific infectious and noninfectious causes varies greatly around the world. in the context of infectious uveitis, some uveitis type is logically limited to endemic regions. onchocerciasis, for example, has a limited distribution in africa, south america, and yemen [ ] . lyme disease is almost exclusively found in the northern hemisphere. leptospirosis occurs most frequently in tropical and subtropical area. brucellosis remains prevalent in the developing world, mostly in the mediterranean basin, the arabic gulf countries, india, and central america. htlv- infection is endemic in the caribbean, central and south america, south and intertropical africa, and japan. similarly other infectious agents such as dengue, west nile virus, rift valley fever, or chikungunya virus, as well as rickettsia only infect patients in limited endemic regions. there are thus only reported as causes of uveitis in studies from those regions. in the series of rathinam sr and namperumalsamy from india, leptospirosis was the most frequent cause of infectious uveitis but remains very rare in the united states and europe [ , ] . however, due to evolution in our societies, such as globalization, those causes of infectious uveitis begin to emerge in non-endemic regions in patients having traveled in endemic regions (see sect. . . . ) [ ] . in contrast some organisms have spread worldwide, some with a relative stable incidence and others with period of increase and/or decrease incidence. for example, across the world, toxoplasmosis and herpesvirus remain major causes of posterior and anterior uveitis, respectively [ ] [ ] [ ] [ ] [ ] [ ] . tuberculosis and syphilis are discussed in the next paragraph as classic examples of worldwide cause of uveitis with period of burden and decrease. an important example of decreased incidence of a ubiquitous infectious uveitis is cmv retinitis which made a steep decline in incidence following the introduction of haart [ ] . in europe, it is believed that syphilis has emerged around . interestingly, it has been reported that in its early years, the disease was much more severe that nowadays, suggesting the selection of a milder strain of treponema pallidum occurred. since that time, syphilis has continued to spread around the world and became one of the major health problems, illustrated by the fact that, in the nineteenth century, an entire medical subspecialty, syphilology, was devoted to its study [ , ] . the discovery of penicillin has been associated with a significant decrease of syphilis rate to the point that some authors have postulated that the disease might disappear. unfortunately, this was not the case and the incidence of syphilis has been the subject of important variation with frequent outbreak [ , ] . for example, in the united kingdom, there has been a % increase in the incidence of syphilis between and . this exponential increase has been attributed to unsafe sexual practices mainly among men who have sex with men (msms) [ ] . the same trend was found in other countries. as a consequence, many reports have warned the uveitis community of what was called by narsing rao and colleague "the reemergence of an old adversary" [ , ] . meanwhile, a tremendous number of studies have been published improving our knowledge on the epidemiology and clinical presentation of ocular syphilis. acute syphilitic posterior placoid chorioretinitis was in this context rediscovered with an exponential rate of publication from , the year of its publication by gass, to [ ] . tuberculosis is another old infectious disease which had a major impact on global human health. overall, the worldwide burden of tuberculosis is still growing, as control of the disease in many regions of the world is offset by the increase incidence in another part, mainly sub-saharan [ ] . tuberculosis remains one of the most important infectious causes of morbidity and mortality worldwide. in contrast with syphilitic uveitis, where the diagnosis can be easily made based on serological evidences, there is a great confusion regarding the diagnosis and treatment of ocular tuberculosis. progress in systemic and ophthalmological investigation together with a more accurate description of clinical signs has permitted to better define guidelines for the diagnosis and treatment of intraocular tuberculosis [ , ] . nowadays, tuberculosis is a leading cause of uveitis in endemic countries, but tuberculosis uveitis can also be found in non-endemic countries with a probable recent increased frequency [ , [ ] [ ] [ ] . this recent increment of tuberculosis uveitis in non-endemic countries is mainly attributed to the development of immigration and postulated by llorenc and coworkers to be one of the challenges of globalization [ , ] . there is thus an increased awareness of ocular tuberculosis among uveitis specialists all around the globe. one of the major recent breakthroughs in the uveitis field was the discovery that two entities, namely, posner-schlossman syndrome (pss) and [ ] . a possible role played by cmv infection in the development of pss was suggested by early work of bloch-michel in the eighties [ ] . since that time, several works have confirmed this hypothesis [ , , ] . in addition to pss, it was found in those studies that cmv-positive anterior uveitis can also present the clinical characteristics of fhi or chronic granulomatous uveitis. altogether, those data indicate that several previously thought idiopathic uveitis (pss, fhi, and some chronic granulomatous anterior uveitis) have indeed a viral origin. this evidence has not only important implications for the epidemiology but, of course, also for the management of uveitis. we have seen earlier that the success of humanity in terms of demographic expansion has create favorable conditions to increase the speed for the emergence and spreading of infectious diseases. in other terms, diseases might quickly jump between very distant part of the world and confront clinicians with diseases unusual in their region. fortunately, the dissemination of information has also been progressively accelerated allowing a quick exchange of information between specialist from endemic regions and recently affected countries. in this context, a series of infectious uveitis, mainly rickettsioses, west nile virus, dengue, or chikungunya, has been the subject of an increase awareness and careful descriptions from both endemic and non-endemic regions [ , , ] . the recent outbreaks of ebola and zika virus have been similarly associated with uveitis cases and those pathogens should be now included in the list of emerging infectious uveitis agents [ , ] . the epidemiology of infectious uveitis is a dynamic process and the consequence of the complex relationship between microbes and human. on one hand, some pathogens such as toxoplasmosis or herpesvirus remain major causes of uveitis, while others, such as tuberculosis, seem to progress despite our efforts to eradicate them. on the other hand, infectious uveitis previously limited to particular geographical niches can now be found almost all around the globe. this is clearly due to evolution of our lifestyle which has also important impact on the emergence of new infectious diseases which might become someday new uveitis causes. the decrease of cmv retinitis among aids patients following haart highlights that, in addition to this negative aspect, our civilization also has a positive impact on infectious uveitis epidemiology and is able to reduce the incidence of some devastating infectious uveitis causes. indeed, we should not forget that the development of our human society has also created better ways to diagnose, control, and eventually eradicate infectious diseases. diagnosis and treatment of uveitis. wb sauders company population biology of emerging and re-emerging pathogens? human metapneumovirus: a ubiquitous and long standing respiratory pathogen consensus document on the epidemiology of sars severe respiratory disease associated with middle east respiratory syndrome coronavirus (mers-cov) th update ecdc. communicable disease threats report isolation of a t-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (aids) reflections on years of aids joint factsheet on lyme borreliosis global climate change and infectious diseases chikungunya in europe: what's next? chikungunya: a re-emerging virus chikungunya outbreak in caribbean region global trends in emerging infectious diseases epidémiologie. in: brezin ap (ed) les uvéites. société française d'ophtalmologie elimination of onchocerciasis from africa: possible? global variation and pattern changes in epidemiology of uveitis leptospiral uveitis in the developing world emergent infectious uveitis epidemiology of ocular toxoplasmosis causes of uveitis at the eye center in saudi arabia: a retrospective review pattern of uveitis in a referral centre in tunisia etiology and clinical features of ocular inflammatory diseases in a tertiary center in lebanon uveitis subtypes in a german interdisciplinary uveitis centeranalysis of patients pattern of uveitis in a university-based referral center in southern thailand declining incidence of aids-defining opportunistic illnesses: results from years of populationbased aids surveillance syphilis in renaissance europe: rapid evolution of an introduced sexually transmitted disease? syphilis in the united states syphillis: a reemerging infection british ocular syphilis study (boss): -year national surveillance study of intraocular inflammation secondary to syphilis syphilis: reemergence of an old adversary syphilitic uveitis acute syphilitic posterior placoid chorioretinitis intraocular tuberculosis -an update classification of intraocular tuberculosis patterns of uveitis in patients admitted to a university hospital in riyadh, saudi arabia the manchester uveitis clinic: the first patients-epidemiology and casemix epidemiology of uveitis in a western urban multiethnic population. the challenge of globalization fuchs heterochromic cyclitis: rubella virus antibodies and genome in aqueous humor rubella virus-associated uveitis: clinical manifestations and visual prognosis epidemiologic relationship between fuchs heterochromic iridocyclitis and the united states rubella vaccination program clinical features of cytomegalovirus anterior uveitis in immunocompetent patients associations of fuchs heterochromic iridocyclitis in a south indian patient population possible role of cytomegalovirus infection in the etiology of the posner-schlossman syndrome long-term oral therapy with valganciclovir in patients with posner-schlossman syndrome cytomegalovirus anterior uveitis: long-term follow-up of immunocompetent patients west nile virus-associated optic neuritis and chorioretinitis dengue eye disease ebola virus disease and the eye uveitis associated with zika virus infection the cause of infectious uveitis varies greatly around the world. some widespread microbes continue to threaten vision in almost every part of the globe. some infectious uveitis previously limited to particular geographical niches can now be found almost all around the globe. this evolution is the consequence of changing in our lifestyle which has also important impact on the emergence of new infectious diseases as well as their diagnosis and management. key: cord- - e xb d authors: mahmood, imran; jahan, mishal; groen, derek; javed, aneela; shafait, faisal title: an agent-based simulation of the spread of dengue fever date: - - journal: computational science - iccs doi: . / - - - - _ sha: doc_id: cord_uid: e xb d vector-borne diseases (vbds) account for more than % of all infectious diseases, causing more than , annual deaths. lack of a robust infrastructure for timely collection, reporting, and analysis of epidemic data undermines necessary preparedness and thus posing serious health challenges to the general public. by developing a simulation framework that models population dynamics and the interactions of both humans and mosquitoes, we may enable epidemiologists to analyze and forecast the transmission and spread of an infectious disease in specific areas. we extend the traditional seir (susceptible, exposed, infectious, recovered) mathematical model and propose an agent-based model to analyze the interactions between the host and the vector using: (i) our proposed algorithm to compute vector density, based on the reproductive behavior of the vector; and (ii) agent interactions to simulate transmission of virus in a spatio-temporal environment, and forecast the spread of the disease in a given area over a period of time. our simulation results identify several expected dengue cases and their direction of spread, which can help in detecting epidemic outbreaks. our proposed framework provides visualization and forecasting capabilities to study the epidemiology of a certain region and aid public health departments in emergency preparedness. each year, millions of people are exposed to serious health risks due to emerging infectious and communicable diseases. this poses a severe threat to the public health security at local, regional or national level; especially in underdeveloped countries. this is primarily due to the lack of infrastructure for timely collection, reporting, and analysis of epidemic data; non-existent early warning and forecasting systems; inadequate preparedness and emergency response management [ ] . . billion people in countries are at risk of contracting dengue, with estimated million cases annually. the worldwide incidence of dengue has risen -fold in the past years. pakistan is among the countries in the world which are badly affected by the mosquito-borne dengue virus. the first outbreak of dengue fever (df) in pakistan was confirmed in . the country is currently experiencing among worst-ever dengue outbreaks, recording about , confirmed cases [ ] . even today, an effective dengue vaccine offering balanced protection is still elusive. unfortunately, existing dengue vaccines are known to have limited efficacy and cure [ ] . this underscores the critical need of preventing dengue transmission and eventual outbreak by: (i) investigating favorable conditions for the dengue epidemic to occur [ ] ; (ii) plummeting the vector population [ ] ; and averting the vector-human contact [ ] , all of which are perceived as daunting challenges of epidemiology. due to the lack of ict enabled governance, the existing infectious disease surveillance systems in pakistan are unable to perform epidemiological spread analyses and effective emergency response planning [ , ] . researchers have started exploring latest techniques like artificial intelligence for diagnostic screen of dengue suspects [ ] , but these methods are still in their infancy. to mitigate these challenges, we need to develop a reliable health surveillance and rapid emergency response infrastructure, that monitors and responds to known endemic diseases in the country, and evolves to cater potential new outbreaks. this infrastructure should have the capability to collect spatio-temporal epidemiological data, analyze it using computational methods, forecast possible outbreaks and generate early warnings for rapid emergency response management. due to the sparsity of data, the dynamics of the vector population and its interaction with the human population is quite difficult to capture. we therefore need to build models that incorporate the vector population, disease transmission and the spread direction of the infectious disease, and that support the application of preemptive strategies and countermeasures. in this study we present a simulation approach to analyze and predict the mosquito population density and its consequence on dengue spread. we also simulate the pathogen transmission, and observe the dynamic interaction of human and mosquito population, both of which we use to forecast outbreaks in a spatial environment. our proposed agent-based simulation framework allows modeling of both human and vector population dynamics, using separate layers. human agents evolve between different states, from susceptible to exposed, infected and eventually recovered states while mosquito agents evolve from egg to larva, pupa and adult state. both population layers are spatially distributed and we model the interaction between both layers using our proposed algorithm. in addition, we expose both layers to exogenous variables such a temperature, humidity, rainfall and the permeable water surfaces in the region. from our simulation results we can reproduce predicted dengue cases across age groups and highlight them using spatio-temporal visualizations. we validate our results using data of an existing study of the local region [ ] . our proposed framework can be re-used for simulation, visualization and forecasting of any region and aid public health departments in emergency preparedness. the rest of the paper is organized as follows: sect. outlines the background concepts used in this paper and the literature review. section discusses our proposed framework. section provides simulation results and model validation and sect. provides conclusions and future work. this section provides key concepts used in our modeling approach. epidemiology is the study of models, causes, effects, risk factors, transmission, spread and outbreaks of infectious diseases in a particular population [ ] . denv is transmitted to humans through the bite of infected female aedes mosquitoes primarily aedes aegypti and aedes albopictus. a susceptible mosquito can acquire infection from an infectious person and transmit it further, or human gets infection from the bite of already infectious aedes aegypti. it spends its lives around or in side houses, becomes adult and typically flies up to m [ ] . adees aegypti life cycle is composed of four stages as shown in fig. . aedes aygepti proliferates around - • c. the number of eggs laid per batch depends on the weight of mosquito and other factors. details of the dengue epidemiology can be viewed at [ ] . various meteorological factors also influence the growth of the vector population and the spread of dengue fever. temperature and humidity influence the incidence of dengue fever by modifying adult feeding behavior, larval development and mosquito survival. the average life span of aedes mosquito is days, with a range from one day to days. population density of aedes aegypti rapidly increases in summers as rising temperatures shortens the incubation period of mosquitoes and they take less time to emerge from eggs to adults. this increase the overall risk of dengue transmission [ ] . the mortality rate of mosquitoes increases at high temperatures. for temperatures • c, the feeding frequency of mosquitoes increases resulting in greater risk of viral transmission. mosquito life cycle consists of two stages one of which is aquatic i.e they require stagnant water in order to develop and reproduce. rainfall plays a vital role in the development of mosquitoes and dengue transmission. there is an increase in dengue cases during and after rainy seasons. pakistan is unfortunately experiencing severe forms of above stated changes. relative humidity, temperature and rain remained noteworthy prognosticators of dengue occurrence in pakistan. surge of cases occurred from september to october [ ] , as shown in fig. . traditional non-spatial epidemiology models have been used use to represent epidemics of communicable diseases [ ] . a susceptible, exposed, infectious, recovered (seir) is an epidemiological model that describes the transmission process of an infectious disease [ ] . the individuals enter or leave the compartment based on flow rates defined. there is a decrease in susceptible individuals when individuals get infection, or they die. number of individuals in the exposed compartment increases when they get infection and decreases as soon as they show the symptoms of infection and decreases with the death rate. the infection compartment increases by the infection events of exposed and decreases by the death and recovery rate. there is an increase in recovered compartment with the recovery rate and decreases with the natural death. another extension to the sis model was proposed in [ ] . it contains three population components: humans (h), vectors (m) and eggs (e). 'l' represents the number of latent mosquitoes that are in incubation period, as shown in fig. . at first a susceptible human gets infection from a vector moves to the infectious compartment. while at infectious state, a human may get recovered and move to the recovered state or may die. an infectious human may spread infection to a susceptible vector which would move to the latent compartment, where it stays for the time between getting infection and becoming infectious, called latency period; the vector then moves to the infectious compartment. a susceptible mosquito if lays eggs increases the population of susceptible vectors, whereas an infectious mosquito if lays eggs would increase the population of infectious vectors. it is also possible that an infectious mosquito lays normal eggs. the main goal of modeling the life cycle of mosquitoes is to estimate the growth of the vector density at a place and time; and the interaction with the hosts to predict the rate of spread of disease. our proposed approach is based on the foundation of this principle. most existing mathematical models focus on non-spatial macro-level aspects of the system. because we are strongly interested in the micro-level aspects of our agents (a level where we can more easily extract rules and behaviors), we therefore use agent-based modelling. an agent-based model consists of autonomous decision-making entities: agents, each able to perceptively assess situations and make decision according to a set of predefined rules. abm is decentralized and produces collective behavior by agents communicating and interacting with each other in their environment [ ] . the interest in using abm has been recently renewed due to their ability to model complex geospatial structures and interacting networks [ ] . many researchers have proposed different dengue epidemic simulation models. however, selection of the methodology and platform greatly depends upon the purpose of the study. jacintho, et al. [ ] propose an agent-based model of the dengue spread, using the swarm platform that models the micro-level behavior of agents in the spread and transmission of dengue fever using a rule-based approach, however it lacks gis based spatial representation. almeida, et al. [ ] propose an individual-based approach to model aedes aegypti population considering vectors, humans and objects as agents, using repast framework. kang and aldstadt [ ] proposed an approach to validate spatially explicit abm for several specifications of vector-borne disease transmission models, using multiple scale spatio-temporal patterns. hunter et al. [ ] developed a data driven agent-based seir model that resulted in the emergence of patterns and behaviors that are not directly programmed into the model. lima, et al. [ ] developed dengueme, a collaborative open source platform to simulate dengue disease and its vector's dynamics. it supports compartmental and individual-based models, implemented over a gis database, that represent aedes aegypti population dynamics, human demography, human mobility, urban landscape and dengue transmission mediated by human and mosquito encounters. yein ling hii [ ] proposed a machine learning approach to study dengue fever considering climatic factors: temperature and rainfall using poisson multivariate regression and validated through multiple statistical models. guo, et al. [ ] presented a comparison of various machine learning algorithms for the accurate prediction of dengue in china, and shows that support vector regression achieved a superior performance in comparison with other forecasting techniques assessed in this study. our proposed framework uses the mathematical model proposed by [ ] , as underlying foundation and extend it using an abm approach, which consists of two population layers: (i) human and (ii) vectors (mosquitoes and eggs). both layers express the population dynamics, mobility and microscopic behavior of human and vector agents separately, yet provide a common spatial environment for their interactions, to study the spread of disease within the desired spatiotemporal resolution. this section discusses the details of our proposed framework which is composed of three layers: (i) host layer (human population); (ii) vector layer (mosquito population); and (iii) pathogen layer (dengue parameters), as shown in fig. . the framework further integrates: (i) gis based spatial environment for agent distribution and mobility; (ii) time step using a user defined temporal resolution (from min to year); (iii) simulation engine to handle change of states and dynamic event processing; (iv) database for importing input data and exporting simulation results; (v) exogenous variables for weather and climate data; and (vi) validation data for model validation. the framework also provide a visualization dashboard for viewing the change of states of the distributed population of agents in real-time (or virtual time a.k.a faster than real-time) and for the graph visualization of the simulation results. this layer concerns with the structure, behavior and the interactions of host agent and allows the modelers to initialize a host population (e.g., human or animals) using variable configurations. the behavior of the host agent is represented by a state chart, as shown in fig. which consists of six states: susceptible, exposed, infected (or immune), recovered (or dead). in this paper we assume the entire host population is initialized in susceptible state. in the future, we intend to support a distribution of initial states so that we can use more realistic model configurations of a study area. when at 'susceptible' state, a host agent receives an incoming message from an infectious mosquito, representing the 'infectious bite', it transits to an 'exposed' state. after a certain period, defined by the incubation period parameter ( - days [ ] ) either the host will transit to 'infected' state or go to immune state (if resolved immune by the immunity probability). when at infected state, an incoming 'bite' message causes a self-loop transition, which is used to transmit the virus to an uninfected mosquito, with a given probability. after a certain duration, defined by the illness duration parameter ( days) the host will transit to 'recovered' state, if resolved true by the survival probability ( . ) or 'dead' otherwise. we implement the interactions between host and vector agents using message passing and a distance based network type [ ], which implies that a vector is connected with multiple hosts that are situated within a given range ( m), and can communicate i.e. bite with infection or acquire an infection through a bite, as shown in fig. . the detailed bite algorithm is presented later in this section. this layer concerns with the structure, behavior and the interactions of vector agent. the behavior of the vector agent is represented by a state chart, as shown in fig. . it consists of states: egg, larva, pupa and adult (male or female). a vector agent can be initialized in any of these states. in this paper we assume initialize the vector population with the probability of . eggs, . larvae, . pupas and . adults ( . male and . female). the vector agents are uniformly distributed over the space, however this distribution can be fine tuned if the data of the concentrations of the mosquitoes nests is available. from egg, the agent moves on to the larva state between - days. from larva it takes days to transit to pupa state, where it resides for days and moves to the adult stage, with a . probability to be a male or a female [ ] . the male aedes aegypti neither makes a bite nor transmits infection and dies after a lifespan of days and then go to the final state 'dead '. a female mosquito can enter into the 'oviposition' state when it is ready to lay eggs. a susceptible female will lay susceptible eggs whereas an infected female lay eggs with infectious probability = . . the spawning of eggs is triggered by the event 'eggspawn'. the initial state of an egg (infected or not) depends on whether the female mosquito is in susceptible or infected state. the lifespan of the female mosquito is assumed to be between - days. inspired from the helmersson's mathematical model [ ] , shown in fig. , the 'susceptible', 'latent' and 'infected' states of the female mosquito are implemented. if not initially infected (i.e., isinfected = false), an adult female mosquito enters into 'susceptible' state. it goes to 'latent' state if bites an infected human and acquires the virus (with a transmission probability of . ). the latent period is the delay from transmission to infection and is assumed to be days, after which the agent enters into the 'infected' state. while at 'susceptible' or 'infected' states, a female mosquito bites human and have her fill of blood after each meal, at the rate of a bite after days. aedes aegypti is an intermittent biter and prefers to bite more than one person during the feeding period, therefore we assume it bites all the connected hosts. this bite is triggered by the event 'bite' at random intervals until the mosquito is dead when a 'bite' occurs the interaction between host and vector is implemented as shown in algorithm . it takes vectorid and a list of connectedhosts as input. a vector is connected to all the hosts that lie within the range of m. this algorithm determines infectivity of the vector after the bite using a boolean variable 'infected'. line assigns the existing state (infected or not) of the vector. line - iterates a list of all the connected hosts and evaluate two scenarios as shown in fig. . if the vector is infected it will transmit an 'infectious bite' through message passing, and cause the host to transit from 'susceptible' to 'exposed' state. else, if the host is infected the vector will acquire infection (with a . probability), and transit from 'susceptible' to 'latent' state. otherwise it will just 'bite' the host without the transmission of any infection. the number of times mosquito will bite human is defined by bite rate [ ] , which is temperature dependent and is calculated as: this layer deals with the modalities of the pathogen under study i.e., 'dengue' in our case. in this paper the structure and the behaviour of the pathogen is limited only to initialize the serotype (i.e., denv , denv , denv or denv ) and key parameters such as infectivity, transmisiability, survivability and incubation period. in future, we aim to extend this layer for dealing with the complex logic of the cross-immunity with different serotypes. our simulation is implemented using anylogic university edition, and performed for a population of , persons and , mosquito agents, for a period of days, on an intel core i - cpu@ . ghz, . gb ram, and a -bit windows operating system. the human and mosquito populations are randomly distributed within a selected region in the city of islamabad. a simulation run is shown using spatial and temporal visualization in fig. and . initially the person agent population is susceptible, as soon as it is bitten by infectious mosquito it becomes exposed (orange), after completing its incubation period of - days in exposed state it either becomes infectious (red) or immune (gray). from infectious state after completing - days it either becomes recovered (green) or dead (black). the simulated results obtained are compared with the actual results of confirmed cases obtained from the dengue outbreak occurred in the local region in . the actual cases were , out of the total population of , , while the simulated cases were out of the total agents' population of , . in order to compare the data results of actual and simulated dengue cases, we calculated the prevalence of both data sets: no. of dengue cases total population × ( ) fig. . comparison of dengue cases -source of actual data [ ] for comparison we present a graph containing both cases in fig. . we observe a similar trend in the prevalence of dengue cases between the actual and simulated results. the root mean square error (rmse) of both actual and simulated prevalence for the days is . . the results show that the dengue transmission is temperature dependent. it is to be noted that with the increase in temperature, the biting rate of aedes aegypti increases that give rise to the dengue cases. in this paper we presented a framework for modeling, simulation, visualization and forecasting of dengue spread, using an agent-based modeling approach. our framework incorporates the structure, behaviour and interactions of key entities of disease epidemiology: (i) host (humans); (ii) vector (mosquitoes); and (iii) pathogen (dengue virus), using a separation of concern through independent layers. our open-ended framework offers greater flexibility to the modelers for modification and extensibility of the disease under study, and can be used as a research tool by stakeholders (e.g., clinicians, microbiologists and public health professionals) to study the epidemiology of a region. the unique feature of our framework is its ability to model the life-cycle and population dynamics of both host and vector population, while incorporating extended mathematical models for the study of the epidemic spread. in the absence of vector population data, this tool provides means to synthesize vector population, and help improve the understanding of the spread of diseases. in the future, we plan to improve our proposed framework further by adding the mobility layer to incorporate movements, both in the host and vector layers. we also aim to extend our framework to support populations of a million agents or more. multiagent modeling and simulation of an aedes aegypti mosquito population ud din, i.: dengue epidemic in postconflict swat district agent-based modelling and geographical information systems: a practical primer proactive vector control strategies and improved monitoring and evaluation practices for dengue prevention is dengvaxia a useful vaccine for dengue endemicareas? dengue and dengue hemorrhagic fever developing a dengue forecast model using machine learning: a case study in china knowledge and attitude of the public towards dengue control in urban and rural areas of punjab artificial intelligence based diagnostic screening for dengue fever mathematical modeling of dengue -temperature effect on vectorial capacity climate and dengue fever: early warning based on temperature and rainfall an open-data-driven agent-based model to simulate infectious disease outbreaks an agent-based model for the spread of the dengue fever: a swarm platform simulation approach using multiple scale spatio-temporal patterns for validating spatially explicit agent-based models epidemiological trends and risk factors associated with dengue disease in pakistan ( - ): a systematic literature search and analysis mathematical models in infectious disease epidemiology dengueme: a tool for the modeling and simulation of dengue spatiotemporal dynamics assessing potential countermeasures against the dengue epidemic in non-tropical urban cities surveillance of dengue fever virus: a review of epidemiological models and early warning systems sustained reduction of the dengue vector population resulting from an integrated control strategy applied in two brazilian cities monitoring the diversity of malaria and dengue vector in karachi: studying variation of genera and subgenera of mosquitoes under different ecological conditions epidemiology: beyond the basics who: who scales up response to worldwide surge in dengue world health organization: dengue and severe dengue-fact sheet key: cord- - nb qy authors: hedayat, kamyar m.; lapraz, jean-claude title: infectious diseases of the ear, nose, throat, and bronchus date: - - journal: the theory of endobiogeny doi: . /b - - - - . - sha: doc_id: cord_uid: nb qy infectious diseases occur based on the interrelationship of the capabilities of the host and the virulence of the microorganism. each person has a terrain that determines the susceptibility to infection and response to an infection. according to the theory of endobiogeny, the majority of symptoms related to an infectious disease are related to the patient’s response to the infector and not the intrinsic agent itself. this chapter discusses common infectious maladies: rhinopharyngitis, sinusitis, otitis media, tonsillitis, and bronchitis. for each of these disorders, the neuroendocrine and emunctory elements in the precritical and critical terrain are discussed. treatment options are discussed based on treating the patient rather than the microorganism. we define infection as a pathogenic interaction of one living system within the terrain of another living system. the term "infection" is derived from the latin inficere meaning to taint. what is tainted is the coherence of the metaself (self + symbiotes-cf. chapter ) and the metastable functioning of this terrain. from this unitary definition, we derive the actors in the dyad: the nonself organism (the infector) and the terrain of the aggressed organism(s) (the infected). infections are the dynamic of the virulence of the infector relative to the adaptive capabilities of the infected. the greater the virulence is, and the less competent adaptive capabilities are, the greater the risk of infection. since the time of koch and pasteur, the exclusive line of evaluation and treatment has been the infector, with no consideration for the terrain of the infected. this is like while having a hole in one's roof and clogged gutters on a rainy day, focusing on dispersing rain clouds rather than fixing the house. we must make a distinction between infection and infectious disease. infection is the presence of an organism within another organism(s) due to insufficient defense capabilities. virchow (d. ), physician-pathologist and the founder of cellular pathology, recognized that organisms exist in tissues without causing disease. infectious disease, then, is the syndrome that results from both the specific virulence of the infector and the adaptive and adaptative responses of the infected organism(s). the endobiogenic approach to infectious disorders is rich, combining teleological, anatomical, and functional considerations of each area of the organism. it involves ascertaining the answer to seven queries: ( ) why this structure is infected: teleology of structure and function, ( ) why this patient is infected: precritical terrain, ( ) why this organism infected: the organism and its virulence-absolute and relative to the competency of host defenses, ( ) why these symptoms are manifested: critical terrain during an infection, ( ) what is the benefit of the infectious symptoms: its adaptive or adaptative role, ( ) what is the current net state of the terrain: mechanisms and consequences of endogenous response of the infected, and response of the infector, and ( ) how to manage: personalization of treatment based on the reality of both the infected and the infector. we discourage a view of seeing potential pathogens as enemies to be eliminated, or the external environment as one needing to become sterile. the world is full of life. each living being has its own path of existence and environment for survival. we cannot alter this fact of nature. to make it sterile is to sterilize life. what can be done is to strengthen the buffering capacity and adaptability of the patient for the fullest expression of their life and vitality. this allows for the greatest degrees of freedom with respect to where they go, how they live, what they do, and what they eat, without fear of invasion, infection, and disease. rhinopharyngitis is an infectious disorder of the nasal (rhino-) and pharyngeal (pharynx-) mucosa. a congestive terrain with insufficient peripheral cortico-thyrotropic adaptation of immunity favors infections in this region of the body. the nasal cavity consists of folds of mucosal tissue situated inferior to the sinus cavities and superior to the oral cavity ( fig. . ). it has a contiguous relationship with the pharynx. it is surrounded by cartilage in the most anterior position and bone in the inferior and superior regions. the posteriorinferior portion has a wall of soft tissue. the nasal cavity is the origin of the airways. respiration is an unceasing and essential function. the integrity, patency, and safety of the nasal cavities are essential to this activity. the nose extends more anterior from the surface of its origin than any other part of the body. it is literally the vanguard of chemical surveillance of the quality of air chapter and risk of exposure to nonself actors with each inhalation: microorganisms, particulate, and gaseous chemical entities. due to the constant aggression on the nasal airway, it has a high turnover rate and is subjected to permanent, intermittent relative adaptive congestion, one nostril alternating with the other. the nasal airway has three primary functions: respiration, defense, and olfaction. respiration is divided into inspiration and expiration. the functions of the mucosa during inspiration are three: ( ) determination of air quality, ( ) humidification, and ( ) filtration of air. the purposes of exhalation are two: ( ) egress of carbon dioxide (acid-base balance) and ( ) intonation of speech. the requirements of defense arise from the first function of respiration. the purpose of olfaction is to determine information crucial to the survival of the organisms: location and integrity of foods, the presence of organism of the same or different species, and reproduction. , ans parasympathetic activity is implicated in the passive nutritive congestion of the sinuses. this allows for this tissue to maintain its high rate of turnover. because it is inefficient to congest both sinuses at the same time, the organism alternates the relative tonus of para and alpha. for example, the right nostril will be congested (para > alpha) for repair and growth, while the left is open (para=alpha). the alternation of ans function is crucial to maintain a physiologic congestion. the induction of rhinopharyngitis occurs when there is a confluence of adaptative congestion and insufficient immunity and the presence of a virulent organism. the pharynx is implicated because of its contiguous anatomical and functional relationships with the nasal airway. the precritical ans state is spasmophilia with elevated histamine. the elevated histamine can be local to the mucosa as a defense mechanism, associated with alpha-sympathetic as an autacoid, or both. the emunctory terrain is oversolicitation of the exocrine pancreas, and, congestion of the gallbladder and intestines. the primum movens of the precritical terrain is a local spasmophilia with para > alpha and beta that is delayed or insufficiency relative to the alpha tone. related to the nutritive congestive activity of para (and histamines), one finds a hyperinsulinism, which favors congestion, hyperemia, and infections. the excess presence of glucose favors both the growth of tissue and pathogens. thus, the endocrine pancreas is implicated in rhinopharyngitis. oversolicitation of the exocrine pancreas favors mucous production (cf. the theory of endobiogeny, volume , chapter ). biliary and intestinal congestion favor autointoxication and diminished extracellular communication networks. in our experience, a diet that strains the gallbladder (high fat, fried foods, etc.) or the pancreas (high fat, high glycemic, hard to digest animal proteins) can contribute to nasal congestion. table . summarizes the rhinopharyngitis terrain. given the precritical terrain, the etiology of rhinopharyngitis is in three factors: pathogenic organisms, environmental irritants, and structural factors. these include nasal polyps, deviated septum, and tonsil hypertrophy. the later impairs the flow of nasal secretions through the pharynx. the critical terrain involves adrenal cortex and peripheral thyroid. thymus and spleen may also be implicated. dysregulation of immune activity involves the two catabolic axes. there is peripheral adrenal cortex insufficiency, which exacerbates hyperhistaminemia. peripheral thyroid activity is insufficient. because of the importance of thyroid activity in children from to years of age, they are particularly susceptible to ent disorders, especially when there is a latent hypothyroidism (chapter , table . ). finally, one may find insufficiency of thymic response to immune development (children) or acute infection (children and adults). congestion of the spleen can diminish the filtering of pathogenic organisms as well as the development and function of immunity. when alpha activity is quantitatively elevated in the ent region, it can congest lymphatics and lymph nodes, compromising local immune defense mechanisms. the majority of pathogenic organisms implicated in rhinopharyngitis are viruses. thus, antibiotics are not applicable unless they are used as a secondary treatment for inflammation, which we do not recommend as routine practice. our preferred approach to treatment is to address the underlying elements of the pre-and critical terrain noted earlier. because the interior of the nose is directly accessible, essential oils are a particularly efficient treatment. sinusitis is an infectious disease affecting the sinus cavities. the physiologic factors are similar to rhinopharyngitis but with a more intense active congestion by alpha-sympathetic. there are four symmetrical pairs of sinus cavities: frontal, sphenoid, ethmoid, and maxillary. the maxillary sinuses are contiguous with the nasal mucosa via the middle nasal concha ( fig. . ). the activity of the sinuses is closely aligned with that of the rhinopharynx. sinusitis is implicated as a source of rhinitis and vice versa. the sinuses serve five primary functions: ( ) ventilation, ( ) information, ( ) humidification, ( ) structure, and ( ) defense. ventilation allows for air exchange and equilibrium of pressure between the cranium and the general cephalic unit. information refers to the provision of chemical information about quality of air. the sinuses serve as a secondary source of humidification, which keeps nasal mucous hydrated. the light-weight cavities of the sinuses form a lightweight structural support for the nose and first cranial nerve. finally, the sinuses are a source of defense and containment: it contains exogenous aggressors to protect the body through its own defense system, which includes macrophages, immunoglobulins, mucous, antimicrobial secretions, etc. , , the precritical terrain is similar to that of rhinopharyngitis. patients with chronic type allergies are susceptible to sinus congestion for reasons discussed in prior chapters. local and regional agents that exacerbate the precritical terrain in sinusitis, the nature of aggression can either be a single substantial aggression, or prolonged and repetitive aggressions that fragilize the terrain : . allergy flare-up . rhinopharyngitis . adaptive demands that increase alpha . metabolic demands that increase para with a reactive alpha . weather and geographic changes with a sudden increase in hydrostatic pressure . altered ventilation . blocked drainage: that is, nasal endothelial edema and inflammation ( fig. . ), adenoid hypertrophy ( fig. . ). due to the partially or fully enclosed nature of the sinus cavities, those susceptible to sinusitis are those in whom the alpha-sympathetic activity is quantitatively more elevated than parasympathetic and as compared to those who only experience rhinopharyngitis with the same terrain. recall that in rhinopharyngitis, para is greater than alpha. . ans a. para: hyperfunctioning with congestion and hypersecretions b. alpha: hyperfunctioning to isolate the sinuses and protect the regional tissues c. beta: hypofunctioning, prolongs: i. congestion ii. obstruction iii. stagnation of secretions . endocrine: cf. rhinopharyngitis . emunctory: cf. rhinopharyngitis there is a potential role for the use of antibiotics in acute sinusitis, though even this is questionable, both in adults and children. a majority of cases resolve without treatment. in chronic sinusitis, or, chronic recurrent sinusitis, antibiotics are not effective in resolving the recidivistic nature of the infection. considering the long-term risk of cancer in patients correlating with total life-time utilization of antibiotics, [ ] [ ] [ ] we don't recommend antibiotics as an exclusive method of treating chronic recurrent sinusitis. given the risk of evolution of chronic sinusitis to allergic (extrinsic) asthma (cf. the theory of endobiogeny, volume , chapter ), it become all the more capital to treat the underlying precritical terrain. according to the theory of endobiogeny, the order of priority and intensity of therapy in sinusitis is at variance with that of rhinopharyngitis due to the location and function and accessibility of the sinuses. the top areas of focus are the sinuses and gallbladder. tonsillitis is an infectious disorder involving the lymphoid tissue of the naso-oral region-the very tissue designed to protect the ear nose and throat from infections. there refers to three sets of lymphoid tissues which are commonly referred to as "tonsils": adenoids, palatine, and lingual. as becomes readily apparent ( fig. . ): tonsil enlargement, even when noninfected, creates a terrain that favors rhinopharyngitis, sinusitis, otitis media (om), and airway obstruction with all that that implies. the tonsils sit at the cross roads of digestion, respiration, and immunity. they serve as the primary immune-protection against respiratory and digestive pathogens. they are a lymphoid tissue containing b and t lymphocytes, and macrophages. the precritical terrain develops from adaptative neuroendocrine-emunctory imbalances meant to regulate the structure and function of lymphoid tissue. the endocrine imbalances are different from the upper airway conditions. the follicular nature of lymphoid tissue and implication of thyroid-stimulating hormone (tsh) in lymphoid activity implicates gonado-thyrotropic coupling that plays an important role in the growth of lymphoid tissue. the exocrine pancreas and endocrine pancreas are implicated because of their role in the adenoidal tissue growth. om is an infectious disorder involving the serosal tissue of the eustachian tube resulting in tympanic pressure, pain, inflammation, and fever. the tympanum and inner ear cavity are serosal structures of mesodermal origin, which implicates the gonadotropic axis. the serosal structures produces secretions that act as a defense against infections from the nasopharynx. ciliary activity moves the fluid and anything trapped within it. it also equalizes ear pressure and allows for appropriate tympanic response to sound. the eustachian tube also allows for passive drainage of serosal fluid and participates in equalization of pressure. it is supported by muscles that can become dysfunctional in spasmophilic states, favoring om due to stasis of fluid. while there are numerous contributing factors, the diminished angle of drainage in infants and toddlers compared to older children and adults makes them particularly susceptible ( fig. . ). eustachian tube anatomy in infants vs adults. infants have a narrower angle to the eustachian tube that is more susceptible to stasis and stagnation, allowing microorganisms to grow in its protein-rich environment. (courtesy of netter medical illustration used with permission of elsevier. all rights reserved.) the ans dysfunction is spasmophilic, as with the other ent disorders discussed. however, the role of the ans is not only in congestion of the serosa, but stasis of serosal fluid. compromised immunity from lack of, or, insufficient duration of breast feeding, and maternal postnatal diet are correlated with increased risk of om in infancy and early childhood. there are two general categories: impaired drainage and increased exposure to potential pathogens: serosal fluid is rich in protein. in a precritical terrain, when there is simultaneously substantially diminished or blocked drainage of serosal fluid and establishment of virulent organisms a patient is susceptible to otitis media with effusion (ome). adaptative response exacerbates the precritical emunctory imbalances drainage of the liver is more imperative in om than in other ent disorders symptomatic local treatments distention of the tympanic membrane can cause significant discomfort for children. as with treatment of the nasal cavity, ready access to the tympanum from the ear canal allows for direct application of therapeutics with rapid onset of action for relief. local application of symptomatic therapies is preferred because it allows for the regional and systemic response to infections to continue and reach its natural conclusion. a. dexamethasone . %/ciprofloxacin . % . analgesic/antipyretic/decongestant a. antipyrine %/benzocaine %/phenylephrine % in the face of the fragilization and congestion of the bronchopulmonary unit, exposure to aggressors further degrades the bronchi and solicits a local and global neuroendocrineemunctory response. this response will determine the type of bronchitis. viruses are the most common cause of acute bronchitis. noninfectious agents can trigger an acute-on-chronic bronchitis. the four key factors to consider are: ( ) pathogens, ( ) particulate matter and gasses (allergens, tobacco smoke, etc.), ( ) gastric secretions with micro-aspiration, and ( ) cold. acute bronchitis develops as a maladapted response to the local aggression on the airways. it can be divided into two categories: wet or dry ( fig. . ) based on the ans response during illness. dry, inspiratory coughing is related to hyperalpha predominance. wet, expiratory coughing is related to a hyper-para predominance. the quality and quantity of mucous is further determined by the endocrine and exocrine pancreatic response that predominates in the adaptation response. the treatment must be tailored to the type of bronchitis. pharmacologic treatment with antibiotics is only modestly effective, and carries the typical short-and long-term risks associated with antibiotics already discussed. , given the self-limited nature of most cases of acute bronchitis, then, a nonpharmacological approach is worth considering. both symptomatic treatment as well as that of the terrain has been quite effective. , inflammation is the common local histopathology. all forms of acute bronchitis should be treated with antiinflammatory and antiinfectious agents when implicated. key symptomatic treatments are listed in table . with indication of symptom(s) treated. , for more severe symptoms, essential oils can be nebulized in a % concentration ( drops per ml of solution). in our experience, two highly efficient essential oils are cupressus sempervirens and lavandula angustafolia. for wet bronchitis, use % normal saline, as it helps dissolve inspissated mucous. for dry bronchitis, . % normal saline suffices. also see the theory of endobiogeny, volume , chapter for additional approaches to nebulization of essential oils. drainage is listed in order of importance (table . ). one will note that many of the medicinal plants listed are the same as those used for symptomatic treatment of the critical terrain. , fig. . bronchitis terrain. the precritical terrain (yellow) of bronchitis is shown in the upper / th of the image, where the factors related to global disequilibrium of anabolism are presented. in the second section, around oxygen demand are the fragilizers that allow for the aggressor to lead to the critical terrain. the lower half of the image shows the critical terrain specific to acute vs chronic bronchitis and acute wet vs acute dry bronchitis. acute dry bronchitis (purple) has an inspiratory cough and a predominance of alpha > para. acute wet bronchitis is an expiratory cough with a predominance of para > alpha that occurs in vagotonic individuals. the quality of mucous then further differentiates the particularities of the critical terrain in the individual and allows for a personalized approach to treatment. (© systems biology research group.) . support adrenal cortex especially in the young, the elderly and frail, seasonal bronchitis (fall and winter), strong spasmodic component neuroendocrine-infectious: passiflora incarnata mt ml, vibernum lantanum gm ml, cornus sanguinea gm ml, lavandula angustafolia eo . ml, cinnamomum zeylanicum eo ml, dose: ml three times per day for - days. emollient-drainage-infectious: agrimonia eupatora mt ml, malva sylvestris mt ml, eucalyptus smithii or globulus eo ml, cupressus sempervirans eo ml, dose: ml three times per day for - days. medicine: an illustrated history observations on the reaction of normal nasal mucous membranes nasal immunity, rhinitis, and rhinosinusitis hazardous events associated with impaired olfactory function attractiveness of women's body odors over the menstrual cycle: the role of oral contraceptives and receiver sex regulation of ovulation by human pheromones pathophysiology of nasal congestion pathophysiology of the inflammatory response the cell biology of asthma comparative anti-inflammatory effects of roxithromycin, azithromycin and clarithromycin traité de phytothérapie clinique: médecine et endobiogénie plantes médicinales: phytothérapie clinique intégrative et médecine endobiogénique rhodiola rosea: a possible plant adaptogen anti-inflammatory activity of rhodiola rosea-a second-generation adaptogen nitric oxide and the paranasal sinuses high nitric oxide production in human paranasal sinuses acute sinusitis in children: do antibiotics have any role? fibronectin: a multidomain host adhesin targeted by bacterial fibronectin-binding proteins association between antibiotic use prior to breast cancer diagnosis and breast tumour characteristics (united states) hypothesis: is antibiotic use associated with breast cancer? cancer causes control genetic testing for breast cancer: where are health care providers in the decision process the diagnosis and management of sinusitis: a practice parameter update modern assessment of tonsils and adenoids otitis media age-related morphologic differences in the components of the eustachian tube/middle ear system complementary and integrative treatments: otitis media tonsillectomy and adenoidectomy. changing indications incidence of acute otitis media and sinusitis complicating upper respiratory tract infection: the effect of age upper respiratory tract infections in young children: duration of and frequency of complications passive smoking after tympanostomy and risk of recurrent acute otitis media relationship of passive cigarette smoking to otitis media efficacy of naturopathic extracts in the management of ear pain associated with acute otitis media pulmonology web site antibiotics in acute bronchitis: a meta-analysis are antibiotics effective treatment for acute bronchitis? a meta-analysis are antibiotics effective in the treatment of acute bronchitis? retrouver et garder la santé hypertonic saline nasal provocation stimulates nociceptive nerves, substance p release, and glandular mucous exocytosis in normal humans bronchitis is an infection of the upper airways of the lungs that occurs due to local inflammation and congestion. the bronchi are the main airways leading to the lobes of the lungs ( fig. . ). they have a series of cartilaginous rings that provide structural support during the negative pressure of inspiration. the main bronchus is contiguous with the trachea, which is superior to it. the main bronchus splits into two branches: left and right. the left bronchus further splits into left superior and left inferior branches. further divisions of the airway are referred to as bronchioles. they have a considerably smaller diameter and lack the cartilaginous rings. with respect to gas exchange, the bronchi are "dead space." its roles are centered around qualifying the air and protecting the lungs and the body. it conducts oxygen into the lungs during inspiration and carbon dioxide out during expiration. it provides additional conditioning of air (after the nasal airway) by further humidifying it. it provides immunologic and environmental defense in three ways: bronchial-associated lymphoid tissue (balt), mucous, and cilia. mucous traps particulate matter and the cilia move it cephalad allowing for it to be expectorated. the precritical terrain is a global neuroendocrine hyperfunctioning with fragilization of the bronchi. this may occur via numerous factors, discussed below in the order of importance in the general rate of anabolic functioning. all factors listed are overfunctioning the net effect is a local congestion and fragilization of the bronchi. regardless of the wet or dry nature, when the cough is spasmodic, the endocrine-infectious treatment can be modified to address the spasm:neuroendocrine-infectious: ribes nigrum gm ml, populus niger gm ml, satureja montana eo . ml, cinnamomum zeylanicum eo . ml, dose: ml three times per day. children are more taste sensitive. remove the essential oils from the tincture and utilize a topical blend of antispasmodic essential oils. eucalyptus ssp. eo drops, lavandula angustafolia eo drops, cupressus sempervirans eo drops in tbsp ( ml) carrier oil: mix in a glass bowl, apply with friction rub in circular and cephalad/caudal motions for - min, then cover chest with a shirt or blanket, then a heated pad or towel. repeat up to every hour as needed. may also diffuse in an aromatherapy diffuser placed within . m from the child. diet . free of sugars, cooked animal fats . liquid diet during acute phase with root vegetables: turnip, black radish, and juices of carrot, quince, chervil, cabbage, lettuce, mulberry, apple, and turnip from the perspective of the theory of endobiogeny, infectious diseases are best viewed as arising from a triadic interaction between the infector, the terrain of the infected, and the environmental factors that favor the former and adversely effect the latter. among the infectious diseases presented here, few have been shown to be effectively managed with antibiotics as first-line treatment in uncomplicated cases. there is, then a quandary which the physician faces. to use antibiotics may induce harm and is likely not effective. to not treat leaves the patient suffering and is a burden on the family, work and thus on society as a whole. if not this, then what to use? we have found in our nearly five decades of clinical practice the rational clinical usage of medicinal plants quite effective. they can be applied symptomatically, to the critical terrain, or precritical terrain to prevent recurrent infections. the approach laid out involves both anti-infectious treatments and drainage, but also regulation of the neuroendocrine determinants of the infectious terrain. in the out-patient population, this approach proves efficient and compassionate to alleviate the burden faced by the patient. key: cord- -dde nlhh authors: antabe, roger; ziegler, bianca rosa title: diseases, emerging and infectious date: - - journal: international encyclopedia of human geography doi: . /b - - - - . - sha: doc_id: cord_uid: dde nlhh emerging and infectious diseases have persisted as leading causes of global morbidity and mortality. caused by pathogens including bacteria, viruses, parasites, or fungi, they are known to pose serious health threats to the world's population dating back to ancient egypt. in the th century alone, infectious diseases were responsible for decimating – % of the world's population. the discovery of vaccines, coupled with improved sanitation, hygiene, and health care, witnessed the eradication of several infectious diseases, although some have resurfaced or are resurfacing since the latter part of the th century. while geography partly define hotspots for emerging and infectious diseases, low socioeconomic development, poverty, and underfunded health care systems remain driving forces for the reoccurrence of these diseases among vulnerable populations who experience material deprivation. to eradicate infectious diseases, a global response will have to prioritize the allocation of resources by way of expertise and technology to areas that are most affected. furthermore, an effective surveillance system, and a rigorous vaccine deployment regime targeting vulnerable persons and regions is desirable in mitigating the impacts of these diseases. infectious diseases are illnesses, which are spread directly or indirectly, from person to person. infectious diseases can be classified under one of the following origins: zoonotic, vector-borne, or drug-resistant. the majority (over %) of emerging and reemerging infectious diseases are caused by bacteria, viruses, parasites, or fungi, which were passed from animals to humans, known as zoonotic pathogens. zoonotic pathogens, which originated in wild life, are the causative agents for diseases such as severe acute respiratory syndrome (sars) and ebola. as a result, zoonotic infectious diseases have led to epidemics that drew attention to the interactions between humans and wildlife, including the domestication of animals, food production and intensive farming, moving animals and plants to foreign environments, urban sprawl and migration, and climate change and deforestation. vector-borne infectious diseases are spread between humans and animals by vectors such as mosquitoes and ticks. these diseases, including malaria and lyme disease, impact specific geographic regions. tropical and subtropical areas are disproportionately affected, and the poorest and most vulnerable tend to face the highest burden of these diseases. the history of these diseases includes widespread illness and high mortality rates affecting populations on a global scale. the history of infectious diseases goes back as far as smallpox being found on egyptian mummies and the plague infecting and killing - % of the world's population in the th century. however, by the end of the s, most infectious diseases were considered a health issue of the past. with improved public health measures including sanitation processes and sewage treatments, as well as improved healthcare services and the introduction of antibiotics and vaccination protocols, the prevalence of infectious diseases appeared to be declining. as a result, health care professionals and researchers turned their attention and available resources toward the rising issue of chronic disease. yet, during the last quarter of the th century, infectious diseases began to reemerge with new and resurgent diseases cited as causes of morbidity and mortality for large populations. since this time, infectious disease rates have continued to rise, new diseases have emerged, and previously eradicated diseases have reemerged. the emergence and reemergence of infectious diseases has mostly been attributed to the unintentional consequences of human behavior, activities, and development. the threat of emerging and infectious diseases (eids) to human health, society, and the global economy is increasing as infectious diseases continue to evolve and spread. to illustrate, in alone over million people died from hiv, and million people contracted malaria. furthermore, the sars outbreak in resulted in death for out of the infected patients within months, with the survivors experiencing ill health and, in some cases, disability. clearly, infectious diseases such as sars place added stress on healthcare systems in affected countries as these systems must mobilize resources to effectively deal with the epidemics. they also create tensions within communities and decrease economic prosperity. for example, travel, tourism, and retail sales dropped dramatically during the sars epidemic, especially in asia where the disease originated and was most prevalent. globally, the economic impact of sars was estimated to be $ - billion usd. emerging and reemerging infectious diseases are largely preventable, and yet with their profound impact and increasing prevalence, they remain a threat to global health, which must be addressed. humans and pathogens have always been in a dynamic state of interaction; however, current trends reveal that this relationship has become unbalanced as human activities are causing pathogens to appear and spread at an increasingly alarming rate. as aforementioned, the st century has seen a rise in infectious disease, largely due to the societal and global trends that are reinforced by an increasingly technological, globalized, and interconnected world. between and , infectious diseases, such as tuberculosis, sars, and h n , emerged or reemerged in both the developed and developing world. these diseases caused the death of an estimated million people per year, with % of these deaths occurring in the concentrated region of south-east asia and the sars outbreak in china affecting other countries. by the end of april , a measles outbreak in the united states affected people, % of whom were unvaccinated. similarly, in the european region, the who reported a total of , measles cases by march , with related deaths in the preceding year. additionally, the world is still battling with diseases such as hiv/aids, malaria, ebola, h n , and dengue fever. each year, approximately million travelers transport pathogens between places and provide a means for infectious disease to spread across borders. the increased globalization of the world has resulted in travel and trade being facilitated on a global scale, which has caused infectious diseases to spread more easily to countries that were previously unaffected. moreover, there is a higher prevalence of infectious diseases in low-income and developing countries due to increased poverty, social inequality, and conflict, leading to increased susceptibility and a decreased capacity to effectively provide sufficient treatment. additionally, environmental variability due to climate change has lengthened the season in which vectors are present and impacted agricultural practices, allowing for increased transmission. furthermore, vectors have also become resistant to numerous pesticides making it harder to control the spread of the diseases, which they carry. another important issue that is feeding the emergence and reemergence of infectious diseases is the issue of drug resistance to treatment. increasingly microorganisms are evolving and adapting which makes it difficult to treat these diseases, thus increasing their rate of transmission. many factors lead to drug-resistant infectious diseases including antibiotic misuse (such as not finishing an entire dose of antibiotics), over-prescription of antibiotics, and the use of antibiotics for agriculture and animal production that can lead to antimicrobial resistance. moreover, vaccinations not being kept up to date or not being administered to the majority of the population to maintain herd immunity has led to drug-resistant diseases, which have evolved and rendered current vaccines ineffective. many infectious diseases are evolving more quickly than effective treatments can be created and tested, as a result, as drug-resistant diseases continue to increase in prevalence, their threat to human health continues to increase. other health trends have also contributed to the infectious disease epidemic. an aging population with a higher life expectancy has resulted in an increased proportion of the population being elderly, thus susceptible to infectious disease, and less likely to have the capacity to combat sickness. much of the world also suffers from multimorbidities, with chronic diseases such as diabetes and heart disease on the rise, once again increasing susceptibility. similarly, the hiv/aids epidemic has resulted in a large immunocompromized population who are vulnerable to contracting multiple infectious diseases. the prevalence of hiv/aids declined globally by % between and . however, as of , . million people were infected globally with hiv/aids, with africa having the highest proportion of hiv/aids cases, a trend which like the general trend of emerging and reemerging infectious disease prevalence is not declining quickly or equitably enough. eids have been posited by researchers to persist as a global health concern for the next couple of decades particularly in poor and under-resourced settings in the global south. however, efforts at the global level yield the potential to address incidences of eids. in line with these objectives, there have been proposed strategies to address current trends of eids. the sustainable development goals (sdgs), created in , identified infectious diseases as a priority area for health policy; sdg . set out to end numerous infectious disease epidemics, such as hiv/aids and malaria by . the sdgs posit that through increased surveillance and allocating more resources and funding to this health issue, diagnostic and treatment programs will be improved, and the epidemic of emerging and reemerging infectious diseases will once again begin to decline. in the meantime, there is urgency in building a global network consisting of a team of specialists in eids. this network will be hinged on improved communication surrounding risks of outbreaks in global hotspots that are difficult to access. this will be foundational to addressing outbreaks, as the who has observed that areas with more frequent outbreaks and endemic cases of reemerging infectious diseases such as hiv, hbv, and ebola tend to be in low-and middle-income countries. budget constraints in allocations for emergencies and laboratory research may therefore be undermining efforts at total eradication of eids in these areas. the lack of coordinated effort in understanding the nature and extent of outbreaks among specialists may be a major contributory factor where isolated cases of eids easily escalate to full-blown epidemics. therefore, a global network of specialist and experts is key in designing future responses to eids. the introduction of vaccines led to the eradication of major infectious disease such as smallpox and measles that plagued earlier centuries as leading causes of death. currently, immunizations alone are estimated to avert two to three million global annual deaths. targeting populations at increased risk, including high-density areas and those in the geographies of elevated risk of zoonosis, with vaccines will lead to a substantial decline in new outbreaks. the trial of ebola vaccines marks a major milestone in reducing mortalities associated with the current perennial outbreak of the ebola virus in west and central africa. as well, after an initial trial of malaria vaccines ended in , the who has recommended an expanded trial in three countries in sub-saharan africa, based on this trial, deployment of this vaccine could be sanctioned across the globe to eradicate malaria. similarly, discussion on the deployment of preexposure prophylaxis (prep) and post exposure prophylaxis (pep) for hiv in both endemic and nonendemic contexts in the global south and north respectively, and among exposed populations, holds the key to achieving sections of the sdgs and the unaids - - . it is worth noting that, an effective surveillance system of people and areas at risk, will lead to early detection of instances of microbial and drug resistance in vaccines and treatment of eids. particularly for eids that are asymptomatic, providing access to testing and screening services is desirable to obtain an early warning and to devise a response to outbreaks. this is largely dependent on available resources at the locale by way of laboratory or clinical technology that will be most effective in the timely detection of new incidences of eids. for instance, only % of people with viral hepatitis have been diagnosed due to limited access to testing services. given that a large percentage of eids are concentrated in countries where governments are under-resourced in responding to outbreaks, well-equipped testing and screening facilities for the public at risk are needed. currently in low-income settings where health infrastructure is under-developed, point-of-care (poc) diagnostics have emerged with the potential for inexpensive, effective, and timely diagnoses of infectious diseases. this also calls for the development and deployment of diagnostic techniques that are suitable for specific regions or geographies. in view of the disproportionate global burden of infectious diseases where some regions are more prone relative to others, a key consideration in eradicating eids may be the reallocation of resources, including expertise and clinical technology to areas that are most impacted. currently, areas least affected by eids receive a higher allocation and concentration of resources to respond to outbreaks. in this regard, in the context of developing countries, hbv, hiv, and ebola have persisted largely due to the absence of funding to secure vaccines and treatment for populations at heightened risk of infection. this is in sharp contrast to the context of the global north where eids are less prevalent but have control of global resources in eradicating infectious diseases. zoonotic pathogens account for . % of all eids, of which an estimated . % are contracted through contact with wildlife. in this context, understanding human contact with wildlife and how to minimize it in hotspots with highly biodiverse fauna can help contain new incidences. moreover, the limited outbreak of eids in areas where conservation efforts have drastically reduced anthropogenic contacts with wildlife means more conservation efforts will lead to a substantial decline of eids. it is also crucial to institute smart surveillance in areas of high population density to avoid new strains of infection from reemerging. see also: epidemiological transition; medical geography. emerging and re-emerging infectious diseases: the third epidemiologic transition emerging infectious diseases: public health issues for the st century global trends in emerging infectious diseases point-of-care testing for infectious diseases: past, present, and future thomas hepatitis b virus epidemiology, disease burden, treatment, arid current and emerging prevention and control measures geography, ecology and emerging infectious diseases emerging infectious diseases: threats to human health and global stability factors in the emergence of infectious diseases the epidemiology of hiv and other sexually transmitted infections in african, caribbean and black men in toronto developments in the diagnostic techniques of infectious diseases: rural and urban prospective shweta sustainable development knowledge platform. www.who.int/whr/ /media_centre/press_release/en/ world health organization www.who.int/news-room/fact-sheets/detail/immunization-coverage world health organization: immunization coverage key: cord- - ozkly authors: walker, d.h. title: principles of diagnosis of infectious diseases date: - - journal: pathobiology of human disease doi: . /b - - - - . - sha: doc_id: cord_uid: ozkly infectious diseases are diagnosed by detection of a bacterium, virus, fungus, protozoan, or helminth in a patient with a compatible clinical illness. the methods of detection include cultivation of bacteria and fungi on growth medium, isolation of viruses in cell culture, and identification of the agent biochemically, antigenically, or genetically. infectious diseases can also be identified by detection of a specific immune response, usually antibodies, that develop during the course of illness. visualization of an agent in infected tissue can provide a diagnosis based on specific morphological characteristics or identify the category of organism, for example, gram-positive or gram-negative bacterium or virus (e.g., eosinophilic cytoplasmic inclusion bodies in neurons in rabies virus infection). methods that detect and allow visualization of antigens (immunohistochemistry) or nucleic acid sequences (in situ hybridization) provide more specific diagnoses. detection of specific nucleic acid sequences amplified by polymerase chain reaction is a powerful molecular diagnostic tool. since the elucidation of the etiology of the first infectious disease, anthrax, more than years ago, koch's postulates have been applied and modified as novel technologies and agents have emerged. during the last years, more than previously unknown agents of infections have been identified in emerging infectious diseases, a phenomenon that is likely to continue. dh walker, university of texas medical branch, galveston, tx, usa elsevier inc. all rights reserved. contagion the ability of a disease to spread by exposure of a person to an infected patient. cytopathic effect the microscopic observation of damage to a cell in culture after infection by a pathogenic agent, usually a virus. differential diagnoses a list of potential diagnoses in a patient who develops a particular set of clinical manifestations. immunohistochemistry a method by which antigens such as those of a particular agent are detected in a tissue section by microscopy by reaction with an antibody and subsequent colorimetric or fluorescent signal-generating methods. in situ hybridization a method for the detection of a genetic sequence in tissue by annealing with a complementary nucleic acid probe coupled with colorimetric, fluorescent, or radiographic detection. opportunistic infection infection with a normally nonpathogenic organism that occurs in an immunocompromised host. prior to the work of koch and pasteur demonstrating in that anthrax is caused by the microscopic bacterium bacillus anthracis, the concept of infectious diseases did not exist. indeed, at that point, there was only one curiosity that could be called an infectious disease, namely, anthrax. robert koch's teacher, jacob henle, had published in a theoretical treatise, 'on miasmata and contagia,' in which he put forth the criteria that one would have to meet to establish that a microorganism caused disease. these criteria now known as koch's postulates are considered the fundamental steps by which an agent is proven to cause a particular infectious disease (table ) . three centuries earlier, hieronymus fracastoro had described clearly the principles of contagion, that is, that exposure of a person to a specific disease such as measles could result in the individual's development of measles, not smallpox, and exposure to smallpox resulted in cases of smallpox, not measles. the scientific identification of viruses, bacteria, fungi, algae, protozoa, and helminths as etiologic pathogens of specific diseases then exploded after elucidation of the etiology of anthrax from the late nineteenth century to today. progress employed available tools such as microscopy, experimental animals, and microbial cultivation techniques and advanced more rapidly with the knowledge of the nature of viruses, immunologic methods, electron microscopy, and molecular methods. when a patient seeks medical attention because of illness, the physician searches for evidence to establish a diagnosis that leads to treatment that will cure or ameliorate the illness. prior to the medical encounter, the diagnostic possibilities are enormous ranging from medical and surgical diseases to the field of psychiatry. infectious diseases in theory offer the greatest opportunities for specific nonsurgical treatment of illness. the key to a favorable outcome is an astute clinician who seeks appropriate clinical, occupational, social, and travel history; considers wisely the potential epidemiological exposures; and gathers incisive data from the physical examination, radiological studies, and laboratory testing. the intermediate result is a prioritized list of differential diagnoses with focus on identifying diseases with the highest clinical consequences and those that are amenable to treatment. specific diagnoses require isolation of the agent in culture, microscopic visualization of the pathogen in tissue lesions, and/or detection of a specific host immune response to the organism. these tasks are accomplished by clinical microbiology and immunology laboratories and pathologists. bacteria comprise the group of agents of the greatest volume and therapeutic consequence that are cultivated in the microbiology laboratory. the culture results must be interpreted with knowledge of the pathogenic potential of the bacterial species isolated and the normal microbial flora at the anatomical site that was the source of the cultured sample. the recognition of contaminants and opportunistic pathogens requires specific knowledge and judgment. escherichia coli could be the cause of septic shock or enterocolitis or merely normal flora or a contaminant. on the other hand, mycobacterium tuberculosis is always a pathologically significant isolate. there are numerous approaches to the isolation of bacteria that are designed to recover particular pathogens that involve the appropriate media containing particular nutrients, salts, inhibitors of other organisms, and growth conditions (e.g., temperature, ph, and anaerobic atmosphere). selection of culture media (nonselective, selective, and differential) for a particular specimen is mostly based on the clinical history and the specimen source (blood, feces, csf, and sputum). automation of blood culture systems has greatly expedited and improved the isolation of infectious agents from blood. it is necessary to specify whether the culture requested is routine, anaerobic, or other specific microbial groups (e.g., mycobacteria) or a particular agent (e.g., brucella). some bacteria grow slowly requiring that cultures be requested to be held longer if certain organisms are suspected. some bacteria have yet to be cultivated (e.g., treponema pallidum). although a few fungi grow on some standard bacterial media, most fungi are recovered in the mycology laboratory on media designed especially for their propagation. fungi that are widely disseminated as spores in the environment and may contaminate cultures or normal yeast flora of some body sites require judgment to initiate or withhold antifungal treatment. identification of fungi has been accelerated greatly in microbiology laboratories by performing either hybridization tests or polymerase chain reaction (pcr) on media growing a fungus that is not identifiable by conventional morphological techniques such as blood culture bottles that contain yeast growth. identification of mycobacteria has also been greatly improved by the availability of dna-based tests on specimens inoculated into liquid medium. once mycobacterial growth is flagged by the automated system, molecular identification is possible, shortening the time until appropriate treatment is initiated. viral infections can be diagnosed by propagation of viruses in cell culture. the presence of viral replication in monolayers of cells in the virology laboratory is classically recognized by injury to the cells caused by the viral infection, known as cytopathic effect. many viruses do not cause microscopically detectable injury to the cell monolayer, and there is no cell type that is universally susceptible to all families of viruses. moreover, there are viruses that have yet to be recovered in cell culture. it is wise to provide the name of the patient's condition (e.g., meningoencephalitis or pneumonia) to the virology laboratory and to indicate the particular viruses that are suspected in order that appropriate cells and procedures will be employed. viruses that are recovered in cell culture can be identified by immunologic and molecular methods. direct detection by such methods has replaced a large portion of viral isolation efforts. some viruses (e.g., the herpes viruses including herpes simplex virus types and , cytomegalovirus, varicella-zoster virus, and epstein-barr virus) cause infections that persist long after the acute illness. recovery of any of these viruses other than in the classic acute infection may reflect asymptomatic viral shedding or an opportunistic reactivation causing clinical illness. the viral quantities are greater in clinically significant conditions. the immune system, which evolved to control infectious diseases, also provides an approach to determine the diagnosis of an infectious disease. the adaptive immune response recognizes antigens of the infecting agent by production of antibodies and generation of antigen-specific t lymphocytemediated cellular immunity. the antigens that are recognized range from epitopes that are present on only one species, subspecies, or strain to antigens that are shared by agents in a genus, family, or larger group. the patient's antibodies to particular antigens that are detected and measured in the serology laboratory frequently identify the agent of the infection. various serological tests employ the methods of immunofluorescence, enzyme immunoassay, agglutination, western immunoblot, or others. the drawbacks and pitfalls of the serological diagnostic approach include the frequent absence of antibodies in serum at the time of the patient's presentation for medical diagnosis early in the course of illness prior to their production, the occurrence of cross-reactive antibodies stimulated at an earlier time by other organisms that may be misinterpreted as diagnostic of the current illness, the occurrence of persistent specific antibodies stimulated by a previously resolved infection, and misinterpretation of the reported results owing to lack of knowledge of the levels of antibodies that are generally considered diagnostic. although it is sometimes possible to observe infectious organisms by direct examination of a clinical specimen macroscopically (e.g., worms passed in feces) or microscopically (e.g., t. pallidum by dark-field microscopy of a genital lesion of suspected syphilis), diagnostic evaluation usually begins with a stained smear of sputum, cerebrospinal fluid, urine, wound exudate, or other specimen. the pathologist examines microscopic sections stained routinely with hematoxylin and eosin (h&e). large organisms such as helminths are readily observed and can be identified by their specific morphological characteristics by one with particular expertise. routinely stained sections reveal brown-pigmented fungi, which stand out from the pink and blue of eosin and hematoxylin. table henle-koch postulates for the demonstration that a microorganism causes a disease . the organism occurs in every case of the disease in question and under circumstances that can account for the pathological changes and clinical course of the disease . it occurs in no other disease as a fortuitous and nonpathogenic parasite . after being fully isolated from the body and repeatedly grown in pure culture, it can induce the disease anew some eukaryotic protozoa and fungi can be detected and identified by the presence of pigment (e.g., some malarial parasites), subcellular structures (e.g., kinetoplasts of leishmania), or particular size, reproductive process, and cell wall structure (e.g., broad-based budding and refractile cell wall of blastomyces dermatitidis and large sporangiophores containing endospores of coccidioides immitis). some viruses cause pathological changes in the infected cells such as the formation of syncytial multinucleated giant cells and accumulations of proteins often of viral origin that are stained with eosin or hematoxylin (viral inclusions) in the nucleus or cytoplasm. recognition of the cytopathic effects and eosinophilic or basophilic cytoplasmic or intranuclear inclusions can lead to a specific diagnosis such as rabies or cytomegalovirus infection or point to a group of viruses that cause similar pathological changes such as herpes simplex viruses and and varicella-zoster virus. more often, infectious organisms are detected in smears of clinical samples or histological sections that have been stained by methods such as the gram stain that color gram-positive bacteria dark blue and gram-negative bacteria pink. the morphology of the bacteria as cocci or bacilli further characterizes the agent. the acid-fast stain is particularly useful for detecting mycobacteria and diagnosing tuberculosis. bacteria that stain poorly or not at all by the gram method can be visualized after silver impregnation staining (e.g., the warthin-starry method), which can detect treponema, legionella, leptospira, and indeed nearly all bacteria. a separate silver-staining technique (e.g., gomori's method) is very useful for detecting fungal yeast and hyphae. the only pathogenic fungus with a mucin capsule, cryptococcus, is identified by a stain such as mucicarmine. the most powerful tool for specific microscopic diagnosis of infectious diseases is immunohistochemistry. antibodies to antigens of particular bacteria, viruses, fungi, and protozoa have been produced, standardized, and made commercially available to react with the agents after appropriate processing of the tissue sections. after incubation of the antibody with the appropriately prepared microscopic section, the unbound antibody is washed away. only antibody bound to the infectious agent's antigens remains bound to the tissue section. the bound antibody is reacted with a series of reagents that deposit a colored precipitate on the antigen, allowing the detection, anatomical localization, and morphological analysis that has the ability to identify the agent and establish the diagnosis. the location of the agent is often very particular, and the expected size and shape of an organism add weight to confidence in the diagnosis. each infectious species contains a unique genome, dna for bacteria, fungi, protozoa, and some viruses and rna for the other viruses. transcription of the genetic dna into messenger rna results in many copies of some rna sequences. in situ hybridization is the method of detecting specific dna or rna sequences by annealing complementary dna or rna containing a label that is used to generate a visible product at the location of the target nucleic acid sequence in infected tissues. those powerful techniques have not been exploited for the diagnosis of infectious diseases as extensively as immunohistochemistry. however, they are very effective and can be used to distinguish among even closely related organisms. detection of dna or rna with nucleic acid sequence of a specific infectious agent powerful methods for the amplification of the nucleic acid sequences of few genomes of a bacterium, virus, or other agent to produce and detect millions of copies of the targeted sequence have provided a sensitive approach to the diagnosis of infections. the key to the technique is polymerase chain reaction (pcr), a heat-stable dna polymerase from organisms that reside in thermal springs. thirty or more thermal cycles of dna synthesis initiated by primers with specific dna sequences yield logarithmic increase in the particular dna fragment. for rna genomes such as those of rna viruses, a step of enzymatic conversion of rna to dna is performed using reverse transcriptase. identification of a novel, causative agent of a previously unknown infectious disease is a special challenge. in , the us surgeon general stated, "it's time to close the book on infectious diseases. the war on infectious diseases is over, and we have won." it was believed for the next quarter of a century that vaccines and antibiotics had controlled infectious diseases. in reality, approximately previously unknown agents of infectious diseases have been identified beginning in with marburg virus, the original agent of an african viral hemorrhagic fever. because it is clear that the emergence of infectious diseases will be a continuing occurrence, medical personnel should understand how these mysteries are solved. there are four steps in the discovery of emerging pathogens: ( ) awareness of the presence of an unknown disease, ( ) detection of an infectious agent in association with the disease, ( ) determination that the agent causes the disease (koch's postulates revisited), and ( ) determination that the etiologic agent is novel. awareness of an unknown disease may occur because of the abrupt onset of a cluster of cases of a severe illness or recognition of distinctive gross or microscopic pathological lesions. severe acute respiratory syndrome caused by a novel coronavirus is a recent example. in contrast, a syndrome of unknown etiology may have been well defined clinically for many years prior to discovery of an infectious etiology. gastric and duodenal ulcers caused by helicobacter pylori and cat scratch disease caused by bartonella henselae are examples of such diseases for which a microbial agent was unsuspected or long elusive, respectively. the methods for the initial detection of a previously unknown agent have included microscopy, bacterial culture, cell culture, animal inoculation, electron microscopy, cross-reaction of antigens in serological tests, immunohistochemistry, and pcr amplification followed by dna sequencing of the products. these are the same methods used to diagnose infection experimentally and characterize the agents. the methods used to support the etiologic role of the pathogen have included experimental animal infection, self-experimentation, laboratory accident, and demonstration of the development of a specific immune response to the agent. demonstration that the pathogen is novel includes classical biochemical phenotyping, antigenic analyses, dna or rna gene sequencing, unique ultrastructural morphology, and identification of a novel toxin. the field of emerging infectious diseases is where diagnostic infectious diseases and basic science meet to solve current biomedical infectious challenges. the roles of the astute clinician, pathologist, and laboratory technologist have been important. knowledge of microbiology, virology, immunology, molecular biology, and both cutting-edge and classic technologies has been critical to effective application to the discovery of novel pathogens. often, identification of the genus of the agent allows the selection of effective antimicrobial treatment that would have been previously unknown. the payoff of knowledge is noteworthy. pathology of infectious diseases infectious diseases: atlas, cases, text. the mcgraw-hill companies emerging pathogens: challenges and success of molecular diagnostics immunohistochemistry of infectious diseases diagnosing emerging and re-emerging infectious diseases: the pivotal role of the pathologist koneman's color atlas and textbook of diagnostic microbiology infectious disease pathology: clinical cases detection of infection or infectious agents by use of cytologic and histologic stains key: cord- -y pzsoqa authors: adalja, amesh a. title: biothreat agents and emerging infectious disease in the emergency department date: - - journal: emerg med clin north am doi: . /j.emc. . . sha: doc_id: cord_uid: y pzsoqa the challenges faced by the emergency physician with recognizing and treating category a biothreat agents and emerging infectious disease are summarized and reviewed. emergency physicians in every location in the world, in developed and developing countries alike, will undoubtedly be confronted with the possibility of an emerging infectious disease in their career. a subset of these physicians may be faced with a patient who has potentially been exposed to biological weapons. of the myriad infectious disease emergencies an emergency physician contends with, these possibilities are the gravest and most impactful. in such scenarios, the emergency department (ed) clinician can be the key in recognizing or containing an outbreak. the challenge inherent with emerging infectious diseases presenting in the ed is that such cases can be camouflaged, lurking amongst innumerable infectious disease clinical syndromes, from common colds to viral rashes. this article provides guidance to emergency physicians as to how to approach this challenging problem as well as familiarizing readers with specific microbial threats of high consequence. a key method for detecting the presence of an emerging infectious disease syndrome or a biological weapons exposure in an ed patient is to develop a general approach that seeks out key historical and physical examination clues. this approach is not different from what is included in a full history and physical examination but requires meticulous attention to certain aspects of the history. travel history becomes a key focus of the history because many infectious diseases, especially of the emerging variety, have delimited borders in which they are prevalent. the travel history must be coupled, however, with situational awareness as to what infections are known to be present in specific parts of the world. such a task is daunting for most physicians and, therefore, it is important that they know where such resources can be found. both the centers for disease control and prevention (cdc) (www.cdc.gov/travel) and promed (program for monitoring emerging diseases) (www.promedmail.org) are such resources that are easy to access and continually updated. using these resources, a busy provider can quickly assess which specific infection risks any given country might confer. an important component of the travel history is understanding the dates of travel and how they relate to the incubation period of specific infections. travel must be contextualized and integrated with incubation period, because domestic infections acquired before or after travel might be mistaken for a travel-related infection. additionally, eds in a given geographic locale (eg, metropolitan area, county, or state) should develop a mechanism to have insight into changes in ed volume, chief complaint mix, and unusual diagnoses at other eds in the region. much of this can be accomplished through leveraging emergency health care coalitions and local or state health departments to develop tools to enhance insight into the vicissitudes of a given region's ed-relevant infectious disease problems through syndromic surveillance programs. an important component of an individual's risk for particular infections is related to exposures. attention must be paid to animal exposures (domestic and wild), eating habits, occupation, and hobbies. additionally, it is essential to determine if a person has had any sick contacts or has attended a mass gathering, because an ed physician might be seeing one of the first formal presentations of a wider outbreak. of the specific biological agents, the category a agents (anthrax, plague, tularemia, and botulism), and certain viral hemorrhagic fevers (vhfs) (eg, ebola, marburg, machupo, and lassa fever) are of the highest priority. table provides salient points regarding the treatment of the category a biothreat agents. in all cases of uncertainty, prompt consultation with an infectious disease physician is recommended. anthrax is caused by the gram-positive bacillus, bacillus anthracis. it is a ubiquitous spore-forming gram-positive bacterium that is found naturally in the soil worldwide. it is a disease of herbivores. humans can contract of forms of the infection: cutaneous, inhalational, injectional, and gastrointestinal. , of these forms, cutaneous is by far the most common and represents a majority of cases. an intentional release of anthrax is expected to result in primarily inhalational cases. anthrax is not contagious from person to person and no special precautions are required. adalja cutaneous anthrax is characterized by a painless black ulceration ( fig. ) that occurs on the site of exposure. infection is more common in those exposed to animal products contaminated with spores, such as meat, drum skins, or wool. after an incubation period of approximately days, the lesion characteristically begins as a papule and progresses to a black eschar. diagnosis is often clinical, although culture, biopsy, polymerase chain reaction (pcr), and serology confirm the diagnosis. mortality is low if the disease is recognized and treated with appropriate antimicrobials. treatment regimens include oral ciprofloxacin or doxycycline (although penicillin may be used if susceptibility is known) for days. if exposure was through a biological attack, treatment duration is extended to days to cover incubating spores that may have been inhaled. injectional anthrax has been exclusively linked to use of contaminated illicit drugs whereas gastrointestinal anthrax is due to ingestion of contaminated food. , inhalational anthrax is the deadliest form of anthrax and occurs on inhalation of as little as spore. anthrax was historically known as wool sorter's disease because of its linkage with the occupation of wool sorting, in which spores on sheep's wool became aerosolized. the disease is characterized not by pneumonia but by mediastinal widening (fig. ) that can progress rapidly to shock. toxin-laden pleural effusions may be present. the disease begins after a week-long incubation period and is typically biphasic with flulike symptoms (with the notable exception of rhinorrhea) occurring before a terminal phase. when anthrax of any form progresses, the grave complication of hemorrhagic meningitis can occur. the treatment of systemic anthrax syndromes (inhalational, gastrointestinal, and injectional) involves first ruling out the presence or absence of meningitis via a lumbar puncture. if meningitis is confirmed or cannot be ruled out, the treatment regimen should include central nervous system penetrating drugs, of which should be a protein synthesis inhibitor (eg, linezolid) and of which should be bactericidal (eg, meropenem). the third drug could be ciprofloxacin. if meningitis has been ruled out, ciprofloxacin and clindamycin or linezolid could be used for treatment (with deescalation of ciprofloxacin to penicillin once drug susceptibility is known). treatment is for weeks to weeks. adjunctive antibody therapies, available from the cdc, such as anthrax immune globulin, raxibacumab, and obiltoxaximab, also should be given. additionally, if present, pleural effusions, pericardial effusions, and ascites should be drained, a factor that has likely improved survival rates from inhalational anthrax in the modern era. postexposure prophylaxis, for those exposed to anthrax spores, includes both an abbreviated -dose regimen of the vaccine coupled with days of oral ciprofloxacin or doxycycline (antibody therapies can be used in this manner when no other prophylaxis method can be used). in a mass event the post-exposure prophylaxis regimen for adults can be shortened to days after the first vaccine dose or weeks after the last vaccine dose, which ever comes later. plague is caused by the gram-negative bacillus yesinia pestis and is endemic in many parts of the world, including the western united states. this zoonotic infection is naturally spread from rodents, such as prairie dogs, to humans via the bite of a flea. there are forms of plague: bubonic (the most common), pneumonic, and septicemic. if used as a bioweapon, plague is expected to present in its pneumonic form. bubonic plague is characterized by marked painful lymphadenopathy (fig. ) that develops after a -day to -day incubation period whereas pneumonic plague (fig. ) may be indistinguishable from ordinary community-acquired pneumonia but has a mortality rate that can reach %. pneumonic plague has a -day to -day incubation period. pneumonic plague is transmissible from person to person through respiratory droplets and requires patients be placed in droplet isolation. , diagnosis of pneumonic plague in an intentional attack requires a high index of suspicion and can be made through pcr, serology, and/or culture. , the treatment of plague is with aminoglycoside antibiotics, such as gentamicin or streptomycin, for days to days, whereas postexposure prophylaxis of those exposed to an aerosol in a bioweapon attack consists of oral ciprofloxacin or doxycycline. , tularemia tularemia is caused by the gram-negative bacillus francisella tularenesis and is naturally a zoonotic infection that is common in many parts of the united states. naturally, tularemia may occur through tick, fly, and mosquito bites or through contact with reservoir animals (eg, rabbits). contaminated uncooked food or water can also be a vehicle for spread. the most common presentation of tularemia is the ulceroglandular cutaneous form whereas a biologic attack likely results in pneumonic tularemia. tularemia is not contagious between humans. tularemia is notable for its low infectious dose in which inhalation of just a small number of bacilli can result in disease. because of this, it is important to notify laboratory personnel about the possibility of tularemia, so they are able to don appropriate personal protective equipment when working with clinical specimens. pneumonic tularemia occurs after a -day to -day incubation period and is essentially indistinguishable from community-acquired pneumonia. even physicians who live in endemic areas often miss the diagnosis of tularemia in its various form, highlighting the need for tularemia to be in the differential diagnosis of compatible syndromes in endemic areas. temperature-pulse disassociation may be present and can serve as a clue to diagnosis. the treatment of tularemia is aminoglycoside antibiotics, such as gentamicin or streptomycin, for days to days. postexposure prophylaxis, to those exposed to an aerosol in a biological weapons attack, is with oral doxycycline or ciprofloxacin. , botulism botulism is caused by the acetylcholine release-blocking neurotoxin released by clostridium botulinum, a ubiquitous spore-forming gram-positive rod. there are several forms of naturally occurring botulism: infant, wound, and gastrointestinal. these forms result from exposure to spores of the bacteria, which then germinate and elaborate toxin. in a biological attack, inhalational botulism is expected, and it manifests similar to gastrointestinal botulism. botulism is not contagious. , after hours to hours postexposure to spores, clinical botulism occurs. it is characterized by a symmetric, flaccid, descending paralysis without sensory symptoms. patients are afebrile and not tachycardic. cranial neuropathies are common. paralysis progresses to involve respiratory muscles and can be prolonged, requiring long durations of mechanical ventilation. diagnosis is largely clinical. confirmatory mouse bioassay testing is used to determine which of the several botulinum toxinotypes is responsible. , heptavalent antitoxin, which neutralizes toxinotypes a to g, is obtainable from the cdc and can neutralize toxin. antibiotics and babybig (california department of public health, a bivalent botulinum antitoxin used in infant botulism) are not indicated. , there was controversy over the existence of an eighth toxinotype (h) but it has been shown to be a hybrid toxin and is neutralized by a-type antitoxin. more recently, a toxinotype x has been described and is unable to be neutralized by any available antitoxin. smallpox is the only human infectious disease that has been eradicated from the planet. as such, there is little current clinical experience with this disease. smallpox is a significantly contagious disease that is spread via airborne, respiratory droplet, or direct contact route. fomites are also known to spread the virus. , the clinical presentation of smallpox begins with flulike symptoms after a -day incubation period which is followed by the characteristic rash. the rash begins in a papular form and then progresses to umbilicated lesions and finally to pustules that crust and scab. a person with smallpox is contagious only from the appearance of the rash until the rash is scabbed, a key factor that led to its control. , the rash of smallpox (fig. ) must be distinguished from similar rashes that can be seen with varicella. several points of distinction are important. the rash of smallpox is centrifugal with more lesions on the face and extremities while the varicella rash is centripetal. the lesions of the smallpox rash are all at identical stages with identical appearances whereas the rash of varicella may have lesions of different stages. the case fatality rate of smallpox was historically %. , a diagnosis of smallpox would be a national security emergency of the highest order because even case represents either a laboratory accident or a biological attack. because smallpox vaccination is no longer routine, there is a sizable amount of the world population that lacks immunity. any suspicion of smallpox should prompt infectious disease consultation, airborne isolation procedures, and notification of local, state, and national public health authorities. the cdc has a telephone consultation service in place to discuss potential cases with experts. a diagnosis of smallpox initially is based on clinical suspicion while confirmatory testing by pcr, viral culture, or electron microscopy is performed under appropriate biosafety conditions. , there is no food and drug administration-approved treatment of smallpox currently, although several experimental antiviral compounds are in late stages of clinical development and might be accessible. the smallpox vaccine is effective as postexposure prophylaxis, even during the incubation period, and should be given to all patient contacts, who also will be placed under public health surveillance. the vaccine is contraindicated in the immunosuppressed and pregnant and those with eczema. experimental attenuated vaccines may be more suitable for these individuals. [ ] [ ] [ ] additionally, the smallpox vaccine carries a risk of myocarditis. vhfs are caused by a diverse group of viruses, each with its own unique microbiological, epidemiologic, and clinical features. of this group, which ranges from yellow fever to ebola, certain are more important as potential biological weapons than others. in the biological weapons context, it is the filoviruses (ebola and marburg) as well as the arenaviruses (lassa fever, machupo, and others) that merit concern. despite their differences, this group of viruses is characterized by a clinical presentation that often includes general malaise, fever, rash, prostration, pharyngitis, nausea, vomiting, and diarrhea. disease can rapidly progress to shock and multiple organ dysfunction syndrome with disseminated intravascular coagulation and hemorrhagic manifestations. diagnosis can be made using molecular tests, but a high index of suspicion is needed to differentiate these infections from ordinary septic shock. in the ed patient, travel to endemic areas, exotic animal exposure, or laboratory work with vhfs might be the only clue to the etiology. in a biological attack, a cluster of patients with similar symptoms may present to several eds in a given region. any suspicion of a vhf should prompt immediate consultation with an infectious disease physician and state and local health authorities. although these viruses are spread via blood and body fluid exposure and do not spread between humans via the airborne route, the experience of the united states during the west africa ebola outbreak has influenced infection control recommendations. the nosocomial infections at a hospital in texas have led to recommendations for strict airborne and body fluid isolation for patients suspected of having a vhf, with transfer to definitive care at specialized units for confirmed cases. treatment is generally supportive and has proved life-saving in the case of ebola. the recent experience with ebola highlighted the fact that simple supportive care with fluids and electrolytes brought fatality rates down from % to less than %. there are several experimental treatments and vaccines (which can be used for postexposure prophylaxis) that are available for filovirus infections and arenavirus infections that would likely be used in any domestic vhf cases caused by these groups of viruses. for ebola exposures, the experimental vaccine would be indicated for postexposure prophylaxis whereas a combination of experimental antiviral agents (eg, favipiravir) and antibody-based therapies, such as zmapp, might be indicated after consultation with cdc. lassa fever can be treated with intravenous ribavirin, which is available via cdc. the possibility of vhf infection should be considered in those with severe illness and travel to areas in which these infections are endemic, such as parts of africa (eg, democratic republic of congo, uganda, and nigeria) or south america (eg, brazil and argentina). consultation of the cdc travel web site (www.cdc.gov/travel) is advised to determine specific vhf travel risks. coronaviruses (covs) are major causes of the common cold and rarely cause severe disease in immunocompetent hosts. there are, however, covs that have the capacity to cause severe disease: severe acute respiratory syndrome (sars)-cov and middle east respiratory syndrome (mers)-cov. although both sars and mers present to the ed as ordinary upper or lower respiratory tract infections, they have distinct geographic and epidemiologic features that should alert an ed physician to the possibility of their presence. sars, which emerged in china in , was a worldwide infectious disease emergency that led to more than cases worldwide, with approximately % of cases fatal-including in the united states. the virus was zoonotic in origin and linked to human consumption of palm civet cats. the spread of the virus was abetted by the presence of superspreading events in which certain individuals infected a disproportionate number of others. the epidemic extinguished once infection control measures were instituted in health care settings and the consumption of palm civet cats ceased. mers is also a zoonotic respiratory cov that emerged in the arabian peninsula in and has been linked to contact with both bats and camels. all cases have an epidemiologic link to the arabian peninsula, including a multiple-ed superspreading event that occurred in south korea. mortality rates are approximately %. in the united states, imported mild cases have been diagnosed in travelers returning from the middle east. mers should be suspected in individuals with upper or lower respiratory infection after travel to the middle east in the prior weeks, and confirmatory molecular testing can be done in conjunction with state and local health authorities. many respiratory viral panels have the capacity to identify the presence of a cov and may be helpful in the work-up. infectious disease consultation and institution of droplet or airborne precautions are advised. there are no antivirals or vaccines available for any cov. influenza is often considered one of the highest pandemic threats. prior influenza pandemics have killed millions and have caused severe societal disruption. each modern pandemic ( , , , and ) has been linked to the emergence of a novel influenza a variant of zoonotic (avian, swine, or a combination) origin. zoonotic influenza viruses, in their first forays into humans, can cause a range of illness, ranging from ordinary influenza to fulminant disease, including pneumonia and acute respiratory distress syndrome. poor to limited nonsustained human-tohuman transmission characterizes these viruses in the prepandemic stage, with most cases linked directly or indirectly to poultry exposure. it is when sustained human-to-human transmission occurs that a pandemic is eminent. because of this threat, monitoring and surveillance efforts exist for avian influenza infections in humans and poultry. currently, of the myriad zoonotic influenza infections, the h n strain of influenza a has been deemed the highest threat amongst these viruses currently, although others (such as h n ) are also important to track. the ed physician should suspect avian influenza in travelers from china and other areas in which avian influenza is known to circulate, who present within approximately week after travel with upper or lower respiratory tract infection. additionally, domestic agricultural workers or those with agricultural contact with flulike symptoms (eg, children at fairs) also may harbor zoonotic influenza infections. diagnosis is similar to ordinary influenza, but a rapid or standard molecular test may or may not be able to detect influenza. confirmatory testing is via health authorities. treatment involves supportive care coupled to antiviral therapy with either oral oseltamivir or, if disease severity is high, intravenous peramivir. infectious disease consultation and institution of droplet precautions is advised. mosquito-borne arboviruses have increasingly taken on importance in the field of emerging infectious disease with the explosion of cases of west nile, chikungunya, and zika in the western hemisphere. additionally, local transmission of dengue fever has occurred in florida, texas, hawaii, and new york. , chikungunya, dengue fever, and zika are all spread by the aedes species of mosquitoes, which have habitats both within and outside the united states and cause clinically indistinguishable syndromes. these syndromes all involve fevers, rash, myalgias, and arthralgias. conjunctivitis has been noted with zika. prolonged debilitating arthralgias can occur with chikungunya whereas severe illness, including shock and hemorrhagic manifestations, can occur with dengue fever (especially with repeat infection with disparate strains). , zika has been linked to guillain-barré syndrome and requires special counseling regarding sexual transmission and pregnancy given its ability to cause a devastating congenital syndrome. , travel history and residence in an endemic area (eg, key west, hawaii, and texas) are important elements of the history. diagnostic testing is commercially available for each infection. consultation with the cdc travel web site is advised to assess specific risks for individual patients' travel history. no vaccines or antiviral therapies are available for these infections. emergency physicians play a crucial and unique role in the defense against emerging infectious disease and are most likely to encounter the first cases of any new infectious disease syndrome. the challenge that the emergency physician faces is that these cases do not announce themselves and are hidden among the sea of chief complaints that any ed sees on a given day. with many clinical scenarios, a busy physician may not be inclined to pursue a specific diagnosis if it "doesn't change treatment," may lengthen ed length of stay, and will not produce a result while a patient is in the ed, creating follow-up logistical problems. failing to diagnose an epidemiologically important emerging infectious disease or biological attack, however, can have tremendous cascading effects involving all sectors of society (health care, government, and economy) that can be minimized or averted with a proactive approach. in the current era, there are several molecular multianalyte tests available, some of which are clinical laboratory improvement amendments (clia) waived and available at point of care for specific infectious disease syndromes, such as gastrointestinal infections, meningitis, and respiratory infections, that can be used to increase the rate of microbial specific diagnoses in ed settings. biodefense cartridges, which probe for select bioagents, are also available. these tests, in the hands of an astute physician, can improve the nation's resiliency to infectious disease emergencies, and negative results in the right clinical context may prompt further investigation for a specific etiology. by having a working knowledge of emerging infectious disease and biothreat landscape, an emergency physician becomes a key component of the infectious disease emergency system. injectional anthrax in heroin users clinical management of potential bioterrorismrelated conditions mandell, douglas, and bennett's principles and practice of infectious diseases centers for disease control and prevention expert panel meetings on prevention and treatment of anthrax in adults systematic review: a century of inhalational anthrax cases from to mandell, douglas, and bennett's principles and practice of infectious diseases s principles and practice of infectious diseases clinical recognition and management of tularemia in missouri: a retrospective records review of cases mandell, douglas, and bennett's principles and practice of infectious diseases a novel botulinum neurotoxin, previously reported as serotype h, has a hybrid-like structure with regions of similarity to the structures of serotypes a and f and is neutralized with serotype a antitoxin identification and characterization of a novel botulinum neurotoxin orthopoxviruses: vaccinia (smallpox vaccine), variola (smallpox), monkeypox, and cowpox acam : the new smallpox vaccine for united states strategic national stockpile safety and immunogenicity of imvamune smallpox vaccine using different strategies for a post event scenario safety and immunogenicity of lc m , an attenuated smallpox vaccine in vaccinia-naive adults acam prescribing information mandell, douglas, and bennett's principles and practice of infectious diseases systems for rapidly detecting and treating persons with ebola virus disease -united states evidence-based guidelines for supportive care of patients with ebola virus disease experimental therapies for ebola virus disease: what have we learned? including severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) summary of influenza risk assessment tool (irat) results outbreak of influenza a (h n ) variant virus infections among persons attending agricultural fairs housing infected swine -michigan and ohio lessons learned during dengue outbreaks in the united states health commissioner reports dengue virus case japanese encephalitis, west nile encephalitis, st. louis encephalitis, tick-borne encephalitis, kyasanur forest disease, alkhurma hemorrhagic fever, zika) mandell, douglas, and bennett's principles and practice of infectious diseases guillain-barre syndrome associated with zika virus infection in columbia zika virus and birth defects-reviewing the evidence for causality key: cord- -v lahyw authors: van seventer, jean maguire; hochberg, natasha s. title: principles of infectious diseases: transmission, diagnosis, prevention, and control date: - - journal: international encyclopedia of public health doi: . /b - - - - . - sha: doc_id: cord_uid: v lahyw infectious disease control and prevention relies on a thorough understanding of the factors determining transmission. this article summarizes the fundamental principles of infectious disease transmission while highlighting many of the agent, host, and environmental determinants of these diseases that are of particular import to public health professionals. basic principles of infectious disease diagnosis, control, and prevention are also reviewed. an infectious disease can be defined as an illness due to a pathogen or its toxic product, which arises through transmission from an infected person, an infected animal, or a contaminated inanimate object to a susceptible host. infectious diseases are responsible for an immense global burden of disease that impacts public health systems and economies worldwide, disproportionately affecting vulnerable populations. in , infectious diseases resulted in over million years lost due to disability and over million deaths (naghavi et al., ) . lower respiratory tract infections, diarrheal diseases, hiv/ aids, malaria, and tuberculosis (tb) are among the top causes of overall global mortality (vos et al., ) . infectious diseases also include emerging infectious diseases; diseases that have newly appeared (e.g., middle east respiratory syndrome) or have existed but are rapidly increasing in incidence or geographic range (e.g., extensively drug-resistant tuberculosis (xdr tb) and zika virus (morse, ) . infectious disease control and prevention relies on a thorough understanding of the factors determining transmission. this article summarizes some of the fundamental principles of infectious disease transmission while highlighting many of the agent, host, and environmental determinants of these diseases that are of particular import to public health professionals. a classic model of infectious disease causation, the epidemiological triad (snieszko, ) , envisions that an infectious disease results from a combination of agent (pathogen), host, and environmental factors ( figure ). infectious agents may be living parasites (helminths or protozoa), fungi, or bacteria, or nonliving viruses or prions. environmental factors determine if a host will become exposed to one of these agents, and subsequent interactions between the agent and host will determine the exposure outcome. agent and host interactions occur in a cascade of stages that include infection, disease, and recovery or death (figure (a) ). following exposure, the first step is often colonization, the adherence and initial multiplication of a disease agent at a portal of entry such as the skin or the mucous membranes of the respiratory, digestive, or urogenital tract. colonization, for example, with methicillin-resistant staphylococcus aureus in the nasal mucosa, does not cause disease in itself. for disease to occur, a pathogen must infect (invade and establish within) host tissues. infection will always cause some disruption within a host, but it does not always result in disease. disease indicates a level of disruption and damage to a host that results in subjective symptoms and objective signs of illness. for example, latent tb infection is only infectionevidenced by a positive tuberculin skin test or interferon gamma release assaybut with a lack of symptoms (e.g., cough or night sweats) or signs (e.g., rales on auscultation of the chest) of disease. this is in contrast to active pulmonary tb (disease), which is accompanied by disease symptoms and signs. recovery from infection can be either complete (elimination of the agent) or incomplete. incomplete recovery can result in both chronic infections and latent infections. chronic infections are characterized by the continued detectable presence of an infectious agent. in contrast, latent infections are distinguished by an agent which can remain quiescent in host cells and can later undergo reactivation. for example, varicella zoster virus, the agent causing chicken pox, may reactivate many years after a primary infection to cause shingles. from a public health standpoint, latent infections are significant in that they represent silent reservoirs of infectious agent for future transmission. when a potential host is exposed to an infectious agent, the outcome of that exposure is dependent upon the dynamic relationship between agent determinants of infectivity, pathogenicity, and virulence, and intrinsic host determinants of susceptibility to infection and to disease (figure (b) ). environmental factors, both physical and social behavioral, are extrinsic determinants of host vulnerability to exposure. environment disease figure the epidemiological triad model of infectious disease causation. the triad consists of an agent (pathogen), a susceptible host, and an environment (physical, social, behavioral, cultural, political, and economic factors) that brings the agent and host together, causing infection and disease to occur in the host. infectivity is the likelihood that an agent will infect a host, given that the host is exposed to the agent. pathogenicity refers to the ability of an agent to cause disease, given infection, and virulence is the likelihood of causing severe disease among those with disease. virulence reflects structural and/or biochemical properties of an infectious agent. notably, the virulence of some infectious agents is due to the production of toxins (endotoxins and/or exotoxins) such as the cholera toxin that induces a profuse watery diarrhea. some exotoxins cause disease independent of infection, as for example, the staphylococcal enterotoxins that can cause foodborne diseases. agent characteristics can be measured in various ways. infectivity is often quantified in terms of the infectious dose (id ), the amount of agent required to infect % of a specified host population. id varies widely, from organisms for shigella dysenteriae to - for vibrio cholerae (gama et al., ; fda, ) . infectivity and pathogenicity can be measured by the attack rate, the number of exposed individuals who develop disease (as it may be difficult to determine if someone has been infected if they do not have outward manifestations of disease). virulence is often measured by the case fatality rate or proportion of diseased individuals who die from the disease. the outcome of exposure to an infectious agent depends, in part, upon multiple host factors that determine individual susceptibility to infection and disease. susceptibility refers to the ability of an exposed individual (or group of individuals) to resist infection or limit disease as a result of their biological makeup. factors influencing susceptibility include both innate, genetic factors and acquired factors such as the specific immunity that develops following exposure or vaccination. the malaria resistance afforded carriers of the sickle cell trait exemplifies how genetics can influence susceptibility to infectious disease (aidoo et al., ) . susceptibility is also affected by extremes of age, stress, pregnancy, nutritional status, and underlying diseases. these latter factors can impact immunity to infection, as illustrated by immunologically naïve infant populations, aging populations experiencing immune senescence, and immunocompromised hiv/aids patients. mechanical and chemical surface barriers such as the skin, the flushing action of tears, and the trapping action of mucus are the first host obstacles to infection. for example, wound infection and secondary sepsis are serious complications of severe burns which remove the skin barrier to microbial entry. lysozyme, secreted in saliva, tears, milk, sweat, and mucus, and gastric acid have bactericidal properties, and vaginal acid is microbicidal for many agents of sexually transmitted infections (stis). microbiome-resident bacteria (a.k.a. commensal bacteria, normal flora) can also confer host protection by using available nutrients and space to prevent pathogenic bacteria from taking up residence. the innate and adaptive immune responses are critical components of the host response to infectious agents ( table ) . each of these responses is carried out by cells of a distinct hematopoietic stem cell lineage: the myeloid lineage gives rise to innate immune cells (e.g., neutrophils, macrophages, dendritic cells) and the lymphoid lineage gives rise to adaptive immune cells (e.g., t cells, b cells). the innate immune response is an immediate, nonspecific response to broad groups of pathogens. by contrast, the adaptive immune response is initially generated over a period of - days, it recognizes specific pathogens, and it consists of two main branches: ( ) t cell-mediated immunity (a.k.a. cell-mediated immunity) and ( ) b cellmediated immunity (a.k.a. humoral or antibody-mediated immunity). the innate and adaptive responses also differ in table comparison of innate and adaptive immunity innate immune response adaptive immune response immediate response; initiated within seconds gradual response; initially generated over - days (primary response) targets groups of pathogens targets-specific pathogens no memory memory progression from one stage to the next is dependent upon both agent properties of infectivity, pathogenicity, and virulence, and host susceptibility to infection and disease, which is in large part due to both protective and adverse effects of the host immune response. credit: modification of original by barbara mahon, md, mph. that the latter has memory, whereas the former does not. as a consequence of adaptive immune memory, if an infectious agent makes a second attempt to infect a host, pathogenspecific memory t cells, memory b cells, and antibodies will mount a secondary immune response that is much more rapid and intense than the initial, primary response and, thus, better able to inhibit infection and disease. immune memory is the basis for the use of vaccines that are given in an attempt to stimulate an individual's adaptive immune system to generate pathogen-specific immune memory. of note, in some cases the response of the immune system to an infectious agent can contribute to disease progress. for example, immunopathology is thought to be responsible for the severe acute disease that can occur following infection with a dengue virus that is serotypically distinct from that causing initial dengue infection (screaton et al., ) . an immune host is someone protected against a specific pathogen (because of previous infection or vaccination) such that subsequent infection will not take place or, if infection does occur, the severity of disease is diminished. the duration and efficacy of immunity following immunization by natural infection or vaccination varies depending upon the infecting agent, quality of the vaccine, type of vaccine (i.e., live or inactivated virus, subunit, etc.), and ability of the host to generate an immune response. for example, a single yellow fever vaccination appears to confer lifelong immunity, whereas immune protection against tetanus requires repeat vaccination every years (staples et al., ; broder et al., ) . in malariaendemic areas, natural immunity to malaria usually develops by years of age and, while protective from severe disease and death, it is incomplete and short-lived (langhorne et al., ) . functionally, there are two basic types of immunization, active and passive. active immunization refers to the generation of immune protection by a host's own immune response. in contrast, passive immunization is conferred by transfer of immune effectors, most commonly antibody (a.k.a. immunoglobulin, antisera), from a donor animal or human. for example, after exposure to a dog bite, an individual who seeks medical care will receive both active and passive postexposure immune prophylaxis consisting of rabies vaccine (to induce the host immune response) and rabies immune globulin (to provide immediate passive protection against rabies). an example of natural passive immunization is the transfer of immunity from mother to infant during breastfeeding. vaccination does not always result in active immunization; failure of vaccination can be due to either host or vaccine issues. individuals who are immunosuppressed as, for example, a result of hiv infection, malnutrition, immunosuppressive therapy, or immune senescence might not mount a sufficient response after vaccination so as to be adequately immunized (protected). similarly, vaccination with an inadequate amount of vaccine or a vaccine of poor quality (e.g., due to break in cold chain delivery) might prevent even a healthy individual from becoming immunized. environmental determinants of vulnerability to infectious diseases include physical, social, behavioral, cultural, political, and economic factors. in some cases, environmental influences increase risk of exposure to an infectious agent. for example, following an earthquake, environmental disruption can increase the risk of exposure to clostridium tetani and result in host traumatic injuries that provide portals of entry for the bacterium. environmental factors promoting vulnerability can also lead to an increase in susceptibility to infection by inducing physiological changes in an individual. for example, a child living in a resource-poor setting and vulnerable to malnutrition may be at increased risk of infection due to malnutritioninduced immunosuppression. table provides examples of some of the many environmental factors that can facilitate the emergence and/or spread of specific infectious diseases. a unique characteristic of many infectious diseases is that exposure to certain infectious agents can have consequences for other individuals, because an infected person can act as a source of exposure. some pathogens (e.g., sti agents) are directly transmitted to other people, while others (e.g., vectorborne disease (vbd) agents) are transmitted indirectly. from a public health standpoint, it is useful to define stages of an infectious disease with respect to both clinical disease and potential for transmission ( figure ). with respect to disease, the incubation period is defined as the time from exposure to an infectious agent until the time of first signs or symptoms of disease. the incubation period is followed by the period of clinical illness which is the duration between first and last disease signs or symptoms. with respect to transmission of an infectious agent, the latent (preinfectious) period is the duration of time between exposure to an agent and the onset of infectiousness. it is followed by the infectious period (a.k.a. period of communicability) which is the time period when an infected person can transmit an infectious agent to other individuals. in parasitic infections, the latent and infectious periods are commonly referred to as the prepatent period and patent period, respectively. the duration of disease stages is unique for each type of infection and it can vary widely for a given type of infection depending upon agent, host, and environmental factors that affect, for example, dose of the inoculated agent, route of exposure, host susceptibility, and agent infectivity and virulence. knowledge of the timing of disease stages is of key importance in the design of appropriate control and prevention strategies to prevent the spread of an infectious disease. for example, efforts to control the recent ebola west africa outbreak through contact tracing and quarantine were based on knowledge that the infectious period for ebola does not begin until the start of the period of clinical illness, which occurs up to days following exposure (figure (a) ; pandey et al., ) . a carrier is, by definition, an infectious individual who is not showing clinical evidence of disease and, thus, might unknowingly facilitate the spread of an infectious agent through a population. incubatory carriers exist when the incubation period overlaps with the infectious period, as can occur in some cases of chicken pox (figure (b) ). convalescent carriers occur when the period of infectiousness extends beyond the period of clinical illness (figure (c) ). carriers of this type can be a significant issue in promoting the spread of certain enteric infections, such as those caused by the bacterium, v. cholerae. healthy carriers, infected individuals that remain asymptomatic but are capable of transmitting an infectious agent, occur commonly with many infectious diseases (e.g., meningococcal meningitis and typhoid fever) and are also significant challenges to disease control ( figure (d)). a variety of terms are used to describe the occurrence of an infectious disease within a specific geographic area or population. sporadic diseases occur occasionally and unpredictably, while endemic diseases occur with predictable regularity. levels of endemicity can be classified as holoendemic, hyperendemic, mesoendemic, or hypoendemic depending upon whether a disease occurs with, respectively, extreme, high, moderate, or low frequency. for some infectious diseases, such as malaria, levels of endemicity are well defined and used as parameters for identifying disease risk and implementing control activities. malaria endemicity is quantified based upon rates of palpable enlarged spleens in a defined (usually pediatric) age group: holoendemic > %, hyperendemic - %, mesoendemic - %, and hypoendemic < % (hay et al., ). an epidemic refers to an, often acute, increase in disease cases above the baseline level. an epidemic may reflect an escalation in the occurrence of an endemic disease or the appearance of a disease that did not previously exist in a population. the term outbreak is often used synonymously with epidemic but can occasionally refer to an epidemic occurring in a more limited geographical area; for example, a foodborne illness associated with a group gathering. by contrast, a pandemic is an epidemic that has spread over a large geographic region, encompassing multiple countries or continents, or extending worldwide. influenza commonly occurs as a seasonal epidemic, but periodically it gives rise to a global pandemic, as was the case with h n influenza. two fundamental measures of disease frequency are prevalence and incidence. prevalence is an indicator of the number of existing cases in a population as it describes the proportion of individuals who have a particular disease, measured either at a given point in time (point prevalence) or during a specified time period (period prevalence). in contrast, incidence (a.k.a. incidence rate) is a measurement of the rate at which new cases of a disease occur (or are detected) in a population over a given time period. usually measured as a proportion (number infected/number exposed), attack rates are often calculated during an outbreak. in some circumstances, a secondary attack rate is calculated to quantify the spread of disease to susceptible exposed persons from an index case (the case first introducing an agent into a setting) in a circumscribed population, such as in a household or hospital. during the sars epidemic, secondary attack rates in toronto hospitals were high but varied from % to % depending upon the hospital ward (cdc, b) . the basic reproductive number (basic reproductive ratio; r ) is a measure of the potential for an infectious disease to spread through an immunologically naïve population. it is defined as the average number of secondary cases generated by a single, infectious case in a completely susceptible population. in reality, for most infectious diseases entering into a community, some proportion of the population is usually immune (and nonsusceptible) due to previous infection and/or immunization. thus, a more accurate reflection of the potential for community disease spread is the effective reproductive number (r) which measures the average number of new infections due to a single infection. in general, for an epidemic to occur in a population, r must be > so that the number of cases continues to increase. herd immunity (a.k.a. community immunity) refers to population-level resistance to an infectious disease that occurs when there are enough immune individuals to block the chain of infection/transmission. as a result of herd immunity, susceptible individuals who are not immune themselves are indirectly protected from infection ( figure ). vaccine hesitancy, the choice of individuals or their caregivers to delay or decline vaccination, can lead to overall lower levels of herd immunity. outbreaks of measles in the united states, including a large measles outbreak at an amusement park in california, highlight the phenomena of vaccine refusal and associated increased risk for vaccine-preventable diseases among both nonvaccinated and fully vaccinated (but not fully protected) individuals (phadke et al., ) . an important public health consequence of herd immunity is that immunization coverage does not need to be % for immunization programs to be successful. the equation r ¼ r ( À x) (where x equals the immune portion of the population) indicates the level of immunization required to prevent the spread of an infectious disease through a population. the proportion that needs to be immunized depends on the pathogen (table ) . when the proportion immunized (x) reaches a level such that r < , a chain of infection cannot be sustained. thus, ro and r can be used to calculate the target immunization coverage needed for the success of vaccination programs. proper diagnosis of infectious illnesses is essential for both appropriate treatment of patients and carrying out prevention and control surveillance activities. two important properties that should be considered for any diagnostic test utilized are sensitivity and specificity. sensitivity refers to the ability of the test to correctly identify individuals infected with an agent ('positive in disease'). a test that is very sensitive is more likely to pick up individuals with the disease (and possibly some without the disease); a very sensitive test will have few false negatives. specificity is the ability of the test to correctly identify individuals not infected by a particular agent ('negative in health'); high specificity implies few false positives. often, screening tests are highly sensitive (to capture any possible cases), and confirmatory tests are more specific (to rule out false-positive screening tests). broadly, laboratory diagnosis of infectious diseases is based on tests that either directly identify an infectious agent or provide evidence that infection has occurred by documenting agent-specific immunity in the host ( figure ). identification of an infecting agent involves either direct examination of host specimens (e.g., blood, tissue, urine) or environmental specimens, or examination following agent culture and isolation from such specimens. the main categories of analyses used in pathogen identification can be classified as phenotypic, revealing properties of the intact agent, nucleic acid-based, determining agent nucleic acid (dna or rna) characteristics and composition, and immunologic, detecting microbial antigen or evidence of immune response to an agent ( figure ). direct phenotypic analyses include both macroscopic and/or microscopic examination of specimens to determine agent morphology and staining properties. cultured material containing large quantities of agent can undergo analyses to determine characteristics, such as biochemical enzymatic activity (enzymatic profile) and antimicrobial sensitivity, and to perform phage typing, a technique which differentiates bacterial strains according to the infectivity of strain-specific bacterial viruses (a.k.a. bacteriophages). nucleic acid-based tests often make use of the polymerase chain reaction (pcr) to amplify agent dna or complementary dna (cdna) synthesized from messenger rna (mrna). the ability of pathogen-specific pcr primers to generate an amplification product can confirm or rule out involvement of a specific pathogen. sequencing of amplified dna fragments can also assist with pathogen identification. restriction fragment analysis, as by pulse-field gel electrophoresis of restriction enzyme-digested genomic dna isolated from cultured material, can yield distinct 'dna fingerprints' that can be used for comparing the identities of bacteria. the cdc pulsenet surveillance program uses dna fingerprinting as the basis for detecting and defining foodborne disease outbreaks that can sometimes be quite widely dispersed (cdc, ) . most recently, next-generation sequencing technologies have made whole-genome sequencing a realistic subtyping method for use in foodborne outbreak investigation and surveillance (deng et al., ) . the objective of immunologic analysis of specimens is to reveal evidence of an agent through detection of its antigenic components with agent-specific antibodies. serotyping refers to the grouping of variants of species of bacteria or viruses based on shared surface antigens that are figure herd immunity occurs when one is protected from infection by immunization occurring in the community. using influenza as an example, the top box shows a population with a few infected individuals (shown in red) and the rest healthy but unimmunized (shown in blue); influenza spreads easily through the population. the middle box depicts the same population but with a small number who are immunized (shown in yellow); those who are immunized do not become infected, but a large proportion of the population becomes infected. in the bottom box, a large proportion of the population is immunized; this prevents significant transmission, including to those who are unimmunized. source: national institute of allergy and infectious diseases (niaid). identified using immunologic methodologies such as enzymelinked immunosorbent assay (elisa) and western blotting. immunologic assays are also used to look for evidence that an agent-specific immune response has occurred in an exposed or potentially exposed individual. serologic tests detect pathogen-specific b cell-secreted antibodies in serum or other body fluids. some serologic assays simply detect the ability of host antibodies to bind to killed pathogen or components of pathogen (e.g., elisa). others rely on the ability of antibodies to actually neutralize the activity of live microbes; as, for example, the plaque reduction neutralization test which determines the ability of serum antibodies to neutralize virus. antibody titer measures the amount of a specific antibody present in serum or other fluid, expressed as the greatest dilution of serum that still gives a positive test in whatever assay is being employed. intradermal tests for identification of t cell-mediated immediate type (type i) hypersensitivity or delayed type (type iv) hypersensitivity responses to microbial antigen can be used to diagnose or support the diagnosis of some bacterial, fungal, and parasitic infections, such as, the mantoux (tuberculin) test for tb. based on the classic model of leavell and clark ( ) , infectious disease prevention activities can be categorized as primary, secondary, or tertiary. primary prevention occurs at the predisease phase and aims to protect populations, so that infection and disease never occur. for example, measles immunization campaigns aim to decrease susceptibility following exposure. the goal of secondary prevention is to halt the progress of an infection during its early, often asymptomatic stages so as to prevent disease development or limit its severity; steps important for not only improving the prognosis of individual cases but also preventing infectious agent transmission. for example, interventions for secondary prevention of hepatitis c in injection drug user populations include early diagnosis and treatment by active surveillance and screening (miller and dillon, ) . tertiary prevention focuses on diseased individuals with the objective of limiting impact through, for example, interventions that decrease disease progression, increase functionality, and maximize quality of life. broadly, public health efforts to control infectious diseases focus on primary and secondary prevention activities that reduce the potential for exposure to an infectious agent and increase host resistance to infection. the objective of these activities can extend beyond disease control, as defined by the dahlem workshop on the eradication of infectious diseases, to reach objectives of elimination and eradication (dowdle, ; box ). as noted earlier, the causation and spread of an infectious disease is determined by the interplay between agent, host, and environmental factors. for any infectious disease, this interplay requires a specific linked sequence of events termed the chain of infection or chain of transmission ( figure ). the chain starts with the infectious agent residing and multiplying in some natural reservoir; a human, animal, or part of the environment such as soil or water that supports the existence of the infectious agent in nature. the infectious agent leaves the reservoir via a portal of exit and, using some mode of transmission, moves to reach a portal of entry into a susceptible host. a thorough understanding of the chain of infection is crucial for the prevention and control of any infectious disease, as breaking a link anywhere along the chain will stop transmission of the infectious agent. often more than one intervention can be effective in controlling a disease, and the approach selected will depend on multiple factors such as economics and ease with which an intervention can be executed in a given setting. it is important to realize that the potential for rapid and far-reaching movement of infectious agents that has accompanied globalization means that coordination of intervention activities within and between nations is required for optimal prevention and control of certain diseases. the cause of any infectious disease is the infectious agent. as discussed earlier, many types of agents exist, and each can be characterized by its traits of infectivity, pathogenicity, and virulence. a reservoir is often, but not always, the source from which the agent is transferred to a susceptible host. for example, bats are both the reservoir for marburg virus and a source of infection for humans and bush animals including african gorillas. however, because morbidity and mortality due to marburg infection is significant among these bush animals, they cannot act as a reservoir to sustain the virus in nature (they die too quickly), although they can act as a source to transmit marburg to humans. infectious agents can exist in more than one type of reservoir. the number and types of reservoirs are important determinants of how easily an infectious disease can be prevented, controlled, and, in some cases, eliminated or eradicated. animal, particularly wild animal, reservoirs, and environmental reservoirs in nature can be difficult to manage and, thus, can pose significant challenges to public health control efforts. in contrast, infectious agents that only occur in human reservoirs are among the dahlem workshop on the eradication of infectious diseases defined a continuum of outcomes due to public health interventions targeting infectious diseases: " ) control, the reduction of disease incidence, prevalence, morbidity or mortality to a locally acceptable level as a result of deliberate efforts; continued intervention measures are required to maintain the reduction (e.g. diarrheal diseases), ) elimination of disease, reduction to zero of the incidence of a specified disease in a defined geographical area as a result of deliberate efforts; continued intervention measures are required (e.g. neonatal tetanus), ) elimination of infections, reduction to zero of the incidence of infection caused by a specific agent in a defined geographical area as a result of deliberate efforts; continued measures to prevent re-establishment of transmission are required (e.g. measles, poliomyelitis), ) eradication, permanent reduction to zero of the worldwide incidence of infection caused by a specific agent as a result of deliberate efforts; intervention measures are no longer needed (e.g. smallpox), and ) extinction, the specific infectious agent no longer exists in nature or in the laboratory (e.g. none)" (dowdle, ) . the chain of infection (a.k.a. chain of transmission). one way to visualize the transmission of an infectious agent though a population is through the interconnectedness of six elements linked in a chain. public health control and prevention efforts focus on breaking one or more links of the chain in order to stop disease spread. those most easily targeted, as illustrated by the success of smallpox eradication. humans are the reservoir for many common infectious diseases including stis (e.g., hiv, syphilis) and respiratory diseases (e.g., influenza). humans also serve as a reservoir, although not always a primary reservoir, for many neglected tropical diseases (ntds) as, for example, dracunculiasis (a.k.a. guinea worm). from a public health standpoint, an important feature of human reservoirs is that they might not show signs of illness and, thus, can potentially act as unrecognized carriers of disease within communities. the classic example of a human reservoir is the cook mary mallon (typhoid mary); an asymptomatic chronic carrier of salmonella enterica serovar typhi who was linked to at least cases of typhoid fever (soper, ) . animals are a reservoir for many human infectious diseases. zoonosis is the term used to describe any infectious disease that is naturally transmissible from animals to humans. these diseases make up approximately % of all infectious diseases, and an estimated % of recently emerging infectious diseases (burke et al., ) . zoonotic reservoirs and sources of human disease agents include both domestic (companion and production) animals (e.g., dogs and cows) and wildlife. control and prevention of zoonotic diseases requires the concerted efforts of professionals of multiple disciplines and is the basis for what has become known as the one health approach (gibbs, ) . this approach emphasizes the interconnectedness of human health, animal health, and the environment and recognizes the necessity of multidisciplinary collaboration in order to prevent and respond to public health threats. inanimate matter in the environment, such as soil and water, can also act as a reservoir of human infectious disease agents. the causative agents of tetanus and botulism (clostridium tetani and c. botulinum) are examples of environmental pathogens that can survive for years within soil and still remain infectious to humans. legionella pneumophila, the etiologic agent of legionnaires' disease, is part of the natural flora of freshwater rivers, streams, and other bodies. however, the pathogen particularly thrives in engineered aquatic reservoirs such as cooling towers, fountains, and central air conditioning systems, which provide conditions that promote bacterial multiplication and are frequently linked to outbreaks. soil and water are also sources of infection for several protozoa and helminth species which, when excreted by a human reservoir host, can often survive for weeks to months. outbreaks of both cryptosporidiosis and giardiasis commonly occur during summer months as a result of contact with contaminated recreational water. soil containing roundworm (ascaris lumbricoides) eggs is an important source of soil-transmitted helminth infections in children. early steps in preventing exposure to an infectious agent include interventions to control or eliminate the agent within its reservoir, to neutralize or destroy the reservoir, and/or to stop the agent from exiting its reservoir. central to these interventions are surveillance activities that routinely identify disease agents within reservoirs. when humans are the reservoir, or source, of an infectious agent, early and rapid diagnosis and treatment are key to decreasing the duration of infection and risk of transmission. both active surveillance and passive surveillance are used to detect infected cases and carriers. some readily communicable diseases, such as ebola, can require isolation of infected individuals to minimize the risk of transmission. as part of the global effort to eradicate dracunculiasis, several endemic countries have established case containment centers to provide treatment and support to patients with emerging guinea worms to keep them from contaminating water sources and, thereby, exposing others (hochberg et al., ) . contact tracing and quarantine are other activities employed in the control of infections originating from a human reservoir or source. during the west africa ebola outbreak, key control efforts focused on the tracing and daily follow-up of healthy individuals who had come in contact with ebola patients and were potentially infected with the virus (pandey et al., ) . one health emphasizes the importance of surveillance and monitoring for zoonotic pathogens in animal populations. for some diseases (e.g., rift valley fever) epizootics (analogous to epidemics, but in animal populations) can actually serve as sentinel events for forecasting impending human epidemics. once animal reservoirs (and sources) of infection are identified, approaches to prevention and control include reservoir elimination and prevention of reservoir infection. zoonotic diseases exist in nature in predictably regular, enzootic cycles and/or epizootic cycles and are transmitted to humans via distinct pathways. the focus of prevention and control activities for these diseases reflects the extent to which a zoonotic pathogen has evolved to become established in human populations (wolfe et al., ) . for some zoonotic diseases (e.g. anthrax, nipah, rabies), primary transmission always occurs from animals, with humans acting as incidental (dead end) hosts; control of these diseases thus concentrates on preventing animal-to-animal and, ultimately, animal-to-human transmission. currently, most human cases of avian influenza are the result of human infection from birds; human-to-human transmission is extremely rare. thus, reservoir elimination by culling infected poultry flocks is a recommended measure for controlling avian influenza in birds and preventing sporadic infection of humans (cdc, ) . other zoonotic diseases demonstrate varying degrees of secondary human-to-human transmission following primary transmission (a.k.a. spillover) from animals. both rates of spillover and the ability to sustain human-tohuman transmission can vary widely between zoonoses and, in consequence, control strategies can also be quite different. for example, outbreaks of ebola arise following an initial bush animal-to-human transmission event, and subsequent human-to-human transmission is often limited (feldmann and geisbert, ) . in contrast, the four dengue viruses originally emerged from a sylvatic cycle between non-human primates and mosquitoes, and are now sustained by a continuous human-mosquito-human cycle of transmission with outbreaks occurring as a result of infected individuals entering into naïve populations (vasilakis et al., ) . thus, while ebola outbreak prevention efforts would include limiting contact with bush animals, such efforts would not be useful for prevention of dengue outbreaks. hiv is an example of a virus that emerged from an ancestral animal virus, simian immunodeficiency virus, but has evolved so that it is now hiv is an example of a virus that emerged from an ancestral animal virus, simian immunodeficiency virus, but has evolved so that it is now only transmitted human to human (faria et al., ) . infectious agents exit human and animal reservoirs and sources via one of several routes which often reflect the primary location of disease; respiratory disease agents (e.g., influenza virus) usually exit within respiratory secretions, whereas gastrointestinal disease agents (e.g., rotavirus, cryptosporidium spp.) commonly exit in feces. other portals of exits include sites from which urine, blood, breast milk, and semen leave the host. for some infectious diseases, infection can naturally occur as a result of contact with more than one type of bodily fluid, each of which uses a different portal of exit. while infection with the sars virus most frequently occurred via contact with respiratory secretions, a large community outbreak was caused by the spread of virus in a plume of diarrhea (yu et al., ) . control interventions targeting portals of exit and entry are discussed below. there are a variety of ways in which infectious agents move from a natural reservoir to a susceptible host, and several different classification schemes are used. the scheme below categorizes transmission as direct transmission, if the infective form of the agent is transferred directly from a reservoir to an infected host, and indirect transmission, if transfer takes place via a live or inanimate intermediary (box ). direct physical contact between the skin or mucosa of an infected person and that of a susceptible individual allows direct transfer of infectious agents. this is a mode of transmission for most stis and many other infectious agents, such as bacterial and viral conjunctivitis (a.k.a. pink eye) and ebola virus disease. direct droplet transmission occurs after sneezing, coughing, or talking projects a spray of agent-containing droplets that are too large to remain airborne over large distances or for prolonged periods of time. the infectious droplets traverse a space of generally less than m to come in contact with the skin or mucosa of a susceptible host. many febrile childhood diseases, including the common cold, are transferred this way. diseases spread by direct contact and droplet transmission require close proximity of infected and susceptible individuals and, thus, commonly occur in settings such as households, schools, institutions of incarceration, and refugee/displaced person camps. infectious agents spread exclusively in this manner are often unable to survive for long periods outside of a host; direct transmission helps to ensure transfer of a large infective dose. direct contact to an agent in the environment is a means of exposure to infectious agents maintained in environmental reservoirs. diseases commonly transmitted in this manner include those in which the infectious agent enters a susceptible host via inhalation (e.g., histoplasmosis) or through breaks in the skin following a traumatic event (e.g., tetanus). animal bites are another way in which some infectious agents are directly transferred, through broken skin. this is the most common means of infection with rabies virus. transplacental (a.k.a. congenital, vertical) and perinatal transmissions occur during pregnancy and delivery or breastfeeding, respectively. classic examples include mother-to-child transmission of the protozoa toxoplasma gondii during pregnancy, hiv during pregnancy, delivery, or breastfeeding, and zika virus during pregnancy (rasmussen et al., ) . case finding and contact tracing are public health prevention and control activities aimed at stopping the spread of infectious diseases transmitted by either direct contact or direct spread of droplets. once identified, further activities to limit transmission to susceptible individuals can involve definitive diagnosis, treatment, and, possibly, isolation of active cases and carriers, and observation, possible quarantine, or prophylactic vaccination or treatment of contacts. patient education is an important feature of any communicable infectious disease control effort. environmental changes, such as decreasing overcrowded areas and increasing ventilation, can also contribute to limiting the spread of some infectious diseases, particularly respiratory diseases. central to prevention of transplacental and perinatal infectious disease transmission is avoidance of maternal infection and provision of early diagnosis and treatment of infected women prior to or during pregnancy. for example, public health efforts targeting congenital toxoplasmosis focus on preventing pregnant women from consuming undercooked meat or contacting cat feces that may be contaminated. current who guidelines for prevention of mother-to-child hiv transmission recommend that hiv-infected pregnant and breastfeeding women should be maintained on antiretrovirals (who, ) . there are three main categories of indirect transmission: biological, mechanical, and airborne. box provides definitions of the different types of hosts, vectors, and vehicles involved in the life cycle of agents that are transmitted indirectly. biological transmission occurs when multiplication and/or development of a pathogenic agent within a vector (e.g., biological vector or intermediate host) is required for the agent to become infectious to humans. the time that is necessary for these events to occur is known as the extrinsic incubation period; in contrast to the intrinsic incubation period which is the time required for an exposed human host to become infectious. indirect transmission by mosquito vectors is the primary mode of transmission of a large number of viruses (arthropod-borne viruses or arboviruses) of public health concern (e.g., west nile, zika). a number of ntds are also transmitted by biological vectors including lymphatic filariasis (a.k.a. elephantiasis) by mosquitoes. ticks are biological vectors for many bacterial etiological agents (e.g., lyme disease and ehrlichiosis), and the parasitic agent causing babesiosis. the infectious agent of the helminthic ntds, schistosomiasis, and dracunculiasis are transmitted indirectly via intermediate freshwater snail and copepod hosts, respectively. mechanical transmission does not require pathogen multiplication or development within a living organism. it occurs when an infectious agent is physically transferred by a live entity (mechanical vector) or inanimate object (vehicle) to a susceptible host. classic examples of diseases spread by mechanical vector transmission are shigellosis (transmission of shigella spp. on the appendages of flies) and plague (transmission of yersinia pestis by fleas). many diarrheal diseases are transmitted by the fecal-oral route with food and water often acting as vehicles (figure ) . other types of vehicles for infectious disease agents are biologic products (e.g., blood, organs for transplant) and fomites (inanimate objects such as needles, surgical instruments, door handles, and bedding). transfusion-related protozoal infection resulting in chagas disease has been of increasing concern to the us blood banks that have instituted screening measures (cdc, ) . airborne transmission involves aerosolized suspensions of residue (less than five microns in size, from evaporated aerosol droplets) or particles containing agents that can be transported over time and long distance and still remain infective. tb is a classic example of an infectious disease often spread by airborne transmission. vbds comprise approximately % of the global burden of infectious diseases (townson et al., ) . for some diseases (e.g., dengue, zika, chagas), chemoprophylaxis and immunoprophylaxis are not prevention and control options, leaving vector control as the primary means of preventing disease transmission. integrated vector management is defined by the who as, "a rational decision-making process to optimize the use of resources for vector control" (who, ) . there are four major categories of ivm vector control strategies: biological, chemical, environmental, and mechanical. ivm interventions are chosen from these categories based upon available resources, local patterns of disease transmission, and ecology of local disease vectors. two key elements of ivm are collaboration within the health sector and with other sectors (e.g., agriculture, engineering) to plan and carry out vector control activities, and community engagement to promote program sustainability. another core element is the integrated approach which often permits concurrent targeting of multiple vbds, as some diseases are transmitted by a single, common vector, and some vector control interventions can target several different vectors. in addition, combining interventions serves not only to reduce reliance on any single intervention, but also to reduce the selection pressure for insecticide and drug resistance. table , adapted from the who handbook for ivm, illustrates some of the many types of ivm activities and provides examples of vbds that might be controlled by such interventions (who, ) . diarrheal diseases primarily result from oral contact with water, food, or other vehicles contaminated with pathogenic agents originating from human or animal feces. most ($ %) of diarrhea-associated deaths are attributable to unsafe drinking water, inadequate sanitation, and insufficient hygiene (black et al., ; prüss-Üstün et al., ) . interruption of fecaloral transmission through provision of safe water and adequate sanitation, and promotion of personal and domestic hygiene are fundamental to diarrhea prevention and control. fecaloral transmission of a diarrheal agent can occur via one of several routes. in , wagner and lanoix developed a model of major transmission depicted in what has become known as the 'f-diagram,' based on steps within the fecal-oral flow of transmission starting with the letter 'f': fluids (drinking water), definitive host: a host in which a parasite reproduces sexually. humans are definitive hosts for roundworms. by strict definition, mosquitoes are the definitive host of malaria as they are the organism in which sexual reproduction of the agent protozoa, plasmodium spp., occurs. reservoir host: a host that serves to sustain an infectious pathogen as a potential source of infection for transmission to humans. note that a reservoir host will not succumb to infection. lowland gorillas and chimpanzees can be infected by ebola virus, but they are not a reservoir host as they suffer devastating losses from infection. bats are a suspected reservoir for ebola virus. intermediate dead-end host: a host from which infectious agents cannot be transmitted to other susceptible hosts. humans are a dead-end host for west nile virus which normally circulates between mosquitoes and certain avian species. vector: a generic term for a living organism (e.g., biological vector or intermediate host) involved in the indirect transmission of an infectious agent from a reservoir or infected host to a susceptible host. biological vector: a vector (often arthropod) in which an infectious organism must develop or multiply before the vector can transmit the organism to a susceptible host. aedes spp. mosquitoes are a biological vector for dengue, chikungunya, and zika. mechanical vector: a vector (often arthropod) that transmits an infectious organism from one host to another but is not essential to the life cycle of the organism. the house fly is a mechanical vector in the diarrheal disease shigellosis as it carries feces contaminated with the shigella spp. bacterium to a susceptible person. vehicles: inanimate objects that serve as an intermediate in the indirect transmission of a pathogen from a reservoir or infected host to a susceptible host. these include food, water, and fomites such as doorknobs, surgical instruments, and used needles. fingers, flies, fields (crops and soil), floods (representative of surface water in general), and food (wagner and lanoix, ; figure ). other f's that can be considered include facilities (e.g., settings where transmission is likely to occur such as daycare centers) and fornication. the f-diagram is useful for depicting where water, sanitation, and hygiene (wash) interventions act as barriers in the fecal-oral flow of diarrheal pathogens. safe excreta disposal and handling act as primary barriers to transmission by preventing fecal pathogens from entering the environment. once the environment has become contaminated with pathogen-containing feces, secondary and tertiary barriers to transmission include water treatment, safe transport and storage of water, provision of sewage systems to control flooding, fly control, and good figure the 'f-diagram' illustrates major direct and indirect pathways of fecal-oral pathogen transmission and depicts the roles of water, sanitation, and hygiene interventions in providing barriers to transmission. primary barriers prevent contact with feces, and secondary barriers prevent ingestion of feces. source: water, engineering and development centre (wedc), loughborough university. personal and domestic hygiene (e.g., food hygiene) practices (requiring adequate water quantity) ( figure ) . as with ivm, the control of diarrheal diseases increases with integration of control measures to achieve multiple barriers to fecal-oral transmission. the basic approach to preventing transmission of an infectious agent from a contaminated vehicle is to prevent contamination of, decontaminate, or eliminate the vehicle. food is a common vehicle for infectious agents, and it can potentially become contaminated at any step along the food production chain of production, processing, distribution, and preparation. production refers to the growing of plants for harvest and raising animals for food. an example of contamination at this step includes the use of fecally contaminated water for crop irrigation. processing refers to steps such as the chopping, grinding, or pasteurizing of food to convert it into a consumer product; if the external surface of a melon is contaminated, chopping it into pieces for sale can result in contamination of the fruit. distribution, in which food is transferred from the place where it was produced and/or processed to the consumer, can result in contamination if, for example, the transportation vehicle is not clean. finally, preparation is the step in which food is made ready to eat; not cleaning a cutting board after cutting raw chicken can result in microbial pathogen crosscontamination of other food items. food hygiene is the term used to describe the conditions and activities employed to prevent or limit microbial contamination of food in order to ensure food safety. decontamination includes sterilization, the destruction of all microbial agents, and disinfection, the destruction of specific agents. control of airborne diseases focuses on regulating environmental airflow and air quality to minimize contact with infectious droplet nuclei. in health-care settings, negative pressure isolation rooms and exhaust vents can be used to manipulate airflow. recirculating, potentially infectious air can undergo high-efficiency particulate air (hepa) filtration and/or be mixed with 'clean' (noncontaminated) air to remove or dilute the concentration of infectious particle to below the infectious dose. health-care workers should use n masks. on commercial aircraft, airborne pathogen transmission is minimized by methods including regulating airflow to prevent widespread dispersal of airborne microbes throughout the cabin, hepa filtering recirculating air, and mixing recirculating air with fresh air (considered sterile) (dowdall et al., ) . the portal of entry refers to the site at which the infectious agent enters a susceptible host and gains access to host tissues. many portals of entry are the same as portals of exit and include the gastrointestinal, genitourinary, and respiratory tracts, as well as compromised skin and mucous membrane surfaces. some infectious agents can naturally enter a susceptible host by more than one portal. for example, the three forms of human anthrax can be distinguished according to the route of agent entry: cutaneous anthrax due to entry through the skin, gastrointestinal anthrax resulting from ingestion of spores, and pulmonary anthrax following inhalation of spores. standard infection control practices target portals of exit (and entry) of infectious agents from human reservoirs and sources. cdc guidelines suggest two levels of precautions to stop transmission of infectious agents: standard precautions and transmission-based precautions (siegel et al., ) . standard precautions prevent transmission of infectious agents that can be acquired by contact with blood, body fluids, nonintact skin, and mucous membranes. they can be used to prevent transmission in both health-care and non-health-care settings, regardless of whether infection is suspected or confirmed. hand hygiene is a major component of these precautions, along with use of personal protective equipment (ppe). common ppe include gloves, gowns, face protection (e.g., eye-protecting face shields), and respiratory protection using n masks to prevent inhalation of airborne infectious particles (e.g., from mycobacterium tuberculosis). of note, depending on the circumstance, ppe can be used to prevent dispersal of infectious agents from their source by providing a barrier to the portal of exit, or to protect a susceptible individual by placing a barrier to a portal of entry. respiratory hygiene/cough etiquette is used to prevent spread of infection by respiratory droplets. main elements of respiratory hygiene/cough etiquette include covering the nose and mouth area with one's elbow during coughing or sneezing or using a surgical mask to limit dissemination of infectious respiratory secretions, and hand hygiene after contact with respiratory secretions. other components of standard precautions include needle stick and sharp injury prevention, safe injection practices, cleaning and disinfection of potentially contaminated equipment and other objects, and safe waste management. a susceptible host is an individual who is at risk of infection and disease following exposure to an infectious agent. as discussed previously, there are many determinants of host susceptibility, including both innate factors determined by the genetic makeup of the host and, acquired factors such as agent-specific immunity and malnutrition. important prevention and control interventions that target the susceptible host include both those that address determinants of susceptibility in the host (e.g., immunoprophylaxis, provision of adequate nutrition, treatment of underlying diseases) and those that target an infecting agent (e.g., chemoprophylaxis). immunoprophylaxis encompasses both active immunization by vaccination and passive immunization through provision of pathogen-specific immunoglobulin. malnutrition is a strong risk factor for morbidity and mortality due to diarrheal disease, and a vicious cycle exists between infectious diarrheal disease leading to malnutrition and impaired immune function which, in turn, promotes increased susceptibility to infection (keusch et al., ) . consequently, breastfeeding and safe complementary feeding play crucial roles in protecting infants and young children from infectious diseases, particularly in resource-poor settings. micronutrients are required for normal immune function, and vitamin a and zinc supplementations have been shown to decrease some types of infections in children deficient in these micronutrients (mayo-wilson et al., ; imdad et al., ) . in certain circumstances, chemoprophylaxis is employed to protect a susceptible host in anticipation of, or following exposure to an infectious agent. antimalarial drugs are routinely used in combination with personal protective measures to prevent malaria in travelers and established guidelines exist for antibiotic prophylaxis prior to surgery. another important element in the prevention and control of infections is the recognition and management of patients with underlying diseases and conditions that can weaken host barriers to infection. for example, tb is the leading opportunistic infection in hivinfected individuals, and antiretroviral therapy reduces risk of developing tb and mortality due to tb disease. infectious complications are a major cause of morbidity and mortality in cancer and transplant patients, often resulting from immunosuppression that can be primary or related to drug and/or radiation therapy. infectious disease control is also critical in individuals with compromised physical barriers to microbes as, for example, burn patients and patients with cystic fibrosis. dr william h stewart, the one-time surgeon general of the united states, has been quoted (perhaps mistakenly) as saying in the s "it is time to close the book on infectious diseases, and declare the war against pestilence won (spellberg, ) ." these words clearly do not hold true today, and public health practitioners wage an ever-growing fight against emerging pathogens, drug-resistant organisms, and vaccine-preventable diseases. in this light, it is all the more important that we have the tools needed to understand transmission dynamics and implement effective prevention and control programs. clear definitions of terminology and elucidation of fundamental principles lay the foundation for effective public health interventions. hopefully, this article helps strengthen the armamentarium of the public health practitioner. narrative review: tetanus-a health threat after natural disasters in developing countries protective effects of the sickle cell gene against malaria morbidity and mortality revisiting leishmaniasis in the time of war: the syrian conflict and the lebanese outbreak estimating the reproduction number of ebola virus (ebov) during the outbreak in west africa chagas disease and transfusion medicine: a perspective from non-endemic countries prediction, assessment of the rift valley fever activity in east and southern africa - and possible vector control strategies environmental (saprozoic) 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chickens: multiple system disease with immune suppression date: - - journal: pathogens doi: . /pathogens sha: doc_id: cord_uid: lyxje u in the early s, infectious bronchitis (ib) was first characterized as a respiratory disease in young chickens; later, the disease was also described in older chickens. the etiology of ib was confirmed later as being due to a coronavirus: the infectious bronchitis virus (ibv). being a coronavirus, ibv is subject to constant genome change due to mutation and recombination, with the consequence of changing clinical and pathological manifestations. the potential use of live attenuated vaccines for the control of ibv infection was demonstrated in the early s, but vaccine breaks occurred due to the emergence of new ibv serotypes. over the years, various ibv genotypes associated with reproductive, renal, gastrointestinal, muscular and immunosuppressive manifestations have emerged. ibv causes considerable economic impacts on global poultry production due to its pathogenesis involving multiple body systems and immune suppression; hence, there is a need to better understand the pathogenesis of infection and the immune response in order to help developing better management strategies. the evolution of new strains of ibv during the last nine decades against vaccine-induced immune response and changing clinical and pathological manifestations emphasize the necessity of the rational development of intervention strategies based on a thorough understanding of ibv interaction with the host. infectious bronchitis virus (ibv) belongs to the family coronaviridae and order nidovirales [ ] . ibv infects chickens and pheasants and induces a clinical disease known as infectious bronchitis (ib) [ ] . the infected chickens may appear depressed with various levels of breathing difficulty and have ruffled feathers [ ] [ ] [ ] [ ] . younger chickens show the most severe clinical manifestations [ ] . in addition, there is serological evidence that poultry workers may develop anti-ibv antibodies following exposure to infected birds, although there is no evidence of active infection in humans [ ] . however, experimentally, certain ibv strains (i.e., massachusetts (mass) and gray) have been found to be capable of replicating in human cell lines [ ] . the first ib case caused by the mass serotype was recorded from north dakota, usa [ ] . since then, hundreds of ibvs with heterogenous genomes have been emerging continuously as a result of mutations and recombination [ , ] . consequently, high ib-associated losses are recorded in spite of control attempts using live attenuated vaccines. different strains of ibv demonstrate varying properties with differences in pathogenesis, virulence, tissue and age tropisms and receptor figure . phylogenetic tree based on the s nucleotide sequences (from the atg start codon to the cleavage site of the spike protein). the phylogeny contains a total of infectious bronchitis virus (ibv) strains from different countries around the world. the ibv strain and genbank accession number are given for each strain. the sequences were aligned using clustal omega, and the phylogenetic tree was constructed using the maximum likelihood method available in raxml with bootstrap replicates for branch support (the numbers on the nodes represent the bootstrap values). the analyses were constructed using geneious ® v . . (https://www.geneious.com/). it is well established that, following the initial infection in the respiratory tract, the virus is disseminated to other tissues due to viremia [ , ] (figure ). however, the exact mechanisms by which ibv leads to viremia are not understood. recently, reddy et al. ( ) showed that a belgian nephropathogenic ibv strain, b , could infect blood monocytes and that these monocytes may facilitate the dissemination of ibv to visceral organs, including the kidney [ ] . in agreement with this finding, another study [ ] showed tropism of ibv towards monocytes by the mass , california phylogenetic tree based on the s nucleotide sequences (from the atg start codon to the cleavage site of the spike protein). the phylogeny contains a total of infectious bronchitis virus (ibv) strains from different countries around the world. the ibv strain and genbank accession number are given for each strain. the sequences were aligned using clustal omega, and the phylogenetic tree was constructed using the maximum likelihood method available in raxml with bootstrap replicates for branch support (the numbers on the nodes represent the bootstrap values). the analyses were constructed using geneious ® v . . (https://www.geneious.com/). ibv is typically transmitted to the host by inhalation, whereupon it attaches to the respiratory epithelium and enters by receptor-mediated endocytosis [ ] . once ibv enters the upper respiratory tract, it targets the epithelium, which is ciliated and includes mucus-secreting glands [ ] , causing ciliostasis and mucus accumulation. the virus replication in the respiratory epithelium peaks - days post-infection (dpi) depending on the infecting ibv strain [ , , ] . consequently, respiratory signs result within dpi and peak around dpi [ ] [ ] [ ] . these respiratory clinical manifestations include sneezing, gasping, coughing, tracheal rales, nasal discharge, conjunctivitis, and dyspnea [ ] . it is not uncommon to observe non-respiratory clinical manifestations such as depression, weight loss, lethargy and huddling together [ , , ] . the morbidity and mortality associated with respiratory tract ibv infection depend on the age of infection; young chickens are severely affected compared to adult chickens [ , ] . at post-mortem examination, hemorrhages and the accumulation of caseous, serous and catarrhal exudates in the trachea, nasal passage and sinuses [ , ] are evident, as well as gross changes in air sacs (i.e., the accumulation of foamy or cloudy exudates) [ ] . depending on the time of sampling, histological features include deciliation and dislodgment of epithelial cells, as well as mononuclear cell infiltration. these changes are visible around - dpi. further development of the lesions, with hyperplasia and hypertrophy of the epithelium and prominent mononuclear cell infiltration in lamina propria, are visible around - dpi. these stages are followed by recovery with repopulation of the mucosa with pseudostratified ciliated epithelium and goblet cells ( - dpi) [ , , ] . it is well established that, following the initial infection in the respiratory tract, the virus is disseminated to other tissues due to viremia [ , ] (figure ). however, the exact mechanisms by which ibv leads to viremia are not understood. recently, reddy et al. ( ) showed that a belgian nephropathogenic ibv strain, b , could infect blood monocytes and that these monocytes may facilitate the dissemination of ibv to visceral organs, including the kidney [ ] . in agreement with this finding, another study [ ] showed tropism of ibv towards monocytes by the mass , california (cal) , connecticut (conn) and iowa ibv strains. using the mass and conn ibv strains, amarasinghe et al. ( ) showed that ibv could infect low numbers of respiratory tract macrophages [ ] . it is also possible that ibv dissemination beyond the respiratory tract may involve the lymphatic system and infected macrophages, similar to marek's disease virus dissemination via infected lung macrophages [ ] . ) showed that ibv could infect low numbers of respiratory tract macrophages [ ] . it is also possible that ibv dissemination beyond the respiratory tract may involve the lymphatic system and infected macrophages, similar to marek's disease virus dissemination via infected lung macrophages [ ] . subsequent clinical manifestations of ibv infection related to the reproductive tract depend on the infecting ibv strain. for example, the m , aust t and qx-like strains are known to cause reproductive tract defects in long-lived chickens [ , , ] , leading to low egg production and quality, whereas ibv strains such as conn and iowa do not cause reproductive tract abnormalities [ ] . the mechanisms that lead certain ibv strains to establish reproductive tract infection are unknown. in different body systems. all the ibv strains primarily infect the respiratory tract, and based on the genotypes, the ibv infection can extend to various tissues, either persisting or leading to clinical and pathological manifestations. the solid arrows indicate paths that have been confirmed. the empty arrows indicate paths that have been suggested. the text boxes with continuous borders summarize histological changes, and the text boxes with discontinuous borders represent clinical manifestations. ses, shell-less egg syndrome; fls, false layer syndrome; git, gastrointestinal tract. subsequent clinical manifestations of ibv infection related to the reproductive tract depend on the infecting ibv strain. for example, the m , aust t and qx-like strains are known to cause reproductive tract defects in long-lived chickens [ , , ] , leading to low egg production and quality, whereas ibv strains such as conn and iowa do not cause reproductive tract abnormalities [ ] . the mechanisms that lead certain ibv strains to establish reproductive tract infection are unknown. however, ibv replication in reproductive mucosa has been documented in several studies [ , , ] . depending on the infecting ibv serotype, localization of ibv antigens in the oviduct can vary, and evidence of higher ibv replication has been observed in chickens infected at a younger age when compared to adults [ ] . this age difference in ibv replication is reflected in differences in clinical and pathological outcomes in chickens. for example, chickens infected with certain strains of ibv such as mass, qx-like strain or aust t at ages of - days develop cystic oviducts without impaired ovarian functions, which leads to false layer syndrome with no egg production [ , [ ] [ ] [ ] . such flocks with false layer syndrome do not reach peak production, with a consequence of premature culling [ , ] . infection with ibv in laying hens can negatively influence egg production, resulting in poor-quality eggs, such as misshapen, miscolored, thin, rough-shelled or shell-less eggs and eggs with watery albumin, meat or blood spots, which can peak at around two weeks post-infection [ , , ] . in addition, egg production in laying hens can drop by - % [ , ] . although production bounces back close to normal within nine weeks, there can be a - % decline relative to normal production [ , ] . ibv infection of the reproductive tract of laying hens leads to shorter, hypoglandular oviducts and regressed ovaries [ , ] . histologically, deciliation of the epithelium and a reduction in the height of the epithelial cells, along with epithelial desquamation and degeneration, are common in infected oviducts between and dpi [ ] with occasional follicular destruction and microbleeding [ , ] . fibroplasia and edema of infected lamina propria are also evident [ ] . in contrast to the development of false layers, chickens with patent oviducts were found to have an intact surface epithelium with localized hypoplasia of glandular areas [ ] . later, following around dpi, lymphoid nodules are seen in the oviduct [ ] . although the consequences of ibv targeting the reproductive tracts of female chickens is known, little attention has been given to changes corresponding to the reproductive tracts of male chickens, which may cause impacted sperm production, infertility and venereal transmission of ibv [ , ] . recent studies have found, depending on the infecting ibv strain, that ibv targets the testes and causes low sperm production and infertility [ , , ] . ibv replication in the efferent duct epithelium and the formation of epididymal stones lead to low sperm production and infertility [ ] . gallardo and colleagues observed ibv replication in cells of the seminiferous tubule (i.e., sertoli cells) infected with arkansas (ark) and mass ibv strains; moreover, they demonstrated ibv transmission to layers via infected semen, indicating the possibility of venereal transmission of ibv [ ] . ibv-induced changes including mononuclear cell and heterophil infiltration, necrosis and microbleeding of testes have been documented [ ] . the nephropathogenic ibv strains include b , aus t, qx-like, / , holte and gray [ , , , , ] . the ibv b strain is known to spread from the respiratory tissues via blood monocytes [ ] . following dissemination, ibv strains could infect ciliated cells of the nephron, including proximal, distal and collecting tubules, depending on the infecting ibv strain [ , , , ] . ibv strains that target the kidney have received increased attention due to their higher virulence in young chickens when compared to other ibv strains [ , , ] . apart from the general signs associated with ibv infection, nephropathogenic ibv strains result in weight loss, watery droppings, increased water consumption and an increase in the incidence of mortality [ , ] . the nephropathogenic ibv pathogenesis also varies according to the breed of the chickens; for example, the clinicopathological manifestations of nephropathogenic ibv are more severe in rhode island red chickens when compared to white leghorn chickens [ ] . at post-mortem examination, ibv-infected kidneys are pale, discolored and enlarged [ , ] . urate deposits are also commonly observed with tubular distention [ , , ] . histologically, tubules develop degenerative changes, ureters become distended with cellular debris and urate crystals are seen in the tubules; in addition, mononuclear cell recruitment in interstitial tissues in the medulla and cortex has been observed [ , , ] . although ibv has been isolated from cloacal swabs, there is no indication that ibv is transmitted via the fecal-oral route. it is possible that gastrointestinal infection follows respiratory infection, subsequent infection of monocytes and macrophages and the spread of ibv via the blood or lymphatics [ , ] . ibv strains such as qx-like strains, /b ( / ) and moroccan g are known to infect the gastrointestinal tissues, leading to clinical and pathological manifestations [ , [ ] [ ] [ ] . the qx-like strains are capable of targeting the proventriculus and ileum, leading to proventriculitis and, occasionally, diarrhea [ , ] . moroccan g ibv has also been shown to target the gastrointestinal tissues, such as the esophagus, jejunum, ileum and rectum [ ] . other experimental studies that used moroccan g ibv indicated that the virus targets the epithelial covering of the tips of villi of the ilium and rectum, leading to atrophy of the villi and desquamation of epithelial cells, with lymphocyte, macrophage and heterophil infiltration in the mucosa [ , ] . ibv /b (i.e., / ) has also been shown to replicate in the esophagus and ileum, leading to enteritis in young broiler chickens [ ] . in the early s, broiler chickens infected with ibv strain /b were found to develop bilateral pectoral myopathy [ ] . the disease was characterized by edema, due to a gelatinous material, followed by facial hemorrhage and mild separation of muscle fibers [ ] . although bilateral myopathy could not be reproduced with ibv /b, mild gross changes were observed with no indication of histological changes or muscle damage [ ] . further, a study that collected samples with bilateral pectoral myopathy from a slaughter plant in brazil could not establish an association of this condition with ibv infection, although ibv was detected in muscle tissues using molecular techniques [ ] . consequently, the muscle lesions were suggested to be caused by type iii hypersensitivity involving the deposition of immune complexes in the capillary walls of pectoral muscles, rather than lesions induced by viral replication [ ] . depending on the ibv strain, the virus can persist in the tissues of chickens for an extended period [ , , ] . for example, ibv (i.e., aust t strain) can persist, particularly in the cecal tonsils and kidney, for more than seven months [ ] . the mass ibv strain can persist in the cecal tonsils, spleen and kidney for about a month [ ] . although the period of ibv persistence is influenced by the age at infection [ ] , the length of persistence does not depend on the systemic anti-ibv antibody concentration [ ] . the implications of ibv persistence in chickens are twofold. first, persistently infected chickens are a source of infection for naïve chickens [ ] . second, persistent ibv infection promotes viral evolution [ ] . the ibv-induced potential immune-suppressive mechanisms are summarized in figure . ibv strains / , qx-like, strain g and mass infect various immune organs, such as the cecal tonsils [ ] , spleen [ ] , harderian gland and bursa of fabricius [ , ] . it is not known whether the tropism of ibv for these immune organs depends on the virulence of the infecting ibv strain or whether ibv replication in these immune organs impacts immune functions. it is very well documented that avian viruses that replicate in immune organs, such as marek's disease virus [ ] , chicken anemia virus [ , ] and infectious bursal disease virus [ ] , are immunosuppressive, impacting vaccine-mediated immune response and resulting in secondary bacterial infections [ ] . however, recent investigations provided molecular and cellular evidence that ibv, in fact, directly interferes with the host's innate response at various levels, potentially impacting the elicitation of adaptive host response. the toll-like receptors (tlrs) and are innate receptors and have a role in detecting ibv-associated molecular patterns, such as double-stranded (ds) and single-stranded (ss) ribonucleic acid (rna), respectively [ ] . certain brazilian strains of ibv are capable of inhibiting tlr signaling, leading to decreased proinflammatory cytokines and decreased mrna expression linked to the development of cell-mediated immune response, leading to increased pathology in the kidney [ ] . similarly, a conn strain of ibv has been shown to downregulate mrna expression of tlr , interleukin (il)- β and interferon gamma (ifn-γ), leading to increased ibv genome accumulation and more severe pathology in the respiratory tissues [ ] . certain strains of ibv can inhibit the expression of pathogen recognition receptors such as toll-like receptors (tlrs) or their signaling pathway, leading to reduced expression of proinflammatory cytokines, which eventually interferes with the innate immune response and induction of the adaptive immune response. ibv is also capable of replicating in respiratory tract macrophages, inhibiting their functions and inducing apoptosis. ibv is capable of incorporating cd molecules into its envelop during egress from the host cells, shielding it against lysis via complement-and antibody-dependent mechanisms. protection against ib is mediated by both antibody-and cell-mediated immune responses [ , ] . although the antibody-mediated immune response predominantly depends on a response , enabling it to persist in the host for a longer period. epithelial cells are the primary target sites of ibv replication, which results in deciliation and destruction, leading to inhibition of the mucociliary escalator mechanism. certain strains of ibv can inhibit the expression of pathogen recognition receptors such as toll-like receptors (tlrs) or their signaling pathway, leading to reduced expression of proinflammatory cytokines, which eventually interferes with the innate immune response and induction of the adaptive immune response. ibv is also capable of replicating in respiratory tract macrophages, inhibiting their functions and inducing apoptosis. ibv is capable of incorporating cd molecules into its envelop during egress from the host cells, shielding it against lysis via complement-and antibody-dependent mechanisms. one of the immune cell types that bridges innate and adaptive host responses is the macrophages, and the available data show that certain ibv serotypes (i.e., mass and conn) target respiratory tract macrophages and replicate within them, thus leading to a productive infection [ , ] . although the impact of immune cell targeting of ibv has not been studied completely, ibv replication in macrophages could decrease type ifns activity [ ] , similar to ibv's ability to hinder type ifns response in epithelial and fibroblast cells [ ] . type ifns are the main antiviral molecules synthesized in the host in response to viral replication, and, previously, it has been shown that ibv is sensitive to the antiviral activity of type ifns given as a treatment to prevent ib in chickens [ ] . although it is not known how ibv inhibits the function of type ifns in macrophages, one potential explanation is that the accessory proteins of ibv could play a role in this immune evasion strategy. in agreement with this view, the ability of ibv accessary proteins a and b to interfere with type ifns production in target cells other than macrophages has been shown [ , ] . other than this interference with the production of type ifns, ibv is capable of inhibiting the downstream signaling of type ifns, minimizing the expression of interferon-stimulating genes (isgs) by preventing the functioning of signal transducer and activator of transcription (stat ) [ ] . another implication of ibv replication in macrophages is the destruction of macrophages due to apoptosis. ibv could induce programmed cell death in avian macrophages via intrinsic and extrinsic routes involved in apoptosis [ ] . although the mechanisms of the destruction of macrophages by ibv require further investigation, evidence has shown that macrophage numbers increase at h and then decline in the trachea and lungs in response to ibv infection [ ] . it is important to understand whether this decline is related to the apoptosis of ibv-infected macrophages. the complement system functions as a part of the innate arm of the immune response and also plays a role in adaptive immune functions. the components of the complement pathway aid in the host immune response via complement-and antibody-mediated lysis of viruses [ ] [ ] [ ] [ ] . since host cells are shielded from lysis via this strategy due to the expression of cd in the host cell membrane, ibv is capable of incorporating cd into its envelop during exit from the host cells, negating lysis via complement-and antibody-dependent mechanisms [ ] . previous studies showed that ibv is vulnerable to attack by this strategy [ ] . ibv replication impacting the respiratory tract brings forth a defective clearance mechanism by the deciliation of the respiratory epithelium, thereby increasing the vulnerability of respiratory surfaces to secondary bacterial infections [ ] . the co-infection of respiratory pathogens with ibv causes complications and worsens the clinical and pathological manifestations [ , ] . the infection of chickens with mycoplasma gallisepticum followed by ibv infection can result in coryza, tracheitis and airsacculitis in the host [ ] . in addition, secondary infections with pathogenic escherichia coli can lead to prominent lesions in respiratory surfaces, pericarditis and death [ ] . in addition, the co-infection of haemophilus paragallinarum with ibv could result in severe lesion development and increased mortality rates [ ] . protection against ib is mediated by both antibody-and cell-mediated immune responses [ , ] . although the antibody-mediated immune response predominantly depends on a response to the ibv s protein, the main cell-mediated response, cd + cytotoxic t cell response is elicited by the ibv n protein [ ] . following ibv infection, memory b [ ] and t cells [ ] are formed and are present in peripheral blood and the spleen. following ib vaccination, the number of b and t cells increases in the harderian gland [ ] . increased recruitments of cd + and cd + t cells in the trachea have also been shown following application of live ib vaccines [ ] . vaccination is the primary choice for the control of ib in the poultry industry. the chickens receive multiple ib vaccinations, and the frequency of vaccination depends on the expected production life of the chicken. for broilers, day-old vaccination in the hatchery is commonly practiced followed by a booster vaccination at - weeks of age [ ] . multiple vaccinations with live attenuated vaccines are usually given to layers and breeders followed by a killed vaccine just before the onset of the laying period [ , ] . the live attenuated vaccines are administered via drinking water, eye drop, or coarse spray and inactivated vaccines are given parenterally. for example, in eastern canada, the layer and breeder pullets are vaccinated with various combinations of live attenuated ib vaccines starting at one day of age and then, at two, five and nine weeks followed by an inactivated ib vaccine given at fourteen weeks of age. during the lay, the chickens are not vaccinated. the goal of such layer and breeder vaccination strategies is to ensure the transfer of maternal antibodies to the offspring [ ] as well as provide the extended protection during the lay [ , ] . however, vaccination of day-old chickens is controversial for three reasons. first, maternal antibodies could be protective against potential ibv infection during the first few days of life while early vaccination could enhance the decay of the maternal antibodies [ ] . second, early vaccination (i.e., day of age) induces poor b cell and t cell responses when compared to later vaccination (i.e., day of age) [ ] . third, ib vaccination at the day of age can induce severe vaccine reactions [ ] . despite these reasons, live attenuated ib vaccination in the hatchery can be critical for the prevention of severe respiratory illness and cystic lesions in the oviduct that results from very early exposure to virulent ibvs [ , ] . since the introduction of vaccination against ib using live attenuated (mass serotype) vaccines, different vaccine serotypes such as / , ark, conn, d and d have been developed and made available commercially [ ] . based on the prevalence of the various ibv serotypes, and the availability of licensed vaccines in a geographical area, different areas within countries use different combinations of live attenuated and inactivated vaccines. in certain regions in europe, vaccines against mass and / serotypes are widely used, while, in certain states within usa, vaccines against mass, ark and conn serotypes are extensively used [ ] . the serological response to ibv is mainly induced by the s protein [ , ] and, consequently, cross-protection induced by ib vaccines against heterologous strains varies widely. the study of cook and colleagues indicated that the use of more than one vaccine serotype can produce better cross-protection against challenge with heterologous ibv serotypes [ ] . therefore, priming with more than one heterologous live vaccines and boosting with inactivated or live attenuated vaccines are practiced particularly by layer and breeder industries [ ] . it has also been shown that vaccination protocols that involve more than one serotype induced better immune cell recruitment in the respiratory mucosa when compared to vaccination with a single serotype vaccine [ ] . although control of ib relies on vaccination [ ] , several limitations of ib vaccination have been observed. the steady increase of ibv variants leading to frequent outbreaks in vaccinated flocks has become a concern increasingly [ , , ] . in addition, attenuated ibv strains used for vaccination can spread among individual birds within flocks [ ] , and changes in virulence during bird-to-bird passage can lead to production problems [ , ] . coinfection of host cells with live attenuated ib vaccines and wild type ibv can also result in genomic recombination contributing to the virus evolution [ , ] as well as mutations that can occur under the effect of immune pressure [ ] [ ] [ ] . although the global poultry industry practices hatchery vaccination against ib, day may not be the optimum time for vaccination in terms of inducing systemic and mucosal immune responses against ib [ ] because of the developing immune system [ ] . the availability of a limited number of licensed vaccines to choose in a geographical area is also a constraint. for example, in canada, various ibv variants including mass, conn, / , ca and dmv/ [ , , [ ] [ ] [ ] are circulating in poultry flocks and only live attenuated vaccines developed against mass and conn serotypes and inactivated vaccines developed against mass and ark serotypes are available for optimizing on farm ib vaccination strategies. given the limited efficacy of existing ib vaccination strategies, it is critical to establish an ibv surveillance system that characterizes the different ibv strains circulating in various geographical areas and that we understand the antigenic and/or genetic similarities between the circulating ibvs and the available ib vaccines. these data will lead to the optimization of ib vaccination strategies to prevent vaccine breaks. if the existing vaccines are not useful in optimizing vaccination strategies, it would also worth developing autogenous vaccines (inactivated) using characterized unique ibv isolates prevalent in a given geographical area in order to include in the existing vaccination regimes. given the available scientific evidence against ib vaccination at the hatchery [ , ] , it may also be appropriate to postpone the first ib vaccination to a barn vaccination done at seven days of age relying on maternal antibody response to protect the chickens during the first week of life [ ] . there are numerous issues surrounding the use of live attenuated ib vaccines [ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , and relying on inactivated vaccines can be an option, but they inherently lack the ability to induce mucosal immune response, which is critical for the control of ib [ ] [ ] [ ] . it is possible that inactivated vaccines can be used for the induction of mucosal immune response when combined with various nanoparticles [ ] . after decades of research into ibv and numerous studies on vaccine efficacy for the control of ib, this disease is still a major economic concern globally. although many studies have been conducted on ibv pathogenesis, there is little specific information on ibv receptors that determine macrophage tropism and tissue tropism, mechanisms that allow ibv dissemination from the respiratory tract to secondary tissues, ibv persistence in the cecal tonsils and kidney and the immunopathogenesis and immunosuppressive mechanisms of different strains of ibv. novel and sensitive assays and other necessary tools are now available for in-depth investigations of the mechanisms involved in these pathogenesis events. given the concern of vaccine breaks and the emergence of heterogeneous ibv strains, investigations leading to an in-depth understanding of the pathogenesis of ibv are necessary. studies of host-ibv interaction lead to the understanding of tropism of ibv for various body systems, severity of lesions produced in each of these tissues and ways the virus is shed to the environment [ , , , ] . for example, certain ibv variants impact tissues such as kidney and reproductive tract in addition to the respiratory tract [ , , , ] . we are not aware if the current vaccination protocols induce adequate mucosal immune responses in each of these tissues to minimize consequences of ibv replication. it is critical to optimize ib vaccination strategies that induce adequate immune responses in target body systems of these ibv variants minimizing the impact. in addition to secondary bacterial infections, vaccine induced immune response to any pathogen can be impacted by immune suppression induced by ibv. it is necessary to determine if ibv induced immune suppression impact the immune responses intended to be generated by a variety of vaccines used in chickens [ ] . 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bronchitis virus isolated in japan transmissibility of infectious bronchitis virus h vaccine strain among broilers under experimental conditions molecular epizootiology of infectious bronchitis virus in sweden indicating the involvement of a vaccine strain ion channel activity of influenza a virus m protein: characterization of the amantadine block genetic mutations in live infectious bronchitis vaccine viruses following single or dual in vitro infection of tracheal organ cultures different evolutionary trajectories of vaccine-controlled and non-controlled avian infectious bronchitis viruses in commercial poultry avian coronavirus infectious bronchitis attenuated live vaccines undergo selection of subpopulations and mutations following vaccination hatchery vaccination against poultry viral diseases: potential mechanisms and limitations genotyping of infectious bronchitis viruses identified in canada between vaccine efficacy against ontario isolates of infectious bronchitis virus using phylogenetic analysis to examine the changing strains of infectious bronchitis virus infections in ontario over time vaccination against infectious bronchitis virus: a continuous challenge inactivated infectious bronchitis virus vaccine encapsulated in chitosan nanoparticles induces mucosal immune responses and effective protection against challenge etiology and immunology of infectious bronchitis virus comparison of the pathogenicity of qx-like, m and /b infectious bronchitis strains from different pathological conditions this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license the authors declare no conflict of interest. key: cord- -uxxrpfl authors: resta-lenert, silvia title: diarrhea, infectious date: - - journal: encyclopedia of gastroenterology doi: . /b - - - / - sha: doc_id: cord_uid: uxxrpfl nan diarrheal diseases are a major cause of morbidity and mortality around the world, especially in developing countries where children suffer the greatest brunt of infectious diarrhea, malnutrition, and death. annually, approximately million children and infants die worldwide due to diarrheal diseases. in north america, the rate per year is still . diarrheal episodes per child, and in special circumstances (daycare centers, institutions), the incidence is as high as episodes per year. fourteen hospital admissions per children younger than months, per year, result from acute diarrhea. among the adult population, most patients developing acute diarrhea are managed as outpatients or will not seek medical attention. however, . million hospital admissions per year, or . % of all adult hospital admissions annually, are due to diarrhea. in developing countries, inadequate water supply, inef®cient or nonexistent sewage removal systems, chronic malnutrition, and lack of access to oral rehydration are responsible for the high incidence of infectious diarrheal diseases. in the industrialized world, acute diarrhea is still one of the most frequent diagnoses in general practice and children, elderly, and immunocompromised patients are the most vulnerable individuals and account for the majority of these cases. regardless of the etiology, diarrhea is de®ned clinically as the occurrence of three or more episodes of loose stool or any loose stool with blood during a h time period. symptoms lasting less than days represent acute diarrhea, whereas persistent diarrhea lasts more than days but less than weeks, and chronic diarrhea is de®ned by a duration of symptoms greater than weeks. infectious diarrheas are miserable illnesses of overwhelming impact on the general survival of entire populations. throughout history, thousands-strong armies have been defeated by raging diarrheal diseases: from the greeks and macedons under alexander (tucidides), to the romans in the campaigns against the gauls ( julius caesar), to the hundred years war in th century europe, to napoleon, the civil war in america, world war ii, and the vietnam war. scores of previously healthy men suffered and died from the scourge of diarrhea and dysentery in all of these con¯icts. twenty years ago, million to billion episodes of infectious diarrhea and nearly million deaths occurred per year worldwide, primarily in developing countries. ten years later, survival had improved, but the incidence was virtually unchanged despite greater knowledge of the pathophysiology of diarrhea and greater intervention by the world health organization (who). approximately million episodes of acute diarrhea occur in the united states yearly, with an incidence of . to . diarrheal episodes per person-year. medical costs/analyses show that . million americans sought physician care for diarrhea yearly and , required hospitalization. hospitalization and medical costs approached $ million, whereas lost productivity totaled $ million. approximately another million people sought physician care but were not hospitalized. these patients incurred $ million in medical costs and $ billion in loss of work hours. an estimated million cases occurred in people who did not seek physician care, costing nearly $ billion in lost productivity. approximately % of all these cases were presumably of infectious origin. thus, the total cost estimate for diarrheal diseases exceeds $ billion annually in the united states alone. although the elderly have an increased risk for death from diarrhea, death from diarrhea is rare among young children in industrialized countries. in fact, of all pediatric admissions for diarrhea, . % resulted in death, compared with % in patients older than age . increased age was the most important risk factor for death with an odds ratio of . ( % con®dence interval, . to . ) for age or older versus children b years. the national mortality ®gures for the -year period À in the united states show % of diarrheal deaths occurring in individuals older than age . acute infectious diarrhea is transmitted mostly through the fecalÀoral route and by ingestion of contaminated water and food. infection via the fecalÀoral route occurs by direct contact with index cases, especially under conditions of crowding, such as daycare centers or nursing homes. waterborne and foodborne outbreaks are another important source of disease transmission and result from general and/or individual failures in proper standards for the safe handling of foods. in most developing nations, acute diarrhea is endemic due to poor sanitation. furthermore, epidemics of signi®cant proportions often result from natural disasters in areas where water and food supplies are already chronically jeopardized. in some areas of the world, such as asia, africa, and latin america, certain infectious diarrheas (e.g., cholera) have become ongoing pandemics lasting several decades, notwithstanding who efforts at eradication. in most parts of the world, a de®nite seasonality is recognized in the incidence of acute diarrhea. in industrialized nations, the highest incidence of hospital admissions for diarrhea occurs in august and september and in the winter months. in developing nations with warmer climates and endemic conditions, variations in incidence occur from year to year in relation to precipitation indices and crop failures. infectious diarrheas may be classi®ed according to various criteria: duration, underlying mechanism, clinical presentation, etiology, and history. table i summarizes the various criteria for classifying diarrheas in general and infectious diarrheas in particular. in this section, infectious diarrheas are described according to the duration of the main gastrointestinal symptom. acute diarrheas last, by de®nition, less than days and the majority are due to infectious agents. most of these infections are self-limited and generally do not require medical intervention, unless severe dehydration and toxicity develop. however, immunocompromised patients, the elderly, and the very young may develop complications from enteric pathogens that warrant prompt and decisive medical intervention. a list of the major organisms involved in the etiology of acute infectious diarrheas is presented in table ii . not listed is a type of acute enteritis, waterborne and of presumed infectious origin, that has been responsible for several outbreaks of traveler's diarrhea, known as brainerd diarrhea. the etiologic agent of this disease still escapes de®nition. many of the acute infectious diarrheas observed worldwide are diagnosed in the course of local or epidemic outbreaks. three major situations may be encountered: ( ) waterborne infections; ( ) food-borne diarrhea; and ( ) traveler's diarrhea. whereas foodborne diarrhea is often associated with residual microbial toxins, waterborne and traveler's diarrheas are more often caused by active infection via the fecalÀoral route. table iii summarizes the most common causes in these epidemiological situations. a successful enteric pathogen possesses well-developed abilities to colonize, grow, and compete for nutrients in a crowded environment and to interact effectively with the host's enterocytes, inducing changes in the balance between absorption and secretion of water and electrolytes. in most gut infections, a pathogen enters via the oral route and colonizes an area of the ]. in addition to direct effects by microorganisms and their products, enteropathogens induce intestinal damage indirectly via the mucosal in¯ammatory response, which involves secretion of various powerful mediators of secretion and apoptosis. a summary of the current knowledge about the pathogenesis of the most common acute infectious diarrheal syndromes is shown in fig. . on the basis of these three mechanisms, acute infections present as watery, nonin¯ammatory diarrheal syndromes or in¯ammatory diarrheal syndromes. the majority of watery, nonin¯ammatory diarrhea cases are self-limited diseases characterized by low-grade fever, nausea, vomiting, large-volume diarrhea, and the absence of blood and leukocytes in the stools. this presentation is typically reported in patients infected with enterotoxigenic escherichia coli, v. cholerae, clostridial and staphylococcal food poisoning, rotavirus, norwalk virus agent, giardia lamblia, and cryptosporidium. on the other hand, the in¯ammatory diarrheal syndrome is characterized by frequent, small-volume stools that may contain blood and leukocytes, tenesmus, fever, and severe abdominal pain. the most common microorganisms causing this syndrome include salmonella, shigella, campylobacter, enterohemorrhagic e. coli, eiec, clostridium dif®cile, entamoeba histolytica, and yersinia. table iv describes the basic biologic, pathophysiologic, and clinical characteristics pertinent to the most common enteric pathogens. persistent diarrhea is emerging as a major world health problem. children are more likely to develop persistent diarrhea and suffer malnutrition, wasting, and immunocompromise as a consequence. persistent diarrhea is de®ned by looseÀsoft stools occurring at increased frequency and lasting for more than postinfectious persistent diarrhea is a poorly de®ned syndrome that occurs as a sequela of an acute episode with de®nite infectious etiology. patients may develop mild to severe degrees of malabsorption, from lactose intolerance to inability to absorb proteins, fat, and sugars, as well as permanent blunting of villi as assessed by histopathology. the condition is characterized by watery, malodorous stools and progressive wasting. chronic infectious diarrhea occurs mostly in immunocompromised patients. after an acute infectious episode, patients sometimes develop chronic symptoms that are independent of the etiologic agents of acute diarrhea (irritable bowel syndrome with diarrhea, or, occasionally, ulcerative colitis). table vi lists the most common agents isolated from cases of chronic infectious diarrhea. by de®nition, chronic diarrhea lasts more than weeks and patients developing this syndrome quite often are hospitalized and have undergone antibiotic therapy for other reasons. elderly, human immunode-®ciency virus (hiv)/acquired immunode®ciency syndrome (aids), transplant, and cancer patients are easy targets for reinfections or reactivation of only partially subdued infectious organisms. in addition to the causes listed above, bacterial overgrowth can occur in areas of bowel stasis or impaired bowel motility. postsurgery patients, diabetics, posttrauma patients, and intensive care patients are more likely targets of chronic infectious diarrheas from bacterial overgrowth. infectious diarrhea causes high morbidity and mortality among the aging population worldwide. multiorgan complications from an acute episode of infectious diarrhea are also more frequent among the elderly. life expectancy in the united states has risen from an average of years in the th century to years at present. by the year , % of the u.s. population will be older than age . gastrointestinal physiology and gut colonization change constantly with aging and contribute in a signi®cant way to increasing the susceptibility of elderly people to enteric infections. furthermore, the gastric acid barrier in the elderly is impaired. the most frequently isolated organisms and most deadly in elderly patients with diarrhea are c. dif®cile, salmonella, and toxigenic e. coli. these three agents top the list of figure infectious diarrhea: mechanisms of action of major enteric bacteria and viruses. enteric pathogens can induce intestinal injury with consequent diarrhea in three ways: ( ) by producing enterotoxins that interact with receptors located on the gut epithelial cells and evoke anion secretion, such as v. cholera, epec, eaec, stec, c. dif®cile, and s. aureus (a); ( ) by invading the gut epithelium and m cells, thus altering the cell cytoskeleton and activating intracellular pathways through virulence factors. organisms that lead to diarrhea through these mechanisms include eiec, shigella, epec, salmonella, and rotaviruses (b); ( ) by invading mucosal macrophages and inducing in¯ammatory responses leading to intestinal epithelial damage and anion secretion. campylobacter and yersinia use this mechanism (b). outbreaks in long-term and short-term care facilities and salmonella by itself accounts for more than % of cases and more than % of deaths in food-borne outbreaks in nursing homes. more than % of hiv/aids patients in the united states experience infectious diarrhea and this estimate may approach % in developing countries where the hiv epidemic is currently raging unchecked. these patients are more likely to develop persistent or chronic diarrhea after an acute episode because of their impaired immunity, with a signi®cant increase in morbidity and mortality. table vii lists the most common causes of infectious diarrhea in aids patients. the american gastroenterological association (aga) has published a set of general guidelines for the management of chronic diarrhea in aids patients. at least three sets of stool samples should be secured for common enteric bacteria and parasites, including microsporidia, cryptosporidia, and c. dif®cile. febrile patients with diarrhea should have blood cultures for common enteric bacteria. patients with cd lymphocyte counts of cells/mm are at high risk for disseminated mycobacterial infection. the most important ®nding in patients presenting with acute diarrhea is the degree of volume depletion, i.e., dehydration. postural changes in blood pressure are a reliable sign of dehydration. fever, abdominal tenderness, increased bowel sounds, or blood on rectal examination should alert the physician to acute infectious diarrhea. microscopic examination of a stool sample or rectal swab is a traditional and helpful tool in the rapid, bedside investigation of diarrheal illness. the specimen is placed on a glass slide and mixed thoroughly with two drops of methylene blue. the presence of ova, cysts, and/or leukocytes may point directly to a diagnosis. the aga guidelines on managing acute diarrhea indicates empiric antimicrobial therapy in the case of positive fecal leukocytes in a febrile patients. endoscopy has limited utility in the investigation of acute infectious diarrhea and is not cost-effective. it may have a place, however, in cases of persistent or chronic diarrhea. preventative measures against infectious diarrhea must include improvements in sanitation (water supply, sewer systems, housing), education of the general population and, where applicable, vaccination campaigns. unfortunately, no effective vaccines are available for the organisms that cause infectious diarrheas, with the exception of typhoid fever. treatment most acute diarrheal illnesses are self-limited and no speci®c therapy is required. water and electrolyte loss can be prevented or treated with oral¯uidÀelectrolyte solutions. intravenous salineÀglucose solutions are recommended in cases of moderate to severe dehydration. glucose in the intestinal lumen facilitates the absorption of sodium and the cotransport mechanism for these solutes appears to be unhampered by infection with microorganisms or by their toxins. antimotility therapy should be reserved for severe cases and chronic diarrheas and avoided in infants and children. antibiotic or antiviral treatment should be considered in moderate to severe cases in which a microbiological diagnosis is obtained or strongly see also the following articles aids, gastrointestinal manifestations of anti-diarrheal drugs campylobacter cholera cryptosporidium cytomegalovirus diarrhea foodborne diseases food poisoning food safety giardiasis rotavirus salmonella shigella traveler's diarrhea further reading anonymous epidemiology of clostridium dif®cile-associated infections ef®cacy and tolerability of racecadotril in acute diarrhea in children practice guidelines for the management of infectious diarrhea principles and practice of infectious diseases microbes and microbial toxins: paradigms for microbialÀmucosal interactions. viii. pathological consequences of rotaviral infection and its enterotoxin traveler's diarrhea due to intestinal protozoa the role of antibiotics in the treatment of infectious diarrhea infectious diarrhea in children pathogenesis of infectious diarrhea key: cord- -qilq q h authors: taniguchi, kiyosu; yoshida, makiko; sunagawa, tomimasa; tada, yuki; okabe, nobuhiko title: imported infectious diseases and surveillance in japan date: - - journal: travel med infect dis doi: . /j.tmaid. . . sha: doc_id: cord_uid: qilq q h surveillance of imported infectious diseases is important because of the need for early detection of outbreaks of international concern as well as information of risk to the travelers. this paper attempts to review how the japanese surveillance system deals with imported infectious diseases and reviews the trend of these diseases. the cases of acquired infection overseas were extracted from the surveillance data in – . the incidence and rate of imported cases of a series of infectious diseases with more than one imported case were observed by the year of diagnosis and place of acquired infection. during the period , cases that could be considered to be imported infectious diseases were identified. shigellosis ranked as the most common imported disease, followed by amebiasis, malaria, enterohemorrhagic escherichia coli infection and the acquired immunodeficiency syndrome, typhoid fever, dengue fever, hepatitis a, giardiasis, cholera, and paratyphoid fever. the annual trends of these diseases always fluctuated but not every change was investigated. the study reveals that the situation of imported infectious diseases can be identified in the current japanese surveillance system with epidemiologic features of both temporal and geographic distribution of cases of imported infectious diseases. however, further timely investigation for unusual increase in infectious diseases is needed. because of the current global travel and trade, there is no border for infectious diseases. even in japan, which belongs to a temperate climate zone many tropical infectious diseases are found in the local hospitals. but there have been several case reports describing difficulty of early diagnosis and treatment. e it is important to provide information to travelers on particular risks and to increase protection, as well as information for local clinicians on the current situation of endemicity of infections in the foreign countries in order to facilitate early diagnosis and to avoid nosocomial infection. from the viewpoint of public health, the introduction of new pathogens may result in their establishment in the country. public health surveillance is one of the essential components for infectious disease control and no doubt a starting point for control. because of current circumstances a surveillance system should be designed not only at the national level but also at the global level of infectious disease control. current national epidemiological surveillance for infectious diseases (nesid) in japan requires that all notifiable diseases should be reported with the presumptive place of infection. this report summarizes the data from the nesid from to on the situation of imported infectious diseases in japan. the national epidemiological surveillance for infectious diseases (hereafter referred to as nesid) is conducted based on the law concerning the prevention of infectious diseases and medical care for patients of infections (hereafter referred to as the infectious disease control law) enacted in april . infectious disease surveillance system before then is described elsewhere. infectious diseases included in this law were categorized into iev with specific means for control based upon the public health impact of each disease as shown in table . all physicians must report cases of categories ieiv immediately and va within days after identification to local public health centers which are the primary level institution for disease control and prevention located strategically throughout the nation. local public health centers are expected to enter data into the nationwide electronic surveillance system, which enables data to be shared throughout the system including all local public health centers, local and national governments, quarantine stations, local infectious disease surveillance center, local public health laboratory and central infectious disease surveillance center, which is the infectious disease surveillance center of national institute of infectious diseases. category vb diseases, which include sentinel reporting diseases, should be reported by designated sentinel medical institutions weekly or monthly with the number of clinical cases aggregated by sex and age groups. all reports should be compatible with the reporting criteria which were documented in detail for each disease including clinical and laboratory case definitions for categories va and vb of hospital sentinel reporting disease, and only clinical case definitions for other vb sentinel reporting diseases. cases of category ieva diseases should be reported with sex, age, method of laboratory confirmation, symptoms on diagnosis (descriptive), date of onset, date of consultation, date of diagnosis, estimated date of infection, date of death (if patients died), area of permanent residence (in-country or foreign countries), presumptive place of infection (domestic or foreign countries), contact to the vectors or activities on the fields (yes or no), estimated infection route, another patients in the family members, colleagues, or neighbors (cluster or not). the presumptive place where infection was acquired should be described based on reasonable situation considering travel history and incubation period according to the interview of patients. the cases with the presumptive place of infection in a foreign country (hereafter referred to as imported cases) were extracted from the nesid data from april to march . data in are only available in apriledecember because of the change of the law in april and data in are included until march. finally nine years data are reviewed. annual trend of total, imported, and domestic cases of disease containing one or more imported one are recorded and attributable events and causes are investigated with information in the line listing data and relevant epidemiological reports. incidence rates per , , population are calculated using the census population and imported disease per , , outbound travelers are calculated using the outbound travelers by the japan national tourist organization. in the period observed , cases that could be considered to be imported infectious diseases were identified. these include various infectious diseases as listed in table with reported number of cases (imported, domestic, unknown and total), imported case rate among imported and domestic cases, incidence rate of domestic cases per year per , , population and the incidence rate of imported cases per year per , , outbound travelers. shigellosis ranked as the most common imported infection, followed by amebiasis, malaria, enterohemorrhagic escherichia coli (ehec) infection and the acquired immunodeficiency syndromes (aids), typhoid fever, dengue fever, hepatitis a, giardiasis, cholera, and paratyphoid fever. the rate of imported diseases of malaria, dengue fever and rabies is complete as they are not endemic in japan and over % in coccidioidomycosis, paratyphoid fever, typhoid fever, cholera, shigellosis and echinococcosis (echinococcus granulosus). although coccidioides is not considered to be indigenous, a domestic case is identified with no history of overseas travel. however, this case was a dealer of imported cotton and he may have acquired the infection from fungi attached to the imported cotton. the annual trends of imported diseases always fluctuate because of the local situation and sometimes there is sudden increase because of cluster among the same tour groups. the amebiasis tended to increase recently both in domestic and imported cases. and cases acquired infection through sexual contact represented % of the total cases. there were continuous reports of imported disease of aids, syphilis and hepatitis b. dengue fever is increasing year by year, but malaria is decreasing gradually. typhoid and paratyphoid fever and hepatitis a showed an increase and decrease throughout observation period. although the outbreak among group tours to endemic countries was reported to account for the increase of imported diseases, investigation of attributable events or causes were not always made in a timely manner. retrospective investigation could recognize the increase of cases returning from certain countries, but it was difficult to seek further risk factors because limited information was listed on line. public health surveillance is defined by the world health organization as the ''systematic ongoing collection, collation, and analysis of data and the timely dissemination of information to those who need to know so that action can be taken.'' the basic principle for disease control and prevention is the same no matter where it is acquired. but target groups who need to know differ. the precautionary information should be communicated to travelers with the risk assessed properly. of course rapid detection of cases can lead to rapid response and early containment and finally to prevention of indigenous transmission of exotic pathogens. in this respect, effective infectious disease surveillance is essential. in this study it was not difficult to overview the situation of imported infectious diseases because the current japanese surveillance system requires the presumptive place of infection including the specified country if possible. but there have been no studies on the evaluation of reporting rate. before april when the infectious disease control law was revised, e cases of malaria were reported annually in the framework of the old infectious disease prevention law, but the research group on chemotherapy of tropical diseases reported by their field investigation that approximately patients have been confirmed with malaria annually. it means that cases notified to the ministry of health and welfare were about % in those days. reports of malaria peaked in one year after the new law enactment and steadily decreased to the same level before . on the other hand, dengue fever is increasing. it is not possible to determine whether the reporting rate of malaria has decreased recently or not, it will be necessary to evaluate the surveillance system including assessment of missed opportunity for diagnosis and treatment. it might be better to report febrile illness with travel history abroad for effective detection and evaluation. it is natural that reported imported cases of malaria, dengue fever and rabies are complete. domestic case of coccidioidomycosis is reported to be caused from imported materials. a proportion of typhoid/paratyphoid fever, cholera and shigellosis are acquired inside the country without doubt because there is no travel history abroad. as there is a report of vibrio cholerae from imported food, further is required investigation of the source of infection in each cases. most of the imported cases were reported with the suspected country of infection. analysis using e data showed suspected countries of infection for cholera are india, philippine, and indonesia (in descending order); india, indonesia, and china for shigellosis; india, indonesia and nepal for typhoid/paratyphoid fever; philippine, thailand and india for dengue fever; papua new guinea, nigeria, india and indonesia for malaria. but it depends upon the number of travelers and the local situation in certain countries which might change year by year. more detailed analysis using country specific travelers is necessary. aids, syphilis, hepatitis b, and giardiasis are part of imported infectious diseases. as they have the unique feature as sexually transmitted diseases (std), it might be better to handle these separately. but it is important to monitor imported std because they could increase local infection rates, and to provide information for travelers. in the current study, it was noted that unusual increases of reported imported infectious disease were not fully investigated for attributable events or causes in a timely manner although several events affecting the number of reports were identified. retrospective analysis can provide the country of infection, but more timely information is necessary for travelers. the capacity of timely investigation and risk assessment should be enhanced further. the results of investigation of an outbreak among a tour group sharing common source of infection or cluster in time and of travel place of individual tourists not related each other will be reflected or involved in a local epidemic, which can be linked to international investigation and control activities. under the current circumstances of pandemic alert, the timely sharing of imported infectious disease at the global level will also be necessary. difficulty of proper diagnosis for an imported vivax malaria patient from africa plasmodium vivax malaria with clinical presentation mimicking acute type idiopathic thrombocytopenic purpura clinical characteristics of imported malaria in japan: analysis at a referral hospital overview of infectious disease surveillance system in japan case definitions for reporting in compliance with infectious disease law anonymous. imported mycoses in japan. iasr: e . available from anonymous. cholera e , japan. iasr: e . available from iasr: e . available from enterohemorrhagic escherichia coli infection as of typhoid fever outbreak among group tour member to bangladesh cholera enterotoxin production in vibrio cholerae strains isolated from the environment and from humans in japan the author has no conflict of interest. key: cord- -h dtjt p authors: tupe, christina l.; nguyen, tu carol title: infectious diseases date: - - journal: in-flight medical emergencies doi: . / - - - - _ sha: doc_id: cord_uid: h dtjt p commercial airline travel creates conditions conducive to the spread of infectious diseases: the proximity of passengers in a confined space and the origin of flights from anywhere on the globe. this chapter describes symptoms of infectious diseases that might emerge in an airline passenger and the steps that a responding medical professional can take to stabilize the person and minimize the exposure risk for other passengers and the crew. it also reviews guidelines issued by the centers for disease control regarding infectious diseases that might be encountered during flights, procedures for working with pilots to alert ground crews about passengers’ medical needs, and requirements for reporting incidents to authorities after landing. airline travel has features that are perfect for spreading infectious diseases: the proximity of passengers in a confined space for a long time and the presence of travelers from every region of the world, some of which have high incidences of specific infectious diseases. based on a review of months of data from domestic and international airlines, peterson and colleagues [ ] determined that the most common situations prompting calls to a medical communications center were syncope ( %), respiratory problems ( %), and gastrointestinal symptoms ( %). any of those signs and symptoms could be associated with an infectious disease. the actual prevalence of infectious diseases among the , in-flight medical emergencies in peterson's study group was . %. focusing on children, moore and associates [ ] found that infectious diseases, neurologic emergencies, and respiratory tract problems were the leading reasons for medical consultation among the passengers transported by one airline between and . upper respiratory infections and influenza are spread by coughing and sneezing; therefore, droplet precautions are warranted. most airlines recirculate % of cabin air, passing it through high-efficiency particulate air filters [ ] . zitter and colleagues [ ] found no difference in self-reported infection rates among passengers who had traveled in aircraft with that type of filter and those on aircraft with a single-pass cabin ventilation system. the long-held assumption that passengers seated more than rows in front of or behind the primary patient have a lower risk of being infected than those closer to the sick person is now being challenged [ ] . the centers for disease control (cdc) becomes involved in cases of infectious diseases during air travel when the organization is notified by a public health office at a county health department that a recent traveler has been diagnosed with a contagious disease. the cdc then determines if the person was contagious during the flight and, if so, then launches a search for the other passengers. the diseases most commonly investigated by the cdc are infectious tuberculosis, measles, rubella, pertussis, and meningococcal disease [ ] . during a flight, when evaluating a passenger suspected of having an infectious disease, the person should be treated as potentially contagious, especially if he or she currently has a fever or recently had a fever lasting more than h. if possible, the potentially-infectious passenger should be separated from other passengers by ft [ ] . general infection control measures should be followed, e.g., treating body fluids as infectious, using good handwashing technique, and wearing disposable gloves. if the patient has respiratory symptoms, facemasks should be worn by the care provider, crew members who are assisting, and nearby passengers. interactions with the patient should be brief and a limited number of other passengers and crew should interact with the person. materials that come into contact with the symptomatic individual should be properly disposed. as appropriate, hand washing by the patient should be encouraged. after taking appropriate steps to limit one's own exposure as well as that of the crew and other passengers, the responding provider should evaluate the passenger for airway compromise. if the patient has airway swelling, stridor, drooling, voice changes, or other significant abnormalities, recommending for flight diversion might be necessary. patients with conditions such as croup may benefit from nebulized epinephrine, if available. when assessing the patient's breathing, the responding provider should evaluate for increased work of breathing, tachypnea, and breath sounds, using the stethoscope in the medical kit. passengers who are wheezing could benefit from metered-dose inhalers (mdis) or nebulizer treatments. supplemental oxygen can also be provided. patients who could be septic or hypovolemic from gastrointestinal illness or insensible losses might show signs of circulatory compromise. those who can tolerate oral fluids can be given oral rehydration fluid; for those who cannot, intravenous fluids can be started. infectious disease in children is also not uncommon. they are prone to conditions such as upper respiratory infections and otitis media, which can be quite painful during flight because of atmospheric changes, especially in children with poor eustachian tube function. a nasal decongestant might provide relief to some patients [ ] . with the ease of international commercial travel, airlines have become vehicles for emerging infectious diseases. for example, during the ebola outbreak in africa, airlines became concerned about the transport of ebola-infected passengers. the ebola virus has an incubation period of - days and its symptoms are nonspecific-fever, weakness, muscle pain, headache, sore throat, vomiting, diarrhea, and bleeding. ebola is spread through person-to-person contact and by contact with body fluids or secretions from infected people. providers responding to a passenger who might have ebola or similar disease should wear a facemask and gloves. cabin crew members should be instructed to follow international air transport association guidelines, which include distancing the symptomatic person from other passengers as much as possible, using a facemask, using plastic bags to dispose of tissues, storing soiled items as biohazardous material, and limiting contact with the symptomatic person, including use of gloves and hand hygiene. ground control should be notified of the potential for passengers' exposure to an infectious agent so that authorities at the destination airport can be notified to make preparations to isolate the traveler on arrival [ ] . severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) have also emerged as life-threatening respiratory infections. these conditions are diagnostically similar to other respiratory infections, with fever and symptoms such as cough, shortness of breath, and difficulty breathing. radiographic images obviously cannot be obtained during flight. when a passenger from an area where these conditions are endemic experiences suspicious symptoms he or she should be isolated from the other passengers as best as possible. ground control should also be notified to facilitate isolation upon landing and access to medical treatment. the zika virus is a mosquito-borne flavivirus with the symptoms of fever, rash, conjunctivitis, muscle and joint pain, malaise, and headache. people can be infected with the virus through the bite of a mosquito as well as through sexual contact. the incubation period is currently unknown, but it is likely days. pregnant women face the biggest risk from this virus, in that it has been linked to microcephaly in newborns. the treatment for zika virus infection is typically supportive care. because patients can present with a spectrum of nonspecific symptoms, healthcare providers should obtain a travel history. depending on the person's symptoms, it may be difficult to distinguish zika from other contagious infectious diseases. the us code of federal regulations requires that a report be submitted by the airline to the cdc after an encounter with a passenger exhibiting specific signs and symptoms of infectious disease [ ] . the guidelines differ on domestic and international flights. the cdc requires reporting for passengers meeting certain criteria: if any reportable findings are identified, they should be communicated to the captain and ground control to facilitate appropriate isolation and medical treatment at the destination airport. as with all medical interventions, healthcare providers should document the patient interaction. in-flight care of passengers with known or suspected infectious diseases is primarily supportive, with a focus on isolation and protection of the care provider, crew, and other passengers. many cases of infectious communicable diseases aboard international flights have led to contact investigations to determine the origin of the disease and to identify others who may also be at risk of infection. for example, a measles outbreak in australia in was traced to a -h international flight to that country from south africa [ ] . nine cases of measles were confirmed, of them in individuals who had been on that flight. the initial ("index") case sparked a contact investigation that complied with australian guidelines, i.e., passengers rows in front of and rows behind where the index case as seated were traced, as were children years or younger who were on the flight. the -row proximity rule failed to identify other individuals who were infected, because they sat more than rows away. interestingly, two individuals who became infected on that flight were healthcare workers, who returned to their usual patient care duties after returning to australia. the authors concluded that the -row rule should be reevaluated and that other strategies for contact investigation should be designed, with consideration of cabin layout, flight duration, and flight's origin and destination as well as associated costs in relation to risks and benefits. hertzberg and weiss [ ] calculated that passengers who sit within rows of an infected individual have a % risk of becoming infected and those who sit beyond rows have a risk of about %. thus, priority should be given to individuals seated within rows of the index patient, but passengers seated elsewhere should not be neglected. the authors also pointed out that exposure risk is influenced by movement about the cabin and sharing air for a long period of time. other actions that can aid contact investigations and contain or prevent an outbreak include issuing public service announcements to educate communities about the symptoms of an infectious threat and reducing delays in the diagnosis of a communicable disease that has been brought into a community or country [ ] . when an epidemic occurs, the international community often imposes restrictions on travel and escalates screening processes. in , the ebola epidemic of west africa generated preemptive measures to ensure the safety of the public. all passengers aboard flights associated with confirmed ebola cases in the united states were included in contact investigations and tracings [ ] . in addition, states monitored individuals who had traveled from ebola-affected countries for days after their flight [ ] . among the multitudes of commercial airline passengers are people with infectious diseases. they pose potential risks to their fellow passengers and to the medical professionals who volunteer to help in times of emergency. most passengers who experience acute manifestations of infectious diseases during flight require interventions at the level of supportive care until the flight lands. medical care providers should maintain close contact with the captain so that ground resources can be mobilized if necessary, ready to receive the patient upon landing. federal and international guidelines require the reporting of encounters with patients with specific signs and symptoms. compliance with those guidelines can be beneficial when the need arises to launch a contact investigation involving large numbers of people. the -row focus of established guidelines warrants reconsideration because the characteristics of air travel (close quarters, shared air supply) extend the threat of exposure to all parts of the cabin. outcomes of medical emergencies on commercial airline flights pediatric emergencies on a us based commercial airline aerospace medical association medical guidelines task force. medical guidelines for airline travel aircraft cabin air recirculation and symptoms of the common cold on the -row rule for infectious disease transmission on aircraft preventing spread of disease on commercial aircraft: guidance for cabin crew contact tracing of in-flight measles exposures: lessons from an outbreak investigation and case series public health response to commercial airline travel of a person with ebola virus infection-united states ebola active monitoring system for travelers returning from west africa-georgia key: cord- - me xh authors: wang, wei; chen, jin; sheng, hui-feng; wang, na-na; yang, pin; zhou, xiao-nong; bergquist, robert title: infectiousdiseases ofpoverty, the first five years date: - - journal: infect dis poverty doi: . /s - - - sha: doc_id: cord_uid: me xh although the focus in the area of health research may be shifting from infectious to non-communicable diseases, the infectious diseases of poverty remain a major burden of disease of global health concern. a global platform to communicate and share the research on these diseases is needed to facilitate the translation of knowledge into effective approaches and tools for their elimination. based on the “one health, one world” mission, a new, open-access journal, infectious diseases of poverty (idp), was launched by biomed central in partnership with the national institute of parasitic diseases (nipd), chinese center for disease control and prevention (china cdc) on october , . its aim is to identify and assess research and information gaps that hinder progress towards new interventions for a particular public health problem in the developing world. from the inaugural idp issue of october , , a total of manuscripts have been published over the following five years. apart from a small number of editorials, opinions, commentaries and letters to the editor, the predominant types of publications are research articles ( . %) and scoping reviews ( . %). a total of contributing authors divided between affiliations across countries, territories and regions produced these publications. the journal is indexed in major international biomedical databases, including web of science, pubmed, scopus and embase. in , it was assigned its first impact factor ( . ), which is now . . during the past five years, idp has received manuscripts from countries, territories and regions across six continents with an annual acceptance rate of all contributions maintained at less than %. content analysis shows that neglected tropical diseases (ntds), followed by the “big three” (hiv/aids, malaria and tuberculosis) and infectious diseases in general comprise % of all publications. in addition, a series of thematic issues, covering publications in all, was published as separate parts of the first five volumes. these publications were cited times, which equals an average of . times per publication. the current challenge is to identify cutting-edge research topics and attract and to publish first-rate publications leading to increasing importance and impact of the journal in its field. electronic supplementary material: the online version of this article (doi: . /s - - - ) contains supplementary material, which is available to authorized users. the global burden of disease today is less due to infectious diseases than non-communicable diseases, with chronic disorders such as heart disease, stroke and cancer currently being the leading causes of morbidity and mortality worldwide [ ] . however, infections remain a major global health concern, particularly in the developing world [ ] , where the human immunodeficiency virus and the acquired immune deficiency syndrome (hiv/aids), viral hepatitis, tuberculosis and malaria, still kill millions of people around the globe every year [ , ] . parasitic diseases, e.g., malaria and schistosomiasis, do not always remain limited to their age-old geographic distributions complicating control efforts and challenging the progress towards their elimination [ ] [ ] [ ] [ ] . additionally, emerging and re-emerging infectious diseases like the severe acute respiratory syndrome (sars), influenza, ebola virus disease (evd), dengue, middle east respiratory syndrome (mers) and zika virus disease threaten human health and global security [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . infectious diseases are inextricably linked to poverty in a vicious cycle [ ] . these diseases, characterized by high morbidity and mortality that mainly occur in resource-limited areas, belong by definition to the group of diseases that are more prevalent among poor and vulnerable populations [ ] . they rank within the top ten ailments with respect to years lost due to ill-health, disability or early death, expressed as disability-adjusted life years (dalys) [ ] . in a global perspective, this leads to huge economic losses, both for the individual and society, and a global platform to communicate and share the research on the infectious diseases of poverty was felt to be needed to facilitate the translation of knowledge into effective approaches and tools for the elimination of these diseases. on october , , infectious diseases of poverty (idp) was launched as a new, open-access (oa) journal on infectious diseases by biomed central, in partnership with the national institute of parasitic diseases (nipd), chinese center for disease control and prevention (cdc). its preferential aims are to identify and assess research and information gaps that hinder progress towards new interventions for public health problems, in particular those connected with poverty in the developing world. based on the "one health, one world" mission mentioned in the global report on research for the infectious diseases of poverty [ ] , the journal publishes work on topics and approaches that address essential public health questions related to this issue. along with the actions proposed by this report, idp, aims to achieve the goal of improving research capacity and create a better environment for the research on the infectious diseases of poverty [ , ] . the purpose of this article is to review the publication activities of idp in its first five years by comparing the record with other journals with a similar focus in order to understand the current trends of research in publications on infectious diseases. we performed an in-depth bibliometric analysis of all publications during the first five volumes covering the period from october , to october , through a joint search using the publication name "infectious diseases of poverty" in pubmed, web of science (wos) (formerly isi web of knowledge) and the journal's website. we also compared with two other journals in this area, international journal of infectious diseases and bmc infectious diseases. the publication data and metrics of idp, international journal of infectious diseases and bmc infectious diseases were collected using these journals' homepages, submission systems and the wos citation database as of th february, . we used ordinary descriptive statistics to analyse the performance of idp during its first five years supported by biomed central's databases [ ] . idp is currently managed by an editor-in-chief and two managing editors, one based in china and the other in france. they perform the bulk of the day-to-day activities, including communication with authors, choosing and contacting referees for peer review, and making the final decisions with regard to publication or rejection of manuscripts. this core team is supported by five deputy editors and associate editors from asia, africa, europe, north america, south america and oceania. to assure quality and impact from the start, idp appointed an international editorial board of well-known scientists with expertise within the fields of infectious diseases, parasitic diseases, social sciences and economy. the current editorial board consists of members, based in uk (n = ), usa (n = ), china (n = ), australia (n = ), switzerland (n = ), brazil (n = ), cameroon (n = ), india (n = ), nigeria (n = ), japan (n = ), ghana (n = ), belgium (n = ), thailand (n = ), greece (n = ), democratic republic of congo (n = ), south africa (n = ), kenya (n = ) and senegal (n = ). from the inaugural issue of october, up to and including october, , a total of manuscripts were published in idp. the annual publication record is presented in fig. . out of all publications, research articles ( . %) and scoping reviews ( . %) dominated with the remaining publication being editorials, opinion articles and letters to the editor (fig. ) . a total of contributing authors, divided between affiliations across countries, territories and, regions produced these publications during the five-year period (tables , and ). the publications included countries, territories and regions from the developing world ( %) [ ] . the journal is indexed in major international biomedical databases, including wos, science citation index expanded, medline, doaj, pubmed, scopus and embase. in , it was assigned the first impact factor ( . ), which is now . (fig. ) . up to th february , the publications in the first five idp volumes were cited times in total, i.e. a mean citation of . times per paper. table presents the most highly cited publications, which includes five reviews, two editorials, one opinion article, one research article and one letter to the editor. interestingly, the most highly cited publication in idp is an editorial published in [ ] , which may be explained by the fact that it dealt with surveillance and response defining this approach as a research priority during the stage moving towards elimination of tropical diseases, which received much global attention [ ] [ ] [ ] [ ] [ ] . the importance and significance of the surveillance and response approach are also highlighted by two other highly cited publications in idp [ , ] . we refer here to two reviews, one discussing gap analysis of the chinese three major tropical diseases (schistosomiasis, malaria and echinococcosis), and the other assessing the morbidity due to schistosomiasis japonica in china [ , ] . in addition, an editorial opinion focusing on the chinese schistosomiasis control and health systems and a research article reporting on babesia microti and plasmodium co-infections along the china-myanmar border were also commonly cited [ , ] . among three other publications, which have been cited times and more, are two reviews describing global epidemiology: the burden of infectious diseases of poverty [ ] and that of clonorchiasis [ ] , together with an editorial introducing the mission, aims and scope of idp [ ] . the number of articles of the publications accessed through internet reached a total of accesses up to th february, , with a mean of . times per publication. table summarizes the five most highly accessed publications, which have been accessed more than times. they include three research articles, one focusing on the interplay between infectious disease emergence and global climate change [ ] , one dealing with the risk factors of malaria among pregnant women in nigeria [ ] and one discussing the reaction of chinese social media to the outbreaks caused by the mers coronavirus and avian influenza a (h n ) [ ] . two reviews, one on tuberculosis [ ] and the other on malaria and other vector-borne protozoan diseases [ ] were also often downloaded. interestingly, the most highly accessed publication is a research article exploring the potential correlation between the emergence of infectious diseases and global climate change, perhaps explained by the currently worldwide focus on a large number of emerging and re-emerging infectious diseases in this context [ , ] . during the -year period investigated, countries idp received manuscripts from countries, territories and regions across six continents ( fig. ) that included from the developing world ( %) [ ] . the annual acceptance rate of all submitted manuscripts received was maintained at less than % throughout the period analysed (fig. ). content analysis showed that neglected tropical diseases (ntds), followed by the "big three" (hiv/aids, malaria and tuberculosis) and other infectious diseases, were in the focus of the publications, which consisted of % of total publications (fig. ). idp is dedicated to communicate global health concerns on finding ways for poverty alleviation and to publish papers dealing with the following topics: ( ) approaches addressing essential public health questions related to infectious diseases of poverty; ( ) multi-disciplinary concerns of infectious disease of poverty, such as the biology of pathogens, vectors, diagnosis, surveillance and response, treatment and case management, epidemiology including ecohealth issues and modelling, zoonoses and animal reservoirs, control strategies and implementation of new technologies; and ( ) trans-disciplinary or multi-sectoral effects involving health systems, environmental management and innovative technology. a total of thematic series were published in the first five volumes of idp with - issues appearing each year ( table ). the thematic series were issued to allow the journal to remain in the frontline in the field of swiss tropical public health institute university of basel the aga khan university fudan university the world's currently biggest donor for scientific research, the bill and melinda gates foundation (bmgf) demands that the outcomes of what it supports must be freely available to all. this is set to change scientific research publications at its core, since this requirement bars publication in 'premier-league' journals such as nature and science. increasingly, scientific journals are accepting the oa mandate and idp wisely decided to follow suit when its first volume appeared more than five years ago. as an international, peer-reviewed oa journal, idp has its own specific characters as follows: . the journal provides the abstracts in the six official languages of the united nations (un), which enables clear and convenient communication of public health concerns related to the infectious diseases of poverty [ ] . . fast-track publication is provided for articles of exceptional public health importance and urgency with online publication completed within a month of submission. . the journal focuses on publication of original and empirical trans-disciplinary research for the control of infectious diseases which predominantly affect poor populations. free preprint repository, biorxiv (http://biorxiv.org/), is another revolution quietly taking place and gradually found more and more useful for scientists as it establishes priority and exposure, while, on the other hand, there is no peer-review. this important development must be taken under consideration in the publication world and scientific journals, including, idp, need to find a way to participate in this expansion of how new findings are brought into the public sphere. in , a thematic series issue entitled "ecohealth and eids -dynamics between environmental change, development and eids in asia", which was supported by the international development research centre (idrc) of canada and published with the aim to showcase and encourage trans-disciplinary ecohealth research in asia and beyond. the publications in this thematic series were cited times, with a mean of . times per publication. it attracted downloads and reads in total, with a mean of per publication. since the launch and continuing, idp aims to identify and assess research and information gaps that hinder progress towards new interventions for the particular public health problem of poverty and infections in the developing world. in its first five volumes, the journal published studies from developing economies ( %) and attracted contributions from developing economies ( %); however, there are still more than % of the global developing economies that have not yet contributed a paper to the journal. further work to attract manuscripts from the developing world is urgently needed. in addition, % ( / ) of all manuscripts in the first five years were submitted by african scientists; however, even if only slightly more than % ( / ) of these were finally published, this indicates a strong african interest in publishing with idp as well as a trend of improving quality of research conducted in africa. the journal was assigned a first impact factor of . in ; however, this metric decreased to . in , which can be explained by the large rise in the number the journal may seem less attractive for contributions pertaining to high-impact topics in infectious disease research compared to international journal of infectious diseases and bmc infectious diseases, which may be explained by the fact that it is a relatively new journal, which has not yet garnered an adequate international following. publication of 'hot' research topics and results changing the direction of research should be strived for and this can be achieved through invited manuscripts and thematic series. in the future, work attracting high-quality papers from europe and usa in addition to papers from the developing world, should be strengthened. during the past five years, idp has been strengthening its academic impact; however, its international impact remains to be enhanced relative to other leading journals in infectious diseases. the following priority has been recommended by its editorial board: . invitation of contributions from global health policy makers and high-impact scientists; . publication of thematic series pertaining to global 'hot' topics in public health, emerging or re-emerging diseases and the outcome of international major projects on infectious diseases; finally, the question of a paper's true value must be mentioned as it is at the heart of the collaboration between author(s) and journal. that question extends naturally to the question of what the true value of a scientific journal is. this question has been approached in various ways, not the least by awarding impact factors. this first attempt is still the most utilized metric for assessing a journal's merit, but new developments are telling us that a faster and wider range of researchrelated metrics are needed. the number of clicks, downloads and reads are already providing valuable insights into how published content is being used and shared by fellow scientists. a multitude of commercial companies are already active in this field, for example, altmetric (https://www.altmetric.com/), plum analytics (http:// plumanalytics.com/) and researchgate (https://www.researchgate.net/). meta (http://www.meta.com) has gone one step further by using algorithms recognizing the unique features characterizing widely cited papers, and the company claims that this can predict a paper's future impact before its publication. more than million papers and million researchers have already been profiled by the company (https://en.wikipedia.org/wiki/ meta) to support this claim. idp has achieved its preliminary goal to become a platform for the identification of research and information gaps that hinder progress towards new interventions for public health problem connected to poverty in the developing world. however, there is still a long way to go to further advance research and evidence-building based on improved public health interventions in poor settings. it is believed that idp can significantly facilitate progress towards the elimination of infectious diseases related to poverty. in this process, idp will not only be judged by the quality of the articles published, but also regarding how it fits into the new world of merit assessment. global, regional, and national age-sex specific all-cause and cause-specific mortality for causes of death, - : a systematic analysis for the global burden of disease study global burden, distribution, and interventions for infectious diseases of poverty global, regional, and national incidence and mortality for hiv, tuberculosis, and malaria during - : a systematic analysis for the global burden of disease study mas-coma s. schistosomiasis reaches europe outbreak of urogenital schistosomiasis in corsica (france): an epidemiological case study human schistosomiasis: an emerging threat for europe african schistosomiasis in mainland china: risk of transmission and countermeasures to tackle the risk emerging infectious diseases: threats to human health and global stability nosocomial infection control in healthcare settings: protection against emerging infectious diseases chinese social media reaction to the mers-cov and avian influenza a(h n ) outbreaks prediction of the next highly pathogenic avian influenza pandemic that can cause illness in humans ebola, the killer virus ebola wreaks havoc in sierra leone the global economic burden of dengue: a systematic analysis the global burden of dengue: an analysis from the global burden of disease study zika virus: a new global threat for the global spread of zika virus: is public and media concern justified in regions currently unaffected? combating infectious diseases of poverty: a year on social sciences research on infectious diseases of poverty: too little and too late? global report for research on infectious diseases of poverty surveillance and response systems for elimination of tropical diseases: summary of a thematic series in infectious diseases of poverty elimination of tropical disease through surveillance and response surveillance-response systems: the key to elimination of tropical diseases surveillance and response: tools and approaches for the elimination stage of neglected tropical diseases planning an integrated disease surveillance and response system: a matrix of skills and activities malaria elimination: surveillance and response reaching the surveillanceresponse stage of schistosomiasis control in the people's republic of china: a modelling approach need of surveillance response systems to combat ebola outbreaks and other emerging infectious diseases in african countries research gaps for three main tropical diseases in the people's republic of china assessment of morbidity due to schistosoma japonicum infection in china schistosomiasis control and the health system in p.r. china co-infections with babesia microti and plasmodium parasites along the china-myanmar border the global epidemiology of clonorchiasis and its relation with cholangiocarcinoma prioritizing research for "one health -one world infectious disease emergence and global change: thinking systemically in a shrinking world factors associated with risk of malaria infection among pregnant women in community based interventions for the prevention and control of tuberculosis control of malaria and other vector-borne protozoan diseases in the tropics: enduring challenges despite considerable progress and achievements global climate change and infectious diseases global climate change and infectious diseases we would like to thank the staff from biomed central for their kind provision of some data. authors' contributions ww and py conceived and designed the study. ww, jc, nnw and hfs collected and analyzed the data. ww prepared the first version of the manuscript. py, xnz and rb provided valuable comments on the manuscript. ww and py revised and finalized the manuscript. all authors read and approved the final version of the manuscript. submit your next manuscript to biomed central and we will help you at every step: key: cord- - oldaa i authors: murray, kris a.; olivero, jesús; roche, benjamin; tiedt, sonia; guégan, jean‐francois title: pathogeography: leveraging the biogeography of human infectious diseases for global health management date: - - journal: ecography (cop.) doi: . /ecog. sha: doc_id: cord_uid: oldaa i biogeography is an implicit and fundamental component of almost every dimension of modern biology, from natural selection and speciation to invasive species and biodiversity management. however, biogeography has rarely been integrated into human or veterinary medicine nor routinely leveraged for global health management. here we review the theory and application of biogeography to the research and management of human infectious diseases, an integration we refer to as ‘pathogeography’. pathogeography represents a promising framework for understanding and decomposing the spatial distributions, diversity patterns and emergence risks of human infectious diseases into interpretable components of dynamic socio‐ecological systems. analytical tools from biogeography are already helping to improve our understanding of individual infectious disease distributions and the processes that shape them in space and time. at higher levels of organization, biogeographical studies of diseases are rarer but increasing, improving our ability to describe and explain patterns that emerge at the level of disease communities (e.g. co‐occurrence, diversity patterns, biogeographic regionalisation). even in a highly globalized world most human infectious diseases remain constrained in their geographic distributions by ecological barriers to the dispersal or establishment of their causal pathogens, reservoir hosts and/or vectors. these same processes underpin the spatial arrangement of other taxa, such as mammalian biodiversity, providing a strong empirical ‘prior’ with which to assess the potential distributions of infectious diseases when data on their occurrence is unavailable or limited. in the absence of quality data, generalized biogeographic patterns could provide the earliest (and in some cases the only) insights into the potential distributions of many poorly known or emerging, or as‐yet‐unknown, infectious disease risks. encouraging more community ecologists and biogeographers to collaborate with health professionals (and vice versa) has the potential to improve our understanding of infectious disease systems and identify novel management strategies to improve local, global and planetary health. in a globalized world where the spread of infectious diseases appears to ignore all boundaries and the risk of emerging pathogens is on the rise (jones et al. , fisher et al. , there has been a resurgence in interest by academics, the general public and both national and international government authorities in the geography of human infectious diseases at all spatial scales. since most endemic and emerging human pathogens utilise non-human animal species at some stage in their transmission cycles (e.g. reservoir and intermediate hosts and vector species) (taylor et al. , woolhouse and gowtage-sequeria ) , biogeographers and community ecologists are increasingly involved in this pursuit. their contributions have yielded a range of novel and complementary insights on the spatial and temporal patterns of infectious disease occurrence, emergence and burden, their underlying ecological processes, and their surveillance and management (guernier et al. , smith et al. , peterson , reperant , johnson et al. , murray et al. , stephens et al. b . medical geography has a long and rich history (barrett , cliff et al. , rogers et al. , cliff and haggett and its methods and objectives have numerous parallels to those of modern biogeography, with its broad aim of determining how multiple processes (e.g. speciation, adaptation, extinction, ecology, geology, climate) interact with one another to produce distributional patterns in the world's biota (myers and giller ) . for infectious diseases, this history stretches as far back as to the time of the debate between contagionists and anticontagionists, when experts disagreed about the very existence of infectious disease-causing agents; for example, several 'spot maps' in the context of yellow fever in the us were developed in the late th and early th centuries to identify patterns and attempt to infer environmental causes for the disease, well before pasteur and koch's eventual and definitive development of the 'germ theory of disease' in the late s (howe , jones , lederberg . however, the largely correlative methods and findings of medical geography seemed to lose ground as modern medicine developed in favour of a relatively narrow focus on molecules, individuals, individual diseases or sub-components thereof, and small and homogenous populations and areas (e.g. cohort studies, randomized-and case-control trials, small area health statistics), in which causality is presumed easier to stalk (schwartz , mclaren and hawe ) . as a consequence, and despite the availability of theory and methods in other disciplines to overcome, negate or manage key issues related to correlation and scale complexity (chesson ), modern epidemiology has been arguably caught off-guard in a rapidly changing world. so called 'prisoners of the proximate', in reference to a limiting preoccupation with direct individual-level disease risk factors, mcmichael ( ) suggested that modern epidemiologists and public health managers have been sluggish and ill-equipped to recognise, prepare for and proactively respond to some of the most pressing and emerging health challenges of the st century, such as climate change, habitat alteration and degradation, biodiversity loss, invasive species including vectors, demographic shifts, migration and epidemiological transitions. although many global health metrics, such as life expectancy and childhood mortality, have nevertheless continued to improve, researchers from a range of disciplines are increasingly forecasting a collision between ongoing improvements in human health and a range of large-scale and accelerating global change processes, particularly those relating to environmental factors and declining environmental quality (foley et al. , mea , raudsepp-hearne et al. , suk and semenza , costanza et al. , watts et al. , whitmee et al. . health funders are also beginning to recognise these complex risks to human health (e.g. wellcome trust  https:// wellcome.ac.uk/what-we-do/our-work/our-planet-ourhealth , rockefeller foundation  www.rockefellerfoundation.org/our-work/initiatives/planetary-health/ ). given that this type of multi-scale, multi-disciplinary complexity is commonplace in biogeography, and much precedence exists from the study of parasitism, plant and animal diseases and global change ecology, there has never been a better time for biogeographers and ecologists to contribute their knowledge, theory and methods to public and global health. critically, where strong links between human health and the environment are identified and quantified, such collaborations could stimulate novel streams of funding and yield cost-effective co-benefits for health and the environment (myers et al. , waldron et al. . this is particularly salient for research on human infectious diseases, most of which involve animal hosts and vectors in shaping their distributions and are therefore influenced by many of the same ecological processes that govern biodiversity patterns more generally (guernier et al. , murray et al. . analogous to its utility for understanding wildlife distributions, biodiversity patterns and improving conservation management, biogeography has the potential to improve our understanding of infectious disease distributions, describe and explain patterns and processes underlying pathogen diversity ('pathodiversity') and contribute to infectious disease forecasting, risk management and threat abatement. through the analysis of historical disease, host and/or vector occurrence and co-occurrence patterns, biogeographic approaches could even yield some of the earliest, and in some cases the only, insights into poorly known, burgeoning and future infectious disease risks (murray et al. ) . here, we review the building blocks of biogeography and illustrate how it has and could continue to provide novel insights for the study and management of human infectious diseases, an integration we refer to as 'pathogeography' (resurrecting a term coined by plant pathologist israel reichert; reichert and palti ) . better understanding of pathogeography among ecologists and improved biogeographic knowledge among veterinary and medical scientists and public health managers should help improve disease surveillance, combat the global burden of human infectious diseases, and improve environmental management. it may even help rebridge a divide that has opened between the medical and ecological sciences, two powerful, explanatory and potentially predictive disciplines that ultimately share common roots in basic scientific inquiry. the overarching objectives of pathogeography, following biogeography (myers and giller ) , are to determine how the interactions among varying biotic (e.g. speciation, adaptation, extinction) and abiotic (e.g. topography, geology, climate) factors and processes combine to produce distributional patterns in infectious diseases through time. johnson et al. ( ) and stephens et al. ( b) recently reviewed the community ecology and macroecology of infectious diseases, respectively, and a natural intersection between these disciplines and the biogeography of infectious diseases occurs where these fields become spatially explicit. macroecology deals with ecological questions that demand large-scale analysis (brown , brown and lomolino , cox et al. . the limits between biogeography and macroecology are fuzzy. they converge when biogeography is focused on the study of how population-or community-level parameters vary along geographic dimensions (lomolino et al. ) , or when macroecology deals with spatial patterns (e.g. the geographic distribution of a certain pathogen species or diversity patterns). the divergence occurs when spatially explicit components are not crucial to answering questions being addressed by macroecology (blackburn and gaston ) , and when biogeography does not invoke structural and functional patterns of ecological systems (e.g. areography and some evolutionary biogeography approaches) (morrone ). by contrast, community ecology offers further insights on the mechanisms and processes that bridge fine scale processes of individuals and populations with the ecology and evolutionary processes of species and disease distributions at larger spatial scales (johnson et al. ) . whereas biogeography is concerned with the analysis of spatial patterns of biological diversity, pathogeography (i.e. the biogeography of pathogens) is concerned with the analysis of spatial patterns of pathogen (or disease) diversity ('pathodiversity' being the obvious analogue, but also referred to as the 'pathogen pool', 'pathogen community', 'pathosphere' or 'pathobiome'). taylor et al. ( ) constructed the first list of distinct species at a global scale known to be infectious to and capable of causing disease in humans under natural conditions, tallying species ( viruses and prions, bacteria and rickettsia, fungi, protozoa and helminths). discovery and recognition of new human pathogens occurs regularly (woolhouse et al. ) , with the most recent comprehensive inventory that we are aware of listing pathogens in humans ( viruses, bacteria, fungi, protozoa and helminths) (wardeh et al. ) . a comprehensive global database of clinically relevant human infectious diseases, gideon ( www.gideononline. com/ ), tracks more than of these pathogens (berger , victor and edberg ) . surprisingly, the distributions of most of these are very poorly known. as recently as , only infectious diseases were considered 'comprehensively mapped' (including old world coltiviruses, plasmodium falciparum and p. vivax, monkey pox, dengue, lassa fever and mayaro) (hay et al. ) , fundamentally limiting the ability of public and global health resources to be systematically and efficiently directed towards precise geographic areas and populations at highest risk from other impactful diseases. indeed, distributional patterns of human infectious diseases are generally far more poorly compiled and characterized (e.g. often at only country or regional level and as coarse presence vs absence data) than many plant and animal species, for which numerous global stock takes, status assessments, occurrence databases and detailed distribution maps exist following a long tradition of biogeographic study (wallace , murray et al. ) (see also supplementary material appendix table a ). however, with the development of big data approaches and curated databases, resources are slowly improving for human infectious diseases (wardeh et al. , stensgaard et al. . data may even on occasion be far richer or more geographically precise than for many plant and animal species (especially invasive species) owing, for example, to notifiable disease reporting requirements, such as those in place in eu member states for reporting human cases of certain diseases to ecdc and zoonotic and food-borne diseases to other eu registries (e.g. haemorrhagic cases of dengue and rift valley fever, crimean congo haemorrhagic fever, west nile fever, cholera, campylobacteriosis) (lindgren et al. ). in addition, databases for specific groups of diseases (e.g. helminths, neglected tropical diseases) and host-pathogen (including human) associations are increasing (e.g.  www.thiswormyworld.org/ ). in global studies that have classified pathogens according to their epidemiological traits, the majority of known human pathogens ( - %) are classed as zoonotic, defined as diseases and/or pathogens that are naturally transmissible from vertebrate animals to humans, and % are arthropod vector-borne (who , palmer et al. , taylor et al. , woolhouse and gowtage-sequeria . the close association between animals and human pathogens means that the diversity of potentially pathogenic microorganisms that occur in animals including wildlife is also of major interest for human health (morse , murray and daszak ) . however, at present, the full dimensions of this broader 'pathogen pool' are almost entirely unknown. for example, estimates of the total number of viruses within just nine target viral families from the first intensively sampled wildlife species (the natural host of nipah virus, fruit bat pteropus giganteus) suggest that the number of known human pathogens is just a tiny fraction of the total viral diversity that occurs in wildlife (anthony et al. ). the 'operational taxonomic unit' (otu) of pathogeography may differ somewhat from conventional otus in biogeography (e.g. genes, species). while infectious diseases are all caused by specific pathogenic microbial species (which could, or perhaps should, themselves be the relevant otu), it is their infection/presence in human and in some cases livestock or wild animal hosts or vectors that is of primary interest to health stakeholders and the usual target of surveillance programs. 'occurrence' is the presence of a disease or its causative agent in a particular place at a particular time. this can in turn be represented as a presence (i.e. in a human host or a specific geographic unit) or some measure of relative abundance either within single hosts (e.g. the infection load, particularly for macroparasites, such as helminths), within a defined geographic area (e.g. density), time period (incidence) or within the host population (e.g. prevalence). it might also be represented to reflect the process of transmission itself (e.g. 'force of infection'). with some information on the average impact of infections in humans, public health practitioners often also describe spatial and temporal patterns of disease in terms of 'burden', with various available measures that broadly seek to capture the loss of healthy life (e.g. death and disability) attributable to the presence of certain diseases within a population (e.g. disability adjusted life years, dalys) . conversely, the absence of disease is of equal interest for pattern and process analysis, but harder to obtain given the sampling difficulties of asserting freedom from disease (cameron ). furthermore, occurrence records (and its derivatives) will generally be a subset of actual occurrences, because in most cases they will be heavily influenced by observation effort. given the diversity of health studies, all of these epidemiological metrics could be potentially relevant for pathogeographic analysis. the same units of measure (occurrence, abundance, density) for known or potential hosts and vector species are also relevant and will already be familiar to ecologists. some estimates of disease 'risk' (or, perhaps more accurately, 'hazards') are based on these (e.g. tick nymphal abundance as a measure of lyme disease risk) and their ecologies may contribute directly or indirectly to disease patterns (civitello et al. ) , such that data on their potential occurrence can improve biogeographically-informed risk mapping of disease outcomes in humans (messina et al. , pigott et al. , olivero et al. a . one major challenge for biogeographic analyses of human infectious diseases, however, is the availability and utility of appropriate data, which we discuss further in box . supplementary material appendix table a provides some example data types, and some useful databases and sources relevant to biogeographic analyses of human infectious diseases. the study of infectious disease spatial distributions is not new (barrett ) , nor are integrated approaches to studying infectious disease distributions, whether they are labeled biogeographic (peterson ) or not (lambin et al. ) . indeed, the emergence of informatics, geographic information systems (gis) and satellite technology has increased the availability of tools and high quality spatial datasets relevant to both ecologists and medical geographers, driving a recent convergence in the data and in some cases the methods used to examine the distributions of wild species and infectious diseases alike and for developing or evaluating causal hypotheses underpinning them (hay et al. , kraemer et al. . such developments have facilitated the study of the spatial structure of some infectious diseases in unprecedented detail ( fig. ) . in some cases, there has been innovation in the integration of these approaches with mechanistic models traditionally used to explore the population dynamics of infectious diseases (redding et al. ) , and some analyses have been developed and updated in close to real time (e.g. during the west african ebola outbreak) (pigott et al. (pigott et al. , . these advances complement an already strong suite of tools already used in epidemiological studies, which might equally flow the other way into the toolboxes of ecologists (magalhães et al. , caprarelli and fletcher , bhatt et al. . peterson ( ) defined the first explicit 'biogeographic framework' for human infectious diseases. drawing on the work of soberón ( ) on the grinnellian niche and geographic distributions of species, the framework is characterized by considerations of a pathogen's dispersal ability combined with the abiotic and biotic factors that interact to determine whether a disease is able to fulfill its full geographic potential. although not explicitly demonstrated, peterson ( ) emphasizes that a key difference between pathogens and diseases in comparison to free ranging wild species (with the exception of invasive species) is the relative unpredictability of dispersal events (e.g. rapid, long distance introductions), and the relatively lower importance of abiotic and relatively higher importance of biotic factors. this applies particularly to the high degree of inter-specific interactions, from the infection of a pathogen in a host, to the numerous other species that may be involved in pathogen transmission cycles. the distribution of an infectious disease is thus defined by the joint distributions of all species involved in its transmission cycle as dictated by the suitable ecological conditions and dispersal limitations for each. in contrast, lambin et al. ( ) present an alternative framework for understanding generalized disease risks across landscapes, drawing on principals from 'spatial epidemiology' (ostfeld et al. ) and 'landscape epidemiology' (pavlovsky ) . pavlovsky ( ) proposed that infectious disease occurrence is determined by 'a continuous interaction' of five landscape factors: ) animal 'donors' (e.g. reservoir hosts), ) vectors, ) animal 'recipients' (including humans), ) an infective pathogen, and ) environmental factors that are conducive to transmission. lambin et al. ( ) emphasise the use of biogeographical methods for examining the distributions of human infectious diseases will be dependent on the degree of existing knowledge (e.g. about the epidemiology of a particular pathogen or pathogen assemblage in a particular geographic context), data availability (e.g. from publicly accessible databases, surveillance data) and the potential for new data collection (e.g. targeted field collections). these elements could range from no knowledge, no data and large barriers to the collection of new data (e.g. for many emerging infections in developing country contexts, such as at the beginning of the ebola outbreak in west africa), to high degree of knowledge from existing scientific studies, well developed and accessible databases on relevant geographic/environmental, reservoir host, vector, pathogen, human and disease data, and existing structures to streamline the collection of new data (e.g. high impact diseases in developed country contexts, such as malaria in the eu). data on human infectious diseases are normally collected for the needs of a particular discipline or research focus, which may typically limit the extent to which it can be used laterally or opportunistically for answering non-target questions. this may be particularly the case for macroecological and biogeographical studies, which are often data intensive and conducted at scales that may be difficult or impractical to undertake new data collection. there is thus a clear need to expand the scope of research programmes on infectious diseases to encompass the geographic, biological and temporal scales relevant to biogeographical analysis. this involves informing monitoring and surveillance activities on what types of data would be most useful and urgent. improving data capture and quality with standardized sampling methodologies could help lead to analyses and discoveries that transcend the specific epidemiological details of a single site, geographical context or disease. to this end, the following information would be helpful to allow coherent data collection and analysis of infectious disease occurrence and transmission in space and time: • operational taxonomic units: potential complications for biogeographic pattern and process analysis may arise when the 'presence' of a specific disease type is in fact confounded. this could occur, for example, if multiple causal agents result in disease complexes (e.g. leishmaniasis) or if the causal agent is unknown and diseases are instead classified by their symptoms (e.g. syndromes). distributional data and databases on infectious diseases should thus strive for the highest 'taxonomic resolution' possible (murray et al. , stensgaard et al. ). • observation effort: a persistent issue in robustly quantifying occurrence, in any form, is its relationship to observation effort (allen et al. ) . observation effort could vary spatially, temporally or taxonomically. presence, prevalence, burden and diversity patterns of infectious diseases, hosts and vectors may all increase proportionally to observation effort, and confidence surrounding reported absences also increases with observation effort. failing to account for this has the potential to introduce biases in biogeographic studies. numerous studies have taken steps to incorporate measures of observation effort to limit the potential effects of observation bias in biogeographic studies of infectious diseases, typically by including factors hypothesised to be related to observation effort, such as sampling intensity, gdp, health expenditure or publication output, in statistical models (jones et al. , hopkins and nunn , yang et al. , murray et al. ) (see also o in box ). • sampling protocols: a lack of communication between biostatisticians and field workers in both ecological and health fields before collecting samples can lead to a breakdown in robustness of subsequent analyses. for example, sampling too many host individuals of one species could be as problematic as not sampling enough from a target host (e.g. humans), particularly when research resources are constrained. best practices involving probability sampling should be pursued where possible (nusser et al. ). • geographic coverage and resolution: sampling should cover a sufficiently large area(s) to reproduce in space what really exists in the field; for example, metapopulation or metacommunity geographic distributions with sources and sinks of pathogen transmission. the effects of uneven sampling across space and one-shot sampling should be avoided (peterson ) . at the other extreme, improving precision on available data points is a high priority for developing robust geo-referenced databases of disease (or pathogen, host, vector) occurrence. all data should be collected and stored for subsequent access at the highest spatial resolution possible (i.e. gps coordinate locations). • temporal coverage: infected hosts including humans may travel long distances during disease incubation periods, introducing uncertainty in the attribution of the geographic location of infection (peterson ) . surveillance and sampling strategies should thus allow the capture of appropriate temporal scales (i.e. matching scale of disease-relevant processes) so that data can be better aligned with covariate information such as environmental variables and human activities. • phenology: animal and plant phenology should be monitored; the behavior and biology of most species, including humans, are influenced by often relatively predictable annual changes in climate that determine when they start or finish natural events, such as flowering and fruiting, breeding and mass gatherings. many of these activities and departures from norms due to, for example, unusual weather events have implications for disease risks and spatio-temporal distributions, and could have large implications when considering the influences of large scale change (e.g. climate change). • humans as hosts and dispersers: humans will often serve not only as hosts but also as effective dispersal mechanisms for infectious agents. although this can lead to unpredictability and extreme long distance invasion events (peterson ) , data on human populations and their movement are being increasingly well resolved at both fine and coarse spatial scales and this is proving invaluable in decomposing biogeographical components of many infectious disease systems including emergence risks (e.g. use of flight or road traffic data, mobile phone use data, social media) (colizza et al. , balcan et al. , wesolowski et al. , jurdak et al. ). • concurrent covariate sampling and time-lagging: ideally, assessment of environmental and social variables should be conducted at the same time as human or wildlife disease sampling (if it is not available at the appropriate scale retrospectively i.e. from remote sensing data). peterson ( ) discusses a range of issues relevant to modeling the distribution of infectious diseases, including quality control of input occurrence data, sampling design with the reduction of oversampling in certain areas, and design of analysis (see also hosseini et al. ). the dynamic nature of the spatial and temporal interactions between these 'prerequisites' at multiple scales when assessing the impact of landscape changes on vector-borne and zoonotic diseases. although they did not identify their study explicitly as 'biogeographic', there are clear parallels with peterson's ( ) framework (as well as many others, such as plowright et al.'s ( ) recent treatment of spillover ecology). we develop these ideas further in box , focussing on the interactions between a number of inter-dependent elements, including: physical geography (g), environment (e), reservoir host(s) (r), vector(s) (v), pathogen(s) (p), human factors (h), and the management (m) and observation (o) landscapes, the latter serving as the lens through which all other elements and disease distributions (d) are ultimately observed. from this framework, we can envisage how these elements may act and interact to influence both the real and observed distributions of specific diseases in space and through time, as well as multidisease patterns that may emerge at higher levels of organization (see 'emergent patterns and multiple diseases' below). depending on epidemiological characteristics, not all of the elements illustrated in box will be relevant for all human infectious diseases, resulting in a range of 'biogeographic complexity' among human infectious diseases. whereas g and e will almost always have some kind of modifying influences, single-element transmission source systems (i.e. diseases only involving human-human, environmental, single reservoir species or single vector species transmission) represent the least biogeographically complex examples in this framework. examples include tetanus (e), measles (h), and lassa fever (r). the more biogeographically complex diseases involve multiple elements; for example, multiple reservoir host or vector species (r n and v n , respectively) in addition to human-human or environmental transmission (e.g. dengue (hv n r n ); infection with mycobacterium ulcerans (ev n r n )). we describe the potential utility and demonstrate an application of this general framework further in box , by undertaking a 'disease trait profiling' exercise whereby we classify a large number of clinically relevant human infectious diseases according to their transmission sources (i.e. the e, h, v and r elements described in box ). the trends that emerge illustrate how certain disease characteristics are far more common than others (e.g. transmission from animal reservoirs vs arthropod vectors) and the extent to which mapping efforts are already underway. however, the analysis also highlights some important gaps. for instance, . % of diseases with a strong rationale for mapping (as rated by hay et al. ) have not been mapped in any study (box , fig. panel f) , and declining overall quality of mapping efforts correlates with increasing biogeographic complexity (box , fig. panel g) , highlighting a need to expand the breadth of ecological interactions considered within disease systems to improve mapping quality in future studies. an additional consideration not explicitly included in box is that changes in interactions through time can influence the occurrence, transmission and emergence of many diseases. for example, short or longer term changes in land-use and climate (both components of e) can influence d directly or through their influences on v, r and/or h (epstein , patz et al. , nakazawa et al. , jones et al. , hoberg and brooks , mackenstedt et al. . ebola virus disease (evd) outbreaks, for example, have been closely associated with inter-annual anomalies in meteorological seasonality, whereby sharply drier conditions at the end of the rainy season seem to favour the occurrence of outbreaks (pinzon et al. ). more recently, ebola outbreaks have been linked to fragmentation (rulli et al. ) and recent ( yr) deforestation (olivero et al. b ). a promising approach emerging from ecology warranting additional attention here is the increasingly widespread use of species distribution modelling (sdm) (also called ecological niche modelling (enm)). when applied to pathogens, hosts and/or reservoirs and vectors, sdm is useful for understanding risk factors conditioning the distributions, emergence or the accumulation of new outbreaks of disease. in sdms, the available information on the presence or the incidence of disease is linked to a diverse set of environmental variables and allows the evaluation of the degree to which certain environments are favourable for the occurrence of disease, even in areas where it has not been detected before. in the absence of, or in combination with, local-scale data suitable for (pigott et al. ) . illustrating the detail of modern cartographic projections of disease risk based on models of environmental suitability for the zoonotic transmission of ebola virus (shaded colours) and the spatial variation in disease risk that would be masked from country-level chloropleths (thick black lines). dotted lines indicate regions that have reported no index cases to date but are predicted to be partially at risk based on environmental suitability models that utilize a thresholding approach on the model output that captures % of the occurrence records used for model fitting (see also fig. ). boosted regression trees were used to develop the model based on georeferenced records of ebola virus disease outbreaks in humans and infection records in bat reservoirs and a range of environmental covariates. the scale reflects the relative probability that zoonotic transmission of ebola virus could occur at these locations; areas closer to (dark red) are more environmentally similar to locations reporting ebola virus occurrences; areas closer to (light yellow) are least similar. mechanistic models, sdms can take advantage of the large geographic scale to explore macroecological processes that are able to explain and predict the occurrence of disease. this can reveal emergent patterns and processes not perceptible at the local scale (brown ) , and can help lay a foundation for hypothesis testing or provide a geographic context for further studies on the ground (allen et al. ) . the outputs provided by sdms can be summarized in three main categories: probability (e.g. logistic regression, generalized additive models, random forests, boosted regression trees), suitability (e.g. maxent, garp) and favourability (e.g. favourability function). suitability is an idiosyncratic way of ranking local sites according to their capacity to hold the species or pathogen that is not directly related to the probability of occurrence (guisan and zimmermann , royle et al. ) . in contrast, favourability values can be obtained from probability and prevalence (here defined as the proportion of presences in the set of observations) (real et al. ). probability and suitability are biased in their outputs when working with samples differing in prevalence, which is not the case with favourability (acevedo and real ). this quality of favourability enables direct comparison and combination we may represent the challenge of simultaneously understanding patterns and processes of infectious disease systems with respect to a series of interacting elements; including g, the physical geography context (e.g. topography) and e, the abiotic (e.g. climate) and biotic (e.g. habitat) environment; r n and v n , the single or multiple (denoted by superscript n) species of reservoir hosts or vectors; p, the pathogen being transmitted; h, the human population itself; o, the observation effort that may apply to each of the other elements (e.g. surveillance and data collation from existing sources); and m, the management landscape (e.g. interventions). the combinations of these elements ultimately give rise to d, the observed disease distributions. where these elements have consistent effects across multiple diseases, 'higher order' biogeographic patterns emerge; for example, we can observe biogeographic regionalization as a consequence of the more pervasive effects of components of g (e.g. ocean or mountain barriers to dispersal) or e (e.g. unsuitable climates), while the effects of components of h (e.g. population growth, global movement, socio-economic status, immunity heterogeneity) and m (e.g. health infrastructure, vaccination) have fundamentally reshaped the global diversity and burden patterns of infectious diseases. in addition, each layer potentially has additional modifying elements that could further shape disease distributions and diversity patterns, such as temporal fluxes (see main text), or lifehistory and epidemiological traits of hosts, vectors and pathogens (smith et al. , woolhouse et al. . for pathogeographic analyses and as a starting point for risk assessments, a series of 'profiling' steps could help integrate existing information at a scale relevant to a particular research question. this could include geographic and/or environmental profiling (e.g. detailed assessments of g and e for diseases/hosts/vectors in regions of interest relevant to single diseases or disease assemblages) (eisenberg et al. ), disease trait profiling (classifying epidemiological features of diseases, such as the presence or absence of the e, v, r and h elements as sources of pathogen transmission (see box ), and the species known to be implicated in each), and human profiling (assessments of the human population distribution, density and movement patterns and the existing management and observation landscapes). intersection of these geographic, disease trait or human profiles will ultimately yield yet deeper understanding or management relevant insights (semenza et al. ). when several species are involved in the analytical design; for example, when using models for deriving indices based on multiple species (estrada et al. ) , and for the study of biogeographical relationships between species (real et al. , acevedo et al. , including relationships between pathogen and host complexes (olivero et al. a) . sdm approaches represent one of the major recent advances in infectious disease cartography (hay et al. , peterson , kraemer et al. , producing a diverse range of predictions on the presence or risk of human infectious diseases or their causative organisms (peterson et al. , peterson , neerinckx et al. , reed et al. , samy et al. , zhu and peterson , and their animal hosts and vectors (sweeney et al. , de oliveira et al. , giles et al. . modelling the distribution of biotic interactions is a relatively recent advance in macroecology and biogeography (kissling et al. , wisz et al. , ovaskainen et al. ) and could similarly provide a further way forward for the analysis of pathogens with zoonotic cycles based on joint distributions and multispecies assemblages. other methods of representing potential interactions at a community level (e.g. network modeling) or inferring potential hosts/vectors and host/ vector ranges from geographic co-occurrence are similarly being developed alongside (or in some cases integrated with) niche modeling approaches to yield novel insights disease trait profiling could help synthesize and summarize the range of potential ecological interactions of diseases and highlight important priorities or gaps for biogeographic analyses. to illustrate, we classified all clinically relevant diseases within the gideon database with single causative pathogens (n  diseases) into each of the combinations possible considering whether disease transmission sources included the e, h, v and r elements outlined in box (note, although h is by definition always involved for human infectious diseases, here it is treated more specifically as a transmission source i.e. human-human transmission). we then examined how variations in the complexity of diseases, as indicated by the number of elements involved in their transmission (complexity score, cs), was related to geographic range size (as broadly indicated by the number of countries in which the disease is present), the rationale for mapping, whether mapping efforts had already taken place, and the quality of existing mapping as rated by hay et al. ( ) . consistent with other studies, . % of diseases in our dataset involved (but do not necessarily require) transmission to humans from animal reservoirs (zoonotic) (fig. a) . human-human transmission was also common ( . %), while diseases including potential transmission from vectors ( . %) or environmental sources ( . %) were less common. for diseases involving vectors or reservoirs, the great majority involved multiple vector ( %) or reservoir ( %) species rather than single species (fig. a) . diseases ranged considerably in their degree of 'biogeographic complexity', but only of possible combinations were represented in our dataset (fig. b) . the least complex examples involved transmission from the environment (e) only, a single reservoir (r) only, or humanhuman (h) only (cs  ), while the most biogeographically complex diseases involved multiple vectors, reservoirs and could include either environmental (evnrn) or human-human (hvnrn) transmission as well (cs  ). on average, diseases including humanhuman transmission were the least biogeographically complex ('h' mean cs  . ), followed by diseases including transmission from reservoirs ('r' cs  . ), while diseases involving transmission from the environment ('e' mean cs  . ) and vectors ('v' mean cs  . ) were more complex. on average, complexity was not obviously related to commonness (fig. c) , but more complex diseases tended to be more geographically restricted (fig. d) , and had both a stronger rationale for mapping (fig. e) as well as a higher proportion of diseases that had already been mapped (fig. f) , particularly when human-human or environmental transmission were never involved (traits that can radically increase their distributions to the point of making them essentially ubiquitous). however, the quality ratings of existing mapping efforts for more complex diseases were considerably lower on average than for simpler diseases (fig. g) . these trends illustrate the extent to which mapping efforts are already underway for clinically relevant infectious diseases but also highlight some important gaps. for instance, as of hay et al.'s ( ) study, . % of diseases with a strong rationale for mapping had not been mapped in any study (fig. f) , and declining overall quality of mapping efforts for more restricted and biogeographically complex diseases highlights a clear need to address the breadth of ecological interactions within disease systems in future studies. on the spatial distribution of some infectious diseases (stephens et al. (stephens et al. , a . returning to the framework in box , g, e together with time (t) could each have more pervasive effects through their simultaneous influences on the other elements, giving rise to higher-order biogeographic patterns that are defined by multiple diseases, such as co-occurrences (including co-infection patterns), chorotypes, diversity gradients, or biogeographic regionalisation. while biogeography has already made significant contributions to providing a generalized framework for disease mapping (peterson , escobar and craft ) , we emphasise that it is the comparative power of biogeography that could help take pathogeography a step further, diverging more radically from medical geography, to address the factors that govern the structure, assembly, dynamics and spatial patterns of multiple or entire assemblages of human infectious diseases over a more diverse range of spatial and temporal scales. below we provide some illustrative examples relevant to what has or potentially could be applied to human infectious diseases. a chorotype is a type of distribution pattern that is followed by one or several species (baroni urbani et al. , real et al. , passalacqua . as chorotypes represent the shared geographical, ecological and evolutionary context of several species (real et al. , fattorini , these patterns could be useful for generating hypotheses about the causes and origins of host, reservoir and pathogen distributions. although not yet widely explored for infectious diseases, chorotype analysis could significantly contribute to the study of the complex interactions characteristic of human infectious disease systems (peterson , roche et al. . in the analysis of disease distributions, the relative importance of these interactions, compared to the relevance of other environmental factors, is variable. some studies have raised this issue through the comparative analysis of pathogen models and host models based on their respective responses to environmental conditions (maher et al. , costa and peterson ) . however, with the exception of using host distributions as a simple proxy for the potential distributions of pathogens (daszak et al. ) , the distribution of reservoir species has only recently been used as an explanatory variable, together with other environmental descriptors, to define a pathogen distribution model (e.g. compare peterson et al. walsh and haseeb, and pigott et al.' s models for ebola virus) (peterson et al. , walsh and haseeb , pigott et al. . although we are aware of no studies examining chorotypes of human infectious diseases, mammalian chorotypes have been recently incorporated into an infectious disease distribution model (olivero et al. a) . when the ecology of a pathogen is complex and unresolved (e.g. ebola virus, leroy et al. , groseth et al. , olival and hayman , imposing restrictions to the selection of host or vector species considered in a model might under-represent the zoological substrate conditioning a pathogen's transmission and distribution (roche et al. ) . olivero et al. ( a) thus addressed the mapping of favourable areas for the ebola virus in the wild by combining two biogeographical approaches: sdm and chorotype analysis. mammalian chorotypes in africa were employed as surrogates of the types of distributions shown by reservoirs and any wildlife species implicated in the virus spillover cycle. olivero et al. ( a) found that a model based on a number of diversity patterns, each one associated with a different mammalian chorotype, defined favourable areas for the presence of ebola virus with higher accuracy than did a model based on environmental variables alone (i.e. climate, forest type), concluding that mammalian biogeography contributes significantly to explaining the distribution of ebola virus in africa. in addition, vegetation was identified as a factor placing clear limits to the presence of the virus. favourable areas for ebola virus were thus determined from information provided by both models (fig. ) . it is now widely recognized that multiple pathogens may act independently or interact through a variety of different mechanisms to influence disease outcomes in human populations (pederson and fenton , jolles et al. , scholthof , and yet studies of human infectious disease, host and vector diversity or community assembly patterns are rare in comparison to distributional studies of single infectious diseases (see 'single diseases' above). characterizing diversity patterns can thus provide a range of insights on the distributions and processes underlying multiple species of pathogens or diseases. based on components first proposed by whittaker ( ) , inventory diversity quantifies diversity within an environment, where alpha (α) diversity is used to refer to diversity at the local scale (i.e. smallest scale being measured). α-diversity of human infectious diseases has been analysed in a number of studies, typically by comparing the number of diseases occurring in different countries at a global or continental scale due to limited comparative data availability at higher spatial resolutions. although strongly heterogeneous (fig. ) (see also stensgaard et al. ) , some striking patterns suggest that human infectious disease communities are shaped by the same ecological processes that shape the diversity of life more generally (guernier et al. ) . this is evident, for example, from observations of a clear latitudinal gradient in disease diversity and disease range sizes, whereby disease richness decreases and range size increases towards the poles (fig. ) (guernier et al. , guernier and guégan ) . other patterns are consistent with island biogeography theory, such as a positive relationship between land surface area and disease richness (smith and guégan ) , and reduced richness on smaller islands and with distance to the nearest mainland (jean et al. ). together, these findings likely explain why the strongest predictor of human infectious disease richness known to date is wildlife richness (dunn et al. ) , while some vector groups show similar patterns (foley et al. ). these patterns also illustrate that a correlation between human disease diversity and wildlife/ vector diversity may not necessarily imply direct causation. nevertheless, other evidence points to the importance of animals, particularly mammalian and bird wildlife, as a key source of endemic and emerging human pathogens (taylor et al. , woolhouse and gowtage-sequeria , jones et al. , allen et al. . in addition to the causal links, such parallels in patterns of human disease and other taxa reinforce the importance and potential utility of considering wildlife and vector biogeography alongside or as a central component of studies of infectious diseases, including distributional and diversity studies of known or potential zoonotic hosts and vectors (foley et al. , cooper and nunn , han et al. , olivero et al. a . in contrast to inventory diversity, proportional diversity measures the difference in diversity between environments or across gradients of habitats, commonly expressed as beta (β) diversity (whittaker , jost . β-diversity patterns can be expressed in a number of ways, such as biogeographic regionalisations, which define biotic boundaries according to between-area gaps in species composition, and biotic regions based on biotic similarities (olivero et al. ) . such approaches, however, are yet to be widely applied to human infectious diseases. in one study, β-diversity patterns of human infectious diseases appear to parallel patterns in other taxa, consistent with patterns identified to date for α-diversity (richness); murray et al. ( ) show that human infectious disease assemblages exhibit biogeographic regionalisation reminiscent of zoogeographic patterns, particularly for zoonotic (fig. a, b) , vector-borne and parasitic diseases, and that mammalian assemblage similarity is consistently among the strongest predictors of human infectious disease assemblage similarity among countries (fig. c ). such an effect is very likely predictive of as-yet undescribed patterns of microbial diversity, such as the geographic structure recently demonstrated among novel coronaviruses detected in wild bat hosts (anthony et al. ) . in addition to this dominant explanatory effect of biodiversity, other factors, including environmental (climate, land area, population size), social (human connectivity, health expenditure, observation effort) and epidemiological characteristics (e.g. pathogen type, transmission mode) also affect infectious disease αand β-diversity patterns (fig. c ). the strongest β-diversity patterns, for example, can be observed in zoonotic, vector-borne and parasitic infectious diseases, likely due to a more dominant role of environmental factors and persistence of historical dispersal barriers limiting their geographic distributions, while patterns of humanspecific diseases are far more homogenous at the global scale (smith et al. , dunn et al. , just et al. , murray et al. , jean et al. ) (see also box fig. panel d) . guernier et al. ( ) ); (c) nestedness: a hierarchical pattern of human pathogen composition with the pathogen species found at higher latitudes (darker bars) constituting nested subsets of those in progressively richer communities at lower latitudes (lighter bars) (adapted from guernier et al. ( ) ); (d) disease range size: narrower distributional ranges occur in the tropics (darker circles) for human pathogens compared to higher latitudes (lighter bars) (adapted from guernier and guégan ( ) ). β-diversity can be further decomposed into two separable components, nestedness and turnover, which may further help characterize the processes driving differences in the composition of assemblages between sites (harrison et al. , baselga . nestedness occurs where species assemblages are subsets of the biotas at more diverse sites (wright and reeves , ulrich and gotelli ) , and indicates a non-random process arising from any factor that promotes the orderly disaggregation of assemblages (gaston et al. ) . the latitudinal gradient of human infectious diseases exhibits such a pattern, with disease assemblages occurring at higher latitudes being subsets of those occurring closer to the equator (fig. c ) (guernier et al. ). in contrast, turnover indicates the replacement of some species by others as a consequence of environmental sorting or spatial and historical constraints (qian et al. , baselga ). in the only assessment of nestedness vs turnover undertaken so far for human infectious diseases that we are aware of, both nestedness and turnover appear to contribute to overall differences in infectious disease assemblages among countries at a global scale, with the relative contribution varying between major epidemiological classes (murray et al. ) . for example, nestedness dominates differences in human-specific diseases, whereas turnover dominates differences in zoonotic and vector-borne diseases. biogeographic methods and outputs have already contributed and continue to show great promise for a number of health management or research applications on infectious diseases, which could help direct the allocation of scarce public and global health resources more efficiently and effectively. as our abilities to assemble ecological datasets and conduct infectious disease surveillance and analyses are steadily improving, multidimensional ecological data can be mapped and relationships can be identified as data accumulate in close to real-time, providing decision-relevant information for health managers and researchers to respond to. this has already lead to rapid advances in improving disease mapping for single infectious diseases and a closing of the gap between the data types and methods used to characterise disease and species distributions by medical geographers and ecologists, respectively. many other applications are conceivable albeit so far poorly explored. for example, taking inspiration from conservation and ecological applications, diversity analyses and biogeographic regionalisation could be used to test and propose hypotheses about ecological factors and historical events that could underlie the current organization of disease assemblages or . colours represent statistically supported groups (n  groups) of countries that share similar diseases, as derived by evaluating results from the silhouette, elbow, ch index and gap statistic tests; (b) global pathogeographic realms for zoonotic diseases derived from (a) (colours for mapping match country clusters identified in (a)). legend labels indicate the statistically supported regions (first column) and how these align with 'classic' zoogeographic realms (second column) (note although the realm label for nearctic includes greenland for illustration purposes, the 'islands' group (dark blue) actually includes a large number of small islands plus a few other countries scattered globally (a) that may cluster on the basis of being a depauperate or data deficient group); (c) the relative explanatory value of a range of social and environmental covariates for explaining these global patterns in disease beta diversity, illustrating that mammalian biodiversity is the best predictor of zoonotic disease diversity at a global scale (as derived from a relative importance analysis following multiple regression on distance matrices controlling for the effects of spatial autocorrelation (following murray et al. ( ) ). combined disease risks (e.g. identifying processes of disease dispersal, establishment, and extinction and the 'upstream' risk factors or drivers of novel health threats) (following carmona et al. , báez et al. ; to define contexts for representativeness (e.g. improved disease surveillance design) (following austin and margules , carey et al. , mackey ; to provide consistent units for environmental management and for sampling stratification (e.g. for the optimal discovery of novel pathogens) (following bunce et al. , wright et al. ; and as geographic contexts for imputation/extrapolation or forecasting when data from a unit within a region is missing or unavailable (e.g. where disease surveillance coverage is low or patchy) (cooper and nunn ) . biogeographic approaches may also be useful for examining the risks associated with emerging infectious diseases (eids), since data are often extremely limited on eids and yet the priorities for management revolve around anticipating (through forecasting) when, where and why emergence of pathogens in human populations occurs (peterson , morse et al. . large-scale demographic and environmental factors and changes in these factors are increasingly being recognized as key drivers underlying disease emergence, with shifts in the distributions of disease hosts and vectors being central to this process (jones et al. , semenza et al. . given that most pathogen distributions are very poorly characterized or completely unknown (hay et al. ) , and that most of the microbial diversity from which novel and potentially pathogenic agents could originate are as yet undiscovered (anthony et al. ) , biogeographic pattern definition and process identification based on historical patterns of disease occurrence, recent emergence events, or proxy taxa (e.g. mammalian or arthropod vector biodiversity) may provide some of the earliest and in some cases the only insights into such burgeoning or future disease risks (fig. a , b) (murray et al. ) , which may give way to more refined models as data quality or availability increases (fig. c, fig. ). increasing pathogeographic awareness, participation and collaboration among ecologists, biogeographers and veterinary and medical practitioners could thus contribute to closing the gap between environmental and health management, increased inter-disciplinary research and management efficiency, and reductions in the global burden of disease. data available from the dryad digital repository:  http:// dx.doi.org/ . /dryad.p n dv  (murray et al. ) . fig. for raw model output and description). yellow indicates countries that contain some environmentally suitable areas for ebola. darker colour indicates countries that do not contain areas predicted to be suitable for ebola. the overlap in top priority countries between (b) and (c) is ~ %. the approach taken in (a/b) requires no specific information about the target disease and could provide a relevant biogeographic 'prior' for 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and reemerging pathogens. -emerg on the meaning and measurement of nestedness of species assemblages ecoregions as a level of ecological analysis global distribution of outbreaks of water-associated infectious diseases potential geographic distribution of the novel avian-origin influenza a (h n ) virus supplementary material (appendix ecog- at  www. ecography.org/appendix/ecog- ) key: cord- -y zxipiz authors: dagpunar, j. s. title: sensitivity of uk covid- deaths to the timing of suppression measures and their relaxation date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: y zxipiz in this paper i examine the sensitivity of total uk covid- deaths and the demand for intensive care and ward beds, to the timing and duration of suppression periods during a day period. this is achieved via a seir model. using an expected latent period of . days and infectious period of . days, r_ was first estimated as . using observed death rates under unmitigated spread and then under the effects of the total lock down (r_ = . ) of march. the case fatality rate given infection is taken as %. parameter values for mean length of stay and conditional probability of death for icu and non-icu hospital admissions are guided by ferguson et al.( ). under unmitigated spread the model predicts around , deaths in the uk. starting with one exposed person at time zero and a suppression consistent with an r_ of . on day , the model predicts around , deaths for a first wave, but this reduces to around , if the intervention takes place one week earlier. if the initial suppression were in place until day and then relaxed to an r_ of . between days and , to be followed by a return to an r_ of . , the model predicts around , deaths. this would increase to around , if the release from the first suppression takes place one week earlier. the results indicate the extreme sensitivity to timing and the consequences of even small delays to suppression and premature relaxation of such measures. in order to model the spread of total covid- deaths in the uk over the next days say, one can build a detailed stochastic micro simulation model that includes spatial and age heterogeneity as in davies et al. ( ) and ferguson et al. ( ) . in order to gain some understanding of the sensitivity with respect to the timing of suppression measures and their relaxation, a simple deterministic seir model, see for example hethcote ( ) and blackwood and childs ( ) , can be useful. that is the approach used in this paper. seir is a compartment based model with transitions as shown in diagram . s stands for the number of susceptibles, those who have not yet been infected. initially, almost the entire population is in that category. e is the number who are currently exposed, that is they are infected but not yet infectious. after a latent period, an exposed person becomes infectious and is able to infect susceptible persons. i is the number who are currently infectious. initially, both i and e are small numbers in comparison to n, the population size. each infectious person remains so for an infectious period. an infective person is one who is either exposed or infectious. finally, r stands for those who are removed in the sense they have either recovered or died. in the simple form of the model considered here it is assumed that + + + = . the seir model is more appropriate than a sir model for covid- as sir does not separate the exposed and infectious states. a key controllable parameter is the reproduction number ! which is the expected number of susceptibles that an infector will infect, when the susceptible proportion is close to . it is thought that a significant proportion of those infected may be asymptomatic or presymptomatic in which case they might spend all or part of the infectious period unknowingly infecting susceptibles, although there is a question as to how much virus they shed. on the other hand, those who are symptomatic may spend some of that time in self-isolation which reduces the ! for them. one of the simplifying assumptions of the model developed here is that people can transmit the virus throughout their infectious period. a person will transition between these compartments. the seir model will keep track of how many are in each compartment by noting the rate at which people join and leave a compartment. the key dynamic element of this process is the transmission rate at which an infectious person infects susceptibles. diagram shows the rates of movement between the compartments. the mean latent and infectious periods are respectively ! " and ! # , while " is the probability that an infectious person is admitted to hospital. r is the cumulative number who do not require hospital treatment. it is assumed that all such persons survive, but it may be more accurate to say with hindsight that it may include an appreciable number of people in the community who never went to hospital and did not survive. in that sense the model underestimates the cumulative number of deaths. the model is an idealisation of what happens in practice as some people will enter hospital while still infectious and some will self-isolate during the infectious state. this can be compensated for by a suitable choice of . apart from predicting the number of deaths it is also important to predict the demand for ward and intensive care beds. the uk national health service (nhs) has approximately , ward beds and around , intensive care beds. clearly, one could not expect to access all of these as the occupancy rate is high in normal times. there is the option of building surge capacity. ideally, that would need to be matched by similar increases in medical, nursing, and ancillary staff; equipment such as ventilators; personal protective equipment; and testing for presence of the virus, all of which have become major issues. turning now to what happens in hospitals, diagram gives a schematic view with the transition rates. s e i r . cc-by . 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 may , . an infectious person will move with probability " to hospital. of these a proportion # will never require an intensive care bed and will occupy a ward bed. of those a proportion # will die and the rest will recover. either way their average length of stay will be ! $ days. the remaining proportion − # will spend an average of ! % days in a ward bed followed by an average of ! & days in intensive care. a proportion $ of those entering intensive care will die. for simplicity, those who recover are not re-directed to a ward bed. the symbol in each compartment gives the number of persons currently occupying it, # and $ being the cumulative number of deaths from non-icu and icu patients respectively. cc-by . 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 may , . . https://doi.org/ . diagrams and lead directly to differential equations ( - ) in this section we obtain the important results for the case when / ≈ . equations ( - ) can be written as the negative root will give a solution that decays rapidly and can be ignored, see for example ma ( ) . so, while the susceptible proportion is close to we have the solution and where = ( ) ( ) ' ) $ ( ) that is . cc-by . 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 may , . . https://doi.org/ . / . . . doi: medrxiv preprint ( + )( + ) = . ( ) the expected number of secondary infections from one infectious person is for the special case of = substituting ( ) into ( ) while > the doubling time is and when < the halving time is ( ) from ( ) and ( ) , will all change at rate so one could use any of these to estimate . in the uk there were a large proportion of infectious persons (including asymptomatic and pre-symptomatic) who were never tested and the availability of tests changed markedly over time. therefore, it is felt that the number of positive test results is not a reliable proxy for the number of infectious persons. if is the case fatality rate then the expected number of deaths up to time is [ − ( − )] where is the mean time between exposure and death. differentiating, the death rate at − is − the government told people who showed symptoms to stay at home, without testing for seven days before contemplating hospital admission. . cc-by . 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 may , . . https://doi.org/ . for this reason, was estimated by fitting the logarithm of daily deaths nonparametrically in the period march to april. the dates were selected as to be largely uninfluenced by the gentle suppression introduced on march and the full lockdown beginning march, given that there is a lag between exposure and death of the order of days. the fit gave = . , % confidence interval ( . , . ) with the amount explained by the regression as $ = . . the estimated doubling time in the early stages of unmitigated spread is in order to estimate ! using ( ) we need not only , but estimates of mean latent and infectious periods. ferguson et al. ( ) assumed an incubation period of . days with a hour pre-symptomatic infectious period for some, together with a . day mean generation interval. anderson et al. ( ) thought the incubation period to be around - days with a serial interval of similar duration. davies et al. ( ) assumed a gamma distributed latent period with mean and standard deviation of and days respectively, a mean incubation period of . days, and a serial interval of . days. in this paper we take the mean latent and infectious period to be . and . days respectively, leading to a crude estimate of the serial interval to be . + . x . = . days. using these in ( ) gives ! = . . the death data was that pertaining to english hospital deaths by date of death . this data set was chosen as many other accessible sets are by date of recording the death which can be several days after actual death. we assumed that the growth/decline rate is similar in all four countries of the uk. the model assumes all deaths occur in hospital and applies to the entire uk of population million. for illustrative purposes this is considered reasonable although in the event many deaths occurred in the community including care homes. the model calculates bed occupancy assuming an ideal scenario where all who need hospital care receive it. it is assumed that % of those infected die and . % of those infected require hospital treatment. of these % will never require intensive care and spend an average of days in a ward bed. of these % will die. of the remaining % all will spend days in a ward followed by days in intensive care and % of these will die, these parameter values give a case fatality rate given infection of %. these figures are adapted from those of ferguson et al. ( ) . table summarises the model results over a period of days with an initial condition of one exposed person at time zero and ! = . . figure shows the death rate, required ward and intensive care beds, numbers of susceptible, exposed, and infectious, and cumulative deaths over time. of note is the great speed at which the disease spreads, with almost all deaths occurring within days. secondly, is the fact that at the peak of the wave, the capacity of the heath service, even assuming it was exclusively available to covid- patients, is exceeded by a factor of around and for intensive care and ward beds respectively. https://www.england.nhs.uk/statistics/statistical-work-areas/covid- -daily-deaths/ . cc-by . 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 may , . ( ) , ( ) next we consider the effect of a lockdown such as the one implemented on march . we used death data for the period to april to estimate = − . , with % confidence interval (- . , - . ) and an explanatory $ of . . thus, the estimated halving time in declining the peak, once the effect of the previous ! of . has been largely eliminated, is exposed and infectious . cc-by . 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 may , . . https://doi.org/ . / . . . doi: medrxiv preprint from a behavioural survey of people's distancing following lockdown. table shows summary statistics and figure the associated graphs. ( ) of note is the speed at which peak death rate is reached, some days after starting suppression. figure suppression to ! = . on day we note that icu capacity is exceeded by a factor of , while ward bed demand is approximately % of capacity. exposed and infectious . cc-by . 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 may , . . https://doi.org/ . now suppose that the suppression in table takes place one week earlier on day . table and figure show the model results ( ) we see a very large reduction in absolute death numbers from around , to , , this extreme sensitivity is a result of the exponential rise in infectious numbers and in hindsight clearly illustrates that earlier action was needed and would have saved many lives. the peak death rate occurs days after the beginning of suppression. exposed and infectious . cc-by . 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 may , . . https://doi.org/ . . releasing the suppression to a relaxed of . a lockdown to an ! of . from day to day is unrealistic as it causes great economic and societal damage as well as increasing other mortality and morbidity. now suppose that the suppression of figure is released to a more relaxed ! of . between days and . that will mean there is a second wave so we limit its effect by suppressing again to ! of . between days and . the results are shown in table and figure . . cc-by . 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 may , . . https://doi.org/ . the total deaths have been limited to around , by driving down infectious numbers to very low levels in the first wave. the first suppression was released on day . what happens if the release from the first suppression is brought forward from day to day ? table and figure show the results. exposed and infectious ward beds intensive care beds ward capacity icu capacity . cc-by . 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 may , . . https://doi.org/ . we note that the number of deaths has increased by around , , an increase of approximately %. the model constructed here is a simple one. it cannot compete with detailed micro simulation models. many simplifying assumptions are made. there is much uncertainty about the parameter values for the examples shown. in reality, they will be influenced by the degree of stress a health system is exposed to. rather than precise prediction, the intention has been to show the modelling principles and to demonstrate the extreme sensitivity of the total number of deaths to the timing of suppression measures and their release/relaxation. literally, each day's delay in starting suppression can result in thousands of extra deaths. after the peak has been passed it is equally important to time the relaxation so that the further death toll is not excessive. these conclusions are the incontrovertible consequence of the exponential growth and decline of a managed epidemic. a more sophisticated model will enable more precise predictions on cumulative deaths under a range of control strategies, such as shielding and segmentation of the population. these can then be put alongside the economic and other effects of prolonged suppression. the political decisions can then be well informed. at the time of writing on may some days after the lockdown of march, we note that total deaths were , and rising, which is perhaps quite close to the scenario considered in figure . comparing with figure it does pose the question as to why lockdown did not occur earlier? it is quite possible that the cumulative deaths obtained from the model are an underestimate, since in the event a substantial proportion of deaths occurring in care homes are lagging those in hospitals and were not used in the estimate of ! . further, no account has been taken in the model of a gradual transition from the unmitigated ! of . to the estimated value of . following lockdown. going forward, ! will be monitored to update predictions. a disadvantage of using death data is that one is essentially estimating ! some days previously. but the alternative of using positive test numbers might lead to biased estimates due to the volatility of the proportion of infectious persons who are represented in such figures. perhaps the compromise is to use hospital admissions as a proxy for infectious numbers. how will country based mitigation measures influence the course of the covid- epidemic ? an introduction to compartmental modeling for the budding infectious disease modeler the effect of non-pharmaceutical interventions on covid- cases, deaths and demand for hospital services in the uk: a modelling study impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand the mathematics of infectious diseases quantifying the impact of physical distance measures on the transmission of covid- in the uk. centre for mathematical modelling of infectious diseases, department of infectious diseases, london school of hygiene and tropical medicine, london wc e ht . first online estimating epidemic exponential growth rate and basic reproduction number 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 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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- -a rd kas authors: guo, zuiyuan; he, kevin; xiao, dan title: early warning of some notifiable infectious diseases in china by the artificial neural network date: - - journal: r soc open sci doi: . /rsos. sha: doc_id: cord_uid: a rd kas in order to accurately grasp the timing for the prevention and control of diseases, we established an artificial neural network model to issue early warning signals. the real-time recurrent learning (rtrl) and extended kalman filter (ekf) methods were performed to analyse four types of respiratory infectious diseases and four types of digestive tract infectious diseases in china to comprehensively determine the epidemic intensities and whether to issue early warning signals. the numbers of new confirmed cases per month between january and december were used as the training set; the data from were used as the test set. the results of rtrl showed that the number of new confirmed cases of respiratory infectious diseases in september increased abnormally. the results of the ekf showed that the number of new confirmed cases of respiratory infectious diseases increased abnormally in january and february of . the results of these two algorithms showed that the number of new confirmed cases of digestive tract infectious diseases in the test set did not have any abnormal increases. the neural network and machine learning can further enrich and develop the early warning theory. public health emergencies caused by the continuous occurrence of emerging infectious diseases and unexplained diseases in the world such as severe acute respiratory syndrome (sars), h n influenza a, ebola haemorrhagic fever and h n highly pathogenic avian influenza have already become prominent public health issues in the past years [ ] . in addition, existing © the authors. published by the royal society under the terms of the creative commons attribution license http://creativecommons.org/licenses/by/ . /, which permits unrestricted use, provided the original author and source are credited. infectious diseases such as tuberculosis, dengue fever, malaria and influenza are also jeopardizing human health [ ] [ ] [ ] [ ] . faced with the complex situation of current infectious disease prevention, we should not only strengthen the surveillance of the epidemic information of infectious diseases but also issue early warning signals as soon and as accurately as possible to strive for the timely identification of outbreaks and epidemics in the early stages and to take rapid response measures to minimize the harm to social and economic development. since the sars outbreak, a web-based, daily infectious disease confirmed case surveillance system, which covered notifiable infectious diseases, was instituted in april in china [ ] . by , the number of monitored infectious diseases increased to types [ ] . this system is capable of collecting the number of confirmed cases of various infectious diseases nationwide in real time and greatly increases the timeliness of infectious disease reports. therefore, it establishes an important platform for surveillance of the epidemic intensity, analysing epidemiological patterns and practising the early warning model [ ] . early warning of infectious diseases involves issuing signals before or in the early stages of the infectious disease outbreak to warn that the event may occur or its extent and degree may expand. this is an important prevention measure to avoid or reduce harm to public health and social security caused by infectious diseases. currently, early warning systems of infectious diseases have already been established in many developed countries; these systems include the global outbreak alert and response network established by the who in [ ] , the global public health intelligence network established by collaboration between the who and health canada in [ ] and promed-mail established in and initiated by the international society for infectious diseases [ ]. these systems play important roles in the prevention and control of infectious diseases, particularly the prevention of emerging infectious diseases and bioterrorism attacks. the china infectious diseases automated-alert and response system developed by the chinese center for disease control and prevention began to operate nationwide in april [ ] . it is a more perfect and practical early warning system of infectious diseases established in china for the first time. it plays an irreplaceable role in the prevention and control of infectious diseases in china. the purpose of analysing infectious disease surveillance data obtained from an early warning model is to eventually determine whether the epidemic displays any abnormal increases. currently, commonly used early warning systems include simple control charts, moving average control charts, exponential weighted moving average and space scan statistics [ ] . these systems have already played positive roles in early warnings for poliomyelitis, bacillary dysentery, measles and other public health emergencies. in the twenty-first century, research on artificial neural networks continues to deepen and includes extensive applications in many fields including precision medicine and public health [ ] [ ] [ ] [ ] [ ] . in this study, we used real-time recurrent learning (rtrl) and extended kalman filter (ekf) to perform early warning research on four types of respiratory infectious diseases (measles, influenza, rubella and mumps) and four types of digestive tract infectious diseases (hepatitis a, hepatitis e, typhoid fever and paratyphoid fever, and bacterial and amoebic dysentery) that have higher incidence rates among notifiable infectious diseases in china. currently, these two algorithms have been extensively applied in nonlinear prediction and model establishment [ ] . we used these technologies in the field of epidemiology. the number of new confirmed cases per month was used as a sequential input signal and nonlinearly mapped to an output signal. if an output signal was over the threshold value, it was possible to determine the abnormal increase in the number of cases in the early stage of the disease epidemic. this study enriches the existing early warning theory of infectious diseases to further excavate the application potential of public health big data and increase the level of analysis and prediction of the condition of infectious diseases. the numbers of new confirmed cases of eight types of infectious diseases reported per month between january and december were obtained from the center for national public health scientific data (http://www.phsciencedata.cn). this center only collected data until [ ] . data between january and december were obtained by consulting the national health commission website (http://www.nhc.gov.cn/) [ ] . based on this objective fact, we selected the recurrent neural network model for analysis. the socalled recurrent network indicates that the network uses the output produced after one input as an intermediate variable, which is used as a part of an input layer together with the next input vector for continuous calculation. the recurrent neural network continuously receives input signals; therefore, it is called the dynamically driving recurrent neural network. targeting this model, we used rtrl and ekf to estimate the synaptic weights of the network [ ] . the rtrl learning algorithm indicates that the adjustment of synaptic weights of a fully connected network is real-time. figure a shows that the recurrent network was composed of q neurons and m external inputs. the network had two different layers: the concatenated input-feedback layer and the processing layer for calculating nodes. accordingly, the synaptic connections of the network were also composed of feed-forward and feedback connections. because four types of respiratory and four types of digestive tract infectious diseases were included, the value of m was . the number of neurons, q, in the processing layer was also set to . the output of the network was the last neuron in the processing layer. in addition, the numbers of new confirmed cases of the four types of infectious diseases were used as inputs in the model. because the numbers of cases of different diseases might have correlations and seasonal fluctuations [ ] [ ] [ ] [ ] [ ] [ ] , they were standardized in advance. after standardization was completed, the average value of each input variable should be approximately zero, there should be no correlation between variables, and covariances should be approximately equal. since the learning process in this study was supervised learning, the expected responses of the network should be determined. we calculated the cumulative probabilities of training samples under a multivariate normal distribution. these probabilities were arranged from low to high, and the % quantile was used as the threshold value. all neurons were set to have the same activation function, and a sigmoid odd function in the form of a hyperbolic tangent equation was used as the activation function. the parameters of this function were set to appropriate values such that the expected responses of the network were and − [ ] , which denoted over the threshold value and lower than the threshold value, respectively. furthermore, when the test samples were identified by our network, we consider that an early warning signal will be generated once the output value of the network is greater than zero. moreover, in terms of the learning rate, we selected search-then-converge scheme [ ] . respiratory and digestive tract infectious diseases were separately calculated using sets of numbers of cases between and as the training sets and sets of numbers of cases in as the test set. based on the recurrent network established in figure a , the idea of the sequential state estimation was used to divide the network state space under training into the actual state and the measurement state of the system [ ] . the former could not be directly observed; instead, a set of observation values was measured indirectly to estimate the actual state of the system. the entire set of synaptic weights of neurons was used as the actual state of the system. the value that measured whether the current condition of infectious diseases was at a normal level, i.e. expected response, was used as the observation state of the system. the vector activated by recurrent nodes of the network and the input vector used as the driving force together formed the input signal. the activation function was the same as that in rtrl. therefore, the process of mapping from the input space to the output space was also nonlinear. this task was finished using ekf. figure b displays the basic framework of this algorithm. w n indicates the synaptic weights of the network at the nth time step, which was the state vector of the system. it and dynamic noise together form the state vector of the next time step of the system. the recurrent node activation vector, input vector and state vectors in the system were mapped to the output layer under the function of the nonlinear measurement function. the output vector was influenced by multivariable white noise to form the observable state of the system. the specific model establishment process is shown in the electronic supplementary material. the above algorithms are shown in the electronic supplementary material. figure b shows the time distribution of the four types of digestive tract infectious diseases. they all showed obvious seasonal fluctuations. except for hepatitis e, which had a high incidence in the spring, the other digestive tract infectious diseases all had high incidences in the summer. in addition, except for hepatitis e, the numbers of cases of the other three infectious diseases all showed a decreasing trend year by year. the model was trained after epochs, then the synaptic weights of the network were determined, and data from was used to validate model performance. figure a shows the early warning results of respiratory infectious diseases between january and december of . the rtrl results showed that the number of cases in september was significantly higher than the historical level; although the early warning value in july was higher than zero, the increase in the number of cases was not significantly different from the historical level. the ekf results showed that the numbers of cases in january and february of were significantly higher than the historical level. figure b shows the early warning results of digestive tract infectious diseases. both algorithms showed that the number of cases throughout all of was not significantly higher than the historical level in the same period. figure shows the time distribution of the numbers of cases of the four types of respiratory infectious diseases in the same historical period when the early warning signal was issued. the results showed that the major reason for issuing the early warning was the increase in influenza and mumps cases. particularly in january and february of , a nationwide influenza pandemic occurred in china, which caused a significant increase in the number of influenza cases [ ] . analyses of surveillance data using early warning models are used to eventually make a decision on whether the epidemic is increasing abnormally. two types of calculating principles are employed for commonly used early warning models. one type is the calculation of the threshold value of statistics under a certain confidence level based on some specific statistical distributions and previous surveillance data; if the current statistical level obtained from actual measurement values is higher than the threshold value, the early warning signal is issued. the other type is the calculation of the expected number of cases based on specific statistical distributions and previous surveillance data; when the actual value is higher than the expected value, the early warning signal is issued [ ] . for example, some classical warning approaches, such as the exponential smoothing model, poisson regression and the arima model, that follow the above ideas have been effectively applied and constantly improved to increase the accuracy of early warning [ ] . the innovation of this article is that we broke through the traditional thinking framework. we did not calculate the threshold value or the expected number of cases; instead, the system itself calculated the epidemic intensity and made the decision on whether to issue early warning signals. the neural network has the characteristics of continuous optimization through self-iteration; therefore, when there are more training times on the system, its decision will be more accurate and the system will present a certain intelligent type. furthermore, this method can be used not only to consider multiple types of infectious diseases at the same time, but also to analyse multivariate data, such as the number of patients in outpatient clinics, drug consumption data in hospitals and sales data for over-the-counter drugs in pharmacies. by analysing the complex relationship among multiple factors, we can judge the law of disease development and changes comprehensively. both respiratory and digestive tract infectious diseases have different epidemic patterns in different seasons. the former mainly has epidemics in the winter and spring and the latter mainly has epidemics in the summer. therefore, the standardized processing of input vectors of the model should consider the influence of seasonal factors. according to the epidemic patterns of infectious diseases, we believed that vectors consisting of the numbers of cases of the four types of respiratory infectious diseases or the four types of digestive tract infectious diseases in every month all conformed to the multivariate normal distribution; in addition, the average vector and covariance matrix in every month also differed. after the standardized processing of all input vectors, the influence of seasonal factors on this model could be eliminated. we used month as a unit to perform analyses on the numbers of cases in this study. to improve the timeliness of early warning, week or day can be used as the unit for analysis. the average vectors and covariance matrix should also be adjusted accordingly. the level of the threshold value could be adjusted according to the actual condition. when the threshold value was higher, the number of cases necessary to issue an early warning was higher; when the threshold value was lower, the result was the opposite. the learning rate determined the convergence rate of the network model. if the learning rate was a constant number, the convergence rate was slower. if the learning rate was a constant divided by the times of iteration, although the convergence of the stochastic approximation algorithm could be ensured, fewer iteration times might have the risk of parameter amplification when the constant value was higher [ , ] . therefore, we chose the search-then-converge schedule as the commonly used learning rate annealing programme in online learning. it had the advantage of combining the expected characteristics of the model with the traditional stochastic approximation theory [ ] . in this study, the numbers of cases of some types of infectious diseases were used as the input variables in the model to make an early warning decision through comprehensive analysis. therefore, an early warning was issued only when the numbers of cases of these infectious diseases showed an overall increase and exceeded the threshold value. however, it was not necessary to issue an early warning only when all numbers of cases increased. figure shows that when the system issued an early warning, the numbers of measles and rubella cases not only did not increase but also were at lower levels compared to the historical level in the same period. the model made the decision on the high incidence of respiratory infectious diseases after the numbers of influenza and mumps cases increased. therefore, we should perform the analysis on the actual number of cases of each infectious disease based on the model result to determine which infectious disease epidemic caused the early warning. if the model did not issue an early warning, then it could not indicate that the number of any infectious disease cases did not increase significantly. thus, during the analysis of the epidemic, we should assess actual data for a detailed analysis. if the analysis was performed only based on the results of the model, it would be possible that the number of some infectious diseases already significantly increased but the model did not timely issue an early warning, thus causing delay in the timing of prevention and control. according to figure , we found that the proportion of the same results according to the two algorithms is . % ( / ), indicating that their decisions regarding the epidemic trend of diseases were similar. different results occurred in january, february, july and september of . according to figure a ,b, only the numbers of influenza cases in january and february of greatly increased compared to that in the historical periods; conversely, the numbers of cases of the other three infectious diseases all remained at lower levels. figure c shows that the numbers of mumps and influenza cases slightly increased in september . at these three time points, the results of these two algorithms differed. these results indicated that although the numbers of cases increased, the overall results were not significantly higher than that in the same historical periods. the early warning value of rtrl in july was slightly higher than zero; thus, we ignored its early warning significance. to increase the sensitivity of early warning, these two methods could be used simultaneously for analysis and determination of the epidemic intensity of the disease through a comparison of early warning results between these two algorithms. in this study, we selected eight types of infectious diseases with a higher incidence for analysis. these two models are not applicable for diseases with lower incidences such as anthrax, cholera and the plague; therefore, other methods are necessary for early warning [ ] . because the chinese notifiable infectious diseases surveillance and report system began to operate nationwide in [ ] , only disease data in the recent years could be obtained. the sample size of the training set was small, which may have influenced the calculation results for synaptic weights in the model to a certain extent. this study only references a new modelling approach and was limited in its scope in terms of validation. future work will be focused on gathering more data and cases and providing a more comprehensive model validation. furthermore, we evaluated the epidemic intensities of infectious diseases in the entire nation. however, infectious disease epidemics, such as dengue fever and malaria, might be limited to a certain area, or they may spread throughout the entire country after an outbreak in a certain area, such as sars and h n influenza a. if analysis and judgement were performed only based on the national data of these diseases, prevention and control of the epidemic would usually be delayed. therefore, this model should be implemented in every province and every city to increase the timeliness of early warning of infectious diseases all over the country. in addition, real-time multivariate analysis is currently one of the research focuses in the field of early warnings for diseases, including multistatistical process control, biological change-point detection and some others [ ] . since the application of artificial neural networks in the field of early warnings for diseases is relatively new, further research is required to achieve greater precision. ethics. since there is no experiment of humans and animals in the study, we did not require review by the ethical institutional review board or written informed consent. data accessibility. the raw data required for this study are available in the electronic supplementary material. authors' contributions. z.g. conceived of the study, designed the study, analysed the data and drafted the manuscript; k.h. provided guidance regarding the algorithm; d.x. revised the manuscript and provided comments. all authors gave final approval for publication. competing interests. all authors declare no competing interests. funding. this work was supported by the national science and technology major project (grant no. zx ) and the national key r&d program of china (grant no. yfc ). establishing a web-based integrated surveillance system for early detection of infectious disease epidemic in rural china: a field experimental study world health organization. licence: cc by-ncsa . igo the epidemiological characteristics and 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surveillance data dynamic mortality risk predictions in pediatric critical care using recurrent neural networks. dynamic mortality risk prediction neural networks and learning machines chinese information system for infectious diseases control and prevention seasonal pattern of influenza activity in a subtropical city modeling seasonal measles transmission in china explaining seasonal fluctuations of measles in niger using nighttime lights imagery seasonality of hepatitis: a review update seasonal dynamics of typhoid and paratyphoid fever high mean water vapour pressure promotes the transmission of bacillary dysentery a stochastic approximation method stochastic approximation methods for constrained and unconstrained systems towards faster stochastic gradient search acknowledgements. we would like to thank american journal experts (www.aje.com) for english language editing. royalsocietypublishing.org/journal/rsos r. soc. open sci. : key: cord- -rt i wca authors: tosam, mbih jerome; ambe, j. radeino; chi, primus che title: global emerging pathogens, poverty and vulnerability: an ethical analysis date: - - journal: socio-cultural dimensions of emerging infectious diseases in africa doi: . / - - - - _ sha: doc_id: cord_uid: rt i wca in the last few decades, the world has witnessed the emergence and re-emergence of new and old infectious diseases. emerging infectious diseases (eids) have the capacity to spread rapidly from one region of the world to another, within a very short time, due to world travel and increased global interdependence. the impact of this varies from one region to another. resource poor countries suffer the most due to an already high disease burden, poor infrastructures, lack of clean, potable water and sanitation, as well as an acute shortage of qualified health personnel to manage, control and contain the crisis/spread. poor and marginalized communities are the most vulnerable because infectious diseases cause not only suffering and death, but also severe economic hardship. the outbreak of hiv/aids, tuberculosis and ebola virus disease (evd) in the developing world has shown the extent to which economic and social conditions can affect vulnerable populations. these socio-economic, cultural and environmental conditions accelerate the spread of, and exacerbate the negative impact of emerging pathogens. this chapter will undertake an analysis of the trend in global emerging pathogens, their economic impact, the global vulnerability status and ethical implications. better tackle these diseases and prevent them from assuming epidemic and pandemic levels. socio-economic, cultural and environmental conditions play a fundamental role in the emergence, spread and control/management of eids. in poor communities, a large part of the population live in overcrowded and squalid conditions. in these communities, mostly in the major cities of developing countries, there is a lack of clean drinking water, poor hygiene and sanitation. this environment creates opportunities for waterborne diseases and different forms of pollution. it is in the slums of the main cities of developing countries that most eids begin and spread and it is also in such areas of the cities that the greatest number of deaths are usually recorded. infectious diseases like ebola, hiv, tb, usually spread easily and widely from poor communities in emerging cities and through health workers who serve such communities. hence, poverty creates a favourable condition for the spread of infectious diseases and makes it difficult for affected people to get adequate access to prevention and care (who a, b) . the journal of infectious disease of poverty was launched in with the principal aim of fostering "interdisciplinary and transdisciplinary research that explicitly highlights the intersection of poverty and other ecological factors with disease" (xia et al. ) . in this chapter, we critically examine the socio-economic and environmental factors that influence the emergence and spread of eids and discuss the ethical issues that arise from the global response and management of eids. globally, the trend in the outbreak of eids has been increasing. jones et al. ( ) analysed the trend of eids events from to , identifying a total of eid events. they found that during this period, the number of eid events ranged from just over between and to close to events between and , with a peak of close to events between and as shown on fig. . . this peak was associated with the hiv/aids pandemic. this increasing trend in eid mirrors the overall global trend in all human infectious diseases. for instance, smith et al. ( ) found that within a -year dataset , , outbreaks of human infectious diseases were reported, with more than million cases occurring in nations. emerging infectious diseases are distributed all over the world, although their rate of emergence and spread varies from one setting to another. farmer ( ) observed that their emergence and spread appear to be high in areas with huge social inequalities. additionally, eids are more common in areas rich in wildlife and zoonotic pathogens from wildlife while vector-borne pathogens are more concentrated in lower latitudes, such as tropical africa, latin america and asia (jones et al. ). also, specific eids appear to be common within certain geographical regions. for example, evd has mainly been in sub-saharan africa while the zvd has been largely limited to the americas, situations which might be associated with the geographical location of the vectors that spread the disease. different authors have developed global maps highlighting the areas where eids have originated or are most likely to originate. these areas have been described as eid 'hotpots'. one of those maps has been developed by morse and colleagues, and illustrates the risk of emergence of infectious diseases originating from wildlife as shown in fig. . below (morse et al. ). the emergence of these diseases is driven by socio-economic, environmental and ecological factors (jones et al. ). the major factors include ecological changes (including those due to economic development and land use), human demographics, behaviour, international travel and commerce, technology and industry, microbial adaptation and change, and breakdown in public health or control measures (morse ) . examples of specific factors affecting infectious disease emergence is shown on table . . there is a direct correlation between poverty and the emergence of infectious diseases which can be seen through different factors. for instance, the ecological footprint left by humankind is evident by the direct impact on the land, air and water of a specific area or region, used to sustain the depletion of natural resources for an individual or a community. among the eids of zoonotic origin that make up more than % of all eids, evidence suggests that between and their emergence was largely attributed to changes in land use ( %), human susceptibility to infection ( %), intensification of agricultural practices ( %), and changes in the food industry ( %) (keesing et al. ) . a combination of 'other' factors (international travel and commerce, changes in human demographics and behaviour, changes in the medical industry, climate and weather, breakdown of public health measures, and unspecified causes) accounted for % of the drivers. figure . shows the global percentage of emergence events caused by each driver (a) and the countries in which the emergence events took place, and the drivers of emergence (b) from to (keesing et al. ). this study found that a decrease in the diversity ecosystem that is associated with changes in land use, changes in agricultural and other food production practices such as wildlife hunting, which has led to increasing contacts between humans and other animals has facilitated the emergence of infectious diseases of zoonotic origins (keesing et al. ). there is a close nexus between poverty and infectious diseases. poverty has provoked a wave of rural urban migration of people in search of new opportunities, which has led to population explosion in the major cities of most developing countries. the result of this has been the growth of slums and expanding cities with "new opportunities for infectious diseases to flourish and spread" (eisenstein ) . the concentration of people in squalid conditions leads to waterborne diseases and different forms of pollution. also, the magnitude and pace of the spread of infectious diseases is usually influenced by overcrowding in tandem with poor hygiene and examples of specific factors relationship to poverty ecological changes (including those due to economic development and land use) agriculture, dams, changes in water ecosystems, deforestation/reforestation, flood/drought, famine, climate change due to poverty, humans may move into new areas (eg. in search of food or shelter -forest clearing for agriculture, wildlife hunting) where there is a higher likelihood for infection. for example forest clearing and wildlife hunting exposes humans more to wildlife that may serve as reservoirs for these infections human demographics, behaviour societal events: population migration (movement from rural areas to cities), war or civil conflict, economic impoverishment, urban decay, factors in human behaviour such as the commercial sex trade, intravenous drug use, outdoor recreation, use of childcare facilities and other high-density settings growing urbanisation or conflicts, may force humans, especially the poor into behaviours (risky sexual habits) that may increase the likelihood of mergence and spread of infectious diseases. worldwide movement of goods and people, air travel increasing international travels to major international cities may increase the cost of living and force poorer individuals to areas where there is increased contact with eid vectors or engage in risky behaviours that may lead to infectious disease emergence/ re-emergence technology and industry food production and processing: globalisation of food supplies, changes in food processing and packaging poverty may cause poorer people to sell their organs which may decrease their immunecompetence and enhance the re-emergence of infectious disease health care: new medical devices, organ or tissue transplantation, drugs causing immunosuppression, widespread use of antibiotics microbial adaptation and change microbial evolution, response to selection in the environment poorer people are more likely to be engage in self-prescription of antibiotics due to the cost associated with seeing a qualified health professional. such practices might increase the re-emergence of eids associated with antibiotics resistance. (continued) sanitation. for example, it is reported that the recent ebola outbreak in west africa spread widely and rapidly in densely populated and highly mobile, urban slums in cities like monrovia and conakry (eisenstein ) . it was particularly among poor people in the slums, who lacked basic hygiene and sanitation infrastructure in the cities, that there was a serious outbreak. the un-habitat estimates that million people-one-third of the developing world's urban population live in slums. most slums do not have access to safe and clean drinking water and where there exist, it is usually easily open to contamination. these conditions are favourable for the spread of diseases such as cholera, a bacterial diarrhoea and typhoid infections which are transmitted through food and water. for instance, cholera outbreaks were almost an annual occurrence in the northern part of cameroon during the past years. what accounts for this is extreme water shortage and climate variability, poor sanitation, poor drainage systems with no toilet facilities, in some areas, so that during the rainy season, water carries all human and animal waste into the main sources of water for household use. in some parts of this region, humans and animals depend on the same source of water (nfor ) . this exposes the people to waterborne and food related diseases like cholera and typhoid. moreover, the "urban poor" usually travel far and wide in search of work, greatly increasing the areas that could be affected by the virus and making contact tracing very difficult (eisenstein ) . in slums, there are small ponds, abandoned vehicles, tyres and plastic waste which serve as ideal habitat for the insects that spread dengue and yellow fever as well as malaria. improvement in living conditions-less crowding, fewer animals and higher quality homes and education may help reduce the possibility of people contracting and spreading infectious diseases. in addition to the aforementioned factors, high burden of disease, fragile health systems and socio-economic disparity aids in the proliferation of disease vectors and increases vulnerability which can be seen in the patterns of global warming on the african continent. the earth has an ecological system that is comprised of biospheres that are interconnected and rely on each other. once that is interrupted, for instance, with migration, this disrupts the balance of the biospheres and adds to the burden of this disruption and environmental decay (abayomi and cowan ) . other factors are increased temperatures, rising sea levels, and increased air pollution. these adverse climatic conditions cause food and waterborne diseases as well as regular ruthless natural disasters (tosam and mbih ) . moreover, circumstantial evidence shows that deforestation may have played a role in the west african ebola epidemic of / . the index case for the west african ebola virus disease outbreak, lived in a district known as maliandou, in a village called guéckédou, in guinea-conakry (marí saéz ). this area is known as the forest region, however only approximately % of the trees are still standing. the area has lost most of the vegetation due to the mining of iron ore, bauxite, gold and aluminium (marí saéz ). wild animals have lost their ecosystems and many use the roofs of thatched huts to nest, living in closer proximity to the villagers. the few remaining trees, are colonized by bats and other animals. it is thought that the insectivorous bats in the hollowed-out tree, in the yard of the index case, may have been the reservoir for the ebola virus, zaire strain (ebov). research shows that this particular species (mops condylurus) are able to survive infection by ebov (marí saéz ) . amongst the first twelve evd cases, none were hunters and the index case, was a toddler which led epidemiologists to believe that domestic spaces were in danger for the spread of the disease. clearly, close living proximity between the bats and the people of the village provides circumstantial evidence of the mode of transmission of this disease, given the issues with deforestation (borchert et al. ) . while eids have contributed to exacerbating global health inequalities, inequalities in socio-economic conditions globally have arguably also contributed to the emergence and re-emergence of infectious diseases. as has been demonstrated in the earlier sections, developing regions (mostly low and middle-income countries) and impoverished communities and people tend to bear the brunt of eids and it negative impacts. considering the prevailing situation, it would be expected that any efforts in managing the emergence and re-emergence of infectious disease would place more attention and resources in addressing the root causes, especially in developing and low-resource countries. additionally, one will expect that countries and regions with relatively lower capacity to detect these diseases should receive more attention as the pace with which disease outbreaks are recognized is critical for establishing effective control efforts (kluberg et al. ) . however, existing evidence suggests that global resources devoted to countering the emergence of infectious diseases are poorly allocated, with the majority of the scientific and surveillance effort focused on countries from where the next important eid is least likely to originate (jones et al. ). this raises serious ethical issues as it would be expected that for a more effective global response to the prevention and control of eids, more resources should be channeled to regions and countries with the greatest risk of experiencing the emergence of these diseases. due to our shared elements of vulnerability, there is an urgent need for international cooperative endeavours to promote and preserve health since eids know no geographical and economic borders. in the past, vulnerability to eids and other health challenges was defined by geographic location and economic factors, but because of the high level of international interactions and movement of persons and goods across borders, this is no longer the case. and since those in affluent countries benefited from the accident of geography and climate as well as efficient health infrastructures which protects them from many threats to eids, it is difficult for many to identify with vulnerable people in poor countries. on the contrary, poor people, as a result of their geographical location (mostly in tropical regions) with harsh climatic and economic situations, weak and inefficient health infrastructures; lack access to the health goods needed to prevent them from eids (west-oram and bux , ). however, because of globalization and climate change, the tides are changing and vulnerability is being redefined. today, protection or exposure to eids and other tropical diseases is no longer determined by geographical location or economic situation; "all persons are increasingly united in their vulnerability to emerging threats" (west-oram and bux , ). there is need for global cooperation and solidarity between the affluent and poor nations. this can only be effective if both parties identify with each other and acknowledge their shared vulnerability. for example, with the ease in international air travels, an eid in sub-saharan africa (ssa) or asia can reach europe or the usa within a couple of hours. the recent evd and zika virus pandemics have firmly revealed the extent of global vulnerability and response to eids. while evd-infected expatriate health personnel were flown to their countries for treatment, local evd-infected health personnel were not accorded such treatment. this attitude was motivated by the failure to recognize the similarity between citizens in rich and poor countries which emerging health threats has exposed us to in our increasingly interconnected interdependent world. it further reflects the discrepancy that existed in international health in the past which does not longer hold today. this calls for a paradigm shift from the charity-based approach to a solidaristic one (west-oram and bux , ) . an approach that acknowledges our global interdependence and shared vulnerability to global health threats such as eids; and recognizes that if a neighbour's home is on fire, efforts must be made by all to put off the fire, otherwise it may spread and consume more homes (including ours) that may even be further away from the initial home on fire! in fact, the who has proposed solidarity as one of the key ethical principles in the management of infectious disease outbreaks globally (who ) . this principle justifies engagement in collective action in the face of common threats such as eids, while supporting efforts to overcome inequalities that undermine the well-being of minorities and groups suffering from discrimination. one potential application of this principle globally is the provision of financial, technical, and scientific assistance by high income and developed countries to low-income and impoverished countries to boost their capacities to prevent and manage ongoing and future eids. this is in fact one of the obligations of governments and the international community in the who 'guidance for managing ethical issues in infectious disease outbreaks' (who ) . therefore, ensuring support for low resource and poorer countries in the prevention and management of eids through global solidarity, global health will also be enhanced by reducing the risk of eids spreading to other countries. this can be achieved through strengthening lmics' capacities to adopt and effectively implement the international health regulations, a legally binding instrument of international law that aims among others to assist countries to work together to save lives and livelihoods endangered by the international spread of diseases and other health risks. it is expected that affluent countries have a moral responsibility to support or sponsor research for neglected tropical diseases as well as emerging infectious diseases, and the countries and regions most affected need to take the lead in responding to and in contributing resources to support affected persons, not only as a duty, but on the basis of rational self-interest. moreover, solidarity does not require that only the rich should identify with the poor; it involves identifying with all persons be they rich or poor. for example, during evd outbreak in west africa in - , most african countries and the african union were sluggish in taking the lead in the fight against the disease (metz ) . by the time western countries had pledged billion us dollars, african countries had barely managed to raise $ . .cuba, alone, had sent more than health workers whilst the au had just started deploying only medical personnel (metz ) . developing countries are usually ill-prepared to monitor, prevent and manage the outbreak of these diseases. in this chapter, we have shown that there is an inextricable link between socioeconomic, cultural and environmental conditions and the emergence or re-emergence of eids. eids have contributed in exacerbating global health inequalities as most areas where eids are common are also areas that experience lack of access to basic life-saving and preventive medicines. for any fight against these diseases to be successful, mechanisms must be put in place to redress these determinants as well as bring together the intellectual, financial and health resources of the world for all, especially people from low and middle-income countries where the local capacity to appropriately manage eids is relatively weak. this is because in our interconnected and interdependent world, no individual, group or nation is insulated from the threats of eids. it is important that rich countries play a fundamental role in dedicating resources and increasing funding for research in capacity-building and drugs for eids in developing countries, not only because their own populations are also vulnerable to eids, but also for the sake of global solidarity. also, the countries where eids are more likely to occur and those whose capacity to effectively manage eids is weak, must also play a leading role in addressing the socio-economic, cultural and environmental conditions which facilitate the emergence and spread of infectious diseases. open access this chapter is licensed under the terms of the creative commons attribution . international license (http://creativecommons.org/licenses/by/ . /), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence and indicate if changes were made. the images or other third party material in this chapter are included in the chapter's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the chapter's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. the hiv/aids epidemic in south africa: convergence with tuberculosis, socioecological vulnerability, and climate change patterns a closer look at the ebola outbreak in west africa disease: poverty and pathogens social inequalities and emerging infectious diseases global trends in emerging infectious diseases impacts of biodiversity on the emergence and transmission of infectious diseases global capacity for emerging infectious disease detection identification and diagnosis of newly emerging pathogens how to deal with neglected tropical diseases in the light of an african ethic factors and determinants of disease emergence. revue scientifique et technique-office international des epizooties prediction and prevention of the next pandemic zoonosis recurrent cholera outbreak in far-north cameroon highlights development gaps investigating the zoonotic origin of the west african ebola epidemic climate change, health, and sustainable development in africa guidance for managing ethical issues in infectious disease outbreaks. geneva: world health organization social determinants of health: social exclusion combating infectious diseases of poverty: a year on key: cord- -aoz jbf authors: bartlett, john g. title: why infectious diseases date: - - journal: clin infect dis doi: . /cid/ciu sha: doc_id: cord_uid: aoz jbf infectious diseases is a broad discipline that is almost unique in contemporary medicine with its ability to cure and prevent disease, to identify specific disease causes (microbes), and to deal with diverse, sometimes massive outbreaks. the value of the infectious disease practitioner is now magnified by the crisis of antibiotic resistance, the expanding consequences of international travel, the introduction of completely new pathogen diagnostics, and healthcare reform with emphasis on infection prevention and cost in dollars and lives. infectious disease careers have great personal rewards to the practitioner based on these observations. it is unfortunate that we have been so effective in our work, but relatively ineffective in convincing the healthcare system of this value. students of medicine have multiple career options with various attractions and concerns. so it is with the discipline of infectious diseases. as with all medical specialties, infectious diseases has unique features that are important to highlight: among medical specialties, this one is consistently changing, often unpredictable, usually exciting, and incredibly rewarding for health impact. it is also often challenging and seemingly underappreciated, at least until needed. these facts appear to be relatively idiosyncratic to this discipline with a menu of priority pathogens that is in constant flux and weaponry that will change in unpredictable ways. the extraordinary kinetics and ability to intervene successfully using public health, preventive vaccines, and disease-limiting antimicrobials are its great strengths. the following are some of the highlights and unique features of a career in the science and practice of infectious diseases. the menu includes the litany of epidemics, heroic efforts to conquer disease, our expectations with antimicrobials, vaccines and public health, and challenges that may lead to transformative interventions. the field of infectious diseases is kinetic, unpredictable, and layered with surprises that sometime require heroic efforts from a diverse field of scientists and practitioners. • on october , a patient with fever and confusion was seen at a florida medical center by dr larry bush, an infectious disease physician. he examined the cerebrospinal fluid, saw boxcar gram-positive rods, diagnosed anthrax, and predicted bioterrorism [ ] . this was strong stuff at a time no one had thought much of bioterrorism anywhere in decades and especially in an obscure, small town in florida. the ensuing epidemiologic investigation showed anthrax spores in this patient's workplace, the local postal service, and a letter received by the patient. this was the index case of the anthrax bioterrorism epidemic that shook the country in .the result was a major national preparedness response to not only bioterrorism, but also preparedness for natural disasters, epidemics, and other major public health threats. • in , dr alan steere, a rheumatologist from yale school of medicine, led an investigation of an outbreak of arthritis involving children and adults in connecticut. most of the patients had asymmetric swelling and pain of large joints, especially knees, and some also had an erythematous, annular rash [ ] . it was initially called "lyme arthritis," but most physicians thought it was simply juvenile rheumatoid arthritis. dr steere was convinced it was an infection and moreover, that it was arthopod-born based on epidemiology and clinical features. his relentless pursuit of the pathogen was finally rewarded with the discovery of the newly recognized spirochete in the blood and in typical skin lesions [ ] . the specific agent was subsequently defined in a another extraordinary effort, this time by dr willie bergdorfer, who had spent much of his career studying the microbiology of the hindgut of ticks; he successfully isolated the pathogen that he considered his last and most important scientific project [ , ] . that agent is named in his honor: borrelia burgdorferi [ ] . • dr robin warren, a pathologist in australia, made the historic discovery that gastric biopsies from patients with gastritis showed a large burden of curved bacteria. no one paid attention until a young gastroenterologist, dr barry marshall, agreed to study the association. this pairing was considered an "odd couple"; dr warren was described as quiet, thoughtful, and persistent whereas dr marshall was self-described as brash and determined [ ] . subsequent studies consistently showed the association between this curved microbe with gastritis and peptic ulcer disease, but there was almost uniform opposition from both gastroenterologists and infectious disease physicians. larry altman, noted medical editor for the new york times, wrote that never in his experience had he witnessed such fierce opposition from the medical community to the possibility that peptic ulcer disease was caused by a microbe (l. altman, personal communication, may ) [ ] . this prompted proponents, drs barry marshall and alan morris, to perform the ultimate experiment-they swallowed a flask of helicobacter pylori (and suffered from the experience; l. altman, personal communication, may ) [ ] . the long-term result of this unrelenting battle is now well known: h. pylori is accepted as the cause of peptic ulcer disease and its sequela, guidelines for diagnostic testing and treatment are based on h. pylori as the pathogen, this agent is listed as a class carcinogen, and nobel prizes were awarded to drs warren and marshall [ ] . • in early september , dr april pettit, an infectious disease physician in tennessee, saw a patient with aspergillus meningitis following an epidural steroid injection [ ] . this prompted her to notify dr marion kainer at the tennessee health department, who then set up shop with a sleeping cot in the health department to facilitate a nonstop investigation [ ] . this was the beginning of the infamous national epidemic of exserohilum rostratum meningitis associated with the contaminated steroids that led to cases and deaths in states. credit here is to dr pettit for recognition and prompt notification, to dr kainer for her aggressive response on behalf of the victims, and to the centers for disease control and prevention (cdc) for the hasty intervention. (somewhat disappointing is the fact that compounding pharmacies are still unregulated.) • in , dr anthony fauci read the july edition of morbidity and mortality weekly report [ ] describing gay men with kaposi sarcoma or pneumocystis carinii pneumonia in california. for the first time in his life, dr fauci had what he called "chill pimples" ("chill bumps"), and this led to a career change to find the cause, treatment, and prevention of aids. this must be now viewed as possibly the most remarkably successful attack on an important infectious disease since fleming discovered penicillin. • in february , severe acute respiratory syndrome (sars) was a newly described, severe disease in humans that was often fatal and appeared to travel by air routes, but had no established pathogen or treatment. dr klaus stohr at the world health organization (who) identified the finest virology laboratories in the world and asked them to collaborate to define the pathogen with the condition that all information would be shared on the internet and there was no ownership of the data. the participating labs with varying skills were spread throughout the world, so the daily conference calls started with "good morning, good afternoon, and good evening." the etiologic agent was described in an unauthored "global alert" on april and in the lancet with "multicentre collaborative network" as the authors (see [ ] ). this unselfish collaboration under strong leadership is credited with the rapid solving of a global crisis that eventually showed cases with deaths in countries. • these anecdotal experiences (bioterrorism, lyme disease, peptic ulcer disease, iatrogenic fungal meningitis, human immunodeficiency virus [hiv]/aids, and sars) illustrate the unpredictable challenges and some of the unique responses that have left a major imprint on medicine. it is noteworthy that all started with strong leadership and came to closure with either elimination or successful management. epidemics of infections are predictable to occur, but largely unpredictable in time, place, microbe, and consequences. the following highlights some of the recent epidemic records and surprises in this category: • west nile virus was first reported in new york city in and reached a -year zenith for reported cases in with cases, including % with the dreaded neuroinvasive form of the disease [ ] . • coccidioidomycosis: the total number of reported cases increased -fold in years, from in to in [ ] . • malaria reported in us travelers reached a record high of cases in [ ] . • chikungunya virus reached a record number of cases in the caribbean with > reported cases, including in us travelers to st martin [ ] . this pathogen is highlighted because global warming is expected to make it endemic in the southern united states and because of its substantial morbidity with possible long-standing arthritic complications [ ] . • measles: the largest number of annual reported cases in the united states in years was noted during - . it now appears that will be worse [ ] . measles was declared eradicated in but has now become a problem, primarily in those refusing vaccination, but also in some with documented vaccination [ ] . measles continues to be an important infectious disease challenge due, in part, to the extraordinary public health issues that cost one health system $ to deal with the potential epidemiologic consequences of a single case [ ] . • pertussis: this infection is resurgent in the united states and europe, with increased cases including epidemics in children and adults and involving both vaccinated and unvaccinated individuals [ ] . this is thought to reflect waning immunity to the acellular vaccine and the need for a new vaccine [ ] . • meningitis: - reporting showed outbreaks of neisseria meningitidis meningitis, on college campuses and among gay men in new york city and los angeles [ ] . • influenza: this is a continual concern based on the everpresent threat of pandemics with devastating consequences ( - , - , - , - , - ) that seem difficult to predict or control [ , ] . limitations of current expertise were illustrated with influenza a(h n ) swine flu, as the standard concept based on historic precedent is that new influenza epidemics come from asia in the wintertime, but this one came in the eastern hemisphere in the summertime [ ] . the more recent threats that could pose serious consequences are influenza a(h n ) and influenza a(h n ) [ ] [ ] [ ] . both show high mortality rates, but little evidence so far of that single critical mutation permitting attachment to the hemagglutinin antigen to permit sustained person-to-person transmission [ ] . • middle east respiratory syndrome (mers) coronavirus: this coronavirus is a major global concern with analogies to the sars coronavirus in terms of its perceived potential to become a global epidemic with high mortality and no apparent treatment [ , ] . of immediate importance in the united states is recognition of risk with appropriate diagnostic testing, isolation, and management of persons with severe, unexplained pneumonia associated with recent travel to the arabian peninsula (mers) [ ]. • foodborne disease: widespread foodborne epidemics are now a common consequence of the massive food distribution system that permits contaminated beef or lettuce from mexico to reach stomachs in distant multistate areas, with medical consequences involving hundreds or thousands of people. this includes the more recent emergence of the gii. sydney strain of norovirus. these outbreaks seem likely to continue, with unpredictable pathogens in unpredictable places [ ] [ ] [ ] . • heartland virus: a recently encountered tick-borne disease in tennessee and missouri with cases and deaths [ ] . • polio-like virus infection with extremity paralysis has been recently reported in and possibly children in california [ ] . • ebola virus: who has reported an outbreak in guinea involving a new clade of this usually fatal infection [ ] . this listing could continue almost indefinitely. the point is that epidemics are the domain of infectious diseases and public health, with the expectation for management or prevention of outbreaks with requirements for detection, reporting, isolation, and case management. the listing here includes diverse pathogens, some life-threatening diseases, infections with important public health implications, an upsurge of pediatric infections in adults, many travel-related infections, multiple public health threats, and the continuous concerns for influenza and foodborne disease. the major weaponry of the infectious disease catalog includes antibiotics, vaccines, and public health. these categories are remedial reading, but some facets are worthy of emphasis. the value of antibiotics seems obvious. the first patient to receive penicillin was a young woman with β-hemolytic streptococcal bacteremia with fever of . °c- . °c daily for weeks. she received penicillin intravenously starting march , promptly recovered, and survived to age years [ ] . this would appear to be "evidence-based medicine" with an n = . the following statement from dr walsh mcdermott in summarizes this breakthrough especially well: "penicillin gave more curative power to a barefoot, itinerant care provider in the deepest reaches of africa than the collective powers of all physicians in new york city" [ ] . the more recent experience with bacterial resistance and sparse pipeline threatens this miracle, but antiviral development is quite different, primarily for hiv and hepatitis c virus (hcv). it now appears that patients with hiv can achieve near-normal longevity [ ] . hcv infection is even more impressive in terms of speed of progress and ability to cure. the hcv treatment story reflects the efficiency of basic science to define targets, pharmaceutical skills of industry, well-organized trial networks, and a regulatory agency (us food and drug administration [fda]) that facilitated product development [ ] . the impact of vaccines is also impressive. a comparison of annual incidence of vaccine-preventable diseases in the united states reported for the period prior to availability of the designated vaccine compared with its incidence in shows the decrease in polio as %; diphtheria, %; rubella, . %; mumps, . %; invasive type b haemophilus influenzae, . %; and pertussis, a disappointing %. a recent report concluded that the global total for lives saved by vaccines exceeds million [ ] . the impact could be substantially greater with more global access, fewer refusals, and a better pertussis vaccine. a recent cdc analysis of annual costs associated with major nosocomial infections totaled $ . billion per year in the united states with the following rank order by median cost/case: central line bacteremia, $ ; ventilator-associated pneumonia, $ ; surgical site infection, $ ; clostridium difficile infection, $ ; and catheter-associated urinary tract infection, $ . this illustrates the challenge and the priorities [ ] . another challenge is epidemics involving nosocomial pathogens, as shown with the klebsiella pneumoniae carbapenemaseproducing bacteria (kpc) in the national institutes of health (nih) clinical center. this began with a patient transferred from a new york city hospital with a kpc infection and became the source of an institutional outbreak that required extraordinary efforts to control, including a wall constructed to isolate cases, removal of plumbing (as a possible source), use of matrix-assisted laser desorption/ionization time-of-flight (maldi-tof) molecular diagnostics to detect cases and carriers, hydrogen peroxide room aerosols, and "whole house" surveillance cultures. the epidemic was finally halted, but the toll was cases and fatalities over months [ , ] . another kpc epidemiologic investigation showed widespread distribution of this microbe from a long-term acute-care facility in the chicago area [ ] , and others have demonstrated distribution of kpc by air travel from india to europe [ ] . these epidemics require extensive resources and specialized skills; they will be expected to increase substantially in the era of "bad bugs." there is no specialty field in medicine that demonstrates shifting priorities like infectious diseases. to illustrate this point, i have summarized the "hot topics" discussed in the "what's hot in infectious diseases" presentation to the annual meeting of the american college of physicians in , compared with the presentation in , to illustrate the nearly complete change of priorities in a relatively short time. avian influenza, rabies (first survival without vaccine), west nile virus, bioterrorism, transfusion-associated jacob-creutzfeldt disease, usa strain of methicillin-resistant staphylococcus aureus (mrsa), sars, and chlamydia pneumoniae and its role in coronary artery disease and influenza. carbapenemase-producing gram-negative bacilli, colistin, constant infusion of β-lactam antibiotics, molecular diagnostics, a litany of epidemics, new pathogens (mimivirus, borrelia miyamotoi, emmonsia species, and bradyrhizobium enterica), c. difficile gene sequencing, the microbiome, and hcv. note that the -year interval resulted in a completely new agenda for what was considered timely and important in the field based on rapid changes in topical microbes, new epidemics, and new diagnostics, (but not new antimicrobials). it is impossible to predict the menu for . it is now known that genes for resistance to antimicrobial agents were well established in bacteria at least million years before evidence of human life [ ] . the use of antibiotics has selected for these genes by mendelian laws, making it increasingly difficult to control previously treatable infections. this problem was predicted by the father of antibiotics, alexander fleming, who, in , wrote that ". . . the public will demand the drug and . . . then will begin an era . . . of abuses. the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out which can be passed to another individual and perhaps from there to others until they reach someone who gets a septicemia or a pneumonia which penicillin cannot save. in such a case, the thoughtless person playing with penicillin treatment is morally responsible for the death of the man who finally succumbs to an infection with penicillin-resistant organisms. i hope this evil can be averted" [ ] . also of note is the prediction by nobel laureate joshua lederberg: "the future of humanity and microbes will likely evolve as . . . episodes of our wits vs their genes" [ ] . it now appears that fleming's prediction is a harsh reality and evolutionary microbial resistance genes are gaining the upper hand, reflecting the combination of massive antibiotic use and lack of new pharmacologic agents. the result is the alarming escalation of antibiotic resistance that is global and applies to nearly all categories of treatable pathogens, leading some to predict "the postantibiotic era." this resistance has been declared a "crisis" by the infectious diseases society of america, the cdc, who, the us congress, and the us president. a disturbing observation in the united states is the conspicuous absence of a national plan to deal with resistance, including the lack of a living record of antibiotic consumption and resistance correlated by location and trajectory. this is in sharp contrast to the european union, which includes countries with official languages and diverse cultures, but has systematically collected data on antibiotic consumption and microbial resistance patterns for years [ , ] . this has resulted in multiple publications with data reviews, studies of interventions, messages to consumers such as an ebug internet program for students, a european antibiotic awareness day, standardized methods to collect data [ ] and a recent -point plan with budget to address the issue [ ] . their data are striking in showing the dramatic association between per capita antibiotic use and national resistance patterns. for example, antibiotic consumption in greece is nearly times that of the netherlands, so we expect more resistance problems in greece, but the magnitude of this difference is alarming: bacteremic carbapenemase strains among all bacteremic k. pneumoniae isolates appear to be about times more common in greece, and mrsa as a percentage of all s aureus isolates is about times higher [ ] . the european union appears to have a mature and substantive model to learn from, with the important caveat that it functions well because there is no claimed ownership, as there are equal partners. there are also some good national programs that have successfully addressed specific problems to learn from: • eu data for showed that france had embarrassingly high antibiotic use rates, accompanied by increasing resistance by s. pneumoniae. this prompted a national campaign targeting prescribers and consumers on antibiotic abuse and its consequences. the goal was a % reduction in antibiotic prescriptions for the entire country; they achieved a % reduced resistance [ ] and also achieved the largest decrease in per capita antibiotic consumption for any nation in the history of the global antibiotic fund [ ] . • a recent report from israel showed a national campaign to reduce the incidence of kpc. analysis of their results with a prevention bundle showed a reduction from per patient-days to . per patient-days [ ] . • the united kingdom addressed the issue of the epidemic nap- strain of c. difficile through gene sequencing and aggressive antibiotic control. the result was a national % reduction in c. difficile infection rates [ ] . the examples given are based on national data addressing major challenges with impressive results. in the united states, this remains a unanswered challenge, but is also an opportunity for the skills of the infectious disease discipline in terms of data collection, evaluation, interventional trials, and policy implementation into practice, primarily in the form of antibiotic stewardship. recent reports using gene sequencing suggest that conventional methods of infection control could substantially improve this effort. examples: ( ) results from the united kingdom have largely disproven conventional teaching regarding the epidemiology of c. difficile infection [ ] ; ( ) this technology also appears to contradict some contemporary concepts about transmission patterns of s. aureus [ ] ; and ( ) it has proven to be a valuable tool in outbreak investigation of kpc infections in a hospital [ ] and in a large community outbreak of kpc involving multiple facilities [ ] . it seems clear that as this technology gets faster and cheaper, it will be embraced as an infection control standard [ ] , although there needs to be caution and skill in interpreting results [ ] . this work in developing countries is another attractive career option based on need, probability of impact, and unique special programs such as the president's emergency plan for aids relief, the bill & melinda gates foundation, and others. some of this is direct patient care, but possibly very attractive targets for impact are the development and implementation of innovative programs that deal with the vast need combined with minimal resources [ ] . the new healthcare system should value infectious disease expertise based on its important role in addressing resistance and costs associated with nosocomial infections. nevertheless, it is feared that the current structure and payment system are not constructed as a good fit to prioritize infectious disease skills. specifically, there is no code for preventing infections, conserving antibiotic use, or preventing resistant pathogens. this might be an erroneous conclusion, or the situation may change as the system matures and becomes serious about addressing the crisis. "bundles" to deal with healthcare efficiencies are in vogue and could be a strength of infectious diseases. an example is the -step central line bacteremia prevention bundle that proved effective in trials [ ] . generalized adoption of this bundle was predicted to save lives and $ . billion per year in us hospitals [ ] , and subsequent actions by clinicians, regulatory agencies, and stakeholders have resulted in an estimated % decline in central line bacteremia rates [ ] . • stewardship: solving or reducing the problem of antibiotic resistance largely depends on antibiotic development and reducing antibiotic abuse. the major on-site forces for improving smart antibiotic use at the point of care are antibiotic stewards-preferably infectious disease or pharmacy personnel trained in this skill to improve the speed of detecting resistant or epidemic pathogens. the tools are obvious to infectious diseases-trained clinicians, but often require methods that are not well inculcated into hospital or clinic practice. methodology with proven value for antibiotic conservation include shortcourse regimens (virtually always wins or ties in trials), use of procalcitonin to facilitate decisions on when to start or stop antibiotics, use of molecular diagnostics to improve pathogentargeted antibiotic decisions, outpatient infusion therapy to reduce inpatient risk (and cost), optimal use of the agents we have, waiting room with notices that the doctor will prescribe antibiotics only according to guidelines, acknowledgement of possible microbiome harm, and possible use of social network media [ , ] . nevertheless, there must be caution: the new us healthcare system represents socialized medicine largely managed by capitalists, which invites both quality and chicanery. for example, the centers for medicare and medicaid services' " -hour rule" for treating community-acquired pneumonia had improved outcome advantages, but also led to overprescribing, declined use of diagnostics, perceived antibiotic abuse, and increases in c. difficile infections. given the priority of cost containment and its relevance to infectious diseases, infectious disease training should probably include attention to the business of medicine. • molecular microbial diagnostics: these are rapidly being developed and introduced into clinical use for detection of epidemic pathogens or resistance genes with advantages of speed, precision, and sensitivity. most polymerase chain reaction (pcr)-based tests define a specific pathogen with extraordinary sensitivity within minutes. the fda has approved these pcr tests to detect at least viruses and bacteria [ ] . these tests may also be useful for early detection of epidemic pathogen or resistance genes [ ] . it seems clear that the introduction of molecular tests for general use may be difficult to interpret in the context of clinical care, so these new tests will require a substantial stewardship from the infectious disease community. this was illustrated in a trial to guide antibiotic decisions based on results of a pcr-based diagnostic to detect mrsa in purulent soft tissue infections that had no significant impact on antibiotic selection [ ] . gene sequencing will be a new and important role for the infectious diseases-trained clinician as it becomes more readily available for defining transmission patterns to inform infection control practice. • microbiome: study of the microbiome at various anatomical sites represents a major nih-sponsored initiative that could possibly translate into important opportunities to treat or prevent multiple conditions [ , ] . this work is at the dawn of development, but the early reads suggest a potential role in obesity, allergies, autoimmune disease, cancer, diabetes, heart disease, and other conditions [ , ] . it is also apparent that antibiotics have a profound and long-lasting impact on the microbiome [ ] . this field requires a transformation in our conventional understanding of infectious diseases, as the "pathogens" are communities of microbes that communicate in contrast to the koch postulate of "one microbe, one infection." an example is a recent report showing that volunteers fed steak and eggs (lecithin) have conversion by gut flora to trimethylamine-n-oxide, which is a marker of atherosclerosis [ ] . this microbial interaction could be altered with antibiotics. the long-term goal is to define associations and intervene possibly with antibiotics and probiotics; this work may also illustrate potential harm to redefine risk-benefit ratios for antibiotics. • bundles: another potentially important role for infectious diseases-trained clinicians is the development of bundles that prevent infectious disease complications. an example is central line bacteremia, as described above [ ] [ ] [ ] . that experience can now be applied to multiple iatrogenic infection risks associated with specific patients or procedures, possibly prioritizing those with the greatest healthcare consequences as described above. the role of infectious diseases is to define the bundle, design the study, and then implement them when results are convincing or even mandated. specialized skills in the management and study of infectious diseases are an increasingly important specialty in contemporary medicine. the roles of practitioners in the discipline are diverse, usually important, and sometimes critical, but commonly undervalued by contemporary priorities in healthcare systems and healthcare reform. it would be difficult to find another discipline in medicine that has such extraordinary diversity, surprises, value in patient care, and clinical relevance for both domestic and international applications. for many trained in medicine, joining the field of infectious diseases is simply the right thing to do. supplement sponsorship. this article was published as part of a supplement titled "the john bartlett festschrift: celebrating a career in medicine," sponsored solely by the department of medicine of the johns hopkins school of medicine in recognition of john bartlett's contributions to medicine. potential conflicts of interest. author certifies no potential conflicts of interest. the author has submitted the icmje form for disclosure of potential conflicts of interest. conflicts that the editors consider relevant to the content of the manuscript have been disclosed. index case of fatal inhalation anthrax due to bioterrorism in the united states lyme arthritis: and epidemic of oligoarticular articular arthritis in children and adults in three connecticut communities the spirochetal etiology of lyme disease interview with willie bergdorfer, ph.d. interview by vicki glaser lyme disease-a tick-borne spirochetosis? how the discovery of borrelia bergdorferi came about nobel prize winners robin warren and barry marshall two win nobel prize for discovering bacterium tied to stomach ailments long-term follow-up of voluntary ingestion of helicobacter pylori 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intestinal microbial metabolism of phosphaditylcholine and cardiovascular risk key: cord- -budyph u authors: bonnaud, laure; fortané, nicolas title: serge morand and muriel figuié (eds), , emergence de maladies infectieuses. risques et enjeux de société (the emergence of infectious diseases. societal risks and stakes): paris, quae, p date: - - journal: nan doi: . /s - - - sha: doc_id: cord_uid: budyph u nan international organisations (world health organization (who), office international des epizooties or world organization for animal health (oie), food and agriculture organization of the united nations (fao)) play a leading role in coordinating the exchange of surveillance information and in facilitating the implementation of tools to fight disease. twenty-five years after stephen morse's seminal work which helped put emerging infectious diseases onto the political and scientific agenda (morse ), contemporary debates were very much influenced by an article published in nature in (jones et al. ). jones and his colleagues presented three major results: the regular and significant increase in the number of infectious diseases that had emerged since the s, the role played by viruses and bacteria (with parasites playing a secondary role), and finally, the animal origin of this phenomenon. in order to understand what might seem to be an inevitable biological evolution, the book takes a multidisciplinary approach: whilst the origin of these infections is definitely animal, it is human societies, through their lifestyles, which are responsible for their propagation-as s. morand immediately points out in the first chapter devoted to a presentation of definitions, the state of scientific debate, and the main available epidemiological data. the following three chapters set out to deconstruct the apparent evidence of international mobilisation against these emerging diseases. claude gilbert and nathalie bender show how the influenza pandemic constituted an interesting opportunity for who, an international organisation in crisis since the s. at the beginning of the s, who decided to reposition itself as a reference centre for biomedical expertise. its management of the sars epidemic, through its network of experts and its alert and response system, enabled it to gradually recover an authority that was both moral and technical. in the case of influenza, national experts-virologists in particular-also became lobbyists for this public issue, linking it to other problems (by presenting it as a model for preparations against bioterrorism) and suggesting solutions, such as mass vaccination. in the french case, the authors analyse the mechanism for countering h n flu and look at different ways of shaping the public problem, depending on whether the pandemic is deemed to be a public health issue, a stake of collective security, or a global problem affecting contemporary societies. these different appropriations nevertheless coexist without really impacting one another. they do not lead to any major redefinition of solutions, and mass vaccination remains the solution that health authorities recommend. in a chapter devoted to the cbrn risks (chemical, biological, radiological, and nuclear) in the usa, patrick zylberman retraces the origin of scenario planning, used by public authorities to prepare against threats. he shows that since the end of the cold war, health issues have been taken on board by national security actors whose tools and concepts have gradually taken over. among the norms, plans, and procedures that constitute the tools with which to prepare for biological, chemical, radiological, and pandemic threats, scenario planning takes pride of place. it is a case of preparing bin order to dissuade^, with the idea of a terrorist enemy being implicit. scenario planning allows one to set probabilities aside and thus bring public authorities into a worst-case logic. p. zylberman is sceptical about the fictional aspect they contain, which serves just as much the political and ideological motives of domestic policy as truly helping institutions to prepare against threats. muriel figuié takes a critical state-of-the-art look at the implementation of international public action in relation to animal health and more particularly at epidemiological surveillance and vaccination. she notes recurring observations by international experts of the difficulties involved in coordinating actors and discusses the literature that attempts to explain these issues. two types of explanations are generally put forward: on the one hand, those which relate to individual determinants and on the other, those which focus on cultural aspects. in the first group, we find cognitive and psychological factors, along with those relating to individual economic calculation. the second group concerns everything relating to inherited beliefs and know-how which prevent any proper understanding of the solutions suggested by experts from international institutions. m. figuié confronts these analyses with a reflection on conditions for collective action, talking for example about her works on the informal epidemiological surveillance networks which were developed in vietnam when avian influenza emerged. she reveals the many ambiguities surrounding the mechanisms proposed by southern countries and the controversies and conflicts between actors who are supposed to work together to protect animal health, now regarded as a global public good. we are thus moving away from the vision of a coherent project that local actors cannot or do not want to support, in favour of putting more nuance into the definition of what constitutes the implementation of global health policy instruments. in vietnam, poultry culling is a tool aiming at preventing the spread of the flu as well as a mean to modernise agricultural system by fostering the development of agri-food industrial actors. this viewpoint is examined in greater depth in the final chapter by françois roger, who focuses on the north/south inequalities that are embedded in plans to monitor and fight infectious diseases. all of these chapters form a coherent book which offers a very solid introduction to the examination of public action against emerging infectious diseases. they open the road to new research, be it disciplinary or interdisciplinary, which might throw further light on certain aspects currently left in the shadows; they will also be of use to experts and decision-makers. the analysis of this new global public health model is therefore a convincing one, even though its circulation and eventual local variants remain unknown. the priority given to international institutions might therefore be bolstered by an analysis of regional evolutions which at the very least would appear to have laid the ground for this new model: the european union's animal health strategy was thus perfectly adapted to a reclassification of animal diseases-but for internal budgetary reasons rather than to fight emerging diseases! (ollivier ) . the book also opens the way for in-depth studies of the roles played by the market and by private actors. it very rapidly sets out the foundations, the pharmaceutical laboratories, and the agri-food industry which are vital stakeholders in the fight against infectious diseases-or in their emergence (such as the development and spreading of antimicrobial-resistant bacteria, for example!). their role could in itself be a research object. finally, epidemiological surveillance networks aside, the book pays little attention to the implementation of other devices or policies to fight against emerging infectious diseases. in the northern countries, changes to healthcare systems, the medical and paramedical professions, the ngo relating to public health, and more broadly, migratory policies might also throw light on how certain infectious diseases are managed (aids is one well-documented example: gelly et al. ) . similarly, countries in the southern countries use a variety of devices to fight infectious diseases-such as triage centres or clinical trials set up as part of the fight against the ebola virus in africa (lakoff et al. )-which clearly demonstrate the social, political, technical, and biological complexity surrounding contemporary emergences. the next step towards understanding emerging diseases might therefore be to compare this new global health model with existing devices, in both the northern and southern countries. it nevertheless remains that this book, both through the concepts and policy instruments it presents and the perspectives it offers, marks an important step forward in the analysis of emerging infectious diseases. how did international agencies perceive the avian influenza problem? the adoption and manufacture of the bone world la fin du sida ? global trends in emerging infectious diseases ebola's ecologies, limn quand les vétérinaires et les animaux font l'europe: l'action publique européenne en santé animale key: cord- -la vi j authors: brower, jennifer l. title: the threat and response to infectious diseases (revised) date: - - journal: microb ecol doi: . /s - - - sha: doc_id: cord_uid: la vi j the threat from microorganisms is complex, and the approaches for reducing the challenges the world is facing are also multifaceted, but a combination approach including several simple steps can make a difference and reduce morbidity and mortality and the economic cost of fighting infectious diseases. this paper discusses the continually evolving infectious disease landscape, contributing factors in the rise of the threat, reasons for optimism, and the policies, technologies, actions, and institutions that might be harnessed to further reduce the dangers introduced by pathogens. it builds upon and updates the work of other authors that have recognized the dangers of emerging and re-emerging pathogens and have explored and documented potential solutions. in just the past year, the united states has been bombarded with headlines on the dangers of infectious diseases: "hiv 'epidemic' triggered by needle-sharing hits scott county, indiana [ ] ;" "american with ebola now in critical condition [ ] ;" "seasonal flu vaccine even less effective than thought: cdc [ ] ;" "'superbug' outbreak at california hospital, more than exposed [ ] ;" "deadly cre bugs linked to hard to clean medical scopes [ ] ;" "painful virus [chikungunya] sweeps central america, gains a toehold in u.s. [ ] . " the ebola outbreak that began in and the measles outbreak initiated at disney world in particular brought the threat of "exotic" infectious diseases back to the american and global consciousness. this coupled with the fact that the most commonly circulating strains of the influenza a virus h n drifted [ ] from that used in the - influenza vaccines serve as reminders that the threat from microorganisms is continuously evolving and is persistent. the threat of emerging and re-emerging pathogens has been discussed in the scientific literature, the medical community, by policy makers, and the general public over the past years, but much of the discussion was among directly affected populations and their caregivers. general interest flourished after a series of events in the s and early s. in , a report by russian general kuntsevich followed by boris yelstin's decree in april of that year to end all offensive biological weapons programs revealed that the former soviet union had an extensive biowarfare program and that facilities and expertise still existed which would enable russia to unleash deadly pathogens on the world [ ] . in when shoko asahara, the spiritual leader of a japanese religious cult, was arraigned, the magnitude of the organization's attempts to deploy anthrax in was exposed [ ] . in october , the united states was transfixed by the first bioterrorism attacks on its own soil: envelopes containing bacillus anthracis spores were sent through the mail to targets ranging from media companies to government officials [ ] . five people died and thousands were treated with prophylactic antibiotics. the attacks and other attempted and planned attacks, along with widely publicized outbreaks such as west nile virus in [ ] and severe acute respiratory syndrome (sars) in [ ] , brought the topic of infectious disease to the forefront. in addition, more incessant threats such as influenza and lower respiratory infections continue to kill and cause economic harm through lost productivity and hospitalizations. furthermore, zoonotic diseases such as salmonella and listeria, which represent more than two-thirds of emerging and re-emerging diseases [ ] , raise the visibility of the economic and human and animal health issues caused by pathogens. in april , the sabra dipping company voluntarily recalled about , cases of hummus potentially contaminated with listeria monocytogenes. at the same time, blue bell recalled nearly products also similarly contaminated. while there were no known casualties as a result of the sabra contamination, authorities in kansas and texas reported that three deaths in each state might be attributed to the blue bell incident [ ] . the threat from microorganisms is complex, and the approaches for lowering the challenges the world is facing are also multifaceted, but several simple steps can make a difference. this paper will discuss the emerging infectious disease landscape, contributing factors in rise of the threat, reasons for optimism, and the actions, policies, technology, and institutions that might be harnessed to further reduce the dangers introduced by pathogens. it builds upon the work of other authors who have recognized the dangers of emerging and re-emerging pathogens and have explored and documented potential solutions [ ] [ ] [ ] . microorganisms pose health and economic threats and may pose a strategic threat if a large percentage of the population is overcome or if the potential transmission of infectious diseases across borders causes an increase in tension among state allies or enemies. one organism alone, clostridium difficile, is estimated to cost the united states between $ and $ billion per year [ ] , with its primary impact on american children [ ] . initially identified in the early s as a commensal organism in the digestive tract, c. difficile infection (cdi) has only been recognized as a significant threat to pediatric health over the last decade [ ] . the threat to both children and adults is global. infections since have become more common, more acute, less treatable by standard therapy, and more likely to reoccur [ ] . initially, the c. difficile infections were associated with the use of the antibiotic clindamycin, but fluoroquinolones and cephalosporins are currently the more likely cause of disturbed gut microbiota, which increasingly lead to colonization with ribotype , a severe variant of c. difficile [ ] . according to the centers for disease control and prevention (cdc), emerging infectious diseases are those "whose incidence in humans has increased in the past two decades or threatens to increase in the near future [ ] ." while there may be debate about the specifics, for the purposes of this article, re-emerging and emerging diseases are distinguished as follows: re-emerging diseases are those that were known to impact humans or animals in the past and were thought to be brought under control with zero or few infections in the past several decades. these include infections resulting from changes or evolution of existing organisms and changes in the geographic distribution of an organism or populations affected by the organisms. previously unrecognized (in the past several decades) infections are considered emerging. according to this definition, c. difficile would be considered an emerging pathogen as its dangers were not recognized when it was first identified. other outbreaks and trends of concern include the following: tuberculosis (tb), while no longer among the leading causes of death in , was still among the leading causes, killing over , people in [ ] . in the united states, while overall tb incidence is decreasing, it is still a large problem for foreign-born residents and for the homeless population at a cost of nearly $ million per year [ ] . lyme disease caused by the spirochete borrelia burgdorferi was recently recognized as an epidemic. the disease is difficult to diagnose, causes long-term disability if untreated, and may impact as many as , people in the united states [ ] . more than % of lyme disease patients continued to exhibit symptoms after six months, and for % of infected people, symptoms continued for more than three years [ ] . the spread of diseases such as multidrug resistance acinetobacter in at-risk populations is also of increasing concern. "within the last years, members of the bacterial genus acinetobacter have risen from relative obscurity to be among the most important sources of hospital-acquired infections. the driving force for this has been the remarkable ability of these organisms to acquire antibiotic resistance determinants, with some strains now showing resistance to every antibiotic in clinical use [ ] ." acinetobacter resistance to drugs such as imipenem and ampicillin/sulbactam increased % from to [ ] . leptospirosis, one of the most widely distributed zoonotic diseases worldwide, is an emerging public health concern particularly in large urban centers of developing countries [ ] . it is also important in the united states in humans, pets, and wildlife. experts believe incidence in humans is underreported, but the cdc estimates that - leptospirosis cases occur annually with approximately half of those in hawaii [ ] . in , triathletes in illinois were exposed to leptospirosis of which became symptomatic [ ] , representing the largest human outbreak in the united states. recently, cases in pets have caused concern in california [ ], michigan [ ], and florida [ ] . more than a quarter of the tested deer population in michigan was infected with the disease [ ] . west nile virus (wnv) is another zoonotic disease of concern, and the us population and health practitioners have become more aware of this disease over the past decade. birds carry the virus, which is then transmitted by mosquitoes to humans, horses, and other mammals. disease symptoms range from fever to neurological complications, such as encephalitis or meningitis. mortality is observed mostly in older and immunocompromised individuals. in , wnv was introduced to the united states, and its range soon extended across north america [ ] . not only is the number of wnv outbreaks increasing but also novel strains are emerging, which display higher virulence. wnv has also developed sophisticated avoidance mechanisms to avoid its elimination [ ] . noroviruses are the leading cause of foodborne disease outbreaks worldwide and may soon eclipse rotaviruses as the most common cause of severe childhood gastroenteritis, because rotavirus vaccine use is becoming more prevalent [ ] . norovirus rapidly undergoes genetic mutations and recombinations so that new epidemic strains are constantly evolving. although norovirus infection is generally not fatal, infections in children, the elderly, and the immunocompromised can cause morbidity and even death. research into a vaccine or treatment has been impeded by the lack of a cell culture or small animal model. however, vaccines based on norovirus capsid protein virus-like particles show potential and may become broadly available through transgenic expression in plants [ ] . vibrio vulnificus, a common gram-negative bacterium in warm coastal waters globally, is an emerging pathogen [ , ] . up to million vulnerable americans are at risk when consuming raw or improperly prepared seafood tainted with v. vulnificus which can cause primary septicemia [ ] . additionally, all individuals are at risk of serious wound infection that may lead to secondary septicemia [ , ] . even with antibiotic treatment, half of patients may die from primary septicemia and a quarter from secondary [ , ] . other environmental organisms of concern include the waterborne pathogen that causes legionnaires' disease, legionella bacterium; naegleria fowleri, which causes amebic meningoencephalitis; other mycobacterium (hospital environment) such as mycobacterium abscessus and m.massiliense in lung disease; the mosquitoborne chikungunya virus and the tickborne bourbon virus. in addition to causing acute illness, research has uncovered links between infectious diseases and cancer. in one study by wu et al. [ ] , researchers found measurable differences in fecal microbiota between healthy individuals and those with colorectal cancer as determined by pyrosequencing of the s rrna gene v region. as early as , researchers found that hepatitis b surface antigen (hbsag) carriers had a greater incidence of primary hepatocellular carcinoma (phc) than among non-carriers [ ] . the list of emerging and re-emerging pathogens could fill up a tome. these organisms vary in virulence and distribution, but all of them share common characteristics in that the incidence or virulence or both are increasing and humans must find methods of preventing, detecting, and treating them. to combat infectious disease, it is important to understand the factors that are working to increase the occurrence and severity of infections. human behavior has a large impact on the creation of environments where microorganism can evolve and mutate. these changes can sometimes make organisms more infectious and/ or virulent. examples include the following: antibiotics in the environment through overuse and misuse; changes in sexual norms; patterns of drug use and incarceration; global climate change; human incursion into new environments; and changing patterns of human interactions with wild and domesticated animals; expanding travel patterns; vaccination avoidance; and population concentrations in large cities. recent cases are used to illustrate how differences in human behavior have modified the threat from bacteria and viruses. the problem of antibiotic resistance is threefold: there has been a rise in the number or identification of resistant bacterial strains; the pipeline for the development of new medicines to treat infection dried up significantly over the past years; and the most significant problem is the lack of stewardship of existing antimicrobials. these issues have led to a reduction in the efficacy and number of responses available to physicians and their patients. the biological processes that lead to resistance are extremely complicated and not fully understood, resulting in sometimes limited progress in the control and treatment of resistant microorganisms and the diseases they cause [ ] despite recognition of the problem nearly a century ago. davies and davies [ ] compiled a list of "suberbugs," which have increased pathogenicity and are more impervious to treatment. their list includes the following: multidrug-resistant (mdr) m. tuberculosis; nosocomial (hospital-linked) infections with acinetobacter baumannii, burkholderia cepacia, campylobacter jejuni, citrobacter freundii, clostridium difficile, enterobacter spp., enterococcus faecium, enterococcus faecalis, escherichia coli, haemophilus influenzae, klebsiella pneumoniae, proteus mirabilis, pseudomonas aeruginosa, salmonella spp., serratia spp., staphylococcus aureus, staphylococcus epidermidis, stenotrophomonas maltophilia, and streptococcus pneumoniae. their list does not include the new delhi metallo-beta-lactamase- (ndm- ) resistant strains discussed below. as the authors point out, in addition to the direct human toll, treatment is often more costly [ ] when resistant organisms are involved. in fact, the issue has become so acute that new terms have developed over the past decades: microorganisms that are pan-drug resistant (pdr) or extremely drug resistant (xdr). one of the most widely dispersed antibiotic resistant organisms is m. tuberculosis. worldwide, this organism is often resistant to multiple drugs, and in , completely drug-resistant forms of tuberculosis were reported in citizens of four countries: afghanistan, azerbaijan, iraq, and iran [ ] . in many organisms, such as enteric bacteria which are acquired both in community and hospital settings, resistance (often to β-lactam antibiotics in this case) spreads through horizontal gene transfer on plasmids; however, there have been no documented cases of this in tuberculosis, where all resistance occurs by spontaneous mutation [ ] . multidrug resistant pseudomnas aeruginosa is also of concern as it is deadly and widespread [ , ] . m. tuberculosis is one example of the multitudes of resistant organisms. other widespread and dangerous bugs include staphylococcus aureus ( . per inpatient prevalence rate in [ ] ) and c. difficile (in us hospitals in , c. difficile was the most commonly reported pathogen causing . % of health careassociated infections and staphylococcus aureus caused the second highest percentage, . %. klebsiella pneumoniae and klebsiella oxytoca . % and escherichia coli . % followed closely behind [ ] ). at a single hospital in and , resistant acinetobacter baumannii infected . % of patients who were not previously infected [ ] . infections with resistant organisms are harder to control; standard treatments are less effective; illness and hospital stays are longer; and mortality is higher. gram-positive organisms resistant to antibiotics were the first concern, but resistance in gramnegative organisms emerged: gram-negative bacteria resistance increases faster than in gram-positive bacteria [ ] , and there are fewer antibiotics in the pipeline that work against gram-negative bacteria [ ] . cosgrove et al. [ ] performed a meta-analysis of studies published between and on the impact of methicillin resistance on mortality. these studies included nearly patients, a third of whom were infected with methicillin resistant staphylococcus aureus (mrsa). mortality was significantly lower in the group infected with susceptible bacteria. in another study, cosgrove's group found that mrsa bacteremia also increased median length of hospital stay by almost % and not surprisingly (given the longer stay), increased hospital charges from an average of $ , to $ , [ ] . a prospective study found similar results in hemodialysis patients at the duke university hospital [ ] as did a study on orthopedic patients [ ] . vancomycin-resistant enterococci (vre) [ ] and enterobacter species resistant to third generation cephalosporins [ ] showed a similar trend; however, penicillin-and cephalosporin-resistant streptococcus pneumonia results were dissimilar, and the authors surmised that this might be due to the specific use of vancomycin [ ] . chemicals in daily use may also change microorganism susceptibility to antimicrobial agents. for instance, it has been regularly demonstrated in the laboratory that resistance to triclosan, an antimicrobial agent used in many household products including hand sanitizer, and crossresistance to antimicrobials increases with use of triclosan containing products; however these results have not yet been observed in the community. based on the available evidence, the risk of potential antimicrobial resistance outweighs the benefit of widespread triclosan use in antimicrobial soaps [ ] . resistance is not something that can be conquered: bacteria with their relatively short lifespans can mutate quickly; however, with knowledge of the , resistance genes of types [ ] , it may be possible to stay one step ahead of resistance and find new ways to treat bacterial infections. other changes that have impacted infectious disease distribution and prevalence are changes in sexual norms, drug use, and incarceration. needle sharing itself can spread infections, and the use of drugs can affect sexual and risk taking behavior which can put people in jeopardy [ ] . while homophobia is decreasing in the united states and worldwide, homophobia has been one of the major social determinants of infection particularly with hiv/ aids and other sexually transmitted diseases. for example, men sleeping with men accounted for % of new hiv infections in [ ] . historical legal restrictions, which are now being relaxed in this decade, had ostracized gay people, limiting their self-identification and therefore efforts to target gay communities for education and prevention as well as diagnosis and treatment efforts. injecting drug users account for % of new hiv infections often due to inadequate access to sterile needles and syringes and addiction treatment programs [ ] . as noted below, drug use also changes behavior which also leads to increased transmission. drug use and incarceration patterns go largely hand-in-hand. in part because of the united states hard line on drug use, united states incarceration rates are the highest in the world with minorities accounting for a disproportionate percent of the prison population. incarceration rates disrupt community and sexual relationships and compound poverty issues, amplifying the exposure of communities and individuals to hiv infection and other infections [ ] . in a second example, methamphetamine use has been shown to affect a person's judgment and may lead to unsafe behaviors such as reduced condom use, multiple partners, and increased drug injection. methamphetamines also increase physical susceptibility because their use dries mucosa intensifying chafing and abrasions, which, in turn, allow microorganisms to enter the body during sexual and other activity [ , ] . aquaculture contributes to the pollution of rivers, bays, and even our oceans with antibiotics and antibiotic resistance genes (args). from china to the united states, antibiotics and args have been found in surface water of all types. for example, in the coastal water of the bohai bay, china, fluoroquinolones, macrolides, sulfonamides, tetracyclines and chloramphenicoles, and polypeptides were found at concentrations up to several micrograms per liter with higher concentrations where human activity was concentrated [ ] . in a review, comparing aquaculture and land animal production with the respect to type, mechanism, and quantity of antibiotic resistance, done, venkatesan, and halden [ ] found that aquaculture was similar to terrestrial agriculture in terms of the resistance mechanisms, that antibiotics used in aquaculture are important in human health, and that pathogens isolated from the farmed fish were resistant to multiple antibiotics. due to improper use and disposal of antibiotics, the presence of antibiotic-resistant organisms and genes in natural waterbodies, wastewater, and treated municipal water has been widely demonstrated and reviewed [ ] [ ] [ ] [ ] . without additional treatment, this water is commonly used on crops; humans and animals then consume the products, and serious outbreaks have occurred that are difficult to treat because the microorganisms do not respond to commonly used antibiotics [ ] [ ] [ ] [ ] . pruden et al. [ ] found concerning levels of args in colorado (united states) dairy lagoon water, irrigation ditch water, river sediments, treated drinking water, and recycled wastewater. ramsden et al. [ ] similarly found antibacterial resistance in municipal wastewater treatment plants. zuccato et al. [ ] discovered that the concentrations of atenolol, bezafibrate, clofibric acid, cyclophosphamide, diazepam, erythromycin, furosemide, lincomycin, oleandomycin, ranitidine, salbutamol, spiramycin, and tylosin were in the nanogram per liter range in river or drinking water or river sediments in several sites in italy. munir et al. [ ] examined the presence of antibiotic-resistant genes and bacteria in several types of wastewater effluents in michigan and found that advanced water treatment systems such as membrane bioreactors were significantly more effective than conventional wastewater treatment at removing the tetracycline-resistant gene teto and sulfonamide-resistant gene (sul-i) as well as tetracycline and sulfonamide-resistant bacteria. anaerobic digestion and lime stabilization treatment of wastewater was more effective than the conventional dewatering and gravity thickening methods for removing antibiotic-resistant genes and bacteria [ ] . burch et al. [ ] were able to significantly reduce the concentrations of the args tet(a), tet(w), and erm(b) using conventional wastewater treatment (aerobic); however, removal of inti required batch treatment, while the others required relatively long-term semi-continuous treatment. tet(x) increased in concentration. according to the world bank, nearly million travelers visited the united states and approximately one billion people traveled globally in [ ] . the incidence of tuberculosis in the united states is largely due to foreign visitors and citizens and residents born in other countries [ ] . another, travel related resistance threat emerged in the united states in when three patients were reported to have the gene for new delhi metallo-beta-lactamase (ndm- ), an enzyme that destroys beta-lactam antibiotics including commonly used penicillins, cephalosporins, and carbapenems. the first case was reported in india in [ ] , and to date, india and pakistan have reported the most instances of ndm- , but the gene is spreading globally, and cases have now been detected in many countries, including great britain, canada, sweden, australia, japan, and the united states. antibiotics are widely used in india and some researchers [ ] have demonstrated that overuse of carbapenems led to the development of ndm- [ ] . research also points to medical tourism as a cause [ ] [ ] [ ] [ ] . ndm- is a newly identified problem, only recognized since about december in the medical literature, but it is only one example of diseases transmitted through medical tourism which is defined as travel to a country to get medical care that is not available or is more expensive in one's own country. precise data on the economic value and the number of patients seeking medical procedures are not easily available. in , smith et al. [ ] estimated that approximately four million patients crossed borders seeking treatment. in , guidelines to unify definitions of medical tourism and methodologies for reporting its extent were published and accuracy of the types and amounts of medical tourism may improve in the near future [ ] . a greater potential threat is related to the increasing travel of immunocompromised patients. lortholary et al. [ ] illuminated the fact that as more and more people are living with hiv, having organ transplants, using immunodilators, or suffering from diabetes, more individuals are infected when traveling. the authors suggested preparations and responses to prevent severe illnesses when traveling. infections spread within the united states from travel as well. for example, during the period from through , cryptococcus gattii infections were reported to the cdc. c. gattii, an environmental fungus typically prevalent in tropical and sub-tropical regions, can cause an uncommon infection of the lungs and/or the central nervous system in those who inhale the fungus. more than % of the cryptococcosis cases occurred in people who had traveled to the pacific northwest. the infection was fatal for % of the patients [ ] . many factors have reduced the number of new antibiotics approved in the united states each year as well as reduced domestic production including demanding food and drug administration (fda) regulations, the cost and time to market of development, the consolidation in the pharmaceutical industry, and the lack of financial impetus to produce and distribute antibiotics, which are generally used on a one-off basis versus drugs used to treat chronic conditions such as statins, viagra, and allergy medications. in a may speech, janet woodcock, the director of the center for drug evaluation and research (cder), acknowledged that new antibiotics were not sufficient to address growing antibiotic resistance and that fda's approach to approval was a significant factor [ ] . the fda introduced new regulations for clinical trials at the beginning of the twenty-first century, which led to a cooling of antimicrobial development in the pharmaceutical industry [ ] . first, the newly required approach doubled the cost of phase iii clinical trials, already a substantial barrier for development. in phase iii, it is expected that testing will include pairs of relatively large (usually > total subjects per study) groups of people conducted for the selected pathogen at the relevant body location(s). this has become challenging as new antibiotics focus on particular pathogens including resistant pathogens, making it difficult to enroll large numbers of patients [ ] . in part because of the cost of the new regulations, eli lilly, bristol-myer squib, glaxo smithkline, proctor and gamble, roche, and wyeth left the development business [ , ] . in addition, while the amount of antibiotics prescribed has continued to grow, the market value has not changed and was estimated at $ billion in [ ] as compared to a $ . billion market in for statins alone [ ] . companies are getting out of the market because the regulatory burden is high, antimicrobials are typically used for short periods of time, public pressure is building to lower use, and the medicines are often subject to price controls outside of the united states [ , ] . while development has slowed, in the past years, new antibiotics have been brought to market. two approved more recently, fidaxomicin and bedaquiline, have new modes of action. fidaxomicin was shown to effectively treat c. difficile [ ] . because the financial incentives are few, much antibiotic production has been outsourced from the united states to india, china, and other countries where labor, raw material, and energy costs are lower [ ] . in fact, it has been more than years since the active ingredient for penicillin was last manufactured in the united states. this presents a significant strategic problem for the united states in the case of an outbreak, particularly during times of conflict or worldwide scarcity. global climate change is increasingly accepted as causing extreme, unusual weather patterns [ ] . changing weather patterns can impact the presence of infectious agents in many ways. for instance, in may and june , an initially unidentified disease killed ten people in the four corners region of arizona and new mexico. at the outset, % of the patients died of the infection, and after the medical staff developed enhanced protocols, the death rate was only reduced to %. scientists isolated a hantavirus [ ] , and later, researchers determined that an unusually wet spring led to increased rodent carrier density which in turn impacted human infection rates; however, these factors alone are not enough to explain persistent hantavirus infection in the southwestern united states [ ] . ecosystem changes and human interactions with the environment may increase the transmission of infectious disease [ ] . for instance, three studies found robust correlations between the threat to humans from west nile virus and low bird diversity in the united states [ ] [ ] [ ] . the spread of emerging infectious diseases among animals has significant human health and economic costs. zoonotic diseases kill more than two million people per year and transmission occurs from both wild and domesticated animals [ ] . halsby et al. [ ] reviewed the english literature with respect to infectious diseases caused by pet store animals and found discussions of infections related to pet shops. the most commonly observed diseases were salmonellosis and psittacosis: other diseases such as tularemia were also identified. the human animal interaction has impacted civilization throughout history. according to daszak et al. [ ] , "parallels between human and wildlife emerging infectious diseases (eids) extend to early human colonization of the globe and the dissemination of exotic pathogens. in the same way that spanish conquistadors introduced smallpox and measles to the americas, the movement of domestic and other animals during colonization introduced their own suite of pathogens. the african rinderpest panzootic of the late s and s is a paradigm for the introduction, spread, and impact of virulent exotic pathogens on wildlife populations. this highly pathogenic morbillivirus disease, enzootic to asia, was introduced into africa in . the panzootic front traveled km in years, reaching the cape of good hope by , extirpating more than % of kenya's buffalo population and causing secondary effects on predator populations and local extinctions of the tsetse fly." more recently, bovine tuberculosis, while responsible for only cases of human tuberculosis in the uk, prompted the slaughter of tens of thousands of cattle in the first decade of the twenty-first century [ ] . in , throughout the united states, domestic poultry and wild birds have been suffering from a highly pathogenic strain of avian influenza (hpai) h [ ] . through june , , more than million birds were put to death. the cost of the government response is tagged at $ million primarily to fund the work of staffers and contractors [ ] . on the commercial side, analysts used economic models and found that for a million dollars in direct losses there are $ . million in overall economic losses. in mid-may direct losses in poultry production were estimated at $ million leading to overall losses of more than $ million [ ] . transmission to humans in the united states has not been detected, although related viruses have caused serious illness and death around the world [ ] . typically, people have focused on wildlife diseases that affect human health and agriculture. recently, researchers, policy makers, and others have begun to pay attention to wildlife infectious diseases, because a number of endangered species including birds, amphibians, and invertebrates [ ] are impacted [ ] . human's changing relationship with the environment "deforestation and ensuing changes in land use, human settlement, commercial development, road construction, water control systems (dams, canals, irrigation systems, reservoirs), and climate, singly, and in combination have been accompanied by global increases in morbidity and mortality from emergent parasitic disease [ ] ." lyme disease is a prime example of how human destruction of the environment (forests) can lead directly to increased risk for disease exposure. allan, keesing, and ostfeld [ ] found that as forest patch size decreased ioxdes nymphal infection prevalence and nymphal density with increased, resulting in a noticeable rise in the density of infected nymphs and concluded that habitat fragmentation affects human health. as humans change or destroy the local environment, they tend to interact with or disturb wildlife populations, creating further instances for exposure to infectious diseases. goldberg et al. [ ] found increased rates of interspecific gastrointestinal bacterial exchange between people and nonhuman primates when humans visited chimpanzee and ape habitats. chimpanzees carried antibiotic-resistant bacteria although there had never been treatment with antibiotics. many of the factors discussed above coexist to increase the threat from microorganisms. the antivaccine lobby, especially in the united states, has led to a significant decline in the vaccination rates of infants and children, particularly among specific demographics despite the overwhelming success of vaccines in the fight against vaccine-preventable diseases. for instance, in (pre-vaccine), , cases of measles were reported with mortalities. in , there were cases of measles but no deaths. similarly in , cases of diphtheria were reported resulting in deaths. in , there were no reported cases of diphtheria [ ] . up to two % of parents in the united states refuse vaccination completely for their children with up to % more who are cautious or elect to delay vaccination [ ] . the reduction in vaccination coverage is typically attributed to the lack of perceived threat due to the success of vaccination, combined with false medical research and media reporting [ ] . the reduction in vaccination rates has resulted in the highest number of cases of measles in the united states since it was declared eliminated in [ ] . while native measles has been eliminated in canada, several measles cases are imported each year by international travelers and due to inadequate vaccination, these cases often lead to secondary spread. in the first five months of , cases in five provinces from known importations occurred through infected travelers arrived from the philippines, india, the united states, thailand, pakistan, italy, and the netherlands [ ] . travel patterns in canada are exemplary of much of the world. in years, international travel (excluding travel to the united states) more than doubled from . million to million trips [ , ] . if the antivaccine trend does not abate, and in conjunction with widespread global travel, the threat from diseases once thought under control may pose a significant threat to the population. influenza outbreaks kill and hospitalize more than , americans each year. the predominant strategy in the united states is to encourage all eligible populations to get vaccinated; however, for the - flu season, more than half of influenza a (h n ) viruses had drifted from the h n vaccine virus. this mismatch leads to decreased vaccine effectiveness [ ] . it may also discourage individuals from getting the flu vaccine in the future. population growth, urbanization, and travel along with deterioration in public health infrastructure have contributed to the resurgence of infectious diseases. dengue fever provides a prime example of the intersection of the triad. while dengue viruses were dispersed throughout the tropics in the first half of the twentieth century, epidemics were infrequent because urban populations were comparatively small, and the viruses and mosquito vectors were transported on ships versus the air transport of today. the travel of both goods and people during world war ii set the stage for the spread of dengue fever. in the post war era with unparalleled urban growth and travel, serious epidemics occurred more frequently. scarcely years later, dengue hemorrhagic fever became a principal cause of hospitalization and mortality in the pediatric population throughout southeast asia [ ] . with respect to the intentional use of microorganisms as a weapon, the united states and the world have an outmoded threat-view focused on soviet era biological weapons, but travel, medicine abuse, and the lack of a us capability to approve and manufacture new antimicrobial and antiviral agents have changed many dimensions of the threat as discussed above. with the dissolution of the soviet union, the fact that the us biological weapons program ended decades ago, and the intellectual, medical, manufacturing, and weaponization knowledge needed to start a bioweapons program, the threat from naturally occurring organisms is far greater than the threat of bioterrorism or biowarfare in . the threats of infectious diseases dwarf that of terrorism and other asymmetric threats to human life. approximately three million people died in due to lower respiratory infections [ ] , and infectious diseases are the major cause of death of children under five. "the most important pathogens are rotavirus for diarrhea and pneumococcus for lower respiratory infections [ ] ." however, there is hope that new antibiotics will be identified and developed. recent research such as that performed by ling et al. [ ] found new ways to identify antibiotics [ ] in the environment and companies are beginning to invest again. under the direction of dr. kim lewis, ling and colleagues identified teixobactin. to do this, the team used the novel screening method to examine , strains. in both in vitro and in vivo tests, teixobactin was demonstrated to be operative, without major side effects, against the organisms that cause common illnesses such as pneumonia, tuberculosis, and staph infection, diseases which sicken more one million americans yearly. while teixobactin was effective against diseases of public health concern, it was ineffective against gram-negative bacteria. teixobactin binds on several targets triggering cell wall break down. the ability to bind on multiple sites lessens the chance of early teixobactin resistance. in addition to developing the new antibiotic, the researchers commercialized the screening technology, which can examine organisms that cannot typically be cultured in the lab [ ] . researchers are also developing techniques to enhance the impact of probiotics in fighting infections and other diseases such as cancer [ ] . while recent events bring the threat of microorganisms to the forefront of the public mind, the work of doctors, researchers, public health professionals, and other experts have continued unabated for decades. these attempts include scientific, technological, policy, and commercial attempts to reduce or eliminate the deaths and other losses caused by pathogens. to a large extent, these efforts have succeeded. in , the average lifespan in the united states was . for men and . for women, and one of the predominant causes of death was infectious disease. by the end of the century, lifespan had increased to . for men and . for women [ ] . in , infectious diseases accounted for more than half of all deaths: in , this percentage was reduced tenfold [ ] . the increases in life expectancy have been distributed across the world, although some areas have benefitted more than others from breakthroughs in sanitation, nutrition, and medical advances. one of the primary contributors to the reduction in the death rate was the reduction of infant deaths due to infectious diseases. prior to the mid- s, infectious disease played the predominant role in infant mortality with half of the (out of ) infant deaths due to pathogens [ , ] . by , the united states infant mortality rate had decreased to . per live births [ ] . also in the united states, in the midnineteenth century, foodborne and waterborne diseases such as typhoid, cholera, and dysentery resulted in deaths per , . these diseases were eliminated in the united states by the early s [ ] . one noteworthy exception to the steady progress in increased life expectancy is due to an infectious disease: hiv/aids decreased life expectancy dramatically in parts of africa over the past years [ ] . the leading causes of death and illness have shifted from infectious and parasitic diseases to noncommunicable diseases and chronic conditions. with the introduction of widespread antibiotics [ , ] in the s and antivirals in the late s [ ] , a new era of public health was ushered in, and the death rate due to infectious diseases accounted for less than % of mortality worldwide [ ] ; however, the optimism was short lived. even before there was prevalent proof that bacteria could quickly evolve to thwart antibiotics, evidence indicates that bacteria exhibit resistance in nature even without human pressure [ ] ; however, mechanisms of resistance impacting disease treatment were first noticed in the late s with regards to the use of sulfonamides [ ] . due to overuse, underuse, and incorrect disposal, antibiotic resistance has become a worldwide threat to public health [ ] . in addition, the cost and difficulty in developing new antibiotics has stunted the pipeline. finally, environmental [ ] , behavioral, and other physical and cultural changes have fostered situations where new pathogens can emerge and old enemies reemerge or spread to new locations. global climate change is altering where species thrive, and more localized or temporary changes modify infectious disease risk to humans as well. while ndm- strains are difficult to treat, many of them remain sensitive to an older, seldom used antibiotic, colistin, or aztreonam [ , ] years, clinical trial number n c t ; a n d s a f e t y, to l e r a b i l i t y, a n d immunogenicity study of a clostridium difficile toxoid vaccine in healthy adult volunteers, clinical trial number nct (a total of studies were found on www. clinicaltrials.gov when searching for 'c. difficile vaccine [ ] .' improvements are needed in dosage and timing to achieve high level immunity, however the investment required is large with estimates ranging from $ , , to $ , , [ ] to take a vaccine or antibody, respectively, through clinical trials. until a vaccine is developed, antibiotics will be used to treat infections. fidaxomicin, the first new antibiotic approved by the fda to treat cdi was approved in may . it was shown to be as effective as oral vancomycin, previously the only fdaapproved therapy for mild-to-moderately severe cdi. vancomycin is expensive and resistance in enterococci is a concern. oral metronidazole has been used by the medical community off label (it was approved for the treatment of certain anaerobic bacteria and parasites); however, relapse was observed in a quarter of patients within a month following treatment. fidaxomicin, in addition to being as effective as standard treatment, is a narrow spectrum antibiotic, allowing patients to maintain healthy native gut microbiota [ , ] . on a larger scale, according to the world health organization (who), hiv mortality was reduced from . million in to . million in , and diarrhea fell from one of the top five causes of death to number seven, with a similar number of deaths to hiv/aid in [ ] . tuberculosis distribution has declined since the turn of the century, in part because of the reach of the who's directly observed therapy short-course strategy and the implementation of the stop tb partnership plan [ ] . malaria cases and mortality has been meaningfully reduced by over cases and four million people respectively over the years between and through the use of artemisinin-based drugs, distribution of insecticide-treated bed nets, and indoor residual spraying of insecticide [ ] . this demonstrates that research, infrastructure, and other health-based investments have improved prevention and response to infectious diseases. all of this comes at a cost: between and governments including the united states, the uk, australia, canada, france, and germany and large non-profits and international institutions such as the gates foundation and the global fund contributed more than $ billion to the fight against hiv/ aids and nearly $ billion for international maternal and child health, which is in large part funding for vaccination [ ] . in addition, president obama has recognized that infectious diseases pose a national security threat. on september , , in his weekly address [ ] , the president stated, "so this is an epidemic that is not just a threat to regional security-it's a potential threat to global security if these countries break down, if their economies break down, if people panic. that has profound effects on all of us, even if we are not directly contracting the disease. and that's why, two months ago, i directed my team to make this a national security priority." because the challenges of new and re-emerging infections are complicated, a combination of science and technological advances, policy initiatives, and cooperative institutions are required. to make a significant difference, the united states and other countries must invest in technology and have systems capable of making these advancements available to those who need them, build technology development, and public health infrastructure; put in place policies and institutions that encourage these investments both in the public and private sectors. the success of programs such as the malaria initiative that combine these approaches is self-evident, but more needs to be done. an illustrative, but not complete, discussion of recent and additional proposals/initiatives is below. the united states, other countries, states, and international institutions have taken many steps to combat the threat. below are many of the important efforts and characteristics needed for resilience to the microbial threat. most importantly, it is critical to have a well-defined leader who is responsible for directing and monitoring progress as well as communicating risks. in president obama's september executive order [ ] , he directed the "national security council staff, in collaboration with the office of science and technology policy, the domestic policy council, and the office of management and budget to coordinate the development and implementation of federal government policies to combat antibiotic-resistant bacteria [ ] ." the president also created both a task force and an advisory council; however, he did not put a single individual in charge. identifying and developing a central, qualified, trusted person in charge of coordinating the investments in research, infrastructure and outreach; policies to incentivize behaviors to improve medicine development, infection control in medical and community settings; and communicate risks and responses in a directed and trusted manner at the federal government level, will enhance accountability and the likelihood of success. during times of low or chronic threat (e.g., flu season), the named person can develop a trusted relationship with the public, the medical and public health communities, the pharmaceutical industry, the defense department, international peers, and others involved in infectious disease response and defense. this is particularly difficult in diverse countries with divided political parties. a history of purposeful and innocent ethical lapses and scientific mistakes have contributed to a lack of trust such as the inaccurate flu vaccine in the - season and the confusing messages from the texas hospital and the cdc on ebola in . when a man traveled from africa and came down with a high fever and other symptoms, he was sent home by the hospital with antibiotics for two days [ ]: ebola was not well diagnosed in texas. one of the last trusted public health officials was the surgeon general under ronald reagan, dr. c. edward koop. by the time he stepped down in , he had become a household name, a rare distinction for a public health administrator. "dr. koop issued emphatic warnings about the dangers of smoking, and he almost single-handedly pushed the government into taking a more aggressive stand against aids [ ] ." dr. anthony fauci, director of the united states national institutes for allergy and infectious disease, has been a source of trusted and accurate infectious disease related information recently with regards to the ebola outbreak of . fauci is a natural leader for the us infectious disease/public health message, "he is someone who is really trusted by all the different organizations and people surrounding the aids challenge, ranging from the scientific community, the academic community and the activist community," according to louis sullivan, m.d., secretary of health and human services during the first bush administration and president emeritus of morehouse school of medicine in atlanta. "i don't know of anyone as broadly accepted by all those disparate groups [ ] ." the head of the cdc can also be a valuable spokesperson, but the cdc may have lost some of the public's trust during the ebola crisis [ ] . to centralize response, president obama appointed rob klain as the ebola coordinator. he was neither a doctor nor a scientist, and he left the job after six months, while ebola was still spreading in africa. while additional capability was developed at medical centers in the united states under klain's tenure, there were few noticeable signs of progress; he was not open to the media [ ] ; and likely as a result, was not embraced by the public. if the president chose a well-respected individual with healthcare and pharmaceutical industry expertise to serve in the white house to coordinate policies, funding and messages from nih, the cdc, the department of defense, the state department, state public health agencies, and other national and international institutions involved in the chain of prevention, detection, and treatment of infectious disease, it would be optimal. critical manufacturing capabilities have moved overseas, particularly to india and china. the us government could provide tax and other incentives and clear policies for approval for drugs, biologics, and manufacturing facilities to get manufacturing of key ingredients back to the united states. this would allow a faster and more certain response in times of emergency and the allow the government to initiate emergency medicine production under president obama's march executive order [ ] -national defense resources preparedness for manufacturing and distribution of medicines during times of crisis and the defense production act of as amended [ ] . international institutions are making significant efforts in preventing, detecting and responding to infectious diseases, and the continued work and support through the who, un, nato, the pan american health organization, the g , the cdc global health initiative, and other domestic and international bodies will improve international surveillance, reporting, prevention, and response. mechanisms for early reporting would avoid punishment such as travel bans for acknowledgement of dangerous infectious diseases within countries' borders. in addition, leaders in the united states would work to develop trusted relationships with peers in other countries. with more us foreign aid directed towards building public health infrastructure, the funds would have the primary impact of bolstering response and reducing transmission and casualties from infectious diseases within a country and secondary impacts of stabilizing societies (studies have shown that countries with healthy populations are more stable [ ] ). these outcomes would result in a safer and more secure world as there would be reduced disease transmission across borders. there are many existing global and domestic health initiatives such as the following: [ ] . lessons learned from this work can be utilized to further the goals of improving prevention and response to infectious disease. a research and response focus on diseases we encounter in the modern era as opposed to an emphasis on old soviet threats (unless the intelligence community identifies specific threats in the areas of bioterrorism and biowarfare) would enhance prevention and response capacities and funnel limited resources to current health and disease issues. preparations for naturally occurring outbreaks will not only prevent deaths year to year, but will also help exercise countries to fight intentionally introduced diseases by developing policies, procedures, infrastructure, and new technologies that foster quick innovation and therefore response to any microorganism, natural or manmade. each day, there are technological advances for preventing and combatting infectious diseases in addition to the progress specifically in medical research. for instance, adoption of advanced wastewater treatment systems can reduce exposure to antibiotics and args. this can be accomplished by tax incentives and partial payment by the federal government when wastewater treatment systems are replaced and advanced systems are used. in , $ billion federal dollars were spent on water utilities (water supply or treatment) accounting for approximately one quarter of public infrastructure spending [ ] . state and local governments spent $ billion for the operation and maintenance of infrastructure double the spending on capital improvements ($ billion). "although state and local governments rely primarily on their own revenues to purchase capital, federal grants also are an important source of funds. since , federal grants have accounted for one-third or more of the capital spending on infrastructure by states and localities. that share was considerably larger from the mid- s through the mid- s as a result of federal support for water utilities after passage of the clean water act in [ ] ." a renewal of this investment, with a focus on improving water treatment to remove antibiotics, args and other pollutants and destroying resistant organisms, would expand the positive results. regulations limiting the concentrations of antibiotics and args in treated municipal water, if enacted, in concert with meaningful financial penalties for those violating these standards, may significantly reduce the risk of population exposure. this can be difficult because the source of the contamination is often hard to identify. current antiviral drugs have several disadvantages including their specificity, toxicity and expense. researchers at the charles draper stark laboratories developed draco (double-stranded rna activated caspase oligomerizer). in lab-grown cells, draco killed different viruses, including ones that cause the common cold, influenza, polio and dengue fever with minimal effects on healthy cells [ ] ; however, there is still much work to be done before this drug can be fda approved and used by the general public. vectored vaccines use a live-vaccine made with a partial pathogen. they have been developed against sars-cov and demonstrated in mice, but the safety of vesicular stomatitis virus vaccine (vsv) in humans requires further research. newcastle disease virus, a host range-restricted virus, has been developed as a vaccine vector for intranasal immunization against emerging pathogens [ ] . science informs advances in drug development. for instance, authors reviewed a variety of genome sequence and gene knockout data for acinetobacter spp., with a focus on the critical systems to find the most appropriate sequences to target for therapies [ ] . this is just one early example in the explosive field of bioinformatics. in , in recognition of the importance of bioinformatics as a tool to diagnose and develop therapeutics for infectious diseases, the national institute of allergy and infectious diseases established four bioinformatics resource centers (brcs) to collect, store, and share bioinformatics information on bacteria, viruses, eukaryotic pathogens, and invertebrate vectors of human pathogens. as with the factors involved in the rise of the threat the responses are interrelated. the fda is, and must continue to, evolve its policies and regulations in the approval process so that research can proceed to the stage where drugs and biologics are ready for human use. this is discussed in more detail in the policies section below. because infectious diseases do not respect borders, it is in the strategic interest of the united states, the european union, and other countries with developed public health systems to invest in global public health infrastructure. this requires both a long-term investment as well as an acute response capability. president obama recognized both of these in the fall of . first on september , at the global health summit, president obama discussed long-term capacity building: "we, collectively, have not invested adequately in the public health capacity of developing countries." "this speaks to a central question of our global age-whether we will solve our problems together, in a spirit of mutual interest and mutual respect, or whether we descend into the destructive rivalries of the past. when nations find common ground, not simply based on power, but on principle, then we can make enormous progress. [ ] " a few weeks later, president obama discussed the acute strategic needs, "as i have said from the start of this [ebola] outbreak, i consider this a top national security priority. this is not a matter of charity-although obviously the humanitarian toll in countries that are affected in west africa is extraordinarily significant. this is an issue about our safety [ ] ." the president also signed the executive order on combating antibiotic-resistant bacteria in september of [ ] . recent outbreaks of diseases thought banished from the united states demonstrate the need for full vaccination. several communities resist vaccination, and incentives to vaccinate will increase population safety and prevent those who cannot be vaccinated from coming down with vaccinepreventable diseases. one common incentive is the requirement to be vaccinated to enter public school. waivers can be sought, but to boost the vaccination rates, state and local governments can reduce the numbers of exemptions provided. mississippi has already followed this course, and it has the highest vaccination rates in the united states. other potential policies include requiring exemption forms to be filed yearly; requiring parents to complete an education component; and requiring private as well as public school children to be vaccinated [ ] . several states are implementing one or more related measures. while only four states do not recognize a religious exemption from vaccinations, states do not allow exemptions for personal reasons (all states allow exemptions for medical reasons). in part due to the measles outbreak, on july of california will eliminate all non-medical vaccine exemptions. pennsylvania is also pondering eliminating personal exemptions. colorado has made the exemption process more burdensome [ ] . dina fine maron of scientific american [ ] suggested the following common sense approach: improved education and communication, sustain and enhance immunization outreach, maintain vigilance and rapidly contain imported infections. anthony fauci proposed partnerships, among government, industry, and academia to develop additional timely solutions to the threat of new and resurgent infectious diseases [ ] . one example of a successful academia-industry partnership is the response to the hiv/aids epidemic. aids was first recognized in the early s and the death rate steadily increased through the mid- s when it was recognized as a worldwide epidemic. research at and collaboration among academic institutions (including wayne state university) and investment by the public and private sectors (burroughs wellcome which later became glaxosmithkline) led to the development of the antiretroviral treatments used today. the partnerships transformed a deadly infection into a principally chronic disease within two decades [ ] [ ] [ ] . partnerships now work to ensure prevention, testing, distribution of anti-hiv/aids drugs and treatment worldwide. over the years fda has introduced innovations for the development and approval of pharmaceuticals including fast track, parallel track, orphan drugs, surrogate endpoints, noninferiority [ ] . according to the fda guidance [ ] , a non-inferiority (ni) study is used to demonstrate that the degree of inferiority of the drug being tested as compared to the control (an already approved drug) is less than the noninferiority margin. recently, to facilitate the development of biopharmaceuticals, a cross-industry group, including members from astra zeneca, university of texas medical school houston and smaller pharmaceutical companies, proposed a tiered evidence-based regulatory approach. in this approach tier a is the typical large phase iil approach and tier d is equivalent to the animal rule, which states that "for drugs developed to ameliorate or prevent serious or life threatening conditions caused by exposure to lethal or permanently disabling toxic substances, when human efficacy studies are not ethical and field trials are not feasible, fda may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is reasonably likely to produce clinical benefit in humans [ ] ." tiers b and c rely heavily on preclinical data and combined animal and human pharmacokinetic and pharmacodynamic (pk-pd) data fully integrated into a limited clinical program [ ] . in the c. difficile study discussed above, suggestions for prevention include: limit contact, limit inappropriate antibiotic usage, and increase surface cleaning. handwashing with soap from dispensers with sealed refills instead of open refillable dispensers can lower the risk of infection [ ] and is just one example of a common sense technique to prevent the spread of many bacterial infections. another common sense response is increased monitoring. cryptosporidium parvum did not appear to pose a risk until , people became ill, and approximately people died of cryptosporidiosis in milwaukee's water service area in . today, regulators and public health scientists are trying to identify microbes that pose a similar risk in the future. if these microbial contaminants occur in raw water supplies, they may need monitoring and treatment prior to these waters entering the potable water distribution system. the contaminant candidate list (ccl) developed by the united states environmental protection agency outlines a series of biological contaminants of concern that are not currently regulated but may pose a threat. should these contaminants move from the ccl to a regulatory framework, water supply utilities will incur added monitoring and testing of their water supply sources, and potentially added monitoring and treatment costs in their operations, but safety will likely increase as a result of these expenditures. the article discusses many of the problems and solutions due to emerging pathogens with a focus on the impact and response in the united states. these challenges are exacerbated in less well-off countries with poor sanitation, lack of access to preventative health care, unstable governments, or weak public health infrastructure. awareness is key, and this and other articles are working to spread the message. the threat from emerging diseases is continuously evolving as evidenced by the recent appearance of the zika virus. while the virus itself was isolated from the zika forest in uganda in the first half of the twentieth century, it did not begin to take a serious human toll until when it traveled from the pacific islands to brazil [ ] : it is now considered a global threat, with its vector, the aedes species mosquito living on all continents [ ] . there have been more than one million cases in brazil, and researchers noticed a surge in fetal microcephaly, a small head size for gestational age and sex indicating issues with brain growth, in zika-prone locations [ ] . it is now widely accepted that maternal infection with zika can lead to serious consequences for a fetus. for most infected, the effects will be minimal, but in addition to the fetal effects guillain-barre increases have been associated with zika infections. reliable diagnosis is not yet widely available, but reverse-transcriptase polymerase chain reaction (rt-pcr) testing of serum in the first seven days after symptom onset or igm-capture enzyme-linked immunosorbent assay (mac-elisa) analysis of samples are the most promising methods [ ] . animal models for further research, therapeutics and vaccines are required [ ] to stop the negative impacts of the disease since the vector is widespread and difficult if not impossible to eradicate. the general growing awareness of the threat posed by infectious disease because of travel, urbanization and all of the other factors described above combined with the serious consequences, primarily for pregnant mothers and their fetuses led to one of the fastest global responses to an infectious disease in the history of humankind. on april , , president obama announced that he would direct $ million in federal dollars remaining from the fund to fight ebola to fight the zika virus. the money will primarily be used for cdc and nih research on the virus, its role in birth defects, and vaccines for prevention. funds will also go to the formation of cdc response teams. this funding falls short of the $ . billion in emergency money president obama initially requested, and the shortfall is likely to delay a complete, effective response. internationally, the who designed and disseminated a global strategic response framework and joint operations plan, which can be accessed at http://www.who. int/emergencies/zika-virus/response/en/ . compare this to the response to polio, an enterovirus that causes few symptoms in the vast majority of cases, but can cause paralysis and even death in - % of cases. though poliovirus circulated in the population for hundreds of years, it did not reach 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bulk-soap-refillable dispensers zika virus the global distribution of the arbovirus vectors aedes aegypti and ae albopictus acknowledgments dr. ralph mitchell inspired me to look at the world in a new way, from the perspective of the tiny organisms that make the world what it is, but also threaten that world. key: cord- -erpoh he authors: schaback, robert title: on covid- modelling date: - - journal: nan doi: nan sha: doc_id: cord_uid: erpoh he this contribution analyzes the covid- outbreak by comparably simple mathematical and numerical methods. the final goal is to predict the peak of the epidemic outbreak per country with a reliable technique. this is done by an algorithm motivated by standard sir models and aligned with the standard data provided by the johns hopkins university. to reconstruct data for the unregistered infected, the algorithm uses current values of the infection fatality rate and a data-driven estimation of a specific form of the recovery rate. all other ingredients are data-driven as well. various examples of predictions are provided for illustration. this contribution starts in section with a rather elementary reconciliation of the standard sir model for epidemics, featuring the central notions like basic reproduction number, herd immunity threshold, and doubling time, together with some critical remarks on their abuse in the media. experts can skip over this completely. readers interested in the predictions should jump right away to section . section describes the johns hopkins data source with its limitations and flaws, and then presents a variation of a sir model that can be applied directly to the data. it allows to estimate basic parameters, including the basic reproduction number, but does not work for predictions of peaks of epidemics. to achieve the latter goal, section combines the data-compatible model of section with a sir model dealing with the unknown susceptibles and the unregistered infectious. this needs two extra parameters that should be extracted from the literature. the first is the infection fatality rate, as provided e.g. by [ , ] , combined with the case fatality rate that can be deduced from the johns hopkins pointing out certain abuses of these notions. this will not work without calculus, but things were kept as simple as possible. readers should take the opportunity to brush up their calculus knowledge. experts should go over to section . the simplest standard "sir" model of epidemics (e.g. [ ] and easily retrievable in the wikipedia [ ] ) deals with three variables . susceptible (s), . infectious (i), and . removed (r). the removed cannot infect anybody anymore, being either dead or immune. this is the viewpoint of bacteria of viruses. the difference between death and immunity of subjects is totally irrelevant for them: they cannot proliferate anymore in both cases. the sir model cannot say anything about death rates of persons. the susceptible are not yet infected and not immune, while the infectious can infect susceptibles. the three classes s, i, and r are disjoint and add up to a fixed total population count n = s + i + r. all of these are ideally assumed to be smooth functions of time t, and satisfy the differential equationṡ s = −β s n i, where the dot stands for the time derivative, and where β and γ are positive parameters. the product s n i models the probability that an infectious meets a susceptible. note that the removed of the sir model are not the recovered of the johns hopkins data that we treat later, and the sir model does not account for the confirmed counted there. sinceṄ =Ṡ +İ +Ṙ = , the equation n = s + i + r is kept valid at all times. the term β s n i moves susceptibles to infectious, while γi moves infectious to removed. thus β represents an infection rate while the removal rate γ accounts for either healing or fatality after infection, i.e. immunity. political decisions about reducing contact probabilities will affect β , while γ resembles the balance between the medical aggressivity of the infection and the quality of the health care system. as long as the infectious i are positive, the susceptibles s are decreasing, while the removed r are increasing. excluding the trivial case of zero infectious from now on, the removed and the susceptible will be strictly monotonic. qualitatively, the system is not really dependent on n, because one can multiply n, r, i, and s by arbitrary factors without changing the system. as an aside, one can also go over to relative quantities with the two differential equations d dt figure shows some simple examples that will be explained in some detail below. we start by looking at the initial conditions. since everything is invariant under an additive time shift, we can start at time and consideṙ i( ) = +β s( ) n i( ) − γi( ) and see that the infectious decrease right from the start if and this keeps going on since s must decrease anḋ there is no outbreak in this case, because there are not enough susceptibles at start time. the case s( ) = n means that there is no infection at all, and we ignore it, though it is a solution to the system, with i = r = , s = n throughout. if there is a time instance t i (maybe t i = above) where the infectious are positive and do not change, we have =İ(t i ) = β s(t i ) n i(t i ) − γi(t i ), if β < γ holds, this situation cannot occur, and i must be decreasing all the time, i.e. the infection dies out. this is what everybody wants. there is no outbreak. in case of γ = β we go back to the initial situation of the previous section and see that there is no outbreak due to s( )/n < if there is an infection at all. the interesting case is β > γ. then the first part of ( ) shows that as soon as t is larger than the peak time t i , the infectious will decrease due to ( ) . therefore the zero ofİ must be a maximum, i.e. a peak, and it is unique. the infectious go to zero even in the peak situation. it is one of the most important practical problems in the beginning of an epidemic to predict • whether there will be a peak at all, • when the possible peak will come, and • how many infectious will be at the peak. this can be answered if one has good estimates for β and γ, and we shall deal with this problem in the major part of this paper, in real life it is highly important to avoid the peak situation, and this can only be done by administrative measures that change β and γ to the situation β < γ. this is what management of epidemics is all about, provided that an epidemic follows the sir model. we shall see how countries perform. the quotient is called the basic reproduction number. if it is not larger than one, there is no outbreak, whatever the initial conditions are. if it is larger than one, there is an outbreak provided that holds. in that case, there is a time t i where i reaches a maximum, and ( ) holds there. when we discuss an outbreak in what follows, we always assume r > and ( ). if we later let r tend to from above, we also require that s( ) tends to n from below, in order to stay in the outbreak situation. both β and γ change under a change of time scale, but the basic reproduction number is invariant. physically, β and γ have the dimension time − , but r = β /γ is dimensionless. figure shows a series of test runs with s( ) = n · . and r( ) = with fixed γ = . and β varying from . to . , such that r varies from / to . due to the realistically small i( ) being . % of the population, one cannot see the decaying cases near startup, but the tails of the blue i curves are decaying examples by starting value, due to s(t) n < γ β = /r when started at time t. decreasing r flattens the blue curves for i. one can observe that i always dies out, while s and r tend to fixed positive levels. we shall prove this below. from the system, one can also infer that r has an inflection point where i has its maximum, since .. if only r would be observable, one could locate the peak of i via the inflection point of r. figure shows an artifical case with a large starting value i( ) = n/ , fixed γ = . and β varying from . to . , letting r vary from . to . in contrast to figure , this example shows cases with small r properly. the essence is that the infectious go down, whether they have a peak or not, and there will always be a portion of susceptibles. again, we shall prove this below. classical sir modeling this is a number related to the basic reproduction number r by following a special scenario. if a population is threatened by an infection with basic reproduction number r , what is the number of immune persons needed to prevent an outbreak right from the start? we can read this off equation ( ) in the ideal situation that i( ) = and s( ) + r( ) = n, namely r as the threshold between outbreak and decay. this does not refer to a whole epidemic scenario, nor to an epidemic outbreak. it is a condition to be checked before anything happens, and useless within a developing epidemic, whatever the media say. in the peak situation of ( ), the fraction of the non-susceptible at the peak t i of i is exactly the herd immunity threshold. thus it is correct to say that if the immune of a population are below the herd immunity threshold at startup, and if the basic reproduction number is larger than one, the sum of the immune and the infectious will rise up to the herd immunity threshold and then the infectious will decay. this is often stated imprecisely in the media. furthermore, the herd immunity threshold has nothing to do with the important long-term ratio of susceptibles to removed. we shall address this ratio in section . . the most interesting questions during an outbreak with r > are • at which time t i will we reach the maximum of the infectious, and • what is i(t i ), i.e. how many people will maximally be infectious at that time? it will turn out that there are no easy direct answers. from ( ) we see that at the maximum of i the susceptibles s have the value i.e. the portion /r of the population is susceptible. from that time on, the infectious decrease. in terms of r and i, the value of the non-susceptibles marks the peak of the infectious at the herd immunity threshold. "flattening the curve", as often mentioned in the media, is intended to mean making the maximum of i smaller, but this is not exactly what happens, since the maximum is described by the penultimate equation concerning the susceptibles, while for i(t i ) we only know yielding that the left-hand side gets smaller if r gets closer to one. politically, this requires either making β smaller via reducing contact probabilities or making γ larger by improving the health system, or both. anyway, "flattening the curve" works by letting r tend to from above, but the basic reproduction number does not directly determine the time t i of the maximum or the value there. we shall improve the above analysis in section . . in the beginning of the outbreak, s/n is near to one, and thereforė i ≈ +β i − γi models an exponential outbreak with exponent β − γ > , with a solution if this is done in discrete time steps ∆t, one has the severity of the outbreak is not controlled by r = β /γ, but rather via β − γ. publishing single values i(t) does not give any information about β − γ. better is the ratio of two subsequent values and if this gets smaller over time, the outbreak gets less dramatic because β − γ gets smaller. really useful information about an outbreak does not consist of values and not of increments, but of increments of increments, i.e. some second derivative information. this is what the media rarely provided during the outbreak. another information used by media during the outbreak is the doubling time, i.e. how many days it takes until daily values double. this is the number n in i.e. it is inversely proportional to β − γ. if political action doubles the "doubling time", if halves β − γ. if politicians do this repeatedly, they never reach β < γ, and they never escape an exponential outbreak if they do this any finite number of times. extending the doubling time will never prevent a peak, it only postpones it and hopefully flattens it. when presenting a "doubling time", media should always point out that this makes only sense during an exponential outbreak. and it is not related to the basic reproduction number r = β /γ, but rather to the difference β − γ. media often say that the basic reproduction number r gives the number of persons an average infectious infects while being infectious. this is a rather mystical statement that needs underpinning. the quantity is a value that has the physical dimension of time. it describes the ratio between current infectious and current newly removed, and thus can be seen as the average time needed for an infectious to get removed, i.e. it is the average time that an infectious can infect others. correspondingly, are the newly infected, and therefore can be seen as the time it needs for an average infectious to generate a new infectious. the ratio β γ s n then gives how many new infectious can be generated by an infectious while being infected, but this is only close to r if s ≈ n, i.e. at the start of an outbreak. a correct statement is that r is the average number of infections an infectious generates while being infectious, but within an unlimited supply of susceptibles. besides the peak in case r > , it is interesting to know the portions of the population that get either removed (by death or immunity) or get never in contact to the infection. this concerns the long-term behavior of the removed and the susceptibles. figures and if we are at a time t d behind the possible peak at t i , or in a decay situation enforced by starting value, like in ( ), we know that i must decrease exponentially to zero. this follows from showing that log i must decrease linearly, or i must decrease exponentially. thus we get rid of the infectious in the long run, keeping only susceptibles and removed. surprisingly, this happens independent of how large r is. dividing the first equation in ( ) by the third leads to and when setting σ = s/n and ρ = r/n, we get when assuming r( ) = at startup. since ρ is increasing, it has a limit < ρ ∞ ≤ for t → ∞, and in this limit holds, together with the condition ρ ∞ + σ (ρ ∞ ) = , because there are no more infectious. the equation has a unique solution in ( , ) dependent on σ ( ) < and r = β /γ. see qualitatively, we can use ( ) or ( ) in the form to see that the ratio of removed to susceptibles increases with r , but there is a logarithm involved. all of this has some serious implications, if the model is correct for an epidemic situation. first, the infectious always go to zero, but susceptibles always remain. this means that a new infection can always arise whenever some infected person enters the sanitized population. the outbreak risk is dependent on the portion σ ∞ = − ρ ∞ of the susceptibles. this illustrates the importance of vaccination, e.g. against measles or influenza. the above analysis shows that large values of r lead to large relative values of removed to susceptible in the limit. the consequence is that systems with large r have a dramatic outbreak and lead to a large portion of removed. this is good news in case that the rate of fatalities within the removed is low, but very bad news otherwise. when politicians try to "flatten the curve" by bringing r below from some time on, this will automatically decrease the asymptotic rate of removed and increase the asymptotic rate of susceptibles in the population. this is particularly important if the rate of fatalities within the removed is high, but by the previous argument the risk of re-infection rises due to the larger portion of susceptibles. the decay situation ( ) implies that therefore the final rate of the removed is not smaller than the herd immunity threshold. this is good news for possible re-infections, but only if the death rate among the removed is small enough. in a decay situation like in ( ), we get figure : solving for ρ ∞ for fixed c( ) = . and varying r to see that the exponential decay is not ruled by β − γ as in the outbreak case with r > , but rather by −γ + β σ ∞ . this also holds for large r = β /γ because σ ∞ counteracts. the bell shapes of the peaked i curves are not symmetric with respect to the peak. if we go back to analyzing the peak of i at t i for r > , we know and get leading to for standard infections that have starting values σ ( ) = s( )/n very close to one, the maximal ratio of infectious is figure shows the behaviour of the function, and this is what "flattening the curve" is all about. a value of r = gets a maximum of more than % of the population infectious at a single time. if % need hospital care, this implies that a country needs hospital beds for % of the population. the dotted line leaves the log term out, i.e. is marks the rate of the susceptibles at the peak, and by ( ) the difference is the rate r(t i )/n of the recovered at the peak. to analyze the peak time t i , we usė to get an upper bound for the exponential outbreak that implies a lower bound for t i of the form this needs improvement. to get a quantitative result about "flattening the curve", we first evaluate the integral assuming r( ) = , and set it equal to an integral over the constant value at the maximum, i.e. we squeeze the area under the curve into a rectangle of length b −a under the maximal value, i.e. and if we "flatten the curve" by letting r tend to from above, we see that the length b − a of the above rectangle goes to infinity like r /( − r ), because ρ ∞ tends to . if there is no peak, e.g. if r = β /γ is below either at the beginning or after some political intervention, one can repeat the above argument starting with the infectious at some time t looking at the area under i from t to infinity: this needs improvement as well. here is a detour that is well-known in the sir literature. the sir system can be written as and in a new time variable τ with dτ = i n dt, one gets the system the beauty of this is that the roles of β and γ are perfectly split, like the roles of σ and ρ. in the new timescale, ρ increases linearly and σ decreases exponentially. the basic reproduction number then describes the fixed ratio ( ), and the result ( ) of section . comes back as for the case ρ( ) = . this approach has the disadvantage to conceal the peak within the new timescale, and is useless for peak prediction. if data for the sir model were fully available, one could solve for and we shall use this in section . . the validity of a sir model can be tested by checking whether the right-hand sides for β , γ and r are roughly constant. if data are sampled locally, e.g. before or after a peak, the above technique should determine the parameters for the global epidemic, i.e. be useful for either prediction or backward testing. however, in pandemics like covid- , the parameters β and γ change over time by administrative action. this means that they should be considered as functions in the above equations, and then their changes may be used for conclusions about the influence of such actions. this is intended when media say that "r has changed". from this viewpoint, one can go back to the sir model and consider β and γ as "control functions" that just describe the relation between the variables. but the main argument against using ( ) is that the data are hardly available. this is the concern of the next section. now we want to confront the modelling of the previous section with available data. this is crucial for maneuvering countries through the epidemics [ ] . in this text, we work with the covid- data from the cssegisanddata repository of the johns hopkins university [ ] . they are the only source that provides comparable data on a worldwide scale. the numbers there are as cumulative integer valued time series in days from jan. nd, . all these values are absolute numbers, not relative to a total population. note that the unconfirmed cases are not accessible at all, while the confirmed contain the dead and the recovered of earlier days. at this point, we do not question the integrity of the data, but there are many wellknown flaws. in particular, the values for specific days are partly belonging to previous days, due to delays in the chains of data transmission in different countries. this is why, at some points, we shall apply some conservative smoothing of the data. finally, there are inconsistencies that possibly need data changes. for an example, consider that usually covid- cases lead to recovery or death within a rather fixed period, e.g. k ≈ − days. but some johns hopkins data have less new infectioned at day n than the sum of recovered and dead at day n + k. and, there are countries like germany who deliver data of recovered in a very questionable way. the law in germany did not enforce authorities to collect data of recovered, and the united kingdom did not report numbers of dead and recovered from places outside the national health system, e.g. from senior's retirement homes. both strategies have changed somewhat in the meantime, as of early may, but the data still keep these flaws. we might assume that the dead plus the recovered of the johns hopkins data are the removed of the sir model, and that the infectious i = c − r − d of the johns hopkins data are the infectious of the sir model. but this is not strictly valid, because registration or confirmation come in the way. on the other hand, one can take the radical viewpoint that facts are not interesting if they do not show up in the johns hopkins data. except for the united kingdom, the important figures concern covid- casualties that are actually registered as such, others do not count, and serious cases needing hospitalization or leading to death should not go unregistered. if they do in certain countries, using such data will not be of any help, unless other data sources are available. if sir modelling does not work for the johns hopkins data, it is time to modify the sir technique appropriately, and this will be tried in this section. an important point for what follows is that the data come as daily values. to make this compatible with differential equations, we shall replace derivatives by differences. to get a first impression about the johns hopkins data, figure shows raw data up to day (may th , as of this writing). the presentation is logarithmic, because then linearly increasing or decreasing parts correspond to exponentially increasing or decreasing numbers in the real data. many presentations in the media are nonlogarithmic, and then all exponential outbreaks look similar. the real interesting data are the infectious i = c − r − d in black that show a peak or not. the other curves are cumulative. the data for other countries tell similar stories and are suppressed. the media, in particular german tv, present covid- data in a rather debatable way. when mentioning johns hopkins data, they provide c, d, and r separately without stating the most important figures, namely i = c − d − r, their change, and the change of their change. when mentioning data of the infectious from the robert koch institute alongside, they do not say precisely that these are noncumulative and should be compared to the i = c −r−d data of the johns hopkins university. and, in most cases during the outbreak, they did not mention the change of the change. quite like all other media. one can see in figure that germany and south korea have passed the peak of the infectious, while france is roughly at the peak and the united states are still in an exponential outbreak. the early figures, below day , are rather useless, but then an exponential outbreak is visible in all cases. this outbreak changes its slope due to political actions, and we shall analyze this later. see [ ] for a detailed early analysis of slope changes. there are strange anomalies in the recovered (green). france seems not to have delivered any data between days and , germany changed the data delivery policy between days and , and the uk data for the recovered are a mess. it should be noted that the available medical results on the covid- disease often state that confirmed will die or survive after a more or less fixed number of days, roughly to . this would imply that the red curves for the dead and the green curves for the recovered should roughly follow the blue curves for the confirmed with a fixed but measurable delay. this is partially observable, but much less accurately for the recovered. the idea is to define a model that works exclusively with the johns hopkins data, but comes close to a sir model, without being able to use s. since the sir model does not distinguish between recoveries and deaths, we set r sir ⇔ d jh + r jh and let the infectious be comparable, i.e. and we completely omit the susceptibles. from now on, we shall omit the subscript jh when we use the johns hopkins data, but we shall use sir when we go back to the sir model. defining time series γ n and b n that model γ and b = β · s sir /n without knowing s sir . this is equivalent to the model c n+ −c n = b n i n , i n+ − i n = b n i n − γ n i n , (r + d) n+ − (r + d) n − = γ n i n that maintains c = i + r + d, and we may call it a johns hopkins data model. it is very close to a sir model if the time series b n is not considered to be constant, but just an approximation of β · s sir /n. by brute force, one can consider as a data-driven substitute for β γ then there is a rather simple observation: if r n is smaller than one, the infectious decrease. it follows from but this is visible in the data anyway and not of much help. since r n models r s sir n , it always underestimates r . this underestimation gets dramatic when it must be assumed that s sir gets seriously smaller than n. at this point, it is not intended to forecast the epidemics. the focus is on extracting parameters from the johns hopkins data that relate to a background sir-type model. figure shows r s sir n estimates via r n for the last four weeks before day , i.e. march th . except for the united states, all countries were more or less successful in pressing r below one. in all cases, s sir /n is too close to one to have any influence. the variation in r n is not due to the decrease in s sir /n, but should rather be attributed to political action. as mentioned above, the estimates for r by r n are always too optimistic. for the figure, the raw johns hopkins data were smoothed by a double action of a / , / , / filter on the logarithms of the data. this smoother keeps constants and linear sections of the logarithm invariant, i.e. it does not change local exponential behavior. this smoothing was not applied to figure . it was by far not strong enough to eliminate the apparent -day oscillations that are frequently in the johns hopkins data, see the figure. data from the robert koch institute in germany have even stronger -day variations. as long as r n is roughly constant, the above approach will always model an exponential outbreak or decay, but never a peak, because the difference equations are linear. it can only help the user to tell if there is a peak ahead or behind, depending on r n ≈ r being larger or smaller than . if r n is kept below one, the confirmed infectious will not increase, causing no new threats to the health system. then the s/n factor will not decrease substantially, and a full sir model is not necessary. on the other hand, if a country manages to keep r n smaller than some r = b γ < , it is clear that it takes as long as countries keep the r n clearly below one, e.g. below / , this would mean that r ≈ r n n s sir stays below one if s sir ≥ n/ , i.e. as long as the majority of the population has not been in contact with the sars-cov- virus. this is good news. but observing a small r n can conceal a situation with a large r if s sir /n is small. this is one reason why countries need to get a grip on the susceptibles nationwide. it is tempting to use the above technique for prediction in such a way that the b n and the γ n are fitted to a constant or a linear function, and using the values of the fit for running the system into the future. this is very close to extending the logarithmic plots of figure by lines, using pencil and ruler, and thus hardly interesting. so far, the above argument cannot replace a sir model. it only interprets the available data. however, monitoring the johns hopkins data in the above way will be very useful when it comes to evaluate the effectivity of certain measures taken by politicians. it will be highly interesting to see how the data of figure continue, in particular when countries relax their contact restrictions. for cases where one still has to expect r > , e.g. uk, us and sweden around day (see figure ), the challenge remains to predict a possible peak. using the estimates from the previous section is questionable, because they concern the subpopulation of confirmed and are systematically underestimating r . the "real" sir model will have different parameters, and it needs the susceptibles to model a peak or to make the r n estimates realistic. so far, the johns hopkins data work in a range where s/n is still close to one, and the susceptibles are considered to be abundant. but the bad news for countries with r n > is that r n underestimates r . anyway, if one trusts the above time series as approximations to β and γ, one can run a sir model, provided one is in the case r > and has reasonable starting values. but these are a problem, because the unconfirmed infectious and the unconfirmed recovered are not known, even if, for simplicity, one assumes that there are no unconfirmed covid- deaths. for an unrealistic scenario, consider total registration, i.e. all infected are automatically confirmed. then the susceptibles in the johns hopkins model would be s n = n −c n = n − i n − r n − d n . now the estimate for r must be corrected to r n n s n = r n n n −c n = r n + c n n −c n but this change will not be serious during the outbreak. one gets a crude prediction of the peak in case r = β /γ > . figure shows results for two cases. the top shows the case for the united states using data from day (may th ) and estimating β and γ from the data one week before. the peak is predicted at day with a total rate of % infectious. to see how crude the technique is, the second plot shows the case of germany using data up to day , i.e. before the peak, and the peak is predicted at day with about % infected. at day , r was estimated at . , but a few days later the estimate went below ( figure ) by political intervention changing b n considerably. see figure for a much better prediction using data only up to day . to get closer to what actually happens, one should combine the data-oriented johns hopkins data model with a sir model that accounts for what happens outside of the confirmed. we introduce the time series this implies that all deaths occur within the confirmed, though this is a highly debatable issue. it assumes that persons with serious symptoms get confirmed, and nobody dies of covid- without prior confirmation. the removed from the viewpoint of a global sir model including h and m are h +c, and thus the sir model is to run this hidden model with constant n = s + m + h + c, one needs initial values and good estimates for β and γ, which are not the ones of the johns hopkins data model of section . . the johns hopkins variables d and r are linked to the hidden model via c = i − r − d. they follow an observable model with instantaneous case death and recovery rates γ icd and γ icr for the confirmed infectious. these rates can be estimated separately from the available johns hopkins data, and we shall do this below. we call thes rates instantaneous, because they artificially attribute the new deaths or recoveries at day n + to the previous day, not to earlier days. in this sense, they are rather artificial, and we shall address this question. they are case rates, because they concern the confirmed. the observable model is coupled to the hidden model only by c n . any datadriven c n from the observable model can be used to enter the h + c variable of the hidden model, but in an unknown ratio. conversely, any version of the hidden model produces h + c values that do not determine the c part. summarizing, there is no way to fit the hidden model to the data without additional assumptions. various possibilites were tried to connect the hidden to the observable. two will be presented now. recall that the parameter γ icd in the observable model ( ) relates case fatalities to the confirmed infectious of the previous day. in contrast to this, the infection fatality rate in the standard literature, denoted by γ if here, is relating to the infection directly, independent of the confirmation, and gives the probability to die of covid- after infection with the sars-cov- virus. it is γ if = . % by [ ] and . % by [ ] , but specialized for china. recent data from the heinsberg study by streeck et. al. [ ] gives a value of . % for the heinsberg population in germany. the idea to use the infection fatality rate for information about the hidden system comes from [ ] . the way to use it will depend on how to handle delays, and it turned out to be difficult to use these rates in a stable way. let us focus on probabilities to die either after an infection or after confirmation of an infection. the first is the infection fatality rate given in the literature, but what is the comparable case fatality rate γ cf when using the johns hopkins data? it is clearly not the γ icd in ( ), giving the ratio of new deaths at day n + as a fraction of the confirmed infectious at day n. it makes much more sense to use the fact that covid- diseases end after k days from confirmation with either death or recovery. let us call this the k-day rule. suggested values for k range between and . following [ ] , one can estimate the probability p i to die on day i after confirmation, and this works in a stable way per country, based only on c and d, not on the unstable r data. in [ ] this approach was used to produce r values that comply with the k-day rule, but here we use it for estimating the case fatality. the technique of [ ] performs a fit i.e. it assigns all new deaths at day n to previous new infections on previous days in a hopefully consistent way, minimizing the error in the above formula under variation of the probabilities p i . if the p i are known for days to k, the case fatality rate is this argument can also be seen the other way round: the new confirmed c n −c n− at day enter into d n+ − d n with probability q = p , into d n+ − d n+ with probability q = p ( − p ) and so on. the rest enters into the new recovered at day n + k with probability q k+ if we set p k+ = . thus the case fatality rate can be expressed as − q k+ like above. at this point, there is a hidden assumption. persons that are new to the confirmed at day n are not dead and not recovered. the change c n+ −c n to the confirmed is therefore understood as the number of new registered infections. otherwise, one might replace c n−i −c n−i− by i n−i − i n−i− in ( ), but this would connect a cumulative function to a non-cumulative function. furthermore, this would use the unsafe data of the recovered. in fact, equation ( ) is unexpectedly reliable, provided one looks at the sum of the probabilities p i . this follows from series of experiments that we do not document fully here, in [ ] , data for k days backwards were used for the estimation, and results did not change much when more or less data were used or when k was modified. here, the range ≤ k ≤ was tested, and backlogs of up to days from day (as of this writing). see figure below for an example. larger k lead to somewhat larger fatality rates, because the method has more leeway to assign deaths to confirmations, but the increase is rather small when k is increased beyond . it is remarkable that k = suffices for a rather good fit for us, uk, sweden, and italy. in contrast to other countries, this means that days after confirmation are enough to assign deaths consistently to previous confirmations, indicating that a large portion of confirmations concern rather serious cases. in general, the fit gets better when the backlog is not too large, avoiding use of outdated data, and the resulting rate does not change much when backlogs are shortened. roughly, the rule of a backlog of k days works well, together with k = to allow enough leeway to ensure a small fitting error. note that all variations of k and the backlog data have a rather small effect on the sum of the p i , while the p i will vary strongly. see the first column of table for estimates of case fatality rates for different countries, calculated on day (may th ). these depend strongly on the strategy for confirmation. in particular, they are high when only serious cases are confirmed, e.g. cases that need hospital care. if many more people are tested, confirmations will contain plenty of much less serious cases, and then the case fatality rates are low. the values were entered manually after inspection of a plot of the rates as functions of k and the backlog. see figure for how the value . for italy was determined. the instantaneous case death rate γ icd of ( ) for the johns hopkins data comes out around . for germany by direct inspection of the data via table is about . . the deaths have to be attributed to different days using the k-day rule, they cannot easily be assigned to the previous day without making the rate smaller. if the case fatality rates γ cf of table are used with the infection fatality rate of γ if = . , one should obtain an estimate of the total infectious. if the formula ( ) is written as in terms of the previous new infections s n−i− − s n−i with infection fatality probabilitiesq i , one should maintain and this works by setting in general, without using the unstable p i . the quotient γ if γ cf can be called the detection rate, stating the fraction of infectious that is entering confirmation. see the second column of table . note that all of this is dependent on good estimates of the infection fatality rate, and the new value by [ ] will roughly double the detection rate for germany. all of this is comparable to the findings of [ ] and uses the basic idea from there, but is executed with a somewhat different technique. a simple way to understand the quotient γ if γ cf as a detection rate is to ask for the probability p(c) for confirmation. if the probability to die after confirmation is γ cf , and if there are no deaths outside confirmation, then and it is tempting to replace s by m in ( ), but this would make m cumulative. under political changes of the parameters β and γ, the estimation of the case fatality rate should be made locally, not globally. using the experience of [ ] and section . . , we shall do this using a fixed k = for the k-day rule and data for a fixed backlog of k days. we need another parameter to make the model work. there are many choices, and after some failures we selected the constant γ iir in a model equation following what was mentioned about instantaneous rates in section . , this is an instantaneous infection recovery rate, relating the new unregistered recovered to the unregistered infections the day before. a good value of γ iir can come out of an experiment that produces a time series for m and h, i.e. for unregistered infectious and unregistered recovered. then the instantaneous infection recovery rate γ iir can be obtained directly by the infection recovery rate γ ir = − γ if does not help much, because we need an instantaneous rate that has no interpretation as a probability. without additional input, we can look at the instantaneous case recovery rate that is available from the johns hopkins data, and comes out experimentally to be rather stable. the rate γ iir must be larger, because we now are not in the subpopulation of the confirmed, and nobody can die without going first into the population of the confirmed. as long as no better data are available, we use the formula that accounts for two things: . the value γ icr is increased by the ratio of recovered probabilities for the infected and the confirmed, . the value γ ir is multiplied by a factor for transition to immediate rates, and this factor is the transition factor for the confirmed recovered. the above strategy is debatable and may be the weakest point of this approach. however, others turned out to be worse, mainly due to instability of results. in ( ) the rate γ ir is fixed, and the rate γ cr is determined locally via section . . . the rate γ icr follows from the time series r n+ − r n i n ≈ γ icr as in ( ). this works for countries that provide useful data for the recovered. in that case, and in others to follow below, we can take the time series itself as long as we have data. for prediction, we estimate the constant from the time series using a fixed backlog of m days from the current day. since many data have a weekly oscillation, due to data being not properly delivered during weekends, the backlog should not be less than . but for certain countries, like the united kingdom, the data for the recovered are useless. in such cases, we employ the technique of [ ] to estimate the recovered using the k-day rule and a backlog of k days, like in section . . for the case fatality rates. we now have everything to run the hidden model, but we do it first for days that have available johns hopkins data. this leads to estimations of s, m, and h from the observed data of the johns hopkins source. with the parameters from above, we use the new relations the first equation is a priori and determines s. one could run it over the whole range of available data, if the parameter γ cf were fixed, like γ ci . but since we estimate it via section . that resulted in table , we should use section . . to calculate γ cf locally. the second is a posteriori and lets h follow from m, but we postpone it. the third model equation in ( ) will be handled defining γ n by brute force via we then set up the second model equation for m as that can be solved if an initial value is prescribed. the first model equation in ( ) is used to define β n by the model is run by executing ( ) since the populations are large, the starting values for s are not important. the starting value for h is irrelevant for h itself, because only differences enter, but it determines the starting value for m due to the balance equation. anyway, it turns out experimentally that the starting values do not matter, if the model is started early. the hidden model ( ) depends much more strongly on c than on the starting values. see figure for an example. along with the calculation of s, m, and h, we run the calculation of the time series β n and γ n using ( ) and ( ). these yield estimates for the parameters of the full sir model that replace the earlier time series from the johns hopkins data model in section . . the figures to follow in section . show the original johns hopkins data together with the hidden variables s, m, and h that are calculated by the above technique. note that the only ingredients beside the johns hopkins data are the number k for the k-day rule, the infection fatality rate γ if from the literature, and the backlog m for estimation of constants from time series. to let the combined model predict the future, or to check what it would have predicted if used at an earlier day, we take the completed model of the previous sections up to a day n and use the values s n , m n , h n , c n , i n , r n and d n for starting the prediction. with the variable hc := h +c, we use the recursion this needs fixed values of β and γ that we estimate from the time series for β n and γ n by using a backlog of m days, following section . . . the instantaneous rates γ icr and γ icd can be calculated via their time series, as in ( ) and ( ), using the same backlog. we do this at the starting point of the prediction, and then the model runs in what can be called a no political change mode. examples will follow in section . . the first part of the full model ( ) runs as a standard sir model for the variables s, m and h +c, and inherits the properties of these as described in section . it does not use the γ iir parameter of the second equation in ( ), and it uses the first the other way round, now determining c from s, not s from c. the bracket is positive if which is enough for practical purposes. figure shows predictions on day , may th, for germany, sweden, us and uk, from the top. the plots for countries behind their peak are rather similar to the one for germany. the other three countries are selected because they still have to face their peak, if no action is taken to change the parameters. the estimated r values are . , . , . , and . , respectively. note that these are not directly comparable to figure , because they are the fitted constant to the backlog of a week, and using ( ) and ( ) instead of ( ) . the black and magenta curves are the estimated m and h values, while the s values are hardly visible on the top. the hidden m and h in black and magenta follow roughly the observable i and c in blue and cyan, but with a factor due to the detection rate that is different between countries, see table . to evaluate the predictions, one should go back and start the predictions for earlier days, to compare with what happened later. figure shows overplots of predictions for days , , and , each a fortnight apart. the starting points of the predictions are marked by asterisks again. now each prediction has slightly different estimates for s, m, and h due to different available data. recall that the determination of these variables is done while there are johns hopkins data available, following section . , and will be dependent on the data-driven estimations described there. in particular, the case fatality rates and detection rates of table change with the starting point of the prediction, and they determine s, m, and h backwards, see the figure for sweden. all test runs were made for the infection fatality rate γ if = . , the delay k = for estimating case fatalities, and a backlog of days when estimating constants out of recent values of time series. the choice γ if = . is somewhat between . % from [ ] , . % from [ ] , and . % from [ ] . new information on infection fatality rates should be included as soon as they are available. the johns hopkins data were smoothed by a double application of the / , / , / filter on the logarithms, like for figure . for uk and sweden, the data for the confirmed recovered r were replaced by the -day rule estimation via [ ] and a backlog of days. the original data were too messy to be useful, unfortunately. for an early case in germany, figure shows the prediction based on data of day , march th . on the side, the figure contains a wide variation of the starting value h = n − s − c at the starting point, by multipliers between / and . this has hardly any effect on the results. the peak of about million infected is predicted on day , may th , with roughly a million confirmed and about casualties at the peak and about . finally. note that the real death count is about on may th , and the prediction of the day, in figure , targets a final count of below . the parameter changes by political measures turned out to be rather effective, like in many countries that applied similar strategies. but since parts of the population want to go back to their previous lifestyle, all of this is endangered, and the figures should be monitored carefully. of course, all of this makes sense only under the assumption that reality follows the model, in spite of all attempts to design a model that follows reality. so far, the model presented here seems to be useful, combining theory and practically available data. it is data-driven to a very large extent, using only the infection fatality rate from outside for prediction, and the approximation ( ) for calibration. on the downside, there is quite a number of shortcomings: latest data, but it needs changes as soon as new information on the hidden infections come in. • there may be better ways of estimating the hidden part of the epidemics. however, it will be easy to adapt the model to other parameter choices. if time series for the unknown variables get available, the model can easily be adapted to being data-driven by the new data. • the treatment of delays is unsatisfactory. in particular, infected persons get infected immediately, and the k-day rule is not followed at all places in the model. but the rule is violated as well in the data [ ] . • there is no stochastics involved, except for simple things like estimating constants by least squares, or for certain probabilistic arguments on the side, e.g. in section . . . but it is not at all clear whether there are enough data to do a proper probabilistic analysis. • as long as there is no probabilistic analysis, there should be more simulations under perturbations of the data and the parameters. a few were included, e.g. for section . . and figures and , but a large number was performed in the background when preparing the paper, making sure that results are stable, but there are never too many test simulations. • other models were not considered, e.g. the classical ones with delays [ , ] . • under certain circumstances, epidemics do not show an exponential outbreak, in particular if they hit only locally and a prepared population. see figure for the covid- cases in göttingen and vicinity. • estimates for the peak time in section . need improvement. • same for the underpinning of "flattening the curve" in section . . matlab programs are available on request. modellierung von beispielszenarien der sars-cov- -epidemie in deutschland average detection rate of sars-cov- infections is estimated around six percent inferring covid- spreading rates and potential change points for case number forecasts the mathematics of infectious diseases a problem in the theory of epidemics i a problem in the theory of epidemics ii covid- repository at github sars-cov- steckbrief zur coronavirus-krankheit- (covid- ) modelling recovered cases and death probabilities for the covid- outbreak preliminary results from the heinsberg outbreak, cited after göttinger tageblatt estimates of the severity of coronavirus disease : a model-based analysis, www.thelancet.com/infection published online bloß raus hier ! article in the weekly journal die zeit key: cord- -yl jdarm authors: le, aurora b.; brooks, erin g.; mcnulty, lily a.; gill, james r.; herstein, jocelyn j.; rios, janelle; patlovich, scott j.; jelden, katelyn c.; schmid, kendra k.; lowe, john j.; gibbs, shawn g. title: u.s. medical examiner/coroner capability to handle highly infectious decedents date: - - journal: forensic sci med pathol doi: . /s - - - sha: doc_id: cord_uid: yl jdarm in the united states of america, medical examiners and coroners (me/cs) investigate approximately % of all deaths. unexpected deaths, such as those occurring due to a deceased person under investigation for a highly infectious disease, are likely to fall under me/c jurisdiction, thereby placing the me/c and other morgue personnel at increased risk of contracting an occupationally acquired infection. this survey of u.s. me/cs′ capabilities to address highly infectious decedents aimed to determine opportunities for improvement at me/c facilities serving a state or metropolitan area. data for this study was gathered via an electronic survey. of the electronic surveys that were distributed, the overall response rate was n = ( %), with of those respondents completing all the questions within the survey. at least one me/c responded from of states, and the district of columbia. select results were: less than half of respondents ( %) stated that their office had been involved in handling a suspected or confirmed highly infectious remains case and responses indicated medical examiners. additionally, me/c altered their personal protective equipment based on suspected versus confirmed highly infectious remains rather than taking an all-hazards approach. standard operating procedures or guidelines should be updated to take an all-hazards approach, best-practices on handling highly infectious remains could be integrated into a standardized education, and evidence-based information on appropriate personal protective equipment selection could be incorporated into a widely disseminated learning module for addressing suspected or confirmed highly infectious remains, as those areas were revealed to be currently lacking. increased international travel and exchange are factors that escalate the risk for rapid transmission of emerging and reemerging infectious diseases, and highly infectious diseases (hids). while neither the centers for disease control and prevention (cdc) nor the world health organization (who) has formally published a current standard list of pathogens deemed to be highly infectious, multiple 'priority' pathogens (e.g. coronaviruses, viral hemorrhagic fever viruses, bacillus anthracis, yersinia pestis) are frequently cited as requiring advanced resources, protocols, and training to minimize risk of disease transmission and mortality [ ] [ ] [ ] . the - west africa ebola virus disease (evd) outbreak, for example, challenged the capabilities, capacities, and efficacy of healthcare facilities in caring for patients with a highly infectious pathogen both abroad and in the united states [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in addition to the direct clinical care provided to patients with confirmed and suspected evd, public health departments and other affiliated sectors including emergency management, clinical and research laboratories, medical waste management, and mortuary services collaborated with medical providers to optimize and support patient care while reducing the risks to environmental and public safety [ ] [ ] [ ] [ ] [ ] . due to the highly infectious nature of evd, comprehensive aspects of infection prevention-including appropriate handling of highly infectious remains-had to be carefully considered and planned to contain disease spread. careful handling of highly infectious remains was particularly imperative given that viral loads were found to be high immediately after an evd-infected individual died, thereby posing hazardous to pathology and mortuary personnel [ , , ] . the risk of infection for death care sector workers posed by hids was exemplified by the infection of a german mortuary worker with lassa fever following the processing of remains previously unknown to be infected with lassa virus [ ] . at the height of the - outbreak, the cdc published guidelines for handling evd-infected human remains informed by evidence-based best practices to address the transmission risk posed to workers [ ] ; however, a recent gap analysis survey of the u.s. death care sector-specifically of funeral homes and crematories-revealed that most were unaware of these guidelines. overall, the study found a lack of up-to-date education, training and resources provided to this industry to safely manage potential or confirmed highly infectious remains scenarios [ ] . as evd is now re-emerging in other regions of africa [ ] and incidence and mortality of other infectious diseases is globally on the rise, the concerns raised in this study remain ever relevant. thus, it is imperative for those working with potentially infected human remains to receive the requisite training and resources to enable effective disease containment and prevent secondary transmission. in the united states of america (u.s.), medical examiners and coroners (me/cs) investigate approximately % of all deaths. typically, mes are physicians, usually pathologists specializing in forensic pathology, who are appointed government officials. they are charged with investigating unexpected, suspicious, and unnatural deaths in order to determine cause and manner of death and perform autopsies as needed. coroners, conversely, could be non-physicians or nonpathologist physicians who are elected or appointed at the county level; they look into deaths similar to those investigated by mes. coroners largely rely upon pathologists to perform the autopsies. unexpected deaths, such as those occurring due to a deceased person under investigation (pui) for a hid, are likely to fall under me/c jurisdiction, thereby placing the me/c and other morgue personnel at increased risk of contracting an occupationally acquired infection [ , ] . historically, me/cs have often been among the first to encounter infectious disease outbreaks. for instance, me/c offices were instrumental in recognizing outbreaks of diseases such as hantavirus pulmonary syndrome, west nile encephalitis, and novel severe acute respiratory syndrome coronavirus (sars-cov) [ ] [ ] [ ] . while the cdc recommends that no autopsy be performed for a confirmed patient with ebola virus disease, it is likely that if a patient were to die from an unidentified hid that an autopsy would be conducted [ ] . additionally, me/c offices play a critical role in discovering the pathogenesis of infectious diseases as well as providing a means of disease surveillance on a global level [ , ] . in puerto rico, me/c autopsy samples have been used to track dengue virus fatalities, while in south asia they have diagnosed deaths due to emergent nipah virus. me/c offices have also helped demonstrate the lethality of pediatric influenza and confirmed deaths due to creutzfeldt-jakob disease (cjd) [ ] [ ] [ ] . despite the essential role me/c offices play in public health, there have been multiple published reports of considerable obstacles to effective infectious disease and mortality surveillance including the following: inadequate morgue biosafety infrastructure, lack of appropriate staff training/ educational updates, and critical shortages in the numbers of forensic pathologists [ ] [ ] [ ] . uncertainties persist on the capabilities of me/c offices to address increasing baseline case volumes, of which the majority are lower risk infectious disease scenarios. disease containment, in this setting, including prevention of secondary transmission, is critical for the benefit of public health, emergency management, medicine, and the general public. given the critical role me/cs play in this endeavor, and the apparent lack of resources dedicated to this sector of the workforce to protect themselves from potential occupational exposures, this study was conducted to evaluate what protocols are in place for suspected or confirmed highly infectious remains, as well as determining levels of training among u.s. me/cs to handle highly infectious remains. total population purposive sampling was utilized for this nonexperimental design, as each state has its own unique death investigation system [ ] . a contact list of me/c offices serving populations of , or greater was compiled for each state by the national association of medical examiners (name) ad hoc committee for bioterrorism and infectious disease. this minimum population limit was selected in an effort to avoid duplication of survey results, as geographic areas with smaller populations often outsource to larger me/ c offices. an electronic survey with questions created by the authors was distributed via qualtrics© (software version . , provo, ut) through a link in an email solicitation (indiana university institutional review board exemption protocol # ). survey questions included: demographic information (e.g. title, population served, state), personal protective equipment (ppe) worn in different infectious scenarios, procedures performed in different infectious scenarios, duration of training received, biosafety level (bsl) capabilities, and jurisdictional handling of highly infectious remains. the name ad hoc committee for bioterrorism and infectious disease sent email solicitations from december , to february , to encourage responses from me/c offices nationwide, ensuring a comprehensive view of u.s. me/c practices. the survey was closed after weeks. data from qualtrics© was exported and data was analyzed utilizing sas version . (copyright (c) - by sas institute inc., cary, nc, us). frequencies and percentages were used to summarize question responses and chi-square tests were performed to investigate associations between variables; only significant findings were reported and individual states were not named to protect the identity of the state me/c. all responses to questions were voluntary so response rates between questions varied. of the electronic surveys that were distributed, the overall response rate was n = ( %), with of those completing all the questions within the survey. at least one me/c responded from of states, and the district of columbia; three states were excluded because their largest me/c office did not serve a population size of , or greater. medical examiners represented the majority of respondents ( %), followed by coroners ( %) and 'other' titles ( %) (e.g. forensic pathologist, deputy coroner, sheriff-coroner). there appeared to be a difference in distribution of professions across the region, with mes being more evenly distributed than other titles. each u.s. region, as delineated by the department of health and human services, had at least medical examiners, while several regions had zero or one respondent who selected 'coroner" or 'other'. for coroners, % were from the midwest (il, in, mi, mn, oh, and wi) and % of those who selected 'other' were from the west coast (az, ca, hi, and nv) [ ] . twenty-five percent of respondents worked in an office that served a population size between , - , ; % served , - , ; % served , up to million and % of respondents came from an office that served a population greater than million people. when asked which entity was responsible for their office's oversight, % stated a government agency, % public safety or law enforcement, % 'other' (academic medical center or university, city or county health department, political subdivision, or self), % state health department, and % a forensic laboratory. respondents were asked to select all ppe worn when performing standard duties, i.e. when no known infectious disease outbreak was occurring locally or regionally or was reported to the me/c (table ) . 'other' optional items of ppe listed were: a plastic apron over the surgical gown (n = ), waterproof sleeve covers (n = ), hair nets/bonnets (n = ), dedicated autopsy socks (n = ), and one respondent noted use of a tyvek suit for standard duties. for comparison, respondents were asked to select what ppe they would wear when performing duties on suspected or confirmed highly infectious remains (table ) . 'other' optional items of ppe listed were: disposable apron (n = ), waterproof sleeves (n = ), hair net/bonnet (n = ), self-contained breathing apparatus (scba) (n = ), hazardous waste and emergency response standard (hazwoper) gear (n = ), tyvek suit (n = ), and two layers of clothes (cloth and plastic) (n = ). four respondents stated their office would not perform autopsies on such cases. slightly more than half of respondents ( %; / ) stated their office staff had received training on donning and doffing ppe in suspected or confirmed cases of highly infectious remains; nearly one-third ( %) ( / ) reported the amount of cumulative training in hours per person, on average per year, was h or less while % ( / ) spent between and h of training. the entity that provided the ppe training varied widely among respondents. common responses included: in-house staff (n = ), state or local health department (n = ), an affiliated university (n = ), occupational health or a safety and compliance coordinator external to the me/c office (n = ), online-based training (n = ), risk or emergency management (n = ), an infectious disease or infection control specialist (n = ), or individuals highly trained in hazardous materials (hazmat) external to the me/c office (n = ). in the event of suspected highly infectious remains, respondents were asked what procedures would be permissible and performed by their office ( table ). the most frequent responses for 'other' were: dependent on a case-by-case basis/contingent upon suspected pathogen (n = ), sending the remains to the appropriate biocontainment facility (n = ), and one noted a written policy for handling highly infectious remains does not exist and would require discussion with multiple stakeholders, including the safety committee to evaluate risk. for comparison, respondents were asked which procedures or tasks would be performed in the event of confirmed highly infectious remains (table ) . 'other' responses echoed those in a suspected case where it was dependent on the circumstances and suspected pathogen, or only as required by the cdc or local health department (n = ). one respondent stated they would decline jurisdiction if no circumstance beyond the confirmed infectious disease made it reportable. less than half of respondents ( %; / ) stated that their office had been involved in handling a suspected or confirmed highly infectious remains case. the most commonly encountered highly infectious pathogens were: cjd and unclassified prions (n = ); forms of tuberculosis (including extremely drug-resistant [xdr-tb] and multiple drug resistant [mdr-tb]) (n = ); forms of meningitis (streptococcus pneumoniae, meningococcal) (n = ); anthrax (bacillus anthracis) (n = ); suspected cases of ebola and other hemorrhagic fevers (n = ); human immunodeficiency virus (hiv) a percentages add up to more than % because this question was multiple-select a percentages add up to more than % because this question was multiple-select (n = ); h n influenza (swine strain) (n = ); and sars (n = ). while just under half of the respondents stated their office had been involved in handling such remains ( %; / ), those cases do not appear equally distributed across regions. no respondents from upper west coast states (al, id, or, wa) reported office involvement, while all respondents from east coast states (ct, me, ma, nh, ri, vt) reported office involvement. other regions had between % to % of respondents reporting office involvement. eighty-one percent ( / ) of respondents did not have a biosafety level (bsl- ) facility within their office to conduct examinations in suspected highly infectious cases; some did have bsl- capabilities ( %; / ) and bsl- capabilities ( %; / ). table provides definitions of the bsl levels [ ] . in regard to the location at which autopsies were performed in a suspected highly infectious remains case, % ( / ) stated there was a separate autopsy area where no other autopsies were being performed at the same time; % ( / ) stated they do not examine suspected highly infectious remains at their facility; and % indicated 'other', which include not having a separate room/in the regular autopsy area (n = ), altering protocol to limit staff and only have that single case autopsied at the time if there was not a separate room available (n = ), performing autopsy in a negative pressure disaster portable morgue unit (n = ), and that autopsy was contingent on the case load and space available (n = ). one open-ended comment emphasized that it was case dependent, and that "tb gets autopsied, ebola straight to the funeral home" . this statement raises concern as the study by le et al. that surveyed the level of education and training received by u.s. funeral home and crematory personnel on highly infectious disease mitigation and management revealed large gaps in knowledge, including incorrectly marking routes of exposure for evd [ ] . more than half ( %; / ) indicated that their staff was not trained to carry out specialized decontamination procedures following autopsy of suspected or confirmed highly infectious remains. of those who had been trained on decontamination procedures, the most frequent response for the average cumulative length of training in hours per year per person was h or less ( %; / ), followed by h ( %; / ). additionally, a little over one-third of respondents ( %; / bsl- builds upon bsl- but includes additional precautions and facility features which are appropriate for work with moderate-risk microorganisms that are associated with human disease of varying severity. laboratory access is restricted when work is conducted. enhanced engineering controls and personal protection is needed. ppe typically includes lab coats and gloves; eye protection and face shields as needed. in addition to the sink for handwashing, there should also be an eyewash station. all aerosol or splash-generating procedures should be performed in a biological safety cabinet (bsc). there must be an autoclave or alternate method of decontamination for proper waste disposal, and the facility must have self-closing, lockable doors. an example of an organism appropriate for use in a bsl- laboratory is human immunodeficiency virus (hiv). biosafety level- (bsl- ) bsl- builds upon the requirements of bsl- but includes additional precautions and facility features which are appropriate for work with microorganisms which cause serious or potentially fatal disease through respiratory transmission. access to the facility is restricted and controlled at all times. in addition to all the aforementioned ppe, respirators may be worn and are required when experimentally infected animals are present. all microorganisms must be handled within a bsc. a hands-free sink and eyewash station must be available near an exit, exhaust air cannot be recirculated and the facility must have sustained directional airflow from clean areas to more contaminated areas. lastly, entrance into the facility is through two sets of self-closing, locking doors. an example of an organism appropriate for use in a bsl- laboratory is severe acute respiratory syndrome (sars) coronavirus. a these definitions are paraphrased from those provided by the centers for disease control and prevention [ ] ) indicated staff were trained to handle and transport (i.e. package and ship) specimens for suspected highly infectious cases. if staff were trained, specimens were sent most frequently to one or two of the following locations: the cdc (n = ), state reference laboratory (n = ), the national prion disease pathology surveillance center (npdpsc) at case western reserve university for prion diseases (n = ), or an academic medical center/hospital laboratory (n = ). of those that had received training on handling and transporting specimens, the most frequent response for the average cumulative length of training in hours per year per person was h ( %; / ), followed by less than h ( %; / ). there was a statistically significant relationship determined between those answering "no" to their office being involved in handling highly infectious remains and those answering "no" to receiving training to safely handle/transport the specimens. for those who answered "no" to involvement, % had no training for transporting specimens and % did; however, for those who answered "yes" to office involvement, only % had training for transporting specimens and % did not. when asked what their jurisdiction permitted for highly infectious remains, % ( / ) stated embalming was permitted, % ( / ) traditional burial practices, % ( / ) cremation and % ( / ) were unsure. survey respondents also had the opportunity to provide open-ended comments at the end of the survey; respondents did. comments included: a desire for formalized or more frequent training in the area of handling highly infectious remains (n = ); a need for more resources or a lack of preparedness or appropriate facilities to address highly infectious remains (n = ); the difficulty of answering questions pertaining to newly emerging and re-remerging highly infectious diseases because policies had not been written or revised (n = ); a need to formalize and update protocols (n = ); and a need for better funding to attract more prospective forensic pathologists to practice and to purchase greater stocks of ppe since what was available was expired or on back-order (n = ). select direct quotations and themes included that the, "national infrastructure for autopsy biosafety is woefully inadequate" and a perception of being overlooked/neglected in infection control training but still an office "they hand bodies off to" without regard for the limited training and resources. as sudden unexpected deaths fall under medical examiner/ coroner jurisdiction, they may play a fundamental role in the response to infectious disease deaths. if communication between various health sectors is unclear or protocols have not been established by the local health department, there is a risk for occupational exposure for all parties involved, and the potential for a me/c to be exposed to a highly infectious death that has yet to be confirmed. the logistical challenges associated with the response to highly infectious pathogens is demanding for public health sectors focused on the treatment and management of living patients. the role of the death care sector in effective disease surveillance and containment of infectious diseases is often overlooked; including the fundamental role of me/cs. me/cs frequently investigate deaths with little clinical information on the circumstances preceding death. hence, it is crucial to for me/cs to have robust, up-todate education and training in potential highly infectious remains handling, ppe donning and doffing, and clear protocols used when handling human remains that stress universal precautions. to determine what training areas are insufficient or need to be supplemented, this survey evaluated current me/c office capability to handle highly infectious remains. this survey provided a national view of the handling of highly infectious remains by capturing a sample of me/cs from nearly every state and washington d.c. medical examiners comprised the majority of the survey respondents and were more evenly geographically distributed than coroners. nearly half of the respondents served large counties or metropolitan areas with populations of greater than one million people, highlighting the large populations that may be covered by a single me/c office. additionally, most me/c offices, including the body storage areas (morgues), are under government oversight. in order to gauge circumstance-dependent ppe use among me/cs, respondents were asked for standard ppe ensembles worn during routine autopsies and those worn for autopsies on suspected or confirmed highly infectious remains (table ) . slightly more than half ( %) reported wearing an n respirator during routine autopsies and this increased to only % for autopsies on suspected or confirmed highly infectious remains. other higher level ppe such as a powered-air purifying respirator (increased by over %), tyvek suit, hazwoper gear and scba also showed an increase. a surgical mask was worn by % in standard autopsies and by % of me/cs for a suspected or confirmed highly infectious case. typically, at minimum an n is recommended for protection against aerosolized particles arising such as tb, monkeypox, sars and others, rather than a surgical mask [ ] . additionally, an autopsy is inherently an aerosol-generating procedure, even organisms that might normally require only large droplet precautions (i.e. surgical mask) can be aerosolized at autopsy due to oscillating saws, aspirating hoses, etc. and thus require added respiratory precautions (i.e. n respirator or papr) [ , , ] . use of a face shield rather than glasses/goggles also has been shown to reduce contamination of respirators by particles but only % of me/c respondents routinely wear them [ ] . the following ppe changes occurred for suspected or highly infectious remains: the use of inner gloves, a face shield, and boot/shoe cover wear increased by %, %, and %, respectively, while donning eye protection decreased by %. usage of a n respirator increased by more than % and the use of a powered-air purifying respirator notably increased by nearly %. higher level ppe, such as a tyvek suit, hazwoper gear and scba also were used when autopsies were performed on suspected or confirmed highly infectious remains. of concern, these results indicate me/c alter their ppe based on suspected versus confirmed highly infectious remains rather than taking an all-hazards approach. despite some improvements in more protective ensembles in the suspected increased risk cases, the amount of training received by respondents was lacking. little more than half ( %) of respondents had received training on donning and doffing ppe in such scenarios, with the % of those who did have ppe training having spent an average of only h or less per person per year on the topic. additionally, the entity that provided ppe training widely varied (e.g. in-house staff, affiliated university, safety and compliance departments), and no information was collected on the survey on the expertise level of those delivering trainings. the lack of reproducible training time and variability of training entity suggest that more standardized training might be of benefit. designating a knowledgeable public organization to offer standardized training modules could lead to the following: ( ) standardization of the organizational source of training; ( ) content of training materials and modules based on reproducible, evidence-based best practices commonly found in the me/c field; and ( ) subscription to online training as it will likely be the most cost-effective and convenient means of training, as was proven successful in healthcare [ ] . moreover, best practices and evidence-based studies have demonstrated that regular training for donning and doffing high level ppe in highly infectious scenarios provide substantially better occupational safety and health outcomes for the employee [ ] . in the event of suspected or confirmed highly infectious remains, most me/c offices stated that the situation was handled on a case-by-case basis, depending on the pathogen that was suspected and required detailed conversations with all stakeholders. as shown in table , procedures did vary between what would be performed with a suspected highly infectious body versus a confirmed infectious body. in a confirmed case, all but one of the listed procedures as decreased compared to a suspected case (e.g. complete autopsy [ % decrease], washing or cleaning of the body [ % decrease], body storage in freezer [ % decrease]). the only increase was, "bypass office and have body directly transported to funeral home/crematorium" by % which, as previously mentioned, may result in funeral home and crematory personnel being placed at risk. fewer than % of me/c offices having been involved with handling a suspected or confirmed case, demonstrating a lack experience in handling highly infectious remains. when asked which suspected or confirmed pathogens were encountered, however, many noted category a or b pathogens (table ) [ , ] that require specific deactivation and decontamination procedures-of which only approximately onethird ( %) of respondents had received training in. it is possible that after such an event that the me/c office would hire an appropriate contractor to conduct the appropriate deactivation and decontamination; however, the possibility remains [ , ] that the task could go to individuals within the me/c offices without proper training. while most offices did not have a bsl- facility, nearly twothirds ( %) of those without a bsl- did have bsl- capabilities. however, if % have only bsl- capability, then these morgues would essentially be considered appropriate for work only with agents not known to consistently cause disease in healthy human adults per cdc guidelines [ ] . in essence, a sizeable percentage of morgues in the u.s. are not equipped to safely perform autopsies on human remains with a large number of infections, especially those highly infectious disease autopsies. in addition to improved training, more investment in morgue infrastructure would be necessary to enhance their capabilities. anecdotally, some larger me/c offices have a computerized tomography (ct) scanner in which triple bagged sealed infectious remains can undergo virtual autopsy. these bags can be constructed with portals to collect needed specimens for microbiologic/virologic studies. the triple bagging prevents leaks and contamination and the remains can safely be sent to funeral home. it would also be beneficial to have list of pathologists and support personnel in each me/c office who could volunteer to take vaccines to handle certain cases with suspected contagious diseases (i.e. smallpox, etc.). approximately % of respondents reported that they did not examine suspected or confirmed highly infectious remains at their facility. given the lack of proper bsl facilities, this would be appropriate. slightly more than % noted the lack of space and/or a lack of staff in their offices as a limitation for being able to perform autopsies of suspected or confirmed highly infectious remains in a separate room or alone. for biosafety, it is recommended that autopsy facilities should have a minimum of air exchanges per hour, be negatively pressurized relative to surrounding office spaces, and exhaust air outside of the facility and away from areas of high pedestrian traffic. morgue laminar air flow should travel from clean to progressively less clean areas with downdraft table ventilation to decrease personnel exposure to aerosolized pathogens [ , ] . it is likely that significant financial investment would be required to retrofit many existing morgues to meet these standards. another option would be to have jurisdictional planning to transport suspected or confirmed cases to known centers that currently have the necessary bsl capability; again, body transportation would incur costs but likely lower costs than that associated with retrofitting many existing morgues. in addition to improved morgue biosafety, it would also benefit me/c facilities to have better publicized, easily accessed, and clearly laid-out protocols for various infectious scenarios in which limited autopsy (e.g. brain-only in suspected cjd cases) or no autopsy (e.g. evd cases) is currently recommended. when asked about level of training to handle and transport specimens for suspected highly infectious cases, only onethird of respondents had received this training with % spending on average less than h per year per person on the topic. nearly half of respondents ( %) were unsure of what their jurisdiction permitted in the case of highly infectious remains for ultimate disposal, and alarmingly, % of respondents stated their jurisdiction permitted embalming and % traditional burial. for evd, for example, the recommended procedure is cremation to ensure complete deactivation of the virus in order to prevent spread to workers and the environment; those who were killed by the disease will have high viral loads present in their body post-mortem [ ] . while needs for funding, resources, supplies and appropriate capabilities may be universal across the death care sector, this survey's results strongly suggest that it would benefit state or regional-specific me/cs to have standardized education and training throughout the u.s [ ] . likewise, open-ended comments from respondents indicated a need for augmented up-to-date formalized trainings, as well as revised written policies and procedures, and enhanced resources (including facilities and funding). there were general perceptions of unpreparedness to address highly infectious remains, budgetary constraints and a weak national structure regarding autopsy biosafety, and a lack of incorporation of me/c offices into infection control planning despite me/c office involvement with highly infectious remains. there were limitations to this study. because of the study's exploratory nature, the survey was not validated beyond subject matter expert vetting. additionally, the survey only included me/c offices that served larger populations; smaller offices may still encounter hid cases if they do not outsource larger nearby offices. therefore, this study may not be generalizable to smaller offices (i.e. those serving populations < , ). also, the survey instrument was designed to allow respondents to check multiple boxes when asked about the use of ppe. the results, therefore, were not clear whether the respondent meant the ppe would be used simultaneously or one instead of the other. for example, a face shield and respirator may be used simultaneously or a face shield may be used instead of a respirator. additionally, a limitation related to potential response bias may exist. although this study was not funded, there could have been sponsor bias on behalf of the respondents, as the survey was distributed by members of name, thereby potentially affecting the candidness of their responses. lastly, non-responses may have arisen because it would not appeal to prospective participants to take a survey about a topic for which they are not trained out of concern their answers may not be "correct." nevertheless, this study addresses a critical gap about what is known and unknown about u.s. me/c capabilities to handle highly infectious remains. in conclusion, this survey of u.s. medical examiners and coroners' capabilities to address highly infectious decedents presents opportunities for improvement at me/c facilities serving their state or metropolitan area. standard operating procedures or guidelines (sops or sogs) should be updated to take an all-hazards approach, best-practices on handling highly infectious remains could be integrated into a standardized education, evidence-based information on appropriate ppe selection could be integrated into a widely disseminated learning module, and existing relationships with the local health department, funeral homes and crematories could be bolstered to develop a multi-sectoral concept of operations for addressing suspected highly infectious remains. while some issues will require greater capital and resources to address-such as retrofitting facilities to meet better biosafety recommendations, or more financial resources to enhance operation-the hope is that this study will draw attention to these more systemic issues and stimulate a call to action from the appropriate entities. . u.s. medical examiners/coroners play a critical role in death investigation, yet their capabilities to address highly infectious remains are unknown. occupationally-acquired infection. . this survey, with respondents from nearly every u.s. state, revealed current levels of medical examiner/ coroner training and education to address suspected or confirmed highly infectious remains. . questions, and thereby results, focus on permissible autopsy procedures, personal protective equipment, and biosafety-level facility capabilities. . medical examiners/coroners could benefit from updates to standard operating procedures and standardized education on handling suspected or highly infectious remains that taken an all-hazards approach. niaid emerging infectious diseases/pathogens list of blueprint priority diseases infection control in the management of highly pathogenic infectious diseases: consensus of the european network of infectious disease clinical care of two patients with ebola virus disease in the united states ebola virus disease cluster in the united states ebola virus disease: preparedness and infection control lessons learned from two biocontainment units caring for patients with ebola: a challenge in any care facility lessons learned: critical care management of patients with ebola in the united states reflections on interprofessional team-based clinical care in the ebola epidemic: the nebraska medicine experience current capabilities and capacity of ebola treatment centers in the united states safe management of patients with serious communicable diseases: recent experience with ebola virus clinical management of ebola virus disease in the united states and europe nebraska biocontainment unit perspective on disposal of ebola medical waste considerations for safe ems transport of patients infected with ebola virus transport and management of patients with confirmed or suspected ebola virus disease us ebola treatment center clinical laboratory support nebraska biocontainment unit patient discharge and environmental decontamination after ebola care guidance for safe handling of human remains of ebola patients in u. s. hospitals and mortuaries the contribution of ebola viral load at admission and other patient characteristics to mortality in a medecins sans frontieres ebola case management centre control measures following a case of imported lassa fever from togo a gap analysis of the united states death care sector to determine training and education needs pertaining to highly infectious disease mitigation and management ebola situation reports: democractic republic of the congo infectious disease surveillance by medical examiners and coroners overview of medical examiner/coroner systems in the united states: development, current status, issues and needs the pathology of human west nile virus infection hantavirus pulmonary syndrome in the united states: a pathological description of a disease caused by a new agent biosafety level laboratory for autopsies of patients with severe acute respiratory syndrome: principles, practices, and prospects three decades of responding to infectious disease outbreaks operational research during the ebola emergency role of the medical examiner in zika virus and other emerging infections cdc grand rounds: discovering new diseases via enhanced partnership between public health and pathology experts emerging infectious diseases and the medical examiner medical examiners, coroners, and biologic terrorism death investigation systems department of health & human services. regional offices hospital respiratory protection program toolkit: resources for respirator program administrators aerosol generation during bone-sawing procedures in veterinary autopsies biosafety considerations for autopsy efficacy of face shields against cough aerosol droplets from a cough simulator personal protective equipment in health care: can online infection control courses transfer knowledge and improve proper selection and use? guidelines for safe work practices in human and animal medical diagnostic laboratories age and ebola viral load correlate with mortality and survival time in ebola virus disease patients acknowledgments we would like to extend our gratitude to the members of the national association of medical examiners (name) ad hoc committee for bioterrorism and infectious disease for their support of this research and distribution of the survey; these members include: second author erin brooks (chair), paul chui, karen kelly, john matthew lacy, micheline lubin, lakshmanan sathyavagiswaran, leah schuppener, suzanne utley-bobak, and steven white. additionally, we acknowledge the national institute of environmental health sciences (niehs) worker training program (wtp) ebola biosafety and infectious disease response training uh information, grant number uh es . while the grant funding did not contribute to the development and distribution of this gap analysis survey, the program did highlight the need to explore research in this area. lastly, we also thank from the university of nebraska medical center: elizabeth beam and at harvard t.h. chan school of public health: paul biddinger for their partnership and support. conflict of interest none of the authors have any conflicts of interest to disclose.ethical approval this study was deemed exempt by indiana university institutional review board (protocol # ).informed consent survey participants were informed of potential risks and benefits prior to taking the voluntary survey. this informed consent survey was reviewed by the institutional review board and approved as part of the exemption in the aforementioned protocol number. key: cord- - qy nngs authors: raj, g. dhinakar; jones, r. c. title: infectious bronchitis virus: immunopathogenesis of infection in the chicken date: - - journal: avian pathol doi: . / sha: doc_id: cord_uid: qy nngs the immunopathogenesis of infectious bronchitis virus (ibv) infection in the chicken is reviewed. while infectious bronchitis (ib) is considered primarily a disease of the respiratory system, different ibv strains may show variable tissue tropisms and also affect the oviduct and the kidneys, with serious consequences. some strains replicate in the intestine but apparently without pathological changes. pectoral myopathy has been associated with an important recent variant. several factors can influence the course of infection with ibv, including the age, breed and nutrition of the chicken, the environment and intercurrent infection with other infectious agents. immunogenic components of the virus include the s (spike) proteins and the n nucleoprotein. the humoral, local and cellular responses of the chicken to ibv are reviewed, together with genetic resistance of the chicken. in long-term persistence of ibv, the caecal tonsil or kidney have been proposed as the sites of persistence. antigenic variation among ibv strains is related to relatively small differences in amino acid sequences in the s spike protein. however, antigenic studies alone do not adequately define immunological relationships between strains and cross-immunisation studies have been used to classify ibv isolates into ‘protectotypes’. it has been speculated that changes in the s protein may be related to differences in tissue tropisms shown by different strains. perhaps in the future, new strains of ibv may arise which affect organs or systems not normally associated with ib. the study of pathogenesis was formerly regarded as a messy, unsatisfactory area for virus research-a sad state of affairs that was lamented by early enthusiasts (mimms, ) . that view has changed now and there is an urgent need to know how viruses cause diseases. the study of mechanisms of pathogenicity was recently placed at the top of the research objectives proposed for priority treatment by an ad hoc group on vaccinology (bourne, ) . however, pathogenesis cannot be studied without also considering immunology and mechanisms of protection. this review attempts to concisely present the current state of knowl-edge on the immunopathogenesis of infection in chickens with infectious bronchitis virus (ibv). in a 'new respiratory disease of baby chicks' was identified in the usa by schalk & hawn and named infectious bronchitis (ib). following infection of chickens with ibv, falls in egg production and quality were reported for the first time by van roekel et al. ( ) and broadfoot & smith ( ) . in , cumming found that ibv was the cause of nephrosis-nephritis syndrome seen in australia. in more recent years, ibv has also been isolated from cloacal swabs and gut tissues, but while infection has sometimes been associated with diarrhoea, no pathological changes have been described in the alimentary tract. swollen head syndrome (shs) in chickens has generally been associated with infection with the avian pneumovirus (apv), turkey rhinotracheitis virus (trtv) (picault et al, ; lu et al, ) . however, in the first description of shs, morley & thomson ( ) isolated a coronavirus, while in other reports, massachusetts strains of ibv have also been isolated (shirai et al., ; droual & woolcock, ) . recently, a variant strain of ibv, /b was isolated from broiler breeder flocks where the affected birds had bilateral myopathy affecting both superficial and deep pectoral muscles (gough et ah, ) . thus, it is clear that strains of ibv have wide and variable tissue tropisms, and the clinical manifestations of the disease can be diverse. although the name ib does not encompass the varied clinical manifestations observed with ibv infections, for the present this name has still been retained to avoid confusion. replication of ibv in the respiratory tissues causes characteristic, but not pathognomonic signs such as gasping, coughing, tracheal rales and nasal discharge. occasionally, puffy, inflamed eyes and swollen sinuses may be seen (parsons et al, ; capua et al, ) . in uncomplicated cases these signs last for only to days and disappear within to days. the affected chickens also appear depressed, and feed consumption and weight gain are significantly reduced from days after infection (otsuki et al, ) . in uncomplicated cases, mortalities are generally low and have been attributed to asphyxiation due to blocking of the lower trachea or bronchi by plugs of mucus. the upper respiratory tract is the main site of ibv replication, following which a viraemia occurs and the virus gets widely disseminated to other tissues (mc-martin, ) . the virus is primarily epitheliotropic and enters the epithelial cells by viropexis (patterson & bingham, ) . studies using immunofluorescence (if) qones & jordan, ; yagyu & ohta, ) , immunoperoxidase (ip) (nakamura et al, ; owen et al, ) and electron microscopy (purcell & clarke, ; nakamura et al, ) have shown virus replication in ciliated epithelial and mucus-secreting cells. during the clinical phase of the disease, maximum virus titres are recorded in the trachea between and days post-infection (p.i.) (ambali & jones, ; otsuki et al, ), but occasionally virus may be present for up to days p.i. cook, ) . virus also replicates in the epithelial cells of lungs (janse et al, ) and airsacs (nauwynck & pensaert, ) . high virus titres are seen in these tissues between to days p.i. (nauwynck & pensaert, ; otsuki et al, ) . infected chickens have mucosal thickening with serous or catarrhal exudate in the nasal passages, sinuses and trachea. the incidence of nasal exudate in experimentally-infected chickens has been used to assess the severity of disease in different inbred lines (parsons et al, ) and in bursectomised birds (cook et al, a) . small areas of pneumonia may be observed in the lungs. the air sacs may appear cloudy or contain a yellow caseous exudate (king & cavanagh, ) . the progression of lesions in the trachea has been divided into three stages, degenerative, hyperplastic and recovery (nakamura et al, ; purcell & mc-ferran, ) . deciliation and desquamation of epithelial and mucous-secreting cells occur in the first or days with a mild infiltration of heterophils and lymphocytes in the lamina propria. heterophils are often seen infiltrating between ciliated epithelial cells and occasionally in the lumen of the trachea. during the hyperplastic stage, newly-formed epithelial cells are observed which usually have no cilia. by to days the reparative processes begin with complete recovery by to days (chen et al, ) . in affected airsacs, epithelial cell desquamation, oedema and some fibrinous exudate may be seen (king & cavanagh, ) . difficulty in quantifying severity of respiratory infection caused by ibv has always been a problem in studying its pathogenicity . the virus causes stasis of tracheal cilia both in vivo and in vitro, and this parameter has been used to assess severity of respiratory infection. otsuki et al. ( ) found that following infection with the m strain, the duration and severity of tracheal ciliary damage was longer in a susceptible line of chicken ( ) than in a resistant line (c). the authors proposed that this method could be used to compare the pathogenicity of different strains or susceptibility of different breeds to ibv. cubillos et al. ( ) found that in unvaccinated chickens challenged with four ibv isolates from chile (one belonging to the massachusetts serotype and three variants), the tracheal damage in terms of ciliary activity was variable, suggesting differences in virulence of ibv strains for the trachea. while tracheal organ cultures (toc) have been used extensively for cultivation and assay of ibv, distinct differences in virulence among ibv strains have not been observed in this in vitro system. cook et al. ( ) , while standardizing toc for the isolation and assay of ibv, compared three strains of ibv on the basis of their effect on tracheal cilia, but found no marked differences. dhinakar raj & jones ( c) also reported little difference among seven ibv strains using measurement of ciliary activity as a criterion for damage to the tracheal epithelium. of nine strains compared in toc by cubillos et al ( ) , the hyperplasia caused by two viruses was the only histological difference. ibv infections may not occur as a single entity in the field. with the presence of several respiratory diseases in chickens caused by bacteria and viruses, the role of these agents in increasing the severity of ibv or otherwise is an important contributory factor in influencing the pathogenesis of the disease (see later). in layers, ib can cause a severe decline in egg production, and later, a deterioration in shell and internal quality (mcdougall, ; sevoian & levine, ) . such effects may be accompanied by mild (muneer et al, (muneer et al, , or no respiratory signs (cook, ; . some strains produce only a loss in shell colour . the severity of production decline varies with the period of lay, the virulence of the virus involved and other non-specific factors. the response of individual hens varies greatly (mcmartin, ) . production may start to increase after to weeks, but reaches only sub-optimal levels. when laying is resumed, some eggs have soft-shells, while others are mis-shapen or rough-shelled. when laying hens were infected with ibv strain m , viral antigen was demonstrated in the epithelium of the oviducts between and days p.i. (jones & jordan, ) . areas of glandular hypoplasia caused by ibv leads to reduction in the synthesis of albumen proteins especially ovomucin, lysozyme and other major proteins which constitute the structural matrix of the thick albumen (butler et al, ) . hence, there is a decrease in the proportion of both thick and inner thin albumen, and an increase in the amount of outer thin albumen causing 'watery-whites'. presence of blood or meat spots in the egg albumen has also been reported (mcdougall, ; muneer et al, ) . inspissated yolk material may be seen in the abdominal cavity of infected layers. microscopic changes in the oviduct include reduction in the height of the epithelial cells, reduction in number or complete absence of cilia, dilation of glands, lymphocytic foci and cellular infiltration in the lamina propria and inter tubular stroma (sevoian & levine, ) . the mechanisms whereby ibv infection causes egg production of some birds to cease and for varying periods of time have not been elucidated. ibv infection of female chicks of less than weeks of age can cause permanent damage to the developing reproductive tract, resulting in 'false layers' that do not lay normally at sexual maturity (broadfoot et al, ; jones & jordan, ) . following infection of day-old chicks with ibv strain m , virus was isolated between days and p.i. (jones & jordan, ) and was also found to replicate in the epithelium of the oviducts (crinion & hofstad, a,b; jones & jordan, ) . gross changes in the oviduct caused by early infection may vary from the presence of a continuous patent but underdeveloped structure to a blind sac projecting forward from the cloaca (jones & jordan, . the middle third of the oviduct is the most severely affected with areas of localised hypoplasia seen between normal patent oviducts. caudal to the hypoplastic regions, macroscopic cysts filled with a clear serous fluid may be seen (crinion et al., a) . the histopathological changes in the oviduct include decreased height and loss of cilia from epithelial cells, dilation of the tubular glands, infiltration of heterophils, lymphocytes and plasma cells, and oedema and fibroplasia of the lamina propria (crinion et al, a,b; crinion & hofstad, a,b) . the effect of ibv on the male reproductive tract has not been reported. variations in the ability of ibv strains to cause decreases in egg production and quality were reported by guittet et al. ( ) ; d was the least virulent while m and a variant strain pl had the same degree of pathogenicity. found that some variant strains of ibv caused only small decreases in egg production, but had a marked effect on egg colour. in contrast, a more recent variant (parsons et al., ) caused a substantial decline in egg production with little loss of egg colour in the field, although no experimental work has been done with this virus. differences in virulence of ibv strains for the immature chicken oviduct were reported by crinion & hofstad ( a) ; massachusetts and t strains were virulent, while connecticut and iowa were not. embryo passage of ibv strain m reduced its virulence for the oviduct (crinion & hofstad, b) . in vitro, oviduct organ cultures (ooc) were highly susceptible to the h strain of ibv regardless of the age of the chickens and no differences in susceptibility were seen between magnum and uterus regions . pradhan et al. ( ) showed that ibv strain m causes stasis of cilia in ooc prepared from precociously-induced oviducts in young chicks by oestrogen treatment. this work has been extrapolated to compare the virulence of seven strains of ibv in vitro using ciliostasis and a calmodulin assay to quantify the damage to oviduct epithelium (dhinakar raj & jones, c ). an ibv isolate belonging to serotype d was the most virulent while an enterotropic variant strain g was the least. although even those strains of ibv considered primarily to affect the respiratory tract such as m can occasionally cause kidney damage (jones, ) , nephropathogenicity has been associated only with certain strains. greater virulence of the virus for the kidney was first reported in australia (cumming, ) . since then, nephropathogenic ibv (nibv) has been reported from usa and certain parts of europe (butcher et al., ; kinde et al., ; lambrechts et al, ; picault et al, ; zanella, ) . nibv strains initially cause respiratory symptoms followed by signs due to kidney damage which include increased water consumption and wet droppings (winterfield & hitchner, ; cumming, ) . mortalities occur and follow a consistent pattern (cumming & chubb, ) . the first deaths usually occur around days p.i., increase rapidly to a peak around days with the last deaths seen around days p.i. however, the mortality rates depend on several intrinsic and extrinsic factors (see below). virus replication in the kidneys has been shown in the proximal convoluted tubules (chong and apostolov, ) , distal convoluted and collecting tubules (owen et al, ) and collecting ducts (chen et al, ) . structural alterations in the tubular epithelial cells (condron & marshall, ) caused impaired fluid and electrolyte transport leading to acute renal failure. an increase in urinary water losses in chickens infected with nibv was found to be associated with lower urine osmolality and higher rates of urinary excretion of sodium, potassium and calcium (afanador & roberts, ; condron & marshall, ; heath, ) . negative sodium balance was a direct effect of increased output of sodium in the urine, while negative potassium balance was due to decreased intake. the kidneys of chickens infected with nibv are swollen and pale, with tubules and ureters distended with urates (cumming, ) . the relative kidney weight and kidney asymmetry are increased. the haematocrit values of infected birds was decreased and plasma uric acid levels were increased (afanador & roberts, ) . despite lack of gross lesions microscopic changes of nephritis may still be present (winterfield & albassam, ) . chen et al., ( ) proposed that ibv-induced renal lesions can be considered to be a ductotubular interstitial nephritis. the virus causes granular degeneration, vacuolation and desquamation of the tubular epithelium with massive infiltration of heterophils in the interstitium in acute stages of the disease. the changes in the chronic phase were classified as being active or inactive types of interstitial lymphocytic nephritis (albassam et al., ) . the chronic inactive form of nephritis was indicative of ibv replication in the kidneys and subsequent clearance; while the chronic active type suggested a persistent viral replication and damage to epithelial cells of the kidney tubules. virus was isolated from % of the birds with chronic nephritis (chong & apostolov, ) . the histopathological changes in the kidneys following nibv infections have been described by several workers (albassam et al., ; chen et al., ; pohl, ; purcell et al, ; siller & cumming, ) . the type of kidney lesions produced by different nibv strains were similar but their severity varied (albassam et al., ; chandra, ) . the australian strain 't' induced the most rapid and severe lesions following both intra-venous (i.v.) (chandra, ) or intra-ocular (albassam et al, ) inoculations of susceptible chickens. the effect of ibv on the trachea is apparently independent of the effect on kidney (ratanasethakul & cumming, ) . a strain of nibv, 's' virus was less severe on the kidneys than 't', but more severe on the tracheal mucosa. using an i.v. inoculation model to titrate kidney infectivity, lambrechts et al. ( ) found no significant differences in the infectivity among belgian field nibv isolates, but the infectivity of egg-passaged virus was highly reduced. several strains of ibv have been isolated from cloacal swabs, faeces and caecal tonsils alexander et al, ; cook, ; lucio & fabricant, ) . in vitro explants of several gut tissues have been shown to support the growth of ibv (bhattacharjee, ; bhattacharjee & jones, ; darbyshire et al, ) . in studies where virus isolation was attempted from several tissues, maximum virus isolations were obtained from the oesophagus of chickens infected with ecv , an enteric isolate of ibv (lucio & fabricant, ) and /b-like virus (dhinakar raj & jones, a) . oesophageal swabs have also been used to identify ibv using the polymerase chain reaction (d. cavanagh, personal communication). however, it is not clear whether the virus actually multiplies in the oesophagus or whether virus is swallowed after being expelled from the trachea. ibv has also been isolated from proventriculus, duodenum and jejunum (ambali & jones, ; lucio & fabricant, ) . darbyshire et al, ( ) have shown that proventriculus was inferior only to respiratory tissues and oviduct in supporting virus multiplication in vitro. however, the site of virus multiplication in these tissues has not been confirmed, but presumably occurs in the epithelial cells. in contrast, in the tissues of the lower gut, ibv replication has been described (without photographs) in cells resembling histiocytes and lymphoid cells in the caecal tonsils (owen et al, ) and demonstrated by if in apical epithelial cells of the villi in ileum and rectum (ambali & jones, ; dhinakar raj & jones, a) . although ibv has a wide tropism for gut tissues no gross or histological changes have been reported. a variant strain of ibv, strain g, was classified as being enterotropic by virtue of its prolonged persistence in the gut compared to the trachea (el houadfi et al, ) . recently, it was seen that a variant ibv strain /b was more enterotropic than pneumotropic and was even associated with diarrhoea in broilers (dhinakar raj & jones, a) . it seems that studies on the replication of ibv in the gut have been neglected, probably because no ibv strain has been demonstrated to be enteropathogenic. macdonald et al. ( ) reported that following crop inoculation of chicks with h and h vaccines, virus was rarely isolated from the gut or any other visceral tissues and no antibody response occurred. however, the kidneys were found to be resistant to i.v. challenge. more intensive studies on oral infection with enterotropic ibv strains or dual infections with the virus and other enteric pathogens, such as salmonella, coccidia or rotavirus, might yield more information on the effects of ibv replication in the gut. the ability of ibv strains to survive in the presence of low ph, digestive enzymes and bile salts may be relevant to enteric replication. otsuki et al ( a) and cowen & hitchner ( ) showed that some strains suffer a greater loss of titre than others when kept at ph . for or h, but there was no indication that any of the more resistant strains were isolated from the gut. ambali & jones ( a) compared strain m with an enterotropic variant (g). both viruses had a similar sensitivity to trypsin, but the variant showed a -fold greater resistance to sodium tauroglycocholate, which might partly explain its ability to replicate in the gut. the important variant strain of ibv, /b, was recently isolated from a broiler breeder flock where the affected birds had bilateral myopathy affecting both deep and superficial pectoral muscles (gough et al, ) . there was marked swelling and pallor of deep pectoral muscles together with the presence of occasional fascial haemorrhages and a layer of gelatinous oedema over its surface. experimental infection of week old broilers with an isolate of ibv belonging to this group resulted in mild oedematous separation of muscle fibres but with no corresponding increase in serum creatine kinase concentrations (dhinakar raj & jones, a ). it has been clearly shown that the virus was not involved directly in the pathogenesis of the muscle lesions but formation and deposition of immune complexes, such as those found in the kidneys (dhinakar raj & jones, a) , in the capillary walls of the muscle could be a possible reason for the development of this strange lesion. ibv has been isolated from the harderian gland (dhinakar raj & jones, a; gelb et al, b; toro et al., a) and ibv-positive cells have been shown in the stroma of the gland by if staining (toro et al, a) . ibv vaccination by eyedrop resulted in a massive infiltration of lymphocytes, increase in plasma cell numbers (davelaar & kouwenhoven, ; survashe et al, ; montgomery et al, ; toro et al, a) and desquamation of tubular epithelium in the harderian gland with restoration from days after vaccination (toro et al, a) . increased numbers of plasma cells (survashe et al, ) and lymphoid tissue development (montgomery et al, ) were also seen in the lachrymal gland following ibv vaccination. ibv has also been isolated from the bursa of fabricius (el houadfi et al, ; ambali & jones, ) , and gross and histopathological lesions have been shown following experimental h and hi infections (macdonald & mcmartin, ) . although ibv has been isolated from a variety of other tissues such as liver ambali & jones, ) and spleen (otsuki et al, ) it has not been documented to be involved with any functional damage. ibv has been isolated from semen and eggs of infected chickens (cook, ), but vertical transmission appears to be of little importance. several intrinsic (age and breed of chickens) and extrinsic (nutrition, environment and intercurrent infections) factors influence the pathogenesis of ibv infections. all ages are susceptible, but the clinical disease is more severe in young chicks (animas et al., b) although recovery of the virus from the trachea was similar compared to -week old infected chickens (animas et al., a) . however, the duration of virus excretion in the faeces was longer in -week old infected chicks compared to -and -week-old chickens. as age increases chicks become more resistant to ibv-induced mortality (smith et al., ) , nephropathic effects (albassam et al., ) and oviduct lesions (crinion & hofstad, a) . mac-donald et al. ( ) described fewer pathological changes in kidneys of chickens infected at weeks of age than those infected at day-old or weeks of age, although the virus was inoculated i.v., which is an unnatural route of infection. purchase et al. ( ) demonstrated variation in mortality following ibv inoculation of embryos from different inbred lines. bumstead et al. ( ) compared mortalities in several inbred lines of chickens following inoculation with a pool of strains of ibv and/or escherichia coli and found marked differences among them. on this basis, the lines of chickens were classified as being resistant or sensitive to ibv. however, these inbred lines did not show marked differences in susceptibility to the variant strain of ibv, /b (parsons et al, ) . genetic differences in susceptibility to nephritis are also marked, with light breeds being more susceptible than heavy breeds (cumming & chubb, ) . the mortalities in -week-old cockerels of australian commercial egg-laying strains varied from to %. nibv has been shown to cause higher mortalities in broilers than layers (ignjatovic, ; zanella, ) although the virus multiplies to the same extent in both types of birds (lambrechts et al., ) . male chicks are twice as susceptible as females to nephritis (cumming, ) . high protein diets increase mortality from ibv-induced nephrosis; chickens fed meat meal or poultry by-product meal-based diets experience higher mortality than those fed soybean based diets (cumming, ; cumming & chubb, ) . low temperatures have a dramatic effect on mortality due to nibv. reduction in temperature from °c to °c increased mortality from to % (cumming, ) with greater severity of histopathological lesions in kidneys (ratanasethakul & cumming, ) . exposure to cold stress has been used to increase the severity of challenge for assessing protection afforded by ibv vaccines (klieve & cumming, ) . cold stress also increased the severity of ibv-induced tracheal lesions (ratanasethakul & cumming, ) and promoted more extensive air sacculitis after combined infections with ibv and mycoplasma synoviae (ms) (yoder et al, ) . mycoplasmas adler et al. ( ) found that intranasal inoculation of either the massachusetts strain of ibv or m. gallisepticum (mg) given alone produced little by way of clinical signs, but dual infections resulted in coryza, tracheitis and airsacculitis. the incidence of airsacculitis was highest in chickens infected with ibv week after mg inoculation. in adult chickens combined infections with ibv and mg has been shown to cause a more severe effect on egg production and quality than inoculation with either agent alone (blake, ) . olson et al, ( ) exposed chickens to ibv and ms but found that dual infections were not synergistic. in contrast, later work by kleven et al, ( ) found that airsacculitis resulted when chickens were infected with ib and newcastle disease (nd) vaccines after ms infection. hopkins & yoder ( ) , in similar experiments with ms, gave different strains of ibv to days before the mycoplasma. they showed that different strains of ibv had differing abilities to induce airsacculitis. field isolates of ibv had the most severe effects. vaccines of high passage produced very mild lesions while those of low passage caused intermediate lesions. gross ( ) , in one of the first studies, infected -week-old chickens with ibv and gave pathogenic e. coli by aerosol at intervals afterwards. the most severe pericarditis was seen when the bacteria were given to days after the virus. smith et al. ( ) , using a combined inoculation of a pool of strains of ibv and e. coli, developed an experimental model for ibv which closely resembled natural outbreaks of the disease. the damage to tracheal epithelium caused by ibv facilitates e. coli invasion and multiplication leading to death or lesions in surviving chickens. using this model, several reports have described differences in virulence of ibv strains, differences in susceptibility between genetic lines of chickens and detailed interactions between the agents (avellanda et al., ; bumstead et al, ; cook et al, , b cubillos et al, ; smith et al, ) . raggi et al. ( b) showed that when ibv and haemophilus paragallinarum were given together intra-nasally, the incubation period was shorter, there was higher mortality and lesions were more severe. there is no reported evidence of dual infections with ibv and pasteurella multocida, the causative agent of fowl cholera. however, bisgaard ( ) , in a study of chickens in the field, found that where the bacterium p. haemolytica was present with ibv, there was no apparent exacerbation of the viral infection. ibv is known to interfere with the replication of ndv in eggs and raggi & lee ( ) have shown that interference also occurs in chickens, but this is only one way. they found that when ibv was given to chickens with ndb vaccine, there was subsequently no production of haemagglutination-inhibition (hi) antibodies to ndv, but ndv did not interfere with ibv infection. raggi et al. ( a) found no synergism between ibv and infectious laryngotracheitis virus (iltv), but pattison et al. ( ) reported that aerosol vaccination with ibv increased the mortalities due to iltv. apv, the cause of trt and mild respiratory disease in chickens may also occur in respiratory outbreaks involving ibv, but the significance of these two agents being present together is yet to be reported. fabricant & levine ( ) examined triple infections involving ibv, mg and pathogenic e. coli. they reported that with regard to disease lesions the descending order of severity was ibv, mg and e. coli; mg and e. coli; ibv and e. coli; and e. coli alone. a similar study by nakamura et al. ( ) was performed with live ib and nd vaccines given to young chicks with mg and/or e. coli or both. again, the most severe combination was when vaccine, e. coli and mg were given together. thus, it is clear that several respiratory pathogens interact synergistically with ibv or ib vaccines and enhance the severity and duration of the disease. in many instances, the interval between infections is important, as are the challenge doses. however, with few exceptions (e.g. nakamura et al., ) , it is not known whether the synergisms are due to immunosuppression or simply that the epithelial damage caused by one agent permits greater penetration by others. the two classical examples of immunosuppressive viruses of chickens are infectious bursal disease (ii d) which principally affects the b-cells and chicken anaemia virus (cav) which affects the t-cells. there is abundant evidence that ibdv infection impairs the humoral response to ibv. giambrone et al. ( ) infected chicks with ibdv at day-old and ibv at days. compared to single ibv infection with both viruses, antibody titres were lower and airsac lesions greater. rosenberger & gelb ( ) also showed that ibdv at day-old affected the response to ib vaccines so that there was lowered resistance to challenge. furthermore, winterfield et al. ( ) showed that ibdv increased susceptibility to ibv, reduced ibv antibody levels and explained unsatisfactory immunity when replacement and broilers were vaccinated at an early age. there are no reports of dual infection of chickens with ibv and cav. goodwin et al. ( ) reported that there were no significant differences in ibv-specific antibody titres between chicken flocks positive or negative for cav antibodies. however, when chicks infected with ibv strain m were treated with the t-cell immunosuppressor drug cyclosporin a (csa), the clinical signs in these birds were more severe and virus titres in tissues, especially kidneys, were greater than in infected but untreated birds, although the persistence of the virus was not increased (dhinakar raj & jones, a). ibv-induced mortality was also increased. it seems possible that infection with cav at a critical time might induce some of these effects on ib. although ibv has been isolated from lymphoid tissues such as bursa of fabricius and harderian gland, the evidence for a direct immunosuppression is limited. it is not clear whether ibv multiplies in the lymphocytes but cultured macrophages were found to be resistant (von bulow & klasen, ) . a virulent ibv has been shown to induce transitory reduction in proliferative responses of whole blood lymphocytes to t-cell mitogens, pha (wakenell et ah, ) and concanavalin a (dhinakar raj & jones, a). ibv vaccines were found to depress the harderian gland responses to killed brucella abortus (montgomery et al., (montgomery et al., , . however, no correlation between histological responses and hi titres to ibv were found with depression of responses to br. abortus. ibv is a positive-stranded rna virus and is the prototype of the family coronaviradae. it has three structural proteins. the spike 's' glycoprotein is located at the surface of the virion, and consists of two subunits, si and s , with molecular weights of and k, respectively. the membrane 'm' glycoprotein is partially exposed at the surface of the virion with molecular weights ranging from to k, and the nucleocapsid 'n' protein is internally located with a molecular weight of k (wadey & westaway, ; cavanagh, a,b,c) . the si glycoprotein of ibv induces virus neutralizing (vn) and hi antibodies (cavanagh et al, , kant et al, ; koch et al, ; mockett et al, ; niesters et al, ) and has been considered as the most likely inducer of protection (cavanagh et al, ; ignjatovic & galli, ) , but s and n proteins may also be important since they carried epitopes for induction of cross-reactive antibodies (ignjatovic & galli, ) . the time of appearance of si, s and n eljsa-antibodies have been shown to be similar, being detected weeks after live ibv vaccination (ignjatovic & galli, ) . this coincides with the appearance of vn antibodies mockett & darbyshire, ; darbyshire and peters, ) . epitopes on n and s proteins that gave rise to cross-reactive antibodies showed the same degree of conservation while si epitopes were shown to be marginally less conserved (ignjatovic & galli, ) . a t-cell epitope has been identified in the ibv 'n' protein (boots et al, ) and has been shown to induce anti-viral responses (boots et al, ) . cellular immune responses elicited by a live ibv vaccine have also been found to be cross-reactive and the responses varied in magnitude with the serotype of ibv used for in vitro stimulation (dhinakar raj & jones, b) . immunity can be considered to be either innate or acquired. innate immunity comprises a collection of factors which resist invasion by external agents, such as physical barriers provided by skin and mucous membranes, soluble factors like lysozyme, complement and acute phase proteins, and cells such as granulocytes, macrophages and natural killer (nk) cells. the main features of innate immunity are lack of specificity and immunological memory. heterophils (neutrophils) constitute the 'first line of defence' against infectious agents and are the first cells to be recruited to the site of infection, following initiation of an inflammatory response. in ibv-infected chickens, heterophils are the most numerous early inflammatory cells in respiratory lavage fluids (fulton et al, ) . using a heteropaenic chicken model (kogut et al, ) the importance of these cells in limiting ibv replication was studied (dhinakar raj et al., c) . it was found that they had no effect on virus multiplication and, in fact, contributed to the damage in the tracheal epithelium. the role of macrophages in ibv infections is unknown, while no alterations in nk cell activity has been found following ibv infection (wakenell et al, ) . serum levels of an acute phase protein, °° i acid glycoprotein, have been found to peak on day following ibv infection (nakamura et al, ) . acquired immunity results in the activation of antigen-specific effector mechanisms including b-cells (humoral), t-cells (cellular) and macrophages, and the production of memory cells. to ibv infections, measurable by enzyme-linked immunosorbent assay (elisa), haemagglutiation inhibition (hi) or vn tests (de wit et al, ; monreal et al, ; wilcox et al, ) . however, there is a lack of correlation between titres of circulating antibodies and resistance to infection (raggi & lee, ; winterfield & fadly, ; . immunoglobulin g (igg), the major circulating ig, is the antibody detected by hi and an elisa developed to measure it is more sensitive (mockett & darbyshire, ) . anti-ibv igg can be detected as soon as four days pi, reaches a peak at about days but can remain in high titre in the serum for many weeks (mockett and darbyshire, ) . this is the antibody measured in conventional serological tests to monitor ibv infections or vaccine uptake. immunoglobulin m (igm), present only transitorily after infection, reaches peak concentrations about days after ibv infection and levels then decline (mockett and cook, ) . although an igm-specific elisa has been shown to be useful in the diagnosis of recent infections (martins et al., ) , these antibodies needed to be separated either by sucrose density gradient centrifugation (gillette, ) or column chromatography (mockett & cook, ) before performing the elisa. the availability of an antibody-capture elisa for ibvspecific igm assays would facilitate ib diagnosis where demonstration of the virus is time-consuming. the importance of b-cells in ibv infections has been studied by depletion experiments using the hormone testosterone propionate (chubb, ) , the chemical cyclophosphamide (chandra, ; chubb, ) and surgical bursectomy (cook et al, a) . cyclophosphamide-treated chickens showed increased clinical signs and more severe histopathological lesions in the kidney (chandra, ) attributable to the prolonged persistence of virus. ibv infection of a surgically bursectomised resistant chicken line (line c) resulted in increased severity and duration of clinical infection but not mortality (cook et al., a) . however, humoral antibodies seemed to protect the tracheal epithelium following secondary challenge. presence of high titres of humoral antibodies correlate well with the absence of virus recovery from kidneys and genital tract macdonald et al, ; yachida et al, ) and protection against drop in egg production (box et al., ) . ibv-specific antibodies probably prevent the spread of virus by viraemia from the trachea to other susceptible organs such as the kidneys and oviduct. vaccination studies with ibv have always focussed on humoral immune responses in relation to protection. nevertheless, the lack of correlation between antibodies and resistance, discrepancies between in vitro strain differentiation by vn tests and in vivo cross-protection results (darbyshire, ) and re-excretion of virus in the presence of high titres of circulating antibodies (jones & ambali, ) all suggest that while humoral antibodies play a role in recovery from ibv infection, other immunological mechanisms are involved. maternally derived antibodies (mda) can provide protection against ibv, but they are short-lived (darbyshire & peters, ; cook et al, b) . presence of mda has no adverse effect on the efficacy of live ibv vaccines administered at one-day of age (davelaar & kouwenhoven, , cook et al, . maternally-derived igg has been demonstrated in tracheal washes (mockett et al, ) . local immunity in the respiratory tract is of fundamental importance in protection against ibv (gomez & raggi, ; gillette, ; hawkes et al, ) . this has been exemplified by the use of an in vitro challenge model using toc from immunized chickens, for cross-protection studies . ibvspecific iga and igg have been demonstrated in tracheal washes of infected chickens (hawkes et al, ; dhinakar raj & jones, b ) and antibody-secreting cells were shown in tracheal sections (nakamura et al, ) . local immunity at the oviduct level has been shown by demonstration of virus-specific igg and iga in the oviduct washes of infected hens (dhinakar raj & jones, b) . it was found that in addition to local production, antibodies also transuded from the serum later in the course of infection, but their value in protection of the oviduct has not been determined. in young chicks, local antibodies in the oviduct were found to be less protective compared to those in the trachea using in vitro challenge of ooc prepared from vaccinated chickens (dhinakar raj & jones, d) . although ibv has been shown to multiply in the gut (lucio & fabricant, ; ambali & jones, ) , lutticken et al. ( ) could not detect any antibodies in gut washings following vaccination of day-old chicks with hi vaccine and revaccination at weeks of age with live h vaccine, inactivated m in an oil emulsion or inactivated m adjuvanted with avridine. in contrast, dhinakar raj & jones ( b) demonstrated local antibody production in the duodenum and caecal tonsils of -week-old hens infected with an enterotropic strain of ibv (strain g). it is not clear whether the induction of these antibodies is strain-related and their role in limiting the replication of ibv in the gut needs to be investigated. the harderian gland of the chicken contains a large age-dependent population of plasma cells and is the source of immunoglobulins in the lachrymal fluid (baba et al, ) . it plays an important role in the development of vaccinal immunity since vaccines are generally given by spray or eye-drop. davelaar & kouwenhoven ( ) reported that the protection against ibv of day-old ocular-vaccinated chickens was localized mainly in the oculo-nasal mucosa and removal of the harderian gland caused a decreased level of protection (davelaar & kouwenhoven, ) . ibv-specific iga has been demonstrated in the lachrymal fluid davelaar et al, ; and its synthesis in the harderian gland has been shown (davelaar et al, ) . igg in tears was mainly serum-derived (davelaar et al, ; toro et al., ) . iga levels in tears appeared to be better correlated with resistance to ibv re-infection (toro & fernandez, ) than levels of serum antibody (yachida et al, ) and their measurement was recommended for antibody profiling of chicken flocks. cook et al. ( ) found more ibv-specific iga in the lachrymal fluids of chicken lines resistant to ibv while antibody titres in tracheal washes were similar. variation in ibv-specific igg levels in serum and iga levels in lachrymal fluids has also been demonstrated in different chicken lines after ocular vaccination with ibv (toro et al, b) . it was found that light layer (white leghorn) chickens had a significantly higher and more homogenous serum igg response between days and p.i., and lachrymal iga response between days and p.i. than broiler or brown-egg (heavy) layer chicks. reports concerning a role for cell-mediated immunity in protection against ibv are limited. antigen-specific proliferation of t-lymphocytes in ibv-infected or vaccinated chickens has been demonstrated (timms et al, ; timms & bracewell, . in some chickens, a positive correlation between lymphoproliferative responses and resistance to challenge has been shown (timms & bracewell, ) . mouse monoclonal antibodies (mab) that distinguish between chicken tlymphocytes have been described (chan et al., ; iillehoj et al, ) . the cd and cd antigens are found on two main populations of t-cells, t-helper (t n ) and t-cytotoxic / suppresser (tc/ s ) cells, respectively. janse et al. ( ) contended that local immunity to ibv in the trachea is mediated by t-cells. cd and cd cells were shown in sections of trachea and lung of chickens infected with ibv (janse et al, ; dhinakar raj & jones, a) . however, it is not clear which of these cells are more important in virus clearance, since janse et al. ( ) found an increase in cd cells, while dhinakar raj & jones ( a) found higher proportions of cd cells. the differences may be related to the strains of ibv used. when chickens were treated with csa to suppress the t-cells, virus titres in the kidneys were to logio median ciliostatic doses (cd ) higher than in intact birds (dhinakar raj & jones, a) . thus, t-cells may also play an important role in limiting virus replication in the kidneys. chubb et al ( ) demonstrated the presence of cytotoxic lymphocytes (ctl) in the spleen and peripheral blood following ibv infection using adherent cells as target cells and neutral red as indicator of lysis. however, wakenell et al. ( ) could not demonstrate ctl using kidney cells as targets and the conven-tional chromium-release assay. delayed-type hypersensitivity (dth) responses were induced in response to live ibv and to affinity-purified si, s , n and m proteins (igjnatovic & galli, ) . cytokines secreted in response to a general stimulus such as concanavalin a (con a) or by specific antigen are important mediators of cellular immunity. t-cell growth factor (tcgf) or il- and ifn-y are among the most important soluble factors produced by lymphocytes. only ifn-y has been studied in relation to ibv but results are conflicting. otsuki et al ( ) detected variable levels of ifn-y in chickens with various strains of ibv whereas other workers (lomniczi, ; holmes & darbyshire, ) could not detect ifn-y in serum or organ cultures of chickens infected with ibv. furthermore, whether ibv is susceptible to anti-viral effects of ifn-y is controversial (holmes & darbyshire, ; otsuki et al, b) . otsuki et al. ( ) found no differences in ifn-y levels of ibv-resistant and ibv-sensitive lines of chickens. the identification of resistant and sensitive inbred lines of chickens to ibv (bumstead et al, ) has provided an excellent model to study immune mechanisms in relation to resistance of chickens to ibv. otsuki et al, ( ) found that although a resistant line (c) and a sensitive line ( ) were equally susceptible to infection initially, recovery was more rapid in the resistant line. ultrastructural and histochemical studies showed that though the type of damage to the tracheal epithelium following ibv infection was similar in both lines of chickens, lesions were more severe and longer lasting in the sensitive line (nakamura et al, ) . the severity and duration of clinical infection in bursectomised line c chickens were similar to those seen in the sensitive line (cook et al, a) . however, no increase in mortality was observed, in contrast to high mortality recorded in line chickens. comparisons of secretory antibody responses between the two lines of chickens revealed increased local antibody secretion in the saliva and lachrymal fluid of the resistant line . suppression of t-cells by csa in a line of chickens resistant to ibv (brown leghorn; blh), induced them to behave like a sensitive line, in terms of mortality (dhinakar raj & jones, a) . the mortality of intact blh chickens infected with a pool of ten ibv strains was % compared to % in csa-treated blh chickens. the virus titres in kidneys were much higher than in intact birds. the classes of t-cells involved in these effects need to be studied in further detail by analysing the kinetic changes in t-cell subsets following ibv infections using flow cytometry or by specific depletion in vivo by mabs against t-cell subsets. although ib is generally considered as an acute respiratory disease, prolonged virus excretion has been reported (cook, ; alexander et al, ; chong & apostolov, ) . when day-old chicks were infected with an enterotropic ibv, strain g, faecal excretion could not be detected beyond day p.i., but when birds reached sexual maturity re-excretion occurred (jones & ambali, ) . virus re-excretion could not be induced earlier by hormone injections (ambali & jones, b) , but it could after t-cell suppression by csa (bhattacharjee et al, ) . reactivation of virus was confirmed by appearance of ibv-specific igm in the serum (bhattacharjee et al, ) . mainly because of the prolonged or intermittent recovery of ibv from these tissues, candidate sites have been proposed for virus persistence in the chicken, the kidneys (chong & apostolov, ) and/or caecal tonsils (cook, ; alexander et al, ) . however, recent work has suggested that the kidneys are the more likely site. when strain m was used to infect day-old chickens and t-cell immunosuppression by csa treatment was given from weeks p.i., virus was recovered first from the kidneys and then from the trachea and lungs but never from the caecal tonsils (dhinakar raj & jones, a) . the target cells of the virus in the kidneys are in the tubular epithelium (chong & apostolov, ; ambali & jones, ) which provides an ideal site for virus persistence because of its immunologically privileged nature (mimms, ) . occurrence of persistence was also found to be related to the age at infection (dhinakar raj & jones, a) . when chicks were infected at weeks of age and treated with csa from weeks p.i. no virus re-excretion was observed, but when chicks were infected at day-old, virus re-excretion was successfully induced with csa. notably, virus re-excretion was not accompanied by clinical symptoms. the persistence of ibv may have practical implications in the epizootiology of the disease and perhaps a role in evolution of variant strains of the virus. furthermore, re-excretion of persistent virus may serve as an unnoticed source of infection to susceptible chickens. ibv does not constitute a single homogenous antigenic type. the prototype virus is massachusetts m . since the first identification of a different serotype (named connecticut) by jungherr et al, ( ) several new antigenic types have been reported in various countries (see captua et al, ; cook, , gelb et al, a; parsons et al, ; picault et al, ) . the major virus neutralizing antibody site of ibv, which defines serotype, resides in the si subunit of the spike protein (mockett et al, ; cavanagh et al, ) . differences in only a few amino acids in the si protein can result in different vn serotypes (cavanagh et al, a) which accounts for the plethora of ibv strains which exists today. hence, different antigenic types identified by vn tests do not imply that the isolates have substantially different si proteins or overall antigenic properties or greatly different evolutionary lineages. as in other rna viruses, antigenic variation is probably facilitated by the high error rate during the transcription of rna template and the absence of a proof-reading mechanism. it has been shown that point mutations may lead to the generation of ibv variants in the field qia et al, ) . however, both circumstantial (cavanagh & davis, ; cavanagh et al, b; jia et al, ; kusters et al, kusters et al, , wang et al, ) and experimental (kottier et al, ) evidence suggest that the main mechanism of generation of variant strains of ibv is by recombination. this could be promoted by the use of more than one strain of ibv for vaccination or by a mixture of vaccine and challenge viruses. isolates of ibv shown to be distinct by the vn test can still induce partial or complete cross-immunity (arvidson et al, ; darbyshire, darbyshire, , hitchner et al, ; raggi & lee, ; winterfield & fadly, ; winterfield et al, ) . for example, vaccination with h caused a , -fold reduction in titres of the challenge virus, australian 't' strain (darbyshire, ) , while on the basis of vn tests in vitro, no evidence of a serological relationship between these two viruses could be demonstrated . hence, antigenic studies alone do not adequately define immunological relationships between strains. thus, it was suggested that cross-immunization studies could be used to classify ibv isolates into protectotypes (lohr, ) as this would reduce the large number of serotypes to a smaller number of protectotypes and provide more practical information to the field. cross-immunisation tests have been performed in experimental chickens (darbyshire, (darbyshire, , lambrechts et al, ) or in in vitro conditions using toc from immunized birds dhinakar raj & jones, d) to determine protective immunological relationships between ibv strains. arvidson et al. ( ) have described a model to study immunogenic relationships between ibv strains based on the vaccinating dose required to prevent the multiplication of a standard challenge dose of a homologous strain in the lungs of chickens. these cross-immunization tests would help to determine whether an already existing vaccine could offer protection to a new variant. this information is critical before embarking on a long and cumbersome process of new vaccine production. since tissue affinities are a function of the viral peplomer-mediated attachment of virus to cells, changes in the spike protein might lead to altered tropism of the virus. six of ten differences in amino acid sequences of gray and jmk strains of ibv were found between residues and ; hence it was postulated that this region may play a role in differences in tissue tropism exhibited by these viruses (kwon & jackwood, ) . however, no correlation was found by sapats et al. ( ) between si amino acid sequences and nephropathogenicity of nine australian strains of ibv. nevertheless, it is not unreasonable to expect new variant strains of ibv to emerge with unusual tissue tropisms and such an example of this is strain /b. conclusions ibv has been effectively controlled by the extensive use of vaccines but it still remains a major economic problem some years after it was first reported. the constant emergence of variant strains has challenged vaccination strategies. with the advent of molecular techniques much of the recent work on ibv has concentrated on improved diagnostic and strain differentiation methods. however, the appearance and spread of the economically-important variant strain /b has given us a reminder of the need for a more detailed understanding of the immunopathogenesis of the disease and to be prepared for emergence of variants with unusual tissue tropisms and disease manifestations. tionstraktes angesehen wird, können verschiedene ibv-stämme unterschiedliche gewebstropismen aufweisen und, mit ernsten folgen, auch den eileiter und die nieren befallen. manche stämme vermehren sich im darm, anscheinend aber ohne pathologische veränderungen. pektorale myopathie ist mit einer wichtigen neuen variante in verbindung gebracht worden. mehrere faktoren können den verlauf der infektion mit ibv beeinflussen und umfassen das alter, die rasse und die fütterung des huhnes, die umgebung und die interkurrente infektion mit anderen infektionserregern. die immunogenen bestandteile des virus sind die s (spike)-proteine und das n-nukleoprotein. die humoralen, lokalen und zellulären reaktionen des huhnes gegen ibv sowie die genetische resistenz des huhnes werden besprochen. bei der langfristigen ibv-persistenz sind die blinddarmtonsillen oder die nieren als orte der persistenz vermutet worden. die antigenvariation bei ibv-stämmen hängt mit relativ kleinen unterschieden der aminosäuresequenzen im spike-protein s zusammen. antigenuntersuchungen alleine reichen jedoch nicht aus, um immunologische beziehungen zwischen virusstämmen ausreichend zu definieren, und kreuzimmunisierungsversuche sind benutzt worden, um ibv-isolate in 'protektotypen' zu klassifizieren. es sind vermutungen darüber angestellt worden, daß veränderungen im spike-protein s eine beziehung zu unterschieden der gewebstropismen, die verschiedene stämme aufweisen, haben könnten. vielleicht könnten in der zukunft neue ibv-stämme auftauchen, die organe oder systeme befallen, welche normalerweise keinen zusammenhang mit der ib haben. virus de la bronquitis infecciosa: inmunopatogenia de la infeccion en la gallina se revisa la inmunopatogenia de la infeccion por el virus de la bronquitis infecciosa en la gallina. mientras que la bronquitis infecciosa (ib) es considerada primariamente una enfermedad del aparato respiratorio, distintas cepas de ibv pueden mostrar tropismos diversos y afectar tambien al oviducto y el riñón con consecuencias serias. algunas cepas se replican en el intestino pero aparentemente sin producir lesiones. una reciente variante de ibv ha sido relacionada con la miopatia pectoral. diversos factores pueden influir el euros de la infección por ibv incluyendo la edad, estirpe y estado nutritivo del ave, el medio ambiente e infecciones intercurrentes con otros agentes infecciosos. los componentes inmunogénicos del virus incluyen las proteinas s y la nucleoproteína n. se revisan las respuestas inmunes humorales y celulares de las gallinas frente a ibv asi como la resistencia genética de la gallina. en situaciones de persistencia de ibv se considera que las tonsilas cecales o el riñón son los lugares probables de acantonamiento. las variaciones antigénicas entre las distintas cepas de ibv están en relatión con diferencias aminoacidicas pequeñas en la proteína s . no obstante, los estudios antigenicos por si solos no son capaces de definir adecuadamente las relaciones entre las cepas, y se han utilizado estudios de inmunización cruzada para clasificar los aislamientos de ibv en "protectotipos". se especula que los cambios en la proteína s puedan estar relacionados con las diferencias en el tropismo tisular que presentan ciertas cepas. probablemente en el futuro se aislarán nuevas cepas de ibv que afecten a organos o sistemas no asociados normalmente con ib. the effect of infectious bronchitis virus on chickens infected with mycoplasma gallisepticum effect of nephropathogenic infectious bronchitis virus on renal function in male broiler chickens comparison of the nephropathogenicity of four strains of infectious bronchitis virus isolation of avian infectious bronchitis virus from experimentally infected chickens a long-term study of the pathogenesis of infection of fowls with three strains of avian infectious bronchitis virus early pathogenesis in chicks of infection with an enterotropic strain of infectious bronchitis virus effects of trypsin and sodium tauroglycocholate on an enterotropic variant infectious 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associated with turkey rhinotracheitis virus the histopathology of an interstitial nephritis in the fowl produced experimentally with infectious bronchitis virus the experimental infection of chickens with mixtures of infectious bronchitis virus and escherichia coli the response of the harderian gland of the fowl to antigen given by the ocular route. i. histologic changes cell mediated and humoral immune response of chickens to live infectious bronchitis vaccines cell mediated and humoral immune response of chickens to inactivated oil-emulsion infectious bronchitis vaccines cell mediated and humoral immune response in chickens infected with avian infectious bronchitis avian infectious bronchitis-specific lachrymal iga level and resistance to challenge transfer of igg from serum to lachrymal fluid in chickens lachrymal antibody response of specific-pathogen-free chickens and chickens with maternal immunity after infectious bronchitis virus vaccination avian infectious bronchitis-viral persistence in the harderian gland and histological changes after eye-drop vaccination local and systemic antibody response of different chicken lines after ocular vaccination against infectious bronchitis infectious bronchitis effects of avian viruses on cultured chicken bone marrow-derived macrophages structural proteins and glycoproteins of infectious bronchitis virus particles labelled during growth in chick embryo cells embryo vaccination of chickens with infectious bronchitis virus-histologic and ultrastructural lesion response and immunological response to vaccination evolutionary implications of genetic variations in the s gene of infectious bronchitis virus comparison of a microneutralisation test with elisa and precipitin tests for detection of antibodies to infectious bronchitis virus in chickens nephropathogenicity of infectious bronchitis virus some characteristics of isolates of infectious bronchitis virus from commercial vaccines etiology of an infectious nephritis-nephrosis syndrome of chickens immunity to infectious bronchitis virus from spray vaccination with derivatives of holland strain vaccination against infectious bronchitis virus and immunosuppressive effects of infectious bursal disease relationship between several criteria of challenge-immunity and humoral immunity in chickens vaccinated with avian infectious bronchitis vaccines detection of infectious bronchitis virus antigen from experimentally infected chickens by indirect immunofluorescent assay with monoclonal antibodies influence of environment on airsacculitis: effects of relative humidity and air temperature on broilers infected with mycoplasma synoviae and infectious bronchitis avian infectious bronchitis: properties and application of attenuated vaccine prepared with nephropathogenic strain az- / rÉsumÉ virus de la bronchite infectieuse: immunopathogènie de l'infection chez le poulet bien que la bronchite infectieuse (ib) soit d'abord considérée comme une maladie du système respiratoire, différentes souches d'ibv peuvent montrer des tropismes tissulaires variables et affectent aussi l'oviducte et les reins avec des conséquences sérieuses. quelques souches se multiplient dans l'intestin mais apparemment sans troubles pathologiques en ce qui concerne la persistance à long terme de l'ibv, les amygdales caecales ou les reins ont été proposés pour être des sites de persistance. la variation antigénique parmi lès souches d'ibv est reliée à des différences relativement faibles au niveau de la séquence en acides aminés de la protéine de la spicule s . néanmoins, les études antigéniques seules ne définissent pas de façon adéquat les relations immunologiques existant entre les souches, et des essais d'immunisation croisées ont été utilisés pour classer les isolats d'ibv en 'protectotypes'. il a été spéculé que les changements au niveau de la protéine s peuvent être reliés à des différences de tropismes tissulaires mises en évidence pour certaines souches key: cord- -mxdlii authors: arji, goli; ahmadi, hossein; nilashi, mehrbakhsh; a. rashid, tarik; hassan ahmed, omed; aljojo, nahla; zainol, azida title: fuzzy logic approach for infectious disease diagnosis: a methodical evaluation, literature and classification date: - - journal: biocybern biomed eng doi: . /j.bbe. . . sha: doc_id: cord_uid: mxdlii this paper presents a systematic review of the literature and the classification of fuzzy logic application in an infectious disease. although the emergence of infectious diseases and their subsequent spread have a significant impact on global health and economics, a comprehensive literature evaluation of this topic has yet to be carried out. thus, the current study encompasses the first systematic, identifiable and comprehensive academic literature evaluation and classification of the fuzzy logic methods in infectious diseases. papers on this topic, which have been published from to and related to the human infectious diseases were evaluated and analyzed. the findings of this evaluation clearly show that the fuzzy logic methods are vastly used for diagnosis of diseases such as dengue fever, hepatitis and tuberculosis. the key fuzzy logic methods used for the infectious disease are the fuzzy inference system; the rule-based fuzzy logic, adaptive neuro-fuzzy inference system (anfis) and fuzzy cognitive map. furthermore, the accuracy, sensitivity, specificity and the receiver operating characteristic (roc) curve were universally applied for a performance evaluation of the fuzzy logic techniques. this thesis will also address the various needs between the different industries, practitioners and researchers to encourage more research regarding the more overlooked areas, and it will conclude with several suggestions for the future infectious disease researches. fuzzy logic approach for infectious disease diagnosis: a methodical evaluation, literature and classification show that the fuzzy logic methods are vastly used for diagnosis of diseases such as dengue fever, hepatitis and tuberculosis. the key fuzzy logic methods used for the infectious disease are the fuzzy inference system; the rule-based fuzzy logic, adaptive neuro-fuzzy inference system (anfis) and fuzzy cognitive map. furthermore, the accuracy, sensitivity, specificity and the receiver operating characteristic (roc) curve were universally applied for a performance evaluation of the fuzzy logic techniques. this thesis will also address the various needs between the different industries, practitioners and researchers to encourage . an infectious disease can be defined as a situation that is created by the incursion of a human body by harmful agents which will in turn hurt the body and may spread to other people as well [ ] . infectious diseases are the major cause of illness and death for any given population [ , ] . human immunodeficiency virus infection and acquired immune deficiency syndrome (hiv/aids), severe acute respiratory syndrome (sars), h n influenza and poliomyelitis are examples of an infectious disease [ , ] . while globally the incidence of the infectious disease varies greatly between countries, in the st century, the main incidences are hand-foot-mouth disease, hepatitis b, and tuberculosis [ ] . these diseases have a significant impact on the global health and economies [ ] . despite numerous valuable achievements regarding the procedures for preventing and controlling of various diseases, infectious diseases remain a massive threat to a population's well-being [ ] . aspects such as the increasing in antimicrobial resistance, increase in population and environmental changes are important in an infectious disease transmission [ ] . of million mortality reported per year throughout the world, . million were related to infectious diseases; which represent more than % of the overall deaths [ ] . additionally, clinical diagnosis and detection of the contaminated population are critical elements in controlling and supervising an infectious disease [ ] . for the diagnosis of different diseases, there are different essential criteria that should be interpreted by the caregivers [ ] . in a clinical situation, an analysis physician combines a patient's medical history, clinical symptoms, physical examination and laboratory findings [ ] . due to the elusive and complex nature of clinical decisionmaking, they may be accomplished with unwanted errors [ ] . in other word, medical diagnosis is an error-prone process, which occurs as the result of logical thinking [ ] . mathematical models are essential means for demonstrating the cause and effect relationship and evaluating the evidence for decisiveness regarding infectious diseases [ ] . computer-aided methods have the potential for examining the complexity of an infectious disease dynamics [ , ] . computational tools are essential for understanding epidemiological patterns in a disease outbreak [ ] . for handling the uncertainty of decision-making, studies have tried to explain the decision-making process in a medical setting by using the boolean or binary structure [ ] . fuzzy logic is considered as a vigorous technique for modelling ambiguity in medical practice [ ] . in medical field, most medical concepts are fuzzy [ , ] . these concepts usually are difficult to formalize and measure [ ] . fuzzy logic is making a decision in an inaccuracy, uncertainty and incompleteness environment [ ] . fuzzy methods deal with the classes whose boundaries are unclear and elusive [ ] . fuzzy logic concepts were introduced in [ ] . the medical field was one of the first fields in which fuzzy theory was implemented [ ] . fuzzy classes are given a degree of membership that is intermediary between and [ ] . some of the cases for a medical use of the fuzzy set theory are the myci, internist and doctormoon applications [ , ] . therefore, for these application methods, different types of research have been conducted in the disease diagnosis field. so, the major objective of the current study is to examine the researches in which fuzzy logic techniques have been applied in infectious diseases so to determining its trends and methods, through the processes of conducting a systematic literature review (slr). the current thesis is structured in the fallowing order. section exemplifies the procedures or the methodology of the current slr, section will present a complete report of the current systematic review. section will be dedicated to the discussion of this research. section will be dedicated to the implications of this study, its future research prospects and to the limitations of this evaluation and the last section will be the conclusion. we carried out an slr to define the influence of using the fuzzy logic methods in infectious diseases. the three main questions of this slr are as follow: (rq ) which domain of an infectious disease was more interesting in past researches? (rq ) which fuzzy methods were more dominant in infectious disease data analysis? (rq ) which performance evaluation methods were more frequently applied in previous reviews? for the gathering of the relevant information from all the eligible articles, a data extraction method was used for getting the detailed answer of the research questions. (rq ) which domain of an infectious disease was more interesting in past researches? (rq ) which fuzzy techniques were more dominant in an infectious disease data analysis? (rq ) which performance evaluation procedures were more frequently applied in the previous reviews? to answer the research questions and to produce the extracted data, numerous methods were used. generally, a narrative combining approach to answering different research questions was applied. furthermore, various visualization techniques such as tables and charts were used according to the research questions. current part is dedicated to the outcome of the current slr. first, we will demonstrate an overall description of the outcome of selecting the appropriate studies; and then, all the obtained outcomes will be categorized for each study questions independently. by searching for the four aforementioned databases, the candidate paper was removed as shown in fig. . then, based on using the exclusion conditions, studies were excluded. the other articles were investigated meticulously to choose relevant studies. by reviewing the title, abstract and the keywords, merely papers that have at least one of the inclusion measures were used. eventually, papers were used to get an answer to the research questions and data extraction for this methodical evaluation. fig. is showing the distribution of eligible papers per year. according to the diagram below, the frequency of papers relevant to the use of fuzzy logic in an infectious disease was roughly stable during the first years. however, as shown in the next chart, there is a persistent trend in the number of finally, the spread of the relevant articles based on a journal or conference, has been explained in table . based on the obtained results expert systems with applications journal was used by researchers for publishing their studies in the . percent of instances. rq : which domain of an infectious disease was more interesting in past researches? articles related to the precise domain of fuzzy methods application in an infectious disease, which have been considered from the past section, are summarized in the following section. fig. illustrates the distribution of numerous fuzzy techniques that have been used in an infectious disease data analysis. based on this figure, the results revealed that the critical application domain of the fuzzy methods in an infectious disease were relevant to dengue fever ( % of papers), hepatitis and tuberculosis ( % of papers). in addition, the other papers were related to diseases such as pulmonary infection ( . % of papers), urinary tract infections (utis), human immune deficiency viruses (hiv) and meningitis ( % of papers). for all the other diseases, there is one paper per each disease ( . % of papers). appendix a, table a lists eligible articles according to the specific type of disease, their objective, their inward and outward variables and findings. as shown in fig. , the distribution of the different fuzzy methods in various disease data analysis was as fallows. in articles published for dengue fever, . % of the papers applied fuzzy set theory and the adaptive neuro-fuzzy inference system (anfis) method in data analysis while . % of the papers used association rule mining. % of selected papers that related to hepatitis, employed neuro-fuzzy classifier as a fuzzy technique, while the other % were devoted to fuzzy inference system and fuzzy decision support system (fdss). furthermore, in tuberculosis studies, % of the papers used rule-based fuzzy logic and % of the papers applied the gaussian-fuzzy neural network method. rq : which fuzzy techniques were more dominant in an infectious disease data analysis? fuzzy inference systems are increasingly becoming more predominant in the area of fuzzy logic methods where % of the selected papers in the current slr are related to this particular method. fuzzy inference systems are used for the processes of mapping the inward variables to appropriate outward [ , ] . fuzzy inference process incorporates three key concepts: the membership functions, the fuzzy set operations, and the inference procedures [ ] . a fuzzy inference system can be divided mainly to four portions as follows: fuzzification, weighting, assessment of inference procedures, and the de-fuzzification [ ] . dragovit et al. utilized the fuzzy inference system to decide the probability of having peritonitis in patients. by using this system, the fuzzy rules enable the automation of the clinical decision making process in an imprecise and complicated conditions [ ] . urinary tract infections (utis) are considered amongst one of the utmost predominant bacterial infections. ibrisimovic et al. has suggested a fis fuzzy model, to provide the necessary support that the caregivers need for explaining the aftermath of a microscopic urine analysis. to create the model's various variables such as the colony forming units (cfu), white blood cells (wbc) and the red blood cells (rbc) as well as the turbidity of urine specimen used for inward variables, and the risk of a uti as an outward variable. the end result has revealed that the use of the fuzzy methods simplifies and secures the clarification of urine analysis [ ] . putra and munir proposed a method for diagnosis of measles, german measles and varicella. the data for those diseases were used because of the similarity of their infection mechanism and symptoms. a built fuzzy inference system b i o c y b e r n e t i c s a n d b i o m e d i c a l e n g i n e e r i n g ( ) - takes in the inward variables that represent the possible symptoms that may appear in each disease. cough, runny nose, sore throat, conjunctivitis, koplik's spot, diarrhea, headache, swollen neck or ear, loss of appetite, malaise, pimples/crust skin, joint pain used as inward variables. the application effectively identified out of accurate diseases throughout its testing stage [ ] . the anfis method was proposed by jang and its notions then were used in other fields [ ] . this method works by setting a list of features by using an amalgam of learning rules which will incorporate the back-propagation incline in error digestion and a tiniest squares method. this method can be implemented as the basis for creating a set of if-then guidelines with suitable association of functions to brand the inward and outward variables [ ] . anfis method has been notably successful in disease diagnosis in the past few years. as an example, the major groups of hepatitis in human beings are hepatitis a, hepatitis b and hepatitis c with the main symptoms being malaise (a common sick feeling), fever, and muscle pain, loss of appetite, nausea, vomiting, diarrhea, and jaundice. viral hepatitis disease can be diagnosed by blood test analysis and interpretations. dogantekin et al. developed an anfis system to be used for hepatitis diagnosis. the precision achieved in this automated system of diagnosis was at about . % [ ] . faisal et al. conducted a research using an adaptive neurofuzzy inference system to diagnose a dengue fever. the general precision of the developed method is . % with its sensitivity being at . % and its specificity being at . % [ ] . this method was used in the campisi research as well to determine the amount of the risk factors of an infection disease in relationship with oral candidiasis (oc) [ ] . additionally, shariati has recommended a method of diagnosis for both hepatitis and thyroid diseases. the researchers in this study compared the outcome of the anfis technique with the support vector machine (svm) and the artificial neural networks techniques. then, they demonstrate that this technique had an improved outcome in being a precise diagnosis in comparison with the previous techniques [ ] . the information in a fuzzy rule-based system is typically represented by using an if-then statement. rule-based fuzzy logic includes two portions: the precursor portion are the relevant conditions which are known as the inward variable(s), and the subsequent portion which expresses the outward variable(s). mamdani and sugeno are two different types of fuzzy rulebased systems. in the mamdani technique, the precursor, as well as the subsequent section, comprises fuzzy statements that reveal the value of the variables, while in sugeno method, the subsequent portion displays a nonlinear affiliation among both the inward and outward variables [ , ] . because of the complex nature of the numerous diseases, this technique can improve the infectious disease diagnosis and the treatment of such diseases as hiv and tuberculosis. based on this, sloot et al. efficiently used rule-based fuzzy logic to uncover the drug-resistance in hiv patients [ ] . furthermore, semogan et al. has created a clinical decision supporting system based on the fuzzy logic and the rule-based model that determine different classes of tuberculosis to assess respiratory diseases. in this system variables such as cough, cough duration, body temperature, fever duration, sputum discoloration, nose sputum, afternoon chills, night sweats, weight loss, and loss of appetite have been used in the diagnosis [ ] . b i o c y b e r n e t i c s a n d b i o m e d i c a l e n g i n e e r i n g ( ) - the fuzzy cognitive map (fcm) is a modelling technique that defines the connections between concepts such as variables, the inwards and the outwards by the methods of previous knowledge and experience. kosko has introduced fcm in . fcm is usually used to demonstrate the cause and effect relationship between the different concepts in a given system. fcms are used in numerous fields such as in engineering, error detection and medicine [ , ] . in this regard, mei et al. has applied fcm to describe how factors such as people's emotions and cognition functions influence each other to create epidemic infection [ ] . fcm was also used by the mago et al. research to develop the required knowledge-based structure used for recognizing the specific causes and the symptoms of meningitis disease in children. this system can be implemented as a dependable instrument in supporting the physician's to better their decision making processes [ ] . rq : which performance evaluation techniques were more frequently applied in the previous reviews? performance evaluation procedures are among the furthermost significant indicators for determining the quality of the artificial intelligence techniques [ ] . overall, performance evaluation procedures are classified into two main types; the first being the single scaler techniques and second being the graphical techniques. the sensitivity, specificity and the accuracy indicators are grouped into the single scaler techniques. receiver operating characteristic (roc) curve, cost-line, and lift graph are clustered together in graphical methods. anyhow, graphical methods cannot simply be clarified and analyzed as single scalar method [ ] [ ] [ ] . fig. indicates the most noticeable performance evaluation indicators used in eligible papers. for the current slr, most qualified studies did not use any kind of indicators for analyzing the performance of the fuzzy techniques. among the fuzzy techniques, anfis and fis techniques were evaluated by single scaler techniques and graphical evaluation techniques. the major objective of this slr was to select and examine the various studies relevant to the employment of the fuzzy logic techniques in an infectious disease. in this regard, studies were selected and analyzed from an original number of candidate studies. this section is dedicated to the discussion of the major findings of this study. rq : which domain of an infectious disease was more interesting in past researches? in last few years, it has been obvious from the results of analytic studies conducted in our research that there is a growing interest in studying the relevance of the fuzzy logic techniques for an infectious diseases diagnosis applications. the studies have shown that there is an increase in the number of published articles from % in up to . % of the evaluated papers in . this growing trend may prove the popularity of the fuzzy techniques between different academic papers and its valuable effects in identifying the infectious disease trends. additionally, different fuzzy logic techniques have been used in the evaluated papers. from a medical point of view, in fig. we found that the main application domain of fuzzy logic in infectious disease was related to dengue fever, hepatitis and tuberculosis respectively. the other noticeable outcome that we have found was the b i o c y b e r n e t i c s a n d b i o m e d i c a l e n g i n e e r i n g ( ) - fact that the evaluated papers were very diverse in terms of disease types. because of the big impact on global health by infectious diseases, determining the different features of these diseases are a valuable source for improving our knowledge and ability to predict how a disease will spread in a population [ , ] . the ability to comprehend and control an infectious disease can be obtained by the usage of mathematical models [ ] . the newly arising infectious agents such as hiv, the severe acute respiratory syndrome (sars), the mid-eastern respiratory syndrome (mers) coronaviruses; the west nile virus; the nipah virus; the drug-resistant pathogens; novel influenza a strains and the ebola virus outbreak were considered as big challenge to health in the recent century [ ] . using computeraided diagnosis techniques like the fuzzy logic technique can be useful in determining the main factors associated with the infectious diseases occurrence and epidemics. regarding this, in another field of research in relationship to the vaccination strategies for infectious diseases it has been shown that infectious diseases such as influenza have a seasonal pattern in which case mathematical techniques such as the fuzzy logic techniques is considered a vital instrument in the process of forecasting the viral development from one year to another. this technique can also deliver the required scientific confirmation which will help us decide the amount of vaccine treatment, its efficiency, its financial costs and its pattern of contact in any given population [ , , ] . it has been shown that the fuzzy based techniques have an essential part in the determination of infectious disease outbreaks. as an example for that, we have the hiv outbreaks, these techniques can identify at what time a viral transmission has occurred, its outbreak stage and the sexual behavior pattern of the specific population in which a disease is spreading. moreover, the infectious diseases annihilation and elimination techniques dictate that the transmission process itself has to be the target not the disease. regard this, the data sources are typically scattered and the collective effect of the numerous control techniques are complex and are dependent on the rate of transmission [ ] . rq : which fuzzy techniques were more dominant in an infectious disease data analysis? as shown in fig. , there is a various number of fuzzy techniques employed in the chosen papers. based on this studied section we can mostly classify the fuzzy techniques into four main classes; the fuzzy inference system, the rulebased fuzzy logic, anfis and the fuzzy cognitive map. the fuzzy inference system and the anfis technique were used as shown in . % and . % of candidate papers, respectively. fis is based on the 'if-then' rules and it can be used to predict the behavior of a various uncertain situations [ ] . as seen in the distribution of the studied articles, we can say that fuzzy techniques are efficient means for modelling unclear disease conditions such as in the case of transmissible disease diagnosis. additionally, in the last few years, there has been substantial interest amongst the researchers to apply the anfis technique in the case of an infectious disease. anfis combines the positive effects of both ann and fis in an influential tool for disease diagnosis. this technique does not require excessive knowledge in the modelling and training system. these techniques are usually valuable for the situation, which are in many cases complicated, with a nonlinear behavior pattern. this work approach has created a relationship between the inward and the outward features by the means of the neurons [ ] . rq : which performance evaluation procedures were more frequently applied in the previous reviews? performance evaluation procedures are usually employed as a valued method in determining the quality of the numerous fuzzy techniques [ ] . as shown in fig. in the current slr, amongst the single scaler techniques, the sensitivity, specificity and the accuracy are frequently utilized in the evaluation of a developed technique. additionally, in graphical evaluation techniques, the roc curve was the other measure of performance evaluation that was used in the adequate papers. these indicators are to be considered significant when reporting and assessing a diagnostic technique. scientists have to provide suitable information about the sensitivity, specificity, and the projected values when describing a computer based diagnostic technique end results and this information must contain how those metrics are concluded and also what are its appropriate interpretations [ , ] . although those indicators are promising in qualified studies, nonetheless, they typically generate an inadequate image of the indicators performance and thus it is possible to lose a certain amount of valuable information. moreover, it is possible that the employment of a single-scaler technique will not identify the full scope of a performance assessment. therefore, a comprehensive and dependable assessment must reflect all the numerous parts of performance distinctive quality. in this methodical review, the studies related to the employment of the fuzzy logic techniques in an infectious disease were assessed, and depending on the acquired outcomes, we can notice an interest amongst the researchers regarding this specific field of research. in last few years, a large number of the transmissible diseases that were supposed to be eliminated have made a comeback. certain factors such as manufacturing, agricultural practices, wars, changes in lifestyles, development and urbanization, and environmental change are all effective in the appearance and reappearance of an infectious disease [ ] . this slr's result demonstrates that even though these are the most of the infectious diseases that were investigated, but there is still more area that needs to be covered. nevertheless, more work should be carried out on the appearance and reappearance diseases domains such as h n , sars, zoonosis and the rift valley fever. internationally, there is a lack of an integrated framework for reporting infectious disease [ ] . additionally, an infectious diseases information system has an inadequate support for data analysis and generating predictive techniques centered on artificial intelligence. an integrated analytical framework that offers functions as in a progressive data analysis capability and a visualization support is of a critical importance [ , ] . there is serious need for creating an atmosphere for collecting, distributing, reporting, assessing, and picturing the infectious disease data and to provide support for decisionmaking tools regarding disease prevention, recognition, and controlling [ , ] . infectious disease observation and controlling has demanded an interdisciplinary work. to have the ability to achieve those objectives, the employment of geographic information systems (gis), three-dimensional information analysis, machine learning and visualization applications and techniques became a must. because of the significance of the infectious diseases at the global level, it is essential to simultaneously develop an incorporated infectious disease dataset and to make the specialized analytical and diagnostic methods all at the same time. additionally, there was slight conversation in the incorporated literature about three-dimensional information analysis for an infectious disease occurrence. three-dimensional information evaluation techniques may be useful in determining the concentration pattern of a disease occurrence and to make the required association from the determined patterns to the measureable procedures [ , ] . furthermore, the social networks information study has facilitated the evaluation of the association amongst the population in a particular social setting. methods that correlate spatial and social network data analysis are unusual but have the capacity to promote the determination of a spreading progress of an infectious disease [ ] . or we can say, the deployment of a unified spatial and social network structure to define the spreading of an infectious pathogens in a given populace will allow insights into both the understanding to the disease method of distribution and the possible process associated with the observed patterns. since there are various studies regarding social media information analysis, we recommend the use of this dataset for the prediction of an infectious disease epidemic. this research has its limitations. even with the use of a broad search approach, some of the publications regarding the fuzzy logic deployment in an infectious disease could not be recovered, as in the case of grey literature and reports that were not published in surveyed digital databases, which we have reviewed. thus, it is recommended that additional slr papers should be carried out to go through the other noticeable databases. additionally, some studies did not report clearly on the performance assessment technique. in conclusion, only the english language publications were included, therefore future studies could be expanded to incorporate relevant papers which are published in other languages. in this study we have identified, classified, and defined the use of the fuzzy logic techniques in infectious diseases. studies were scrutinized and the main conclusions can be briefed as follows: ( ) the key application field of the fuzzy logic in an infectious disease was related to dengue fever, hepatitis and tuberculosis, ( ) amongst the fuzzy logic techniques fuzzy inference system, rule-based fuzzy logic, anfis and fuzzy cognitive map are commonly used in many studies, and ( ) the major performance evaluation indicators such as the sensitivity, specificity, and the accuracy the roc curve is employed. in addition, this study highlights the absence of an integration of infectious disease information systems in order to provide a valuable datasets in this domain. additionally, using machine learning and visualization applications for information analysis is essential. even though in the current slr there is a diversity of infectious diseases that are investigated, there is only one article per each disease. there is additional need to use the fuzzy logic methods for infectious disease detection and prediction. it appears that one of the causes for a limited number of relevant articles to infectious diseases is in the difficulty in obtaining adequate research data. finally, we expect that a mounting number of infectious diseases datasets will be mostly obtainable in the forthcoming years because of raising collaboration amongst medical practitioners and researchers and that this would lead to additional studies of the machine learning techniques that can be useful in this regard. the generated results are more reliable for the prediction of tb in patients. langarizadeh [ ] meningitis rule-based fuzzy logic this system is used to distinguish between bacterial and aseptic meningitis, by using fuzzy logic. gram stain, white blood cell (wbc) count in cerebrospinal fluid (csf), percentage of polymorphonucleocytes in csf, csf protein, csf/ serum glucose ratio, wbc count in blood, percentage of blood neutrophils, blood c-reactive protein (crp), and platelet (plt) count. bacterial and aseptic meningitis 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genetic-neuro-fuzzy inferential model for diagnosis of tuberculosis application of evolutionary fuzzy cognitive maps for prediction of pulmonary infections supporting meningitis diagnosis amongst infants and children through the use of fuzzy cognitive mapping key: cord- -qjfkvu n authors: tang, lu; zhou, yiwang; wang, lili; purkayastha, soumik; zhang, leyao; he, jie; wang, fei; song, peter x.‐k. title: a review of multi‐compartment infectious disease models date: - - journal: int stat rev doi: . /insr. sha: doc_id: cord_uid: qjfkvu n multi‐compartment models have been playing a central role in modelling infectious disease dynamics since the early th century. they are a class of mathematical models widely used for describing the mechanism of an evolving epidemic. integrated with certain sampling schemes, such mechanistic models can be applied to analyse public health surveillance data, such as assessing the effectiveness of preventive measures (e.g. social distancing and quarantine) and forecasting disease spread patterns. this review begins with a nationwide macromechanistic model and related statistical analyses, including model specification, estimation, inference and prediction. then, it presents a community‐level micromodel that enables high‐resolution analyses of regional surveillance data to provide current and future risk information useful for local government and residents to make decisions on reopenings of local business and personal travels. r software and scripts are provided whenever appropriate to illustrate the numerical detail of algorithms and calculations. the coronavirus disease pandemic surveillance data from the state of michigan are used for the illustration throughout this paper. coronavirus disease , an infectious disease caused by severe acute respiratory syndrome coronavirus (sars-cov- ) (world health organization, ), has become a global pandemic that has spread swiftly across the world since its original outbreak in hubei, china, in december . as of june , this pandemic has caused a total of confirmed cases and fatalities in more than countries. being one of the most lethal communicable infectious diseases in human history, it is expected that the covid- pandemic will continue spreading in the world population, causing even higher numbers of infections and deaths in the future. with no effective medical treatments or vaccines currently available, public health interventions such as social distancing have been implemented in most of the countries to mitigate the spread of the pandemic. one of the central tasks of statistical modelling is to provide a suitable risk prediction model that enables both government and public health workers to evaluate the effectiveness of public health policies and predict risk of covid- infection at the national and regional levels. such information is valuable for governments to assess the preparedness of medical resources (personal protective equipments and intensive care unit beds), to adjust various intervention policies and to enforce the operation of social distancing. modelling for infectious diseases has a profound role in informing public health policy across the world (heesterbeek et al., ; siettos & russo, ) . the outbreak of the covid- pandemic in december has led to a surge of interest in disease projection that ubiquitously relies on mathematical and statistical models. a crucial step in modelling disease evolution is to capture key dynamics of the underlying disease transmission mechanisms from available public health surveillance data, which enables reliable projection of disease infection into the future. a prediction model may help us foresee some possible future epidemic/pandemic scenarios and learn consequent impacts of current economic and personal sacrifices due to various control measures. because of both data quality and data limitations from public surveillance data systems, a statistical model should take the following features into account in its design and development. first, a statistical model should be able to make predictions and, more importantly, to quantify prediction uncertainties. forecasting is known to be a notoriously hard task, which depends heavily on the quality of data at hand and a certain model chosen to summarise the information from observed data and then to reproduce information beyond the observational time period. the chosen model is of critical importance to deliver prediction. this paper concerns a review of the family of classical compartment-based infectious disease models, which have been the most widely used mechanistic models to capture key features of infection dynamics. we begin with the most basic susceptible-infectious-removed (sir) model to build up the framework (section ), and this three-compartment model is then generalised to have more compartments to embrace additional features of infection dynamics (section ), such as the well-known fourcompartment model, susceptible-exposed-infectious-removed (seir) model, which takes the incubation period of contagion into account. given many types of factors potentially influencing the evolution of an epidemic, a single prediction value is insufficient to be trustworthy unless prediction uncertainty is reported as part of forecast analysis. quantification of prediction uncertainty is of critical importance, especially when a forecast is made at an early phase of an epidemic with limited data. building sampling variations in infectious disease models makes a statistical modelling approach different from a mathematical modelling approach. a clear advantage of a statistical model is that the model parameters, including those in the mechanistic model, can be estimated, rather than being specified by certain subjectively chosen prior information. second, the consideration of building sampling uncertainties in the modelling of infectious disease is a fundamental difference of a statistical modelling approach from a mechanistic modelling approach known in the mathematical literature of dynamic systems. a mechanistic model is typically governed by a system of ordinary differential equations, such as the existing three-compartment sir model consisting of three differential equations, which explicitly specifies the underlying mechanisms of an epidemic. this model is assumed to govern an operational system of disease contagion and recovery or death, which, in reality, cannot be directly observed. most of the time, public surveillance data are accessible, which represent only a few snapshots of the underlying latent mechanistic system of an epidemic. such gaps may be addressed by a statistical model that incorporates sampling schemes to explain how observed data are collected from the underlying infection dynamics. in turn, prediction uncertainty will reflect forms and procedures of the chosen sampling schemes specified in the statistical model. in this paper (section . ), we will introduce the state-space model as a natural and effective modelling framework to integrate the mechanistic model and sampling schemes seamlessly. third, given the scarcity of the available data in public health surveillance systems, the complexity of a model used for prediction should be aligned with the issue of parameter identifiability. for example, at the beginning of an outbreak, one should consider a simple model, which may be expanded over the course of an epidemic's evolution with increased data availability. to make the specified model useful to answer a certain question of practical importance, a relevant feature should be included in the model building. for example, in the study of control measures to mitigate the covid- spread, the model specification should incorporate a structure that is sensitive to the influence of a preventive policy. in section . , we will introduce an expansion of the basic sir model in that time-varying control measures are allowed to enter. the flexibility of permitting certain modifications is an important property of a model to be considered in an infectious disease model. in this field, all models need to be tailored with increased data and more knowledge from the literature as a disease evolves over time. from this point of view, compartment-based models are superior to other models because, for example, it is easy to add other compartments, such as an exposure compartment, a quarantine compartment or a self-immunisation compartment, to improve the mechanistic model, to answer specific question of practical importance and to capture distinctive data features for better prediction. fourth, as the epidemic evolves further, surveillance data become abundant and have higher resolution. for example, in the usa, the numbers of confirmed symptomatic covid- cases and case fatalities are recorded for each county. the average county population size in the usa is approximately , so a microinfectious model may be built upon county-level surveillance data to make high-resolution prediction and to assess the effectiveness of control measures at a community level. this paper (section ) will discuss this important extension of the classical sir model, essentially a temporal model, to a spatio-temporal model that enables borrowing of information from different spatially correlated counties in the improvement of risk prediction. this exemplary model generalisation sets up an illustration from a nation-level macromodel to a county-level micromodel. the latter is more relevant and useful for local governments to make decisions of business reopenings and for residents to be aware of local infection risk. last, to make research findings transparent and to place resulting toolboxes into the hands of practitioners, an open-source software package must be a deliverable. this is indeed a rather demanding task, as the ease of implementation and numerical stability impact the choice of statistical models and statistical methods for estimation and prediction. note that not every statistical model permits delivery of a user-friendly computing package that is general and flexible enough to handle various types of data. in this paper, we focus on the discussion of markov chain monte carlo (mcmc) methods that have been developed in the literature to perform estimation and prediction for state-space models (section . ). in this paper, we invite the readers on a journey of surveillance data, modelling, estimation and prediction, implementation and software development. after reading this paper, one should be able to use existing compartment-based models or to expand them in a study of an infectious disease epidemic, to improve estimation and/or prediction methods, or create one's own software. it is our hope that this paper may pave the path to learning, practising or developing new methodologies that are useful for a broader range of infectious disease modelling problems. multi-compartment models have been the workhorse for modelling infectious diseases since the early th century. they are a class of mathematical models used for describing the evolution of masses (in unit of proportions or counts) among the compartments of a varying system, with broad use cases in epidemiology, physics, engineering and information science. this is a dynamic system that is typically represented by a system of ordinary differential equations (odes) with respect to time, and, given a starting condition, the mass in each of the components is regulated by a function over time. an ode is a simple mathematical model to depict a trajectory of a functional trend. one of such examples used extensively in epidemiology is an exponential growth function, f.t/ d e t , which may be viewed as a solution to an ode of the form: df .t / dt d f .t/, or dy dt d y, where y is a function of time t, which obviously is y d f.t/ d e t with an initial condition f. / d . it is worth pointing out that this simple ode explicitly characterises the rate of change (speed or velocity) for function y d f.t/, rather than directly specifying a form for the function f.t/ itself. such rate-based characterisation is termed as 'dynamics' in the mathematical literature. clearly, this ode is not a statistical model as it does not provide a law of data generation; in other words, there is no randomness in this ode to reflect sampling uncertainties. a typical multi-compartment model consists of several odes for a vector of rates that are linked each other. this is referred to as a dynamic system. the forms of odes are specified according to relevant scientific knowledge about the understanding of the underlying dynamic mechanism related to an infectious disease. in the context of infectious disease modelling, the sir model is the most basic threecompartment dynamic system that describes an epidemiological mechanism of disease evolution over time (see figure ). in brief, the model describes the flow of infection states or conditions by (i) moving susceptible individuals to the infectious compartment through a transmission process (the first arrow) and (ii) moving infectious individuals to the removed compartment (either dead or recovered) through a removal process (the second arrow). at a given time, the total population n under a study is partitioned into the three compartments, denoted by s, i and r, and their sizes satisfying s c i c r d n. with a slight abuse of notation, this notation denotes either the type of compartment or the size of compartment, whichever is applicable in a given context. in other words, s, i and r are used to denote the sizes of the mutually exclusive subpopulations of susceptible, infectious and removed individuals, respectively. this compositional constraint, that is, s c i c r d n, may be interpreted in a term of probability (or proportion) as follows: at a given time, an individual in the population is either at risk (susceptible), or under infection by a virus (infectious), or removed from the infectious system due to recovery or death; that is,  s c  i c  r d , where  s ,  i and  r are, respectively, the probabilities of being susceptible, infectious and removed. this presents the primary constraint for a multi-compartment infectious disease model. more details of the sir model will be described in section . often times, the interest for such system lies in the function values over time, but the closedform analytical solution for such functions may not exist. for example, to answer the question of how many individuals will be infected with the covid- by the end of the year (or any future time) requires to know a calculator that computes the cumulative numbers of susceptible, infected and removed cases over time from the past to the future. unfortunately, in reality, functions relevant to this calculator are usually non-linear, and their exact forms are difficult to directly specify. in contrast, a set of odes helps better understand the disease transmission dynamics (i.e. traits of infectious diseases) and more conveniently captures their key features, where each ode may correspond to one mode of disease evolution. such odes for disease spread may be regarded as a model for the expected dynamic mechanism, serving as a systematic component in a statistical model. numerical methods such as the euler discretisation method or the runge-kutta approximation method (stoer & bulirsch, ; butcher, ) can be used to obtain approximate solutions of such odes with given boundary conditions. regardless of methods used, solutions to a dynamic system are deterministic functions. we illustrate a basic mechanistic model of disease spread in the succeeding text. additional review from deterministic and mathematical perspectives of multi-compartment models is given by anderson et al. ( ) and hethcote ( ) . example . consider the sir model for a hypothetical population with a constant population of n d residents and an initial condition of susceptible individuals, infectious individual and individual removed (either died or recovered). here subjects may be also regarded as % if the unit of proportion is used in the interpretation. the transitions between compartments, written in odes as in ( ), represent population movement from one compartment to another (see figure ). we consider an example withˇd : (a rate of moving from s to i) and d : (a rate of moving from i to r), leading to r dˇ= d : . here r is the socalled basic reproduction number that quantifies an average number of susceptible individuals contracting a virus from one contagious person in an environment of no preventive measures. this is a quite infectious scenario as we will see later. the r script in the succeeding text shows a scenario of obtaining the solution to the system of odes by standard ode solvers ( r package desolve) using the first-order euler method (not shown) or the runge-kutta fourthorder (rk ) approximation method (figure ). details about the rk method can be found in appendix a . . figure , on each of these days, the sum of the three values from the three curves is always equal to , presenting a time-varying redistribution of the individuals. with no control measures in this hypothetical infection dynamics, the susceptible compartment quickly drops and reaches an equilibrium state after days of the outbreak, and during the period of first days, the infectious compartment increases to a peak and then decreases to zero (no contagious individuals in the population) as all currently infected individuals move to the removed compartment, which is the exit of the system. despite relying on a valid infectious diseases mechanism, deterministic approaches have several drawbacks: (i) the actual population in each compartment at a given time is never accurately measured because we only obtain an observation around the mean; (ii) the nature of disease transmission and recovery is stochastic on the individual level and thus never certain; and (iii) without random component in the model, it is neither possible to learn model parameters (e.g. r ) from available data nor to assess prediction uncertainty. the latter is of critical importance given many unobserved and uncontrolled factors in surveillance data collection. in an early stage of the current covid- pandemic, the daily infection and death counts reported by health agencies are highly influenced by the availability of testing kits, reporting delays, reporting and attribution schemes, and under-ascertainment of mild cases in public health surveillance databases (see discussions in angelopoulos et al., ; banerjee et al., ) ; both disease transmission rate and time to recovery or death are also highly uncertain and vary by population density, demographic composition, regional contact network structure and non-uniform mitigation schemes (ray et al., ) . hence, statistical extensions are necessary to incorporate sampling uncertainty in estimation and inference for infectious disease models. the main focus of this paper will be given to a statistical modelling framework based on a class of state-space models, in which the systematic component is specified by multicompartment infectious disease models while the random component is governed by a certain sampling distribution of surveillance data. note that multi-compartment infectious disease models present a class of classical mechanistic models widely used in practice and that incorporating certain sampling distributions allows to make statistical estimation, inference and prediction with quantification of uncertainties. we organise the paper as follows. in the first part of the paper, we introduce a class of macromodels. we begin with the most basic sir mechanistic model in details, followed by some important extensions used to address representative scenarios of disease spread and infection evolution. examples include seir model with an additional compartment of exposure accounting for potential incubation period of infection and susceptible-antibody-infectious-removed (sair) model with an additional compartment of antibody accounting for potential self-immunisation after being infected. then, we formally introduce the framework of state-space models, a powerful statistical modelling approach that aims to model available surveillance data from public health databases with the utility of the underlying latent mechanistic model. in the second part of the paper, we introduce a class of micromodels. when an epidemic continues, data become abundant and of high resolution at community level. for example, the surveillance data of the covid- pandemic in the usa are collected from individual counties. this allows building county-level microinfectious models in addition to country-level or state-level macromodels. being a certain subgroup analysis, such micromodelling is appealing to address spatial heterogeneity across the more than counties in the usa and consequently improves the prediction accuracy. as far as the spatial modelling of infection dynamics concerns, we review the classical cellular automata (ca) that is extensively used to describe person-to-person interacting rules associated with epidemic spreading patterns in a population via relevant interlocation connectivity functions. this ca may vary spatially and temporally, which presents a principled way to extend a state-level macroinfectious disease model to a stratified microinfectious model. in addition to the case of geographical subgroups, other types of subgroups by, for example, age, race, income, political party and economy, are also of interest. our main objective of this paper is to introduce to readers the basics of infectious disease models, underlying modelling assumptions, statistical analyses and possible extensions. examples will be provided for demonstration purposes. this review targets readers who have had some statistical training but no prior experience in infectious disease modelling. the first infectious disease model (mckendrick, ; kermack & mckendrick, ) is widely known as the susceptible-infectious-removed model, or in short the sir model (see figure ). it is a three-compartment model for studying how infectious diseases evolve over time on the population level. it defines a mechanism of disease transmission and recovery for a population at risk by a dynamic system of three disjoint states: susceptible, infectious and removed. we note an important distinction between infectious and infected individuals. infectious individuals are those who are currently infected and not yet recovered or dead (currently infected individuals become infectious immediately in the sir model, although it may not be true in reality; see the seir model in section where currently infected individuals become infectious with a delay in time), whereas infected individuals could mean only currently infected or both currently and previously infected. for clarity, we will refer to currently infected as infectious so that the three states in the sir model are mutually exclusive. individuals in the susceptible state are not immunised and can become infected by coming into contact with infectious cases, so they are at risk at a given time. individuals in the infectious state contribute to the transmission of the disease until they ultimately recover or die, so they are contagious. individuals in the removed state include those who either recover or die (without distinction). this is an exit from the infection system, meaning that once an individual leaves this system (recovers or dies), he or she would never return to the system. this is true for people who die from the virus but may not be the case for recovered individuals. thus, in the sir model, there is a technical assumption that a recovered individual would become self-immunised to the virus and no longer impact the disease transmission. a possible way to relax this assumption is to create two separate compartments corresponding to recovery and death states, respectively, leading to a four-compartment infectious disease model. to make our presentation focused on the basic three-compartment model, we make this self-immunisation assumption in this section. given what we said earlier, the current version of sir is only applicable for diseases, where long-term immunity can be developed, and does not apply to recurring infectious diseases, such as the common cold. this is because the disease transmission rate is set as a constant in sir. in this section, we introduce the sir model in its basic deterministic form (section . ), define reproduction numbers (section . ), elaborate its assumptions (section . ) and properties (section . ) and present some technical extensions to the basic sir model. mechanistic extensions, such as modifications to the three-compartment sir model to account for additional components or disease mechanism, are discussed in section . we use s.t/, i.t/ and r.t/ to denote the time-course subpopulation sizes (i.e. the number of individuals) distributed into each of the three compartments at a given time t, where t is continuous. clearly, where n is the total population size, which is a fixed constant. the starting time is denoted as t d . the rates of change among these subpopulations are represented by a system of odes: ( ) ( ), these three odes define a dynamic system of three deterministic functional trajectories over time, including the susceptible trajectory s.t/, the infectious trajectory i.t/ and the recovered trajectory r.t/ for t . this sir dynamic system is well posed in the sense that non-negative initial conditions lead to non-negative solutions of the three functional trajectories. these trajectories collectively demonstrate the evolutionary mechanism of an infectious disease. the sir dynamic system in ( ) may be interpreted as follows. let us consider events occurring instantaneously at time t. in the first ode, the ratio i.t/=n represents the proportion of contagious individuals in the population, which may be thought of as a chance that a person in the at-risk population may run into a virus carrier. if each individual at risk has an independent chance to meet a contagious person, then, according to the binomial distribution, the expected number of susceptible individuals contracting the virus is s.t/i.t/=n. in reality, a person at risk may run intoˇ(say, ) contagious individuals, leading to a modified chanceˇi.t/=n. thus, instantaneously at time t, the system gains an additional number of infected cases equal toˇs.t/i.t/=n, and these cases will leave the susceptible compartment to enter the infectious compartment. such loss to s.t/ is attributed to the negative sign in the first equation. in the second ode, the first term is the number of new arrivals of contagious individuals and the second term is the loss of contagious individuals at a rate who either recover or die and then enter the removed compartment. the third ode is based on an absorbed compartment that always accumulates with new arrivals with no departure cases. in the literature, the transition rate represents the fraction of the infectious population that exits the infectious system per unit time. for example, d : means that the infection compartment will decay (or infectious individuals being recovered or dead) at an average rate %. in other words, = describes the expected duration ( days for d : ) over which an individual stays infectious under the exponential distribution of time for his or her sojourn. variations of the form in ( ) are often seen in the literature. among those, the most important sir specification is given as follows. because the total population n remains constant over the duration of infection, by dividing both sides of the ordinary differential equations by n, the rates of change in terms of population proportions can be derived, without changing the interpretation ofˇand . that is, ( ) where  s .t/,  i .t/ and  r .t/ are the probabilities (or proportions) of being susceptible, infectious and removed at time t, respectively. here the probability of being infectious  i .t/ is also known as the prevalence of disease in the epidemiology literature (see, e.g. osthus et al., ; wang et al., ) . a clear advantage of this alternative form of the sir model ( ) where the population size n is implicitly absorbed into the parameter of disease transmission rateˇ, which may be interpreted as a per capita effective contact in proportion to the population (see, e.g. johnson & mcquarrie, ). despite the differences in notations and presentations, they convey the same infection mechanism, but interpretations need to be given accordingly. although we use these model specifications exchangeably in this paper, the form given in ( ) is recommended to conduct practical studies. based on the two parametersˇand in an sir model, the ratio r dˇ= is termed as the basic reproduction number, which captures the expected number of new individuals who directly contract the virus from one contagious individual in an environment with no preventive measures. intuitively, it is a product of the infection rateˇand the infectious duration = . the basic reproduction number r does not depend on the distribution of people over the three compartments and presents a key appealing disease characteristic for describing and comparing across infectious diseases (see, e.g. chowell et al., ; ferguson et al., ; khan et al., ; liu et al., ). an epidemic is expected to occur when r > , or to disappear when r < . this is because in the sir model ( ), at the condition of s.t/=n , the former is equivalent toˇ> , leading to di.t/=dt .ˇ /i.t/ > , while the latter implies di.t/=dt < . the earlier interpretation of r relies on an implicit assumption that all contacts with a contagious individual are susceptible, which contrasts with the effective reproductive number. the effective reproductive number is defined as r e .t/ d r s.t/ n . it represents the expected number of newly infected individuals who contract the virus directly from a contagious individual at time t, given that each susceptible individual has a chance of s.t/=n to meet this contagious individual. this is not to be confused with the notation r.t/, the removed population. in the early outbreak of an infectious disease in a large population, r e .t/ r because s.t/=n . in contrast to r , which is only descriptive of the disease itself (or the progression of disease near time ), r e .t/ reflects the progression of the infectious disease in a population at any given time because it directs the sign of di.t/=dt corresponding to acceleration or deceleration of the infection dynamics. this may be seen by the second-order derivative d i.t/=dt ; a time, say t , at which d i.t /=dt d or the rate di.t /=dt reaches a peak, is referred to as a turning point (see the peak in the middle panel of figure ). hence, r is of most interest during the early phase of an epidemic, whereas r e .t/ is of most interest later on during the controlling phases of an epidemic. for example, the so-called herd immunity is the natural immunity developed when an epidemic reaches r e .t/ < . in other words, without interventions, it requires the proportion of susceptible individuals to be no more than =r , or the combined proportion of infectious and recovered to be at least =r in order to contain the spread. as another example, if an effective vaccine becomes available at time q t > , knowing r e . q t/ allows us to estimate the remaining proportion of population that needs to be vaccinated in order to control the epidemic (i.e. for achieving r e .t/ < ). figure shows that the effective reproductive number r e .t/ for example decreases as the group of susceptible individuals, s.t/, shrinks over time, eventually reaching below the threshold of at time . the value at time is r d r e . / d : , while r e . / d . the time of reaching this threshold also marks a special time of interest-when the number of active contagious individuals starts decreasing at time after reaching its maximum, as shown in the middle panel of figure . like every mathematical model, there are some assumptions and constraints such as boundary conditions that the sir model needs to satisfy. these restrictions define the circumstances where the sir model may be appropriate to use in practice. although some of them have been mentioned earlier, for the sake of self-contained summarisation, we list all key assumptions as follows. assumption : the population involved in the infection is closed with no additions or leakage of individuals, and the size of the population is fixed, say, n. this assumption may be satisfied by an epidemic that is rapid and short lived, during which disease evolution is not affected or is minimally affected by vital changes (e.g. natural births or deaths) and migration (i.e. immigration and emigration). technically speaking, the three compartments satisfy the condition of the form: assumption : individuals in the population meet each other randomly in that both probability and degree of interactions with one another remain constant over time, regardless of geographical and demographic factors. this is a strong assumption of homogeneity for the sir dynamic system that is governed by the same transmission and recovery param-etersˇand . in practice, such a homogeneity assumption may be easily violated. thus, modelling with heterogeneous dynamics of infection is an important and active research area in the literature on infectious diseases. assumption : one susceptible individual can only develop immunity (or selfimmunisation with antibody against the virus) through infection (i.e. no vaccination). in other words, as shown in figure , the infectious compartment is the only exit of the susceptible compartment, and there is no other state to which an at-risk individual would move next. once recovered from infection, one becomes immune to the virus for the remainder of the study period and would not return to be susceptible again. in effect, this is a rigorous definition of recovered case in the sir model. from a view of the graphic representation in figure , this implies that there is no connection from the removed compartment to the susceptible compartment, or in other words the removed compartment is the terminal state of the infection dynamics. it is worth pointing out that to date the validity of this assumption for the covid- pandemic remains unknown. in the literature, this condition is assumed for a certain period of time over which risk prediction is considered. assumption : the infection has zero latent period in that one becomes infectious once exposed. this is a key distinction of the sir model from the seir model. like many infectious diseases, the covid- has a reported average incubation period of between and days (li et al., ; pan et al., ) , which adds some additional complexity in the modelling of infectious disease dynamics. as a matter of fact, this latency of contagion is really the timing of being contagious and not that of being symptomatic. some studies have found that covid- carriers are most contagious in the early phase of illness prior to the occurrence of noticeable clinical symptoms (ip et al., ; he et al., ) . given these findings, it is tricky to see how the compartment of exposure for incubation would be added to extend the sir model for the covid- pandemic. assumption : because the sir model has constant transmission and recovery parameterš and , which are not time varying, the underlying infection is assumed to evolve in fully neutral environments with no mitigation efforts via external interventions such as a public health policy of social distancing, effective medication or fast testing kits for diagnosis. as far as the covid- pandemic is concerned, this is the biggest restriction of the sir model, which is not reflective of the reality-almost all countries with reported covid- cases have issued various non-pharmacological control measures. many researchers have proposed solutions to overcome this unrealistic assumption of the sir model in the analysis of covid- data (see, e.g. wang et al., ) . assumption : the population size n is large enough to have enough number of incidences, including the number of infections, the number of deaths and the number of recovered cases, so that the sir model parameters can be stably estimated with high precision. technically speaking, this is not a model assumption but a condition of sample size for statistical power. because this mechanistic model will ultimately be used for risk projection, a well-trained model with reliable data is necessary to not only produce an accurate prediction but also to adequately assess the prediction uncertainty. although these six assumptions specifically concern the sir model, most of these discussions or associated insights are useful to understand the restrictions of sir model extensions that will be presented in the remaining sections. knowing possible violations of a certain restriction on a multi-compartment model in data analyses gives rise to potential new research problems for further investigation. to further understand the mechanism of infection governed by the sir model, we now give a brief summary of its analytic properties that provide useful guidelines for us to build statistical models and methods to learn the sir model from available surveillance data from public health databases. ( ). more importantly, although the dynamic system defined by the sir model is continuous over time, available surveillance data are reported at discretised measurements over discretised time points. for example, most of the covid- public databases update data on a daily basis, in which 'a day' is the unit of time for measurement. knowing this discrepancy between the continuous time underlying mechanistic model and the sampling frequency at discrete times for available data is essential to create a statistical framework to link the sir model with the data at hand. property : the sir model is deterministic and does not contain any probabilistic components. it is noteworthy that dynamics and stochasticity are two different mathematical properties; a dynamic system (e.g. the sir model) is not necessarily stochastic, while a stochastic system is not necessarily dynamic. as shown in figure , the compartment sizes s.t/; i.t/ and r.t/ are time-varying functions with no random fluctuations, which are completely determined by the model parameters and the initial conditions of the sir model. obviously, this is a limitation of the sir model when it is applied for data analysis, where data collection is subject to profuse uncertainties and random errors. property : it is easy to show that the number of individuals at risk (in the entry of the system), s.t/, is monotonically non-increasing and that the number of removed cases (at the exit of the system), r.t/, is monotonically non-decreasing (see figure ). hence, the total number of individuals who have been exposed to a virus is equal to n s.t/ d i.t/ c r.t/, which is monotonically non-decreasing. i.t/, the number of active contagious cases, or the difference between the two groups of the exposed cases and the recovered cases, can be either increasing or decreasing. the middle panel of figure nicely conveys such directionality of movements, in which the time of i.t/ reaching the peak and the time of i.t/ reducing to zero are two important turning points of interest in epidemiology. the former indicates the turning point of disease mitigation, and the latter corresponds to the turning point of disease containment. property : it can be shown that i. / d (or equivalently,  i . / d ), meaning that the disease will eventually die out. this is because when t ! , the rate of prevalence  i .t/, given by .ˇÂ s .t/ / in ( ), will become negative at a certain time and then become more and more negative until converging to zero because  s .t/ is a decreasing function and  i .t/ is bounded in the succeeding text by zero. however, this property of decaying to zero is conditional on the assumptions listed earlier. violation of assumptions and are most likely to cause a disease to persist because the monotonicity of s.t/ used in the earlier argument is no longer valid. an example of such diseases includes seasonal influenza, where immunity does not last long. property : the sir model has a recursive property in that at any given time, disease progression (i.e. shapes of the three functions) is only dependent on their current values and not on other information from the past. this property of recursion should not be confused with the markov property that has exclusively used in the literature of stochastic processes under the conditional probability law. here there is no probability law involved in the recursive operation, which is indeed a fully deterministic recursion. such conceptual distinction may help understand the differences between dynamics and stochasticity. during an epidemic, various control measures are typically issued by governments to mitigate or contain the spread of the disease. a direct impact of these external interventions is that both the transmission and recovery rates are no longer constant over time. thus, an important generalisation of the sir model is to accommodate different degrees of mitigation policies, including social distancing, limiting transportation, mandatory mask wearing and city lockdown. as observed in the ongoing covid- pandemic, mitigation strategies are changing over time. limiting mobility of susceptible individuals and medically isolating contagious individuals in the population would reduce the rate of contracting virus, leading to a decreasing disease transmission rateˇ.t/. at the same time, gaining better knowledge on both treatment and self-management of symptoms and improving medical resources may increase the rate of recovery .t/ over the course of an epidemic. incorporating time-varying parameters into the sir model leads to an important extension of the basic sir model ( ): the form ofˇ.t/ can be specified mainly in two ways. one is to letˇ.t/ be either a parametric function (e.g. exponential decaying function) or a non-parametric function (smirnova et al., ; sun et al., ) , both of which may be estimated from available data. one useful feature for the use of a parametric function ofˇ.t/ is to incorporate seasonality in the transmission rate. it is well known that many infectious diseases spread most quickly in some of the winter months. especially, respiratory infectious diseases caused by some coronaviruses exhibit seasonal behaviours that are consistent with the trends of temperature and humidity (barreca & shimshack, ; sajadi et al., ) . accounting for such seasonal periodicity in the model would produce a better long-term prediction of an epidemic. as the public attention for covid- pandemic projection gradually shifts from the short term to the long term, it becomes increasingly important to take seasonality into account. following dietz ( ) , a simple way to introduce seasonality is to assume that the transmission rateˇfluctuates over the period of a year:ˇ. t à ; t d ; : : : ; ; whereˇ is the average contact rate, oe ; is the degree of seasonality with d reducing the model to the basic sir model, and oe ; / is the offset in time horizon so that peak transmission occurs at t d . other periodic functions or their combinations can also be used to model seasonality. as an alternative to a fully non-parametric function, wang et al. ( ) assume a form .t/ dˇ .t/, < .t/ Ä , where .t/ is a known function specified according to given control measures. this specification allows to assess the effectiveness of a target preventive measure, as well as to compare different preventive strategies. clearly, the model with .t/ Á represents disease progression in the absence of any mitigation effort, which sets up the baseline situation in the policy assessment and comparison. the flexibility in specifying .t/ allows easy incorporation of future business reopening events; for example, in the covid- pandemic, this function may be specified as a u-shaped curve in that control measures (e.g. social distancing) gradually relax after a certain time point (see more details from wang et al., , and some numerical results of the covid- data analysis). more discussions on the time-varying transmission rate are given in section . . the assumption of a fixed population size is restrictive, especially when an epidemic remains for a long period of time before it is contained. in this setting, inclusion of natural birth and death dynamics is needed to adequately characterise the time-varying size of each compartment in the sir model. first, let be the natural birth rate and let be the natural death rate. so, the population size will change according to the ode of the form in this case, there are three exits for natural deaths, each occurring at one compartment. an extension of the basic sir model is given as follows: ; as desired. note that when model ( ) is used, n.t/ will be automatically absorbed into the proportions and thus no longer appears in the model formulation. in this section, we review several four-compartment mechanistic models as extensions of the basic sir model introduced in section . being a simple version of a mechanistic model with three compartments, the sir model has some limitations in real-world applications. thus, extensions of this basic type to account for different disease mechanisms and assumptions have been widely considered in the literature. the commonly studied seir model takes into account an incubation period by adding an exposed compartment in between susceptible and infectious compartments (see figure ). the underlying assumption here is that individuals in this exposure subpopulation have contracted the virus but are not yet contagious and are bound to become contagious. in the current literature, most infectious diseases that are suitable for the sir model are believed to fit in the seir model. the exposed compartment may be regarded as a waiting room for virus carriers who are about to spread the virus in the population. let ı be the rate for an exposed individual becoming contagious. then, the basic sir model can be extended to a four-compartment model consisting of the following four odes: where e.t/ is the size of the exposed compartment at time t. in this case, the compositional constraint becomes this constraint is clearly satisfied by the seir dynamic system defined in ( ). let  e .t/ be the probability (or proportion) of being exposed to the virus. then, the rates based sir model ( ) can similarly be extended from the model ( ) earlier. technically, the seir model often suffers from the issue of parameter identifiability because determining a correct incubation period of an infectious disease and thus the parameter ı is a rather difficult task in practice. first, incubation period varies from one person to another; in the case of covid- , the incubation period ranges from to days, with a median of . days (lauer et al., ) . in another study of covid- patients in china, guan et al. ( ) have reported that the estimated incubation period is between to days with a median of days. it is clear that this quantity is very person dependent. second, ascertainment of contagion may be largely delayed because of shortage of virus testing sources. this length-biased sampling problem is notoriously challenging for the estimation of the incubation period (qin et al., ) . third, in the literature (e.g. he et al., ) researchers found that covid- carriers tend to be more contagious right after contracting the coronavirus than a week later because they are not self-quarantined in the absence of clinical symptoms. in other words, in the case of the covid- , the incubation period (or sojourn at exposed state) is too short to play a substantial role in the modelling of the pandemic. not all infectious diseases will develop long-term immunity. individuals may develop immunity after recovery only for some time and could lose immunity such that they become susceptible again. thus, recovered individuals rejoin the susceptible compartment after a certain duration of immunity. this disease evolution is intuitively called the susceptible-exposed-infectious-removed-susceptible (seirs) model. we assume no death in the removed compartment (see figure where the recovered branch in the removed compartment is connected to the susceptible compartment). an example of diseases studied using this model includes the common cold. this seirs model is defined as follows: where is the rate of losing immunity and becoming susceptible again after recovery. different from the seirs model, there are some infectious diseases where long-term immunity is yielded by individuals who survive from their infection. to build the self-immunisation into the infection dynamics, introduce an antibody (a) compartment to the sir paradigm, shown in the bottom thread of figure . because individuals who enter the antibody compartment will no longer be at risk of infection for a certain period of time, this compartment is indeed an exit compartment, at least over a certain time window within which immunity is active, in addition to the removed compartment. in some infectious diseases such as the covid- , the subpopulation of self-immunised individuals is not directly observed or clinically confirmed by the viral rt-pcr diagnostic tests because of mild or absent clinical symptoms. they are self-cured at home with no clinical visits. adding this compartment in the modelling can help to greatly mitigate the issue of under-reporting for the actual number of infected cases in the population. this dynamic system consists of four compartments, that is, susceptible, self-immunised, infectious and removed, with the following odes: where˛is the rate of self-immunisation, which is not identifiable because of the lack of observed data. an approach to estimating the rate parameter˛is to collect data of antibody serological surveys from the population. refer to for more discussions. this section mainly focuses on an introduction of statistical models to analyse surveillance data of an epidemic. each statistical model consists of two components: a systematic component and a random component. in the context of infectious disease data analysis, the former may be specified by a dynamic infectious disease model from sections and . the latter is built upon a random sampling scheme that enables a stochastic extension of the mechanistic model (e.g. sir model) given in the systematic component. essentially, the notions about disease transmission, recovery or other characteristics are used to define key population attributes or parameters in an infection dynamic system of interest, which will be estimated by available data via a statistical modelling framework, where some covariates may be incorporated to learn some subgroup-specific risk profiles. a clear advantage of statistical and stochastic extensions is the ability to quantify uncertainty in both estimation and prediction in connection to sampling variability. this added uncertainty is crucial to policymaking as models not only generate an average estimation or prediction but also present the best and worst possible scenarios for more robust and confident handling of epidemics, given that surveillance data are subject to various issues in the data collection. an example presented in britton ( ) vividly shows the uncertainty in the progression of an infectious disease. consider patient zero, who will go on and infect on average r number of other individuals, as defined by a certain disease mechanism. the number of individuals who contract the virus from this patient is in fact stochastic, varying around the expected number of infections r , which could be described by a distribution (e.g. poisson or negative binomial) with mean r on the support of non-negative integers. with a non-zero probability of taking the value zero due to the variability in human activities, there is a non-negligible chance that an epidemic is completely averted. the opposite could be an outbreak with a non-zero probability that infects tens of thousands of people. without modelling such uncertainty, we cannot see all these possibilities and associated likelihoods of their occurrences during the course of an epidemic (roberts et al., ) . infectious disease systems governed by the class of multi-compartment models, though describing the population average, are useful to describe individual-based stochastic processes if certain random components are introduced into the modelling framework. thus, the resulting statistical models present more natural approaches to the analysis of surveillance infectious disease data. before introducing statistical methodologies that are commonly used for parameter estimation, we distinguish model parameters into two categories. those that can be determined a priori with no need for estimation, which we term as hyperparameters. those that cannot be fully determined and need to be estimated using the data at hand, which we term as target parameters. the choices of which parameter should be a target parameter versus a hyperparameter vary widely across methods. intuitively, the more we know about the biological characteristics of a disease, the more parameters can be held fixed a priori in the analysis. it is however very difficult to determine most of the model parameters early in an outbreak because of the limited amount of knowledge and data about the disease. indeed, many model parameters are not identifiable because of the lack of relevant data availability. one such example is the rate parameter of immunity˛in the sair model ( ). as relevant knowledge accumulates, literature reveals increasingly precise characterisation of the disease, such as its latency period, recovery rate, death rate, immunity duration and antibody acquirement. such information is typically obtained from surveys of high-quality individual-level data, which may provide much better quantification of these hyperparameters than having to be re-estimated by epidemic models, which, on the other hand, are largely based on much coarser surveillance data. in the case of the covid- pandemic, this survey-based approach may be too costly to carry out in countries with large and heterogeneous populations. in general, target parameters are mostly those that are location specific, for example, transmission rate and fatality rate. they vary largely across regions because of non-uniform mitigation effort and hospital resources; hence, datadriven estimations are preferred. in section , we introduce an areal spatial modelling approach to account for spatial heterogeneity in the analysis of infectious disease data. because of the issue of parameter identifiability in some mechanistic models, specifying hyperparameters in the model fitting is inevitable. however, holding hyperparameters fixed at certain values according to some external data sources is indeed controversial, and the validity of consequent analyses is highly dependent on the appropriateness of these certain prior values. to relax this technical weakness, later in section , we introduce a bayesian framework in which such prior information (e.g. hyperparameters) enters the statistical model via certain prior distributions rather fixed values, so that the uncertainty on those hyperparameters is adaptively compensated with the amount and quality of observed surveillance data. such flexibility has a great advantage in synthesising prior evidence and observed data. to present this section at a reasonable technical level, most of the discussions in the succeeding text are given in the setting of the basic sir model, and generalisation to other compartment models should follow with slight modification. in closing, it is noteworthy that the frequentist statistical methods discussed in the succeeding text are based on a fundamental assumption of data collection; that is, the population-level compartment data s.t/, i.t/ and r.t/, and others if relevant, can be directly collected from the study population. in other words, at given time, every individual in the population can be observed directly for his or her current status of being susceptible, infectious, recovered or died. this is practically impossible. thus, the interpretation of the estimation results should be carried out with caution. in the sir model ( ), the transmission rateˇand recovery rate are two target parameters of interest. estimation ofˇand can be carried out through optimisation in search for a model that best fits to the data. a commonly used minimisation criterion is the least squares loss. giveň and , numerical approximations (e.g. runge-kutta methods) can be used to solve for the trajectories, s.t/; i.t/ and r.t/. these expected trajectories are then compared with the observed trajectories to compute a discrepancy score, such as the sum (over time) of the squared errors, represented as a loss function of target parameters. now, it remains to find the estimates of these parameters that give rise to the curve that best fits the data through standard optimisation tools. in this case, the optimisation pertains to a two-dimensional search, which should be computationally straightforward. even a greedy search is computationally cheap. we illustrate using both simulated data and real data in examples and , respectively. example . we first generate an observed sequence of cumulative infectious counts following example , namely, the sir model with the true parameter valuesˇd : and d : . for simplicity, we fix d : in this example. we then evaluate the sum of squared error (sse) loss between the expected cumulative infectious count i.t/ and its sample counterpart i obs .t/, and the value that minimises this loss gives an estimate ofˇ. figure plots the sse loss versusǔ sing the simulated data i obs .t/, t d ; : : : ; t, with t d ; ; , respectively. it is found that the sse loss is minimised at Ǒ d : as expected. the longer the observed sequence, the more curved around . the sse appears, so the better we can identify the minimum of the sse curve. the r script shows the example for the case of t d . note that the sequence we used to define the fit is i.t/, but s.t/ and r.t/ can also be used in the estimation. similarly, a two-dimensional grid search can be used for estimatingˇand jointly when is not fixed in which the data of r.t/ must be used in the estimation. here we present only one replicate for illustration. example . we apply the same approach as given in example for analysing the daily time series of the covid- cumulative infectious counts in michigan during march to may . details of the data are described in appendix a , including the i.t/ sequence. the already defined sir function from example is used as the dynamic model, and the already defined sse function from example is used as the loss function. by fixing d : (i.e. average contagious period of days) the following code computes the solution Ǒ d : using the first observations ( to march). we then increase the number of observations in the estimation; as shown in figure , the value of Ǒ decreases when more data are used. this is noticeably different from example where Ǒ remains constant regardless of the number of observations used. the gradual decrease in our estimate ofˇindicates a potential reduction in the transmission rate over time in michigan due to the enforcement of statewide social distancing. in other words, the assumption of a constant transmission rateˇis inappropriate for the michigan data. this result suggests a need for using a more proper modelling technique, which will be demonstrated in section . . being often used as a classic textbook example, this least squares approach is equivalent to the maximum likelihood estimation (mle) under the assumption that measurement errors are independent and normally distributed with a homogeneous variance. in general, this approach gives consistent estimation and does not require a distributional assumption for the data generation and thus can be applicable to non-normal data. however, the ordinary least squares loss used in the earlier example assumes that data are independently sampled over time, which is not true because the observations are time series and are thus temporally correlated. because of this, the least squares estimation is not efficient. cintrón-arias et al. ( ) have discussed the use of a generalised least squares approach to account for more complex error structure, including temporal autocorrelations. it is not always the best practice to directly use data of i.t/ and r.t/ in the estimation of the model parameters. the covid- projection by gu (https://covid -projections.com/) adopts a loss optimisation approach based on the seir model using only death counts due to quality concerns with infection counts (e.g. under-reporting issue). the model uses a discrete state machine with probabilistic transitions to minimise a mixture of loss functions, such as mean squared error, absolute error and ratio error. in the literature, there are many other estimation procedures (e.g. wallinga & teunis, ; cori et al., ; thompson et al., ) . some of these alternatives do not estimateˇand , but more directly target the effective reproductive number r e .t/ in estimation and inference. here we present the method of moments, another routine estimation approach in the statistical literature for estimating the model parameters in the sir model ( ). during the early phase of an epidemic, one may assume s.t/=n and set dt d (e.g. a time unit of day for discretisation), so that the second ode of ( ) leads to the approximate exponential function solution: ( ) at discrete times at which data are actually recorded. after estimate o is obtained, we obtain Ǒ immediately. however, the estimation of is only accurate during the early phase of disease outbreak because the approximation of s.t/=n is used. in the literature, other types of moments are also used to derive parameter estimates. for instance, using the approximation from the first ode of the sir model ( ) at discrete times, one can easily obtain the following expression: an estimate ofˇmay be obtained by averaging the quantities given in the right-hand side of the equation earlier. in the case whenˇ.t/ varies over time because of changes of a certain mitigation measure, the earlier method of moments estimator may still be applied locally with a possible utility of a kernel weighting function such as the nadaraya-watson estimator (nadaraya, ; watson, ) . a very similar approach leads to the following approximation: which may give rise to a non-parametric estimator of the effective reproductive number. although r e .t/ can be identified at each time point using data solely from t, for numerical stability, the same idea of a kernel weighting (e.g. running-bin method) smoother is applied to estimate r e .t/ at t (see, e.g. wallinga & teunis, ) . linear approximations are easy to implement; however, the variances produced from such linear fits are typically inadequate in describing the true randomness of an infectious disease to allow valid inference and prediction. alternatively, it is promising to investigate the local linear fitting method (cleveland & devlin, ) that produces non-parametric estimates of the time-varying model parameters to better reflect temporal dynamics of the infection. in both the least squares estimation and method of moments estimation, there are no explicit assumptions about probability laws for data sampling. implicitly, both methods are based on the sampling scheme on the entire population; that is, the current status of every individual in the study population is recorded. this is certainly not true in practice. to overcome this, some estimation methods are proposed to account for sampling variability under certain parametric distributions. distribution assumptions can be made for many quantities in an infectious disease model. some are fully specified based on given knowledge. for example, the distribution of incubation period of a disease can be represented as a probability mass function by days (lauer et al., ) . on the other hand, some distributions are only specified to be from a family of shapes, with the exact form to be estimated. we illustrate the latter using a stochastic sir model. stochastic sir models typically require the same assumptions as a deterministic sir model (section . ). to reflect the stochastic nature of disease transmission and recovery, stochastic processes such as a poisson process are used to model the accumulation of cases. following the earlier definitions ofˇand , the number of effective contacts in the population is a poisson process with rateˇn. of these contacts, only those between the contagious and susceptible will lead to new infections. hence, the counting process defined by the number of exposed (i.e. i.t/ c r.t/, or equivalently n s.t/) follows a poisson process with ratě s.t/i.t/=n. hence, the number of newly exposed in an instantaneous duration of dt follows a poisson distribution with meanˇs .t /i.t / n dt. on the other hand, the duration of time individuals staying infectious is assumed to be independent and identically distributed according to an exponential distribution with rate , and hence, the mean infectious duration is = . when we jointly consider all i.t/ infectious subjects at time t, exit events occur independently with a rate i.t/, and the gap times between two adjacent exits are exponentially distributed with mean =f i.t/g. in summary, the number of removed individuals is a counting process following a poisson process with rate i.t/. such stochastic formulation is commonly used, for example, in bailey ( ) and andersson and britton ( ) . through the earlier definitions, s.t/; i.t/ and r.t/ are now random variables that can be directly sampled. in fact, it suffices to assume only two of the three counting processes in order to define a stochastic sir model due to the constant sample size constraint. for demonstration, at time t, in an instantaneous time interval oet; t c dt/, we may specify a stochastic sir model as follows: where i.t/ d n s.t/ r.t/. as a result of this probabilistic formulation, the effective reproductive number is now defined as an expectation, that is, r e .t/ d efˇs.t/i.t/=ng. the stochastic sir model ( ) is specified in continuous time, and we would hope that dt is very small. in practice, approximation to ( ) is used by letting dt d or a unit of day, which is typically the smallest time unit used in public surveillance data. as a result, s.t/ and r.t/ at time t are used to approximate the average in the entire duration of oet; t c /. this approximation turns a continuous time stochastic model into a discrete time scholastic model to proceed with statistical analysis. other distributions, such as negative binomial or general dispersion family (song, ) , may be considered to handle the issue of overdispersion in the counting processes. with distributions in place, we turn the focus to estimation and inference by the maximum likelihood approach. maximum likelihood estimation is often preferred in a parametric model where the underlying probability distribution is properly chosen. for convenience, we take day as the time of unit. by discretising time based on observed sequences, that is, t d ; ; : : : ; t, observed daily increments of counts s.t/ d s.t/ s.t c / in the susceptible compartment and r.t/ d r.t c / r.t/ in the infectious compartment are conditionally independent, given historical accumulated counts s.t/ and i.t/, according to the definition of model ( ). the second model in ( ) contains only the removal parameter , so the log-likelihood function of with respect to the data of daily increments in the removed compartment, r.t/, and daily cumulative counts of infections, i.t/, can be written as where s. / d n and i. / d . however, one caveat in the simplistic likelihood formulations earlier is that the cumulative time series s.t/ and i.t/ are assumed to be directly measured without errors. in other words, the earlier likelihood accounts only for the sampling uncertainties in the increments not those in the cumulative counts, so the resulting statistical inference may suffer from underestimated standard errors. there are two types of statistical inference theory considered in this context, namely, the infill asymptotic theory and the outreach asymptotic theory. the former pertains to the situation where the sampling points increase within a fixed time window (i.e. fixed t), while the latter is a situation of practical relevance where the time window of the data collection tends to infinity (i.e. t ! ). britton et al. ( ) discuss the infill large-sample properties under the assumption that the complete epidemic data, that is, continuously observed counting processes .s.t/; i.t// t [ ,t] , are available. under such setting, the asymptotic distribution of the mle based on continuously observed trajectories is established. obviously, it is really rare in practice to collect infectious disease data via such infill sampling schemes. nevertheless, for the sake of theoretical interest, we refer readers to britton et al. ( ) and references therein. the outreach large-sample theory for the mle with discrete time series data provides a statistical inference relevant to most of infectious disease applications. as an epidemic evolves, the number of equally spaced time points (say, daily) for data collection increases. when sampling errors in both i.t/ and s.t/ are allowed, the likelihood earlier is indeed a kind of conditional composite likelihood (varin et al., ) . thus, the standard theory of composite likelihood estimation implies that the asymptotic covariance of the estimator is given by the inverse godambe information matrix (or a sandwich estimator). the sensitivity matrix in the godambe information is hard to obtain analytically because of the serial dependence in the time series. instead, one may take a non-parametric bootstrap approach similar to that considered by gao and song ( ) to evaluate the standard errors in order to conduct a valid statistical inference. conditional independence is a strong assumption for mathematical convenience in the mle. relaxing it has drawn some attention in the literature. for example, lekone and finkenstädt ( ) and allen ( ) construct likelihood-based approaches using discrete time markov chain seir models; becker ( ) and becker and britton ( ) consider the mle in the sir model using martingale methods when all transition events for each individual are observed. it is however unlikely that such individual-level details are observed in most surveillance data used for modelling of infectious disease mechanisms. estimators using less detailed data have been proposed (e.g. becker, ; rida, ) . as part of efforts on further relaxing strong conditions in the earlier stochastic sir model ( ), in section . , we review a state-space modelling approach that generalises the current likelihood model and estimation framework, where s.t/, i.t/ and r.t/ are not directly measured and rather treated as markov latent processes. also, hyperparameters are included via their prior distributions instead of fixed values, and a bayesian estimation similar to the mle is established through the mcmc approach. this class of state-space models is so far one of the most flexible statistical modelling frameworks to analyse infectious disease data. we highlight several software packages that are publicly available for estimation of parameters in the multi-compartment models. overall, additional efforts in this computational domain are needed. several packages focus on the estimation and inference for r and r e .t/. for example, obadia et al. ( ) , in their r package r , implements multiple methods, including a method of moments-type approach (dietz, ) , a bayesian method (bettencourt & ribeiro, ) and likelihood-based estimation procedures (forsberg white & pagano, ; wallinga & teunis, ; wallinga & lipsitch, ) . along this line, cori et al. ( ) and thompson et al. ( ) develop bayesian methods to estimate the effective reproductive number and are made available through the r package epiestim and microsoft excel (https://tools.epidemiology.net/epiestim.xls). their methods use a moving window approach, assuming that the reproduction number r t, in this window oet c ; t is constant. a gamma prior distribution is used to derive the posterior distribution of the r t, given new infectious counts. state-space models refer to a class of linear or non-linear hierarchical stochastic models with parametric error distributions. the conventional state-space model is not formulated as a bayesian model, but later, its bayesian formulation has gained great popularity because of the availability of mcmc methods for the estimation of the model parameters (carlin et al., ) . this class of models primarily attempts to explain the dynamic features of the state-space model framework is advantageous over the stochastic compartment models introduced in section . in the following aspects of statistical modelling: (i) state-space model does not assume that the compartment processes s.t/, i.t/ and r.t/ are directly observed, which are treated as latent processes to be estimated from observed data. (ii) state-space model allows an explicit sampling scheme to be part of the model specification, which enables the quantification of both estimation and prediction uncertainties in the statistical analysis. (iii) state-space model is built upon the compartment probabilities (or rates or proportions) that automatically adjust for potentially varying population sizes. this conveniently relaxes the condition of a constant population size in the basic sir model. (iv) state-space model provides a flexible statistical modelling framework that embraces time-varying model parameters and integrates prior knowledge of disease mechanisms (e.g. r value from other studies) via prior distributions of the model parameters. (v) implementation of mcmc methods in statespace modelling provides a powerful approach to parameter estimation and predictions using conditional distributions given the history. this is different from all estimation methods in section that are always formulated via marginal distributions under strong assumptions of sampling rules. a state-space model consists of two stochastic processes: a d-dimensional observation process fy t g and a q-dimensional state process f t g given as follows: the state process  ;  ; : : : is a markov chain with initial condition  p .Â/, and transition (conditional) distribution is given by y t j t f t .yj t /: the observation process fy t g is conditionally independent given the state process f t ; t g, and each y t is conditionally independent of  s ; s ¤ t; given  t , the conditional distribution is y t j t f t .yj t /. this model can be graphically presented by a comb structure shown in figure . according to cox et al. ( ) , the state-space model is a parameter-driven model in that the processes of the compartment proportions are unknown population parameters to be estimated, while the stochastic multi-compartment model such as the stochastic sir model in ( ) is a data-driven model where the compartment proportions are directly observed. as pointed out earlier, the validity of the latter is questionable in practice, especially in the analysis of the covid- pandemic data. let y s be the collection of all observations up to time s, namely, y s d .y ; : : : ; y s /. let be a generic notation for the set of model parameters. denote the conditional density of  t , given y s d y s , by f t|s .Âjy s ; /. then, the prediction, filter or smoother density is defined, respectively, according to whether t > s, t d s or t < s. this conditional density f t|s . jy s ; / is the key component of statistical inference in state-space models. to develop the maximum likelihood inference for model parameters in state-space models, the one-step prediction densities f t|t are the key components for the computation of the likelihood function (see chapter of song, ) . given a time series data fy t ; t d ; : : : ; ng, the likelihood of y n is where f .y i / is expressed as follows: where by convention, g . i / d f | . jy i /, conditional on an initial observation y at time . in the earlier likelihood evaluation, one-step prediction densities, f t|t , and filter densities, f t|t , can be respectively given by the recursions ( ) with the recursion starting with f | . / d p .Â/. in general, exact evaluation of the integrals in ( ) and ( ) is analytically unavailable, unless in some simple situations, such as both processes being linear and normally distributed. for the linear gaussian state-space model, all f t|s are gaussian, so the first two moments of ( ) and ( ) can be easily derived from the conventional kalman filtering procedure, as discussed in chapter of song ( ) . however, with some computational costs, all integrals in the earlier likelihood and the filter can be evaluated numerically by mcmc methods. recently, wang et al. ( ) have developed an extended sir (esir) model that is built upon a state-space model with two (d d ) observed time series of daily proportions of infectious and removed cases, denoted by y i t and y r t , which are generated from the q-dimensional underlying infection dynamics f t ; t g governed by a mechanistic sir model. in the case of the sir model, q d . as shown in figure , the latent process is a time series of the three-dimensional latent vector of population probabilities  t d  s t ;  i t ;  r t > that satisfies a three-dimensional markov process of the following form: where parameter Ä scales the variance. the function f. / is a three-dimensional vector as a solution to the sir model ( ), which determines the mean of the dirichlet distribution via the rk approximation. in comparison with the stochastic sir model in ( ), here the compartment proportions  t are unobserved and explicitly modelled by a markov process to account for temporal correlations, so the parameter estimation can be carried out with multivariate likelihood functions. because the serial dependence is accounted for in the statespace model, the resulting estimation and prediction are more powerful than those given in section . . two observed time series y i t ; y r t > that are emitted from the underlying latent dynamics of infection  t are assumed to follow the beta distributions at time t: where  i t and  r t are the respective probabilities of being infectious and removed at time t, and i and r are the parameters controlling the respective variances of the observed proportions. it is easy to see that y i t and y r t are conditionally independent given  t , and e y i t j t d  i t and e.y r t j t / d  r t , and d . i ; r ; Ä;ˇ; /. because y i t and y r t share a common latent variable  t , their marginal correlation is modelled. in fact, these two beta distributions define a sampling scheme of observed data, including daily empirical proportions of infectious cases and removed cases, which are a collection of daily signals from the underlying latent sir infection dynamic system. the earlier state-space model ( ), ( ) and ( ) is useful to assess the effectiveness of control measures (e.g. social distancing) via the projected epidemic evolution in the future time. to process, one can replace the constant transmission rateˇby a time-varying transmission rateˇ .t/, where .t/ is a given transmission rate modifier. it is specified as a function in time to reflect different forms and strengths of control measures. this results in an esir model proposed by wang et al. ( ) : where .t/ . obviously, the basic sir model is a special case with no intervention in place, .t/ Á . in general, the .t/ may be specified by a practitioner to reflect a particular control measure. for an example of the covid- in hubei province, china, a possible choice of .t/ given in the following is a step function that reflects government-initiated macroisolation measures: .t/ d figure (a)-(c), we obtain different types of transmission rate modifiers. alternatively, .t/ can be a continuous function, say, .t/ d exp. t/ or .t/ d expf . t/ ! g; > ; ! > , that reflects steadily increased community-level surveillance and personal protection (wearing face masks and washing hands) as shown in figure (d)-(f). note that this modifier function does not have to be a monotonic decreasing function and may take a u-shape to capture the relaxation of control measures. with such a modelling framework, one can carry out comparisons of different preventive protocols via the resulting projected infection risk  i .t/ or other epidemic features such as the time of the effective reproduction number r e .t/ < and the time of a disease recurrence associated with relaxed control measures. a clear advantage of the state-space model is that it enjoys the resilience of mcmc being a primary method for statistical estimation and prediction. in other words, the statistical analysis methods can be easily modified to accommodate changes made in the latent multi-compartment models and/or in the observed time series models. one example of the covid- pandemic modelling given in wang et al. ( ) is to extend the three-compartment esir model to a four-compartment model by incorporating stringent quarantine measures issued by the hubei government via a new addition of in-home quarantine compartment. this new model is termed as susceptible-quarantined-infectious-removed (sqir) model. this quarantine compartment collects in-home isolated individuals who would have no chance of meeting any infectious individuals in the infection system. so, it is another exit from the dynamic system in addition to the removed compartment. let .t/ be the chance of a susceptible person being willing to take in-home isolation at time t. the basic sir model in equation ( ) is then extended to include a four-dimensional latent process where  s t c  q t c  i t c  r t d . the quarantine rate .t/ may be specified as a dirac delta function with jumps at times when major quarantine policies are issued by the government. for example, one may specify the time-dependent quarantine rate function .t/ for hubei province as follows: .t/ d note that at each jump, the respective proportion of individuals would leave the susceptible compartment and enter the quarantine compartment. figure (g)-(i) shows three different types of in-home quarantine rates during the period of the covid- pandemic in hubei province. in a similar spirit to the sqir example of application ii earlier, consider an interesting extension of the basic sir model in the analysis of the us covid- data to include an antibody compartment to handle the subpopulation of self-immunised individuals. this four-compartment model is termed as sair model, which has been discussed in detail in section . . because the antibody compartment is also a second exit from the infection system, similar to the quarantine compartment, one can turn the sair model given in ( ) into a similar form of the sqir model in ( ), where .t/ is replaced by˛.t/, the rate of self-immunisation. it is known that the population immunity rate cannot be estimated from observed surveillance data, which needs to be figured out by using large-scale serological surveys in the population. thus,˛.t/ may be specified as a dirac delta function (e.g. figure (g)-(i)) with jumps at times when the surveys are conducted and function values based on the survey results. it is worth pointing out that although the sqir and sair models have very similar model structures, their interpretations are very different. the former is applicable to the case of very stringent self-isolation control measures in hubei, while the latter is reflective to the situation of selfimmunisation due to mild control measures in the usa, so that a substantial proportion of individuals who contracted the virus, recovered and became immunised. markov chain monte carlo has been extensively used for the estimation and prediction in the state-space model (see, e.g. carlin et al., ; chan & ledolter, ; czado & song, ; de jong & shephard, ; zhu et al., , for a vast literature on this topic). such popularity of mcmc in the state-space model is rooted in its power to handle the evaluation of high-dimensional integrals involved in the likelihood function ( ). the essential strategy for the calculation of each high-dimensional integral is to approximate it by a sample mean of the involved integrand. this sample average is obtained from many mcmc sample draws from posterior distributions of the model parameters, including the time series of the latent probability vector  t . let t be the current time up to which we have observed data . ( ) draw  .m/ t from the posterior h  t j .m/ t ; .m/ i of the q-dimensional latent process, at t d ; : : : ; t ; t c ; : : : ; t; ; .m/ i according to the observed process, at t d ; : : : ; t ; t c ; : : : ; t, respectively. prior distributions are specified for some of the hyperparameters; for example,  dirichlet y i y r ; y i ; y r , r dˇ= and follow some log-normal distributions, and i , r and Ä follow some gamma distributions or inverse gamma distributions, respectively. convergence diagnostics of the mcmc algorithm may use standard diagnostic tools such as the gelman-rubin statistic based on multiple chains with different initial values, monitoring trace plots of the model parameters and so forth. the r package coda provides a comprehensive toolbox of convergence diagnostics (brooks & gelman, ) . using the mcmc draws collected after the burn-in, various summary statistics may be obtained to estimate model parameters, conduct inference and make prediction. the summary statistics (e.g. posterior mean and posterior mode) from the in-sample draws of the model parameters can provide point estimates and % credible intervals with the left and right limits set respectively at the . th percentile and . th percentile, and those of the observed processes may be used to check the goodness of fit of a proposed model and to perform model selection via the deviance information criterion (spiegelhalter et al., ; gelman et al., ) . more importantly, the summary statistics from the out-sample draws of the latent process  t ; t > t provide point predictions and their % credible prediction intervals. it is interesting to note that the earlier mcmc implementation does not depend much on the form of the runge-kutta solution f. t ;ˇ; / in the latent process ( ). as long as a mechanistic infectious disease model has an approximate analytic solution f. /, the bayesian estimation and inference can be carried out using mcmc. such flexibility is appealing to develop software applicable for a broad range of practical studies. mcmc procedures are well suited for the estimation and inference in the setting of statespace models because of fast and reliable numerical performances. for the michigan data analysis example in section . , using an average personal computer, we spend . h completing all mcmc calculations of draws with thinning bin size of after the burn-in judged by four separate mcmc chains. this computing speed can be improved by using highperformance computing facilities and/or some recent posterior sampling methods. as suggested by zhou and ji ( ) for a state-space sir model, one may set a more efficient sampler over highly correlated posterior spaces by parallel-tempering mcmc algorithm (geyer, ) , which provides rapid mixing in mcmc chains. also, along the line of online learning, sequential monte carlo methods for posterior sampling (doucet et al., ; dukic et al., ) are promising, as they permit efficient updating of existing posteriors with sequentially arrived data, in the hope to avoid refitting the model by running mcmc from scratch using the updated complete data. wang et al. ( ) and have developed a series of extended sir models by introducing time-varying transmission rate, quarantine process and asymptomatic immunisation process (details in section . ). the proposed methods have been established in an open-source r package esir, available on github (https://github.com/lilywang /esir). this package calls rjags to generate mcmc chains and retains a few mcmc controllers from rjags. the package is also updated weekly with new summarised us state-level count data for the covid- pandemic. several robust methods that are developed specifically for the prediction of the covid- are cited by the centers for disease control and prevention (https://www.cdc.gov/coronavirus/ -ncov/covid-data/forecasting-us.html). to name a few, the bayesian approach (verity et al., ) developed by researchers at imperial college london (featured in adam, ) and the hybrid modelling approach (ihme covid- health service utilization forecasting team & murray, ) adopted by the university of washington institute for health metrics and evaluation (ihme) (discussed by jewell et al., ) have attracted great public and government attention. we refer to their original work for modelling details. it is difficult to appreciate the original work and followed comments without running real covid- data using their software, which is lacking for the ihme models, among some others. to increase research transparency, releasing software or computing code used in statistical methods to the public is strongly encouraged. we now illustrate the use of r package esir to analyse the covid- surveillance data during the period of march to june from michigan state, usa. the michigan data used in this analysis are listed in appendix a , including both i.t/ and r.t/. in the data analysis, we demonstrate the use of both the state-space model described in application i and the mcmc method, where the transmission rate modifier .t/ is set as exponential functions. from package esir, we can extract many useful statistics related to estimation and forecasting. for example, we can obtain both mean and median projections of the prevalence curve  i .t/; t > t as well as their % credible prediction intervals. in addition, this package provides the estimated first and second turning points of an epidemic. the former is the time when the daily number of new infectious cases stops increasing, while the latter is the date when the daily number of new infections becomes zero. mathematically, the first corresponds to the time t at which r  i t d or the gradient of p  i t is zero, and the second is the time t at which the rate of prevalence is zero p  i t .t/ d : the following is the r script to perform the data analysis: in the above program, we consider a time-dependent declining transmission rate with the modifier value .t/ d exp. t/ where the parameter is chosen so that the modifier equals to . on may. this value is determined based on the social distancing scoreboard posted by unacast, inc. (https://www.unacast.com/covid /social-distancing-scoreboard). one needs to set exponential d true, to activate such setting. alternatively, as shown in figure (a)-(c), one may use a step function by providing a vector of pi , values and the corresponding vector of changes dates in change_time. in the main function above, we let the starting date be march and conduct the estimation and projection of days ahead (t_fin d ) on june and after. we run four separate mcmc chains with different initial values, each with length of , kept from every draws (thn d ) (a thinning operation to reduce autocorrelations) after draws are dropped. thus, with a relatively squandering setting, we expect a better performance of convergence and reliable quantification of prediction uncertainty using sample quantiles. there are two different prior settings for sensitivity analysis. one follows the example code earlier, with the prior mean for the log-normal distribution of the basic reproduction number to be . , the removal rate . and thus the mean transmission rate . , and the other with all these values to be , . and . , respectively. the two distinct settings provide similar estimating and forecast results as can be seen in figure . their estimated reproduction numbers are . ( % credible interval [ . , . ]) and . ( % credible interval [ . , . ]), respectively, which are similar considering that their prior settings are quite different. the output gelman-rubin statistic developed by gelman and rubin ( ) are close to (data not shown). both pieces of evidence as well as stationary trace plots warrant the convergence of the the michigan covid- data have been preprocessed to smooth away some unnatural gaps caused by the clustered reporting issue as discussed in appendix a . figure shows an adequate model fitting, where all observed numbers of confirmed infections fall in the % insample credible intervals of prevalence  i t ; t Ä june. in contrast, the % out-sample credible intervals of the projected proportion (y i t ) are much wider, reflecting to the significant amount of uncertainty in the prediction. such uncertainty elevates as the time moves further away from the present time. despite the large uncertainty, the projected mean and median prevalence curves show a decreasing trend over time, which means that the social distancing works to mitigate the epidemic in michigan although the rate of improvement is moderate. also the fact that the two estimated turning points have occurred before june is another piece of evidence for the positive effects of the series of social distancing orders issued by the state governor since march . model diagnosis is an important part of a statistical analysis, which is typically conducted using various residual plots. as illustration, in this michigan data analysis, let n  t be the posterior means over the period of march to june. we consider residuals of the two observed processes, defined by figure shows that there are dominant lag- autocorrelation (the three coefficients are about . ) and no any additional significant autocorrelations beyond the lag- dependence. this confirms the assumption that the three latent processes are all the first-order markov processes. all mechanistic models discussed in the previous sections are useful to analyse the infection dynamics for a large population such as a country or a state in which most of model parameters may be assumed to be homogeneous and representing the entire population. this type of macromodelling approach is particularly valuable at the early phase of disease outbreak when the national public health administration aims to come up with nationwide macrointervention protocols with very limited amounts of relevant data available. once an epidemic evolves further into its middle phase, with more and more surveillance data collected from local communities, a macromodel is no longer suitable for an in-depth analysis of microinfection dynamics owing to the existence of substantial heterogeneity across local communities. this section concerns a review of significant extensions of infectious disease models by incorporating spatial heterogeneity across different geographical locations into modelling and analysis. the focus will be on the recent development of integrating the classical spatial cellular automata (ca) (von neumann & burks, ) with the previously discussed temporal multi-compartment models, leading to an important class of spatio-temporal multi-compartment models. this class of models is useful to predict local infection risk. technically speaking, the majority of existing macromechanistic models to study the spread of infectious disease are based on the assumption that the system is homogeneous in space. this means that the spatial characteristics that could potentially play a non-trivial role in the development and outcome of disease infection are not taken into consideration. this is a valid assumption if the population vulnerable to the infectious disease is mixed well and the human interventions (e.g. vaccination strategies) are homogeneous across different spatial locations. however, in reality, there exists substantial heterogeneity in the urbanisation, ethnic distribution, political views, governance and economic composition across different subgroups of individuals distributed over geographical locations, all of which will influence the spread of infectious disease and make the previous macromechanistic model not appropriate to address the dynamics spatially. one possible extension is to utilise partial differential equations (pdes) (murray et al., ) in spatial homogeneity, which is relaxed to allow area-specific spread patterns of epidemics. as noted in the literature, one limitation of pdes is that this approach ignores the fact that infectious disease is spread through person-to-person interactions, rather than by a continuous population. thus, pdes may lead to impractical results about the dynamics of an epidemic (mollison, ) . a natural strategy is to embrace a micromodel mimicking an interactive particle system, and ca is one of the well-studied systems with the strength of modelling spatially varying infection dynamics. originated in the works of von neumann and burks ( ) and ulam ( ) , the ca paradigm has been used in many applied fields, including the modelling of infectious diseases. when applied to model spatial variations of epidemic spread, ca has three distinctive features: (i) it treats individuals as discrete entities in order to study person-level movements in the infection dynamics. this high-resolution paradigm necessitates the incorporation of individual's heterogeneity such as residential address, age, race, pre-existing medical conditions and others in the modelling. in surveillance data, geographical information is publicly available (e.g. county that an individual lives), so it is feasible to utilise this variable in the extension of the macromechanistic model. (ii) ca allows to introduce local stochasticity; for example, the ca paradigm may be built upon a person-to-person infectious mechanism if individual-level information is available; otherwise, it may be based on a group-group infection process. (iii) ca is formulated in a network of particles (e.g. individuals, groups, villages and counties) with certain rules of connectivity and stochastic laws of disease transmission. this network topology is well suited for computations and simulations. because of these unique advantages, the ca paradigm has been employed by researches as an efficient method to study spread patterns of epidemics (beauchemin et al., ; ahmed & agiza, ; boccara et al., ; quan-xing & zhen, ; fuks & lawniczak, ; willox et al., ; rousseau et al., ; sirakoulis et al., ; fuentes & kuperman, ; liu et al., ; yakowitz et al., ; sun et al., ) . in the modelling of infectious diseases, the basic ca formulation involves three primary components: (i) a two-way array of cells (e.g. an age group or a county) that contain groups of individuals under study, and each individual belongs to one cell; (ii) a set of discrete states (e.g. susceptible, self-immunised, contagious, recovered and death) that describe different conditions of individuals during an epidemic; and (iii) some specific rules or updating functions that determine spatially how local interactions with a target cell from its neighbouring cells can influence and change the states of individuals in the target cell; all cells in a ca system achieve a global propagation of infection status updates instantaneously and continuously. in the application of the ca, determining neighbouring cells is tricky, and different types of neighbourhood topology have been proposed in the literature, including von neumann neighbourhood, moore neighbourhood, mvonn neighbourhood and extended neighbourhood (hasani & tavakkoli, ) (see figure for an example of these four neighbourhood types). in the modelling of influenza a viral infections, beauchemin et al. ( ) use a simple two-dimensional ca model to investigate the influence of spatial heterogeneity on viral kinetics. their study population consists of two types of cell species, the epithelial cells and the immune cells. the epithelial cells are the target of viral infection, and the immune cells are those fighting the infection. the ca model is built upon a two-dimensional square lattice with the moore neighbourhood (see figure (b)), where the condition of a certain cell will only be influenced by the eight closest cells around it. the set of states for the epithelial cells include healthy, infected, expressing, infectious or dead, while an immune cell can be in any of two states: virgin or mature. decision rules of updating the ca system are governed by parameters, such as infect_rate that models the probability of a healthy epithelial cell being infected by contacting each infectious nearest neighbour. detailed updating functions are discussed in beauchemin et al. ( ) . simulations show that the proposed ca model is sophisticated enough to reproduce the basic dynamic features of the cell-to-cell infection. different from the modelling of the influenza a viral infection earlier, fuks and lawniczak ( ) propose a lattice gas ca that is closely connected to an sir framework of an epidemic, where the interacting patterns of individuals are modelled. it is assumed that the status of individuals will change between three types, susceptible, infectious and recovered, denoted as fs; i; rg. the space where the epidemic takes place is set as a group of regular hexagonal cells, in which the individuals are located at the centre of each cell and can move through a channel that is created by connecting two centres of adjacent cells. the evolution of the ca occurs at discrete time steps under the operation of three basic functions, including contact c, randomisation r and propagation p. with the application of function c, an individual who is susceptible can become infected with probability . ˇ/ n i , whereˇis the transmission rate and n i is the number of infectious individuals within the same cell. meanwhile, an individual who is infectious can recover with probability , where is the recovery rate. the function r randomly assigns individuals in each cell to move through the channels, which contributes to modelling the mixing process of individuals. in the final propagation step, individuals simultaneously move to the cells that they are randomly assigned to by r. in addition to the basic epidemic dynamics modelled by the proposed lattice gas ca, fuks and lawniczak ( ) also study the effect of heterogeneous spatial distribution of individuals with states s, i and r and the influence of different types of barriers in controlling the spread of an epidemic. whereˇis the population macrotransmission rate and is the population macrorecovery rate. first, when the set v d ∅, that is, an empty set, the ca-sir model for cell .i; j/ reduces a celllevel sir model similar to that given in ( ). second, the numerator n i cp;j cq  i i cp;j cq .t / is the expected number of infectious cases yesterday (time t ) in a neighbouring cell .p; q/ v whose cell population is n i+p,j+q . so, the ratio is an empirical probability that a person in cell .i; j/ randomly runs in a contagious person from its neighbouring cell .p; q/. third, this random chance is weighted by a factor of intercell connectivity, denoted by ! .i;j / pq ; the stronger tie of cell .i; j/ with cell .p; q/, the higher likelihood of a person from cell .i; j/ running in contagious individuals in cell .p; q/. fourth, summing up all such likelihoods gives a total likelihood that an individual from cell .i; j/ would run in the virus carriers from all the neighbouring cells. a typical form of the intercell connectivity coefficient is given by ! .i;j / pq d c .i;j / pq m .i;j / pq , where c .i;j / pq and m .i;j / pq are broadly defined as a connection factor and a movement factor, respectively. they are used to characterise the intercell mobility or how easily individuals in the cells can move between the centre cell and its neighbouring cells. this ca-sir system, which is integrated with the sir model, can serve as a basis for the development of useful algorithms to emulate real-world epidemic infection spatially. . assume that there is a square array of cells that hold the population under the study of a certain epidemic. our target cell is the one at the centre (see figure ) we illustrate the predicted risk of infection with the covid- for all counties in michigan state using the state-space model with the mechanistic ca-esair latent process . in the first step, we apply the mcmc method to estimate the model parameters (ˇand ) and the vector of four probabilities  t of being susceptible, self-immunised, infectious and removed by fitting the esair model with the state-level surveillance data since march. this can be performed easily using the r package esir, which has been illustrated in section . . both the antibody rate function˛.t/ and the transmission rate modifier .t/ are pre-specified using other data sources with the detail given in the succeeding text. after getting the estimates of the model parameters, we use them as the initial values to make county-level risk prediction by the ca-esair model ( ). in this example, we consider only a -day ahead infection rate prediction (i.e. may ) for all the counties in michigan, namely,  i c .t c /. given that the covid- pandemic evolves fast in the state of michigan in early may , this kind of short-term forecast or nowcast is of great interest to the michigan government for timely decision making on either extending an existing governor's 'stay-at-home' order or relaxing this executive order. to perform the prediction, one important task is to specify the inter-county connectivity coefficient ! cc .t/. as discussed in , it is challenging to define ! cc .t/ objectively, as it involves many variables. in this illustration, we specify this coefficient as ! cc .t/ d cc expf Ár.c; c /g, where Á is a tuning parameter to be determined. briefly speaking, the first factor c,c is the inter-county mobility factor characterising the decrease of human encounters in terms of their potential movements between counties, which has been given online (https://www.unacast.com/covid /social-distancing-scoreboard). the second factor r.c; c / is a certain travel distance between two counties c and c in terms of both geodesic distance (karney, ) and 'air distance' based on the accessibility to nearby airports. in addition, the tuning parameter Á enables to adjust the scale of the travel distance by minimising the sum of (county-level) weighted absolute prediction error for the one-step ahead risk prediction of the infection rate. in addition to the specification of the connectivity coefficient ! cc .t/, the self-immunisation rate˛c.t/ is calculated based on the results of the new york statewide antibody test surveys released by the new york governor andrew cuomo on april (new york state report, ), and the transmission modifier function c .t/ is specified by the effectiveness score of state-specific social distancing using cell phone data in the usa from the transportation institute at the university of maryland (https://data.covid.umd.edu/). additional details of the determination of c,c , r.c; c /,˛c.t/ and c .t/ and the tuning of Á can be found in . figure (a) shows the -day ahead projected infectious rate for counties in michigan on may, and figure (b) plots the corresponding county-level weighted prediction errors (wpe), which is at the order of for the counties. the r package ca-esair is available on github (https://github.com/leyaozh/ca-esair). in this paper, we have presented the basics of multi-compartment infectious disease models from both deterministic and stochastic perspectives. we emphasise on the probabilistic extension of mechanistic models, which opens the door to a suite of statistical modelling techniques while still preserving the infectious disease dynamics in multi-compartment models. within the stochastic modelling framework, both the frequentist and the bayesian schools of modelling considerations and statistical methods are visited, along with high-level review and illustrative examples. epidemic models have played a key role in the past century to provide understanding of past and ongoing infectious diseases, and it is our belief that they will continually be valued and be improved to help us better understand the current covid- pandemic as well as future infectious diseases. we conclude with several remarks on future directions of stochastic infectious disease modelling. although publicly available surveillance data are useful to build preliminary models for the understanding of spreading patterns of infectious diseases, their data quality in terms of measurement biases and under-reporting has been known an outstanding issue that significantly impacts the validity of statistical analysis results (angelopoulos et al., ) . this is indeed an open problem to date with no appropriate solutions yet. with no insurance of reliable data, statistical methods, regardless of macromodels or micromodels, would fail to produce meaningful results. one potentially promising solution to such a fundamental concern is to build reliable and well-validated open-source benchmark databases that include not only traditional surveillance data but also personal clinical data from various sources such as hospital electronic health records, drug trials and vaccine trials. in addition, data from serological surveys and data from mobile devices or as such are also useful to increase information resolution and reliability, to remove major measurement biases and to calibrate data analytics. this task requires also efforts of data integration and international collaborations. research on the covid- pandemic certainly gives rise to a new opportunity of developing data integration methods to not only address challenges of data multi-modality but also overcome many data-sharing barriers and data confidentiality concerns. the population of self-immunised individuals is a significant source of bias in covid- surveillance data; they have never been captured by public health monitoring systems. according to survey results (new york state report, ), % of individuals in the city of new york have been tested antibody positive to the coronavirus. this simply means that a nationwide serological survey is a must in order to come up with an appropriate assessment for the underlying epidemiological features of the covid- pandemic in the usa. the design of this nationwide serological survey is a challenging statistical problem. solving it requires some innovative ideas and methods; for example, a cost-effective design of pooling several serum samples to perform a pooled test (e.g. gollier & gossner, ) , and an efficient design of hierarchical stratified survey sampling schemes. the sair model introduced in section . presents a basic framework for statistical models incorporating antibody serological surveys into the multi-compartment dynamics of infectious diseases. large-scale tracking data have played an important role in evaluating the effectiveness of social distancing in communities. the precision of intervention efficacy helps improve both estimation and prediction that directly impact government's decisions on tightening, extending or lifting control measures. one emerging data source pertains to the information of real-time cell phone locations, which allows better contact tracing so that individual data sequences can be recovered and used for modelling of personal risk and regional hotspots. a research group in the university of maryland (https://data.covid.umd.edu/) proposes several algorithms to process the cell phone data in the usa to extract key features of personal mobility, including location identification, trip identification, imputation of missing trip information, multilevel data weighting scheme, comprehensive trip data validation, and data integration and aggregation ghader et al., ) . however, these types of data are proprietary and subject to the issue of personal privacy (ienca & vayena, ) . integrating such data type or its summary statistics into infectious disease models should be encouraged, but in a cautious and responsible manner. in this field, statistical learning methods with differential privacy (dwork, ) are of great interest. statistical methodologies have been greatly challenged in the modelling and analysis of infectious diseases; almost every methodological troubling issue known the statistical literature surfaces, which presents new opportunities to statisticians and data scientists to develop innovative solutions. among many challenges, we emphasise a few of critical importance, which may be easily ignored in the new methodology development. we strongly advocate for the urgent need to build models that are transparent and reproducible (peng, ) . as most methods and models for the covid- pandemic are fairly recent and many have not yet been carefully peer reviewed, researchers should document the sources of data used, data preprocessing protocols, source computing code and sufficient modelling details to allow external validation from the public. such details are also necessary to allow others, who may have better quality data but without sufficient statistical expertise, to easily adopt new methodologies to obtain high-quality results. as mentioned in an original post by dr nilanjan chatterjee (https://link.medium.com/hquqilead ), transparency, reproducibility and validity are three criteria to assess and assure the quality of prediction models. his essay also mentioned the difficulty in reproducing the work given by the ihme to obtain accurate predictions and appropriate confidence intervals. similar to the ihme method that has no software available, gu's method for the covid- prediction (https://covid -projections. com/) that has recently received much attention does not provide software, either, unfortunately. without clear guidance and full reproducibility, even models that currently do well might fail in the future because predictions are relying on certain kinds of extrapolation assumptions that need to be unveiled to the scientific community with full transparency for validation and comparison. given that model projections for the covid- pandemic have been changing dramatically from day to day primarily because the underlying models are changing, the primary aim may be set at optimising prediction models for nowcasting or short-term projections and be aware of the probable worst case scenarios for longer-term trends. as shown in the data example in section . , the optimal tuning parameter is determined by the minimal short-term -day ahead prediction error. as pointed out by huppert and katriel ( ) , transmission models with different underlying mechanisms may lead to similar outcome in one context (e.g. short term) but fail to do so in another (e.g. long term). the further we project, the more we are uncertain about the validity of model assumptions. hence, extra caution is needed when reporting and interpreting long-term projection results. with the available surveillance data, making a nowcast of infection risk in next few hours is difficult; but it may become feasible when certain data sources of local information are accessible, such as electronic health records from local hospitals, viral testing results from local testing centres and mobile tracking data from individual cell phones. this requires a finer-resolution prediction machinery that may be established by generalising the ca to certain spatial point processes. despite being challenging, such prediction paradigm would be very useful and worth a serious exploration. because of the potential bias in surveillance data, either delayed reporting of infected case or inaccurate ascertainment of death caused by a virus, there are many measurement errors in data. this calls for statistical methods that can directly handle various data collection biases or are robust to such biases. there is little work performed in this important field of statistical modelling and analyses. in the current literature, model diagnostics for infectious disease models are largely lacking. given that most of the existing mechanistic models are based on certain parametric distributions (e.g. poisson processes), checking model assumptions is required. for example, for the proposed poisson process, the assumption of incremental independence and overdispersion should be checked. in addition, procedures of validating prediction accuracy are also important in which the choice of test data is tricky and needs to be guided by some objective criteria. a major weakness noted for the existing mechanistic models is the inflexibility of adding individual or subgroup covariates (e.g. age and race). the current strategy of handling these extra variables is via stratification, which would end up with strata with small sample sizes, so that subsequent statistical analyses lose power in both estimation and prediction of infection dynamics. an extension from the ca seems promising as the ca presents a system of particles distributed in different cells (or strata), where individual characterisations on particles may be added via covariates. the resulting model would assess and predict personal risk, as well as identify hotspots of new infection. this is worth serious exploration in the future with appropriate data available (e.g. electronic health records from hospitals). for a global pandemic such as the covid- that affects over countries in the world, an integrative analysis is appealing to understand common features of the pandemic so to learn different control measures. given the fact that a pandemic evolves typically in a certain time lag, experiences from countries with earlier outbreaks may be shared with countries with later outbreaks, where statistical methods may borrow relevant information to set up prior distributions in the model fitting. for example, the estimated reproduction number estimated from the european covid- data may be a hyperparameter in the statistical analysis of the us covid- data. there is a clear need of more comprehensive meta-analysis methods to better integrate data from different countries than using the data to create hyperparameters. along this line, one of the earliest attempts is to combine covid- forecasts from various research teams using ensemble learning (see, e.g. https://github.com/reichlab/covid -forecast-hub). most investigation efforts made by quantitative researchers have been relatively independent in an academic setting, and it is high time that policymakers and stakeholders are involved and play an active role in such modelling efforts. long-term projection of the covid- is most sensitive to and highly dependent on public health policy. a major source of uncertainty is due to the conflicting demands between public health (disease mitigation) and the need to sustain economic growth (livelihood), and the balance of the two is a moving target. one way to account for the modelling uncertainty is to factor in economic planning as a time-varying modifier of projection models. although some efforts have been made to incorporate economical data, most are retrospectively oriented, and we believe more efforts should be spent to prospectively incorporate expert inputs and economic forecasts. this is a research area of great importance worth serious exploration. we like to close this review paper by casting a few open questions of great interest to the public (at least to ourselves) that statisticians may help deliver answers with existing or new data to be collected by innovative study designs. we also hope that these questions motivate new methodological developments. question : how would researchers assess both timing and strength of the second wave of the covid- pandemic? is the second wave worse than the first one? answers to these questions need a relatively accurate long-term prediction of the infection dynamics. among so many different statistical models being able to predict future spreading patterns, we need to identify few ones or their combinations that are particularly useful to make long-term predictions. question : as many countries and regions started to reopen business, how would government monitor the likelihood of a recurring surge of covid- caused by business reopenings? does the social distancing measure help reduce a potentially rising risk? answers to these questions require adequate data that may not be easily collected by routine approaches. statisticians may work with practitioners to develop good sampling instruments and schemes for community risk surveillance. question : is face mask protective? if so, how to assess the compliance of face mask wearing? questions about the causal effect of face mask wearing on disease progression are very challenging. this is because there is no randomisation in the intervention allocation and many confounding factors are unobserved. question : is there evidence that the contagion of the coronavirus decays over time because of an increasing recovery rate of virus carriers and a decreasing rate of case fatality? statisticians ought to work out some thoughtful and convincing answers to the public. such surveillance data, there are data reporting gaps shown in figure a that are possibly caused by the so-called clustered reporting; that is, the recovered cases have not been released on the daily basis. to mitigate this data reporting artefact, we invoked a simple local polynomial regression procedure (loess) to smooth such unnatural jumps, resulting in a smooth fitted curve shown in figure a . the calibrated cumulative 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this research is partially supported by the national science foundation grant dms . although the two applications discussed earlier in section . give a framework of how ca models the dynamics of epidemic spread, white et al. ( ) provide a more direct incorporation of spatial ca with the temporal sir compartments at the population level, where each cell stands for a small population (e.g. a county) with different proportions of susceptible, infectious or recovered individuals. the resulting ca-sir given in white et al. ( ) is formulated by four parts (c, q, v and f). first, c d f.i; j/; Ä i Ä r; Ä j Ä cg defines the cellular space, or a collection of r c cells on a two-way array, where r c is referred to the dimension of the cells. second, q represents a finite set that contains all the possible states of a cellular space. in the case of the sir model, q d fs; i; rg corresponding to the susceptible, infectious and removed states. third, v d f.p k ; q k /; Ä k Ä ng is the finite set of indices defining the neighbourhood of each cell, and consequently, v ij d f.i c p ; j c q /; : : : ; .i c p n ; j c q n /g denotes the set of neighbouring cells for the central cell .i; j/. specifically, v d v f. ; /g represents all the neighbouring cells without the cell at the centre of consideration. fourth, function f stands for certain updating rules to govern the dynamics of interactions between cells in the a ca-sir system. for each cell at a discrete time t (say, today), its current status is described by three cell-specific compartments f s ij .t/,  i ij .t/ and  r ij .t/g, where  s ij .t/,  i ij .t/ and  r ij .t/ oe ; represent the cell-specific probabilities of being susceptible, infectious and recovered, respectively. clearly,  s ij .t/ c  i ij .t/ c  r ij .t/ d to form a microcell-level sir model. the ca-sir model is updated based on the following transition functions: for cell .i; j/ v, based on the basic ca-sir model proposed in white et al. ( ) , extensions can be easily applied to better model the dynamics of infectious diseases using real data. propose a spatio-temporal epidemiological forecast model that combines ca with an extended sair (esair) model to project the county-level covid- prevalence over counties in the continental united states. this model is termed as ca-esair model in which a county is treated as a cell. to carry out cell-level infection prevalence updates, the macroparametersǎ nd need to be estimated from the macromodel esair model. in comparison with the esir model discussed in section . , a new antibody compartment (a) is included in the esair model to account for the individuals who are self-immunised and have developed antibodies to the coronavirus. the inclusion of the antibody compartment can address the under-reporting issue known for available public databases and to build self-immunisation into the infection dynamics. in this way, better estimation of the macromodel parameters can be obtained. the esair model can be described using the following odes, which govern the law of interactive movements among four compartments or states of susceptible (s), self-immunised (a), infectious (i) and removed (r):where˛.t/ is the self-immunisation rate, .t/ is a time-varying transmission rate modifier,ˇis the basic disease transmission rate and is the rate of being removed from the system (either dead or recovered). the earlier esair model is an alternative expression of model ( ) based on the compartment probabilities. in order to apply the ca-esair system to model the epidemic spread in the usa, relax the classical ca-esair from spatial lattices (or cells) to areal locations of counties. let c be the collection of counties. here we consider the extended neighbourhood type (all counties are neighbouring ones given high mobility in the us population). for a county c c, n c denotes the county population size, and c c denotes the set of all the other counties except county c. for county c at time t, the county-specific probability vector is denoted by  c .t/ d . s c .t/;  a c .t/;  i c .t/;  r c .t// > . the ca-esair model at discrete times is expressed by the following form:where˛c.t/ is the county-specific self-immunisation rate and c .t/ is the county-specific transmission modifier. same as the parameter mentioned in the ca-sir model ( ) earlier, ! cc .t/ is a connectivity coefficient that quantifies the inter-county movements between counties c and c . by applying the proposed ca-esair model, have proposed a t-day ahead risk forecast of the covid- as well as a personal risk related to a travel route. the runge-kutta method is an efficient and widely used approach to solving ordinary differential equations when analytic closed-form solutions are unavailable. it is typically applied to derive a numerical functional system of high-order accuracy with no need of high-order derivatives of functions. the most well-known runge-kutta approximation is the runge-kutta fourth-order (rk ) method. for example, in the case of the mechanistic sir model ( ) where y is an unknown function in time t, which can be either a scalar or a vector. then for a preselected (small) step size h > , a fourth-order approximate solution of y satisfies at a sequence of equally spaced grid points y n ; n d ; ; : : : ; with jy n y n j d h, y nc d y n c h.k c k c k c k /; n d ; ; : : : ;where k d f .t n ; y n /;k d f .t n c h; y n c hk /:because four terms k , k , k and k are used in the approximation, the earlier method is termed as an rk method of the ode solution to function y. for a general rk approximation, refer to stoer and bulirsch ( ) . in the succeeding text, we list michigan data from march to june . the numbers of daily confirmed cases and deaths are obtained from the github repository jhu csse (https://github.com/cssegisanddata/covid- ), and the daily recovery data are collected from point acres (https://coronavirus. point acres.com). the daily cumulative numbers of deaths and recovered cases are then summed as the cumulative number of removed cases. in key: cord- -t yioyl authors: rohr, jason r.; barrett, christopher b.; civitello, david j.; craft, meggan e.; delius, bryan; deleo, giulio a.; hudson, peter j.; jouanard, nicolas; nguyen, karena h.; ostfeld, richard s.; remais, justin v.; riveau, gilles; sokolow, susanne h.; tilman, david title: emerging human infectious diseases and the links to global food production date: - - journal: nat sustain doi: . /s - - - sha: doc_id: cord_uid: t yioyl infectious diseases are emerging globally at an unprecedented rate while global food demand is projected to increase sharply by . here, we synthesize the pathways by which projected agricultural expansion and intensification will influence human infectious diseases and how human infectious diseases might likewise affect food production and distribution. feeding billion people will require substantial increases in crop and animal production that will expand agricultural use of antibiotics, water, pesticides and fertilizer, and contact rates between humans and both wild and domestic animals, all with consequences for the emergence and spread of infectious agents. indeed, our synthesis of the literature suggests that, since , agricultural drivers were associated with > % of all — and > % of zoonotic — infectious diseases that emerged in humans, proportions that will likely increase as agriculture expands and intensifies. we identify agricultural and disease management and policy actions, and additional research, needed to address the public health challenge posed by feeding billion people. i nfectious diseases are emerging at an unprecedented rate with significant impacts on global economies and public health . the social and environmental conditions that give rise to disease emergence are thus of particular interest, as are management approaches that might reduce the risk of emergence or re-emergence . at the same time, undernutrition -the insufficient intake of one or more nutrients -remains a major source of global ill health [ ] [ ] [ ] [ ] . together, the unprecedented rate of infectious disease emergence and the need to sustainably feed the global population represent two of the most formidable ecological and public health challenges of the twentyfirst century [ ] [ ] [ ] [ ] [ ] (fig. ) , and they interact in complex ways (fig. ) . although modern agricultural technologies have reduced hunger, improved nutrition and spared some natural ecosystems from conversion to agriculture, current global agricultural production and distribution infrastructure still leaves billions of people's diets deficient in one or more crucial nutrients, with major consequences for global morbidity and mortality , and these deficiencies are expected to worsen with climate change [ ] [ ] [ ] [ ] . credible estimates are available for specific nutrient shortfalls -for example, . billion people suffering iron-or vitamin b -deficiency anemia , . billion people with insufficient dietary energy (that is, calorie) intake , % of pre-school age children and % of pregnant women at risk of vitamin a deficiency -but the world still lacks a rigorous, recent assessment of the population suffering shortfalls of any one or more nutrients, although the number is surely in the billions. by , the united nations projects that the global population will grow by nearly billion, to exceed billion people . meeting the united nations' sustainable development goal, to "eradicate hunger" (https://sustainabledevelopment.un.org/) for this expanding human population will necessitate a large increase in food supplies, with major changes to agricultural production and distribution systems, infrastructure and social protection programmes (fig. ) . despite large and, in many cases, growing inequalities, the global population is on average expected to become richer, and historically, with greater affluence has come greater consumption of food products in general and more animal-sourced foods in particular, both of which further increase food demand and thus the requirement for agricultural expansion and/or intensification . agriculture already occupies about half of the world's land and uses more than two-thirds of the world's fresh water , and recent studies have suggested that agricultural production might need to double or triple by to keep pace with projected population growth and food demand [ ] [ ] [ ] (fig. ) . meeting this demand using present agricultural production systems could require replacing > hectares of natural ecosystems with agricultural production, approximately % of the global land area, which is larger than the continental united states, although continuous efficiency improvements in agriculture will compel re-evaluation of these estimates. in turn, this agricultural expansion could result in an estimated ~ -fold increase in irrigation, ~ . -fold increase in fertilizer , , and -fold increase in pesticide use (fig. ) . the challenges of feeding > billion people and managing infectious diseases intersect in several ways ( figs. and ) . first, the expansion and intensification of agriculture are disproportionately occurring in tropical, developing countries , , , where % of deaths are attributable to infectious diseases , where the risk of disease emergence might be greatest, and where disease surveillance and access to health care, particularly for those infections that accompany extreme poverty, are most limited , . second, agricultural expansion and intensification have historically come with massive habitat conversion, contamination with animal waste and increasing use of agricultural inputs, such as pesticides and antibiotic growth promoters. beyond their direct adverse effects on human health , , agricultural biochemical inputs are known to have direct effects on emerging human infectious diseases, and can also serve as indirect drivers by contributing to the emergence of wildlife diseases that constitute important sources of emerging infections in humans , . however, the strengthening of agricultural production systems can also improve nutrition, which has pronounced benefits for combating many infectious diseases at the individual and population levels , . although concerns have been raised regarding the environmental impact of agricultural expansion and intensification , - , , , their effects on infectious disease risk have not been synthesized. here, we review both the beneficial and adverse effects of agricultural expansion and intensification on the transmission of human infectious diseases. we synthesize the pathways through which agricultural practices influence human infectious diseases, and vice versa, and identify opportunities to minimize the adverse consequences of agricultural growth while maximizing the human health benefits of agricultural development (fig. ). agricultural development can yield direct improvements to nutrition, and through several mechanisms, nutrition can be a critical determinant of infectious disease susceptibility and progression , (figs. and ). for example, immune responses are energetically costly and thus undernutrition often reduces the development and effectiveness of immune responses that can limit or clear infections. the relationship between infectious disease and nutritional agricultural production can improve human health by reducing food prices and enhancing nutrition, which can increase resistance to infectious diseases. however, freshwater habitats established for irrigation, as well as other agricultural inputs, often increase the risk of vector-borne diseases, such as malaria and schistosomiasis. in general, rural residents are most vulnerable to these increases in infectious disease, whereas consumers some distance away derive most of the benefits from increased food production. to maximize human health given the impending billion humans projected on the planet by , society must minimize the adverse consequences of agricultural growth while maximizing the health benefits. images by kate marx. status can function in reverse as well, because many parasitic infections place direct demands on host nutrition, causing undernutrition when food is limited . in fact, some parasites, such as helminths, can even cause eating disorders, such as geophagy (desire to eat soil), bulimia and anorexia . enduring infections often require rapid and effective repair of tissue damage caused by parasites, which is also costly. hence, certain infections can cause undernutrition, which itself can compromise both resistance and tolerance to infections , . by improving nutrition, agricultural development should facilitate combating many infectious diseases. for example, death rates from acute respiratory infections, diarrhoea, malaria and measles, diseases that on average kill more than a child every seconds ( million per year) , are much higher in children who suffer undernutrition than in those that do not , . in addition, poor maternal nutrition and associated impaired fetal growth are strongly associated with neonatal death from sepsis, pneumonia and diarrhoea ; undernourishment is a well-understood risk factor for . although the traditional green revolution approach to food production has succeeded in reducing undernourishment arising from insufficient calorie and protein intake, it has been very slow in reducing micronutrient deficiencies , which can be have significant effects on defence against disease. to make matters worse, where violence, unrest and terrorism impede access to food, such as in parts of africa and central asia, morbidity and mortality attributed to communicable diseases can be further exacerbated . although research suggests that improving nutrition will generally improve responses to infectious diseases, there may be important exceptions. for certain diseases, such as schistosomiasis and many respiratory infections, pathogenesis is a product of host immunity, often from hyperinflammation , . thus, undernutrition can actually decrease symptoms by reducing the strength and pathogenicity of immune responses . in addition, as nutrition improves, some parasites might proliferate faster than immunity can increase , resulting in more, rather than less, morbidity, with the classic example that dietary intake of iron can increase malariainduced mortality . in this section, we review the links between rural economy, infrastructure and infectious disease. , phosphorous (c), fertilizer and pesticide use (d), cropland area (e), and irrigated land area (f) and associated % prediction bands (light blue bands). 'nitrogen' refers to the normalized estimated global amount of nitrogen nutrients in fertilizers produced (originally reported in thousands of tonnes, now in metric tonnes). 'phosphorous' refers to the normalized estimated global amount of p o nutrients in fertilizers produced (originally reported in thousands of tonnes, now in metric tonnes). for a, data were collected from the world bank. for b-f, data were collected from the food and agriculture organization of the united nations and statistical models were developed based on the relationships between these variables and global human population density. after the best model was identified, year was substituted for human population density based on the fit in a. these projections should be evaluated with considerable caution because the models assume that human population size is the only factor that affects fertilizer and pesticide use and the amount of arable and irrigated cropland, when in reality, many factors affect these responses (for example, climate, diets, type of crops grown and so on). they merely illustrate that even an extremely parsimonious model seems to track past patterns tolerably well and thus could serve as a basis for coarse projections. see supplementary methods for details of the statistical models used to generate these figures and supplementary table for coefficients and statistics for the best-fitting models. economic development. economic development, especially agricultural development, has historically driven reductions in both infectious diseases and poverty across many settings. in fact, the poor financially benefit more from economic growth in the agricultural sector than in industrial or service sectors , . the early stages of economic development often involve the construction of infrastructure to facilitate food production and distribution, including roads, dams and irrigation networks , . more recently, the early stages of rural development often include rapid expansion of telecommunication, and to a lesser degree, electrification, both of which are promising but underutilized resources for disease monitoring and control in the developing world . other rural infrastructure that is more crucial to infectious disease prevention, such as safe water, sanitation and energy supplies, often follows or is developed concurrently , . in developing countries, rural infrastructure that provided access to sanitation and safe water explained % and % of the difference in the prevalence of malnutrition and child mortality rates between the poorest and richest quintiles, respectively . moreover, clean water, sanitation and electricity can also facilitate the construction of schools and health clinics that can help to further reduce disease through education, prevention and treatment. hence, if the history of the developed world repeats itself in the developing world, then it seems plausible that agricultural development necessary to feed billion people might help to reduce infectious diseases by promoting economic development and rural infrastructure. there are several important assumptions to this hypothesis, however, such as: ( ) it is possible to feed billion people; ( ) the rate of economic development will match or exceed the pace of human population growth; and ( ) developing countries are not in an infectious disease-driven 'poverty trap' , which is the notion that poverty increases the chances of acquiring and succumbing to disease, and chronic disease traps humans in poverty [ ] [ ] [ ] [ ] [ ] . if agricultural development lags behind population growth or if clean water supplies, sanitation and electricity do not immediately follow road, dam and irrigation construction, then the prevalence of many infectious diseases could remain unchanged or even increase as human populations grow . agricultural irrigation and freshwater redistribution. one major change in rural infrastructure that often accompanies agricultural development is the redistribution of fresh water, which has well-known consequences for the transmission of infectious diseases. for example, because % of crop production comes from only the % of agricultural land that is irrigated, and irrigated lands accounted for much of the increased yields experienced during the green revolution , the potential for increased irrigation infrastructure to exacerbate infectious diseases is a critical concern (fig. ) . importantly, agricultural development has caused both declines of certain types of fresh water, such as wetlands, and increases of others, such as dams, reservoirs and irrigation schemes. one of the largest drivers of global wetland losses has been conversion to agriculture , which has led to declines in diseases that rely on wetland habitats. for example, japan's successful eradication of schistosomiasis during the mid-twentieth century relied in part on conversion of wetlands to orchards in schistosomiasis-endemic areas , although replacing oxen with horses, which are less susceptible to schistosoma japonicum, as draft animals is also thought to have contributed substantially . similarly, some of the earliest successes in malaria control at the turn of the twentieth century occurred in the southern united states, where wetland drainageincluding for agricultural conversion -was one of a suite of antitransmission strategies used by the rockefeller foundation in its landmark malaria control efforts . although wetlands often decline with agriculture, dams, reservoirs and irrigation networks often increase, and this redistribution of fresh water has been widely associated with increases in some vectors and hosts of human pathogens . for example, construction of the aswan high dam in egypt and the accompanying irrigation network was associated with a rise in mosquito vectors and the disfiguring mosquito-borne disease lymphatic filariasis, commonly known as human elephantiasis . likewise, dam and irrigation construction resulted in increases in malaria in sri lanka and india , , and a sevenfold increase in malaria in ethiopia . a meta-analysis of studies revealed that humans living near irrigation schemes or in close proximity to large dam reservoirs had significantly higher risk of schistosome infections than humans that did not live near these water resources , at least partly because of increased freshwater habitat for intermediate snail hosts. similarly, a recent analysis of schistosomiasis case data from the past years across sub-saharan africa showed far-reaching effects of dams and irrigation schemes, with increases in schistosomiasis risk extending up to hundreds of kilometres upstream from the dams themselves . hence, dams, reservoirs and irrigation networks related to agricultural expansion are likely to increase vector-borne and waterborne diseases unless water resources are developed in deliberate and coordinated ways to mitigate these risks . urbanization, globalization and the movement of agricultural products. the world's population became majority urban in and urbanization continues to outpace population growth, especially in developing countries. urbanization necessarily extends food supply chains, as consumers reside further from farms and fisheries. although only % of the food produced globally for human consumption is traded across international borders , globalization is likewise elongating food supply chains. furthermore, as the costs of international travel have declined over time, the movement of people across borders has likewise increased. the expanded spatial scope and increased frequency, speed and volume of people and agricultural products moving within and among countries necessarily facilitates the spread of pathogens. for example, in ecuador, there is evidence that the construction of new roads has affected the epidemiology of diarrheal diseases by changing contact rates among people as well as between people and contaminated water sources . each year in the united states, there are already an estimated million people with illnesses, , hospitalizations and , deaths from food-borne infections , and imported foods -especially from developing countries with poor sanitation infrastructure and weak food safety enforcement -have been associated with a rise in food-borne illness . in addition, globalization is already thought to be a factor in the spread of human influenza viruses that spillover from poultry and swine , . although modernization of food supply chains, especially those linking farms in developing countries to high-income consumers in cities and high-income countries, has typically accelerated the diffusion of stricter food safety and quality standards , , as urbanization and globalization further extend food supply chains, enhanced monitoring for the spread of pathogens across transportation networks and strengthened food safety regulations will be needed. in this section, we review the effects of agricultural industrialization. anti-parasitic and antibiotic drug use. as the global human population increases, there will almost certainly be an increase in high density, industrialized livestock and aquaculture operations. currently, such livestock operations are vulnerable to devastating losses of animals to disease. for instance, in just the last years, an influenza a virus (h n ) and a foot-and-mouth outbreak led to the destruction of more than . million chickens and million livestock in china and great britain , respectively, and a 'mad cow disease' epizootic led to the slaughter of million cattle worldwide . similar scenarios have occurred in aquaculture. in the past three decades, there has been more than fourfold growth in industrial aquaculture worldwide , which should continue to increase as food demand grows and wild fish and shellfish captures push the limits of renewable production . bacterial outbreaks in aquaculture are common, especially in developing countries where there are sanitary shortcomings . in an effort to prevent these catastrophic disease-associated losses and improve animal growth, the agricultural industry uses a larger proportion of global antibiotic and anthelmintic production than human medicine, and most of the antibiotics are provided at non-therapeutic doses in the absence of any known disease , . in fact, although estimates are lacking for most countries in the world, in the united states, nearly nine times more antibiotics are given to animals than humans and, of the antibiotics given to animals, more than times as many are used nontherapeutically as therapeutically . this widespread use of antibiotics and anti-parasitic drugs (for example, anthelmintics) in industrialized agriculture and aquaculture could have important implications for human infectious diseases because it seems to be driving microbial resistance to these drugs, some of which are also used in human medicine , , . for example, livestock are a primary source of antibiotic-resistant salmonella, campylobacter and escherichia coli strains that are pathogenic to humans . there is evidence that antibiotic-resistance genes acquired from aquaculture are being transferred to human systems and these pathogens have subsequently caused outbreaks . anthelmintic resistance is also rife among parasitic worms of livestock and is strongly implied for parasitic worms of humans . as livestock and aquaculture production expand to address growing food demands, it is likely that current antibiotics and anthelmintics will become less effective because of evolved resistance, and thus infectious diseases of domesticated animals and humans will be more difficult to treat . pesticides, fertilizers and disease. pesticides, particularly insecticides, have shared value for suppression of agricultural pest populations and disease-carrying insect vectors, such as mosquitoes and other flies. because of the anticipated sharp increase in pesticide use by (fig. ) , insecticide resistance is also expected to increase, with important implications for the control of diseases carried by insect vectors. insecticides with widespread shared use for both crop protection and vector control include pyrethroid, organophosphate and organochlorine insecticides . several mosquito vectors of human and livestock pathogens have already evolved some resistance to these compounds . if agricultural expansion and intensification is accompanied by an increased use of insecticides, vector resistance may become more common and the control of vectorborne diseases more challenging. in addition to potentially driving vector resistance, increased pesticide use is likely to cause numerous other effects on host-parasite interactions. pesticides can alter disease risk by modifying host susceptibility to parasites [ ] [ ] [ ] . for example, many pesticides are immunomodulators that can increase infectious diseases of wildlife and humans , , or are endocrine disruptors of humans with potential downstream effects on immunity . even if pesticides do not directly affect immunity, detoxification of pesticides is energetically 'expensive' for the host, and thus pesticide exposure can reduce available energy resources for humans and zoonotic hosts to invest into parasite defences , . pesticides can also affect human disease risk by altering the densities of hosts or parasites or their natural enemies or mutualists , . several pesticides can alter host behaviours or be directly toxic to hosts and parasites, which in turn can modify contact rates between parasites and human hosts. in addition, pesticides can alter community composition, which can indirectly affect behaviours or densities of intermediate and zoonotic hosts and parasites. although chemical contaminants can be deadly to many free-living stages of parasites, both empirical trends and theoretical models suggest that stress associated with pesticide exposure can increase non-specific or generalist pathogens , , . in addition to the impacts that pesticides can have on infectious diseases, they can also contribute to non-infectious diseases, such as cancers, birth defects, miscarriages and impaired childhood development , which can further strengthen the poverty-infectious disease trap. indeed, among african agricultural households, there is evidence of an association between increased pesticide use and increased time lost from work due to sickness . in addition to an increase in pesticides, nitrogen-and phosphorous-based fertilizers are expected to increase threefold by to boost food production, and most of this increase will occur in tropical regions already rich with pathogens , , . although the effects of environmental nutrient enrichment on disease are indirect and complex, with some infections increasing and others decreasing, two reviews on the subject suggest that elevated nutrient levels more often than not exacerbate the impact of infectious disease , . for example, phosphorous enrichment can benefit mosquitoes that transmit malaria and west nile virus , . in addition, nitrogen-and phosphorous-based fertilizer use can increase the number of snails that transmit flatworms that cause human schistosomiasis , . conversion of natural habitat to agriculture can increase the abundance of ecotones (boundaries between ecological systems), change species composition and reduce native biodiversity , . ecotones play an important role in a number of important emerging infectious diseases , , and reduced biodiversity that accompanies agricultural intensification can increase zoonotic disease emergence and can worsen already endemic diseases [ ] [ ] [ ] . a recent global meta-analysis suggests that, based on the available literature, such biodiversity losses generally increase infections of wildlife and zoonotic infections of humans . however, studies of the relationship between biodiversity change and infectious disease risk tend to focus on a single parasite or disease, often of non-human animals, which limits the ability to determine more broadly the effects of agricultural intensification on the overall burden of infectious disease in human populations . recent studies have found that the local loss of dense forests, largely from agricultural expansion, affected diarrheal diseases, acute respiratory infections and general fever in cambodian children and infectious disease incidence in nigerian children over a decade , . proximate causes probably included reduced regulation of microbial contaminants in surface and ground waters, increased smoke from biomass burning, shifts in the ranges of insect vectors and decreased access to forest ecosystem services. a major concern is the potential for positive feedbacks between poverty, biodiversity loss, soil degradation and infectious disease , . several mechanisms can underpin these reinforcing relationships. the first arises as a result of poor rural peoples' reliance on limited biophysical assets for their livelihoods. as households clear forests, deplete soils or overharvest biota to meet near-term consumption needs, this resource degradation can compromise future economic productivity and increase disease risk. in addition, poverty, environmental degradation, biodiversity loss and disease can quickly become mutually reinforcing responses to natural shocks, such as droughts or floods, or to protracted conflict in a region. there are also more direct examples. for instance, global net losses of tropical forests remained unchanged during the s and s (at approximately million ha yr − or . % annually ; also see https://glad.umd.edu/projects/global-forest-watch and https:// www.globalforestwatch.org) and forest clearing can lead to transmission of zoonotic disease by increasing contact with wild animals. conversely, encroachment of people and domesticated animals into natural areas can introduce diseases to wildlife that can devastate wild populations and create reservoirs for the disease to be transmitted back to domesticated animals (see next section for further discussion and citations). especially as the agricultural frontier expands, considerable attention must be paid to monitoring and managing these biodiversity-poverty-disease feedbacks . a central tenet of epidemiology is that the incidence of many infectious diseases should increase proportionally with host density because of increased contact rates and thus transmission among hosts . hence, increasing human and livestock densities could cause increases in infectious diseases unless investments in disease prevention are sufficient to prevent these increases. given that most of the increase in human and livestock densities are expected to occur in developing countries where disease surveillance, pest control, sanitation, and medical and veterinary care are limited, there is little reason to expect that control efforts will keep up with the expected increases in infectious diseases associated with increasing densities of these hosts. as host densities and thus transmission increase, theory suggests that parasite virulence should also increase under some circumstances . when virulence of a pathogen is tied to its propagule generation within the body (such as occurs with many viral infections), the intermediate virulence hypothesis posits that an intermediate level of virulence maximizes parasite transmission because it balances producing many parasite offspring (increasing parasite fitness) with detriments to host survival due to pathology (decreasing parasite fitness). the balance in this trade-off determines parasite persistence. hence, as host densities increase and transmission becomes more frequent, the cost of increased virulence declines, shifting the optimum towards higher virulence . consequently, for pathogens that experience this virulence trade-off, increases in human, crop and livestock densities have the potential to augment both the incidence and severity of infectious diseases. feeding billion people -and the associated increase of land converted to agricultural production and livestock grazing -is expected to cause a surge in human-livestock, human-wild animal and livestock-wild animal contact rates, increasing the likelihood of 'spillover' events, which are defined as pathogen transmission from a reservoir host population to a novel host population , . as natural ecosystems are converted to crop land or range land, interactions among humans, and domesticated and wild animals, could increase . furthermore, if developing countries follow a trajectory similar to developed countries, then their demand for meat will increase, further increasing human-livestock, human-wild animal and livestock-wild animal contact rates . these interactions are crucial because % of livestock pathogens are capable of infecting multiple host species, including wildlife and humans , and based on published estimates from the s, over half of all recognized human pathogens are currently or originally zoonotic , , , as are - % of recent emerging infectious disease events , , (fig. ) . examples of recent zoonotic disease emergences with enormous impacts on either livestock, humans or both, many of which might have agricultural drivers, include avian influenza, salmonellosis (poultry and humans), newcastle disease (poultry), swine flu, nipah virus (pigs and humans), middle east respiratory syndrome (camels and humans), bovine tuberculosis, brucellosis (mostly cattle and humans), rabies (dogs and humans), west nile virus, severe acute respiratory syndrome (sars) and ebola (humans) , . to quantify the relationship between agricultural factors and disease emergence in humans through time, we used the human disease emergence database of jones et al. . we classified land-use change, food industry and agricultural industry as agricultural drivers of human disease emergence (see supplementary methods) . these analyses revealed that agricultural drivers were associated with % of all diseases and nearly % of zoonotic diseases that emerged in humans since (fig. ) . these values are even higher if we include the use of antimicrobial agents as an agricultural driver of human disease emergence, given that agricultural uses of antibiotics outpace medical uses in the developed world nearly nine to one , . several factors have materialized that facilitate spillover events associated with disease emergence . spillover appears to be a function of the frequency, duration and intimacy of interactions between a reservoir and novel host population . for example, influenza is believed to have jumped from horses to humans soon after domesticating horses and then made additional jumps to humans from other domesticated animals, such as poultry and swine . similarly, when free-range turkeys were prevented from interacting with wild birds and when interactions between domesticated pigs and wild fruit bats were reduced, influenza and nipah virus incidence , human pathogens that are currently or originally zoonotic , , and recent emerging pathogens that are zoonotic , . dropped, respectively, suggesting wild-animal sources of these infections , . in sub-saharan africa, the high frequency and duration of environmental interactions between different species of schistosoma worms infecting humans and cattle has undoubtedly facilitated their hybridization, and these hybrid schistosomes are more virulent to humans than their non-hybrid counterparts . these factors associated with spillover and disease emergence could be targeted to reduce transmission potential as human populations and agricultural productivity increase. given that most human population growth is expected to occur in developing, tropical countries, hunting, fishing and gathering pressures will almost certainly rise in subsistence economies , . the consequences of these pressures might initially increase contact rates between humans and wildlife. this could increase disease risk as bushmeat hunting is already thought to be responsible for several emerging human infectious diseases . to make matters worse, bushmeat hunting is the second biggest threat to biodiversity behind habitat loss, and biodiversity losses can contribute to disease emergence . however, if humans overexploit these natural resources, then human-wildlife interactions could eventually decline as species go extinct, which could reduce spillover events. changes in the composition of biodiversity associated with overhunting and overfishing can also have complex indirect effects on disease risk mediated by species interactions. for example, empirical evidence supports the notion that defaunation of large vertebrates in africa should increase zoonotic disease risk by reducing the predators and competitors (large herbivores) of rodents, a common reservoir of human pathogens . similarly, overfishing of snail-eating cichlids in lake malawi in africa seems to have been a causal factor in snail population and human schistosomiasis increases there . investigations of the effects of overexploitation on infectious diseases remain in their infancy, but the consequences for human populations could be profound. up to this point, we have focused on the effects of feeding billion people on infectious diseases, but the relationship is bidirectional. that is, human infectious diseases can also impact the agricultural and economic development necessary to feed the growing human population (fig. ) . for example, the overuse of antibiotics, anthelmintics and pesticides to prevent diseases is driving resistance to these chemicals that will compromise future crop, livestock and aquaculture production. in sub-saharan africa, areas with higher historical tsetse-fly abundance, the vector of the parasite (trypanosoma brucei) that causes african sleeping sickness in humans and cattle, experienced greater lags in the adoption of animal husbandry practices (for fertilizer and labour in agricultural enterprise) that hindered agricultural development and prosperity in africa long before and after europeans colonized . in rural subsistence communities, any source of ill health can significantly impact people's productivity, yields and agricultural output [ ] [ ] [ ] . for example, human immunodeficiency virus/aids has reduced average life expectancy in sub-saharan africa by years since , and a kenyan study found that crop production by rural subsistence-farming families dropped % after the death of a male head of household . many neglected tropical diseases (ntds) impose devastating productivity losses for affected people that can impede agricultural development from local to national to regional scales . some low-income communities appear mired in this poverty-disease trap, and thus might require substantial investment in health systems to promote the necessary agricultural and economic growth to pull them out of the povertydisease cycle [ ] [ ] [ ] [ ] [ ] . the goal of identifying potential changes to infectious disease risk associated with feeding the growing human population is not only to draw attention to this important current and future problem but to also encourage preparation for these changes by stimulating agricultural-and disease-related research, management and policy that could maximize the human health benefits of agricultural development . one urgent challenge is the problem of antibiotic, anthelmintic and pesticide resistance. analyses demonstrate that, in some cases, improvements in growth and feed consumption can be achieved by improved hygiene instead of antibiotics . indeed, all antibiotics as growth promoters were banned in the european union in . to curb antimicrobial consumption in food animal production, van boeckel et al. suggest: ( ) enforcing global regulations to cap antimicrobial use, ( ) adhering to nutritional guidelines leading to reduced meat consumption, and ( ) imposing a global user fee on veterinary antimicrobial use. in addition, as recommended by the world health organization, international organization for epizootics, and food and agriculture organization, national and international policies based on best management practices should be developed and implemented that document when and how antibiotics should be used, and agencies should be established to monitor their use, mandate reporting and enforce these policies . finally, given that host genetic variability can reduce disease risk , large-scale industrial livestock operations could add genetic variability into their artificially selected food animals in an effort to reduce epidemics and epizootics. these changes promise to secure the long-term viability of antibiotics and anthelmintics for curing diseases of humans and non-human animals. another challenge that seems surmountable is to enhance education and health literacy. not surprisingly, education has been documented as a major contributing factor to reducing infectious diseases, especially ntds, and reducing ntds can have reinforcing positive effects on the ability of humans to fight more deadly diseases, such as aids, malaria and tuberculosis . limiting ntds could also have knock-on effects for education and health literacy because ntds impede cognition, learning and school attendance . indeed, an investment of just us$ . per child for ntd control can result in the equivalent of an extra school year of education . this is likely an underestimate because of unaccounted for indirect effects of deworming on learning. a recent study revealed large cognitive gains among children who were not dewormed but had older siblings who were . thus, enhanced education and ntd control have the potential to synergistically fuel agricultural and economic development and facilitate escape from the poverty-disease trap. national and international shifts in investments could also potentially pay large dividends for nutrition, infectious disease control and poverty reduction. there is considerable evidence that the developing world will struggle to feed its growing human population because of the poverty trap of infectious disease . however, evidence also suggests that this trap might be broken through investments in health infrastructure and preventive chemotherapy [ ] [ ] [ ] . curing worm diseases has the potential added benefit of reducing nutritional needs of cured individuals by ceasing the feeding of their parasites. by reducing food demand, these drugs could also protect the environment by reducing the conversion rate of natural areas to agriculture. this, in turn, might help to curb climate change, which is one of the greatest threats to global food security and might also increase disease risk , . understanding the economic relationships among infectious disease treatment and prevention, food production, poverty and climate change in the developing world are important areas of future research. as human populations increase, there might be more pathogen spillover events that could result in new emerging human infectious diseases. historically, humans have combated emerging diseases through early detection followed by coordinated quarantine, as demonstrated by the sars outbreak in and the ebola outbreak in . we recommend continued and improved coordinated international disease surveillance, but this approach reacts to rather than prevents disease. we recommend a shift in both research and disease management efforts towards proactive management approaches. one proactive approach that has promise for preventing zoonotic disease emergence is biodiversity conservation , , but more research is needed to evaluate its effectiveness across various types of zoonotic diseases and its costs and benefits relative to more proven reactive public health interventions. ultimately, science needs a better understanding of pathogen spillover, the origins of disease emergence and post-spillover evolution so that human disease emergence can be better predicted and prevented , , . improved and diversified plant and animal genetic material could also help to simultaneously reduce hunger and disease. many efforts are already well underway; for example, introducing c traits into rice to enhance higher photosynthetic capacity in a warming world, and breeding drought-and flood-tolerant cereals, pulses and vegetables better suited to increased frequency of extreme weather events that can help sustainably enhance productivity. crops and livestock genetically adapted to resist more pests can reduce pesticide and antibiotic use. in addition, given that micronutrient deficiencies are now the most widespread source of undernutrition globally, commodity research must diversify beyond merely boosting productivity of staple cereals. far greater attention is needed on approaches that add mineral and vitamin content to foods . other, perhaps more challenging, interventions also merit attention. closing 'yield gaps' on underperforming lands, increasing cropping efficiency, eating less meat and excess per capita food consumption -which also have adverse health impacts on noninfectious diseases, such as high blood pressure, diabetes and heart disease -and reducing food waste and loss have the potential of doubling global food supplies , , , , while simultaneously allowing financial savings to be redirected towards health infrastructure to control disease. in addition, family planning, promoting female education and job market prospects, and enhancing early childhood survival have proved very effective at reducing human population growth . finally, producing food in more urban and suburban environments through vertical farming (the practice of growing produce in vertically stacked layers) also has potential to enhance food production locally, and might have reduced agrochemical and transportation costs and non-target effects relative to more traditional farming . investments into predictive models could also pay dividends. agricultural environments are complicated, multi-species systems that exhibit interactions at many levels. the complexity further increases from the tensions that arise in balancing expanding agricultural systems, social benefits and infectious disease risk. all of this complexity can overwhelm many analytical tools and experiments, which makes advances in mathematical modelling especially crucial to addressing these issues. box describes several examples of advances in mathematical modelling that illustrate their promise for analysing the links between agricultural practices and the dynamics of infectious diseases, projecting risks to future decades, influencing risks through either intentional (policies and interventions) or unintentional (continued habitat box | modelling tools for quantitative analysis of agriculture-infectious disease systems mathematical models facilitate the investigation of a complex web of interactions between agricultural systems, social dynamics and infectious diseases in the presence of the substantial nonlinearities inherent in these disparate processes. a notable example is a body of theory and analyses that have emerged to examine the links between agricultural systems and the dynamics of infectious diseases in the context of global development . the approach combines ecological and economic theory to model population subsistence and health, with the goal of examining the conditions under which subsistence and health needs of populations are met. the fundamental consumer-resource relationships that underlie the biological generation of capital via agricultural production can be formalized in ordinary differential equation models, which can be coupled with similarly structured models that estimate the gains and losses in human capital associated with population health and the increasing risk of acquiring and succumbing to infectious diseases associated with poverty. key insights emerge from such integrated models. high prevalence of infectious diseases among populations that rely heavily on subsistence, labour-intensive agriculture can reduce agricultural productivity, degrade human capital, undermine economic growth and generate conditions that systematically reinforce poverty . poverty, in turn, increases disease transmission as the lack of access to clean water and preventive care often associated with the lifestyle of the poor make them continuously exposed to parasites and pathogens embedded in the environment . malnutrition, a common consequence of poverty, may weaken immune response and increase susceptibility to disease. poor education and lack of resources lead to further reduction of health-seeking behaviour. modelling shows that the reinforcing feedback between poor health, labour productivity and capital formation triggers a cycle of increasing poverty and disease, known as disease-driven 'poverty trap' . it also shows that poverty traps are reinforced by the asymmetry between the slow pace of investment in disease protection associated with increasing capital due to agricultural development, and the relatively faster ecological changes in transformed landscape that foster disease transmission . modelling can also reveal the impact of temporary versus lasting structural interventions in changing the development trajectories of poor populations. these intrinsically quantitative and mechanistic investigations can indicate specific conditions for economic growth or resilience that can inform development strategies, via, for instance, targeted investments in agricultural development, human health or ecological conservation that may reinforce globally stable development equilibria . a final major contribution of such models is to encourage primary data collection in support of deeper understanding of system dynamics, and greater inference of underlying determinants of health and wealth. because there are strong traditions of primary data collection in population biology, epidemiology and other disciplines wherein mathematical modelling is being advanced, the expansion of model-based research on coupled agricultural-health systems is likely to yield new field data collection efforts and direct the design of experiments, which, in turn, will yield greater opportunities for model parameterization and validation. these new empirical field data are what are desperately needed to explore whether the predictions of highly stylized models are supported in settings far more complex than modelled. simulation modelling, in turn, can also permit exploration of the uncertainty intrinsic to field experiments that generate data in a specific place and time, advancing understanding of system performance under a range of feasible weather, market and other conditions not realized during the period of data collection. conversion and antibiotic use) actions, and incorporating economic and social costs of various public health or agricultural interventions. these models should help direct field experiments, which are desperately needed to parameterize and validate these models and to quantify key sources of uncertainty. ultimately, we believe 'win-win' scenarios for controlling infectious diseases, increasing agricultural productivity and improving nutrition are attainable. although this sort of integrative thinking has been historically rare because agriculture and public health have been perceived as disparate disciplines, it is beginning to slowly penetrate these distinct fields of study. for example, several agrochemicals seem to increase the risk of human schistosomiasis and agriculturally derived zoonotic pathogens, and thus researchers are actively attempting to identify agrochemicals that might 'kill two birds with one stone' , reducing crop pests and thus increasing food production while not increasing or even decreasing human pathogens [ ] [ ] [ ] . similarly, researchers are beginning to consider the introduction of prawns as biological control agents of schistosomiasis, which could simultaneously decrease disease and increase nutrition -because restored prawns can be fished, harvested and consumed without compromising their diseasecontrolling benefits , . we believe that more resourceful and creative thinking and interdisciplinary interactions (among medicine, public health, agriculture professionals, economists, anthropologists, sociologists, modellers, empiricists and wildlife biologists, in the developed and developing world) have great promise for sustainably and simultaneously improving human nutrition while controlling infectious diseases. in conclusion, we hope that by synthesizing the complex intersection of food production and human health, we have highlighted the value of increasing agricultural-and disease-related research, management and policy, maximizing the benefits of agricultural development while minimizing its adverse effects on human health and the environment, and preparing for the imminent changes driven by the billion people expected to inhabit earth by . global trends in emerging infectious diseases nigeria's invisible crisis hunger in africa: the link between unhealthy people and unhealthy soils maternal and child 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institutional affiliations. key: cord- - rsrx m authors: shulman, stanford t title: the history of pediatric infectious diseases date: journal: pediatr res doi: . / .pdr. . . sha: doc_id: cord_uid: rsrx m the history of pediatric infectious diseases closely parallels the history of pediatrics at least until the last century, because historically infections comprised the major causes of childhood morbidity and mortality, as they still do in the developing world. this history reviews developments in the field through the centuries and is writen so that it does not overlap the contribution to this series by baker and katz entitled ‘childhood vaccine development in the united states.' remarkable descriptions of selected pediatric infections existed long before the invention of printing, and early pediatric texts included many chapters devoted to various infections. coincident with the establishment of pediatric organizations in america in the late (th) and early (th) centuries, major attention was focused on diphtheria, infant diarrheal illnesses, tuberculosis, streptococcal infections and their complications, and other pediatric infections, and substantial progress was made. the american pediatric society ( ), the american academy of pediatrics ( ), the society for pediatric research ( ), and the american board of pediatrics ( ) all contributed to the evolution of the discipline of pediatric infectious disease, and numerous leaders of these organizations had significant infectious diseases interests. the establishment of the pediatric infectious diseases society, the pediatric infectious diseases sub-board, and an accreditation process for training programs, as well as sub-specialty textbooks and journal, further validated the development of this specialty, particularly in north america. the many remaining challenges related to infectious diseases in children (including hiv, emerging infections, antimicrobial resistance, opportunistic infections, and infections in the developing world) insure the future of the specialty. the genomic era of medicine and the tools of molecular biology will lead to new insights into pathogenesis, diagnosis, and treatment of infections. pediatric infectious diseases physicians can celebrate the past triumphs of the discipline and future achievements, all contributing to improved health for children. noted the complications of these illnesses; and the th century works of the prominent arab physician avicenna (ibn sina), who wrote on children's illnesses including tetanus, cough and catarrh, aphthae, ear drainage, seiriasis, fevers, pustules, throat inflammation, worms and diarrhea (flux) ( , ) . for the next almost y, there were virtually no pediatric writings. the invention of printing in the mid- th century revived learning, and the first printed work on diseases of children was published in by the italian paolo bagellardo, including chapters on many common infections, including tinea capitis, otorrhea, ear abscess, cough, rheumatism and diarrhea ( ) . two other similar books followed, that of metlinger (german) in and of roelans (belgian) in . eucharius roesslin (german) opened the th century of pediatric texts with a text on midwifery and pediatrics, with reviews of the most common ailments of children, including many infections, of course ( ) . the book by leonellus faventinus de victoriis (italian) was published posthumously in and included a chapter on aphthae and another on measles and smallpox. the first english-language pediatric book was published in by thomas phaer, "the boke of chyldren" and included chapters on aposteme of the brayne (meningitis), scalles of the heed, styfnesse of the lymmes, bloodshoten eyes [kawasaki disease?], diseases in the eares, canker in the mouth, quynsye or swelling of throte, coughe, feblenesse of the stomacke and vomiting, fluxe of the belly (diarrhea), wormes, small pockes and measels, fevers, and consumpcion ( , ) . in giovanne p. ingrassias (italian) differentiated scarlet fever (rossalia) from measles ( ) . hieronymus mercurialis (italian) in published a pediatric text that mentioned the king's evil (scrofulous glands) and included chapters on worms ( ) . at the end of the th century, understanding of disease in children had barely advanced beyond the theories and observations of the greeks and romans, restated by the arab physicians, and clinical observation seemed of little value. significant advances, however, were made during the th century. the works of guillaume de baillou (french) published in were important for the first detailed description of whooping cough as a distinct entity, as he described an epidemic in , as well as rubeola and scarlet fever. several important descriptions of diphtheria (morbo strangulatorio, angina puerorum) were made, with its epidemic nature highlighted by johannes sgambatus (italian) in , its pathologic anatomy in by thomas bartholin (danish), who also commented on its contagious nature ( ) , and its method of killing children (paedanchone or child-throttling) by marcus a. severinus (italian) in . the second english language pediatric book, published by robert pemell in , included chapters on lice, scab and itch, ulcers and sores in the head, pain and inflammation of the ears, oral ulcers, feavers, small pox and measels, rheums and cough, flux, worms, inflammation of the naval, and saint anthonie's fire (erysipelas or ergotism) ( , ) . the third english book appeared in , written by j. starsmare and included much the same topics but making the first mention in english of scrofula. franciscus sylvius de le boe (dutch) was a careful clinician and anatomist who published a book on diseases of infants in that included the usual topics. sylvius is remembered best for the aqueduct of sylvius and the sylvian fissure. thomas sydenham, the most respected english physician of the th century, deserves mention here for his careful description of chorea ( ), his very detailed description of measles ( ), and his account of scarlet fever ( ), which surprisingly failed to mention pharyngitis. thomas willis, who described the circle of willis, wrote a careful account of pertussis (chincough) in and said, "the plan of treatment which is usual in other varieties of cough is seldom of any use in this, which is the reason why old women and gypsies are consulted more often than doctors" ( ) . near the end of the th century a small book on diseases of infants was published in london in by walter harris and became very popular, with editions over years. harris also wrote an essay on venereal diseases, a treatise on plague, and in strongly advocated inoculation against smallpox ( ). his comments about summer diarrhea of infants are described below. in summary, the th century was associated with a rebirth of medicine, and for the first time since hippocrates clinical observations became important. anatomists laid a foundation for morbid anatomy/pathology, and there was initial rejection of some of the ancient theories of disease ( ) . in the field of pediatric infectious diseases there was slow progress, but chorea, scarlet fever, scrofula, and pertussis had been recognized clearly as specific diseases. the history of pediatric infectious diseases (but not the medical specialty) in america predates the establishment of the united states. colonial children were afflicted by many epidemic contagious diseases, and a number of very graphic descriptions have been recorded, many referred to in thomas e. cone's history of american pediatrics ( ) . smallpox that affected children was described in on the talbot, a ship en route from gravesend, england, to new england. during the voyage, the reverend higginson wrote an account of his children who became ill with smallpox, including his young daughter who died at sea. epidemics of smallpox, endemic in england through the th century, were described in massachusetts in and again in , when about one-fifth of boston's population succumbed to this scourge ( ) . the first american medical publication, a broadside on smallpox that discussed diagnosis and therapy, was written in by the pastor-physician reverend thomas thacher ( - ) of boston, who practiced part-time pediatrics ( ) . measles was recorded in boston and connecticut in - and again in - , with many children afflicted but apparently relatively few deaths. diphtheria, which was often confused clinically with scarlet fever, was associated with great mortality. the first recorded north american epidemic of diphtheria occurred in in roxbury, ma, with subsequent probable outbreaks documented in in virginia and in new london, ct. scarlet fever, often mistaken for both measles and diphtheria, was first reported in the colonies by shulman both john marshall and cotton mather, who wrote of an epidemic in boston from september to december, . the next epidemic in new england did not occur until . whooping cough caused an extensive epidemic in in young children, but there are no records of subsequent epidemics until ( ) . summer diarrhea in infants was a very serious problem, with very high mortality rates. in england, walter harris ( - ), one of the earliest great "pediatrists" wrote in "from the middle of july to about the middle of september, the epidemical gripes of children are so rife every year, that more of them usually die in one month, than in three or four at any other time. . ." ( ) in the colonies, john josselyn in and john marshall around wrote about children dying of bloody flux (dysentery) and fever ( ) . the pace of progress regarding infectious diseases of children accelerated during the th century, particularly with respect to prevention of smallpox by inoculation or variolation. smallpox was an almost inevitable illness of childhood and was one of the most common causes of death because of its high mortality rate. it was reported, for example, to kill % of swedish children yearly. inoculation with matter from a smallpox subject was introduced into western europe from constantinople around , with limited mortality from the procedure and resulting immunity ( ). other advances were being made as well. richard wiseman (english) , surgeon to king charles ii, wrote extensively about the king's evil (scrofula) and mesenteric adenitis. jean astruc (french) in published an english edition of his lectures on diseases of children that included pertussis, infant diarrhea, worms, purulent lung disease, and scrofula. astruc was among the first to emphasize the importance of a thorough and methodical clinical exam of children. john fothergill (english) in published an important work on ulcerative pharyngitis, with descriptions of diphtheria and scarlet fever ( ). the mid- th century saw the identification of varicella as a disease distinct from smallpox. françois boissier de sauvages (french) in a book on diseases of children described what he thought was a variety of smallpox that he termed "la vérole volante" or the fleeting variola (smallpox). the description is of varicella, which was very clearly distinguished as a separate illness by william heberden the elder (english) in ( ) ( ) ( ) . nils rosen von rosenstein (swedish) published a very important pediatric work in , which was the most progressive and scientific book on pediatrics up to that time ( ). it included a detailed description of a epidemic of scarlet fever, varieties of infant diarrhea (obviously he was a splitter rather than a lumper), and also described varicella but considered it "the chrystalline or watery smallpox" ( ). he described postscarletina dropsy with bloody urine (poststreptococcal nephritis) and had sufficient insight about pertussis to state that "the true cause of this disease must be some heterogeneous matter or seed which has a multiplicative power as is the case with smallpox. . . we find that it is communicated by infection and that a part of it is attracted by the breath down into the lungs." robert whytt (scottish) in published what some consider the finest clinical description of any disease to that time in his "observations on the dropsy in the brain," tuberculous meningitis, in which he detailed the three clinical stages of this disease as well as the autopsy findings ( ) . around this time hugh smith (english) importantly focused public attention upon the staggeringly high mortality rates among children. he showed that from to about two-thirds of children born in london died before the age of five years and that about % of the deaths occurred before two years of age ( , ) . at this time george armstrong founded the first dispensary for children in , which ultimately led to the establishment of children's hospitals. he published a work on the diseases most fatal to infants in , and he wrote in detail about the treatment of the chin-cough (pertussis). michael underwood (english) was probably the most advanced th century writer on the diseases of children ( ) . his treatise, first published in , was reprinted in editions until . he provided the first description of sclerema and poliomyelitis and wrote about coryza maligna, which was either congenital lues or nasal diphtheria. joseph clarke (irish) in described an outbreak of fatal "nine-day fits" among neonates (neonatal tetanus) at the lying-in hospital of dublin. hyacinthus andreas (spanish) had published an account of this condition at the end of the th century ( ). it was in that edward jenner published his report of years of observation and experimentation with the variolae vaccinae, or cowpox, to prevent smallpox. this proved much safer than the procedure of inoculation with smallpox matter (variolation) used earlier in the th century, as described above. at the end of the th century, pediatrics was characterized by increased awareness of the value of children's lives, the beginning of institutions to provide medical care for children and the beginning of instruction of medical students in children's diseases. additional important pediatric infectious diseases had been described, including tuberculous meningitis, varicella, neonatal tetanus, and poststreptococcal nephritis ( ). jenner's studies provided the means to prevent the great morbidity and mortality related to the dreaded smallpox. epidemic diseases were better described during the th century in colonial america compared with the earlier period, and there was clear recognition of the impact of smallpox, diphtheria, scarlet fever, measles, influenza, tuberculosis and whooping cough, particularly upon children. a very severe new england epidemic of diphtheria in - killed more than individuals, mostly children, and was later called "the most horrible epidemic of a children's disease in american history" ( ) . early accounts by jabez fitch ( ) of new hampshire and jonathan dickinson ( ) described these events ( ) . samuel bard ( ) . this work about diphtheria emphasized its infective etiology, "drawn in by the breath of a healthy child," and urged prevention by immediate removal of the young children in the family as soon as a first case appeared in a household. in william douglass ( - of boston provided what is considered the earliest complete description of scarlet fever, terming it angina ulcusculosa ( ) . in , dr. benjamin rush ( - ) described a widespread epidemic of scarlet fever ("scarlatina anginosa") occurring in philadelphia in and , while pertussis was described in detail in by lionel chalmers ( chalmers ( - in an account of the weather and diseases of south carolina ( ) . dysentery ("bloody flux") was emphasized as a serious and very common problem of children particularly in summer when benjamin rush wrote in detail about "cholera infantum" (and coined the term) in ( ) . rush was the most influential american physician of his day and a signer of the declaration of independence, and he lectured and published regarding pediatric disorders, including cholera infantum and diphtheria ( ) . cholera infantum, or summer diarrhea, appeared each year in epidemic form and emerged later as a particularly important problem for young children, as more crowded urban areas developed. in rush also described a major epidemic of yellow fever in philadelphia which killed about one-eighth of the population ( ) . particularly severe epidemics of measles were noted in , , , , and . more than children in charleston, sc died in the epidemic alone ( ) . cotton mather's diary in recorded the death of his wife, the maid, his neonatal twins, and another child in his family within a -d period ( ) . this serves as a striking reminder about this now-preventable illness. other primarily pediatric illnesses including thrush, mumps, tinea capitis, and worm infestations also were clearly described in the colonies of the th century ( ) . in contrast to europe, where smallpox was an endemic illness of childhood, in the colonies smallpox occurred in large epidemics with about -year periodicity and affected children as well as older susceptible individuals. this became an important issue during the revolutionary war, when the troops of the continental army (but not the british forces) were ravaged by smallpox until general george washington at valley forge decided to inoculate all susceptible troops. this act probably saved the war effort ( ) . from to about , the major causes of death in children were tuberculosis, diarrhea of infancy, bacillary dysentery, typhoid fever, and the highly contagious diseases of childhood, especially scarlet fever, diphtheria, and lobar pneumonia ( ). significant fluctuations occurred. for example, for the first three decades of the th century, the severity of scarlet fever was less than observed previously but then around increased dramatically. by scarlet fever had become the leading cause of death among the infectious diseases of childhood in the u.s., great britain, and europe ( ) . changes in the virulence of prevalent group a streptococcal strains would seem most likely responsible for such fluctuations, as seen in new york city, for example, where only scarlet fever deaths were recorded from - , but deaths by ( ) . reports about other pediatric infections also exist. in nathan smith of lebanon, nh, founder of dartmouth medical school, successfully treated joseph smith ( - ), an unrelated -year-old boy, for osteomyelitis, removing bone from the left lower leg but avoiding amputation. long-term drainage apparently occurred with discharge of additional pieces of bone, and crutches were used by the child for more than three years. joseph smith, who retained a slight limp, later founded the mormon church ( ) . for a period of about years, from - , eli ives, the first u.s. medical school faculty appointee in pediatrics, lectured yale medical students on the diseases of children. the surviving lecture notes show that these lectures included a number of infectious diseases topics as they impacted children ( ) . also in the first half of the th century, william potts dewees ( ), george logan ( ), and john eberle ( ) each published very early pediatric texts, each of which included sections on the infectious illnesses of children. dewees of philadelphia was an adjunct professor of midwifery, and his text, the first truly comprehensive american pediatrics book, has more than pages devoted to infections, including not only epidemic illnesses but also abscesses of the hip joint and ear, worms, and whitlow (paronychia) ( ) . epidemic spotted fever, or cerebrospinal meningitis, was described in detail by elisha north ( - ), who reported the connecticut outbreak of meningococcal infection ( ) . in william wood gerhard ( - ) provided the first american description of tuberculous meningitis (actually describing children he saw in paris), and in and he distinguished typhus from typhoid in children at the pennsylvania hospital. gerhard also in was perhaps the first to record percussion and auscultation findings in pediatric pulmonary diseases ( ) . his parisian training clearly exposed him to laennec's critically important invention, the stethoscope ( ). very substantial advances were made in european pediatrics, particularly with respect to infectious diseases, throughout the th century. john cheyne (scottish, irish) published a number of important works, including "the pathology of the membranes of the larynx and bronchia" in , a description of the - dublin fever epidemic, and three studies of cynanche trachealis (croup), and described cheyne-stokes respirations ( ). pierre bretonneau (french) described the contagious nature of typhoid fever ( - ) and of diphtheria ( ). he performed the first successful tracheostomy for diphtheria on july , , on a child, elizabeth de puységur ( ). in he distinguished typhoid from typhus clinically. the most important pediatric text of the early th century was by charles-michel billard (french). this work built upon that of bichat and laennec, who provided the initial scientific basis of shulman medicine, and classified pediatric disorders (including infectious diseases) based not upon symptoms but upon pathologic lesions, i.e. upon autopsy findings ( ) . armand trousseau (french) performed the first tracheostomy in paris ( ), described laryngeal tuberculosis, cutaneous and mucosal diphtheria, pediatric cholera, and he originated the technique of thoracentesis in pleurisy. frédéric rilliet (swiss) wrote on typhoid in children ( ), epidemic measles ( ), mumps ( ), and cholera ( ). his text ( - ) with antoine-charles-ernest barthez (french) included classic descriptions of tuberculosis of the bronchial glands, bronchopneumonia, and chronic pleurisy. charles west (british) ( - ) was considered the greatest english "pediatrist" of the second half of the th century. in he established the children's hospital in great ormand street, london. his pediatric text of , which went through seven editions and numerous translations, included outstanding descriptions of infantile tuberculosis and poliomyelitis and emphasized the importance of breast feeding in the prevention of infantile diarrhea. johann rehn (german) studied epidemic jaundice (infectious hepatitis) in children ( ), while his countryman eduard heinrich henoch, a pupil of schönlein, described abdominal purpura (henoch-schönlein purpura) in . nil f. filatoff (or filatow) (russian) published a series of lectures on the infectious diseases of children ( - ), in which he described "scarlatinal rubella" termed "fourth disease" or filatoff-dukes disease ( ). marie-jules parrot (french) described the pseudoparalysis of congenital syphilis ( ) that still bears his name ( ) . jacques-joseph grancher (french) wrote extensively on tuberculosis ( - ) and pioneered isolation and antisepsis (infection control) at the hôpital des enfants malades, paris ( - ), housing infectious patients in wire cages and using surgical gowns for staff ( ) . bernard-jean-antonin marfan (french) wrote important works on pediatric typhoid ( ), peritonitis ( ), congenital infections ( ), infantile gastroenteritis ( ) and diphtheria ( ) . friedrich bezold (german) in provided the first clear description of mastoiditis ( ) . henry ashby (british) was a pediatrician and public health officer who led the movement in britain to advocate for a pure milk supply during the s and early s. sir arthur newsholme (british) in the late th century and early th century provided extremely important data related to changes in infant, child, and maternal mortality primarily due to infectious diseases, particularly rheumatic fever ( ), epidemic diphtheria ( ) , and tuberculosis ( ) ( ). before , there was no organized group of physicians for children in the u.s. and, of course, no specific subspecialty fields within health care for children. the section of diseases of children of the american medical association was organized in at a meeting of the ama in richmond, va, with abraham jacobi chosen as president and thomas morgan rotch as secretary ( , ( , ) . he was the first to teach medicine at the bedside ( ). jacobi is often called the "father of american pediatrics" and wrote extensively on a variety of pediatric problems, with his most frequent subjects related to infectious diseases, notably diphtheria. he advocated the use of boiled milk for infants (for nutritional reasons as well as to prevent the gastroenteritides). the inaugural issue of the ama's american journal of obstetrics and diseases of women and children in , the first partially pediatric journal in the u.s., included an article on croup by jacobi. jacobi was an ardent social and political activist, striving to improve the circumstances of children. because the ama group began to flounder and the membership of the obstetrics and gynecology sections refused to allow pediatrics to form a separate section, a new group, the american pediatric society, the parent of organized pediatrics in the u.s., held an organizational meeting on september - , , at the arlington hotel in washington d.c., with physicians present ( , ) . credit for forming the group is given to job lewis smith ( - ) of bellevue medical school and william booker ( - ) of baltimore, the first clinical professor of the diseases of children at johns hopkins. jacobi was elected the first president, and there were founding members, predominantly from the northeast, including william osler, who later served as the fourth aps president ( ) . four papers were scheduled to be presented (although it is not clear from the minutes that any of them in fact was presented), including "treatment of whooping cough by antipyrin" by l. emmett holt, sr., of new york ( ) . holt was professor of pediatrics at the new york polyclinic hospital and attending physician at babies hospital in new york. he was a founder of the american pediatric society and served as president in and then again in . holt's presidential address in recapped his personal experiences with new york city children's hospitals, pointing out the discouraging % mortality for hospitalized infants and the very frequent nosocomial infections that occurred. he advocated care in the country, away from the crowded cities, during the summer months ( ) . this theme was echoed by henry koplik of new york, aps president in , who reported the continued problem of summer diarrhea and recommended ambulatory care and a "colony or camping system" with care provided by live-in mothers ( ) . although it had improved somewhat compared with colonial times, the plight of children at the time of the founding of the american pediatric society in continued to be hazardous. coincident with the industrial revolution, mortality rates had climbed substantially from early in the th century to the later years of the th century as major crowded urban areas developed. life expectancy around was less than years, infant mortality approached per births, and neonatal mortality was about per births ( , , ) . the infant mortality rate in in new york city, a particularly crowded urban area, was history of pediatric infectious diseases as high as per live-born infants, primarily related to various infectious processes. infectious diseases such as diarrhea, diphtheria, scarlet fever and tuberculosis dominated as the major causes of morbidity and mortality among children, and they had yet to be impacted by the just-emerging scientific base of medicine. the science of bacteriology, founded on the landmark discoveries of louis pasteur in paris, robert koch in berlin, and others in the early s, had not yet impacted child health. roentgen had not yet discovered x-rays. biochemical analyses were not available for infants and children. inadequate sanitation, impure water and unsafe milk supplies all contributed very significantly to the spread of infectious diseases among infants and children, and particularly to those living in the very crowded circumstances that promote transmission. the early years of organized u.s. pediatrics were marked by a number of landmark advances in the diagnosis and treatment of infectious diseases of children, with substantial reduction in infant mortality rates, to / live births in new york city in , with rates as low as in chicago and as high as in biddeford, me ( ). the importance of infectious diseases to the relatively small number of founding members of the american pediatric society, a group of distinguished physicians who devoted much or all of their effort to the improvement of the health of children, is reflected by analysis of the topics of the papers presented at the early annual scientific meetings of aps. the first scientific meeting of the aps held in washington on september , , and the next day in the then-new johns hopkins hospital included many presentations devoted to classic infectious diseases. these included two papers devoted to diphtheria, two elaborate bacteriologic studies of the stools in infant diarrhea (booker isolated bacterial varieties and jeffries different organisms), a paper on malaria in new york city, two papers related to infant feeding and prevention of infant diarrhea, and assorted case reports ( , ) . at least of the papers delivered at the first five annual scientific meetings ( - ) directly addressed infectious diseases topics, including diphtheria ( ), diarrhea ( ), scarlet fever and rheumatic fever ( ), tuberculosis ( ), pneumonia and empyema ( ), typhoid fever ( ), pertussis ( ), lues ( ), vulvo-vaginitis ( ), malaria ( ), and miscellaneous infections ( ) ( ). this dominance of the scientific agenda by infectious diseases topics attests to their extreme importance as the major causes of morbidity and mortality in childhood at the end of the th century. hippocrates had recognized the unfavorable implications of a sort of spiderweb (or membrane) in patients with tonsillar ulcers ( ) , and both bard's contribution and the introduction of tracheostomy for laryngeal diphtheria in france in the s have been noted (vide supra). diphtheria was of particular concern at the early american pediatric society meetings, as the laryngeal form of the disease in that era was almost invariably fatal, despite the use of tracheostomy. the few years just before the founding of the aps and the early years of the organization represented a period of landmark advances in understanding the etiology of this illness and in the development of markedly improved treatment modalities. in friedrich loeffler proved that a specific bacterium was the etiologic agent of diphtheria. the introduction of the o'dwyer intubation tube in received great attention because for the first time it enabled successful treatment of the suffocation that was associated with laryngeal diphtheria ( ) . joseph o'dwyer ( - ), attending physician at the new york foundling hospital, a facility for unwanted children, was a founder of american pediatric society, and he served as president of aps in ( ) . o'dwyer's presidential address reviewed his invention and experience with the intubation tube ( , ) . at the th annual scientific meeting of the aps in , papers from four groups regarding the dramatic, even revolutionary, effects of diphtheria antitoxin for therapy and prevention were presented. this led to the adoption of a formal resolution: "resolved, that, in the opinion of the society, the evidence thus far produced regarding the effects of diphtheria antitoxin, justifies its further and extensive trial" ( , ) . a committee was apparently appointed, as the annual meeting included a report from the american pediatric society's collective investigation of the antitoxin treatment of diphtheria in private practice, chaired by l. emmett holt. this confirmed the spectacular results of the french report by roux, martin, and chaillou from the pasteur institute in paris. the meeting received a report from the committee on collective investigation of the antitoxin treatment of laryngeal diphtheria in private practice, chaired by william p. northrup ( ) . these clinical studies of diphtheria equine antitoxin represented the first pediatric investigations in the u.s. of a national scope. the four committee members analyzed cases of laryngeal diphtheria treated with antitoxin who were submitted by aps members and concluded that antitoxin lowered the necessity for intubation from % to % and the mortality rate from % to % in this severest form of diphtheria ( ) . the schick test to assess susceptibility to diphtheria was introduced by bela schick in . emil von behring of germany, who initially discovered diphtheria toxin and developed the diphtheria antitoxin that was of such great interest and importance, was awarded the first nobel prize in medicine in for this work. tuberculosis and meningitis. tuberculosis was another very common and serious problem of childhood, and william osler was very actively involved in its study before moving to oxford, england, in to become the regius professor. osler's commitment to pediatrics is apparent from his frequent participation in the aps meetings to discuss tuberculosis, pertussis, chorea and carditis, croup, peritonitis and other topics, as well as from the % of his writings which are on pediatric subjects. he was particularly interested in tuberculosis of childhood and presented a paper at the third aps meeting in on pulmonary tuberculosis in children, in which he divided it into acute, subacute, and chronic or protracted forms ( , ) , and another in that included autopsy findings ( ) . papers on childhood tuberculosis were presented at virtually all of the aps scientific meetings during the early decades. shulman particularly noteworthy milestones included walter carr's presidential address that reported a % decline in extrapulmonary tuberculosis, the report by the parisian armand-de lille of the diagnostic value of gastric aspirates in infants, the report by bela schick and colleagues on the bcg vaccination introduced three years earlier in france, detroit's joseph johnston's discussion in of the evolution of pediatric tb to the adult type by endogenous reactivation, and the exciting initial report in by john lyttle and colleagues from los angeles of the recovery of a patient with miliary tb after streptomycin treatment ( ) . meningitis, including the invariably fatal tuberculous meningitis, was also a common affliction of children in the late th century. abraham jacobi wrote about meningitis that the u.s. "more than any other country has been invaded by this plague" ( ) . at the meeting of aps, august caillé ( - ) presented a paper on "tapping the vertebral canal in the lumbar region" and the following year a paper on "local treatment for tubercular meningitis" ( ). these were the first reports to the aps of diagnostic lumbar puncture, after it had been introduced by quincke in as a treatment modality ( , ) . two additional papers presented in discussed lumbar puncture in the subarachnoid space, which provided a scientific basis for studying meningitis, with measurement of sugar and protein, and a potential route of administering therapy, such as it was in the late th and early th centuries ( ). summer diarrhea and the milk supply. in addition to the introduction of intubation techniques and diphtheria antitoxin, an exceptionally important advance during the late th century and early th century was the result of efforts by concerned pediatricians and others to secure a safe and sanitary milk supply for infants ( ) . nonbreast-fed infants experienced particularly high mortality rates, because much of the cow milk supply was "swill milk," which came from cows fed only distiller's mash, housed in incredibly filthy conditions, without fresh air, exercise or hay, many of which were also infected by bovine tuberculosis ( , , , ) . job lewis smith, who was one of the first to differentiate rubella from rubeola and wrote several papers on neonatal tetanus, served as the second aps president in , years after he had written in his textbook that more than half of new york's infants who were spoon-fed (i.e. not nursed or wetnursed) in the summer, died before fall ( ) . he strongly urged milk sterilization and wrote and spoke about the dangers of artificial infant feeding. bacteriologic studies of milk began to establish a scientific basis for the association of impure milk with infant diarrheal illnesses, including the work of the pediatrician escherich in , shiga in , and flexner in . the genera escherichia and shigella (as well as the species shigella flexneri) honor these pioneer bacteriologists. william d. booker's major area of interest was summer diarrhea of infancy. he presented a paper at the first aps scientific meeting in on that topic ( ), and he devoted his presidential address in to the early history of summer diarrhea in america from colonial times ( ) . the problem of summer diarrhea and its increasingly clear relationship to contaminated milk in the urban poor was highlighted by the report of infant deaths per week in new york city during the hot weather summer months that were associated particularly with bottle feeding ( ) . considerable attention of organized pediatrics was focused on this issue, particularly by henry l. coit ( - ) , smith, rotch, isaac abt, schick, and others, who advocated movement toward certified safe milk ( , ) . coit began as early as to work tirelessly to ensure a safe milk supply for infants, after the death of his young son, by educating the public, lawmakers, and the medical community ( ) . he coined the term "certified milk" and established the first medical milk commission in new jersey ( ). henry koplik (president of aps in ) established the first american clean milk depot in new york in (called gouttes de lait), and thomas morgan rotch (a founder of aps and president in ) organized the walker-gordon farms that led to the first milk laboratory for preparing safe milk formulas. pasteurization of milk by heating was introduced in europe before (and had been used for wine since !), and it was promoted particularly by jacobi in the u.s. during the s for its ability to prevent milk-borne infections. many other academics preferred certification as an alternative to pasteurization, fearing that the latter would alter the chemical composition of milk and promote gastroenteritis. this proved wrong ( ) . jacobi collaborated with the philanthropist nathan straus to establish pasteurization plants and milk stations for poor infants in new york beginning in . a reduction in infant mortality of % was observed in just one year in the foundling hospital on randall's island after a pasteurization plant was established there by straus ( , ). however, it was not until that chicago became the first city in the world to require pasteurization of milk, with many cities following thereafter ( ) . controversy in this area was apparent early on, best exemplified perhaps by the resignation from the aps in of arthur v. meigs of philadelphia, who argued vehemently against milk sterilization and who continued to reject the germ theory of disease until his death in ( , ) . thomas m. rotch ( - ) was america's first full professor of pediatrics, appointed at harvard in . rotch published a major textbook of pediatrics in as well as early reports of the value of the roentgen ray in pediatrics, in addition to his detailed studies of milk. although extremely focused on the biochemical composition of milk, calculating in minute detail the precise amounts of protein, fat and sugar content of milk for infants, he also recognized the importance of a safe milk supply and worked to achieve that goal. the improved milk supply was complemented by studies, primarily at johns hopkins, by holt, james gamble, w. mckim marriott, john howland, and others, that led to understanding the roles of acidosis and dehydration in contributing to the mortality of infants and children with acute diarrhea. this led directly to effective rehydration and correction of electrolyte imbalances in such children with improved outcomes ( ) . scarlet fever. in the latter decades of the th century, case-fatality rates for scarlet fever were very high, particularly in the youngest children. holt's textbook, the diseases of infancy and childhood, indicated the case-fatality rate to be as high as % in those under one year and % to % in those under three years ( ) . wide year-year fluctuations were some- history of pediatric infectious diseases times observed, with annual death rates during the decade of the 's, for example, from as low as / , to a high of / , population. representative case-fatality rates during the latter years of the th century were . % in new york in , % in - in providence, ri, and . % in philadelphia in ( . % for those - years old) ( ) . in addition to person-person spread of streptococcal infections including scarlet fever, contaminated milk was also shown to produce explosive epidemics of very acute streptococcal pharyngitis with high mortality. this provided an additional reason to support pasteurization of milk ( ) . by the close of the th century, scarlet fever had overtaken diphtheria as a cause of death, occurring with great frequency and often with high case-fatality rates. the pediatric text of louis starr ( - ) described scarlet fever as the most widely disseminated of the childhood exanthems and "the most dreaded of all the diseases of children." ( ) poliomyelitis. poliomyelitis, which was initially described in underwood's first edition in , was brought to general medical attention by jacob von heine (german). von heine was a pioneer of orthopedics who published a classic monograph on infantile paralysis and its resultant deformities in , and he recognized the spinal cord localization of the pathology ( ). the classic french pediatric text of rilliet and barthez ( - ) provided an early account of polio, and guillaume-benjamin-amand duchenne (french) localized the lesion in polio to the anterior horn cells in ( ) . later in the th century, oscar medin (swedish) first noted the epidemic character of polio when he observed an outbreak of cases in stockholm in ( ) . in a larger epidemic of cases occurred in rutland county, vt ( ). from the turn of the century until about , the pediatric community focused particularly upon major public health and welfare issues that adversely affected children, working particularly hard to improve the milk supply. walter l. carr's presidential address to the aps very clearly spelled out the impressive improvements in the health of children that had occurred during the early years of the th century ( ) . infant mortality in greater new york city declined % from / live births in to in . as a consequence of the efforts to improve the milk supply, diarrheal deaths had declined %. mortality from measles, scarlet fever, pertussis, and diphtheria had declined %, while that from acute respiratory disease including pneumonia fell % ( ) . during the period from to , the etiologic agents of more than infectious diseases were identified ( ) . as microbiologic advances were made, american pediatric society meetings continued to include many papers related to epidemic infectious diseases including summer diarrhea, poliomyelitis, typhoid fever, gonococcal infection, and meningococcal meningitis. increasingly large u.s. poliomyelitis epidemics occurred, primarily affecting children, for example in new york city in , with almost cases and up to % mortality ( ) . this peaked in a epidemic in the northeast with almost , cases and , deaths, many in the new york city area, leading to massive public anxiety and aggres-sive public health measures including quarantine and travel restrictions ( ) . progress in understanding the etiology and pathogenesis of polio was made early in the th century. in vienna in landsteiner and popper transmitted polio to monkeys by intraperitoneal injection of spinal cord material from a child who died early in the course of polio. also in simon flexner (of shigella flexneri fame) and paul lewis in new york extended those studies to show transmission to monkeys also after s.c., i.v., or intracerebral routes of inoculation and produced disease using filtrates of nasopharyngeal washes from polio patients ( ) . additional flexner studies from - showed that sera from monkeys that recovered neutralized the infectivity of polio material, that intrathecal injection of convalescent sera within h of inoculation prevented paralysis, that recovered monkeys were protected against subsequent inoculation, and that recovered human patient sera contained antibodies to the infectious agent ( ) . great effort was devoted by several groups to use intrathecal administration of convalescent polio sera to treat children with acute poliomyelitis but this proved unhelpful ( ) . the development of the iron lung by philip drinker in the late s was a noteworthy therapeutic advance for affected patients. during the period from to , the application of serum therapy to the management of diphtheria, meningococcal and streptococcal infections served as topics for many aps presentations ( ). jacobi's second aps presidential address, in , was entitled "the tonsil as a portal for microbic and toxic invasion," while that of j. l. morse in reviewed the high mortality of pertussis, especially in infants, and proposed stringent isolation ( ) . specific therapy for congenital syphilis with salvarsan, introduced by ehrlich two years earlier, was reported by lafétra in , with dramatic benefit ( ) . in his aps presidential address in , l. emmett holt summarized the dramatic improvement in mortality in those less than five years old from infectious diseases in manhattan and the bronx from - to - , with approximately an % decline in diarrheal deaths, diphtheria and croup, and % for pneumonia ( ) . over the next decades (~ - ), academic pediatricians and their research were focused particularly upon nutrition and the biochemistry of health and disease, which during this time somewhat eclipsed infectious disease concerns ( ) . nevertheless, syphilis, tuberculosis, pertussis, measles, rheumatic fever, streptococcal infections, polio, and meningitis continued to interest those caring for children, as reflected by papers presented at the annual aps meetings. active immunization against diphtheria using toxin and antitoxin was introduced by alfred hess in the u.s. in ( ) . at the end of this era, a particularly interesting paper was presented in by francis schwentker, who reported the treatment of meningococcal meningitis with s.c. and intrathecal para-aminobenzenesulfonamide (sulfanilamide) ( ) . the first use of an antimicrobial agent in the u.s. was by future aps president a. ashley weech, whose unsuccessful treatment of a physician's child with h. influenzae meningitis with the sulfanilamidecontaining compound sulfachrysoidine in has been well documented ( , ) . the actual administration of this agent was by the chief resident at babies hospital in new york, f. shulman howell wright, who later served as chair of pediatrics at the university of chicago and president and executive secretary of the american board of pediatrics ( ) . during this era, several aps presidential addresses concerned infectious disease issues, including that by linnaeus lafétra in regarding the need for preventive measures against infectious diseases and rheumatic fever in children two to six years old; by thomas s. southworth in on the communicability of acute pneumonia and the need for isolation of such patients, as was done for tuberculosis patients; by l. emmett holt in highlighting the decline in infectious diseases, particularly diarrhea, diphtheria and acute respiratory disease (as discussed above); and by henry f. helmholtz in on infections of the renal parenchyma and the importance of stasis in predisposing to urinary tract infection ( , ) . during this period the first pediatric department with several identified subspecialists was developed by edwards a. park at johns hopkins beginning in . under the previous leadership of john howland from - , there had not been any special clinics or pediatric subdepartments at hopkins, with the exception of a clinic for the treatment of congenital syphilis. curiously it was lawson wilkins, later known as the father of pediatric endocrinology, who initiated and organized the congenital syphilis clinic as an intern ( ) . as a discipline, infectious diseases did not figure as prominently as cardiology, endocrinology, neurology and other nascent subspecialty areas under park's leadership. this theme was replicated in most other academic departments as subspecialization began to develop. a few exceptions were pediatricians known for their expertise in contagious diseases, some of whom were particularly interested in vaccine development. these included bela schick at mt. sinai and at albert einstein in new york, hattie alexander and horace hodes at columbia university, joseph stokes at university of pennsylvania, russell blattner at baylor, william bradford at rochester, amos christie at vanderbilt, katherine dodd at vanderbilt and cincinnati, edith lincoln at new york university, louis sauer at evanston, il, and john zahorsky in st. louis. by , when the american pediatric society was a halfcentury old, life expectancy had increased to over years, infant mortality had declined to about / and neonatal mortality to about / ( ) . sewage and sanitation had improved greatly, which along with much safer milk supplies had led to a marked fall in diarrheal illnesses of infancy. a few vaccines had been introduced, but antibiotic therapy was limited to the early use of sulfanilamide. at the th annual meeting of aps in , the first held in conjunction with the young society for pediatric research (spr), important papers presented included that of trask and paul, reporting the isolation of poliovirus from nasal washes and stools of asymptomatic patients, several related to the pathogenesis of pertussis, that of lyttle showing elevated aso titers in acute glomerulonephritis, hodes' report of an irradiated rabies vaccine, and stokes' isolation of various strains of influenza virus. these works served as the prelude to the much more dramatic advances to come, related to the pathogenesis, diagnosis, and treatment of viral and bacterial infections of children ( ). between and , three new pediatric organizations emerged: the american academy of pediatrics in , the society for pediatric research in , and the american board of pediatrics in . the eastern society for pediatric research, organized in , became a national organization (also including mexico and canada) called the society for pediatric research (spr) in , with the goals to foster research in pediatrics and to serve the younger pediatric faculty (Ͻ years old), as the aps meetings were quite closed to junior investigators. the first meeting of the spr was held in may, , and since the aps and spr have held joint meetings, with greater prominence of infectious diseases as a separate subspecialty in more recent years. presidents of spr who have been associated with a particular interest in infectious diseases are shown in table . the american academy of pediatrics (aap) was founded in to promote the welfare of children. this occurred after the american medical association house of delegates severely chastised the pediatric section of the ama for taking pro-active stances favoring the sheppard-towner act, which supported maternal and child health. isaac abt of chicago became the first president of the aap, which had charter members and held its first meeting in atlantic city, nj, on june - , ( ) . early in its existence, the aap declared its interest and involvement in infectious diseases issues. the aap established a special committee on prophylactic procedures against communicable diseases in , chaired by edward b. shaw of san francisco and including j.e. gordon of detroit and j.a. toomey of cleveland. this committee was disbanded after its report "routine measures for the prophylaxis of communicable diseases" was published in the journal of pediatrics in april ( ) . this six-page report dealt with diphtheria, scarlet fever, typhoid fever, whooping cough, measles, smallpox, polio ( lines), epidemic meningitis ( line), mumps and chickenpox ( lines), rabies, and tetanus. the committee on immunization procedures was then established in , with john a. toomey as chair. three years later the committee name was changed again to the committee on immunizations and therapeutic procedures for acute infectious diseases, in it was modified again to the committee on control of infectious diseases, and then in to the committee on infectious diseases, the current name, although it is now most commonly referred to as the red book committee. since , this aap committee has published a report every one to five years (every three years for the past five editions), which because of the color of its binding has been known as the red book for many editions. after world war ii came the postwar boom, noteworthy for the expanded availability of federal research funds (especially from the national institutes of health), increasingly sophisticated research and technology, the development of vaccines against polio and measles, and the discovery of ever-moreactive antibiotics and other anti-infectives, with the initial emergence of antibiotic resistance, e.g. penicillin-resistant s. aureus. the period from to about heralded the era of modern infectious diseases and coincided with the increasing trend to subspecialization within pediatrics and the development of full-time pediatric departments. antimicrobial advances included the discoveries of streptomycin, isoniazid and then other agents to treat tuberculosis, as well as penicillin, chloramphenicol, streptomycin and other antibiotics for treatment of bacterial infections. virtually universally fatal infections such as bacterial meningitis and endocarditis became amenable to therapy. american pediatric society presidential addresses during this period that dealt with infectious diseases topics included that by jean v. cooke in discussing the impact of specific therapy including antimicrobials upon the common contagious diseases and reviewing mortality statistics ( ). this era was associated with the virtual elimination of congenital syphilis, early studies of bacterial resistance to antibiotics, improved methods of viral cultivation, but also large poliomyelitis epidemics. the control of acute rheumatic fever and rheumatic heart disease was a consequence of the studies of floyd denny, lewis wanamaker, and others that proved that recurrent attacks could be prevented by antibiotic prophylaxis. edith in the period from to about has been termed the era of specialization and fragmentation of pediatrics by howard pearson ( ) . at the onset of this era, the program of the society for pediatric research listed no infectious diseases subspecialty session per se but rather one session devoted to "microbiology/immunology" that included a handful of papers (out of the in total that were presented) on topics that can be considered infectious diseases issues. several aps presidents during this era were closely linked to the emerging field of pediatric infectious diseases. (see table ). warren wheeler in in his presidential address dis- shulman cussed the epidemics of enteropathogenic e. coli in the s and s and those of s. aureus / in the s, recommending surveillance to detect emergent bacterial "hot strains" ( ) . saul krugman, aps president in , devoted his distinguished career to the field of infectious diseases, especially to the study of hepatitis viruses. fred robbins ( ) and horace hodes ( ) were each responsible for signal discoveries in virology, the former having received the nobel prize in with john enders and tom weller for the development of tissue culture technology that led to viral vaccine production, and the latter devoting his life to investigations of viral gastroenteritis of infants and vaccine development ( ) . margaret h. d. smith ( ) worked tirelessly in the field of pediatric tuberculosis and advocated for social activism by organized pediatrics. c. henry kempe ( ) was instrumental in the eradication of smallpox, and floyd denny ( ) contributed to the understanding of group a streptococci and to the conquest of rheumatic fever. during this era, infections in the immunocompromised child began to emerge as an important clinical problem, as increasing numbers of cancer patients and other compromised patient populations were generated by improved treatment modalities ( ) , and these were accompanied by increasing numbers of opportunistic viral, fungal and bacterial infections requiring expert management. it was during this time that many subspecialty organizations within pediatrics were born, including the pediatric infectious diseases club. formal organizations within the field of pediatric infectious diseases emerged gradually as the subspecialty became more clearly defined and differentiated from the rest of pediatrics during the s and s. in - plotkin of philadelphia led the establishment of the pediatric infectious diseases club, which held its first election of officers in - . this club evolved into the pediatric infectious diseases society (pids) in , and it has grown into a very active organization to which the vast majority of those in the field belong. the modern era, from about to the present, is the period of modern molecular biology and genomics, with advances based upon new diagnostic modalities such as dna hybridization and sequencing, cloning, pcr, magnetic resonance imaging, pet scanning and many others. laboratory techniques for research related to pediatric illnesses have used these and other increasingly sophisticated molecular methods. the elucidation of the first bacterial genome, that of hemophilus influenzae, in heralded vast new opportunities to understand the pathogenesis of infectious diseases ( ) . although many classic pediatric infectious disease disorders have virtually disappeared, new (or apparently new) clinical challenges such as opportunistic infections in the ever-increasing populations of immunocompromised patients, lyme disease, kawasaki disease, sars and hiv/aids have emerged. the onset of the aids epidemic in the early s and the identification of hiv as its causative agent had a substantial impact upon the specialty of pediatric infectious diseases. identifying perinatal vertical transmission risk factors, dealing with transfusion-associated hiv infection (particularly in the hemophiliac population), and determining the clinical, virologic and immunologic parameters of pediatric aids occupied the first decade or so of the pediatric aids experience. the landmark report of the pediatric aids clinical trials group protocol that demonstrated the marked effectiveness of zidovudine administered to pregnant women to prevent vertical transmission of hiv led to dramatic reduction in the number of perinatally infected children within several years in developed countries. in other areas of the world, where antiretroviral therapy during pregnancy is not being utilized, vertical transmission of hiv continues unabated. in recent years, in the u.s., the field of pediatric aids has focused increas- ingly upon prevention and treatment of adolescent hiv infection as well as upon the highly effective multi-drug therapies. table provides a listing of presidents of aps with major interests in infectious diseases issues. recent aps presidents have included sam katz ( ), whose career has been devoted to vaccine development and implementation; paul quie ( ), a bacterial phagocytosis scholar; vince fulginiti ( ) , who advanced the fields of prenatal infections and viral vaccinology; and ralph feigin ( ), an authority on meningitis and many other aspects of pediatric infectious diseases. the american board of pediatrics (abp), which was founded in , first certified general pediatricians in . it then provided its first subspecialty certification in (cardiology). in may the abp approved a proposal from the pediatric infectious diseases society to certify individuals in pediatric infectious diseases, and the abp then applied to the american board of medical specialties (abms). abms approved this application on march , , and the abp established the sub-board of pediatric infectious diseases in ( ) . the initial certifying examination in pediatric infectious diseases was offered on november , with candidates taking the examination and passing ( ) . by , after program applications were submitted and reviewed, a number of training programs for pediatric infectious diseases fellows were accredited by the accreditation council for graduate medical education (acgme). several publications have been developed within the field of pediatric infectious diseases, sponsored by various organizations. the aap's report of the committee on infectious diseases (the red book) is mentioned above. the pediatric infectious diseases society organized the establishment of the report on pediatric infectious diseases, published by churchill-livingstone ten times yearly, beginning in january . in the report was changed to concise reviews of pediatric infectious diseases and was incorporated within the monthly pediatric infectious diseases journal. the latter journal had been the discipline of pediatric infectious diseases has a great many remaining challenges. these include the conquest of illnesses that affect children in the developing world, most notably hiv infection, tuberculosis and falciparum malaria, but also a wide array of other infections. opportunistic infectious diseases that affect immunocompromised children will also continue to demand attention, and this host population will likely increase. medicine has entered the genomic era, and the quantity of genomic data available, both microbial and mammalian, is increasing at a phenomenal pace. this has had, and will continue to have, profound implications for the study and practice of pediatric infectious diseases. since the elucidation of the h. influenzae genome with . million base pairs in ( ) , almost bacterial genomes have become available, including that of group a streptococcus ( ) and other important human pathogens. the group a streptococcal genome work was led by joseph ferretti, who trained at the university of minnesota with elia ayoub and lewis wannamaker. additionally, the human genome project published drafts of the dna sequence of homo sapiens in ( , ) . these developments unlock the potential for significant advances with impact on all aspects of the field of pediatric infectious diseases. pathogenesis of infections, new insights into the host-parasite relationship, mechanisms of host susceptibility and resistance, resistance to current and development of new anti-infective therapies, new vaccines, and the identification of new drug targets are some of the areas that will be impacted directly. utilization of dna microarray analysis as well as new methodologies of proteonomics will facilitate new insights into the characterization of gene expression during health as well as in disease states, with identification of new antimicrobial targets and identification of infectious disease risk factors for individuals. additionally, the field of pediatric infectious diseases will be impacted for the foreseeable future by issues related to the threat of bioterrorism and the public health response to this threat. this includes the renewal of smallpox immunization in the u.s. as well as focus upon prevention and treatment of anthrax and other potential bioterrorism threats. the unex-pected appearance of new infectious diseases (e.g. severe acute respiratory syndrome -sars) highlights the potential for previously unknown agents to emerge as major threats, and the discipline must learn whether they can cause congenital infection, transfusion-associated infection, and if they particularly target vulnerable populations such as children. pediatric infectious disease physicians can rightfully celebrate the past triumphs of their discipline and should anticipate future outstanding achievements, all of which contribute directly and indirectly to improved health for children. post-script. this history of the development of the field of pediatric infectious diseases in the united states has been written so that it does not overlap the contribution of baker and katz entitled "childhood vaccine development in the united states" ( ) . therefore, it includes little if any information related to the highly successful development and implementation of vaccines for children that have been so instrumental in improving the health of children. rather, this history is focused upon infectious diseases of children per se and upon the development of the subspecialty. viral infections and vaccines hodes-viral vaccines viral infections robbins-viral vaccines rheumatic fever/streptococci steve kohl-herpes viruses hostetter-candidal infections fleisher-bacterial infections job lewis smith-diarrheal illnesses william osler-tuberculosis, etc walter carr-epidemic diseases other infections freeman-infectious diseases churchill-bacterial infections linnaeus lafétra-infection prevention viral infections bacterial infections fred robbins-viral vaccines horace hodes-viral vaccines kempe-smallpox eradication james cherry recipients for the distinguished service award the history of paediatrics nurturing children, a history of pediatrics abt-garrison history of pediatrics thacher t a brief rule to guide the common-people of new england how to order themselves and theirs in the small pocks or measles enquiry into the nature, cause and cure of the angina suffocativa or sore throat distemper an account of the weather and diseases of south carolina rush b an inquiry into the cause and cure of cholera infantum history of pediatrics in the united states pox americana: the great smallpox epidemic of - acute communicable diseases. in: wr bett (ed) the history and conquest of common diseases dewees wp a treatise on the physical and medical treatment of children on the pneumonia of children parrot's pseudoparalysis semi-centennial volume of the american pediatric society osler and children the centennial history of the american pediatric society infectious diseases and the last years in the american pediatric society diphtheria and theories of infectious disease: centennial appreciation of the critical role of diphtheria in the history of medicine the american pediatric society's report of the collective investigation of the antitoxin treatment of laryngeal diphtheria in private practice the first full-time academic department of pediatrics: the story of the harriet lane home the history of cerebro-spinal meningitis in america smith jl a treatise on the diseases of infancy and childhood baker sj fighting for life save the babies: american public health reform and the prevention of infant mortality the diseases of infancy and childhood an american text-book of the diseases of children by american teachers kretchmer n (eds) history of pediatrics - a retrospect and a forecast a historical note on chemotherapy of bacterial infections the first use of an antibiotic in america report of special committee on prophylactic procedures against communicable diseases routine measures for the prophylaxis of communicable diseases history of pediatric hematology oncology whole-genome random sequencing and assembly of haemophilus influenzae rd the first certifying examination in pediatric infectious diseases complete genome sequence of an m strain of streptococcus pyogenes the sequence of the human genome international human genome sequencing consortium initial sequencing and analysis of the human genome childhood vaccine development in the united states ( ) for rapid viral diagnostic methods, ann arvin ( ) for pathogenetic and immunologic studies of herpes viruses, margaret hostetter ( ) for studies of the pathogenesis of candidiasis, and elaine tuomanen table . the first committee on rheumatic fever of the american heart association was organized in , with t. duckett jones (famous for his jones criteria proposed in ) serving as the first chair. over the subsequent years, this committee has expanded its scope to include infective endocarditis and kawasaki disease, and its membership has been weighted heavily to include pediatric infectious diseases experts as well as cardiologists. in contrast to many other organizations, world war ii actually accelerated the activities of this group because of the severity of rheumatic fever and rheumatic heart disease nobel laureates. four members of the american pediatric society (including one honorary member) have been awarded the nobel prize in physiology and medicine, and all of them were recognized for research related to infectious diseases and their prevention. in , thomas weller, frederick robbins, and john enders received the nobel "for their discovery of the ability of poliomyelitis viruses to grow in cultures of various types of tissues." enders, a basic virologist, was elected to honorary aps membership in , and weller and robbins are full members. additionally, d. carleton gajdusek received the nobel "for discoveries concerning new mechanisms for the origin and dissemination of infectious diseases," specifically for the study of kuru and slow virus infections.howland award. the john howland award of the american pediatric society "for distinguished service to pediatrics" was initiated in , and a number of howland awardees have been honored particularly for contributions to the conquest of infectious diseases of childhood. these key: cord- -bie veti authors: nan title: ecc- abstracts date: - - journal: int j antimicrob agents doi: . /s - ( ) -x sha: doc_id: cord_uid: bie veti nan f spain introduction: the prevalence of erythromycin resistance (er-r) in group a streptococci (gas) has increased in spain since early s with current rates exceeding % in some regions. this study determined the emm -types associated to erythromycin resistance in spain. material and methods: isolates belonged to the sauce* surveillance collection. rapid sequence analysis of specific pcr products was used to deduce emm -types corresponding to the majority of the known gas m serotypes. pcr primers used: gasm ( ?-tattgcgct-tagaaaattaa- ?) and gasm ( ?-gcaagttctt-cagcttgttt- ?). sequencing was done with the big dye terminator mix and autosequenator (applied biosystems). dna sequences were subjected to homology searches against the bacterial dna database. results: overall, gas isolates ( er-r) were analysed. three m-types (m , st and m ) accounted for . % of the er-r isolates, whereas they just represented a . % of the ery-s. for er-r isolates the strongest association was seen with m (or / ; % ci . Á/ . ), and m was second after m only in the last temporal period of the study ( Á/ ) . no homogeneous distribution of er-r m-types by centres was seen. conclusions: few m-types (leading by m ) are responsible for the er-r in spain. but for m , the remaining er-r m types (st , m and m ) did not show a temporally nor geographically homogeneous distribution. *sauce is an acronym standing for 'sensibilidad a los antimicrobianos utilizados en la comunidad en espana' (susceptibility to the antimicrobials commonly used in the community in spain ) and is the spanish word for the willow tree. significant increase in the prevalence of erythromycin-resistant, clindamycin and miocamycin-susceptible (m-phenotype) streptococcus pyogenes in spain ( ( Á/ purpose: a variety of methods is used for a molecular typing of enterococcus spp. and related gram-positive bacteria. these include dna-based methods such as macrorestriction analysis using pulsedfield gel electrophoresis (pfge), ribotyping, and amplification-based methods such as rapid amplification of polymorphic dna (rapd) and amplified fragment length polymorphism (aflp). we used a homogeneous strain collection of transconjugants resulting from filter-matings with different antibiotic-resistant e. faecium and a recipient isolate from our lab. the influence of transferred antibiotic-resistance determinants on the outcome of different typing methods was investigated. results: fragment patterns resulting from pfge indicated minor differences between the transconjugants and the recipient. in respect to different primers used for rapd, none or only a single fragment shift was detected in the resulting fragment patterns. aflp clusters all transconjugants into a group of major relatedness, but the result was strongly dependent on the mathematical method used for cluster analysis. fragment patterns of digested plasmids showed the possession of different or only widely related plasmids in the transconjugants. conclusions: the results of this study clearly show that under certain situations typing methods commonly used for enterococci and related gram-positive bacteria come to their limits. the sasss network aims to set up a national surveillance study to obtain standardized information on antimicrobial susceptibility to various bacterial pathogens. currently, hospitals are participating in the project from different geographical regions in saudi arabia. during the st year ( ), the sasss focused on setting up this network. overall, high frequencies of resistance to antibiotics to different bacterial pathogens in saudi arabia were seen. geographical variations of resistance were noticed, which could be related to different prescribing practices. approximately, and % of escherichia coli and k. pneumoniae , respectively, were extended spectrum â-lactamases (ebls) producers. resistance of enterobacteriacae group to carbapenem and pipracillin/tazobactam is low. resistance of pseudomonas aeurginosa to various anti-pseudomonal antibiotics including carbapenem is high and alarming. methicillin resistant staphylococcus aureus (mrsa) comprised % of s. aureus isolates. no vancomycin intermediate s. aureus (visa) was detected. high level resistance to gentamicin in enterococcus were seen in % of the isolates and only % of enterococcus facieum were glycopeptide resistant. resistance of streptococcus pneumoniae to penicillin ranged between % to almost %. surveillance of antibiotic resistance on a national level is necessarily to give guidance to practicing physicians on the best agents to use. the world-wide problem of betalactam resistance (r) in streptococcus pneumoniae (sp) has been complicated by increasing r to macrolides and some older fluoroquinolones (fq) (ciprofloxacin cip). aim of our study was to evaluate rate of acquisition of resistance to different fq: cip, sparfloxacin (spx) and levofloxacin (lev) of sp strains with different levels of susceptibility to penicillin (p). fifteen strains were serially and daily passaged in subinhibitory concentrations of these four antibiotics by a gradient plate method until acquisition of resistance. clinical strains isolated from children in day-care centers were used. five strains were susceptible (s) to penicillin (p) (one reference strain, four clinical isolates: p micsb/ . mg/l): five were intermediate (i) to p (one reference strain: p mic . mg/l, four clinical strains p mics: . Á/ mg/l), five were resistant (r) to p (p mics . mg/l). mean of number of passages (n ) necessary to reach i or r level with each fq as selecting agent are in the following table: spx and lev induced resistance but more slowly than cip. our results show that rate of acquisition of resistance to fq is strongly related to alteration of susceptibility to p, probably by modification of cell wall. these results are concordant with clinical results. clinical relevance of phase variation in pneumococcal opacity: nasopharyngeal (np) colonization in children from day care centers (dcc) soa . carsenti h, mancini g, bensoussan m, dunais b, pradier ch, dellamonica p. archet hospital, infectious disease, nice, france streptococcus pneumoniae (sp) adherence to nasopharyngeal (np) epithelium is a prerequisite for induction of otitis transparent sp (t) have been shown to colonize the np of infant rats better than opaque (o) sp. opaque sp has proven more virulent than the t form during systemic infection in a mouse model. aim of this study was to evaluate phase variation in the nasopharynx of children. sp strains were isolated during a winter epidemiology study of np samples in children from family dcc. mics determinations were performed by e -test for penicillin (p), amoxicilline (amx) and ceftriaxone (cro). serotypes were performed using the quellung reaction. upon oil immersion microscopic examination short chains of six to eight cocci were noted as , '/, '/'/, '/'/'/ for absence, , , !/ chains by field, respectively. phase variation was detected on catalase trypticase soja plates, amx and cro mics and bactericidal activity was determined for pairs of o and t variants with different serotypes and susceptibility to penicillin. seventy strains of sp were screened for phase variation. nine out of with chain length , '/ had o variants while out of strains with chain length '/'/ or '/'/'/ showed o variants. proportion of o variants was predominant when chain length increased. serotype f was prevalent. bactericidal activity of o variants showed a four-to eightfold increase of mbc. o variants may be present in np of children while t are predominant form for colonization. these virulent variants with lower level of autolysis showed less susceptibility to killing by antibiotics. they may persist in np and explain the absence of eradication by active molecules. antimicrobial resistance among clinical strains of s. pneumoniae isolated from patients with community-acquired respiratory tract infections (carti) in russia soa . kozlov rs a , bogdanovitch tm a , sivaya ov a , agapova ed b , ahmetova li b , furletova b , gudkova lv b , gugutsidge b , ilyina vn b , marusina b , multich ig b , ortenberg ea b , schetinin ev b , shturmina purpose: to determine the antimicrobial resistance of pneumococci causing carti in different russian cities. methods: a total of non-duplicate strains isolated in russian cities in were studied. antimicrobials tested included penicillin (pen), amoxicillin (amo), erythromycin (ery), azithromycin (azi), clarithromycin (cla), midecamycin (mid), spiramycin (spi), clindamycin (cli), levofloxacin (lev), vancomycin (van), rifampicin (rif), tetracycline (tet) and co-trimoxazole (sxt). susceptibility testing was performed by broth microdilution with interpretation of the results according to nccls guidelines ( ) a map of bacterial resistance in a hungarian region soa . farkas a a , juhasz a b , orosi p a , miszti c c , balogh m d . a kenezy teaching hospital, hygienie, debrecen, hungary , b kenezy teaching hospital, laboratory, debrecen, hungary , c university of debrecen, microbiology lab, debrecen, hungary , d regional hospital berettyóújfalu, laboratory, debrecen, hungary background: regional trends of microbiological resistance pattern constitute basic data and qualifying criteria for effective infection control. purpose: the aim of our study was to establish an internationally compatible regional database in a hungarian county hajdú -bihar. methods: our model is the national nosocomial infections society publications' format from the u.s. published in . it contains data regarding various icu types, ambulatory patients and hospitalised patients. the same format is used for antibiotic utilisation data and device related infections' rates as well. we collected cleaned data of years Á/ from all the microbiological laboratories of our county. results: ciprofloxacin p e. coli . . . Á/above susceptibilities not significantly different from u.s. data were as follows: mr cns, streptococcus pneumoniae /penicillin and rd generation cephalosporin, pseudomonas aeruginosa /piperacillin and enterobacter spp. and escherichia coli /ceftriaxon. conclusions: this database proved to be a very useful tool for choosing primary wards of active surveillance including places for infectious disease physician's visit (icu, rehabilitation unit). additional analysis is needed at an individual institution's level for other heavily used (or useable) antibiotics and bacteria as well (aminoglycosides, beta-lactam Á/beta lactamase inhibitor combinations, nd generation cephalosporins, corynebacteria . to compare epidemiological, clinical, and immunological features of add before and after haart introduction, between the patients (p) diagnosed in Á/ , and the p detected since , in a case-control study. though the mean number of newly diagnosed aids p had a sharp drop in the haart era, from p/year in Á/ to p/year since (p b/ . ), the distribution of add and underlying immunodeficiency showed limited changes. when excluding a greater frequency of tuberculosis (tb) (p b/ . ) and wasting syndrome (p b/ . ), all other add did not show a different frequency before and after . a tendency towards a higher mean cd count at aids disease was noticed: vs cells/ml (p b/ . ), with a significant difference for candida esophagitis , toxoplasmosis, kaposi sarcoma and tb (p b/ . Á/b/ . ). the limited variation of clinical and immunological presentation are attributable to the poor impact of haart before aids recognition: . % of p detected since did not receive haart or had insufficient compliance to antiretrovirals, so that . % of p were aids presenters. during the haart era, an increase of mean age and sexual transmission was found (p b/ . ). notwithstanding the effects of haart on the natural history of hiv disease, the consequences on add distribution and related immunodeficiency were negligible, since most p could not benefit from haart before aids onset. a high clinical suspicion for add should be maintained when facing p with missed or undertreated hiv disease. radata */communication internet platform management of resistance analysis guided haart switch for implementation in clinical practice of hiv-infected individuals soa . paech v, lorenzen t, stoehr a, plettenberg a. ifi, interdisciplinary infectiology and immunology, hamburg, germany purpose: hiv-resistance analyses are indicated to prepare switch of haart in hiv-infected individuals with failure to ongoing haart regimen. specialists at several responsible sites often feel lack of complementary informations if interpretation of resistance analyses is done independent from each other. clinical benefits from resistance analysis assays are sigfnificantly higher for those physicians, who can access external advice from hiv-experts for possible treatment options. the database concept 'radata' (www.radata.de) was developed in germany to generate expert advice for implementation in haart switch. results: fifteen hiv-treatment centres, seven laboratories and high ranked authorities in hiv-medicine contribute to radata database since it is started in january in germany. hiv-infected subjects are eligible to participate at the project after presentation of failure to haart (viral load !/ c/ml). expert advice is generated after all data are evaluated and based on recommendations of Á/ external hiv-experts. observation after therapy switch is scheduled for a period of months. conclusions: radata is a novel database concept with features for evaluation of data and availability of complementary information to participating sites. the project is designed to provide its proficiency to patients and centres from germany and foreign countries. further information will be provided after the number enclosed subjects have enlarged. in vitro effects of hiv infection on abc transporter expression and antiretroviral drug efficacy soa . therefore, we evaluate in primary cultures of human monocytederived macrophages (mdm) and lymphocytes, effects: ( ) of retroviral infection and haart on the expression and activity of p-gp and mrp; and ( ) of specific inhibitors of these host proteins on antiretroviral activities of nrti, non-nrti and ip. results: on the one hand, we evidenced a transitory increase of p-gp mrna expression in lymphocytes and mdm in response to in vitro hiv infection. this was correlated to an increased p-gp cell surface expression and activity, and an increased tnf-alpha production and mrna. in contrast, no significant modulation of mrp was observed. on the other hand, psc and probenecid potentiated in vitro the anti-hiv activity of azt and indinavir. these effects were accentuated when psc and probenecid were combined. conclusion: these results showed that: ( ) hiv infection by increasing abc transporter expression could favorise the efflux of antiretroviral drugs and decrease their pharmacological effects; and ( ) specific inhibitors of these transporters could reverse these deleterious effects. effects of interferon alpha plus ribavirine therapy on frequencies of hcv, hiv and cmv specific cd -t-cell responses in peripheral blood of hiv/hcv coinfected patients after months of treatment soa . methods: two groups of patients with chronic hcv infection were studied: hiv coinfected progressors with antiretroviral therapy and hiv-negative controls. twelve hcv/hiv and hcv patients have already reached months of ifn-alpha'/ribavirine therapy. virusspecific cd -t-cells in peripheral blood were analyzed by ifngamma-elispot-assays using hiv-p , one cmv and three hcv (core, ns , ns ) antigens. results: ( ) at baseline, hcv-specific cd -th -cells frequencies were significantly lower than hiv-and cmv-specific ones; ( ) frequencies of cd -th -cells against hcv as well as against cmv were similar in the two groups; ( ) in hcv'//hiv'/, hcv specific cd -t-cell frequencies did not change between baseline and th month of anti-hcv treatment, decreased in three and increased in only one case. hiv-and cmv-specific frequencies were decreased in seven patients. similar results were observed in hiv-negative group. conclusion: ( ) hcv-specific immune responses might be more prone to tissue compartmentalization than hiv-specific ones; ( ) immune defects induced by hiv infection might not be responsible for the low level of hcv-specific responses observed in hiv-progressors; ( ) ifn-alpha'/ribavirine therapy influence on hcv-and hivspecific cd -t-cell frequencies after months of treatment will be discussed. frequencies of hiv- -p specific th cells (elispot) are correlated with plasma hiv- viral load in a cohort of lt-np and slow progressors soa . martinez v a , alatrakchi n a , costagliola d b , bonduelle o a , agut h c , autran b a , alt study group a . a hopital pitié-salpêtrière, laboratoire d'immunologie cellulaire, paris, france , b faculté de medecine saint-antoine, inserm sc , paris, france , c hopital pitié-salpêtrière, laboratoire de virologie, paris, france background: hiv- -specific t helper- cell responses have been associated with long-term-non-progression (lt-np) in hiv infection but the correlation between frequencies of hiv- -p -specific th cells and viral load has not yet been studied. we prospectively quantified these frequencies by using an ifn-gamma elispot assay in a cohort of lt-np. methods: a cohort of lt-np and slow progressors (infection !/ years and cd counts !/ /mm ) was analysable. hiv- -p specific t cells were analyzed using: proliferation, ifn-gamma eli-spot assays and ifn-gamma production in cell supernatants. results: wide ranges were observed in the frequencies of hiv- -p -specific cd th cells as assessed by elispot ( - sfc/ pbmc) with a median of sfc/ pbmc. these frequencies were negatively correlated with viral load (r /(/ . , p / . ) but not with cd counts and associated with a low level of t cell activation assessed by cd on cd cells (r /(/ . , p / . ). similar results were obtained with t cell proliferation and ifn-gamma production. conclusion: interestingly, the numbers of hiv- -p -specific th cells correlate with plasma viral load, independently of cd counts indicating that: ( ) the defect in hiv- -specific cd th cells does not reflect the global cd depletion; and ( ) these responses are strongly correlated to the control of virus replication. impact of drug Á/drug interactions on therapeutical management of active tuberculosis in hiv infected patients soa . martinez v a , truffot c b , caumes e c , katlama c c , jarlier v b , bricaire f c , jouan m d . a department of infectious and tropical diseases, pitié salpêtrière hospital, institut pasteur, unité de génétique mycobactérienne, paris, france , b department of bacteriology, pitié salpêtrière hospital, paris, france , c department of infectious and tropical diseases, pitié salpêtrière hospital, paris, france , d institut pasteur, unité de génétique mycobactérienne, paris, france since and the use of haart, management of hiv patients with active tuberculosis raised the question of drug Á/drug interactions and therapeutical management of both infections. retrospective cohort study: follow-up of hiv patients with active tuberculosis diagnosed between and . studied data included evolution of tuberculosis and hiv, cd cell counts, plasma hiv viral loads, antituberculosis and antiretroviral regimens. ninety-four percent of patients were treated by quadruple combination antituberculosis drug with rifabutin for five patients. fourteen patients were treated by double antiretroviral therapy of nucleoside reverse transcriptase inhibitors (nrtis) and by triple or more drugs (nrtis and/or nonnucleoside reverse transcriptase inhibitors nnrtis and/or protease inhibitors pis). the median follow-up was months. there was no difference on cd cell counts and viral loads in the two groups and between the patients treated by nnrtis and pis at the diagnosis of tuberculosis, at the time of antituberculosis drug discontinuation and concerning cure rates of tuberculosis. on the other hand, the plasma hiv viral load was significantly better controlled in patients with nnrtis than with pis (p b/ . ). in hiv patients with active tuberculosis receiving haart, antiretroviral combination including nnrtis allows a better control of viral replication than regimen including pis without impact of the use of rifampin or rifabutin. adherence is essential to the effectiveness of antiretroviral therapy. a pharmacy visit would improve the patient advisement. a survey was carried out over a period of months in the u.m.i.t. a self-report was distributed to patients. ninety were evaluated. for %, information's given by the clinician were sufficient and for % the treatment advice cards were useful. however, % of them would like to attend a pharmacy visit. the topics they would prefer to be tackled were drug interactions ( %), side effects ( %) and effect of forgetting ( %). the treatment was well accepted and tolerated for, respectively and % of the patients. the viral load and the cd count were well known by, respectively and %. however, inaccurate pattern of treatment was frequent ( !/ %) and bad adherence was observed: treatment forgotten occasionally ( %), regularly ( %) or inadequate attitude when the treatment was forgotten ( %). number of pills, dose frequency, length of the treatment would be risk factors of nonadherence. for the majority of patients, a pharmacy visit is necessary and beneficial. the first result shows a better understanding of the treatment, an improvement of the adherence and an enhancement of plasma concentration of antiretroviral drugs. in vivo activity of glycopeptides against s. aureus infection in a rabbit endocarditis model: is mic predictive for in vivo efficacy? soa . asseray n, caillon j, lemabecque v, jacqueline c, batard e, potel g, bugnon d. laboratoire antibiologie, faculte de medecine, nantes, france we have studied the in vivo efficacy of vancomycin (v) and teicoplanin (t) against five staphylococcus aureus (sa) strains: two methicillin-susceptible (mssa and ), two methicillin-resistant (mrsa and ) and one glycopeptide-intermediate (gisa ) strain, in a rabbit endocarditis model. mics of v and t (v/t) were . / . , / . , / , . / . , and / , for mssa , mssa , mrsa , mrsa , and gisa , respectively. the animals were randomly infected with one of these strains, then treated for days by v or t. a continuous infusion of v, simulating a mg/kg/ h human dose was used. t was infused as a continuous infusion allowing simulating a mg/kg human dose, following an initial bolus. these regimens achieved clinically relevant serum steady-state concentrations of glycopeptides ( !/ mg/ l). results were as follows: expressed in log cfu/g of vegetations (mean /sd, followed in parenthesis by the number of rabbits used). purpose: to determine the prevalence of the decreased glycopeptides susceptibility among clinical isolates of staphylococcus aureus collected from patients hospitalized in strasbourg university hospital between / / and / / . the susceptibility to glycopeptides of s. aureus isolates collected from hospital environment during approximately the same period was also investigated. methods: the susceptibility to glycopeptides was studied among the mrsa isolates, using: Á/ detection of the decreased susceptibility to glycopeptides using agar plates containing mg/l teicoplanin, Á/ detection of hetero-visa strains using agar plates containing mg/ l vancomycin, Á/ determination of the mics of vancomycin and teicoplanin using the agar dilution and the e -test strips methods. results: thirty-nine percent of s. aureus clinical isolates ( out of strains) are mrsa. no visa or hetero-visa strain was detected. six percent mrsa isolates are teicoplanin intermediate s. aureus strains. in the environment, % s. aureus isolates are methicillinresistant (five out of ). the five strains are all susceptible to glycopeptides. conclusion: the results regarding vancomycin are reassuring. however, the high rate of mrsa and the presence of teicoplanin intermediate s. aureus isolates prove that prevention and control measures need to be improved. comparative investigation of polymerase chain reaction and a conventional methods for detection of methicilin resistant staphylococcus amont clinical isolates soa . kantardjiev tv a , vacheva-dobrevski rs b , panajotov sv a , bachvarova am a , velinov ti a , levterova vs a . a national center of infectious and parasitic diseases, microbiology, sofia, bulgaria , b military medical academy, clinical microbiology, sofia, bulgaria purpose: identification on methicillin resistant staphylococci has a great clinical implication and significant impact of antibiotic therapy. the aim of this study is to compare the disc-diffusion test (ddt), oxacillin agar screen test (oast) and pcr for detection of mec a gene. fifty selective clinical isolates ( staphylococcus aureus and nine s. epidermidis ) determined as methicillin resistant by ddt were enrolled in the study. ddt was performed with oxacillin disk ( mkg/ml) on mueller-hinton agar (mha) without nacl (nccls, ) . oast was performed on mha with % nacl, oxacillin mkg/ ml, t c. these strains was genotypically characterized for the mec a gene presence by pcr method using the mec a - ?-aaa atc cat ggt aaa ggt tgg c- ? and the mec a Á/ ?-agt tct gca gta ccg gat ttg c- ? primers (gibco, brl) . results: in the group of mrs isolates, detected by pcr, positive results were as follow: s. aureus and six s. epidermidis . for six s. aureus isolates ddt and oast were positive; pcr-negative. for two s. aureus and two s. epidermidis isolates pcr was positive; phenotypic methods-negative. conclusions: accurate and rapid detection of mrs is a constant challenge for laboratories. the pcr assay (first time in our country) appears to be more reliable than routine susceptibility testing for the rapid diagnosis of mrsa infections at hospitals, particularly due to the heterogeneous resistance of many strains. . / . ( ) . / . ( ) . / . ( ) . / . ( ) . / . ( ) v . / . * ( ) . / . ( ) . / . * ( ) . / . ( ) . / . ( ) t . / . * ( ) . / . ( ) . / . * ( ) . / . ( ) . / . ( ) distribution and antibiotic susceptibilities of bacteria isolated from suspected urinary tract infections of inpatients in hungary soa . rozgonyi f, csukás z, kamotsay k, szabó d, ostorházi e, berek z, maródi c. institute of medical microbiology, semmelweis university, budapest, hungary between l january and december , a total of , urine samples were cultured % as native urine (nu) and % as uricult-plus (up) (orion diagnostica, finland) . cultivations were negative in % of nu and % of up specimens, while contamination was revealed in % of nu and % of up. in the clinical bacteriologically evaluable positive nu and up cultures, the distribution of the gram-negatives was very similar with the predominance of escherichia coli ( and %) followed by enterobacter spp. the distribution of gram-positives differed significantly according to the types of specimens. nu resulted in % group-d and % group-b streptococcus while up did and . %, respectively. third generation cephalosporins and fluoroquinolons were equally very effective against e. coli strains, while ampicillin inhibited growth of % only. carbapenems, cefepime and the fluoroquinolons were the most active against enterobacter strains. interestingly, trimethoprim'/ sulfarmetoxazole combination could inhibit more than % of enterobacteriaceae strains. piperacillin'/tazobactam ( %), imipenem ( %), and ciprofloxacin ( %) could be the drog of choice against pseudomonas aeruginosa . enterococcus strains were highly sensitive to glycopeptides ( %), nitrofurantoin ( %), imipenem ( %) and amoxicillin'/clavulanic acid ( %). antimicrobial susceptibility levels of escherichia coli isolates cultured from urine at a tertiary care teaching hospital. temporal trend and comparison between community-acquired and nosocomial urinary tract infection soa . nanetti a, manfredi r, valentini r, calza l, chiodo f. uni versity of bologna, infectious diseases, bologna, italy in order to assess the local temporal trend of antibiotic sensitivity of the most common urinary tract bacterial pathogen, all urine-cultured escherichia coli isolates were reviewed as to susceptibility profile, and specimen source (community-versus hospital-acquired infection). when evaluating sensitivity levels of community-acquired pathogens ( Á/ ), a significant resistance rise was limited to cotrimoxazole (p b/ . ) and nalidixic acid (p b/ . ), while a tendency towards increased resistance regarded norfloxacin (p / . ) (fig. ) . when community-acquired e. coli isolates were compared with nosocomial strains (tested in the years Á/ ), a greater susceptibility of community-acquired e. coli isolates was limited to cotrimoxazole versus all other compounds in the year (p b/ . ), while it was extended to amoxicillin, cephalotin, nitrofurantoin and piperacillin in the year (p b/ . ) (fig. ) . on the whole, e. coli showed an elevated sensitivity rate ( !/ % of tested strains) to nitrofurantoin, gentamicin, amikacin, and nd-and rd-generation cephalosporins, while only amoxicillin and piperacillin had a mean resistance rate !/ %, regardless of the community or nosocomial origin. a permanent surveillance of sensitivity levels of the most common pathogens responsible for infectious diseases enables to identify local antimicrobial activity and its temporal variations, and plays a key role in starting empiric therapy, pending bacterial identification and in vitro assays. conclusion: in uti, the antimicrobial agents such as st cg combined with aminoglycosides are recommended as initial treatment as well as the rd cephalosporin generation at monotherapy. in addition, the fluoroquinolones and aminoglycosides are effective in uti. prevalence of resistance mutations to antirretrovirals and relation to virological failure s . garcia f a , suarez s a , alvarez m a , martinez nm a , valera b b , pasquau j b , hernandez quero j a , maroto mc a . a hospital san cecilio, microbiology, granada, spain , b hospital virgen nieves, microbiology, granada, spain purpose: to investigate the prevalence of resistance mutations in the reverse transcriptase (rt) and protease (p) genes of hiv and to relate it with the type of virological failure (vf), we have studied patients ( % naïve or pregnant women, % were first vf, % were second vf, % more than two vf. resistance mutations were investigated using trugene hiv- genotyping kit (visible genetics). results: global prevalence of resistance mutations for rt inhibitors (rti) has been !/ % for m l, d n, k n, m v, l w, t yf, and for l i, m i, l p, a vt, l m for p inhibitors (pi). the prevalence of resistance mutations for the naïve patients studied was very low (a g, v i for rti and l i, m i, m i */all n / */and l p n / for pi). for patients on first vf only k n, m v, t yf (rti) were !/ %, as well as l i, d n, l p (pi); when patients on second vf were studied, then m l, e d, k n, m v, g a, l w, t yf, k qe (rti) and m i, l p, a t (pi) were !/ % prevalence; finally, when patients with more than two vf were studied, the following resistance mutations were !/ %: m l, d n, k r, k n, v i, y c, m v, g a, l w, t yf (rti), and l i, m i, m il, l p, a t, l m (pi). conclusions: the prevalence of primary resistance in the population studied is very low; the prevalence of mutations in the reverse transcriptase and protease genes increase in parallel to the type of virological failure. genotypic resistance in hiv- rna from patient plasma compared with rapid virus isolation and phenotypic resistance in patient pbmcs s . stuermer m, groeschel b, cinatl j, doerr hw. institute for medical virology, university clinic frankfurt, frankfurt, germany objective: to compare hiv- virus isolation in the presence of antiretroviral drugs with plasma hiv- genotyping. materials and methods: hiv- genotyping was performed using the viroseqtm vers. from applied biosystems. interpretation of genotype was done according to international standards. cd -cells were purified from patient plasma and cultivated in microtiter plates coated with anti-cd and anti-cd antibodies in the presence of different concentrations of antiretroviral drugs. virus production was measured using a p antigen assay. phenotypic activity was expressed as % reduction of p concentrations. results: seventeen samples were analyzed. for samples results were obtained from both methods, two samples could not be analysed by phenotyping and four samples not by genotyping. only / samples showed total and / samples partial concordance, / samples showed discordance between the two assays. in discordant samples the genotype gave a definite interpretation. conclusion: hiv- virus isolation and phenotyping from pbmcs may overcome the problem of currently used resistance assays, which analyse only the reverse transcriptase and the protease gene of hiv- . possible mutations in other regions may influence viral fitness and therefore contribute to the growth of the virus population present. the lack of concordance between the two assays is related to the different blood compartments used. the clinical value of resistance tests using pbmcs is under investigation. interleukin- co-operates with a new type i ifn, ifn-tau to inhibit early steps of hiv-i biological cycle s . rogez c a , clayette p a , martin m a , dereuddre-bosquet n a , martal j b , dormont d c . a cea, drm, fontenay-aux-roses, france , b inra, physiologie animale, jouy-en-josas, france , c cea, crssa, ephe, drm, fontenay-aux-roses, france background: type i interferons (ifn) exhibit efficient antiviral activities notably against hiv, but severe side effects restrict their clinical uses. ifn-tau is an ovine or bovine non-cytotoxic type i ifn which displays higher inhibitory effects towards hiv replication than ifn-alpha, particularly in human monocyte-derived macrophages (mdm). the antiretroviral activity of ifn-tau seems to involve antiviral and immunomodulatory mechanisms: il- synthesis is increased in dose-dependent manner in mdm treated with ifn-tau and a specific inhibition of il- biological activity decreases its antiretroviral efficiency. results: after a -h infection, a significant decrease of intracellular hiv rna amount was found in mdm treated with ifn-tau. in parallel, no additive inhibition was observed with ifn-tau during the elongation of proviral dna. these results suggest either an inhibition of hiv nucleocapsid uptake or an immediate hiv rna degradation, and the expression of ?, ?-oas, mxa protein and pkr was then measured. ifn-tau induced the expression of these three host cell factors. the role of il- on these different steps was evaluated and we showed that il- co-operates with ifn-tau during the very early step of hiv biological cycle. conclusion: altogether, these results evidence that ifn-tau uses the same antiretroviral pathway as others type i ifn in mdm, and that il- takes part to its inhibition of early steps of hiv biological cycle. actinomycin-d as a modulator of resistances due to cell-wall active agents like bacitracin (bc) and lysozyme (lz) s . chakrabarty an a , dastidar sg b . a calcutta university, medical microbiology, calcutta, india , b jadavpur university, pharmaceutical technology, calcutta, india it was observed that development of lzr in the lzr mutants took placed at three different levels and was accompanied with unselected, distinctive and elevated levels of bcr. similarly, bcr in bcr-mutants were also detected at three different levels. although the levels of bcr ( / mg/ml) in the bcr mutants could be raised only by persistent efforts, an increase in the levels of lzr (as cross-resistance) in the same mutants could be easily achieved. a correlation of actinomycin-d resistance with lzr and bcr of the mutant bacteria and the effects of lipase treatment on the same showed a Á/ -fold rise in actinomycin-d resistance of the lzr and bcr mutants of gram-positive bacteria compared with their correspondence wild-types. these findings suggest that lzr and bcr are controlled by several genes accounting for reduced cell-wall and cell-membrane permeability and indirectly, by phenotypic alteration of the lipid content of the cell-wall. thus, the alteration of cell-walls and membranes and a phenotypic extra lipid layer can work in conjunction with the efflux pump mechanisms finally determining the levels of drug-resistance. experimental development of drug resistance to non-antibiotics: a role of alteration of membrane fluidity and efflux systems s . dastidar sg a , mazumdar k a , asok kumar k a , chakrabarty an b . a jadavpur university, pharmaceutical technology, calcutta, india , b department of medical microbiology, calcutta university, calcutta, india drug resistance among clinical strains was studied by selecting mutants resistant to promazine (pr) and methdilazine (md). the results showed that successive step-up mutants of pr and md developed cross-resistance to several unrelated drugs, which in subsequent steps had broader resistance spectra with higher levels of resistance. experiments on the membrane fluidity or permeability of bacterial cells using diphenyl hexatrine (dph), a fluorescent probe on md-mutants showed that three was marked reduction in the membrane fluidity and permeability. when several analogues of the basic phenothiazine structure, e.g. -chlor-methyl-n -methyl-pyrrolidine (cmp), methyl- -methyl- -pyrrolidone- -carboxylate (mmpc), hydroxymethyl-n -methyl-pyrrolidine (hmp) and md with final substitution were tested for antibacterial function on different strains, highest activity was observed with respect to md. with anaerobic bacteria the resistance(s) dependent on efflux pumps showed higher levels of resistance even to md. we have found the non-antibiotic agents triflupromazine, trimeprazine and diclofenac sodium have high degree of activity against vibrios, staphylococci and pseudomonads. the explanation of such a phenomenon in terms of possible efflux pumps will be discussed. csf, plasma and urine pcr in lyme neuroborreliosis s . pícha d a , moravcová l a , lásiková Š a , marešová v a , Ž ïárský e b . a charles university, nd medical school, st clinic for infectious diseases, prague, czech republic , b department of cellular and molecular biology, charles university, rd medical school, st clinic for infectious diseases, prague, czech republic the main reason for high diagnostic value of pcr in neuroborreliosis (nb) is the direct way of spirochete detection. two sets of primers in nested pcr were used: one for plasmide gene encoding ospc protein and second for chromosomal gene s rdna. so far patients with clinically manifested involvement in nb were enrolled into the prospective designed study (being continued). the main including criterion was positive prove of intrathecal specific antibody secretion (in patients) and pcr positivity in csf (in ). all patients were repeatedly examined by neurologist and samples of csf, plasma and urine were taken: ( ) before treatment; ( ) after treatment; ( ) after months. before treatment were patients pcr positive in csf, six in plasma, and in urine. five were parallel positive in csf and plasma and four in all three body fluids. urine after treatment was positive in seven ( %) cases and completely negative after months. the pcr has had relative high sensitivity ( %), but does not rich the sensitivity of antibody index ( %). supported by grant mzcr ; . consumption of imipenem correlates with b-lactam resistance in pseudomonas aeruginosa s . lepper pm a , hö gel j b , trautmann m a , grusa e c . a department of medical microbiology and hygiene, university of ulm, ulm, germany , b department of biostatistics, university of ulm, ulm, germany , c hospital memmingen, central pharmacy, memmingen, germany purpose: in the present study we investigated the monthly consume of three anti-pseudomonas-active antibiotics, namely imipenem, piperacillin/tazobactam (pt) and ceftazidime during a period of years ( Á/ ) . the use of these antibiotics was correlated to the rate of resistance in pseudomonas aeruginosa . results: inspection of the time series for use of imipenem, ceftazidime, and pt, and the corresponding time series for resistance (each available from july to july ) indicates a remarkable coincidence between use of imipenem and resistance against the three antibiotics mentioned. pearsons's coefficient of correlation for the use of imipenem and the resistance against imipenem was . (p b/ . ), between imipenem use and pt resistance was . (p b/ . ), and between imipenem use and ceftazidim resistance . (p b/ . ). we found positive regression coefficients quantifying an association with imipenem use in the same month (p b/ . ) and with the use during the preceding month (p b/ . ). the same was true when checking dependence of ceftadizime resistance (p b/ . ) and pt resistance (p b/ . ) on imipenem use observed during the same month. neither the use of ceftadizime nor of pt could be identified as factors creating resistance to one of the three antibiotics under consideration within a reasonable period of time. conclusion: there might be a strong pressure towards resistance created by carbapenems. this could limit the use of carbapenems for initial empiric therapy. treat hard and fast: short course antibiotic treatment and its relation with patient compliance and effectiveness s . perez-gorricho bpg a , ripoll m b , pechere jc c . a niño jesus hospital, infectious diseases, madrid, spain , b insalud, outpatient consult, madrid, spain , c university of geneve, microbiology, geneve, switzerland 'treat hard and fast ': short course antibiotic treatment and its relation with patient compliance and effectiveness. finding the important implications for the way in which physicians manage patients with mild Á/moderate respiratory tract infections, and the relation of this management with the perception of antibiotic effectiveness, and the compliance with the antibiotic regimen has been the main purpose of the research. in a pan-european market research study of more than patients, designed to determine behaviour to the antibiotic management of mild-moderate respiratory tract infections, patient expectations of antibiotic therapy were identified, particularly those aspects that relate to efficacy and compliance. the study identifies three key drivers of patients perceived antibiotic efficacy: length of antibiotic course, time to onset of symptom relief and time to complete resolution of symptoms. the results demonstrate that once daily treatment for short periods is perceived by patients to be significantly more effective than longer antibiotic courses and thus better meets patient expectations of therapy. in this study, a macrolide, azithromycin, was selected as the drug therapy of shortest course, being the antibiotic with the shortest dosage schedule for common outpatient infections. the perception of efficacy with short course therapy also correlates with overall satisfaction with management by the physician and with patient compliance with antibiotic therapy. purpose of the study: group b streptococci (gbs) remain a major cause of neonatal infections. consensus guidelines have recommended an intrapartum antibioprophylaxis by amoxicillin, which has reduced the incidence of early-onset neonatal gbs infections. however, an increased incidence of beta-lactam-resistant gram-negative neonatal sepsis has been reported. the aim of our study was to analyse the consequences of this antibioprophylaxis on the intestinal microbial colonization of newborns. a study of the fecal flora was carried out on stools samples from days-old newborns divided into groups: group a intrapartum treated mothers (n / ); and group b untreated mothers (n / ). both groups were matched with regards to known factors affecting intestinal microbial colonization: gestational age, type of delivery and feeding. results: colonization by enterobacteria and enterococci was not significantly different and occurrence of amoxicillin-resistant enterobacteria was similar ( / and / in groups a and b, respectively). however, the colonization by clostridia was modified: the number of newborns colonized was significantly less important in group a than in group b (group a: / and group b: / p b/ . ). conclusion: in our study, intrapartum antibioprophylaxis did not affect intestinal colonization by aerobes but reduced significantly colonization by clostridia, potentially anaerobic pathogens. impact of an antibiotic policy restricting the use of b-lactams and macrolides on the incidence of clostridium difficile associated diarrhoea in general medical, renal and elderly patients s . boswell tc a , pacey s b , broomfield s c , westmoreland d c , yates c c . a nottingham city hospital, microbiology, nottingham, uk , b nottingham city hospital, pharmacy, nottingham, uk , c nottingham city hospital, infection control, nottingham, uk the purpose of the study: to investigate the short-term impact of a new antibiotic policy for the treatment of urinary and respiratory infections on the incidence of clostridium difficile associated diarrhoea (cdad) in hospitalised medical, elderly care and renal patients. the results obtained: a policy restricting the use of b-lactams (except parenteral penicillin), and promoting alternative antibiotics including levofloxacin for pneumonia, and doxycycline for non-pneumonic respiratory infections, was launched in july . as a result there was a significant and sustained reduction in use of aminopenicillins, cefuroxime and macrolides, with a corresponding increase in doxycycline and levofloxacin. the incidence of cdad was determined during the st months of the new policy and compared to the last months of the old policy. the incidence of cdad fell from . to . per patients, and from . to . per in-patient days (p b/ . ). in contrast, there was no change in the incidence of cdad in other specialties (surgery, oncology etc.) that had not introduced the new policy. there was no change in the incidence of nosocomial bacteraemia with quinolone-resistant coliforms or mrsa, despite the increased use of levofloxacin. conclusions: hospital-wide reduction of b-lactam and macrolide use in medical patients can result in a significant and immediate reduction in cdad. longer follow-up will determine if this effect is sustained. use of imipenem/cilastatin i.v. (tienam i.v.) for the treatment of low respiratory tract infections in intensive care units s . izzo l a , orsetti r b , boschetto a a , binda b a , della casa u a , caramanico l a , la mazza a a . a department of surgery, universitá degli studi di roma 'la sapienza','p. valdoni', rome, italy , b s. camillo-forlanini, intensive care unit, rome, italy ventilator associated pneumonia (vap) is considered the most frequent infection in the intensive care unit (icu), occurring in Á/ % of patients intubated for longer than h besides nosocomial pneumonia is a common complication in the critically ill surgical or trauma patient. inadequate treatment can lead to the complications of acute respiratory distress syndrome (ards), empyema, and lung abscess. the most important aetiological agents both in vap and in pneumonia which arise as complication in surgical or trauma patients are bacteria, whit a marked predominance of staphylococcus aureus and pseudomonas aeruginosa . the authors present their experience ( cases) on the employment of imipenem/cilastatin i.v. (tienam i. v.) as initial empirical monotherapy at the dose of mg)/ /day or g)/ / day for the treatment of the serious lower respiratory tract infection in an icu. tienam is a well tolerated broad spectrum antibacterial agent that is effective against the majority of gram-positive and gram negative aerobic and anaerobic bacteria including most pseudomonas species. except one patient deceased for causes related to his very poor general conditions and three cases in which has been necessary the addition of an aminoglycoside, in all the other patients the imipenem/ cilastatin (tienam) monotherapy has shown satisfactory clinical and bacteriological responses. clinical auditing of the impact of recommendations on antibiotic treatment s . kinoo j a , david-ouaknine f a , hacquard b a , echard y a , decazes jm b . a centre hospitalier lagny marne la vallée, lagny sur marne, france , b hospital saint louis, paris, france the aim of this study was to assess the impact of curative antibiotic recommendations on suitable prescriptions at lagny-marne la vallée hospital (general hospital, beds). two prospective exhaustive audits were made (all complete hospitalizations, excluding psychiatry, february Á/may and ) of the detailed curative antibiotic prescriptions, before and after distribution of internal recommendations. the same methodology, designed by a multidisciplinary team, was used for both periods. the same antibiotics were available at the pharmacy. the prescriptions were assessed by an infectious diseases specialist and a pharmacist using pre-established criteria: literature recommendations ( audit), internal recommendations ( audit). six hundred and fifty-six prescriptions for patients were collected and analysed in , for patients in . exhaustivity of the recovered prescriptions was over %. patient characteristics, infection sites and microbiological findings were similar for both groups. suitable prescriptions were significantly increased ( Á/ %, p b/ . ). unsuitable prescriptions (economic reasons, too short or too long course, incorrect administration, or underdosage) were significantly reduced. prescriptions for incorrect indications were unchanged and necessary combined treatment not being prescribed, increased. local recommendations improved prescriptions, but efforts have to be done in order to go on the improvement of the practice behaviour. cost-effectiveness analysis of antibiotic therapy in hospitalized patients with copd exacerbations (ae-copd) s . beghi g, aiolfi s, maghini l, patruno v, aiolfi e. s marta hospital, pulmonary rehabilitation unit, a.o., rivolta d'adda, italy antibiotic costs represent a high burden of total drug costs for hospital administrations. a scientific approach considering also the economic aspects of each therapeutic decision may gain optimal treatment objectives at pondered costs. in our study we retrospectively evaluated the clinical effectiveness and costs of antibiotic therapy in patients with ae-copd. from to , our retrospective study results support previous pharmaco-economic considerations according which in choosing an antibiotic regimen for ae-copd we must take into consideration the expected clinical and microbiological results without forgetting to consider the economic burden of our decisions. significant increase in fungaemia due to non-albicans candida species s . shah pm. klinikum der j.w. goethe universitaet, schwerpunkt infektiologie, frankfurt am main, germany until , predominant candida species in blood cultures was candida albicans . it accounted for . % of all candida species cultured from blood. since then we have observed a gradual increase in number of non-albicans candida species. from , onwards nonalbicans candida species out-number c. albicans . this observation is especially important as non-albicans candida species are generally non-susceptible to azole derivatives and empirical use of azoles in suspected candidaemia should not be recommended. amphotericin b is uniformally active against almost all candida species. echinocandin may be an alternative. see figure below. a search for newer antifungal chemotherapeutics s . chakrabarty an a , dastidar sg b , saha b b , basu l b . a calcutta university, medical microbiology, calcutta, india , b jadavpur university, pharmaceutical technology, calcutta, india fungal infections due to the mucor-rhizopus (m-z) group present formidable problems due to lack of appropriate and effective drugs against them, as seen in increasing number of clinical situations; death due to mycoromycosis is nearly inevitable. we analysed the biological 'weak-spots' of the mucor-rhizopus group and attempted to devise suitable drugs using their weak-spots. we have noted that like many free-living fungi, the m-z fungi are facultatively chemoautotrophic (can grow on simple sources of carbon and nitrogen and a solution of mineral salts), like the human pathogenic chemoautotrophic nocardioform bacteria. we devised a minimal medium based on that of davis and mingioli, supplemented with simple chemical compounds as sole sources of carbon and nitrogen. the key chemical here was diphenylamine with trypan blue (dpa Á/tb) and other similar sources of c and n. we found that while media free of these chemicals (controls) allowed good growth of different strains of m-z fungi, a mixture of dpa Á/tb completely prevented their growth over a wide concentration range. experiments with immunocompromised mice showed that these drugs at the concentrations used are well tolerated; mice experimentally infected with several clinical isolates of m-z fungi and receiving these chemicals showed that these fungi could not grow in vivo. in vitro activity of newer fluoroquinolones against multi-drug resistant salmonella typhimurium s . nolones resistance is being also reported. we have studied the in vitro activity of b-lactams and fluoroquinolones against multi-drug resistant s. typhimurium from human sources. material and methods: fifty multi-drug resistant s. typhimurium were tested against cefazolin, cefuroxime, cefotaxime, cefepime, ofloxacin, levofloxacin, and moxifloxacin, by the agar dilution method according nccls guidelines. results and conclusions: all the strains were resistant to four or more of the following antibiotics: ampicillin, tetracyclines, chloramphenicol, streptomycin, sulphonamides and nalidixic acid. a high proportion of strains were intermediate or resistant to amoxicillin/clavulanate. we found no resistance to cephalosporins. nevertheless, % were intermediate to first and/or second gen. cephalosporins. cefotaxime and cefepime were the most active cephalosporins (mic : . mg/l). though increasing fluoroquinolones resistance has been described among this kind of strains, no resistance to fluoroquinolones was found here. levofloxacin was the most active fluoroquinolone (mic : . mg/l), followed by ofloxacin (mic : . mg/l) and moxifloxacin (mic : . mg/l). high rates of resistance to antibiotics by salmonellae from diarrhoeic children in zliten-libya s . ghenghesh ks a , ben ali m b , abuhelfaia a b , dufani ma a . a faculty of medicine, al-fateh university, medical microbiology, tripoli, libyan arab jamahiriya , b faculty of arts and sciences, el-ghomes university, biology, el-ghomes, libyan arab jamahiriya salmonellae are major bacterial cause of diarrhoea in libya particularly in children. included in the present study salmonella species isolated from children with diarrhoea in zliten city-libya. the children aged between a few days to years. the organisms were tested for their susceptibility to antibacterial agents using the disc diffusion method. of the isolates examined, ( %) were resistant to ampicillin, ( . %) to amoxicillin Á/clavulanic acid combination, ( %) to cefoxitin, ( . %) to chloramphenicol, ( . %) to doxycycline, ( . %) to gentamicin, ( . %) to nalidixic acid, ( . %) to trimethoprim Á/sulphamethoxazole and none ( . %) were resistant to norfloxacin. a strong relationship was observed between the availability of antibiotics in the pharmacies of the city and resistance of the isolated salmonellae to these drugs. the misuse of the antibiotics by the community may be an important factor (among others) in the emergence of these high rates of resistance by the salmonellae examined. effect of ceftriaxone along with probiotics administration on intestinal ecosystem and betalactamase activity s . bertazzoni minelli e a , benini a a , zoppi g b . a department of medicine and public health-pharmacology section, university of verona, verona, italy , b department of paediatrics, university of verona, verona, italy oral bacteriotherapy during antibiotic treatment is a much debated topic. aim: to study whether different probiotics can prevent imbalance of the intestinal ecosystem (dysbiosis) in children during therapy with ceftriaxone (cx). methods: fifty-one children (mean age . years) with febrile respiratory tract infections were treated with cx mg/kg/day iv, alone (therapy ) and along with the following preparations: saccharomyces boulardii ( ); enterococcus spp. ( ); lactulose ( ); l. casei gg ( ); l. rhamnosus , l. bifidus and l. acidophilus ( ); b. bifidum and l. acidophilus ( ); and a mixture of various lactobacilli and bifidobacteria at high concentrations ( ). faecal samples, collected before and after treatment, were analysed for microflora composition, cx concentration, and beta-lactamase (bl) activity. results: cx causes intestinal dysbiosis. no c. difficile was found. faecal bl increased after therapy in all treated groups. cx alone increased bl activity in % ( / ) of children (no activity before treatment); a higher incidence ( Á/ %) was found in groups and . after therapies , , , , and , bl activity was found in or more children. cx was detected in % of faecal samples. conclusions: the probiotics administration seems to protect against dysbiosis caused by cx and to contain the increase in faecal bl activity. the effects differ according to the probiotic administered and are peculiar to certain bacterial species. these preliminary data need further studies. comparative study of initial and acquired drug resistance in pulmonary tuberculosis in iran s . mansoori d, arami s, mirabolhasani z. nritld, infectious disease, tehran, islamic republic of iran purpose: resistant to anti-tuberculosis agents particularly multiple drug resistant (mdr) is a major obstacle in treatment tuberculosis in the world. between september and march for smear and culture positive pulmonary tuberculosis patients (old / , new / ) pretreatment susceptibility tests of isolated bacilli to inh, rif, emb and stm were performed by standard proportional method and the results were attributed to three groups: (i) newly diagnosed without any history of treatment; (ii) patients with history of treatment for one course; (iii) patients with history of treatment for two or more courses supposed to be mdr cases. the results were collected for each drug individually and different combinations of two, three and four medications. results: resistance to one, two, three and four drugs was significantly increased in group iii comparing to groups ii and i, also in group ii compared to group i. we observed a high rate of primary resistance to inh and stm in groups i and ii and a high rate of mdr (inh and rif resistance) in groups ii and iii. conclusion: the duration of bacilli exposure to antituberculosis agents in the past is a major factor in developing resistance. in contrast to who's guideline, due to high rate of primary resistance especially to stm in our area, we do not recommend addition of stm for treatment of patients whose initial four-drug regimens have been failed (group ii). donors, to understand host interactions with this bacteria, to develop new methods of diagnosis and define new vaccine candidates. nineteen tb patients and seven healthy donors were enrolled in french hospitals. cellular immune responses were evaluated by lymphoproliferation and ex-vivo quantification of specific th cells by elispot-ifn-gamma assays. four recombinant proteins of m. tuberculosis were tested: esat- , b, erp and tb b . and compared with tuberculin. we confirmed that b (but not esat- in our study) gives higher responses in tb patients compared to donors according to the results in proliferation assay (p / . ). in addition, frequencies of th cd specific cells for esat- and tuberculin were statistical different between the two groups (p / . and . , respectively). . % for b and . % for esat- of the patients tested were responders in elispot-assay versus . % for both in proliferation assay. for the new antigens erp and tb b . , no difference was observed between the two groups. in conclusion, b and esat- are recognised by a large number of our patients. they seem to be promising antigens for the development of new methods of diagnosis or for the development of new vaccines. erp and tb b . are not preferentially recognised by tb patients. other exported antigens will be tested. the incidence of tuberculosis (tb) is increasing worldwide. in recent some years, geographical differences in the incidence of tb in former yugoslavia have been observed. an important rise in tb cases was registered in the bordering region of bosnia. it is likely that poorer living conditions, influenced by war and emotional stress, may promote such rising incidence of tb. renal tuberculosis was diagnosed in patients (female , male ) from district brcko in bosnia, during the period of years, Á/ . at the same time none patient had active pulmonary tb lesions, fibrous lesions were noticed in patients, but we did not diagnose any signs of previous pulmonary tb in seven patients. seven patients developed relapse of renal tb after Á/ years of previous treatment. guided by clinical parameters, precisely done renal echosonography enabled early suspicion and searching for renal tb, by radiological and other methods. bacteriological diagnosis was performed by detection mycobacterium tuberculosis on loewenstein Á/jensen medium in patients. pcr as simple, fast and highly sensitive method enabled diagnosis in incipient stadium of disease, so antituberculous therapy could be instituted some months earlier. prompt diagnosis of renal tuberculosis (using pcr, besides standard methods) is necessary, otherwise delayed diagnosis may be dangerous. a study on resistance to first generation anti-tuberculosis drugs in mycobacterium kansasii s . mirsaeidi sm, farnia p, mohammadi f, mansoori sd, jabbari r, taghizadeh r, masjedi mr, velayati aa. national research inistitute of tuberculosis and lung diseases, infectious diseases and immunology (nritld ), tehran, islamic republic of iran purpose: this research has been performed to determine antibiotic resistance of atypical mycobacteria especially mycobacterium kansasi . results: twenty-three pigmented colonies which indicated atypical agents from nritld's mycobacterium culturebank were selected, they then underwent type identification and antibiogram for inh, rif, etb, stm. nine samples were m. kansasi and were other non-mtb, was m. gordonei , m. xenopi , mac, m. bovis , m. tererra , m. asiatioum , m. marinum and . mean age in m. kansasi cases was '/ . year and in non-kansasi cases '/ . year and in whole society ntm was . '/ . . frequency of resistance in kansasi group were to inh ( %), to rif ( %) to etb ( %), to stm ( %) and prevalence of mdr was ( %) and in non-kansasi group frequency of resistance were ( %) to inh, to rif ( %), to etm ( %) and to stm was ( %), to mdr was ( %). conclusion: a significant difference was seen between the age groups of patients who are affected with m. kansasi and non-kansasi (p b/ . ), also in frequency of resistance to first generation anti-tb drugs. m. kansasi is detected as the most common atypical mycobacterium agent in pulmonary infections and attention to antibiogram is recommended before treatment. buruli ulcer caused by mycobacterium ulcerans , is the third most common mycobacterial after tuberculosis and leprosy in west africa. nowadays, the only effective treatment is surgery. it consists in a large excision of the lesions, often followed by a skin transplant. in this study, the effectiveness of rifampin, amikacin and their combination were estimated in the treatment of mice, which were infected experimentally by m. ulcerans . after weeks of treatment with rifampin, amikacin or their combination, no more viable bacilli were found in infected tissues. the animals were kept for other months. among the mice treated with rifampin alone, two mice out of relapsed. the minimal inhibitory concentration of these isolated strains went from . to mg/ml. the dna sequence, obtained from a -pb of the rpob gene from these strains, showed a missense mutations, which affect a ser- replaced by a phenylalanine. this modification on the gene leads to an important inefficacy of treatment when rifampin was used alone. this study showed that rifampin and amikacin have a bactericidal action on m. ulcerans and that a combination of these antibiotics is necessary to avoid the selection of resistant mutants. histopathologic and electron microscopy studies of a severe isolated hiv enteropathy detected in an aids presenter. favorable response to haart introduction or . manfredi r, calza l, chiodo f. university of bologna, infectious diseases, bologna, italy advanced hiv infection was detected in a heterosexual female with a -year history of chronic diarrhoea and severe wasting, as expressed by a body weight of kg, a cd '/ count of cells/ml, and a plasma viraemia of . million copies/ml. a malabsorption syndrome was confirmed by d-xylose test, but repeated pathogen search tested negative at stool examination and light microscopy, scanning electron microscopy (em), and transmission em study of enteric mucosa. em assays detected an ultrastructural modification of duodenal mucosa never reported to date: an extensive thinning of enterocytic microvilli, disappearance of glycocalix, and large vacuolization of the enterocyte cytoplasm. two weeks after starting an indinavir-based haart, diarrhoea disappeared and our patient significantly gained body weight: kg after months, kg after , and kg after year, paralleling a cd '/ increase to cells/ml, and undetectable hiv viraemia. the subsequent -year follow-up confirmed absence of gut disturbances, a stable body weight, a cd '/ count of Á/ cells/ml, and hiv viraemia persistently b/ copies/ml. repeated endoscopy and related histopathologic and em assays documented a notable improvement of mucosal damage, with complete cure reached after years of haart. a direct intestinal localization of hiv may be responsible for severe diarrhoea, malabsorption, and wasting, though the morphological features of hiv enteropathy are still unclear. haart acts favourably also against isolated hiv-related enteropathy. kaposi's sarcoma in a non-hiv immunocompetent adult: relapsing due to the development of a squamus cell carcinoma or . sioula e a , magira ee a , georgopoulou c a , rontogiani d b , gounaris t a . a evagelismos, internal medicine and infectious diseases, athens, greece , b evagelismos, pathology, athens, greece a -year-old heterosexual hiv negative girl was diagnosed with cutaneous kaposi's sarcoma. the disease was started years earlier with the appearance of lesions on the left feet and on the right knee. absolute number of cd and cd were and cells/dl, respectively with a decreased lymphocyte proliferation. human herpesvirus type had been detected in biopsy specimens and she placed on recombinant interferon alpha- b. follow up few months later the lesions decreased in size. two years after the onset of the disease the patient readmitted because of a mass on the left paratracheal region along with mediastinitis. her body temperature was increased. the patient underwent thoracic ct scan, which demonstrated mediastinal well defined soft tissue infiltration associated with mediastinitis and a well-defined mass in the left paratracheal region. the mass biopsy revealed squamous cell carcinoma. several violaceus lesions were observed on the arms, hands and face. severe bilateral lymphedema of the legs with a reddish papules nodules and tumors from . to cm in diameter on the soles, toes and calves were present. this case illustrates the significant relapsing of the cutaneous kaposi's sarcoma soon after the appearance of and the carcinoma and the mediastinitis. a -year-old male patient with insulin-dependent diabetes underwent cardiac surgery for aortocoronary bypass years ago. two weeks after surgery he developed mediastinitis and sternal osteomyelitis caused by methicillin-resistant staphylococcus aureus (mrsa). twice, revisions and plastic surgery for sternal osteomyelitis were performed. the patient received initially treatment with vancomycin. then the patient received intravenous outpatient treatment with teicoplanin for weeks followed by by treatment with fusidic acid and then trimethoprim/sulfametrol. the fistula was closed. four months later he presented again with substernal pain and purulent discharge. the culture revealed the growth of staphylococci which were first mistaken for coagulase-negative staphylococci. after closer investigation these staphylococci were identified as small variant mrsa. computer tomography (ct) revealed multiple mediastinal abscesses. the patient was treated with intravenous linezolid mg bid for days and then switched to oral linezolid mg bid. the oral therapy was pursued for weeks under close surveillance. the patient improved substantially, the purulent discharge disappeared. the mediastinal abscesses were not detected any longer by ct at the end of treatment. the treatment with linezolid was well tolerated. platelets decreased initially but rose to normal values without treatment modification. nosocomial pneumonia due to stenotrophomonas maltophilia in a profound granulocytopenic patient hospitalized for community-acquired staphylococcus aureus severe sepsis or . radulescu a a , sasca n b , lupse m c , tatulescu d c . a university of medicine and pharmac, epidemiology, cluj-napoca, romania , b the teaching hospital of infectious diseases, laboratory, cluj-napoca, romania , c university of medicine and pharmacy, infectious diseases, cluj-napoca, romania objective: to present the diverse opportunistic infections in immunocompromised patients and treatment difficulties. findings: a -year-old women was admitted to the teaching hospital of infectious diseases cluj with a -day history of fever, myalgia, lumbar pain, hemorrhage syndrome. severe sepsis was diagnosed and the conditions that evolved in it were paronychia in a patient with chronic leukemia having prolonged and profound granulocytopenia due to aggressive treatment with ifn. the condition at admission was critical due to trombocytopenia ( b/ platelets/ml) and hemorrhage syndrome. the evolution was favorable under antimicrobial treatment (imipenem), blood and platelet transfusion, intravenous immunoglobulins, granulocyte colony-stimulating factor, antifungal prophylaxis and supportive care. blood and pus cultures revealed mssa. in the th day of hospitalization she developed bronchopneumonia and respiratory failure. the sputum culture was positive for stenotrophomonas maltophilia susceptible to ceftazidime, fluoroquinolones. treatment was unsatisfactory until introducing ticarcilline Á/clavulanate and ciprofloxacine. she had uneventful recovery despite remaining granulocyto-trombocytopenic. conclusions: treatment of infections with emerging agents in immunocompromised patients is difficult, guidance by results of susceptibility testing being misleading with a poor correlation between the tests and treatment outcome. early disseminated listeriosis in a liver transplant recipient (ltr): a rare case due to an in vitro multiresistant strain or . manfredi r, de ruvo n, vivarelli m, bellusci r, montalti r, la barba g, abtueli aden a, cucchetti a, attard l, calza l, cavallari a. university of bologna, infectious diseases, bologna, italy a ltr receiving cyclosporin, azathioprine and steroids, developed an extraordinary episode of sepsis and pleural effusion due to a multiresistant listeria monocytogenes (lm) isolate. a lm strain serov. showing the same, extensive resistance pattern (all penicillins and stand nd-generation cephalosporins), was isolated from multiple blood cultures and pleural fluid weeks after surgery, while stool exam was negative. our p spent her life in countryside and bred some animals, but denied consumption of uncontrolled food. iv cotrimoxazole administration achieved a complete clinical and microbiological cure in days. underlying immunodeficiency may prompt unusual/severe lm infection, but because of its usual community-acquired origin, lm disease remains infrequent in hospitalized p. only seven anecdotal reports of lm infection were described in ltr, Á/ , all but occurring months Á/years after surgery. an early respiratory and systemic infection caused by a community-acquired lm strain which proved resistant to first-choice antibiotics, but had a favorable response to cotrimoxazole (used only once in a ltr with lm sepsis), characterized our episode. an epidemiological survey retrieved the possible source of this usually community-acquired infection. lm should be regarded as an emerging opportunistic pathogen in ltr, and specific risk factors should be seeked. when immunodeficiency is of concern, the unpredictable sensitivity of lm should prompt in vitro assays to adjust antimicrobial therapy problems for discussion hbv Á/hcv and liver carcinogenesis: where does the viral influence end? or . pappas ga. university hospital, internal medicine, ioannina, greece hepatocellular carcinoma (hcc) is a major clinical problem worldwide, usually evolving over a long-standing liver pathology, in the latter stages in the form of cirrhosis. hbv and hcv chronic infection is a common etiology of cirrhosis, and hence, hcc. a number of studies have attempted to clarify the role of these viruses into the progression towards hcc. does their end in the stage of cirrhosis? is progression towards hcc independent of the etiology of cirrhosis (since alcoholic cirrhosis also proceeds to hcc)? do the trials with interferon alfa for patients with hbv or hcv cirrhosis exhibit a favorable result due to the antiviral properties of interferon, or is interferon exhibiting anti-oncogenic potential?, and is hcc cytokine and hormone sensitive (view ongoing trials with somatostatine analogues versus hcc)? (hence, if we treat alcoholic cirrhosis patients with interferon could we have a favorable response?). which patients with hbv or hcv cirrhosis are eligible for interferon treatment?: interferon treatment is a potential hazard for those with thrombocytopenia. how ethical is it to conduct a randomised trial where one leg of cirrhotic patients is left without antiviral therapy? and on the basis of which classification system should the two legs of such a trial be separated? moreover, do viral proteins with oncogenic potential exist (the controversy over the recently discovered hbv protein is still, unresolved)? a major topic awaiting for a major debate. to assess the role of hiv-associated campylobacteriosis (c) according to haart availability, patients with positive culture were identified since . compared with the Â/ hiv-infected p followed in the last decade, no epidemiological differences were shown, save a greater sexual exposure to hiv (p b/ . ). the introduction of haart caused a drop of frequency of c (from . to . episodes per p-year; p b/ . ), and modified clinical features, with disappearance of dissemination and mortality, reported in and patients before (p b/ . ). hiv-related immunodeficiency and disease stage were significantly related to c features before and after haart availability: p b/ . for cd and neutrophil count, p b/ . for aids diagnosis. most cases ( ) were community-acquired, but alimentary or environmental risk factors were never found. ten patients received cotrimoxazole prophylaxis (nine before ; p b/ . ), while no relationship occurred with steroid or antibiotic use, caused cases out of . a % sensitivity was found to quinolones, followed by cephalosporins ( . %), gentamicin ( . %), macrolides ( . %), and cotrimoxazole ( . %). a Á/ -day antimicrobial therapy cured p , but relapses caused by similar strains occurred in patients within Á/ weeks, all in the pre-haart era (p b/ . ). c still occurs in the haart era, probably due to its varied mode of transmission. the frequency of c is greater in hiv-infected patients, but less frequent visceralization, recurrences, and mortality characterized the haart era. objective: to determine the incidence and risk factors for nosocomial viral respiratory infections (nrvi) and involvement of human coronaviruses (hcov) in a neonatal and pediatric intensive care unit. methods: prospective observational study. nasal samples were obtained by cytological brush at admission and weekly thereafter for all hospitalized infants. nasal samples were taken monthly from staff. virological studies were performed, using immunofluorescence for respiratory syncitial virus (rsv), influenza viruses, paramyxoviruses, and adenoviruses; both immunofluorescence and rt-pcr were used for hcov detection. results: during , hcov related nrvi were detected in nn and six in children. three hcov-related outbreaks were observed (february, august and december), associated with a high prevalence of infection in staff. during august outbreak, hcovinfected nrvi were detected over hospitalized infants. seventy-five of hospitalized preterm nn with gestational age under weeks and . % of staff members were infected. risk factors for nrvi in nn were birth weight, gestational age, ventilation, oxygenation and hospitalization length. ninety-two percent of infected preterm nn were symptomatic, mainly with bradycardia and respiratory worsening. conclusions: these data provide additional evidence for a significant role of hcov in nrvi occurring in hospitalized preterm nn. strain typing and screening of dna targets to assess echinococcus sp transmission in new and old geographic endemic foci or . bart jm a , piarroux r a , dia l b , benchikh-elfegoun mc c , vuitton da a , bardonnet k a . a serf, parasitology, besancon, france , b national centre of veterinary study, parasitology, nouakchott, mauritania , c university of mentouri, parasitology, constantine, algeria purpose: cystic echinococcosis is due to echinococcus granulosus. parasite cycles depending on the main intermediate host species involved in different foci have been described promoting mixed infection in the same definitive host. strain typing is a tool to identify the main intermediate host involved via the dogs in the human infection route and to focus the control measures. many dna targets have been used to compare samples and to access the parasite cycle in different countries. but no study has compared the value of each of these targets. eight targets have been tested in mauritania where echinococcosis is an emergent disease, and in algeria where strain typing has never been done. thirty-five cyst samples from human, ovine, camel and bovine have been tested with six nuclear and two mitochondrial targets. results: the two mitochondrial targets and four out the six nuclear targets have allowed to discriminate the different foci. two strains have been found infectious to human : the 'sheep' strain in algeria and the 'camel' strain in mauritania. conclusion: although overlapping geographically sometimes, this raises the question of the respective genetic evolution of the different strains and of their involving in human infection. alveolar echinococcosis in france: an update or . bardonnet k, bresson-hadni s, bartholomot b, gérard a, watelet j, beytout j, saurin jc, piarroux r, vuitton da, who centre collaborating for prevention and treatment of human echinococcosis, university of franche-comté, besançon, france introduction: the highest prevalence rate for alveolar echinococcosis (ae) in europe has been found in france. in , a french observatory of human ae was done in order to get data that could be used to evaluate presentation, evolution and management of ae. material-methods: french cases were collected for the period Á/ . registration of every case was performed with the subject's agreement. a questionnaire was filled in by referring to the patients' medical files or to practitioners or to patients themselves. completeness of the collection of cases was ensured by multiplying the sources of information. results: two hundred and sixty nine french patients were registered. sex ratio averaged . mean age at diagnostic was . years. . % of diagnosis was performed in 'echinococcosis free' french areas. symptoms, but not always specific liver symptoms, were present at diagnosis in . % of cases. the liver was the main location of lesions in . % of cases. a wide spectrum of management of the patients was observed, accounting for regional differences. conclusion: this french observatory of human ea will facilitate a better management of the disease at the national level. it shows new epidemiological trends, and especially an extension of the endemic area. can coins and paper currency transmit bacillus anthracis ? or . ghenghesh ks. faculty of medicine, al-fateh university, medical microbiology, tripoli, libyan arab jamahiriya anthrax is an often fatal bacterial infection caused by bacillus anthracis . recent events that began in september in us has gained the organism worldwide attention and heightened awareness of and concern about anthrax. many cases of anthrax with a number of deaths have been reported as a result of contact with envelopes, sent through postal mail, containing b. anthracis endospores. a number of studies have shown that currency is colonized with bacterial organisms, that include enteropathogens (e.g. shigella sp.), other enteric flora (e.g. escherichia coli ) and potential pathogens (e.g. staphylcoccus sp. , pseudomonas sp. and bacillus sp.). furthermore, methicillin-resistant s. aureus (mrsa) isolates that produced enterotoxin (seb) and toxic shock syndrome toxin- also been reported. all of these studies do agree on that currency may be considered as a method of spreading potentially pathogenic and pathogenic bacteria in the community. therefore, currency could also be a vehicle for spreading other highly pathogenic organisms that include b. anthracis . in addition, the introduction of the 'euro' could also allow such bacteria greater freedom to travel across the euro zone. the threat of using currency, particularly paper notes, in spreading lethal organisms should be investigated and proper measures to prevent the use of such a method by terrorists should be implemented. salvage of temporary femoral catheters for haemodialysis using antibiotics in ambulatory patients or . gerasimovska v, oncevski a, dejanov p. department of nephrology, clinical centre, skopje, the former yugoslav republic, macedonia the stay of femoral catheters (fc) for haemodialysis is typically short-term for several days. we used fc as a temporary vascular access (va) for a longer period of time in outpatients going on regular ambulatory haemodialysis, who had a problem with their permanent access. we analysed patients who were discharged from hosptal with fc. duration time of fc was between and days (average . days) with cummulative total of days. the incidence of bacteriaemia was . episodes/ catheter days. in six patients we had signs of infection, so according to our protocol we took blood cultures from peripheral vein, and from catheter (at same time) and started with antibiotic therapy (ab) systemically and locally (ab was 'locked' in catheter) with different duration of time. dominant microorganism was staphylococcus coagulasa negative, and much less staphylococcus aureus , and enterococcus.ab that were frequently used were: cefotaxim, vancomycin and ciprofloxacin. at one of six patients we removed catheter at once without trying to save the catheter. catheter tip was sent for microbiological analysis too. criteria for catheter-related bacteriemia (crb) was found in only one patient, and for possible crb in five patients after we removed the catheters. in the absence of clinical signs of infection, ab treatment was not provided for positive tip culture alone or for positive blood culture of the catheter with negative blood culture from peripheral vein. advances in meningitis education or . holt de a , tait mi b , cavanna al b , worgan-brown s a , hart b a . a the meningitis trust, stroud, uk , b the computer-aided learning unit, school of health science, university of wales, swansea, uk background: meningitis remains an important cause of death worldwide despite improvements in diagnosis, treatment and prevention. clinical and lay awareness of the disease relies on education, however educational delivery has changed and the introduction of material suitable for computer and internet application is now necessary. we have developed educational material on cdrom and on the internet applicable both at tertiary university and secondary school level. application: a computer-aided learning program on cdrom, covering all aspects of meningitis has been produced. it is suitable for undergraduate teaching of healthcare professionals from student nurse and doctors to pharmacists. in order to reach school children in a form acceptable to both pupils and teachers, we have developed a curriculum-linked website. these applications are simple to use and can be incorporated into existing courses of study, so that issues raised can be discussed with tutors and group peers. comment: the introduction of new methods of teaching and learning mean that compatible educational material must be produced. we believe that these applications, focusing on meningitis, are the first of their kind and that they offer tutors the opportunity to progress their teaching of the disease both in methodology and content. brivudin compared to famciclovir for improved therapy of herpes zoster: effects on acute disease and postherpetic neuralgia or . potentially treatment-related adverse events occurred in . % of the brivudin recipients and in . % of the famciclovir recipients (p / . ). conclusions: in zoster patients ]/ years, brivudin )/ mg and famciclovir )/ mg showed equivalent effects on prevalence and duration of phn. brivudin is as effective as famciclovir in stopping viral replication in acute herpes zoster. brivudin offers the advantage of a once daily dosage regimen while being as well tolerated as famciclovir. activity of complexes of pt(ii) and pd(ii) with pyridine- -carbaldehyde thiosemicarbazone (hfotsc) (acta virol., , , ) with selectivity index (si) . times higher than that of acyclovir (acv). in order to evaluate virus specific response and structure Á/activity relationships we continue our investigations with three pt(ii) and three pd(ii) complexes. the activity was evaluated against sensitive to acv hsv (strain bja) and resistant strains r- (hsv ) and pu (hsv ) and compared to that obtained against strain victoria (hsv ) infection. si was indicative for activity. the virus specific response was demonstrated by the fact that viruses sensitive to acv were also sensitive to pt(hfotsc) ]cl , while acv resistant viruses were sensitive to [ptcl(fotsc) ]. the structure Á/activity relationship was proved by the fact that the less active against hsv infection was [pd(fotsc)]. influenza diagnosis, treatment, and the impact of new antivirals on current treatment behaviours during influenza outbreaks or . schaetz l a , sessa a b , a hoffman-la roche f. basel, switzerland , b italian college of general practitioners, italy introduction: annual influenza epidemics severely affect individuals, families, health care systems and society. the availability of new and specific antivirals provides an opportunity for better management of influenza. methods: during the / and / influenza seasons, physicians ( Â/ /country) and public ( Â/ /country) in the usa and europe were interviewed to determine perceptions of influenza and behaviours for its treatment. results: patients recognise influenza illness as severe and identify it by symptoms of fever, muscle aches/pains and cough. physicians use these symptoms to diagnose influenza clinically ( % fever, % muscle aches/pains, % cough); their main treatment objective being to reduce complications. antibiotics for influenza treatment are broadly recommended/prescribed by about % of european physicians, whereas currently available antivirals are only recommended by %. the recommendation of antivirals by us physicians increased from % (season / ) to % ( / ) and markedly decreased antibiotic use (from to %). experience from the two influenza seasons shows that influenza antivirals are only used while the virus is circulating and that the volume of use is proportional to the size of the outbreaks. conclusions: experiences in the usa show that with prompt outbreak information antivirals can be used appropriately in times of influenza activity. influenza treatment with oseltamivir: costs and benefits for the individual as well as for society or . objective: to evaluate the effects of treatment of influenza with antivirals (oseltamivir) on health outcomes and costs to patients and society. methods: based on clinical trial data and data from the literature a simulation model has been developed. the underlying clinical pathway covers morbidity and mortality due to influenza and its specified complications. health outcome data and costs were attached to events in the model. the model compares various scenarios, which are defined by treatment schemes within defined populations and other parameters. application of the model is shown using uk unit cost data simulating an otherwise healthy adult population comparing oseltamivir with usual care. results: early treatment results in reduced morbidity, which translates into faster recovery and return to normal activities ( . days). lower morbidity and mortality make this a cost-effective intervention from a societal perspective. the analysis covers more than different scenarios and the incremental cost effectiveness ratios will be discussed. conclusion: antiviral treatment appears to be effective in terms of health outcome and cost for otherwise healthy adults from the perspectives of both the individual patient and society. however, this effect is very sensitive to time when treatment is started and the accuracy of the diagnosis of influenza. oseltamivir is well tolerated by all patient groups or . thakar b a , dutkowski r b , froelich e c , gilbride j a , ward p a . a roche global development, welwyn, uk , b f hoffman-la roche, nutley, usa , c f hoffman-la roche, basel, switzerland introduction: oral oseltamivir, the ethyl ester pro-drug of a potent inhibitor of influenza virus neuraminidase, is licensed for the treatment and prophylaxis of influenza in the usa. patients and methods: safety data [adverse events, laboratory safety evaluations] derived from clinical trials involving !/ subjects (including Â/ children and Â/ high-risk adults) and healthy volunteers in a large study investigating ecg parameters. spontaneous event reports from medwatch or yellow-card reports following use by Â/ individuals worldwide. an observational case-control study of !/ subjects with influenza-like illness treated with oseltamivir. results: oseltamivir was well tolerated in clinical trials; drug-related side-effects were limited to transient gi effects occurring in / : exposed individuals. these resolved spontaneously and caused drop out in b/ % of treated subjects. no effects on ecg parameters were noted at doses ]/sixfold above the licensed regimen. oseltamivir had no adverse effects on pulmonary function. no additional effects were identified among high-risk adults or children, or following prolonged dosing for prophylaxis. occasional reports of liver dysfunction have been documented post-marketing but causal association has not been established. conclusions: oral oseltamivir is an effective and safe antiviral suitable for influenza management in all patient groups. the decision to stop the vaccination against smallpox and the loss of specific immunity of a high proportion of the population made apocalyptic the perspective of a natural or provoked re-emergence of smallpox. therefore, it is important to improve the current capacities to prevent or to treat the orthopoxvirus infections. uracil dna glycosylase (udg) is one viral enzyme indispensable to the replication of poxviruses. udg of the copenhagen strain of vaccinia virus (vv) was characterized with the aim of defining specific inhibitors susceptible to be used as a new class of active antiviral substances on the viruses of the orthopoxvirus genus. the activity of this enzyme was analysed in real time, in an original method, on a pcr quantitative instrument by digestion of amplified dna revealed by fluorescent intercaled molecules. this technique was used to screen and select several active antiviral substances on udg. moreover, the antiviral activity was estimated by the cytopathic effect of the vv on infected vero cells. the cytotoxicity was determined by inhibition of trypan blue exclusion. the specificity of action of each tested compound was estimated by the selective index ( % cytotoxic dose/ % effective dose). two antiviral compounds were selected for their inhibitory effect on udg activity and on vv replication in vero cell culture : ('/)- -iodo- ?-deoxyuridine and -chlorouracil. these compounds are candidates for the chemotherapy of poxvirus infections. objective: to study the efficacy and tolerance of russian antiviral drugs produced from dna in a limited resources context. results: the drug derinat was produced from salmons' milt. mm of dna was Á/ kda, hyperchrome effect !/ %, protein content b/ . %. the conjugation of the dna with fe '/ resulted in a new drug named ferrovir which influences dna and rna synthesis during early stages of hiv- replication by blocking the virus's action on cells' metabolism and reduces cytomegalovirus titre in fibroblast cells for . Á/ . ig tcid . a protective effect of ferrovir against fatal herpes encephalitis mice was found. the drugs are not toxic. ic !/ mg/ml. ec of ferrovir against hiv- was mg/ml. in limited clinical trials patients received mg of drugs twice daily ( Á/ days). administration was well tolerated and no side effects were observed. derinat in . % cases of herpesvirus infection ( patients) improved the healing and shortened duration of illness. hiv-infected patients ( ) treated with ferrovir showed sustained, elevated cd '/ counts and a significant reduction in hiv- viral load (median . ig). the apparent remission was found in patients with concomitant hiv and herpes virus infection. conclusions: antivirals show good antiviral potency against rnaand dna-viruses; are well tolerated by patients and are useful in case of mixed infections; low price makes them accessible to populations with low financial resources. ortho total hcv core antigen assay can aid early prediction of response in patients treated with interferon/ribavirin or . lunel f a , veillon p b , payan c b . a ahu angers, laboratoire de bacterio-virologie, angers, france , b chu angers, laboratoire de bacterio-virologie, angers, france aim: evaluate the predictive value of total hcv core antigen assay and viral kinetics in patients with chronic hcv. methods: one hundred and twenty two patients infected by genotype , , or pretreatment viral load (bdna . , chiron) !/ meq/ml, with no previous treatment, received mu interferon (ifn) during months (m). ribavirin was given with ifn after months therapy, for months in patients with detectable rna. viral load was expressed as log (ui/ml) and hcv ag as log (pg/ml)/ ). results: pretreatment ag values were correlated with viral load (r / . ). we observed a rapid decrease of ag ( . log pg/ml) and viral load ( . log ui/ml) after m in sustained responders (sr). in patients who relapsed (rr) after ifn alone, the fall was less important ( . log pg/ml, . log ui/ml) during m . in sr and rr to combination therapy, the decrease of ag and viral load at m was, respectively, (ag: . and . log pg/ml; rna: . and . log ui/ml). we did not observed significant variation of ag and viral load in nonresponders. the negative predictive value of hcv rna and ag after m of treatment were %, and positive predictive values were and %. after month of ifn alone, the hcv ag decrease was highly predictive of sr, correlated with rna negativation and early reduction of hcv rna ( !/ log). conclusion: early measurements of total hcv core antigen are useful to predict long-term response to treatment. lamivudine in the treatment of acute hepatitis b or . vincenti a, meini m, luchi s, de gennaro m, ricciardi l, moneta s, scasso a. infectious diseases department, infectious diseases, lucca, italy acute hepatitis b is a self-limiting infection, but in some cases its course may be particularly severe. we report a case of a -years-old woman affected by acute hepatitis b treated with lamivudine. on admission in the hospital the alanino-aminotransferase was u/l, the aspartate-aminotransferase u/l, bilirubin , mg/dl, hbsag, hbcigm and hbeag were positive, hbv dna was . copies/ml. during the following days, the levels of ast and alt gradually rose; on the th day prothrombine time was %, bilirubin mg/dl and the patient developed signs of encephalopathy. four plasmapheresis were practiced without benefit, so the patient was treated with lamivudine, mg/day. after days of therapy, lamivudine was discontinued because of the appearance of diffuse maculopapular rash. at this time the results of liver function tests were normal; after four months hbsag and hbv dna were no longer detectable. in our patient lamivudine prevented an acute hepatic failure. our experience suggests a promising role of lamivudine in the treatment of acute hepatitis b, but how long such therapy have to be practiced and in which patients? prospective, controlled, clinical studies using lamivudine in patients with acute-hepatitis b are necessary. the cost-effectiveness of amantadine versus symptomatic care in the treatment of influenza or . morris s a , carman wf b , barber j c . a city university, london, uk , b west of scotland specialist virology centre, glasgow, uk , c alliance pharmaceuticals, chippenham, uk aim: to assess the cost-effectiveness of amantadine versus best symptomatic care in the treatment of influenza in the uk. methods: we constructed an economic model populated with parameters from the published literature. the model structure is the same as that used in the economic evaluation of zanamivir published by the national institute for clinical excellence in the uk. we conducted a cost-utility analysis (incremental cost per qaly gained) of amantadine versus best symptomatic care. the analyses are conducted for all adults (average-risk group) and the at-risk population (high-risk group), based on the prevalence of influenza over an average season and when the virus is circulating. the perspective is that of the nhs. results: in the average-risk group the incremental cost per qaly gained of amantadine relative to best symptomatic care is uk£ , during an average influenza season and uk£ , when the virus is circulating. for high-risk individuals the figures are uk£ , and uk£ , , respectively. the results are sensitive to the hospitalisation rate. conclusions : if the threshold for cost-effectiveness is £ , per qaly gained amantadine represents value for money in the treatment of influenza in a variety of scenarios, including the baseline for both average-risk and high-risk groups when the virus is circulating. background: surveillance studies all over the world have revealed an extraordinary increase in the prevalence of penicillin resistant streptococcus pneumoniae . the newer quinolones are believed to have broad activity against s. pneumoniae . methods: a total of penicillin resistant clinical strains isolated from patients at hacettepe children's hospital, ankara, turkey between and were tested for their in vitro susceptibility to various antibiotics that are commonly used in the treatment of respiratory tract infections. the minimum inhibitory concentrations (mics) of the penicillin, amoxicillin/clavulanic acid, doxycycline, azithromycin, clarithromycin, ceftriaxone, ciprofloxacin, levofloxacin, moxifloxacin and gemifloxacin were determined using the nccls recommended procedure for e -test. results: the range of mics, mic and mic values for all agents tested against the strains are shown in the table. gemifloxacin and moxifloxacin had the highest in-vitro activity among the quinolones tested. all strains tested were susceptible to b/ . mg/ml gemifloxacin, b/ mg/ml moxifloxacin and mg/ml levofloxacin. conclusions: there is some degree of resistance to all the drugs except the newer quinolones which were active against all isolates studied. purpose: stenotrophomonas maltophilia prevalence is growing, mainly in some hospital areas. s. maltophilia is frequently multidrug resistant. fluoroquinolone (fq) resistance varies from one to another study, but in whole resistance is moderate to high. gyra and parc qrdr partial codes have been recently described. we have studied correlations between fq-resistance and mutations in these sequences in s. maltophilia clinical strains. material and methods: gyra and parc qrdr regions from six fqresistant and two fq-susceptible s. maltophilia clinical strains were amplified and sequenced. mics of ciprofloxacin (cfx), gatifloxacin (gfx) and clinafloxacin (cnfx) were determined by the agar dilution method, according guidelines defined by nccls for p. aeruginosa . results and conclusions: mics ranges of cfx, gfx and cnfx for resistant strains were Á/ , Á/ and . Á/ mg/l. susceptible strains had mics of cfx, gfx and cnfx of , . and . Á/ . mg/l, respectively. most susceptible and resistant strains had no significant mutations in the fragments sequenced. only one resistant strain (mic of cfx mg/l) and one susceptible strain (mic of cfx mg/l) had a significant gyra mutation, the same in both strains (ile Á/val). thus, fq resistance in s. maltophilia shall derive from changes in other areas in the topoisomerases or probably from other mechanisms of resistance, such as efflux pumps. purpose: corynebacterium urealyticum is the cause of encrusted cystitis and other inespecific utis and systemic infections. it is frequently multi-drug resistant, with a high rate of resistance to fluoroquinolones (fq). the mechanisms of resistance to fqs have not been described in c. urealyticum . we describe the c. urealyticum parc gene qrdr region and its relationship with quinolone resistance. materials and methods: the activity of ciprofloxacin (cfx), levofloxacin (lfx), gatifloxacin (gfx), clinafloxacin (cnfx) and moxifloxacin (mfx) against c. urealyticum clinical strains was determined following nccls guidelines for enterococci. we amplified and sequenced their parc qrdr by standard methods. results and conclusions: five strains ( . %) were cfx-susceptible (mic . Á/ . mg/l), had mics Á/ mg/l and ( . %) were highlevel cfx-resistant (mic Á/ mg/l). cnfx was -fold more active than cfx. mfx and gfx had mics of and mg/l. all the strains, including the type strain, showed a c to t change at the position referred to wild type s. aureus parc gene, leading to a ser- -phe change, described as the main parc change in fq-resistant s. aureus . this finding suggest that this mutant sequence, as compared with parc sequences from other grampositives, might be the wild-type for this species, and might explain in part its high resistance rate, and its apparent lightness to develop high-level resistance. purpose: during routine surveillance, we identified ciprofloxacinresistant (mic!/ mg/l) pneumococcal isolates and compared clinical details and resistance patterns. results: they were isolated from sputa ( ) and blood cultures ( ) from adults, most with heart or lung disease. hospital admissions were common; half had been inpatients in the previous months. nineteen patients received quinolones in the preceding months, in part reflecting the local policy (introduced in ) of penicillin and ofloxacin for first line treatment of pneumonia. thirteen patients had radiological signs of pneumonia and were pyrexial with raised inflammatory markers. agar dilution mics for quinolones, including norfloxacin with and without reserpine, penicillin and erythromycin were performed. an increase in norfloxacin mics was noted over the period ( Á/ mg/l) to ( mg/l). fluoroquinolone efflux was suggested in three isolates. resistance to moxifloxacin (mic Á/ mg/l) was noted from onwards. all isolates were serotype v and resistant to penicillin (mic!/ . mg/l). thirty-one were resistant to erythromycin (mic!/ mg/l). conclusion: the policy of using quinolones may have contributed to the development of quinolone resistance and this cluster of isolates. the increasing levels of quinolone resistance observed raise concerns about the future use of newer quinolones for the treatment of respiratory infections. s. maltophilia has emerged in the last years as an important nosocomial pathogen, inherently resistant to most of the antimicrobial agents. new quinolones has been proposed as a treatment of choice because their enhanced activity, but several parameters (t a , atmosphere, method) can affect the results of mics. methods: we have performed mics using two different methods (agar dilution and microdilution) and different conditions: and c of temperature; atmosphere of o and co , and incubation times of , and h. a total of strains were assayed with nine quinolones following standard nccls. comparisons were made between results with Á/ and Á/ h using the x -test (a / . ). results: no differences were found between Á/ and Á/ h results with agar dilution, except with atbs in the case of mics at c co . on the contrary, almost all the atbs showed significant differences in the results with and h using microdilution method, at any condition of ta or atmosphere. comparison of mics (p values, significance level / %) with incubation times of and h at different procedure conditions. the incubation time is a parameter that seems to affect significantly the results of mics of quinolones when microdilution method is used, whereas only few differences can be encountered with the agar dilution method. results: breakpoints were used as proposed by nccls . during the study period the pneumococci resistance was noted as follows: % to pc, % to em and % to sxt. the rank order of activity of the five fqs against multi-drug resistant pneumococci was: cip (mic : mg/l), ofx (mic : mg/l), lvx (mic : mg/l), grx (mic : . mg/l), tvx (mic : . mg/l). conclusions: in romania, fluoroquinolones represent alternative treatment to beta-lactams and macrolides for first-line empirical treatment for respiratory tract infections caused by pneumococci but, continued vigilance for emerging resistance to fqs is further indicated. introduction and material/methods: susceptibility testing (semiautomated broth microdilution method, sensititre, trek diagnostics, usa, following nccls recommendations) was performed with six different quinolones to streptococcus pneumoniae isolates with a ciprofloxacin-cip */mic ]/ mg/l collected in two consecutive sauce$ surveillances in spain ( Á/ / Á/ ). nccls resistance (r) breakpoints were used ( ]/ for ofloxacin-ofl and levofloxacin-lev; ]/ for sparfloxacin-spa; ]/ for gatifloxacin-gat */and moxifloxacin-mox), but for gemifloxacin-gem */where ]/ was used. results were as follows. conclusions: for cip-r isolates gem and mox were the most active agents. gem was the only agent not influenced by cip mic increase regarding prevalence of r , with % resistance for strains with cip mic ]/ mg/l. $sauce is an acronym standing for 'sensibilidad a los antimicrobianos utilizados en la comunidad en españ a' (susceptibility to the antimicrobials commonly used in the community in spain) and is the spanish word for the willow tree. in vitro activity of gatifloxacin and seven other antibiotics against respiratory and urinary tract pathogens from the community. first results of the basic */study ps grimm h, on behalf of a european multicenter study group, institute for med. microbiology, weingarten, germany a total of centers in austria, belgium, france, germany, italy, portugal, spain and switzerland are involved in the basic study (bacterial annual susceptibility information collection). the mics of gatifloxacin (gati), ciprofloxacin (cipro), clarithromycin (clari), benzylpenicillin g (pen), amoxicillin (amox), amoxicillin/clavulanic acid (augm), cefuroxime (cur) and cefixime (cix) were determined using the microdilution method. each center is requested to investigate strains each of the following species: s. pneumoniae (spn), s. pyogenes (spy), s. aureus (sau), e. faecalis (efa), m. catarrhalis (mca), h. influenzae (hin), e. coli (eco), k. pneumoniae (kpn), p. mirabilis (pmi) and p. aeruginosa (pae). so far approximately strains are enrolled. some important mic %/percentage resistance were as follows: from the oral antibiotics tested gatifloxacin has the highest activity and broadest spectrum against all relevant respiratory and urinary tract pathogens. gatifloxacin is a promising alternative for therapy of respiratory tract bacterial infections. in vitro activity of gatifloxacin against bordetella pertussis in comparison with erythromycin, ciprofloxacin and levofloxacin ps bourgeois n, pangon b, ghnassia jc, doucet-populaire f, de versailles ch. microbiologie, le chesnay, france purpose of the study: bordetella pertussis infections are far more common in adults and adolescents than is generally estimated. however, they are often not recognised. infected or colonised adults can act as a reservoir of infection, passing it to children. fluoroquinolones are currently recommended for the treatment of respiratory tract infection in adult patients, which is usually empirical. gatifloxacin is a novel -methoxyquinolone, with a potent activity against both gram-negative and -positive bacteria. the in vitro activity of gatifloxacin was compared with those of erythromycin, the drug of choice for both treatment and prophylaxis of pertussis, ciprofloxacin and levofloxacin, against clinical isolates strains of b. pertussis including erythromycin resistant strains. results: we used the agar dilution method on mueller Á/hinton medium supplemented with % horse blood to determine the mic of each antibiotic. gatifloxacin (mic , . mg/l) was as active as ciprofloxacin and levofloxacin (mic , . mg/l) against both sensitive erythromycin (mic , . mg/l) and resistant erythromycin (mic , !/ mg/l) strains. conclusion: gatifloxacin may be an effective drug in the treatment or prophylaxis of adults with suspected or confirmed pertussis. ex vivo serum activity (killing rates) after gemifloxacin mg versus trovafloxacin mg single doses against ciprofloxacin-susceptible andresistant streptococcus pneumoniae ps calvo a a , giménez mj b , alou l a , gó mez-lus ml a , aguilar l b , prieto j a . a microbiology department, universidad complutense, madrid, spain , b glaxosmithkline, medical department, tres cantos, madrid, spain serum bactericidal activity was measured ex vivo after single dose administration of gemifloxacin (gem) mg and trovafloxacin (tro) mg to healthy volunteers in a randomized, cross-over phase i trial. blood samples were collected h (cmax) after dosing and serum killing rates were determined against a serotype penicillin (pen) Á/ciprofloxacin (cip) susceptible strain (s ) (mics of . , , . and . mg/l for pen, cip, gem and tro) and a serotype pen Á/cip resistant strain (s ) (mics of , , . and . mg/l for pen, cip, gem and tro). tubes with . ml of serum sample and . ml broth ( % todd Á/hewitt'/ % hbss) were incubated over h at c. final inocula was cfu/ml. mean colony counts for samples and controls (k ) are shown in the figure: gem exhibited higher colony counting decrease of the initial inocula, versus tro, for both strains. after h incubation, the initial inocula decrease obtained with tro and the cip susceptible strain was similar to that obtained with gem and the resistant strain, showing a lower influence of cip mic increase in the ex vivo bactericidal activity of gem versus tro. urine bactericidal activity after administration of gemifloxacin and trovafloxacin single doses in a phase i study ps garcía-calvo g a , parra a a , giménez mj b , ponte c a , aguilar l b , soriano f a . a fundación jiménez díaz, medical microbiology, madrid, spain , b glaxosmithkline, medical, madrid, spain urine bactericidal activity after o.d. administration of gemifloxacin (gem) mg and trovafloxacin (tro) mg, was assessed in six adult males in a cross-over phase i trial. urine killing rates (ukr) against escherichia coli atcc (mic mg/l of . and . for gem and tro) and s. saprophyticus atcc (mic mg/l . and . for gem and tro) were performed with samples collected at , Á/ , Á/ and Á/ h. a . ml of iso-sensitest broth and . ml of bacterial logarithmic growth were added to ml sample, giving a final inoculum of cfu/ml. colony counting was performed after , , and h incubation. percentages of initial inocula reduction (iir) were calculated. mean urine concentrations measured by bioassay were (mg/l): . , . and . for gem, and . , . and . for tro. against e. coli , an iir of . % was obtained after h incubation with all samples except with tro at Á/ h. against s. saprophyticus an iir of % was obtained after h incubation with all samples except with tro at Á/ h, where bacterial regrowth was found. the maintenance over h of gem urine antibacterial activity suggests its efficacy in the treatment of uncomplicated cystitis. influence of the decreased susceptibility to ciprofloxacin on gemifloxacin versus levofloxacin efficacy in experimental pneumococcal pneumonia in guinea pigs ps garcia-olmos m a , parra a a , gimenez mj b , garcia-calvo g a , ponte c a , aguilar l b , soriano f a . a fundacion jimenez diaz, medical microbiology, madrid, spain , b glaxosmithkline, medical, madrid, spain the efficacy of ciprofloxacin (cip), levofloxacin (lev) and gemifloxacin (gem) in the treatment of pneumococcal pneumonia was assessed in a guinea pig model using three strains (s) with mics (mg/l) of , and . (s ), , and . (s ) and , and (s ) for cip, lev and gem, respectively. intraperitoneal treatments started h after s. pneumoniae intratracheal inoculation, and continued t.i.d up to four doses. ten animals were included in each group. doses (mg/kg) used were , and for cip, lev and gem, respectively, in order to mimic auc - h and cmax obtained in humans after standard doses. animals that survived h after inoculation were sacrificed and colony counts were performed in lungs ( the purpose of the study levofloxacin (lfx) is a fluoroquinolone whose activity against both gram-negative bacilli and gram-positive cocci enables its use in monotherapy for the treatment of nosocomial pneumonia. our aim was to study the pharmacokinetic Á/pharmacodynamic appropriateness of lfx mg iv bid in the treatment of six inpatients with ventilator-associated pneumonia (vap) ( / years; m Á/ f; / kg). blood and urine samples were collected in steadystate conditions at appropriate intervals. lfx concentrations were analysed by hplc. the aetiological agent was identified in all the cases and its in vitro sensitivity to lfx was always assessed. the results obtained mean values ( /sd) of the major pharmacokinetic parameters were: cmax, . / . mg/ml; vdss, . / . l/kg; t / b, . / . h; cl, . / . ml/min/kg; auc -t, . / . mg/ml h. cumulative urinary excretion was . / . %, confirming that lfx clearance is mainly renal. clinical cure and microbiological eradication were obtained in all the patients after a Á/ day therapy. a suprainfection due to acinetobacter anitratus insensitive to lfx occured in case. the major pharmacodynamic parameters of fluoroquinolone efficacy were significantly higher than the proposed threshold (cmax/mic !/ ; auc/mic !/ ) in all the cases. the conclusion reached the findings suggest that lfx mg bid iv may be considered effective in the treatment of vap caused by sensitive bacteria. comparative pharmacokinetics of levofloxacin in patients with lower respiratory tract infections (lrti) being treated with sequential therapy ps pea f a , brollo l a , lugatti e b , di qual e a , dolcet f b , talmassons g b , furlanut m a . a institute of clinical pharmacology and toxicology, dpmsc, university of udine, udine, italy , b division of pneumology, sm misericordia hospital, udine, italy the purpose of the study levofloxacin (lfx) is a fluoroquinolone whose activity against both gram-negative bacilli and gram-positive cocci enables its use in monotherapy for the treatment of lrti. our aim was to study the pharmacokinetic Á/pharmacodynamic appropriateness of a standard switch lfx iv/os regimen ( mg iv od for Á/ days followed by mg os od for Á/ days) in the treatment of seven inpatients with lrti ( / years; m Á/ f; / kg). blood samples were collected in steady-state conditions at appropriate intervals. lfx plasma concentrations were analysed by hplc. the aetiological agent was identified in / cases and its in vitro sensitivity to lfx was assessed. the results obtained absolute oral bioavailability was . / . , with a cmax of . / . vs . / . mg/ml after iv and oral administration, respectively. no significant difference in the main pharmacokinetic parameters was observed between the two routes. the major pharmacodynamic parameters of fluoroquinolone efficacy were significantly higher than the proposed threshold (cmax/mic !/ ; auc/mic !/ ) in the two assessable cases. all the patients were clinically cured after a Á/ day therapy. the conclusion reached the ad interim findings show that lfx mg od may guarantee per os an exposure similar to that achievable after iv administration, suggesting that sequential therapy may be considered effective in the treatment of lrti. levofloxacine in the exacerbations of copd due to pseudomonas ae ps micheletto c, tognella s, pomari c, dal negro r, ospedale orlandi, div.pneumologia, bussolengo, italy development of antibiotic resistance in bacteria is a problem of great concern. gram-negative bacteria, including multidrug-resistant (mdr) pseudomonas aeruginosa (ps), are responsible for a significant proportion of episodes of copd exacerbations, particularly in elderly ( ). aim was to check the susceptibility to common antimicrobial treatments against ps strains isolated from bronchial secretions in patients with severe exacerbations of copd. methods: microbial investigations were conducted on specimens: spontaneous purulent sputum ( . %), and tracheobronchial aspirates ( . %, collected with a protected specimen brush). results: fifty-seven ps pathogen strains ( cfu) were identified ( . %) and tested over a -month period: ps. aeruginosa . %; ps. putida . %; ps. fluorescens . %, and burkholderia cepacia . %. the assessed susceptibility to most common antibiotics was: levofloxacine ( %), ciprofloxacine ( %), ipenem cil. ( %), ceftazidime ( %); amikacin ( %), and piperacillin'/tazobactam ( %). a much lower susceptibility was found for ticarcillin Á/clavulanic acid ( %), gentamicin ( %), and netilmicin ( %). ( ) at present, levofloxacine proves the most effective antimicrobic option for treating copd exacerbations due to ps infection; ( ) a much more efficient policy of antibiotic prescribing should be promoted in order to prevent the selection of resistant strains in these cases. these results confirm the excellent 'in vitro' activity of levofloxacin against nosocomial gram-negative pathogens, including the esbl producing strains ( % of escherichia coli , e. cloacae and k. pneumoniae were inhibited at . mg/l). levofloxacin was more rapid than ciprofloxacin to determine a bactericidal effect particularly against s. maltophilia . moreover, considering the favourable pk/pd profile, levofloxacin can represent a valid therapeutic option for the treatment of severe gram-negative nosocomial infections. moretti f, quiros-roldan e, casari s, chiodera a, viale p, carosi g. university of brescia, institute of infectious and tropical diseases, brescia, italy a -year-old man, ivdu, hiv positive was attended in aur hospital for fever and toracic pain. a x-chest radiography revealed a round lesion of cm near the lingula with central hyper-diaphan area. lymphocytes cd '/ count was cells/mm and viral load . cp/ ml. hospital stay rhodococcus equi was found in cultures of peripheral blood, faecal and sputum specimens. antibiotic treatment with oral rifampin ( mg/qd) and with intravenous imipenem ( mg tid) was started. due to the persisting fever, immodificated radiography and negativity for p. carinii , mycobacteria and bacteria in bal coltures, imipenem was substituted by parenteral vancomycin ( mg bid). after days, because of persisting fever and increase of the diameter of the lung lesion ( cm) vancomycin was sustituted by oral levofloxacyn ( mg bid), continuing rifampin. after a days course of levofloxacyn therapy the fever remitted. the patient was discharged with levofloxacyn ( mg bid) and rifampin and, after months of follow-up, a radiological control pointed-out a remarkable resolution in the lung lesion. we may suppose that levofloxacyn can be effective for the treatment of r. equi infection, even if more studies (particularly controlled studies) are necessary. liberti a a , izzo b a , loiacono l b , calabria g a , patarino t a , izzo e a . a ii department, naples, d. cotugno hospital, italy , b iii department, naples, d. cotugno hospital, italy the increasing prevalence of salmonella typhi strains with reduced susceptibility of chloramphenicol had prompted the search for other antibiotics with the same efficacy.quinolones are a class of antibiotic with an activity in vitro and in vivo against enteropathogenes. we inwestigated the use of levoxacin in two regimens of treatment of typhoid and paratyphoid infection. patients and methods: thirty-two adult patients were incluted in this study from september to april ; patients had positive culture for s. typhi and six had positive cultures for s. paratyphi . all isolated were fully susceptible to levoxacin. we compared treatment with levoxacin for days, mgr b.i.d. (group , patients), with treatment for days, mgr b.i.d. (group , patients). clinical cure was defined as defervescenze of fever by day of treatment, with an absence of complications and no clinical relapse during the followup. results and conclusion: the clinical cure rate was % ( patients) for group and % ( patients) for group ; the difference in these rates was not statistically significant. the blood cultures of all patients were sterile by day of treatment and remained so until the th month of follow-up, no subjects had clinical or microbiological relapse and all stool cultures remained negative, also. the two regimens of treatment was good tollerated and no adverse event was registered; it was concluded that levoxacin treatment for days in enteric fever is not necessary the mulidrug-resistence of s. typhi led to the use of quinolones as the first-line drug in the treatment of enteric fever. pefloxacin in the treatment of patient with acute infectious diarrhoea ps troselj-vukiae tvb a , strahinja v b , poljak i a , stojanoviae d c , nikoliae n d . a department of infectious disease, university hospital center, rijeka, croatia , b glaxosmithkline, marketing, rijeka, croatia , c dept. rijeka, institute of public health, rijeka, croatia , d dept. rijeka, maritime academy, rijeka, croatia the purpose of the study was to investigate clinical and bacteriological efficiency in and days pefloxacin treatment and to compare it with symptomatic therapy. the results obtained in patients treated with pefloxacin the therapy was clinically effective already in the third day while in the control group this happend in the th day. bacteriological eradication was noted in patients ( %) of the first and patients ( %) of second group in the th days of the treatment. they all had negative cultures and weeks after pefloxacin protocols were completed. only patients ( %) in control group had negative stool cultures in the th day of the treatment and all of them weeks after it ended. there was no statistically significant difference in clinical (p / . ) and bacteriological (p / . ) efficiency between and days pefloxacin treatment protocols. both protocols significantly differed in clinical (p b/ . ) and bacteriological (p / . ) eradication from the control group. the conclusion reached is that the efficiency of pefloxacin (quinolones) in the treatment of acute infectiuos diarrhoea and justifies their use in the more severe forms of the disease. dalhoff a a , ullmann u b , schubert s b . a bayer ag, wuppertal, germany , b university of kiel, institute of med. microbiology, kiel, germany background: the antibacterial activity of moxifloxacin (mxf) was compared to levofloxacin (lev), amoxicillin (amx), clarithromycin (cla) and erythromycin (ery) in an in vitro model. method: pharmacokinetics in bronchial mucosa (bm) and serum (s) following single oral doses of mg mxf or cla and mg lev, amx or ery were simulated using a one compartment model. bacteria tested staphylococcus aureus (nos. , ), streptococcus pneumoniae (nos. , ). aliquots were taken ( Á/ h) and plated on to brain heart infusion agar for enumeration. results: s. pneumoniae was eliminated by all agents studied. significant differences were apparent with s. pneumoniae and the s. aureus strains: objective: to compare the safety and efficacy of once-daily moxifloxacin with once-daily ceftriaxone in the treatment of cap in hiv-infected patients (pts). methods and results: in a retrospective survey, oral moxifloxacin ( mg daily)/ Á/ days) was compared to standard regimen of i.v. ceftriaxone ( g daily)/ Á/ days) for treatment of cap in hiv'/ pts. adults pts with clinical signs and symptoms of cap and consistent chest x-ray findings were included. pts had a median age of years (range Á/ and % were male). demographic characteristics were similar in both treatment groups; pts received mxifloxacin and pts ceftriaxone. clinical success rates were % for moxifloxacin and % for ceftriaxone. at a post-study evaluation approximately weeks later, moxifloxacin-treated pts and ceftriaxone-treated pts had relapsed. the adverse events reported were comparable for both treatment groups. there were four-related adverse events ( gi, headache) for moxifloxacin-treated and ( gi, skin) for ceftriaxonetreated pts. conclusion: the results of this study show that moxifloxacin as oral therapy is as effective and well tolerated as i.v. ceftriaxone in the treatment of hiv'/ pts with cap. therapy with moxifloxacin was not associated with any significant clinical or laboratory abnormalities. these data suggest that once-daily oral administration of moxifloxacin is potentially convenient and cost-effective alternative therapy for cap in pts with hiv infection. moxifloxacin in the treatment of acute maxillary sinusitis after first-line therapy failure or acute sinusitis with high risk of complications ps gehanno p a , berche p b , perrin a b , arvis p c . a ent department, bichat claude bernard hospital, paris, france , b microbiology department, necker enfants malades hospital, paris, france , c bayer pharma, medical affairs department, paris, france the efficacy and safety of moxifloxacin (mxf) mg once daily for days was evaluated in the treatment of acute maxillary sinusitis after first-line therapy failure, or acute sinusitis with high risk of complications. in this prospective, multicenter study, a total of patients with acute bacterial sinusitis confirmed by sinus x-ray were valid for efficacy analysis: one hundred and seventy five patients ( . %) had an acute maxillary sinusitis which failed to respond to a previous antibiotic therapy given for a mean duration of . days, and ( . %) had an acute sinusitis with high risk of complications (frontal: , pan-sinusitis: and sphenoid: ). ninety two patients ( . %) were microbiologically valid. clinical cure and continued clinical cure rates at Á/ and Á/ days post-therapy were . and . %, respectively. clinical cure rates at Á/ days post-therapy were . and . % in sinusitis after first-line therapy failure and in sinusitis with high risk of complications, respectively. bacteriological eradication rate during therapy (day Á/ ) was . %. at Á/ days post-therapy. bacteriological success rates were . % in patients who failed to respond to a previous antibiotic and . % of patients who had sinusitis with high risk of complications. . % of patients experienced drug-related adverse events, abdominal pain ( . %), nausea ( . %) being the most frequently reported events. mxf was rapidly effective and a well-tolerated treatment for this kind of infection. neisseria gonorrhoeae with decreased susceptibility to penicillin and ciprofloxacin: novel mutation patterns in the gyr a and par c genes of ciprofloxacin resistant isolates and plasmid profile of penicillin resistant isolates of n. gonorrhoeae in india (delhi) ps chaudhry u, saluja d. dr. b. r. ambedkar center for biomedical research, university of delhi, delhi, india commercial sex workers (csws) serve as the most important reservoir of gonorrhoea. periodic monitoring of the antimicrobial susceptibility profile of neisseria gonorrhoeae in a high-risk population provides essential clues regarding the rapidly changing pattern of antimicrobial susceptibilities. in india, such a surveillance of the in vitro antimicrobial susceptibility of n. gonorrhoeae was established in . significant increasing trend of penicillin and ciprofloxacin resistance with high mic of Á/ and Á/ mg/ml, respectively were found over the years ( Á/ ) . the molecular basis of ciprofloxacin resistance, i.e. mutations in the gyr a and the par c genes of isolates, were analyzed. four isolates (with an mic of mg/ml for ciprofloxacin) harbored triple mutations (ser- to phe, asp- to asn and val- to leu) in the gyr a gene. the third mutation of val- to leu, lies downstream of the quinolone resistance determining region of the gyr a and has not been described before in gonococcus. in addition, these isolates had a phe- to tyr substitution in the par c, a hitherto unknown mutation. the alterations in the par c gene were seen in these isolates only in the presence of changes in the gyr a gene and comprised amino acid changes at codons , , , , and . the presence of b-lactamase plasmid among the penicillinresistant isolates was determined by their plasmid profiles and further confirmation was carried out by a pcr based protocol. our findings suggest that emergence of penicillin and ciprofloxacin resistance in n. gonorrhoeae isolates from a major std center in india, indicates the need for the increased awareness and prudent use of antimicrobials. in vitro activity of newer antibiotics against methicillin-resistant staphylococcus aureus ps gutierrez zufiaurre mn, sanchez hernandez j, munoz-bellido jl, garcia-rodriguez ja. hospital universitario de salamanca, microbiología, salamanca, spain purpose: mrsa are frequently co-resistant to a number of structurally unrelated antibiotics. more than % mrsa are resistant to gentamycin, ciprofloxacin, macrolides and clindamycin. newer antibiotics active against multi-drug resistant grampositives have been developed. we have tested the in vitro activity of newer antibiotics against genetically-characterized, high level ciprofloxacin resistant mrsa. material and methods: thirty-six ciprofloxacin-resistant, gyra/grla mutant mrsa clinical strains were tested against levofloxacin (lfx), ciprofloxacin (cfx), moxifloxacin (mfx), gatifloxacin (gfx), erythromycin (er), telithromycin (tl), linezolid (lin), synercid (syn) and vancomycin (va). mics were determined by the agar dilution method, according nccls guidelines. results and conclusions: all the strains were resistant to cfx, , % were lfx-susceptible and . % were gfx-susceptible. nevertheless, mics of lfx and gfx for all susceptible strains was in the highest extreme of the susceptibility range. mfx was the most active quinolone. almost all the strains were high-level er-resistant with constitutive mlsb phenotype. tl did not improve significantly its behaviour, although it was -fold as active as er against the only er-susceptible strain. va, lin and syn had excellent activity against all the strains. they showed a very homogeneous behaviour against all the strains that were included in a range of Á/ mg/l of lin and va and . Á/ mg/l. sanchez hernandez j, gutierrez zufiaurre mn, munoz-bellido jl, garcia-rodriguez ja. hospital universitario de salamanca, microbiología, salamanca, spain purpose: corynebacterium urealyticum is the etiologic agent of encrusted cystitis and inespecific utis, and can be also involved in systemic infections. c. urealyticum is frequently multi-drug resistant, so only glycopeptide antibiotics and tetracyclines have high susceptibility rates, while fluoroquinolones resistance rates vary significantly. we have tested the in vitro activity of linezolid, telithromycin, synercid and newer fluoroquinolones against multi-drug resistant c. urealyticum clinical strains. material and methods: sixty-four c. urealyticum clinical strains were tested against levofloxacin (lfx), ciprofloxacin (cfx), moxifloxacin (mfx), erythromycin (er), telithromycin (tl), linezolid (lin), synercid (syn) and vancomycin (va). mics were determined by the agar dilution method according guidelines defined by the nccls for enterococci. results and conclusions: results confirm the high resistance rate to older fluoroquinolones and macrolides, with !/ % cfx resistance and % er-resistance. lfx was more active (mic mg/ml). mfx was the most active fluoroquinolones (mic mg/ml). tl improve its behaviour in respect to er (range . Á/ mg/ml). va, lin and syn had excellent antimicrobial activity. no resistant strains were found. mic were , . and mg/ml, respectively. mics were similar for all the strains independently of their resistance to other antibiotics plasma concentrations, urinary excretion and bactericidal activity of linezolid ( mg) versus ciprofloxacin ( mg) in healthy volunteers after a single oral dose ps wagenlehner fme a , wydra s a , onda h a , kinzig-schippers m b , sö rgel f b , naber kg a . a hospital st. elisabeth, urologic clinic, straubing, germany , b institute for biomedical and pharmaceutical research, (ibmp), nürnberg-heroldsberg, germany purpose of the study: in a randomized cross-over study volunteers received a single oral dose of mg linezolid versus mg ciprofloxacin to assess plasma concentrations (up to h), urinary excretion (by hplc), and urinary bactericidal titers (ubt) up to h. the mean maximum plasma concentration of linezolid was . mg/ ml and of ciprofloxacin . mg/ml. the cumulative renal excretion (mean) of parent drug was %/ % for linezolid/ciprofloxacin. ubts were determined for a reference strain and five gram-positive clinical uropathogens with the following mics (mg/ml) for linezolid/ciprofloxacin: s. aureus atcc ( / . ), s. aureus (mssa) ( / ), s. aureus (mrsa) ( / ), s. saprophyticus (msse) ( / . ), e. faecalis ( / ), e. faecium ( / ). results: median ubts measured within the first h for linezolid were : for enterococcal strains and : to : for the four staphylococal strains. median ubts for ciprofloxacin were : for the two enterococcal strains, : to : for the two ciprofloxacin susceptible, : . for the two resistant staphylococcal strains. areas under the ubt Á/time-curve showed statistically significant differences only for the two ciprofloxacin resistant staphylococcal strains in favour of linezolid. conclusion: linezolid exhibited the same bactericidal activity against ciprofloxacin resistant as susceptible strains. linezolid should be tested for treatment of complicated uti due to gram-positive uropathogens in a clinical trial. whitehouse t a , cepeda ja a , tobin purpose: we performed pharmacokinetics within a double-blind, randomised trial comparing linezolid and teicoplanin in intensive care patients with known or suspected gram-positive infection. they received either mg linezolid intravenously -hourly, or mg teicoplanin -hourly for the first three doses and once daily thereafter (or every rd day if renally impaired). blood samples were collected to create serum pharmacokinetic profiles. linezolid was quantitated by hplc and teicoplanin by fluorescence polarization immunoassay. results: twenty two patients were studied in the linezolid group (m Á/f : , mean age years [range Á/ years]). median treatment duration was . days (range Á/ ). eighteen patients were treated with teicoplanin (m Á/f : , mean age years [range Á/ ]) for median days (range Á/ ). steady state peak concentrations (mean / sd) for linezolid and teicoplanin were . / . and . / . mg/l, respectively. trough concentrations at day were . / . mg/l for linezolid and . / . mg/l for teicoplanin. recommended breakpoints of staphylococcus aureus are mg/l for linezolid and mg/l for teicoplanin. accumulation occurred in one -year-old linezolidtreated patient with impaired renal function. conclusion: current recommended dosing regimens for linezolid and teicoplanin are generally appropriate in the critically ill, though a more detailed analysis is required. stamos g, lebessi e, ioannidou s, paleologou n, kallergi k, foustoukou m, 'p. and a. kyriakou ' children's hospital, microbiology, athens, greece the purpose of the study was to investigate the susceptibility of methicillin resistant staphylococcus aureus (mrsa) isolates from a -bed paediatric hospital to quinupristin/dalfopristin (q/d, streptogramin combination) and linezolid (lzd, oxazolidinone). material: we performed a retrospective analysis of mrsa strains, isolated from patients hospitalized in miscellaneous medical departments [neonatal unit ( ) , surgical wards ( ), orthopaedic wards ( ), oncology unit ( ), other wards ( ) and outpatient clinic ( )], during a -year period ( Á/ ) . the sources of isolation were pus ( ), throat ( ), nasal ( ), bronchial ( ), skin ( ), stool ( ) ear ( ) and other ( ) specimens. all isolates were sensitive to glycopeptides, while . % were resistant to gentamicin and . % to erythromycin. methods: the sensitivity testing was performed by a disk diffusion method (bbl sensitivity disks, becton dickinson), according to nccls guidelines. the breakpoint zone diameters for lzd and q/ d were ]/ and ]/ mm for susceptibility and / and / mm for resistance, respectively. results: all isolates were proved to be susceptible to both antibiotics. the mean inhibition zones were . mm for lzd and mm for q/d. conclusions: lzd and q/d are very promising antimicrobial agents, showing excellent activity against mrsa clinical isolates. the prudent therapeutic use is strongly recommended to avoid the emergence of resistance. in vitro activity of streptogramins and oxazolidinones against streptococcus pneumoniae clinical isolates ps stamos g, lebessi e, paleologou n, psatha m, sanida p, zaphiropoulou a, foustoukou m, 'p. and a. kyriakou ' children's hospital, microbiology, athens, greece the purpose of this study was to evaluate the in vitro activity of linezolid (lzd), a member of oxazolidinones and the streptogramin combination quinupristin/dalfopristin (q/d) against clinical isolates of streptococcus pneumoniae from a tertiary care paediatric hospital. material: a total of pneumococcal isolates exhibiting reduced susceptibility to common antibiotics were included in the study. the strains were isolated from middle ear fluid ( ), eye ( ), nasal ( ) blood ( ) and other ( ) cultures during the last years. the percentages of the isolates that were resistant to penicillin, erythromycin, cotrimoxazole and clindamycin were . , . , . and . %, respectively. methods: the susceptibility testing was performed by a standard disk diffusion method (bbl sensitivity disks, becton dickinson). in case of marginal results or intermediate sensitivity to quinupristin/ dalfopristin, the mic was determined using the e -test method (ab biodisk). results: all isolates were found to be sensitive to lzd. q/d was very active as well, except for two isolates that exhibited intermediate susceptibility, showing cross-resistance to macrolides and clindamycin, as well. conclusions: the new antimicrobial agents show excellent activity against resistant to common antimicrobials pneumococcal isolates, but the clinical use is not suggested, unless no other therapeutic solutions are available. linezolid is a new oxazolidinone with excellent activity against gram-positive organisms including glycopeptide-resistant strains of staphylococci and enterococci. in icu linezolid has been used for the treatment of severe gram-positive infections in a control trial. the susceptibility pattern of all gram-positive isolates from icu patients has been studied. methods: a total of specimens from icu patients were processed, were from patients enrolled in the antibiotic trial. all methicillin-resistant staphylococcus aureus (mrsa), coagulase-negative staphylococci (cons), enterococcus sp and methicillin-sensitive staphylococcus aureus (mssa) were tested. the break point for linezolid was mg/l and for teicoplanin mg/l. isolates were tested for susceptibility by e -test. results: linezolid ( isolates) mic / (mg/l) were as follows: mrsa (n / ) . / , cons (n / ) . / . , enterococcus sp (n / ) . / . , mssa (n / ) . / . teicoplanin ( isolates) mic / (mg/l) mrsa (n / ) . / . , cons (n / ) / . , enterococcus sp (n / ) . / . , mssa (n / ) . / . . all grampositive isolates were inhibited by concentrations of linezolid below the breakpoint including eight strains of staphylococci resistant to teicoplanin. conclusions: linezolid was highly active against grampositive isolates. resistance to teicoplanin was similar to other reported series. there was no emergence of resistance to linezolid. mrsa colonization is often a limiting factor for discharge from icu. clearance of mrsa is seldom achieved with conventional glycopeptide treatment. the oxazolidinone, linezolid, has excellent soft tissue and respiratory tract penetration and might be expected to eradicate carriage in some patients. we recently performed a doubleblind randomized trial in icu patients with known/suspected gram positive infection. received intravenous linezolid, mg b.d., and patients received teicoplanin mg o.d. mrsa clearance was assessed at end of treatment (eot), at -and days follow-up. results: in the linezolid and teicoplanin groups, and were known to be colonized with mrsa at study entry, respectively, while and were not. detection of clearance of mrsa colonization at eot was % for linezolid vs % for teicoplanin group (x b p b/ . ), at days it was % vs % (x b p b/ . ), and at days % vs % (ns). conclusion: short-term mrsa clearance can be achieved in significantly more patients treated with linezolid however this was not maintained at days, either because of incomplete initial eradication or recolonization. further analysis will follow when molecular typing of the isolates is completed. penetration of linezolid into bone, fat and muscle during hip arthroplasty ps lovering am, bannister gc, zhang j, macgowan ap, southmead hospital, bcare, bristol, uk there are limited data describing the concentrations and penetration of linezolid (lzd) into tissues, such as bone, that can be used to guide therapy for non-vascular infections. here we report the concentrations and penetration of lzd for bone, fat and muscle in comparison with cefamandole (cmd). twelve patients received mg lzd as a min infusion and mg cmd as a bolus injection immediately before hip arthroplasty. bone, fat, muscle and blood samples were collected at timed intervals after the infusion and assayed by a validated hplc method. for bone, peak levels of both agents occurred min after administration with mean levels of lzd . mg/kg versus cmd . mg/kg, decreasing to lzd . mg/kg versus cmd . mg/kg at min. correction for blood concentrations gave penetration of lzd % versus cmd % at min and lzd % versus cmd % at min. for fat and muscle, peak levels occurred min after infusion. mean levels were lzd . mg/kg versus cmd . mg/kg (fat) and lzd . mg/kg versus cmd . mg/kg (muscle). correction for blood concentrations gave penetration of lzd % versus cmd % (fat) and lzd % versus cmd % (muscle). we conclude that linezolid exhibits rapid penetration into bone and associated soft tissues achieving levels in excess of the mic for sensitive organisms; with a similar distribution and penetration profile to agents currently used for treatment of infections in these tissues. bacqué e a , barrière jc a , berthaud n b , desmazeau p b , dutruc-rosset g b , dutka-malen s b , ronan b b . a aventis pharma, chemistry, paris, france , b aventis pharma, disease group, paris, france xrp is a new oral streptogramin composed of semi-synthetic synergistic components in a / (w/w) association: rpr ( d-( -morpholino)methyl- d, g-dehydro pristinamycin i e ) from pi a and rpr [( r )- -deoxy- -fluoro pristinamycin ii b ] from pii b by original synthetic routes. the association has antibacterial activity against staphylococci including methicillin */mls b -resistant strains (mic range: . */ mg/ml), streptococci (mic : . mg/ml), pneumococci including multidrug resistant strains (mic : . mg/ ml), enterococci including vancomycin-resistant strains (mic : mg/ ml), m. catarrhalis and neisseria spp. (mic : . mg/ml), h. influenzae (mic : mg/ml), legionella spp. (mic : . mg/ml) and anaerobes (mic range: . Á/ mg/ml). xrp is generally bactericidal at the concentration of Á/ )/the mic against s. aureus , s. pneumoniae , h. influenzae and demonstrates consequent pae ( . Á/ !/ . h at Á/ )/mic, following an exposure of . Á/ h). mutants of s. aureus to xrp were isolated at low frequencies ( . )/ ( Á/ . )/ ( ) at )/ and )/mic while no mutant could be isolated at )/mic. these results suggest that xrp ( / w/w) is a promising compound for the treatment of community-acquired infections. ex vivo evaluation of rpr /rpr (xrp ), a new oral streptogramin ps berthaud n, diallo n. aventis pharma sa, infectious disease group, paris, france the intra cellular activity of xrp , was assessed in j murine macrophages containing ingested staphylococcus aureus (three strains) or l. pneumophila (one strain). at the concentration of )/ the mic, growth of s. aureus was strongly inhibited after a -h period of incubation (d log cfu/ml vs t controls range: (/ . Á/(/ . , according to the strain tested). at the concentration of )/ the mic, growth of intracellular l. pneumophila was inhibited after a Á/ -h period of incubation (d log cfu/ml vs t controls about (/ . and (/ . at and h, respectively). rpr and rpr alone had also inhibiting effect on bacterial growth (d log cfu/ml vs t controls after h of incubation about (/ . and (/ . , respectively). the bactericidal activity of xrp was also assessed against slowly growing s. aureus , under experimental conditions mimicking those observed in patients with an infected indwelling device (first step of infection: adherence to inert support; declared infection: biofilm model). under the experimental conditions, xrp demonstrated a rapid and potent bactericidal effect against s. aureus adherent to an inert support or included in biofilm. this effect was observed at each of the three concentrations tested ( , , and , and )/ mic, respectively). in vivo evaluation of xrp (rpr /rpr ), a new oral streptogramin ps berthaud n, huet y, aventis pharma sa, infectious disease group, paris, france the oral efficacy of xrp , was assessed in staphylococcus and pneumococcal murine infections. mice were challenged ip ( )/ , and )/ times ld ). abscesses were established by intramuscular injection of about bacteria into the right thigh of mice. pneumonia was established by intranasal injection of about bacteria. mice were treated twice a day for (staphylococcus aureus septicaemia and abscesses), (s. pneunomoniae septicaemia) or days (s. pneumoniae pneumonia). six to days post infection, for septicaemia and abscesses the results were expressed as ed , whereas for pneumonia they were expressed as the dose yielding an average survival time (ast) significantly longer than that of the untreated infected controls. xrp was efficacious in the treatment of experimental infections in mice caused by mls b -sensitive and -constitutively resistant s. aureus (ed range: Á/ and Á/ mg/kg/administration in septicaemia and abscess models, respectively). it was also efficacious in the treatment of infections caused by s. pneumoniae whatever the serotype and the resistance profile of the strains tested (ed range: Á/ mg/ kg/administration in septicaemia, ast: mg/kg/administration). these results suggest that xrp might be effective for the treatment of staphylococcal and pneumococcal community-acquired infections. xrp (rpr /rpr ), a new oral streptogramin: bactericidal activity and pharmacokinetics in a model of streptococcus pneumoniae mouse pneumonia ps berthaud n, huet y, diallo n. aventis pharma sa, infectious disease group, paris, france the bactericidal activity against streptococcus pneumoniae of xrp , a new oral streptogramin composed of two semi-synthetic synergistic components in a / (w/w) association (rpr , pristinamycin i derivative and rpr , pristinamycin ii derivative), was assessed in lungs of mice with pneumonia. mice were inoculated intranasally with about cfu of strain - (mls bresistant). eighteen hours later (t ), animals received xrp ( mg/kg p.o). the administration was repeated , , , and h afterwards. to study the influence of varying the ratio of pi to pii component administered on activity and pk parameters, ratios of rpr to rpr ranging from / to / were also administered under the same conditions. after an oral unitary administration at mg/kg, xrp , as well as ratios of rpr to rpr ranging from / to / , demonstrated strong and quick bactericidal activity in lungs. lung levels of rpr and rpr were generally equal or two times higher than blood levels. resulting rpr /rpr ratios in blood and lung, although not in accordance with the initial ratio administered, were synergistic for Á/ h in blood and for Á/ h in lungs explaining the activity observed. conclusion: based on in vitro data, telithromycin is a good candidate for the treatment of rti. in vitro evaluation of abt- , telithromycin and azithromycin against streptococcus pneumoniae , moraxella catarrhalis , haemophilis influenzae and methicillin-resistant staphylococcus aureus ps steele-moore l, berg d, barnes i, couch k, klein j, holloway w. christiana care, infectious disease, wilmington, us macrolide resistant streptococcus pneumoniae (sp) is a worldwide concern predominantly because these isolates tend to be multiply drug resistant. new agents with increased activity against these pathogens are clinically important. the ketolide class of antimicrobial agents demonstrate excellent in vitro activity against sp, even those that are macrolide resistant. the in vitro activities of the ketolides abt- (a) and telithromycin (t) were compared to azithromycin (az) against clinical isolates of sp, moraxella catarrhalis (m.cat), haemophilis influenzae (h.flu) and mrsa. organisms tested: strains of sp (including az resistant), h.flu, mrsa and m.cat. microdilution mic tests were performed following nccls recommendations using freshly prepared plates containing haemophilis test medium for h.flu, cation adjusted mueller-hinton broth (camhb) with laked horse blood for sp and camhb for m.cat and mrsa. the new ketolides, a and t had superior activity against sp including the az resistant strains (mic s: a / . mcg/ml, t / . , az / ). all compounds had excellent activity against m.cat while none demonstrated activity against mrsa. h.flu activity was comparable among a, t and az. these new ketolides are not currently approved by the fda; however t has been approved in europe. ló pez h, vidal gi, salomó n jm, scaglione m, zitto tr. centro de infectología, infectious diseases, buenos aires, argentina objective: we evaluated the impact of the initial treatment failure rate, hospitalisation and costs in outpatient treatment of adult cap in argentina comparing amoxicillin, clarithromycin and telithromycin. method: a probabilistic model was implemented in outpatient treatment of cap. we estimated an initial treatment with amoxicillin, clarithromycin or telithromycin. we assumed expected clinical cure at . , . and . %, respectively. for those patients with failure treatment we evaluated a second-line of antibiotics (amoxicillin followed by clarithromycin and clarithromycin followed by new fluorquinolone) or hospitalisation. patients with telithromycin and failure treatment must be hospitalised without a second line of outpatient treatment. costs of cap included drug's costs by days, medical visits, chest radiographies, analysis and hospitalisation. results: we estimated treatments in patients and first-line drug failure in , and patients with amoxicillin, clarithromycin and telithromycin, respectively. costs in outpatient treatment were: hospitalisation $ , and $ , . ; second-line drug $ and $ ; second-line hospitalised $ . and $ with amoxicillin and clarithromycin, respectively and hospitalisation with telithromycin $ . conclusions: telithromycin showed lower clinical failure, hospitalisation and costs in cap. some studies suggest shortening cap telithromycin treatment to days helping adherence to treatment and decreasing costs even more. the new macrolides */a good alternative of tetracycline in the treatment of mediterranean spotted fever ps popivanova nip a , petrov aip a , boykinova obb a , kazakova zkk a , baltadjiev agb b . a medical university, infectious disease, plovdiv, bulgaria , b department of anatomy, medical university, plovdiv, bulgaria mediterranean spotted fever (msf) caused by rickettsia conorii appears an endemic disease for some regions in bulgaria. frequently the disease has a severe course with multiple organ lesions. the early and adequate treatment is of extreme importance for the outcome of the disease. searching an alternative antibiotic treatment of this disease we considered macrolides for their good cell and tissue penetration and dose-dependent bacteriostatic and bactericide effect. we treated msf patients with doxycycline )/ mg/day, patients with clarithromycin )/ mg/day, as well as patients with midecamycin )/ mg/day and midecamycin acetate mg/kg/day. as a surrogate marker for treatment evaluation the effect on the febrile syndrome was used. our findings showed that by the th day of treatment the fever normalized in . , . and . % of the patients treated with doxycycline, clarithromycin and midecamycin, respectively. for the same period the patient fever decreased below c in , and . %, respectively. the intoxication symptoms were influenced within the same period equally in all treated patients. conclusions: we suggest that the new macrolides appear a good alternative of tetracycline on patients with msf. erythromycin resistance of gram /'// cocci in bulgaria. benefits of the new macrolides in the treatment of respiratory infections ps popivanova ni a , yovtchev ip b , dobreva md c , argirova ta c . a medical university, infectious disease, plovdiv, bulgaria , b medical university, ear-nose-throat disease, plovdiv, bulgaria , c medical university, microbiology, plovdiv, bulgaria in the recent years we tested erythromycin sensitivity of species of gram /'// cocci isolated from throat and nose secretions, ear and eye effusions, sputa, cerebrospinal fluid and blood cultures, vaginal and urethral secretions, urine and fecal samples from patients with inflammatory diseases of the listed organs and systems. staphylococcus aureus , staphylococcus coagulase /(//, streptococcus â-haemolyticus , enterococcus were isolated. of these microorganisms s. aureus was the most abundant. our resistograms revealed sensitivity of the gram /'// cocci in . and . % for and , respectively, and resistance of . and . %, respectively. in the tests with midecamycin and midecamycin acetat the same microorganisms showed sensitivity of . % and resistance of . %. the clinical findings showed excellent effect of the new macrolides including clarithromycin and azalides */azithromycin. we conclude the resistance of gram /'// cocci and especially of s. aureus to erythromycin increases very quickly and has reached dramatical extent. by now, the new , , and -membered ring macrolides and azalides show high antibacterial activity and good clinical effect. pappas ga, liberopoulos e, tsiara s, elisaf m, tsianos e. university hospital, internal medicine, ioannina, greece quinupristin/dalfopristin (q/d) is a novel injectable streptogramin antibiotic which initiation in therapeutics was hailed as an important step towards treatment of vancomycin-resistant enterococcus faecium (vref) species. initial reports concluded in an excellent response of vref to q/d. reports of q/d-resistant strains of e. faecium have emerged, both in usa and europe. we report two cases of e. faecium bacteremia in which the responsible isolate was not sensitive to q/d. the first patient was a woman with acute leukemia and septicemia. e. faecium was cultured from blood samples: the species was resistant to almost all antibiotics, exhibiting sensitivity only to tetracycline (!), while its sensitivity to q/d was indermediate. the second patient was a man with endocarditis, in whom blood cultures isolated e. faecium sensitive to a number of antibiotics, including ciprofloxacin and vancomycin; still the sensitivity to q/d was indermediate. q/d has not been officially introduced to the antibiotic arsenal of greek medicine. moreover, the drug has never been used in our hospital, not even experimentally. other e. faecium species isolated in our hospital have been sensitive to q/d. how much hope can be put on a drug that seems to be partly useless before its initiation? increasing reports of v/ q-resistant strains of e. faecium from all over europe raises fears that the v/d story might well end before it begins. varadinova t a , diakov t a , karagiozova d a , genova p a , pardon p b , baudry c b , quideau s b . a sofia university, virology, sofia, bulgaria , b et institut du pin, centre de recherche en chimie moleculaire, universite bordeaux , bordeaux, france vegetable tannins posses a wide range of biological activities. the aim of the present study was to evaluate the cytotoxicity of five purified vegetable tannins against mdbk cells. the maximal nontoxic concentrations (mnc) and the concentrations required to inhibit cell growth by % (cc ) were evaluated after , and h periods of action. mnc values after h indicated that compounds stimulated cell surveillance when applied in concentrations lower than . mm. cc values indicated: (i) a decrease in cytotoxicity after h as cc were up to times lower than those observed after the h period, and (ii) a re-increase in cytotoxicity when the period of action was prolonged up to h as cc were times lower than those observed after the h period. these data thus appear to reveal the capability of the investigated natural polyphenolic products to stimulate cell surveillance in a time-dependent manner. antibacterial effect survey of enoxolone on periodontopathogenic and capnophilic bacteria isolated from specimens of patients with periodontitis ps salari mh a , kadkhoda z b , sohrabi n a . a tehran university of medical sciences, pathobiology, tehran, islamic republic of iran , b tehran university of medical sciences, dentistry, tehran, islamic republic of iran objectives: most of the microorganisms associated with periodontitis are capnophilic and anaerobic bacteria. purpose of this study was to detection of antibacterial effect of enoxolone on periodontopathogenic and capnophilic bacteria. methods: in this study periodontopathogenic and capnophilic bacteria were isolated from specimens of patients with periodontitis by culture method. an anti-bacterial activity of enoxolone against these microorganisms was investigated by minimum inhibitory concentration (mic) and minimum bactericidal concentration (mbc) methods. results: based on our findings the mic, mbc and lethal does (ld ) of enoxolone for actinobacillus actinomycetemcomitans , eikenella corrodens and capnocytophaga were ' , , ', ' , , ', and ' , , ' mg/ml, respectively. conclusion: our results show enoxolone has antibacterial effect on a. actinomycetemcomitans , e. corrodens and capnocytophaga spp. sakalova stn. medical university, microbiology, grodno, belarus we have synthesized diamides of dicarboxylic acids, with components such as -nitrothiazole benzolsulphamides and triazol. all the above compounds exhibited bacteriostatic activity towards some microorganisms. for further studies of bacteriostatic activity of amides and diamides of dicarboxylic acids, as well as for determination of 'structure Á/activity' relationship, we have synthesized a range of monoamides. antibacterial activity of the synthesized compounds was studied in vitro by agar dilution methods. for this purpose, approximately various gram-positive and -negative microorganisms including clinical strains of staphylococcus aureus , bacillus subtilis , serratia marcescens , escherichia coli , proteus morganii , micrococcus lisodeicticus , staphylococcus epidermidis , shigella sonnei , salmonella typhimurium , yersinia enterocolitica . minimum inhibitory concentration was expressed in mg/ml. nitazole was used as a comparison substance. analysis that new derivatives of -nitrotiasole have high antibacterial activity relative towards certain microorganisms included strains obtained from infection department's patients. results will be shown. microbial susceptibility to the essential oil of ziziphora clinopodiodes lam. ps purpose of the study: antimicrobial activities of essential oils vary from oil to oil and from one micro organism to another. the antimicrobial and chemical properties of essential oil from ziziphora clinopodiodes lam. has not been studied and hence the present study was planned to evaluate those properties against a series of micro organisms viz, escherichia coli , staphylococcus aureus , pseudomonas aeroginosa , klebsiella pneumonia , bacillus subtilis , bacillus licheniformis , streptococcus faecalis , candida albicans and saccharomyces cerevisiae . results: z. clinopodiodes lam. essential oil was found to have remarkable antimicrobial property against all the microorganisms but p. aeroginosa . the oil exhibited its best antimicrobial activity within a maximum of min. seventeen components were identified by gas chromatography and mass spectrometry (gc and gc/ms) analysis of the oil, out of which pulegone ( . %), neomenthol ( . %), cyclohexene, -methyl- -( -methenyl)trans ( . %), , -cycloheptadien- -one, , , -trimethyl ( . %), piperitone ( . %), and limonene'/ , -cineole ( . %) constitute major parts of the oil. conclusion: monoterpenes seem to have antimicrobial role. it seems necessary to explore antimicrobial properties of new harmless antimicrobial agents from natural sources as substitutes for common chemical drugs. methanol extract of carpobrotus edulis enhances killing of methicillin resistant staphylococcus aureus phagocytosed by thp- human monocyte derived macrophages and promotes the release of modulators of cellular immunity ps although alkaloids from the family mesembryanthemaceae have anti-cancer activity, species of this family have received little attention. because these alkaloids also exhibit properties normally associated with compounds that have activity at the level of the plasma membrane, we have studied a crude methanol extract of carpabrotus edulis , a common plant found along the portuguese coast, for properties normally associated with plasma membrane active compounds. the results of this preliminary study show that the extract is non-toxic at concentrations that prime thp- human monocytederived macrophages to kill ingested methicillin resistant staphylococcus aureus and promote the release of lymphokines associated with cellular immune functions. the extract also induces the proliferation of thp- cells within day of exposure and days earlier than that induced by phytohemagglutinin. similar results were obtained with monocyte-derived macrophages isolated from human peripheral blood. the active component or components of the plant extract may be exploited as intracellular active anti-bacterials as well as modulators of cellular immunity. enhancing of erythromycin production by saccharopolyspora erythraea nur with common and uncommon oils ps hamedi j a , malekzadeh f a,b saghafi-nia ae b . a department of biology, faculty of science, university of tehran, tehran, islamic republic of iran , b shafe-e-sari co., antibiotic production co., teheran, iran enhancing effect of various oils on the erythromycin production by saccharopolyspora erythraea nur were evaluated in a complex medium consisting soybean flour and dextrin as the main substrates. the biomass, erythromycin, dextrin and oil concentrations, and ph value were measured on a daily basis. also, the kinds and frequencies of fatty acids of the oils used were determined. saturated fatty acids in the shark oil were higher than that of vegetable oils used. erythromycin concentration in the melon (cucumis melo var. inderus cultivar mashhad ) seed oil containing medium was . times higher than that of the control medium (without oil) and . times higher than that of rapeseed oil containing medium. erythromycin concentration in the other oil containing media, including rapeseed, soybean, shark (carcharhinus dussumieri ), and safflower oils was . , . , . , . time higher than that of control medium, respectively. the melon seed oil had the least enhancing effect on the biomass production, and thus decreasing the cost of the biomass separation. can varicella be eliminated by universal childhood vaccination ? */ epidemiological and economic data from germany ps wutzler p a , banz k b , neiss a c , goertz a d , bisanz h d . a institute for antiviral chemotherapy, university of jena, jena, germany , b outcomes international, basle, switzerland , c institute of medical statistics and epidemiology, technical university, munich, germany , d glaxosmithkline, pharma, munich, germany purpose: universal varicella vaccination in childhood is expected to reduce substantially the number of uncomplicated cases of chickenpox and to decrease the number of complicated cases requiring hospitalization. to generate fundamental data for decisions of the health authorities epidemiological and health-economic data were collected in two large studies. using an age-structured decision analytic model the benefits, costs and cost-effectiveness of a varicella immunization program over a period of years were assessed. results: it could be shown, that the vast majority of varicella cases occur in children aged less than years. in . % of the cases a severe course was assessed. overall incidence of complications was estimated to be . %. a routine varicella vaccination program targeting healthy children could prevent . % of varicella cases and over major complications per year provided the coverage rate would be %. under these conditions the elimination of varicella is predicted to be achievable within Á/ years. a combined measles, mumps, rubella and varicella vaccine is expected to provide the required coverage. conclusions: routine childhood varicella vaccination appears to be a highly efficient strategy to significantly reduce the sizeable burden of varicella and leads to significant savings from both societal and payer's perspective. bulgakova va, balabolkin ii, sentsova tb. scientific center of child health, russian academy of medical sciences, scientific research institute of pediatrics, moscow, russian federation objective: to estimate efficacy of vaccine influvac at children with allergic diseases. methods: twenty children aged Á/ years with allergic diseases received vaccine influvac (solvay pharma). for the control group of children, with allergic pathology did not receive this vaccine because of an intolerance of chicken protein ( children). results: all vaccinated children for the observable season of months did not get influenza. general and aboriginal reactions to a vaccine did not occur. in control group for the observable season two children were ill with influenza and four children with acute respiratory virus infection ( %). among vaccinated children there was an increase in titre to a protective level ( : and above) to all to three strains of influenza days after injection. vaccine influvac can be recommended for an immunisation against influenza of children with an allergic pathology because of efficacy and absence of side effects. ló pez h, zitto tr, vidal gi, cánepa mc, salomó n jm, scaglione m. centro de infectología, infectious diseases, buenos aires, argentina objectives: our study examines the possible economic impact of the influenza on health working adults in argentina, and the intervention cost saving with immunization. methods: this is a theoretical study based on a mathematical model. population data was published in s national statistics. the global incidence of influenza infection was estimated at %. we have estimated the direct cost on influenza infection (outpatient visits, drugs and hospitalization) and indirect cost (work absenteeism and productivity loss) and projected net saving for the Á/ year-old vaccinated group. the vaccine effectiveness was estimated at and %. the price of vaccine was $ each. results conclusion: influenza vaccination is effective in diminishing cases of flu and reducing working-day loss. its a safe and cost-effective vaccine. ló pez h, zitto tr, cánepa mc. centro de infectología, infectious diseases, buenos aires, argentina flu infection is a major cause of illness and one of the most common cause of work absenteeism, increasing institution costs, healthcare provider visits, use of drugs, and decreasing work productivity. vaccine against flu has an effectiveness between and %, in health adults. objective: evaluate the impact of flu-like respiratory tract infections in a health institution staff during year, comparing vaccinated with not-vaccinated groups. methods: we evaluated all causes of absenteeism along year ( ), based on the written note made by the professional who has evaluated ill people, selecting flu-like respiratory infection causes. we evaluated age, working days loss related to illness, and cost on vaccinated and not-vaccinated groups. results: one hundred and sixty eight of the total staff ( people) were vaccinated, of them had flu-like infection, resulting in working days lost. for not-vaccinated group, people had flu and lost days. lost cost for vaccinated group was of $ , and for notvaccinated group, $ . conclusion: we observed a decrease in working days loss and money waste related to flu-like infections on the vaccinated group. because of safety and effectiveness of vaccine against flu, the implementation of vaccination will be cost-effective for all institution staff. we studied functioning of the interferon system in children with atopic bronchial asthma (ba) at the age of Á/ years. the control group included healthy children. we investigated the interferon status (method of grigoryan s.) and serum concentrations of ifngamma (ifng) (elisa). there was a decrease in the ifn-producing ability of leukocytes to the synthesis of ifna at % and ifng at % of children with ba. serum level of ifn of children with ba during all period of illness is compared to the children without predisposition to atopy ( . / . and . / . pg/ml accordingly) was significantly decreased. production of ifna increased after using viferon (recombinant a b ifn and antioxidants). decreased ability of gammainterferonogenesis in the most children was not affected by the action of immunomodulators. there was shown interferon system's dysfunction in the development of atopy and increasing predisposition to respiratory infections and to persistent of atypical infections in children with ba. harxhi a, pilaca a, pano k. university hospital center of tirana, infectious diseases, tirana, albania congo-crimean haemorrhagic fever is viral disease with a high rate of mortality that is caused by a nairovirus, bunyaviride species. this is a zoonotic disease, which affects sporadically humans and is geographically distributed even in eastern europe and balkan. during the months of may and june , in northeast of albania were reported eight cases of haemorrhagic fever. serologic tests performed in the laboratory of reference in thesaloniki, greece confirmed the diagnosis of congo-crimean haemorrhagic fever. in the mean time, who reported the outbreak in southwest kosovo of cases suspected for haemorrhagic fever from which were confirmed laboratory as congo-crimean haemorrhagic fever. we are describing here the clinical history of one of eight cases with cchf in albania. from the epidemiological point of view this case was considered peculiar, as it was the only one hospitaly acquired, and due to the gravity of the haemorrhagic syndrome was admitted at the intensive care unit at infectious diseases service, university hospital center of tirana. results: in the study were included patients ]/ years of age with documented hbsag-carrier ]/ months (average age */ . years, male */ %, female */ %). hbv dna in serum was tested by qualitative and quantitative pcr (commercial test-system ampli-sens hbv). hbeag, hbeab, hbsag were detected by elisa (hoffmann la roche). hbv dna by qualitative pcr was detected in % patients, by qualitative pcr was detected in % patients in the concentration ]/ copies/ml, in . % ]/ copies/ml, in . % ]/ copies/ml, in . % ]/ copies/ml ( fig. ). hbv dna level distribution among the hbsag carriers. elevated ( . the upper limit of normal) alt level was determined in . % of the hbv dna negative and . % of the hbv dna positive patients. hbeag was detected in . % of the hbv dna positive patients and had not been determined in the hbv dna negative patient. eleven percent of patient had the combination of the biochemical, serological and virology criteria, which are typical for active chronic hepatitis b (hbsag-carrier !/ months, hbv dna ]/ )/ copies/ml, elevated alt). conclusion: in smolensk % of the hbsag-carriers have viral replication confirmed by qualitative pcr. eleven percent of them have active chronic hepatitis b. kandemir o a , polat a b , kaya a a . a medicine of faculty, mersin university, clinical microbiology and infectious disease, mersin, turkey , b medicine of faculty, mersin university, pathology, mersin, turkey the exact potential of nitric oxide in the pathogenesis of chronic viral hepatitis is not known. the elevated nitric oxide production is assumed to be responsible for the pathological changes in many inflammatory conditions, mainly via peroxynitrite, a potential oxidant that is produced by the reduction of superoxyde anion with nitric oxide. the intensity and the distribution of the immunohistochemical staining of intrahepatic inducible nitric oxide synthase were studied in the biopsy specimens obtained from patients with viral hepatitis and patients with elevated transaminase levels from other etiology. hepatic inducible nitric oxide synthase staining was significantly more intense in the viral hepatitis group (p / . ). inducible nitric oxide synthase staining levels correlated well with the severity of the viral hepatitis using the knodell's liver histological activity index (r / . , p / . ). among the viral hepatitis group, the pathological distribution of the inducible nitric oxide synthase staining favored the periportal regions whereas less staining was observed in the bile duct and parenchyma regions. as nitric oxide mediated nitration of hepatocellular proteins is found to be elevated in the inflamed hepatic tissues and it well correlated with the severity of the disease, we suggest that inducible nitric oxide synthase can possibly have a critical role in the pathogenesis of chronic viral hepatitis. there were patients under observation who were divided into two groups, the first of patients (eight chronic virus hepatitis; three chronic virus hepatitis'/steatosis; four steatohepatitis; three chronic cryptogenic hepatitis; there were men and four women aged from to . the second group consisted of patients, eight with chronic virus hepatitis; four with steatohepatitis; six with chronic cryptogenic hepatitis. there were men and three women aged from to . diagnosis was confirmed with the help of clinical data, biochemical tests, serological markers, psr-diagnostics and ultrasound examination and computer tomography of the abdomen. in the first group of patients the treatment with ursofalk was administered at the dosage of mg/kg of body mass from month to years with improvement in general condition of the patients: heaviness, pain under the right rib, nausea and skin itch have disappeared. in all the cases, improvement in the biochemical blood analysis took place during treatment. the average index of alt activity was before */ . u/l, after */ . u/l and ast */ . and . u/l; alp */ . and . u/l; ggt */ . and . u/l; chol */ . and . mmol/l; tg */ . and . mmol/l. in the second group of patients the treatment was carried out with various hepatoprotectors during the courses from to months. before the average index of alt activity was . u/l, after */ . u/l; ast */ . and . u/l; alp */ . and . u/l; ggt */ . and . u/l; chol */ . and . mmol/l; tg */ . and . mmol/l. treatment of patients suffering from hepatitis of viral and other aetiologies with ursofalk produces a positive effect on both clinical symptomatic and biochemical indices. remission was more stable during a long period of taking the preparation. the hepatoprotective effect of ursofalk during the years was sustained for the whole of the period of the treatment. after stopping, an acute attack of cytolytic syndrome was observed. with other hepatoprotectors we did not get any improvement in clinical scene of the disease or in biochemical indices. shavlov nm, kletsky sk. minsk, belarus hsv- and - have possibility to damage different organs and systems. sometimes they cause damage of the liver, which resemble viral hepatitis. the etiology of such hepatitis may be confirmed only by results of liver biopsy. we have diagnosed cases of herpetic hepatitis: eight children and four adults. clinical course was different. in five cases the acute beginning took place: high temperature, the jaundice at the Á/ day (the level of bilirubin was Á/ mkmol, especially direct), cholestasis, the pain in upper right part of abdomen. the ascites was found in three patients with acute hepatitis during st week from the beginning of disease. in seven cases the beginning was gradual. the temperature was subfebrile, prolonged; malaise and moderate pain in upper part of abdomen were constant complaint. the jaundice was moderate; bilirubin increased until mkmol. the level of alt was moderately increased ( Á/ times). the blood analysis showed moderate leukocytosis with neutrophilia, and increased sre. the serological markers of hepatitis a, b, c, d were negative in all cases. hsv- and - were found in the blood. the diagnosis was defined by the results of hystochemical investigations, when the viruses were found in liver bioptat, and confirmed with the results of specific treatment. specific damage of liver cells was found: protein dystrophy and specific inclusions in cell nucleus. in all cases the treatment with acyclovir were given. the results we have observed during st week: the temperature became normal, the jaundice decreased and bilirubin was normal during Á/ days. in one case the recidive took place weeks later after treatment. the second course of acyclovir with intron a gave good results. nesic z a , delic d b , prostran m a , vuckovic s a , stojanovic r a . a department of pharmacology, school of medicine, university of belgrade, belgrade, yugoslavia , b clinical center of serbia, institute for infection and tropical disease, belgrade, yugoslavia the large number of unsolved cases of acute and chronic hepatitis has most probably the viral etiology. in mid s, two independent groups of authors reported a new human hepatotropic virus, with flavivirus like genomes, hepatitis g virus (hgv). the aim of this pilot study was to determine the prevalence of hepatitis g viral infection among patients at high risk of exposure to blood and blood products, as well as to evaluate if the risk of hgv infection was higher among them than in the general population. immunoenzyme test on microtitration plate for detection antibodies against hgv e antigen in plasma or sera (r&d systems, minneapolis, usa) was used for evidencing anti-hgv igg antibodies in sera. anti-hgv antibodies were detected in the control group (blood donors) in . % ( / ) patients. prevalence of anti-hgv antibodies among i.v. drug users was evidenced in . % ( // ), in hemophiliacs . % ( / ), in patients acquiring multiple blood transfusion . % ( / ), in hemodialyzed patients . % ( / ) and in patients with transplanted organs . % ( / ). our results suggest that patients exposed to blood or blood products have a higher risk of hgv infection than general population. evaluation of ortho total hcv core antigen assay in assessment and follow-up of patients treated for chronic hcv ps lunel f, veillon p, payan c. chu angers, laboratoire de bactério-virologie, angers, france an assay to quantitate 'total' hvc core antigen (hcv ag) in serum or plasma, may reflect viral load, has been developed by ortho-clinical diagnostics. methods: we evaluated hcv ag with two quantitative assays for hcv rna: bdna . (bayer) and monitor . (roche). we studied samples from untreated patients and from patients with chronic hcv treated with ifn or ifn/ribavirin. results: correlation of ag and quantitative assays was high (r / . for bdna . and . for monitor . ). no difference between the levels of rna and ag among hcv genotypes (r / . Á/ . ) was found. ag values, before treatment, were significantly lower in sustained responders (sr) than in other groups ( . log versus log, p b/ . ). in patients treated with ifn or combination therapy, we found very good correlation between decrease and negativation of ag and viral load: log iu/ml decline after m of interferon was significantly correlated with the negativation of hcv ag and sr. thirty-eight/ of sr had a rna load decrease !/ log iu/ml and / had a negativation of hcv ag after m . conclusion: total hcv core ag appears to be a new tool for monitoring patients with hcv infection. hepatitis c virus rna and hcv core antigen kinetics predict the efficiency of interferon-alfa and ribavirin therapy in naive patients infected by hcv genotype or ps fifty-five patients infected by genotype or were treated with a primary dose of (if hepatitis c virus (hcv) rna b/ meq/ml) or million units of interferon alfa- b (ifn) thrice weekly for months. ribavirin was added at month (m), until m if hcv rna was found positive after m of ifn. the viral kinetic was assessed during the follow up by serial measurements of hcv rna (bdna . and monitor . ) and using a new assay from ortho-clinical diagnostics which is able to quantify total hcv core antigen. sustained virologic response was observed in % of the patients ( / ). after month of ifn treatment, sustained responders had a fall of hcv rna and hcv core antigen higher than non-responders ( . / . log ui/ml versus . / . log ui/ml, p b/ . , for hcv rna) and ( . / . log (pg/ml)/ ) versus . / . log (pg/ml)/ ) p b/ . , for hcv core antigen). after month of ifn, the positive and negative predictive values of sustained response were, respectively, and . % for hcv rna negativation and . and . % for hcv antigenemia negativation. these results suggest that both kinetics of viral load and antigenemia are highly predictive of sustained response. theodorou m, petinelli i, pontikaki d, mela c, blana a, papanastasiou a, toliopoulos a, stavrakaki m, sagkana e. microbiology department, western attika general hospital, greece, egaleo, greece greece has accepted a big number of economic immigrants lately. we investigate the prevalence of hepatitis b/c as well as the epidemiological features that might influence the public health. . economic immigrants from: albania , eastern europe and from asiatic-african countries , visited our hospital to be checked in order to get a health certificate to obtain the green card. they where tested for hepatitis b/c. the serological markers were determined by immunoenzymatic method. all hbsag('/) and anti-hcv were further tested for hbv dna and hcv rna by competitive rt pcr. hcv rna('/) were genotyped by strip hybridization immunoassay. in albanians . % were hbsag('/), . % hbv dna('/), . % anti-hcv('/) and . % hcv rna('/). in east europeans . % were hbsag('/), . % hbv dna('/), . % anti-hcv('/) and . % hcv rna. in asians-africans, . % were hbsag('/) and % hbv dna('/). in pakistanis, . % were anti-hcv('/) and . % hcv rna('/). of the rest of asians-africans, . % were anti-hcv('/) and . % hcv rna('/). albanians: higher prevalence of hbv infection ( . %). greek blood donors: % pakistanis: hcv infection is % (predominance of a type), general greek population: %. public health services in greece and europe must take appropriate measures. el zawawy la a , mohamed on b , ali sm a , eissa me a , allam sr a . a faculty of medicine, parasitology, alexandria, egypt , b high institute of public health, microbiology, alexandria, egypt the purpose of the study was to investigate the influence of schistosomal suppression on the antibody response to hepatitis-b vaccine (hbv) and to study if the vaccine has any protective effect on experimental () infection. the results obtained revealed that infection reduced the serum antibody level against hbv. parasitological and histopathological findings showed significant protection against infection. the conclusion reached was; in order to reduce the incidence of virus-b infection especially in schistosomiasis endemic areas, public health officials should evaluate a policy for regulation of hbv booster vaccination to enhance the population immunity against hepatitis-b infection. cooper e, fisher t, shingadia d. newham general hospital, family clinic, london, uk sustained anti-retroviral combination chemotherapy requires excellent adherence to the regimen so as to suppress viral replication sufficiently to delay the emergence of resistance. if chemotherapy were taken to scale, e.g. in africa, erratic adherence might soon lead to multi-resistant circulating virus. we reviewed our experience in a well established london family clinic with a team including community nurses. we reviewed the records of the african immigrant children, aged Á/ , treated with anti-retrovirals exclusively at our centre throughout . whereas had undetectable hiv rna within the year, only four had undetectable rna throughout the year. four failed therapy through proven resistance mutations, but nine were considered through circumstantial evidence to have rising viral loads primarily because of poor adherence. three were known to have stopped taking drugs for extended periods. the three boys over years were unreliable in adherence, but the one girl in this age-group was fully adherent. our preliminary assessment is that for the children in our families, despite a team approach and home visits, nonadherence to haart may be twice as common as selection of a dominant viral mutant as a primary cause of failure to sustain viral suppression. quiros-roldan e, moretti f, castelli f, el-hamad i, carosi g. the prevalence of hiv related lipodystrophy-syndrome depending on the definition and severity of lipodystrophy ranges from to %. we have retrospectively reviewed the medical records of african patients followed. the characteristics are shown in the . % of africans had triglycerides !/ mg/ml and . % had cholesterol !/ mg/ml, none had both metabolic alterations. glycemia !/ mg/ml was observed in . % patients. it is interesting highlight that in any the africans morphological changes were noted and all of them showed weight stable. although the low prevalence of metabolic alterations may be attributed to the different ethnic alimentary behavior if self-body perception by african is not as accurate as by caucasian on the estimation of the body changes have to be investigated. alabaz d a , alhan e a , yaman a b , evliyaoglu n a , kocabas e a , aksaray n a . a division of pediatric infectious diseases, cukurova university, adana, turkey , b department of microbiology, cukurova university, adana, turkey hepatitis a virus (hav) infection is usually asymptomatic in children. however, it may occasionally cause a severe disease with high morbidity and mortality, and loss of school or business days. in a previous study, we have shown that every one of two to three school children from upper social classes living in adana carries high risk of hav infection. it is well known that maternally transmitted anti-hav antibodies interfere with hav vaccination. in an effort to determine the optimal age for hav vaccination, babies ( % girls and . % boys) born in our hospital were prospectively followed up at least months for the presence of maternal antibodies to hepatitis a (anti-hav igg). anti-hav igg titers were measured from the blood specimens obtained at birth from the mothers and from the offsprings at months, , , , , , , , and . the prevalence of positive anti-hav at birth ( %) was similar to those of hav seroprevalance studies carried out in adults in our area. the disappearance of antibodies occurred between the st and st month of life. the prevalence of anti-hav igg among children aged , , , , and months were , , , , and %, respectively. in light of these findings, we suggest that hepatitis a vaccination be given after months of age. earlier vaccination may be ineffective due to interference with maternally transmitted anti-hav antibodies. ghaderi b, alaghebandan r, rastegar lari a. department of microbiology, iran university, tehran, islamic republic of iran diarrhoea is a major public health problem in developing countries. amoebiasis is one of the most common causes of diarrhoea in iran as an endemic area for amoebiasis. little, however, is known about the extent of the condition in our society. the aim of this study is to determine socio-demographic and clinical characteristics of patients with intestinal amoebiasis. during july and august , we collected patients with diarrhoea among patients who visited at a referral hospital in shahriar area (in countryside of tehran), iran. thirty out of patients ( %) had intestinal amoebiasis and were followed up prospectively until the resolution of the illness. nineteen of ( . %) patients were male and the remaining of . % was female. the patients were aged Á/ with mean of . years. most of the patients ( %) were below years of age and the peak of occurrence was between the age of and years. watery diarrhoea with abdominal cramps was the main clinical feature. seventy percent of patients were resident in urban area and the remaining ( %) in rural area. average family income was low and all patients were in low socioeconomic level. water supplying system for all patients was pipeline water. low socioeconomic level associated with poor personal hygiene was the most important factor for highly prevalence of this problem in our society. also it seems that food plays important role in transmission of protozoa then water. the new strategy for allele identification of the genes coding for pertactin and pertussis toxin subunit s in bordetella pertussis ps bordetella pertussis strains demonstrate a significant polymorphism in toxin s subunit and pertactin, which are major protective antigens of the organism. monitoring the changes in prevalence of particular alleles of genes coding for these proteins in local b. pertussis populations is an essential issue in cases of the observed decrease of vaccination effectiveness. we have developed a new method for allele identification of these genes, which eliminates the necessity of dna sequencing. the approach is based on the identification of the number of repeats or the presence of specific nucleotides in the polymorphic regions or residues, respectively, of the genes and utilises products of their full or partial pcr amplification. the nucleotide heterogeneity in each polymorphic site is analysed either by the differential digestion of the amplicons or by the arms (amplification-refractory mutation system) methodology. numbers of repeats in particular regions of the genes are revealed by the size analysis of the adequate pcr products or their restriction fragments. in all cases the presence, size or pattern of dna molecules obtained is visualised by the agarose gel electrophoresis. the preliminary analysis of the recent and archival b. pertussis strains identified in poland was performed using the described approach. the presented strategy provides a much easier, faster and more cost-effective than dna sequencing mean to study the polymorphism of the major b. pertussis antigens. vaccination coverage and history of vaccine preventable infectious diseases among students in second year of medicine and pharmacy of tours university ps borderon jc a , hamed a b , ragot s b . a centre hospitalier universitaire, tours, france , b médecine préventive universitaire, tours, france the purpose of this study was to determine the level of infectious risk in students who will be exposed to patients. information was obtained by a questionnaire for each student, and by checking medical records for immunization coverage and vaccine preventable infectious diseases. answers could be specified for students, of whom females (f) and males (m). the number of non-immunized students was against diphtheria: two, tetanus: three, pertussis: four, poliomyelitis: two, hepatitis b: six, and hepatitis a: , respectively. among the students non-vaccinated against measles, (nine f and five m) had no history of that disease. among ( f and m) non-vaccinated against rubella, ( f and seven m) had no history of that disease, uncertain in seven others (six f and one m). the date of vaccination was often late regarding recommendations. fifteen students had no history of varicella. one student had not received bcg vaccination. fifty-eight students had received two, and three bcg vaccines. post-bcg tuberculin skin testing was missing after first bcg, second and third bcg. the date of the first tuberculin test was often one or several years after bcg vaccination. adverse effects of vaccination were rarely reported: two cases of fever (dt polio, measles); three cases of local reaction (dt polio, dtp polio). one case of contraindication for influenza vaccine: egg allergy. the survey shows failure in immunization coverage actually recommended in health care students. objectives: to present the morbidity of rabies and evaluate the efficiency of our prophylaxis scheme in lasi county. material and method: we made a retrospective study of the rabies cases in the patients admitted in our unit in a th-year period. we have analysed all the clinical, epidemiological and biological aspects. results: in a -year period, cases of rabies were admitted in the clinical infectious diseases hospital lasi. the highest incidence was for Á/ */eight cases ( %); the highest yearly cases were three cases in and . most of the patients were male ( %), came from suburban areas ( patients). eight cases occurred in may Á/june, wild animals were involved in half the cases (fox, wolf). for patients, no prophylaxis was performed and an incomplete course in four cases. the period of time to the appearance of the first symptom was Á/ days. the prophylaxis scheme led to a good protection. conclusions: in lasi county, rabies is a problem with a prevalence of . %/year. trends in the use of antimicrobials in riyadh in were analyzed. data was obtained from a survey of randomly selected families of school children aged Á/ years in a -month period in . one hundred and ninety-nine ( . %) students were on antibiotics in the month preceding the study; ( %) received antibiotics for the diagnosis of pharyngitis; ( %) students antibiotics were prescribed by a physician; and in ( %) the duration of antibiotics was less than week. this study shows a major problem in antibiotics prescription in our community and also the need to establish effective antibiotics policy in general practice to limit the potential emergence of drug resistance bacteria in the community. mir s a , cura a a , erdogan h a , guler s a , sengul gn a , koyu a a , ozinel ma b . a department of pediatrics, ege university medical faculty, izmir, turkey , b department of microbiology, ege university medical faculty, izmir, turkey antibiotic susceptibility spectrum of childhood urinary tract infection agents are geographical variation. the current antibiotic regimens and the selection of antibiotics for prophylaxis should be re-evaluated periodically. the objective of our study was to determine the local resistance rates to antibiotics and to give a direction for the selection of antibiotics in uti treatment. we evaluated urinary culture assays retrospectively, sent from pediatrics and pediatric surgery inpatient and outpatient clinics of our hospital during the last months, and investigated the isolated pathogens and the resistance rates to antibiotics. in addition, the data obtained were compared with of years ago. with respect to the resistance rates to antibiotics of uti pathogens, the resistance rates of e. coli for carbapenems, aminoglycosides and third generation cephalosporins were , and %, respectively as before, but the rates for ampicillin increased from to % and for tmp-smx it increased from to %. we concluded that the resistance profiles to antibiotics should be reviewed every years at least and thus the selection of proper antibiotics would lessen the morbidity as well as the medical expenses. chanturidze tk, tsiklauri r. ministry of labor, health and social affairs, public health, tbilisi, georgia purpose: since infectious diseases (id) are increasing in georgia. this study is aimed to reveal economic barriers of effective id control by assessing financial contribution to id from public and private sources, household's total spending on health and their capacity to pay. sources: ) national household expenditure and revenue survey. ) who fair financial contribution methodology. ) meta-analysis. results: . % of population leaves under the poverty level; % out of total household expenditure (average gel; us$ ) % is spent on food */non-subsistence income covers expenditures on goods and services including health; % of population refuses health services because of inability to pay; public spending on health comprises % of total health expenditures; public spending on id control is below gel per capita; almost all private spending goes to id treatment and equals to . gel per patient. conclusions: insufficient public spending on id control transfers the burden to the population with extremely low capacity to cover health expenses. refusal to utilize health services, and incomplete treatment and increases the threat of id spread and drug resistance. government should increase the allocations to id from public sources for effective id control in georgia. antimicrobial consumption trends in children's university hospital ps ratchina s a , averchenkova l b , jarkova l a . local surveillance of antimicrobial (am) consumption is essential to promote the rational use of this group of drugs. the purpose of this study was to analyze the trends of am use in the children university hospital in and . data on am usage were obtained from the hospital drugstore requests in the -beds multi-ward children university hospital. consumption was expressed as the number of ddd per bed-days (b Á/d). the total am consumption figures were similar in and ( . and . ddds/ b Á/d, respectively) with notable differences in am prescribing patterns. penicillin consumption increased from . to . ddds/ b Á/d mostly due to amoxicillin. the overall aminoglycoside usage remained comparable ( . vs. . ddds/ b Á/d) though amikacin has considerably replaced gentamicin. there was a sevenfold increase of ciprofloxacin ( . vs. . ddds/ b Á/d) along with the evident decrease of tetracycline and co-trimoxazole consumption found ( . vs. . ddds/ b Á/d and . vs. . ddds/ b Á/d, respectively). the tendency to prescribe more effective in respect of the local resistance data and/or more safe am was detected in comparing with that can be explained by the introduction of the local guidelines for infectious diseases management in . clarithromycin in the treatment of chronic prostatitis caused by chlamydia trachomatis */a pilot study ps the aim of this pilot study was to determine the efficacy and tolerability of clarithromycin in the treatment of chronic prostatitis caused by chlamydia trachomatis (ct). fifty-two patients older than years of age with diagnosed chronic chlamydial prostatitis were enrolled. the presence of ct in expressed prostatic secretion or urine specimen voided immediately after prostatic massage was confirmed by isolation on mccoy cells and lugol staining. the majority of patients suffered from suprapubic pain and pain in the groin. twelve patients had no clinical symptoms. according to rectal palpation, prostate gland was normal in patients, tender and soft in and firm in five patients. clarithromycin was administered orally mg twice daily for days. simultaneously the patients' partners received mg orally twice daily for days. clinical efficacy and tolerability of administered clarithromycin were evaluated Á/ days and Á/ weeks after the end of treatment. bactericidal efficacy of administered drug was evaluated Á/ weeks after the end of treatment. the eradication of ct was achieved in out of patients, while patients were clinically cured. two patients had nausea and elevated serum transaminases. in asymptomatic patients, the eradication of ct was achieved in of patients who reported no side effects. this pilot study has shown an excellent efficacy and tolerability of clarithromycin in the treatment of patients with chronic chlamydial prostatitis. women with diagnosis of urinary tract infections (uti) often demonstrate vaginal colonisation with alpha-haemolytic escherichia coli strains. in the present study we decided to evaluate a distribution of virulence genes encoding for cytotoxic necrotizing factor type (cnf ), p-fimbriae, s/f c-fimbriae aerobactin (aer), and afa genes in alpha-haemolytic e. coli strains isolated from gynaecological material in our region and to compare the detected sequences in clinical isolates of other diagnostic groups. of alpha-haemolytic e. coli strains, were isolated from urine, from gynaecological specimen, and were faecal strains. e. coli strains were tested for the production of haemolytic phenotype on blood agar plates. the amplification of virulence factors was performed by pcr according to previously described protocols (le bouguenec et al., ; blanco et al., ; and yamamoto et al., ) . we found that all gynaecological alphahaemolytic strains were positive for cnf , (p b/ . compared to % of urine strains, and p b/ . compared to % of faecal strains). similarly, sfa/foc specific dna sequences were found in % of gynaecological isolates (p / . compared to % of urine strains and p / . compared to % of faecal strains). from this point of view, the female genital tract seems to be a potential reservoir of these uropathogenic e. coli strains. azithromycin in the treatment of pelvic inflammatory disease caused by chlamydia trachomatis ps administered in hospitalized patients with chlamydial pid. the diagnosis was made prior to hospitalization. microbiological analysis of urine, blood and swab specimens collected from endocervix, vagina and urethra confirmed c. trachomatis to be the single suspected causative pathogen of pid. the presence of c. trachomatis in swab specimens from endocervix was examined by dnk/rnk hybridization. azithromycin was administered Á/ days after samples for microbiological analysis were collected in dose of )/ mg iv for days. clinical efficacy and tolerability of therapy were assessed Á/ days after the end of therapy and clinical and microbiological analysis Á/ weeks after completion of therapy. the eradication of c. trachomatis and normalization of gynecological findings were achieved in and disappearance of subjective symptoms in patients. no side effects and deviations from normal values in hematologic and biochemical blood parameters were recorded. this study showed high bactericidal efficacy, rapid clinical effect and good tolerability of once-daily administration of mg azithromycin for days in the treatment of patients with pid caused by c. trachomatis . altindis m a , cevrioglu s b , aktepe oc a , cetinkaya a . a kocatepe university school of medicine, microbiology, afyon, turkey , b kocatepe university school of medicine, obstetrics and gynecology, afyon, turkey diagnosis of the causative organism of the vaginitis is usually based on clinical criteria. a standardized, laboratory based and rapid diagnostic test for the identification of these organisms is desirable. to determine the laboratory method that best predicted the causative organism, we calculated the sensitivity, specificity and predictive value of positive and negative test for clinical criteria, an oligonucleotide probe test (affirm vpiii-bd usa) and compared them with the combination of positive vaginal culture and gram-stained vaginal smear. we evaluated consecutive women aged Á/ years, attending for vaginal discharge. vaginal swab specimens were used for culture of gardnerella vaginalis , trichomonas vaginalis and candida sp, preparation of a vaginal smear for gram-stain interpretation and wet mount evaluation and affirm test. affirm detected g. vaginalis in ( %), candida sp in three ( . %) women and no trichomoniasis case found by any methods. the sensitivity and negative predictive values of affirm test and clinical signs were same ( %) in identifying of bacterial vaginosis. however, affirm test was more specific ( vs %) and also has higher positive predictive value ( vs %) than clinical signs. we did not evaluate the results for patients with candidiasis because of less number. according to these results affirm-microbial identification tests are objective and specific for the rapid diagnosis of the bacterial vaginosis. comparison of efficacy of single dose of tinidazole with standard dose of metronidazole in giardia lamblia infection (preliminary report) ps fallah m a , moshtaghi aa b . a university of medical sciences, parasitology, hamadan, islamic republic of iran , b university of medical sciences, pediatrics, hamadan, islamic republic of iran objectives: giardia lamblia is the most common intestinal protozoa in developing countries. treatment of the infection with metronidazole, the drug of choice, requires a long course of therapy and produced some side effects. the object of this study is to determine efficacy and side effects of tinidazole in g. lamblia infection. this is a preliminary report of an ongoing trial. methods: a randomized controlled clinical trial was carried out and subjects with g. lamblia infection were treated with tinidazole or metronidazole. tinidazole mg/kg single dose and metronidazole mg/kg three times a day for days were given orally to and children, respectively. parasitological cure was documented when there were consecutive negative stool examinations at Á/ weeks after therapy. results: twenty-one of individuals treated with tinidazole and of children treated with metronidazole had parasitological cure. cure rates between two groups were not significant statistically. no major side effects were observed except one case in metronidazole group who had mild headache and abdominal pain for days. conclusions: we concluded, tinidazole at the dose has efficacy equal of metronidazole in the treatment of g. lamblia infection. because of single dose prescription, short course of therapy and good compliance of patients, this preparation is preferred to metronidazole in giardial infection. ebeid fa, seif el-din sh. theodor bilharz research institute, pharmacology, cairo, egypt b-carotein was given in different doses starting from . to mg/kg body weight (b.w.) for different groups of albino mice days before infection with s. mansoni . infection of animals was done by body immersion using egyptian strain of s. mansoni cercariae/mouse. forty-nine days after infection the animals were sacrificed and hepatic and mesenteric worms were extracted and determined. ova count in liver and intestinal tissue and the total number of worms/animals were also determined in experimental groups comparing with infected control animals. the results indicated marked decrease in number of worms and ova count in both liver and intestine comparing with control ones. this reduction increased significantly with increasing dose. it was concluded that b-carotein could be used as a prophylactic agent against s. mansoni infection. barisic z, babic-erceg a, borzic e, zoranic v, carev m, kaliterna v. department of microbiology, public health institute, split, croatia the aim of this study is to determine frequency of pseudomonas aeruginosa urinary tract infection (uti) in outpatient's population in south croatia and to suggest optimal antimicrobial treatment for these patients. during months long observation period, from total number of examined urine specimens, significant bacteriuria was found in specimens. p. aeruginosa was the sixth most common isolate, it was isolated from specimens ( . %). these specimens were taken from different patients. susceptibility testing was performed by disk diffusion method, and the following results were obtained: resistance to cefibuten occurred in . % patients, to norfoxacin in . %, to ciprofloxacin in . %, to gentamicin in . %, to netilmicin in . %, to amikacin in . %, to ceftazidime in . % and to imipenem in . % patients. p. aeruginosa strains showed better susceptibility to tested parenteral antibiotics than to antibiotics for oral use which complicated treatment in outpatients. the best susceptibility was shown to imipenem, but this drug is inappropriate for use in outpatients setting, so the best choice for treatment p. aeruginosa uti in our outpatients is treatment with ceftazidime, and the second choices are aminoglycoside drugs amikacin and netilmicin. silan l a , breza j b , krcmery v jr. c . a department of internal medicine, derer s university hospital, bratislava, slovakia , b department of urology, comenius university school, bratislava, slovakia , c department of pharmacology, st. elisabeth cancer institute, bratislava, slovakia we studied the clinical efficacy of oral treatment with ciprofloxacin/ cpf/ alone and combined with clarithromycin in patients with complicated urinary tract infection/cuti/ with or without an indwelling catherer. patients were randomly allocated to mg cpf/cpf group/ or to mg cpf plus mg cam/combination group/ for days. evaluation was done on day according to the criteria advocated by the japanese urinary tract infection committee. in patients with a urinary catherer, the combination achieved a higher complete bacterial elimination rate / %/ and clinical efficacy rate / %/ than cpf alone / and . %, respectively/. while no significant difference was found in the bacterial elimination rate between the two groups, the clinical effect of the combination / %/ was superior to that of cpf alone / %/ in patients with an indwelling catherer. the better clinical efficacy of the combination may partly be attributed to the antibiofilm effect of cam in the clinical setting. the results also indicated that difficulties still remain in the treatment of cuti in patients with an indwelling catherer. in conclusion, clinical study suggested that cam might have an inhibitory action on biofilm formation in the clinical setting. combination of cam with other appropriate antimicrobial agents may have a favorable effect on the treatment of cuti. vesicoureteral reflux and urinary tract infections */the management of primary vesico-eureteral reflux in children ps the children studied presented with primary vesicoureteral reflux at derer s universitz hospital in bratislava between and . seven hundred and sixty patients, boys and girls, suffering from primary vesicoureteral reflux in age from months to years were tested and systematically analyzed outcomes data for seven treatment alternatives. key outcomes identified were probability of reflux resolution, likelihood of developing pyelonephritis and scarring, and possibility of complications of medical and surgical treatment. available outcomes data on the various treatment alternatives were summarized and the relative probabilities of possible outcomes were compared for each alternative. conclusions: increased of urinary tract infection, vesicoureteral reflux nephropathy includes early diagnosis, appropriate evaluation, effective atb therapy, and surgery indicated. the main determinants of renal damage are bstruction, age, sex, predisposition on renal scarring, reflux grade and laterality, therapeutic delay, individual susceptibility, bacterial virulence and immunogenetic status. ) the one and only absolute indication for surgical management is failure of medical therapy to prevent chronic recurrent pyelonephritis, renal injury or other reflux complications and eliminations of the reflux condition will minimize their likelihood. genetically conditioned immunopathogenic mechanisms are involved in the pathogenesis of the chronic recurrent pyelonephritis in patient suffering from vur. for most children we recommended continuous antibiotic prophylaxis as initial treatment-medical therapy is based on the principle that reflux often resolves with time, and antibiotics maintain urine sterility and prevent infections while the patients awaits spontaneous resolution. ) vur predispose an individual to renal infection, the immunological and inflammatory reaction caused by a pyelonephritic infection may result in renal injury or scarring. silan l a , breza j b . a department of internal medicine, derer s university hospital, bratislava, slovakia , b department of urology, comenius university school of medicine, bratislava, slovakia elderly patients with uti are believed less likely to be cured by antimicrobial therapy than younger patients. the reasons for this poorer outcome have not yet been clarified. we have investigated the efficacy of antimicrobial therapy in elderly patients with complicated uti. five hundred patients, men and women, who had complicated uti/ symptomatic and symptomatic and were Á/ years of age, were treated with one of three different drugs, one was a never quinolone and two were oral cephems. multivariate logistic regression analysis of treatment outcome revealed that the clinical response was significantly related to general underlying diseases and diseases of the urinary tract, but not to age, symptomatic or asymptomatic uti, or infection site such as the kidney or bladder. we concluded that the clinical effectiveness of an antimicrobial agent was not directly related to age, and that urological examination for underlying disease and control of them is quite important for effective treatment and control of complicated utis, especially in elderly patients. the study on the frequency and antimicrobial resistance of escherichia (e ) coli in urine isolates of patients admitted to maribor teaching hospital in and ps rebersek gorisek j a , baklan z a , unuk s a , novak d b . a department for infectious diseases, teaching hospital maribor, maribor, slovenia , b department for microbiology, regional institute of public health maribor, maribor, slovenia purpose: the aim of the study was to determine the frequency and antimicrobial resistance of escherichia coli isolated from urine samples of patients admitted to maribor teaching hospital in and . the frequency and the antimicrobial resistance were compared between years and . methods: in the prospective study going on between and , all urine isolates from patients at maribor teaching hospital were collected and analysed. urine cultures were done using the modified sanford method. the susceptibility testing was performed by disk diffusion method according to nccls. results: in the year , urine isolates and in the year , urine isolates were analysed. e. coli represented . % of urine isolates in and . % of urine isolates in . e. coli resistance rates (%) to amoxycillin was . in the year and . in the year ; to amoxycillin/clavulate was . and . ; to cefalotin was . and . ; to cefaclor . and . ; to trimethoprim sulfamethoxazole was . and . ; to ciprofloxacin was . and . ; to gentamicin was . and . . conclusion: compared to , the frequency of e. coli isolated from urine samples is similar to that in the year . the resistance to amoxycillin, cefaclor and gentamicin is stable. the resistance to trimethoprim sulfamethoxazole and ciprofloxacin is increased and the resistance to amoxycillin/clavulate and cefalotin is decreased. prevalence of the resistance to metronidazole, furazolidone and nitrofurantoin in helicobacter pylori clinical strains ps de la obra sanz p a , roman jl a , lomas e a , villar h b , lopez-brea m a . a hospital de la princesa, microbiology, madrid, spain , b hospital de san agustin, microbiology, aviles, spain the objective of this study was to determine the prevalence of metronidazole, furazolidone and nitrofurantoin resistance in helicobacter pylori clinical isolates. methods: a total of strains of h. pylori were included in this study. all these were tested against metronidazole, and against furazolidone and nitrofurantoin by an agar dilution method. resistance was defined as: metronidazole, mic !/ mg/l; and mic !/ mg/l for furazolidone and nitrofurantoin. results: sixty-eight strains were resistant to metronidazole ( . %). the mic and mic values were and mg/l, respectively. three of strains ( . %) were furazolidone resistant (mic / mg/l), two of these strains were metronidazole resistant (mic / mg/l) and they had mic of mg/l for nitrofurantoin. the mic and the mic were . and . mg/l, respectively for furazolidone. only one of the strains ( . %) was nitrofurantoin resistant (mic mg/l), this strain was metronidazole resistant (mic mg/l) and had a mic / mg/l for furazolidone. the mic and the mic were . and mg/l, respectively for nitrofurantoin. conclusion: the low frequency of furazolidone and nitrofurantoin resistance, compared to metronidazole suggests that the furazolidone and the nitrofurantoin may be good alternatives to metronidazole for treatment of h. pylori infections. antimicrobial resistance of campylobacter isolated from human origins ps zhukhovitsky vg, drabkina iv. department of bacteriology, botkin hospital, moscow, russian federation the purpose of the study was to determine the antimicrobial resistance of thermophilic enteropathogenic campylobacter spp. (tec) isolated from human under acute diarrhoea in in moscow. among tec strains c. jejuni and five c. coli were identified. the antibiotic tested by disk diffusion test on mueller-hinton agar with sheep blood were ampicillin (a), amoxycillin/clavulanate (ac), imipenem (i), meropenem (m), erythromycin (e), clarithromycin (cl), tetracycline (t), doxycycline (d), gentamicin (g), azithromycin (az), chloramphenicol (ch), lincomycin (l), ciprofloxacin (c), nalidixic acid (na). the resistant rate of the tec isolates was highest for na ( %) followed by a ( %), t ( %), d ( %), n ( %) and cl ( %). a moderate resistance rate was obtained for a ( %), ch ( %), az ( %), ac ( %). none of the isolates demonstrated resistance to i, m and g and four of isolates ( %) were sensitive for all the antibiotics tested. mic to na was estimated as mg/l. among na resistant tec strains ( %) were identified as c. jejuni and one ( %) as c. coli . among c. jejuni and c. coli na resistant rate was and %, respectively. one na resistant c. coli and nine na resistant c. jejuni were resistant to ciprofloxacin. ring c, atanassova v. department of food hygiene and microbiology, school of veterinary medicine, hannover, germany aim of the study: poultry meat is known to be often contaminated with salmonella and other foodborne pathogens and thus has to be considered as a possible source for human infections. the aim of the study was to monitor the resistance of salmonella isolates from poultry meat of different european countries to various antibiotics. material and methods: from september to december a total of samples of frozen poultry meat from france, germany, italy, spain, the netherlands and portugal were examined for the prevalence of salmonella using classical cultural detection as well as rflp-pcr. all isolates were tested for their sensitivity towards ampicilline, kanamycine, ciprofloxacine, tetracycline, trimethoprim, sulfamethoxazole, nalidixic acid and erythromycine using standard procedures. results: from . % of all examined samples salmonella spp. were isolated. of these isolates . % were characterized as salmonella , . % as s. hadar and . % as s. typhimurium . nearly % of all isolates were resistant to erythromycin. resistance towards four or more isolates was observed in several cases. discussion: the consumption of poultry meat, if insufficiently prepared, has still to be considered as a major source for human infection with salmonella spp. the question arises whether the resistance of the isolates to various antibiotics is of clinical importance in the treatment of the patients. objective: to provide insight into the epidemiologic situation of salmonellosis for the nis area (the largest area in serbia, with inhabitants */ , ). methods: the material was processed at the institute for public health (epidemiology and microbiology divisions). isolation of microorganisms was performed on apparatus for rapid identification (vitek-biomerieux) and by applying elisa tests and classical microbiological methods. results: in the period Á/ , salmonella laboratory confirmed cases were reported. the greatest number of diseased in the Á/ years group. the most frequent isolated salmonellae were: s. enteritidis ( . %) and s. typhimurium ( . %), s. hadar , s. agona , s. virchow , s. infantis , s. derby , s. enteritidis showed the greatest sensitivity to antibiotics with the infrequent resistance to ampicillin and trimethoprim-sulfamethoxazole. s. typhimurium showed the greater resistance to the wide spectrum of antibiotics and some isolates were resistant to all antibiotics tested. the less common types of salmonella were sensitive to all antibiotics except trimethoprimsulfamethoxazole and ampicillin. conclusion: specific resistance to some antibiotics was related to serotypes. typhoid fever */retrospective study of cases in lebanon ps tohme a, abboud j, ghayad e. hôtel-dieu hospital, internal medicine, beirut, lebanon objectives: to present epidemiological and clinical features of typhoid fever in lebanon. methods: fifty-two patients were seen at hotel-dieu hospital of beirut between and . diagnostic criteria were positive blood culture for s. typhi or paratyphi and/or a somatic o agglutinin titer ]/ / as determined by the widal test with symptoms suggestive of typhoid fever. we also present an epidemiological study of cases registered by the ministry of health during the same period. results: among the cases, % of the patients' ages were between and years and % were less than years. the overall male to female ratio was . and % of cases were seen on january, february and % on august. among the patients, young adults were the most affected. average duration of symptoms before the diagnosis was / days. the main presenting symptoms were: fever ( %), diarrhoea ( %), abdominal pain ( %) and headache ( %). complications were noted in % of cases and digestive complications were the most prevalent. leucopenia was not a helpful diagnostic marker. s. typhi was the most frequent ( %) serotype identified. resistance to ampicilline was %, to cotrimoxazole and chloramphenicol % for each. the mortality rate was %. conclusion: typhoid fever is still an endemic disease in our country and the occurrence of resistant strains of s. typhi will favor ceftriaxone or fluoroquinolones in the treatment. maaloul i a , hammami b a , zambaa f a , elleuch r a , hammami a b , -ben jemaa m a . a chu hedi chaker, service des maladies infectieuses, sfax, tunisia , b chu habib bourguiba, laboratoire de microbiologie, sfax, tunisia although its not very frequent, the psoas abscess is not an exceptional entity. in order to specify its clinical, biological, radiological and evolutionary features, a retrospective study has been led in our service, on a period of years (january Á/december ). on the whole, cases have been listed. they were men and women. the age average was years (extreme Á/ years). the study did not find any underlying diseases, except diabetes mellitus for three patients. the clinical symptoms were dominated by fever with abdomino-lumbar aches ( cases), and psoitis (eight cases). biology showed an inflammatory syndrome in all cases and a hyperleucocytosis in cases. the diagnosis of psoas abscess, evoked on clinical data, has been confirmed by the imagery data: ultra-songraphy ( cases), ct scanning (six cases), magnetic resonance imaging (three cases). the tubercular etiology has been confirmed in six cases, among which two were associated to escherichia coli (one case) and to brucella melitensis (one case). the other etiologic agents were dominated by staphylococcus aureus (eight cases), b. melitensis (two cases), e. coli (one case), bacteroides fragilis (one case), streptococcus anginosus (one case), fusobacterium nucleaticum (one case) and candida glabrata (one case). all patients received an anti-infectious treatment adapted to the micro organism in question. a drainage of the abscess has been realized for patients (percutaneous: nine cases, surgical: six cases). the evolution was favourable for patients. however, two patients had a relapse after stopping the treatment. conclusion: the diagnosis of the psoas abscess, difficult on the clinical data, is based on the imagery techniques (us, ct, rmi). the percutaneous drainage guided by the imagery is recommended (in an etiological and therapeutic aim). associated to an adapted antibiotherapy, it allows to defer a surgical drainage. zezoski mbz, nikolova o, gavriloski pmg. medical center, infectious diseases, prilep, the former yugoslav republic, macedonia purpose: to make a list of the most frequent abdominal changes in patients with human brucellosis. materials and methods: there were new patients with human brucellosis, between and . diagnosis was made using standard clinical, biochemical and serological investigations (bab, wright, coomb's, rvk, -mercaptoethanol, elisa igm and igg), and specially ultrasound examination of the abdomen and retro peritoneum. results: weight loss is the most frequent change, presented in ( . %) patients. follow atypical abdominal pain in ( . %), vomiting in ( . %), diarrhea in ( . %), enlarged liver in ( . %), enlarged spleen in ( . %) and hepatic lesion with increased ast and alt in ( . %). conclusion: although frequent, abdominal changes seldom could be missed in patients with human brucellosis. we recommend routine ultrasound examination with standard biochemical test for liver function, due to avoid unnecessary complications. osteoarticular complications are common in brucellosis. the most common site of involvement is the sacroiliac joint. the osteoarticular complications such as, sacroiliitis and spondylitis are diagnosed with radiologically. in the present study, we aimed to determine the severity (grade) of sacroiliitis by using some laboratory parameters such as esr, crp and tube agg test. seventy-two ( male, female) patients with brucellosis were included in the study. osteoarticular involvement was present in patients. the most common osteoarticular finding was sacroiliitis in the patients ( %). twenty ( ) healthy subjects were formed the control group. there was statistically significant difference between patients and controls regarding esr, crp, and tube agg test (p / . , . , . , respectively). in addition, sacroiliitis has an effect on esr and crp. there was a positive correlation between the grade of sacroiliitis and the value of crp (p / . , r / . ). in conclusion, it has been suggested that, crp may be used as an auxiliary or a secondary parameter in grading sacroiliac joint involvement in brucellosis. magira ee a , papandreoy s a , gounaris t a , spirelis ma a , tasopoulos g a , anagnostopoulou m b , paniara o b , gounari p a , sioulal e a . a evagelismos, internal medicine, athens, greece , b evagelismos, micro- a -year-old greek farmer was admitted to the hospital because of painful scrotal swelling, hepatosplenomegaly, lumbar pain and lowgrade fever accompanied by profuse sweating. his life style included occupational animal exposure ingestion of raw milk and dairy products. the laboratory data were within the normal ranges. focal hypoechoic right testicular lesions, swelling of the concurrent epididimis along with an increase in the vascularity of the right testis were seen on an echo examination. these findings were consisting in unilateral epididimo-orchitis. a ct scan of the lumbar spine area showed a decrease of the signal intensity localized in the anterior aspect of l vertebral body at the diskovertebral junction involving the subchondrial parts of the l and s vertebrae standard tube agglutination test was positive for antibodies to brucella melitensis (titer !/ / ). cultures of blood specimens were positive for b. melitensis . the patient had been given to a combination of antibiotics with doxycycline, streptomycin and rifampin. a remarkable improvement of his clinical condition was showed weeks later. this case illustrates the following point: in areas in which brucellosis is endemic when scrotal abnormalities are seen the possibility of genitourinary tract complications of brucella should be considered. pappas ga a , akritidis nk b , mastora m b , tsianos e a . a university hospital, internal medicine, ioannina, greece , b 'g. hatzikosta ' hospital, internal medicine, ioannina, greece aims and scope: to determine the incidence and forms of complications associated with brucella infection. patients and methods: we studied the most recent patients, in all larger series approaching , diagnosed as suffering from brucellosis, and assessed the presence of signs and symptoms of arthritis and spondylitis, or other forms of bone involvement. the diagnosis of brucellosis was based on serology or isolation of brucella species from blood cultures or cultures from other media. results: osteoarticular complications were noted in patients, presenting with arthritis, and presenting with spondylitis. eight patients presented with genitourinary complications, either orcheoepididymitis (four patients), or hematuria resolving with treatment (four patients). meningitis was present in two patients. gastrointestinal complications (vomit and diarrhea) were present in three patients, while one patient presented with ascites. respiratory tract complications, in the form of pneumonia (four patients) or bronchitis (three patients) were noted in seven patients, while one patient with pneumonia exhibited pleural fluid. skin rashes, of macular type, were present in three patients. no patient presented with complications from the heart. hematologic complications were frequent, in the form of severe (one patient) or moderate (two patients) pancytopenia, isolated thrombocytopenia (three patients), or lymphocytosis (eight patients). akritidis nk a , pappas ga b , mastora m a . a 'g. hatzikosta ' hospital, internal medicine, ioannina, greece , b university hospital, internal medicine, ioannina, greece aims and scope: to determine the incidence and modes of bone and joint involvement in the course of brucellosis. patients and methods: we studied the most recent patients, in all larger series approaching , diagnosed with brucellosis, and assessed the presence of arthritis and spondylitis. the diagnosis of brucellosis was based on serology or isolation of brucella species from blood cultures. results: twenty-three patients exhibited a form of osteoarticular involvement. arthritis was present in patients, most often involving the knees, but also the hips, elbows, even smaller joints as intephalangeal joints of the hand. synovial fluid, when aspirated, was often characterised by an intense mononuclear infiltrate. spondylitis was present in patients, most often involving the lumbar spine, but also the thoracic spine. the characteristic erosion on the upper anterior crest of the vertebral body was visible in plain x-rays in three patients, while mri and bone scan were helpful in other cases. discussion: osteoarticular involvement in the course of brucellosis is the most common focal presentation of the disease. acute brucellosis is often accompanied by bone and joint ache, especially of the lumbar spine, still frank involvement in the form of arthritis and spondylitis is not rare. arthritis usually presents in the acute form of the disease, while spondylitis tends to be characteristic of a chronic form of the disease, often necessitating prolonged use of antibiotics. bosilkovski m, krteva l, caparoska s, grozdanovski k, sajn b. clinic for infectious diseases and febrile conditions, medical faculty, skopje, the former yugoslav republic, macedonia one hundred and twenty-six patients with brucellosis were studied prospectively. seventy-eight ( %) of them had osteoarticular involvement. peripheral arthritis in ( %) patients was the most frequent, followed by spondilitis in ( %), sacroiliitis in ( %), rarely bursitis, tendinitis and osteomyelitis. the overall male to female ratio was : . their average age was (sd ) years. direct contact with animals was the reason for acquisition of the illness in % of patients, in % alimentary or aerogenous route was incriminated, and in % the route of aqisition was unknown. the average duration of the symptoms from the onset to establishing the diagnosis was (sd ) days. the main presenting symptoms were joint pain ( %), sweating ( %), fatigue ( %) and fever ( %). hepatomegaly was present in %. in % of patients, involvement of some other system was evident. comparison with patients, who did not have osteoarticular illness, showed that patients with osteoarticular involvement had significantly more often joint pain, fatigue, weight loss and more prolonged duration of symptoms before the diagnosis was established. doxycycline and chloroquine as combination therapy for chronic q fever endocarditis ps calza l, attard l, manfredi r, chiodo f. division of infectious diseases, university of bologna, s. orsola hospital, bologna, italy introduction: endocarditis is the main clinical manifestation of chronic q fever, occurring in about Á/ % of all reported cases, and it is diagnosed almost exclusively in patients with either cardiovascular abnormalities or an immunocompromised condition. case report: a -year-old caucasian male patient with biological prosthetic aortic valve was first hospitalized because of an interstitial pneumonia. six months later, our patient was re-admitted owing to intermittent fever, chills and weight loss. echocardiographic study showed a small vegetation of mm in diameter on left cusp of aortic valve. serology for coxiella burnetii revealed a complement-fixing igg antibody titer to phase i antigen of more than : , consistent with chronic q fever endocarditis. antimicrobial therapy with i.v. doxycycline and oral chloroquine was started, leading to a clinical and echocardiographical recovery. therapy was continued by oral doxycycline and chloroquine, and the patient remained asymptomatic during a -year follow up. conclusion: the optimal treatment of q fever endocarditis has not been well established: the most effective antimicrobials are fluoroquinolones and rifampin, but chloramphenicol, doxycycline and trimethoprim are also useful. the role of chloroquine in combination with doxycycline seems to be promising, because chloroquine may increase the lysosomal ph, enhancing the doxycycline bactericidal activity. akritidis nk a , pappas ga b , mastora m a , liappis e a , tsianos e b . a 'g. hatzikosta ' hospital, internal medicine, ioannina, greece , b university hospital, internal medicine, ioannina, greece aims and scopes: to review the incidence and the forms of lower respiratory tract infection in patients suffering from q fever, and their clinical and radiological characteristics. patients and methods: twenty-seven patients diagnosed as suffering from q fever, were assessed for the presence of lower respiratory tract infection. the diagnosis was confirmed serologically. results: thirteen patients expressed lower respiratory tract pathology, as confirmed by clinical examination and chest x-ray. in of these patients the main cause of admission was respiratory tract symptoms, ranging from dry cough to hemoptysis. chest x-ray was pathological in patients: patients had lobar pneumonia, two of them multiple nodular opacities, and one of them bronchopneumonia. hepatitis was a common finding. all patients were treated with tetracycline. discussion: although coxiella burnetii infection is acquired via the respiratory tract, it is paradoxical that symptoms attributed to the lung are not invariably positive. q fever pneumonia is an atypical pneumonia that usually follows a benign course. diangostic suspicion is usually raised by the epidemiologic pattern and the accompanying mild hepatitis. pleural effusion is not a common finding. the usual radiologic appearance of q fever pneumonia is that of a lobar or segmental pneumonia. one important aspect of q fever pneumonia is its common presentation in the form of multiple nodular opacities often necessitating the exclusion of malignancy. ( ), culture ( ), and serology'/culture ( ). there were Á/ cases per year, mainly in october ( %). a history of exposition to hare was present in / ( %) and to marmot in / ( %). skinning ( / %), animal contact ( / %), bite ( / ) and wound during bait preparation with frozen meat for hunting ( / ) were noted. the initial clinical presentation was ulceroglandular ( %), glandular ( %) and pneumonic ( %). the involved nodes distribution was axillary ( / ), cubital/axillary ( / ) and cubital ( / ). median incubation period was days (range Á/ ); time to consultation days (range Á/ ), and time for effective treatment days (range Á/ ). an initial diagnosis of tularemia was made presumptively in %. effective antibiotic regimen used was aminoglycosides in % ( / ), and tetracyclines in % ( / ). note that intravenous netilmicin was used in cases. complication rate was % ( / ) with one death ( %), and was associated with delay in effective treatment ( !/ days of illness) (p b/ . ). conclusion: in our area tularemia occured mainly in male population, during autumn, with a short incubation period and history of hare contact. delay before appropriate treatment increased the complication rate. bompolaki i, doukakis s, triantafillidou d, polimili g, kastanakis m, nikiforakis k, vittorakis e, kastanakis s. first medical department, 'saint george ' general hospital, chania, greece a severe frontal and/or retroorbital headache represents the most common neurologic manifestation of murine typhus. other neurologic manifestations as confusion, stupor, nuchal rigidity and in severe cases delirium, extreme agitation or coma appear less commonly. eightyfour patients with compatible clinical status of murine typhus and high serological titers of antibodies against rickettsia typhi, were studied from our team. seventy-four patients ( %) presented headache and nine patients ( %) presented confusion. one patient ( . %) presented nuchal rigidity in combination with severe headache and confusion giving us the suspicion of meningitis. in this case a lumbar puncture was performed emergently and the cerebrospinal fluid (csf) was examined. the findings of csf were proteins: mg/dl, wbc: /ml and glucose: mg/dl and its culture was negative. all patients were treated with a specific anti-rickettsial treatment. the outcome of murine typhus was favorable for all patients ( %). no one patient presented neurologic sequelae. conjunctivitis usually accompany rickettsial diseases such as rocky mountain spotted fever, epidemic typhus and murine typhus. eightythree patients with compatible clinical status of murine typhus and high serological titers of antibodies against rickettsia typhi , were studied from our team, during a period of time between january and the first semester of . the clinical examination of these patients revealed the presence of conjunctivitis in / patients ( . %). in the same time these patients referred retroocular pain and mild photophobia. this study showed that in murine typhus the injection of conjunctivae is rather common. almost a quarter of the patients presented conjunctivitis despite the fact, that this ocular manifestation is less severe than in other typhus and spotted fevers. eighty-three patients with compatible clinical status of murine typhus and high serological titers of antibodies against rickettsia typhi , were studied from our team, during a period of time between january and the first semester of . three blood samples were obtained from each patient for the study of their hematological abnormalities. the first sample was obtained on admission, the second sample weeks after the first, the third sample, month after the second. on admission / patients ( %) presented anemia, / patients ( %) presented leukopenia and / patients ( %) presented thrombocytopenia. the mean value of hematocrit, white blood cells and platelets was . g/dl, . )/ and )/ /ml, respectively. two weeks later anemia was presented in / patients ( %), / patients ( %) presented leukopenia, / patients ( %) presented leucocytosis and / patients ( %) presented thrombocytopenia. the mean value of hematocrit, white blood cells and platelets was . g/dl, . )/ and )/ /ml, respectively. one month later / patients ( %) had anemia and / patients ( %) presented thrombocytopenia. the mean value of hematocrit, white blood cells and platelets was . g/dl, . )/ and )/ /ml, respectively. our study showed that early thrombocytopenia and anemia are frequent in murine typhus and that white blood cells count is usually normal. renal function in murine typhus: a study of cases ps doukakis s, polimili g, triantafillidou d, kastanakis m, vittorakis e, palla k, kastanakis s. first medical department, 'saint george ' general hospital, chania, greece the clinical course of murine typhus is usually uncomplicated and the mortality rate is low ( b/ %). advanced age and prolonged interval before administration of a specific anti-rickettsial treatment are correlated with severity of the disease. renal function in murine typhus is usually unaltered except in elderly patients with prolonged hypotension. eighty-three patients with compatible clinical status of murine typhus and high serological titres of antibodies against rickettsia typhi, were studied from our team, during a period of time between january and the first semester of . three blood samples were obtained from each patient for the study of their renal function. the first sample was obtained on admission, the second sample approximately weeks after the first, the third sample, taken from the half of the patients, was obtained one month after the second. on admission / patients ( . %) presented acute renal failure. the outcome of murine typhus was favourable for all patients ( %). the four patients who presented acute renal failure reversed after the administration of anti-rickettsial treatment and careful administration of fluids. in murine typhus the induction of hypovolaemia insufficiently corrected by normal homeostatic mechanisms may lead to prerenal azotaemia. in these cases the immediate onset of an antirickettsial treatment and the correction of hypovolaemia are essential for the rapid clinical improvement of the patient. experimental ocular toxoplasmosis: clinical, histopathological, immunological and therapeutic studies ps el zawawy lae a , hammoda na a , allam sr a , ali sm a , galal as b . a faculty of medicine, parasitology, alexandria, egypt , b faculty of medicine, ophthalmology, alexandria, egypt the purpose of the study was to investigate clinical, histopathological, immunological and therapeutic features of an experimental model of ocular toxoplasmosis in sensitized and non sensitized rabbits and to assess the influence of treatment by interleukin (il- ) on ocular lesions. the results obtained was that 'toxoplasma' retnochoroiditis developed in both groups of rabbits with more pronounced effect in non sensitized animals. administration of il- improved ocular lesions in both groups with more evident effect in sensitized rabbits. immunological findings were consistent with clinical and histopathological observations. the conclusion reached was that; ocular lesions were manifested in non sensitized rabbits more than in sensitized ones. il- revealed a significant impact on improving the host defense against toxoplasm infection in eye. immunotherapy with il- would open the way for a new range of treatment based on immunomodulation. express-diagnostic of streptococcus antigen for the adequate antibiotic therapy in patients with pharyngitis ps pertseva to, konopkina li, kireeva tv. dsma, internal medicine , dniepropetrovsk, ukraine the purpose of the study: evaluation of effectivness of streptococcus express-diagnostic for the adequate antibiotic therapy in patients with pharyngitis. results: we deal with clinical and microbiological comparison in patients with pharyngitis. using of streptococcus antigen express diagnostic in swabs from the backside of pharynx allowed to get positive results in the seven cases ( . %). following cultural study has confirmed these results. positive test was more probable in patients with pronounced fever (more than c), headache, weakness and in cases associated with chronic tonsillitis. isolated streptococcus pyogenes was susceptible to ampicillin, claritromicin, erytromicin, azytromicin, , clindamicin, ceftriaxon, levafloxacin, oxacillin, cefuroxim, roxytromicin. conclusion: using of the express diagnostic of streptococcus antigen allows to restrict groundless prescription of antibiotic therapy in patients with other types pharyngitis (i.e. viral, candidal etc.). alabaz d a , turgut m a , kocabas e a , tumgor g a , yaman a b , alhan e a . a division of pediatric infectious diseases, cukurova university, adana, turkey , b department of microbiology, cukurova university, adana, turkey chickenpox is a common viral infection that usually follows a benign, self limited course in healthy children. the most common complication in children with varicella is superimposed cutaneous infections with pyogenic bacteria (streptococcus pyogenes and staphylococcus aureus ). varicella gangrenosum, a necrotising soft tissue infection complicating the vesicular eruption of chickenpox, is rare. here we present three cases with necrotising soft tissue infections following chicken pox. these children were admitted because of common crusted lesions and necrotising soft tissue infection over the neck, the back, and the inguinal area. they all had the contact history and ensuing vesiculopapular rush. these infections were caused by group a streptococci in two cases, and s. aureus in one case. after instituting of appropriate antibiotic therapy, each patient underwent a surgical exploration with fasciotomies and debridement. widespread use of varicella vaccine may decrease invasive infections in children, adolescents, and adults, thus decreasing the burden the disease with its complications impose up on the family and the society . cefprozil is a second generation cephalosporin. the aim of this open, multicentre, non-comparative study was to investigate the efficacy and safety of cefprozil in the treatment of streptococcal tonsillopharyngitis. fifty-eight patients were clinically assessed for signs and symptoms of streptococcal infection. laboratory confirma-tion was sought using three tests; culture, rapid strepto test and estimation of antistreptolysin (aso). one or more tests were done in of the patients. treatment was for days, mg/kg per day in children, mg per day in adolescents. patients were again clinically assessed on the th Á/ th day. the results showed clinical success in patients ( . %) and in of the who had laboratory tests ( . %). two patients had treatment withdrawn because of nausea and abdominal pain ( . %). of the patients with laboratory tests at least one test was ositive. the most helpful was the strepto test giving the quickest positive result in % of those tested ( / ). culture was positive in % of those tested ( / ). the aso test was of limited value. in conclusion, cefprozil showed high clinical efficacy and safety in the treatment of streptococcal tonsillopharyngitis. tsiara s, militadou g, milionis c, elisaf m. internal medicine department, university of ioannina, ioannina, greece streptococcus group b agalactiae (gbs) is a rare pathogen for healthy male adults. we present an old man in whom (gbs) was isolated in blood cultures. case report: a -year-old man was admitted to the hospital in order to investigate osteolytic lesions in the lumbar spine. two weeks before, he experienced severe low back pain radiating to the right leg and fever arising to . c with chills and rigors. a gbs was isolated from blood cultures and treatment with penicillin was initiated. a spine ct scan revealed osteolysis in the t and s vertebrae and the patient transferred to us. he was a previously healthy man. he received only antihypertensive therapy. on admission he was afebrile with arthralgias and myalgias. on clinical examination there was tenderness on the right pleurospondylic angle radiating to the right leg. laboratory data on admission: hb: . g/dl, wbc: . )/ /l, esr: mm/h. biochemical values, serum protein electrophoresis, rectal examination and a prostatic specific antigen (psa) were normal. a bone marrow aspiration and biopsy were negative. a transoesophageal ultrasound revealed vegetation on the right cusp of the aortic valve, with low grade regurgitation. an mri of the lumbar spine revealed infectious myositis with concomitant osteomyelitis involving the l , l vertebrae without any evidence of osteolytic lesions. a thorough investigation did not revealed any underlying immunosuppressive disease. treatment with vancomycin and gentamycin iv was initiated and the patient discharged from the hospital in excellent health after weeks. discussion: gbs infections usually occur in neonates and pregnant, or in adults with underlying disease as diabetes mellitus or immunosuppression. the most common site of infection is soft tissue. we present this case because gbs infections are rare in the elderly in the absence of underlying disease. common sites of involvement are soft tissues, while bone, joints, and heart valves account to Á/ % of the involved organs. although our patient had more than one site of involvement he responded well to medical treatment without surgical debriment or heart valve replacement. objective: to evaluate the safety and efficacy of rhugm-csf in combination with broad-spectrum antibiotics for the treatment of ccnf. methods and results: a retrospective review of all patients (pts) with ccnf treated with antibiotics'/rhugm-csf at our hospital from january to december was performed. five patients were identified with the diagnosis of ccnf. ages ranged from to years; there were three women and two men. dental infection was the most common source of ccnf in %. one patient had acute tonsillitis leading to ccnf. all cases studied experienced infection of the neck with spread into the submandibular, submental, sublingual, retropharyngeal, and parapharyngeal spaces. all infections were polymicrobial. diabetes mellitus was a co-morbidity in one case. all pts were treated with dual antibiotic coverage (vancomycin'/meropenem), rhugm-csf ( mcg/kg/daily given s.c.) and aggressive wound care. rhugm-csf was given for Á/ days. in spite of the severity of the infection all pts recovered and do not experienced local or systemic complications. discussion: ccnf is a severe bacterial infection of the cervical fascia resulting in extensive fascial necrosis with widespread undermining of the surrounding tissues. prompt antibiotic therapy combined with rhugm-csf resulted in a % overall survival in our experience. to our knowledge, this is the first report describing the successful treatment of ccnf with use of broad-spectrum antibiotics combined with rhugm-csf. the following case adds to the clinical manifestations and course of meningococcal disease. a previously healthy -year-old girl presented acutely with high fever purpuric rash including conjuctival haemorrhages and hypotension. the child had also neck stiffness. a presumptive diagnosis of meningococcal septicaemia was made and treatment with penicilline, chloramphenicole, fluids and inotropes was initiated. laboratory investigations showed wbc: /ml, hb: . g/dl, hct: . %, esr: mm in the first hour, pt: s, aptt: s. neisseria meningitidis group b was isolated from the blood cultures. csf obtained after antibiotics were started did not grow n. meningitidis . the patient had an adverse outcome. she died after h of hospitalization. this patient developed a fulminating meningococcal septicaemia. shock is a clinical diagnosis arising from the failure of compensatory mechanisms that maintain perfusion of vital organs at the expense of non vital. septic shock results from loss of circulating plasma volume due to increased vascular permeability and maldistribution of intravascular volume. in young children there is a prevalence of serogroup b meningococcal disease which can be explained by the immaturity of the immune system and by the fact the group b capsule synthesis is known to inhibit alternative complement pathway activation. this case emphasizes the need for further protection against n. meningitidis group b. . results: forty-eight patients were included in this study. the etiological agents were: viral (n / , . %, mean ('x ) age / years), streptococcus pneumoniae (n / , . %,'x age / ), neisseria meningitidis (n / , . %, 'x age / ), s. viridans (n / , %, 'x age / ), p. multocida (n / , age ). the peak incidence of bacterial meningitis was in winter (pneumococcal %, meningococcal %, s. viridans %) .the cerebrospinal fluid (csf) findings in viral meningitis were 'x white cells / /mm , 'x pmn / %, 'x glucose csf/ serum . , 'x protein mg/dl and in bacterial meningitis were 'x white cells / /mm , 'x pmn / %, 'x glucose csf/ serum / . , 'x protein / mg/dl, gram stain was positive in %, culture was positive in %. all pneumococcal and meningococcal strains were susceptible to penicillin. the case fatality rates for pneumococcal and meningococcal meningitis were and . %, respectively. conclusions: the cases of bacterial meningitis were according to typical epidemiological features of age and season. the case fatality rate of pneumococcal meningitis appear to be high regardless of susceptibility to penicillin. none had received pneumococcal vaccine prior to becoming ill. diagnosis and therapy of meningococcal meningitis */trend and particularities of a 'romanian model' ps lintmaer i, moroti r, popescu a, popescu c. institute of infectious diseases matei bals , unit , bucharest, romania background: newer diagnosis methods and antimicrobials are expected to change the management of menigococcal meningitis (mm) and to improve its prognosis. objectives: to determine the changes in the diagnosis methods and therapy of mm patients in a infectious diseases hospital. to compare mm management in bucharest with literature data. methods: retrospective rewiew of mm in adult patients hospitalized over a -year period. our results were compared with other studies made in the s, taken from medline. results: there were episodes of mm during the study period ( episodes in Á/ and episodes in Á/ ) . we noticed a defined diagnosis increase and increased blood culture specificity. the antimicrobial monotherapy was maintained but penicilin was replaced by ceftriaxone. hhc was replaced by dexamethasone in pathogenic therapy. we noticed a shorter length of treatment and a reduced lethality. the most important differences between our results and other studies are: monotherapy regimens are less frequent and therapy lengths are longer; however, prognosis is similar. conclusions: the mm management has been modified in the last Á/ years: prognosis is improved, but the changes do not bring clear cost/ effective benefits. tiouiri th, kilani b, amari l, zouiten f, kanoun kf, ghbontini a, ben chaabene t. rabta hospital, infectious diseases, tunis, tunisia objectives: in order to study epidemiological, clinical and therapeutical characteristics of the infective endocarditis (ie). methods: we reviewed all the cases of ie fulfilling the duke criteria. data were collected during a -year period ( Á/ ) in the unit of infectious diseases. results: one hundred and eight cases were identified. the mean age was . years. sex ratio was . . eighty-five ie ( . %) occured in patients with native valve, and ie ( . %) with prosthetic valve. fever was the most common sign, % had a congestive heart failure, . % had cutaneous signs. the most common primary focus of ie was orthodontic. blood cultures were positive in % of cases. in one case, serological test identified rickettsia conori . streptococci and staphylococci were isolated in . and . %, respectively. echocardiography detected abnormalities in . % of cases. rheumatic heart disease was the most predisposing condition. empirical therapy was based on combination of b lactam with aminoglycoside. recovery was obtained for patients. cardiac surgery was performed in cases. overall mortality rate was . %. conclusion: ie affects young persons. prevention needs eradication of acute rheumatic arthritis. a major outbreak of legionnaires' disease in spain: diagnostics aspects ps guerrero c a , toldos cm a , yagü e g b , ramírez c a , rodríguez t a , -segovia m a . a hospital morales meseguer, servicio de microbiología, murcia, spain , b departamento de microbiología, facultad de medicina, universidad de murcia, murcia, spain objective: to evaluate the value of different methods (serological tests, culture of respiratory secretions, blood cultures and urinary antigen testing) for the diagnosis of legionella pneumophila pneumonia during an outbreak in spain. results: we have studied patients from a recent outbreak of legionellosis in murcia (spain). the diagnosis was achieved in patients. urinary antigens were positive in patients. in the patients with urinary antigen negative the serological response was demonstrated by indirect immunofluorescence (ifa) in patients. all blood cultures processed were negative. sputum samples were obtained from patients, of these l. pneumophila was isolated only in six patients. in all of them direct immunofluorescence test (dfa) was positive. conclusions: although the serological diagnosis was the most sensitive method the urinary antigen testing was of great value in the rapid diagnosis of the legionella's outbreak in murcia. the isolation of l. pneumophila by culture showed a poor sensitivity probably because of the low severity of the illness. purpose: to evaluate chloramphenicol for an initial empiric antibiotic treatment of purulent meningitis in adults. study group: one hundred and twenty patients hospitalized for the diagnosis purulent meningitis in the department in years Á/ , males and females, age range Á/ years, mean age . years. children up to years were not included. method: a retrospective analysis of the study group focused on antibiotic treatment both initial and changes during treatment. results: chloramphenicol was used as an initial antibiotic in ( %), rd generation cephalosporin in ( %), penicillin in ( %), ampicillin in five ( %) and other antibiotic in five ( %), respectively. during treatment chloramphenicol was switched for rd gen cephalosporin in seven of patients with streptococcus pneumoniae meningitis and in five of patients with meningitis of unknown etiology. the reason for the change was non-improving csf formula in three, persisting csf culture positivity in two and persisting coma in seven patients. conclusion: because of repeated necessity to switch chloramphenicol for rd gen cephalosporin during treatment of purulent meningitis of pneumococcal and unknown etiology the initial treatment strategy was changed in . third gen cephalosporin is now used as a first choice antibiotic, what is in consent with international recommendation of treatment. to evaluate and compare groups treated initially with chloramphenicol and with rd gen cephalosporin will need several more years. low prevalence of multi-drug resistant mycobacterium tuberculosis in jerez de la frontera-cadiz (spain) ps alados jc, aller ai, de miguel c, de francisco jl, calbo l. hospital del sas-jerez , microbiologia, jerez de la frontera, cadiz, spain introduction and aim: previous reports indicate that multi-drug resistance mycobacterium tuberculosis (mtb) is an worldwide problem. the aim of this study was to review the resistance of mtb to the first-line antimycobacterial agents in our area. material and methods: over a period of years ( Á/ ), strains of mtb isolated from non-treated patients with tuberculosis ( strain in , in , in and in ) were studied. these isolates were tested for in vitro drugs susceptibility to isoniacid-i, rifampicin-r, streptomycin-s and ethambutol-e using the bact/ alert method (organon teknica) as described by the manufacturer. results: our results showed that . % ( / ) strains were resistant to one or more drugs. single drug resistances were detected on nine strains to i ( . %), one to r ( . %), two to s ( . %), one to e ( . %). three mtb strains were resistant to more than one drug but only one was multi-drug resistant (i'/r).the incidence of i-resistant strains over the period fell from % in to . % in . conclusions: ( ) multi-drug resistance is not an important problem in our area. ( ) isoniacid resistance was declined to an admissible level. to investigate the anti-tuberculosis drug resistance pattern of pulmonary tuberculosis isolates in southern taiwan, an area with higher tuberculosis incidence and mortality than other regions of the island, we performed a hospital-based surveillance at a southern taiwan medical center from to . the combined drug resistance rates to at least one of five first-line agents was . %, and to both isoniazid and rifampin (multi-drug resistance, mdr) was . %, indicating high resistance rates compared with those reported in the who/iuatld global project and in northern taiwan. the resistance rates to two second-line drugs, cycloserine, and kanamycin, were . and . %, respectively. a significant decreasing trend in resistance rates to all drugs except streptomycin was observed during the -year period. though combined drug resistance rate may not be the most accurate tool as it includes previously treated cases which inflates the resistance rate, the observation of trends in the susceptibility of pulmonary tuberculosis in accompany with the increasing percentages of tuberculosis patients receiving complete treatment course and the decreasing percentages of cases lost of follow-up in kaohsiung after the institution of new governmental regulations for case management in suggest the usefulness of intervention programs. lipid profile in patients with multidrug resistant pulmonary tuberculosis ps extrapulmonary tuberculosis may sometimes present with confusing clinical manifestations. a -year-old female patient was admitted with a history of recurrent supra-sternal abscess for year. mri confirmed the presence of sternal osteomyelitis and an anterior mediastinal mass. the diagnosis of tuberculosis was proved by histologic examination and acid-fast stain. the patient was treated with first-line agents, which isoniazid, rifampin, pyrazinamide, and ethambutol. tobacco smoking as a factor of the decrease of chemotherapy effectiveness and of the development of the drug resistance in patients with pulmonary tuberculosis ps shprykov as a , zhadnov vz a , shprykova on b . a medical academy, department of tuberculosis and lung diseases, nyzhny novgorod, russian federation , b medical clinic for infectious # , laboratory of bacteriology, nyzhny novgorod, russian federation studies of the effect of smoking on the results of chemotherapy of patients with tuberculosis of lungs. intensive tobacco smoking slowed down clearance of positive sputum and of lung tissue destruction (in smokers . % and . vs. . % and . % in nonsmokers, p b/ . ). drug-resistant mtb strains have been found to be isolated more often in smokers */ . vs. . % in non-smokers, p b/ . . resistance to streptomycin and isoniazid prevailed, reaching in heavy smokers . and . %, respectively. resistance to rifampicin increased . times. the concentration of rifampicin in the blood serum of heavy smokers decreased in . times. clinical data are in complete correlation with the findings of our experiments: % of experimental cultures developed resistance to streptomycin, isoniazid and less to rifampicin in the study of drug sensitivity under the effect of tobacco smoke condensate. thus, our findings show the development of drug resistance in mtb under the effect of components of tobacco smoke and also showed less effectiveness in therapy. kilani kb, ammari la, tiouiri ht , ben chaabène tbc. rabta hospital, infectious diseases, tunis, tunisia guerrero c a actinomycosis is a chronic disease characterized by abcess formation, tissue fibrosis and draining sinuses. it is caused by anaerobic bacteria belonging to the genus actinomyces. thoracic actinomycosis may involve the lungs, pleura, mediastinum or chest wall. the authors present a case of pulmonary actinomycosis complicating a cervicofacial site. a -year-old man with a history of cervicofacial actinomycosis treated by penicillin g years ago was admitted because of right-sided chest pain for months before presentation, cough and fever. physical examination shows a painless indurated mass in the neck with multiple fistula of the sternum. chest radiograph and ct scan revealed a mass in the upper lobe of the right lung with an infiltrate of the upper lobe of the left one. magnetic resonance imaging confirms the previous lesions, with extending process to the sternum and right collar bone. bronchoscopy was performed while patient was on antimicrobial therapy. culture of bronchoalveolar lavage fluid was negative. transbronchial biopsy was not conclusive. fungal serologies were negative for aspergillosis, histoplasmosis, blastomycosis. bacterial examination of purulent drainage from sternal wound shows inclusion bodies identified as actinomyces. he was treated then with penicillin iv for months, than switched to doxycycline. after months of treatment, he is asymptomatic with radiological improvement. kanellopoulou m a , skarmoutsou n a , iglezos i b , mylona e a , martsoukou m a , apostolopoulou f b , papafrangas e a . a laboratory of clinical microbiology, sismanoglio general district hospital of attica, athens, greece , b nd department of pneumology, sismanoglio general district hospital of attica, athens, greece introduction: achromobacter xylosoxidans is a rare human pathogen. it is an important cause of bacteremia in patients with cardiac diseases, malignancies and immunosuppression. it has been recently recognized as an emerging microorganism in cystic fibrosis (cf), whose its pathogenic role is unknown. aim: to investigate the sensitivity to eleven different antibiotics of a. xylosoxidans strains isolated from adults with cf, during . methods: the susceptibility was tested by kirby bauer and microdilution methods (wider i, fransisco soria melguizo, s.a.), according to nccls recomendations. results: the resistance to antibiotics was as follows : gentamicin, tobramycin, aztreonam %, amikacin %, ceftazidime %, ticarcillin %, carbapenems, cotrimoxazole %, colistin % and piperacillin %. conclusions: ( ) a. xylosoxidans isolated from cf patients appeared resistant to the most usually tested antibacterial agents. ( ) colistin which is used as aerolized antibiotic for cf patients seems to be effective in the half of the isolated strains. ( ) piperacillin was the most active antibiotic against a. xylosoxidans . morris ka, perry jd, jain s, gould fk. microbiology department, freeman hospital, newcastle upon tyne, uk alafosfalin, l-alanyl-l- -aminoethylphosphonic acid, is an antibacterial peptide mimetic which inhibits peptidoglycan biosynthesis. we report the in-vitro activity of this compound in combination with ceftazidime, cefsulodin, fosfomycin, piperacillin/tazobactam, aztreonam, ciprofloxacin and timentin. drug combinations were evaluated against burkholderia cepacia strains, and pseudomonas aeruginosa strains isolated from patients with cystic fibrosis. for this purpose a chequerboard technique was adopted using doubling dilutions of each antibiotic incorporated into a highly defined agar medium free of antagonists. the minimum inhibitory concentrations (mics) and fractional inhibitory concentrations (fics) of all the antibiotic combinations were determined which revealed the antibiotic interaction occurring. alafosfalin in combination with ceftazidime, meropenem, piperacillin/tazobactam and timentin demonstrated the highest percentages of synergy in both b. cepacia and p. aeruginosa . synergy was shown to occur in , , and % of b. cepacia strains respectively, and in , , and % of p. aeruginosa strains. these four combinations were re-tested with all isolates and the results were shown to be reproducible. alafosfalin shows potential as a treatment for cystic fibrosis patients colonised with p. aeruginosa and/or b. cepacia , when applied in combination with these agents. community-acquired pneumonia */does its aetiology matter? ps lintmaer i, popescu a, popescu c. institute of infectious diseases matei bals, unit , bucharest, romania the aetiology of a pneumonia is not one of the criteria used to determine pneumonia's severity. however, it is accepted that identified based Á/based therapy is less expensive (and possibly more effective). objectives: our study aims were to: ( ) to evaluate the role of aetiology identification in pneumonia; ( ) to evaluate the first-line therapy in pneumonia. methods: we conducted a retrospective study in an infectious diseases hospital on patients with pneumonia. we excluded all the cases with nosocomial pneumonia. primary end-point was the day clinical failure (deaths, icu admission), secondary end-points were the average time of fever and length of stay and the antimicrobial regimen changes. results: causative agent identification rate was . %. the evolution was different for patients with identified aetiology compared with other patients in terms of: -day failures, length-of-stay and changes of the antimicrobial regimen. the patients with inadequate first-line therapy had a more severe course of illness with a greater rate of day clinical failure, longer fever and length-of-stay. conclusions: pneumonia's treatment was better for the patients with identified causative agent. that is why we should include aetiology among the pneumonia severity criteria, especially at an 'after -day therapy' re-evaluation. results: pneumomococcal aom was detected in children ( . %) and s.pn. was the only pathogen in . %. the resistance rates of the organism to antibiotics were as follows: penicillin . % (micb/ mg/ml; intermediately resistant . %, mic . mg/ml . %, and mic!/ mg/ml; highly resistant . %), erythromycin . %, clindamycin . %, cotrimoxazole . % and chloramphenicol . %. all isolates were uniformly susceptible to rifambicin and vancomycin. the large majority of pneumococcal isolates ( . %) had the mphenotype and the remaining strains ( . %) the constitutive mls phenotype. a various of serogroups were detected; the serogroup was the most predominant one ( . %), followed by serogroups ( . %), ( . %) and ( . %). the non-typable s.pn. strains compromised the . % of the strains. conclusions: high prevalence of resistance to penicillin, macrolides and cotrimoxazole in pneumococcal aom of childhood was recognized. a strategy for preventing aom caused by drug-resistant pneumococci is mandatory to start. material and methods: a total number of strains were examined. the sensitivity test was performed by kirby bauer, microdilution method (pasco, difco) according to nccls guidelines and by e -test. results: a percentage of . % of s. pneumoniae strains revealed high level resistance to penicillin (mic]/ mg/ml), while the % showed intermediate resistance (mic . Á/ mg/ml). the resistance to erythromycin and cotrimoxazole was . % (mic ]/ mg/ml) and . % (mic]/ / mg/ml), respectively. all strains were sensitive to cefotaxime (mic . mg/ml), vancomycin (mic / . mg/ml), meropenem (mic / . mg/ml) and levofloxacin (mic / mg/ml). conclusions: ( ) the prevalence of high resistance s. pneumoniae to penicillin seems to be low in examined strains ( . %). ( ) intermediate resistance to penicillin of s. pneumoniae isolates was high as expected ( %). ( ) most of the strains were sensitive to erythromycin ( . %) and cotrimozaxole ( . %). ( ) s. pneumoniae isolates were completely ( %) sensitive to levofloxacin, vancomycin and meropenem. beghi g, aiolfi s, maghini l, patruno v, aiolfi e. s marta hospital, pulmonary rehabilitation unit, a.o., rivolta d'adda, italy aim: of this study was a retrospective ( Á/ ) evaluation of the more effective and practical antibiotic treatment in ae-copd patients (pts) admitted to our unit. methods: before introducing any antimocrobial drug, sputum specimens were collected for microbiological purposes, while blood analysis, to monitor adverse systemic effects, were performed at the beginning and the end of treatment. antibiotic treatment ranged from to days according to four regimens: regimen a ( pts) /oral therapy only: . % with amc g b.i.d.; . % with cip mg b.i.d.; . % with dox mg u.i.d.; . % with lev mg u.i.d.; . % with cla mg b.i.d.; . % miscellaneous. regimen b ( pts) /sequential therapy (e.v. for days /oral): . % with amc g b.i.d.; . % with cla mg b.i.d. regimen c ( pts) /e.v. therapy only: same drugs. regimen d ( pts) /an association of two antibiotics. results: of evaluated pts, only ( . %) required a second regimen of treatment because of failure of the previous one: . % of regimen a; . % of regimen b; . % of regimen c, and % of regimen d. mild adverse effects were detected only in four pts. our results confirm that oral antibiotic treatment is practical, safe, and effective, and can be considered as the first line regimen also in hospitalized patients with ae-copd. becher g a , gillissen a a , rothe m b . a st. george medical center, robert-koch-hospital, leipzig, germany , b filt, lung and chest diagnostics ltd., berlin, germany patients with severe form of chronic obstructive pulmonary disease (copd) are prone by frequent exacerbations. bacterial infections are judged to cause at least half of exacerbations. haemophilus influenzae and streptococcus pneumoniae are the most frequent isolates, gramnegative bacilli account for the severe cases, aggravating the inflammatory process in the airways eventually leading to respiratory insufficiency. the aim of this ongoing placebo controlled, parallel group, mono center study trial is to evaluate beneficial effect of cefixim to reduce bacterial load and pulmonary inflammation in patients (n / ) with acute bacterial exacerbation of severe copd. thus, patients received in randomized fashion either cefixim ( mg/day) or placebo ( days). on days , , and breath condensate is collected using 'ecoscreen' (jaeger germany) for ltb -, il- -, nitrite-and ph-analysis. in parallel sputum gathered for detection of bacterial strains, and for ltb -, and il- quantification purposes. these data are compared to clinical outcome parameters such as lung function tests, radiographic findings, serum inflammatory markers and length of hospital stay. the preliminary data obtained confirm successful antibiotic therapy with oral cefixim in bacterial related acute exacerbations of copd is a useful approach to reduce bacterial load, and concomitantly lower inflammatory indices of the central and peripheral airways leading to clinical improvement of the patients. soriano garcia f a , fenoll a b , fernandez-roblas r a , coronel p c , gimeno m c , rodenas e c , garcia m a , granizo jj d . a fundacion jimenez diaz, microbiology, madrid, spain , b instituto de salud carlos iii, centro nacional microbiologia, majadahonda, spain , c tedec meiji farma, scientific, alcala de henares, spain , d fundacion jimenez diaz, epidemiology, madrid, spain purpose: to describe the susceptibility of streptococcus pneumoniae against cefditoren and other antimicrobials by serotype a multicenter study in south europe was carried out. a total of strains were collected between september and march from adult patients (more than y.o.) with respiratory tract infection (respiratory tract samples and blood cultures). all the isolates were sent to a central laboratory (fundació n jiménez díaz, madrid, spain) where susceptibility test was performed by broth microdilution (sensititre) following nccls recommendations. serotype was determined by quellung reaction and dot assay in carlos iii institute in strains. results: a total of strains ( . %) were not typable. the most prevalent serotypes were ( . %), ( . %), ( . %), ( . %), ( . %) and ( . %). two hundred and sixty-four strains were grouped in different serotypes. the proportion of susceptible strains by serotype to penicillin, erythromycin and levofloxacin were: serotype ( . , . , %); ( . , . , . %); ( . , . , . %); ( . , . , . %); ( . , . , . %); ( . , . , . %). the mic to cefditoren was / . (serotype ); . (serotype , and ) and mg/l (serotype and ). conclusions: the most prevalent serotype was . the susceptibility was higher in serotype than in serotypes and . community acquired pneumonia */a study among closed military community of young people ps martynova av, turkutyukov vb, vostrikova aa, andryukov bg. vladivostok state medical university, epidemiology, vladivostok, russian federation purpose: the etiology of pneumonia is still partly unknown. we should like to clear up an etiological role of respiratory pathogens in community-acquired pneumonia among youth. and we had chosen for it a model of a closed community both investigation of etiology of disease and for further investigation of mechanisms of transmission drug-resistant mechanisms. methods: we studied adults in age of Á/ from closed military collectives who presented to two public hospitals (one urban and one rural) with acute radiologically confirmed pneumonia during winter Á/ . we did blood and lung-aspirate cultures, mycobacterial cultures, serotype-specific pneumococcal antigen detection, and serology for viral and atypical agents. results: streptococcus pneumoniae is recognized as an important cause of community-acquired pneumonia, it probably accounts for % of cases of community-acquired pneumonia among youth. chlamydia pneumoniae and mycoplasma pneumoniae responsible for approximately % of cases. haemophilus influenzae caused . % sever cases of disease, % of all cases were due to moraxella catharralis . conclusion: pneumococcial infection accounted for % of the cases diagnosed. s. pneumoniae was the most common bacterial infective agent, with a low incidence of both m. pneumoniae and s. pneumoniae . other causative pathogens occurred only within groups of individuals with deficiency of immunological status. berezin en a , cardenuto md a , nobuko e b , guerra ml c , brandileone mc d . a santa casa, pediatrics, s. paulo, brazil , b santa casa, microbiology, s. paulo, brazil , c adolfo lutz, microbiology, s. paulo, brazil , d adolfo lutz, bacteriology, s. paulo, brazil to determine antimicrobial susceptibility of sp isolated from the upper respiratory tract, we collected np swab specimens from children, between months and years old. those children attended the outpatient clinic in s. paulo city, with diagnosis of bacterial infection requiring antibiotic therapy between march , to may , . penicillin susceptibility of isolates was determined by screening with oxacillin mcg disk and performing the minimal inhibitory concentration by the e -test. we performed also susceptibility test for amoxicillin and cefaclor. results: sp was recovered from np of children ( . %). the carriage of sp was more prevalent in children attending day care centers, children with young siblings at home, and children with tobacco users at home. the prevalence of penicillin non-susceptible strains was . % all of them with intermediate resistance. all the strains were susceptible to amoxicillin and . % were resistant to cefaclor. serotypes . b, f, n, , a and were the most common. these findings suggest that nasopharyngeal isolates of streptococcus pneumoniae from children with upper respiratory infections can be used to conduct surveillance for antimicrobial resistance in a defined geographic area. we were able to conclude also that penicillin intermediate resistent strains can be susceptible to amoxicillin. hinojosa rm a , saenz a a , collazo m a , echaniz g b . a universidad autonoma de nuevo leon, infectologia, monterrey, mexico , b instituto nacional de salud publica, epidemiologia, cuernavaca, mexico the emergence of penicillin-and multidrug-resistant pneumococcal strains has become a global concern, necessitating the identification of the epidemiological spread of such strains. material: ninety streptococcus pneumoniae clinical isolates were collected from march through march . typing was done by the capsular reaction with pooled, type, or group antisera. susceptibility testing to antimicrobials was done by the e -test and the disk diffusion method. results: only ( %) s. pneumoniae strains were classified by serotyping; the most frequent types were a/b, f, v, f and . the oxacillin screening test detected . % penicillin-resistant s. pneumoniae strains isolated from children and . % from adults. the susceptibility percentage of s. pneumoniae to ceftriaxone was % in both children and adults. s. pneumoniae isolates from children exhibit a susceptibility of % to azithromycin, while in adults % of the isolates were susceptible. for the rest of the antimicrobial agents, the susceptibility ranged from to %. s. pneumoniae had a lower susceptibility to ceftazidime and ciprofloxacin. conclusions: ceftriaxone and azithromycin had a good in-vitro activity against s. pneumoniae strains. but the percentage of penicillinresistant s. pneumoniae detected in this study is alarming, therefore we conclude that a continuous surveillance system is necessary in mexico. vertkine al, prokhorovitch ea, alexanyan la. a retrospective analyses of cases of ambulant pneumonia with fatal outcome was made. among the patients who died from ambulant pneumonia the prevailing age was over ( . %) and the prevailing sex was male ( . %). . % had pneumonia accompanied with some pathology: chronic lung disease ( . %), alcoholism ( . %), diabetes mellitus ( . %). . % of the patients had a big volume of lungs lesion */ . % of the patients suffered from bilobular pneumonia and . % */from trilobate pneumonia. in . % of the cases pneumonia was complicated with abscess formation and/or exudative pleurisy. we studied the antibiotics therapy used for the patients treatment. the change of antibiotics was made only in cases ( . %) whereas in the other cases no change of preparations was made though the signs of the therapy non-effectiveness were obvious. thus, the rational antibiotics therapy with the timely change of non-effective antibacterial drug is significantly important. while choosing the antibiotics, the patient's age, the accompanying diseases, the volume of the lungs lesion and complications which define pneumonia seriousness are to be taken into consideration. perronne c a , rouveix b b , guillemot d c , zuck p d , reitz c e , tsatsaris a e . a hôpital raymond poincaré, service de maladies infectieuses, garches, france , b hôpital cochin, paris, france , c institut pasteur, paris, france , d hôpital de metz, metz, france , e laboratoires abbott, rungis, france objectives: to describe the management of lower respiratory tract infections (lrti) in healthy adults, by general practitioners (gp). methods: a questionnaire was sent to a representative national sample of gps. this questionnaire assessed their perception and management of lrti, the indication for antibiotics (ab) in a case of lrti in a healthy adult with no focal signs and no signs of severity, knowledge of the micro-organisms responsible for acute bronchitis and knowledge of the afssaps (french agency for the safety of health products) recommendations. results: three thousand seven hundred and thirty-eight gps, who reported seeing an average of patients per week, including . / . patients with lrti, returned the questionnaire. the main results are presented in the following for the majority of gps, the main objective of the visit is to determine the indication for antibiotics. according to gps, alp and whooping cough are rare, while atypical pneumonia is frequent. gps also declare that the diagnosis of alp is often easy right from the first visit, in contrast with that of atypical pneumonia. complementary investigations are not often requested. gps consider that they often delay prescription of antibiotics ( %) and declare that they tend to prescribe a macrolide as first-line treatment. finally, gps have a poor knowledge concerning the micro-organisms responsible for acute bronchitis and the majority of gps declare to be familiar with afssaps recommendations. perronne c a , rouveix b b , guillemot d c , zuck p d , reitz c e , tsatsaris a e . a hôpital raymond poincaré, service de maladies infectieuses, garches, france , b hôpital cochin, paris, france , c institut pasteur, paris, france , d hôpital de metz, metz, france , e laboratoires abbott, rungis, france objectives: to study the management of one case of lower respiratory tract infection (lrti) in adults by general practitioners (gps). methods: prospective study conducted on a representative national sample of gps. each gp had to include the first healthy adult patient seen during the -week data collection period, either on a home visit or in the office for recent cough and acute fever !/ . c. clinical data, the diagnostic perception and the therapeutic approach to the patient were collected by means of a standardised questionnaire, distributed by abbott laboratories. results: three thousand seven hundred and thirty-eight general practitioners included patients. conclusions: during lrti in adults, gps observe few focal signs, confirming the marked predominance of bronchitis compared to pneumonia. in view of the frequency of the signs, the diagnosis of pneumonia appears to be overestimated. one-third of clinical situations were diagnosed as 'bacterial superinfection of acute bronchitis', despite it is not a recognised diagnostic entity. antibiotic prescription was immediate in % of cases and delayed in % of cases. this last point shows that clinical practice differs from the gp's perception of their described prescribing practice shown in a simultaneous survey ( % of gps declared that they prescribed antibiotics immediately, while % delayed this prescription). results: thirty-three patients ( men, mean age b years, mean apache ii score . &bdqup;b . ) during the years Á/ were prospectively studied. thirteen patients ( %) had no identifiable risk factor for severe cap. an etiologic factor was revealed in patients ( %). in of them this was achieved with noninvasive methods. psb cultures were taken from eight patients and were positive in only . the offending organisms included: streptococcus pneumoniae in six cases, gnb as the sole pathogen in six cases, haemophilus influenzae (with s. pneumoniae or klebsialla pneumoniae ) in two cases, s. aureus in two and legionella pneumophila in one patient. initial antibiotic regimen a combination of marcodile '/ rd gen cephalosporin /aminoglycoside was successful in patients who all survived and had to be changed empirically or according to culture results in patients who had a mortality of %. the overall mortality rate was %. the identification of the causative factor did not seem to have any impact on survival. conclusion: severe cap in our icu was most often caused by s. pneumoniae and gbn. the high mortality of this entity seems to be influenced by the immediate use of the appropriate antibiotic combination and not by the identification of the causative organism. this underscores the need for knowledge of topical microbiology which helps in designing an effective empirical initial antibiotic regimen. mily mn a , golubev sa b , lugovoy vy a , voronov gg b . a vitebsk emergency hospital, pharmacotherapy unit, vitebsk, belarus , b basic and clinical pharmacology department, vitebsk state medical university, vitebsk, belarus purpose: the study aims were to assess the spectrum and predictors of the antibiotic use during pneumonia management in a regional emergency hospital in belarus. patients, treatment and physicians characteristics of cases ( Á/ ) were collected and possible associations were examined with using defined daily doses methodology (ddd) and american thoracic society (ats) guidelines. results: the mean treatment duration was . / . days, the total antibiotic ddd/ bed-days was . . the ddd/ bed-days of the most used antibiotics were: penicillins . ; aminoglycosides . ; macrolides . ; cephalosporins . ; tetracyclines . . in manova certain ats categories were associated with ddd/day, but not with frequency of definite antibiotic use. ddd/day was higher in case of multilobar infiltrates ( conclusion: our study indicated the low rate of macrolides and cephalosporins using, and the high one of aminoglycosides. antibiotic prescriptions were associated with disease severity and physician personality rather then with empirical choice rules recommended. acute exacerbation of copd: most frequent infecting agents and their suspectability to the different types of penicillins. analysis of medical documentation ps pertseva to, bogatska ke, gashynova ky. dsma, internal medicine , dniepropetrovsk, ukraine number of copd cases has been increased in ukraine. treatment of acute exacerbation (ae) of copd is not always successful because of inadequate antibiotic therapy. the aim of study was to reveal most frequent infecting agents and their susceptibility to the different types of penicillins in patients with ae of copd. medical documentation of patients with ae of copd (type i) was studied. data of sputum analysis and susceptibility of isolated agents to penicillin, ampicillin, oxacillin and amoxicillin/clavulone acid were evaluated. there were patients with haemophilus influencae/parainfluencae ( . %), klebsiella pneumoniae ( %), staphylococcus aureus ( . %), pseudomonas fluorescens , pseudomonas putida , serratia marcescens , serratia liquefaciens ( . % each), streptococcus agalactiae , acinetobacter baumanii ( . % each) in samples of sputum. in . % cases there was mixt infection. . % had no any bacterial agents. only % of agents were susceptible to penicillin, % */to ampicillin, % */to oxacillin. however, % of microorganisms were susceptible to amoxicillin combined with clavulone acid. this study has shown that most frequent infecting agents caused ae of copd were gram-negative microorganisms and s. aureus . according to antibiogram the prescription of amoxicillin/clavulone acid is most expedient in this case. pertseva to, bogatska ke, konopkina li, kireeva tv, gashynova ky. dsma, internal medicine department, dniepropetrovsk, ukraine we examined patients ( men, mean age . / . years) with acute exacerbation of cob (type i). the most frequently isolated agents were haemophilus influenzae and parainfluenzae */eight patients, gram-negative rods in , staphylococcus aureus in two and mixed in six and one patient had no bacterial agents isolated in their sputum. high susceptibility to azithromycin was found in all cases of gram-positive agents and in h. influenzae and parainfluenzae . other gram-negative agents were resistant to this drug in vitro. however, treatment with mg/day during days was clinically effective in . % of cases. only . % of patients had a further acute exacerbation of cob. there were peculiarities of the infecting agents causing acute exacerbation of cob in this study: klebsiella pneumoniae and s. aureus were found more frequently than in other studies. high efficacy of surnamed in the treatment of acute exacerbation of cob was established in . %. . % had partial positive clinical effect after this therapy. there were no patients with adverse events. efficacy and tolerance of amoxicillin mg/kg bid versus amoxicillin mg/kg tid in the treatment of acute otitis media (aom) in children / years ps borek m a , guggenbichler jp b . a biochemie gmbh, international medical department, kundl, austria , b department of pediatrics, university of erlangen, erlangen, germany five hundred and sixteen patients (mean age / . years) with clinical and otoscopic diagnosis of aom were included in a randomized, double blind, multicentre study, and were treated days either with amox mg/kg bid or amox mg/kg tid. assessments were made during therapy (day Á/ ), after end of therapy (eot, day Á/ ) and follow up (fu, day Á/ ). the primary efficacy endpoint was the clinical response at eot defined as success (cure/improvement) or failure. both regimens were well tolerated; one or more drug-related adverse events (aes) were reported in . % ( / ) of bid patients and in . % ( / ) of tid patients. the most frequently reported drugrelated aes in each group were gastrointestinal symptoms (bid . % vs. tid . %), which were mainly of mild or moderate severity. both regimens were clinically equivalent. the higher cure rates in the bid group suggest a possible higher benefit from bid therapy in children / years. children attending family day-care (fdc) should be less exposed to upper respiratory tract infections than those in group day-care (gdc) and therefore to antibiotic treatment; fewer should thus carry resistant bacteria. to test this hypothesis, np carriage of sp and hi with reduced susceptibility to penicillin (pdsp and hi bl'/, respectively) was investigated among children in fdc (maximum three children) and in gdc ( Á/ children) in the alpes maritimes (france) between november and march . a two stage cluster sample of children attending gdc or fdc was selected. np samples were cultured for sp and hi. penicillin susceptibility was tested by disk diffusion and e -test, and b-lactamase production by api-nh † tests (biomerieux, lyon). two hundred and thirty-five children in fdc and in gdc aged Á/ months were sampled. age and sex distribution were similar in both groups. sp was isolated in children in fdc ( %), and in ( . %) children in gdc (p b/ Á/ ). proportions of pdsp were . and . %, respectively (p / . ). hi was present in . % of children in gdc vs. . % in fdc (p b/ . ). proportions of hi bl'/ were . % vs. . %, respectively (p / . ). antibiotic exposure during the previous months concerned . % of children in gdc vs. . % in fdc (p / . ). there was no correlation between antibiotic use and carriage of pdsp or hi b'/ strains. sp and hi carriage rates are significantly lower among children in fdc than in gdc. advising alternative types of daycare for children attending gdc should reduce exposure and thus limit the spread of resistant bacteria. however, the proportion of pdsp and hi bl'/ is similar in both groups and comparable patterns of antibiotic use are observed. continued efforts must concentrate on parental education and enforcement of recommendations for management of pediatric upper respiratory tract infections. during a period between january and august , invasive haemophilus influenzae (hi) isolates had been collected at the children's hospital of tunis. we used haemophilus test medium to test antibiotic susceptibility. the mic of beta-lactams was measured by e -test. beta-lactamase production was determined by using the cefinase test and biotyping by apinh. presence of capsular antigen was determined by using hi typing anti sera. hi strains were isolated from meningitidis ( ), bacteremia ( ) and arthritis ( ). all strains were serotype b and . % of them belonged to biotypes i and ii. amoxicillin resistance with beta-lactamase producing mechanism occured in . %. mic of beta-lactamase producing strains was vs . mg/l in non-producing one. there is no betalactamasenegative amoxicillin resistant among these invasive isolates. antibiotic resistance concerned chloramphenicol: . %, trimethoprim-sulfamethoxazole: . %, tetracycline: . % and kanamycin: . %. invasive hi infections in tunisian children's were always associated with type b strains. introduction of a hib vaccine programme in tunisia is recommended. the aim of this study was to analyse the clinical picture and treatment of neurological manifestations of neuroborreliosis in children. the study included children ( Á/ years) with neuroborreliosis diagnosed on the basis of the clinical and serologic criteria. symptoms of facial palsy occurred in six children symptoms of iii Á/vi cranial nerves palsy in three children, meningitis in four and paresthesias in three. symptoms of v or viii nerve palsy, mental disturbances, radiculoneuritis or cerebellitis were found in singular cases. all children received ceftriaxone intravenously Á/ weeks. total recovery was obtained in children following the first course of therapy. recovery following the second course of therapy (amoxicillin) occurred in one child with mental disorders and one with vi nerve palsy. improvement was achieved after the second course in the patient with radiculitis, however, muscular atrophy persisted. irreversible, unilateral deafness was found in a child with viii nerve palsy in spite of three courses of therapy applied. infection with borrelia burgdorferi in children causes a wide spectrum of neurological manifestations. facial palsy was the most common sign in our study. applying ceftriaxone in the treatment of neuroborreliosis is characterised by a good effectiveness. double infection by c. pneumoniae and m. pneumoniae as a cause of cystic changes in the lungs ps streharova a, moravcikova d. department of infectious diseases, university of trnava, trnava, slovakia chlamydia pneumoniae and mycoplasma pneumoniae are human respiratory pathogens manifested in early childhood. immunological disbalance could trigger autoaggressive diseases. the authors describe the case of a -year-old girl with development of multiorgan failure and septic state, which followed multiple cystic changes in the lungs. the girl did not have a diagnosis of cystic fibrosis. the authors consider that cystic changes are a consequence of double infection by c. and m. pneumoniae. dzarlieva m, momeva l, temelkovska g, balevska p, pejkovska m. medical centre, neonatology, bitola, the former yugoslav republic, macedonia unicef skopje has supported a nationwide safe motherhood needs assessment in representative samples of hospitals. eighteen of maternity wards and facilities renovated and certified as 'babyfriendly'. all mature newborns with successful adaptation to extra uterine life and satisfactory vital parameters are h during the day with their mothers at rooming-in system. aim: with rooming-in system we reached decreasing of incidence of neonatal infections. material and methods: history records of newborns from our department. for the period of months, neonates have been borne. with suspection of infection there */ babies ( . %). newborns borne through meconium stained liquid */ ( . %). results: microbiological findings: from blood culture */staphylococcus coagulaza negative from swabs */staphylococcus aureus , escherichia coli , staphylococcus epidermidis. conclusion: in , from all babies who had risk factors for infection in newborns ( %) we had positive findings and in year (before rooming-in sistem), in ( . %). after that period (with rooming-in) newborns ( . %). with rooming-in system we reached decreasing in incidence of neonatal infections by breaking the chain of infection */only mothers take care of their babies with help of the staff. newborns are in their micro environment, the same they will have at their home. with this practice we have also reduction of nosocomial infections. a study on antibiotic susceptibility and resistance factor transmissibility among antibiotic resistant salmonellae isolated from children affected to diarrhea ps sharifzadeh a. azad university of shahrekord, microbiology, shahrekord, islamic republic of iran in spite of happened drug resistance, antibacterial therapy still is the best route of treatment of salmonellosis in man and animals. in order to detection of dominants serotypes of salmonellae in children and detection of antibiotic susceptibility and r-factor transmissibility among those isolated salmonellae. this study was conducted on diarrheic stool samples were collected from children affected by diarrhea in ayatollah kashany hospital of shahrekord, during spring of to autumn of . after isolation and identification of salmonellae, seven serotypes were detected. one of those was s. typhi and another six serotypes were s. paratyphi b . in order to detection of antibiotic different antibiotic disks were used in disk diffusion method. best results were taken from ceftizoxim, cephtriaxon, cephazolin and chloramphenichol. the r-factor were transferred from isolated salmonellae to escherichia coli k in all of cases of resistance to penicillin and ampicillin. pharyngeal colonization by streptococcus pneumoniae and group a bhs were evaluated in randomly selected school children aged Á/ years in riyadh, saudi arabia. fifty-six children ( . %) had positive culture for either organisms of the isolates from school children, ( %) were s. pneumoniae , of them ( %) were penicillin-sensitive, three ( %) were penicillin-resistant, and two ( . %) were resistant to two antimicrobials. forty isolates of bhs ( %) were group a bhs. all isolates were penicillin and erythromycin sensitive. the carrier rate among school children for penicillin-resistance s. pneumoniae and resistance to two antimicrobials were ( . %) and ( %), respectively. the carrier rate of group a bhs was ( . %). riyadh has a low rate of antibiotic-resistant s. pneumoniae and a similar rate of group a bhs carriers among school children as that seen in temperate areas. boukadida j a , boukadida n b , hannechi n a , said h b , erraii s a , elmhabrech h a . a chu f. hached, laboratoire de microbiologie, sousse, tunisia , b c s base, sousse, tunisia the acute pharyngitis is a very frequent pathology in which group a streptococcus is the most incriminated bacteria. however, other non a b-haemolytic streptococcus (sbna) could be responsible. the aim of this work is to determine the part of each non a b hemolytic streptococci (sbna) in acute pharyngitis and the related antibiotics susceptibility pattern. the study was realized in sousse-tunisia (north africa) during months from may . the origin materials of isolates are throat swab (transystem venturi, copan, bovezzo). the mean age of patients is years with extremes Á/ years. the samples are cultured on blood agar plates in a delay of h maximum. identification was done to samples that have over than b-hemolytic colonies, groupage with pastorex strep. sanofi pasteur france, susceptibility pattern according to nccls norms, mic is determined by e -test. the control strain is s. pneumoniae atcc . twentyone clinical isolates of sbna are distinguished from clinical isolates of b-hemolytic streptococci recovered from patients with acute pharyngitis without symptoms of viruses' infections (tearing, corysa, sneeze). all b-hemolytic streptococcus represents . % of all collected samples. sbna were . % of the isolates. sbna were strains group g streptococci, seven strains group c streptococci and three strains group f streptococci. susceptibility pattern of each sbna to antimicrobial agents is as follow: group g streptococci: peni g / %, amoxicillin / %, pristinamycin %, clindamycin and erythromycin / . %, tetracyclin / . %, telithromycin . % and levofloxacin / . %. group c streptococci: peni g / %, amoxicillin / %, pristinamycin %, clindamycin / . %, erythromycin / . %, tetracyclin / . %, tel-ithromycin / . %, levofloxacin / %. group f streptococci-peni g / %, amoxicillin / %, clindamycin / . %, erythro / . %, tetracyclin / . %, telithromycin / %, levofloxacin / . %. all sbna have mic to penicillin g under . mg/l. according to available data, penicillin g and amoxicillin still the reference treatment of acute bacterial pharyngitis in spite of the new antibiotics introduction. berezin en a , quevedo sg b , nicolla l b , viegas d c , eizenberg b d , pedrosa f b , santos ag a . a santa casa, pediatrics, s. paulo, brazil , b elly lilly, scientific, s. paulo, brazil , c fac. abc, pediatrics, santo andre, brazil , d university hospital, pediatrics, s. paulo, brazil a multicenter, open label, prospective, randomized trial in which patients Á/ years of age with proven gabhs pharyngitis were randomized to receive either -day course of the broad spectrum oral cephalosporin, cefaclor or a -day course of amoxicillin. patients were included if they have signs and symptoms of streptococcal tonsillopharyngitis and a rapid streptococcal rapid test positive . patients were evaluated at days Á/ , Á/ and Á/ posttherapy. pharyngeal cultures were conducted at baseline and at follow-up visit ( Á/ days). we considered for bacteriologic eradication analysis only patients with positive culture to gabhs. there were patients with a rapid streptococcal rapid test. clinical success were achieved in around % of the patients. for evaluate eradication of the initial pathogen we considered patients of the amoxil arm and patients of the cefaclor arm. thirty-four of patients of the amoxil arm ( . %) and of ( %) patients of the cefaclor arm were considered bacteriological cured at the second culture performed at day Á/ . ten days of a penicillin or amoxicillin therapy may not be the best therapeutic choice for all pediatric patients. in developing countries where rheumatic fever is still an important problem to evaluate the bacterial eradication achieved with the different antibiotics may be important. prophylactic affect of saccharomyces boulardii for antibiotic-associated diarrhea in a paediatric age group ps erdeve o, tiras u, camurdan mo, tanyer g, dallar y. ankara education and research hospital, pediatrics, ankara, turkey the process resulting in antibiotic associated diarrhea is the alteration of enteric flora due to bacteria. saccharomyces boulardii is a yeast, isolated from cover of a kind of hazelnut and its usage became widespread recently. there is no enough study about s. boulardii activity at pediatric ages. we aimed to define s. boulardii activity on azithromycin and sulbactam-ampiciline, and associated diarrhea at pediatric age group. the . % of cases only with antibiotic usage developed diarrhea, whereas rate was . % for probiotic using group (p b/ . ). all of the clostridium difficile toxin a defined cases were from sulbactam-ampiciline using group. the rate of diarrhea for sulbactam-ampiciline using group was . %, while it was . % for group used s. boulardii as probiotic beside sulbactam-ampiciline (p b/ . ). it was observed that probiotic usage decreases diarrhea rate four times (p b/ . ). when age groups considered, the rate of sulbactamampiciline associated diarrhea increased at Á/ ages and s. boulardii effect on preventing diarrhea was significant at Á/ ages (p b/ . ). antibiotic associated diarrhea is a common clinical problem at pediatric age group. s. boulardii is a hope giving probiotic especially for sulbactam-ampiciline associated diarrhea. grey e a bilikova e a , hafed bm a , kovacicova g a , chovancova d b , huttova m b , krcmery v a . a school of health, trnava university, trnava, slovakia , b postgraduate academy of medicine, neonatal clinic, bratislava, slovakia the purpose of the study: the aim of the study was to find out, whether artificial abortion of a mother has impact on neonatal infection of her future baby. the results obtained: therefore, we compared neonates with infection, who were born to mothers with past history of abortion ( Á/ artificial abortions within years), with the babies of mothers, who have not experienced abortion before. control group consisted of neonates hospitalized at the same clinic, at the same time period. according to the analysis of risk factors for neonatal infections, it was found, that prematurity ( Á/ weeks of gestation) ( . vs. . %, p . ) and low birth weight- Á/ g ( . vs. . %, p . ) were significantly more frequently observed in babies of mothers with past history of abortion. drug abuse (heroin) ( . vs. . %, p . ) and nicotine use ( . vs. . %, p . ), were more significantly related to neonatal infections in babies of mothers with past history of abortion. etiological analysis showed that only candida albicans ( . vs. %, p . ) was significantly related to neonatal infections in mothers with past history of abortion. the conclusion reached: in conclusion, artificial abortion has not only direct impact to the health of the mother, but also on her next pregnancy. bacteraemia and patient mortality in a peadiatric intensive care unit ps armenian sh, singh j, arrieta ac. children's hospital of orange county, infectious disease, orange, usa purpose: this study will identify the factors that significantly contribute to mortality in patients with bloodstream infections (bsi) at a pediatric intensive care unit (picu). results: medical records of patients who were admitted to the picu and had a documented bsi were reviewed. there were separate episodes of bsi's, with nine patients having multiple bsi's during their hospital stay. a casecontrol model was used. cases were bsi's with eventual mortality (n / ; . %) and controls were those who survived bsi (n / ; . %). patients who died were older ( . vs. . years; pb/ . ), more likely to have a nosocomial bsi ( . vs. . %; pb/ . ), longer hospitalization prior to bsi ( . vs. . days; pb/ . ), and have a polymicrobial bsi ( . vs. . %; pb/ . ). infection related mortality (irm)-defined as death within days of bsi */was significantly higher in those receiving inadequate antibiotic treatment at the time of diagnosis of bsi ( . vs. . %; p b/ . ), as well as in those with gram negative bacteremia and/or fungemia ( vs. %; p b/ . ). logistic regression was used to adjust for potential confounding variables. conclusions: we found that being older, multiple organisms, and a longer hospitalization prior to the bsi were significantly associated with overall patient mortality. irm was significantly higher for those with inadequate initial antibiotic coverage and in those with gram negative bacteremia and/or fungemia. somer a a , gü r d a , diri s a , yalcýn i a , salman n a , ongen b b , gü rler n b . a department of pediatric infectious diseases, istanbul university istanbul medical faculty, istanbul, turkey , b department of microbiology and clinical microbiology, istanbul university istanbul medical faculty, istanbul, turkey teicoplanin is a glycopeptide antibiotic active against a broad range of gram-positive pathogens including methicillin-resistant staphylococci and offers the advantages of once daily administration, choice of administration route, lack of requirement for routine therapeutic drug monitoring and lower propensity to cause nephrotoxiticy and anaphylactoid-like reactions. in this study the efficacy and safety of teicoplanin were evaluated retrospectively in children with serious bacterial infection. sixty-three children ( girls, boys) aged between month and years were treated with teicoplanin (three loading dosages of mg/kg at h intervals, followed by a maintenance dosage of mg/kg/day). the infections treated were pleural empyema (n / ), joint and bone infections (n / ), septicemia (n / ), skin and soft tissue infections (n / ), and lung abscess (n / ). the pathogens isolated were staphylococcus aureus (n / , of which were methicillin resistant), coagulase-negative staphylococci (n / ), s. pneumoniae (n / ), and group a hemolytic streptococci (n / ). the duration of therapy ranged from to days (median days). clinical success (cure plus improvement) was achieved in . % of cases. no side effects attributable to teicoplanin therapy were encountered. teicoplanin appears to be an effective and well-tolerated treatment for serious gram-positive infections in children. the risk of infection is present in all children with acute leukemia. two hundred and sixty episodes of febrile neutropenia were analyzed in children (aged . Á/ years) with aml */ cases and all */ cases over years during cytostatic therapy (protocols: mbfm */ aml and mbfm */ all). a degree of fn occurred in % of cases in aml, in % */in all. the sites of infection were: blood'/ central venous catheter ( %) and respiratory tract ( %). pathogens isolated from blood were: gram-positive */cns */ %, streptococcus spp. */ . %, gram-negative */enterobacteria */ %, pseudomonas aeruginosa */ %, candida spp. */ . %, aspergillus spp. */ . %, other */ . %. for the treatment of fn we used empirical antibiotics regimens. clinical response was noticed: in st line of therapy */ cephalosporins Á/ generation used */ %, carbapenems used */ % as nd Á/ rd lines */vancomycin */ %, amphotericin b */ %. thirtytwo percent of children with aml and . % children with all died because of sepsis. conclusion: carbapenems are more active in the st line of antibiotics therapy both for patients with aml and all. vancomycin is useful in the nd line for patients with all. amphotericin b and vancomycin are useful in combination in the nd line for patients with aml. pavlenishvili ivp. medical academy, pediatrics, tbilisi, georgia our drug of choice in cases of complicated neonatal sepsis i. pavlenishvili, g, iobashvili tbilisi, medical academy georgian society of pediatrics chemotherapy (gspc) with collaborations of drug and therapeutic committee (dtc) of childers hospital 'republic' finished the observation study about nosocomial infections of neonatal icu in above mentioned hospital. study begins from november . during this period we observe cases of neonatal sepsis, most of them were due gram-negative bacteria. thirty-four cases of neonatal sepsis were cause different stains of escherichia coli , proteus spp. and acinetobacter . we notice that during last years the role of acinetobacter in etiology of neonatal sepsis and nosocomial complications of neonatal sepsis in our hospital is gradually increased. as our observation reveals most optimal in the case of complicated neonatal sepsis was (according criteria of dts) use of ceftasidime. almost in all cases we used ceftasidime with success. we have only one case of mortality. since the macrolide resistance (mr) in streptococcus pyogenes has been increasing in europe, we studied the incidence and genetic basis of mr in s. pyogenes in russia. s. pyogenes isolated at baseline and during follow-up visits from children with acute pharyngitis receiving penicillin or midecamycin ( -membered macrolide) were studied. mr was evaluated by agar dilution (nccls), resistance mechanisms */by pcr. a total of s. pyogenes were obtained at the baseline, ( %) of which were erythromycin-resistant: strains ( %) were erm (a)-positive, one */mef (a)-positive, and one was negative for all primers used. all erm (a)-strains were inducibly resistant to clindamycin and represented seven pfge profiles with one profile found in / strains. in three midecamycin treated patients mr was selected during the therapy (one strain had erm (a), one */mef (a), one */ unknown resistance determinant). mef (a)-strain obtained during follow-up visit had different pfge pattern with mef (a) strain isolated at baseline, while both the baseline and follow-up strains with unknown mechanism of resistance had unique pfge pattern. these data showed moderate incidence of erythromycin-resistant s. pyogenes in smolensk. ribosomal methylation (erm (a)) was the most common mechanism and though the polyclonal nature of mr was established, most erm (a)-strains belonged to only a few clones. bacillus cereus infections in traumatology-orthopaedy department: retrospective study and re-evaluation of healthcare practices ps bacillus cereus was cultured for patients from traumatology department who had developed postoperative wound infections between august and march . all patients presented inferior members open fractures, frequently contaminated with telluric material and requiring external fixators. genomic study of clinical isolates by pulsed field gel electrophoresis and random analysis polymorphic dna, allowed us to eliminate an outbreak. furthermore, the reduced delay in which patients developed the infection ( days'//- ) led us to re-evaluate the procotols used in our institution. indeed, all patients had received amoxycillin '/ clavulanate iv g for antibioprophylaxis during anesthetical induction then relayed per os for hours. because of the production of a potent beta-lactamase by the bacteria, this association could not be efficient. furthermore, accordingly to the afnor en norm, we have tested clinical isolates' sensitivity to the principal antiseptics used for antisepsis and disinfection (iodophors, chloride derivated and biguanidines) and observed a major resistance of all strains tested. even if these postoperative wound infections are considered as nosocomial because of the delay in appearance, we actually think that bacillus cereus were initially present in telluric material. this fact led us to propose a systematic screening for bacillus at admission for this type of wound and to administrate quinolones such as ciprofloxacin for prophylaxis. internal thiols and reactive oxygen species in the candidacidal activity exerted by a n-terminal peptide of human lactoferrin ps the purpose of the study: the emergence of candida albicans strains resistant to current antifungals points to the need for new antifungal agents, e. g. antimicrobial peptides. the results obtained : we report that hlf( - ), a synthetic nterminal peptide of human lactoferrin, displays excellent killing effect against fluconazole-resistant c. albicans and that sub-optimal concentrations of this peptide combined with fluconazole act synergistically. previous investigations revealed that hlf( - ) required an energized mitochondrion, atp release by candida , and ligation of atp receptors for its killing effect. we now report that reactive oxygen species (ros) are involved in the killing effect of hlf( - ). since internal thiols protect cells from oxidative damage, our observation that hlf( - ) caused a % reduction of internal thiols in candida is of interest. as expected, n-acetyl-l-cysteine (nac), which is a precursor of glutathione and a ros scavenger, inhibited the killing effect of hlf( - ). diamide, which oxidizes internal thiols, was candidacidal and hlf( - ) and diamide acted synergistically in killing c. albicans and ros production. moreover, the hlf( - )-induced activation of mitochondria was inhibited by nac, indicating that internal thiols/ros affect mitochondrial activity. the conclusion reached : the candidacidal activity of hlf( - ) involves ros production and reduction of internal thiols. objective : an audit was conducted to explore the observation of increasing resistance to ciprofloxacin in enterobacteriacea isolated from specimens from such patients in the hematology unit. results : enterobacteriacea isolates in specimens from such patients processed over the years to were examined. number of specimens per year was */ , , , and respectively and the annual percent ciprofloxacin resistant enterobacteriacea from these was %, %, %, % and %. conclusion : conclusion drawn from the audit was that rapid rise in ciprofloxacin resistance may possibly be attributed to the use of this fluoroquinolone as a single agent in dose of / mg [cut off patient weight kg] twice a day in neutropenic patients till neutrophils exceed /c.mm. subsequent to the audit, prophylaxis protocol was modified to use of oral colistin -mega units/twice a day in combination with ciprofloxacin / mg twice a day. a prospective audit is proposed to test the benefits of this combination. rhinocerebral zygomycosis: diagnostic dilemma for emergency physician: can the associated morbidity and mortality in this rare but deadly disease be reduced? ps samavedam s, guleri as. western infirmary, clinical microbiology, glasgow, united kingdom rhinocerebral zygomycosis [rcz] is a rare, invasive, rapidly progressive opportunistic infection caused by ubiquitous fungi of the order mucorales. it usually occurs in diabetics or immunocompromised patients. the emergency physician will typically see patients with rcz in its earliest stages masquerading as a variety of other less serious diseases. the key markers like necrotic patch on hard palate, nasal septum or turbinate, marked facial pain, and cellulites with marked eye and neurological signs may present late in disease. we report a case of rcz caused by rhizopus arrhizus [oryzae] in an year old woman with poorly controlled diabetes. she presented with a right-sided facial droop of short origin and being generally unwell. ct scan was non-conclusive and delayed presentation of key markers of rcz permitted disease to rapidly progress. despite an intensive antifungal therapy with ambisome and insulin sliding scale, patient rapidly succumbed within days. fine needle aspiration cytology is less invasive, easier and equally effective alternative to pre op biopsy. the key to successful reduction in morbidity and mortality associated with this rapidly fatal disease is -increasing awareness of the disease, an early diagnosis, correction of underlying metabolic derangement, prompt intensive antifungal therapy with amphotericin b and radical surgical debridement of the necrotic tissue. an 'optimal dosage' of ambisome requires discussion. clinical audit in the haematology ward of a tertiary care hospital: study of degree of correlation between bacteraemia and oro-pharyngeal screens in immunocompromised patients over five years and role of antibiotic prophylaxis ps guleri as, butcher i. western infirmary, clinical microbiology, glasgow, united kingdom introduction : a clinical audit was carried out over -years [ ] [ ] [ ] [ ] [ ] in the immunocompromised patients including neutropenic patients and bone marrow [autograft] transplant recipients in hematology ward of gartnaval general hospital, glasgow, a tertiary care center. objective : it was aimed to establish the degree of correlation between bacterial isolates in oro-pharyngeal screen during bacteraemia episodes and role of antibiotic prophylaxis. methods purpose : to assess whether antiretroviral therapy (art) intensification, gm-csf use and remune initiation before stopping art lead to viremia containment, and long periods off art. methods : ten adults with chronic hiv disease, hiv- rna levels (vl) b/ . log copies/ml and median cd '/ -t cell count of /ml were enrolled. after art intensification with ddi ( months) '/ hydroxyurea [hu]( mo.) '/ gm-csf ( mo.) and a remune dose, art was stopped but remune continued. art was resumed if rebound vl did not decrease to b/ . log in months or if cd '/ counts decreased to b/ . results : vl rebounded in all patients after stopping art, and developed an acute retroviral syndrome (ars). cd '/-t cells decreased, and cd '/ '/ increased ( -fold). after a median stoppage of weeks, art was resumed in patients and vl decreased to b/ . log, cd '/ counts were regained, il- and il- levels rose. at the nd interruption, / patients had a rebound, and / had a nd ars, but peak vl and loss of cd '/ were lower (p / . ). after . weeks off art, patients resumed therapy. the breadth and magnitude of hiv-specific activity increased and thymus size grew. the patients were off art for a median of . out of weeks. two of them are off art for and weeks respectively ( vlb/ log). conclusions : this approach led to a high ars incidence, long periods off art, increases in hiv-specific responses, il- and il- levels, and thymus size. urinary tract infection in hospitalized population is a significant problem. this is a study of catherized patients urinary infection in corfu hospital. in Á/ , urine cultures were sent to our bacteriology laboratory. of them were collected from the catheters. clinical data of age and type of disease were analysed. the samples were cultured on mc conkey agar-urotube and vitek cards. the organisms identified with vitek automatic system. the sensitivity was tested with vitek and kirby-bauer method. results: no growth of organisms in . %. positive cultures %. . % of the bacteria were gram((/) rods ( . % e. coli , pseudomonas spp. %), % were gram('/) cocci (enterococcus spp.) and % was candida spp. the resistance of e. coli was: % to ampicillin , % to co-trimoxazol and % to quinolons. e. faecalis was resistant % to vancomycin . conclusions : ( ) the possible interference of acetaminophen in the amoxicillin/ clavulanic acid (a/c) or erythromycin (ery) efficacy in the treatment of acute otitis media (aom), and its possible role in the evolution to otitis media with effusion (ome), were determined in a gerbil model. a f streptococcus pneumoniae strain exhibiting a mic of a/c and ery of / . and . mg/l, respectively, was used. both antibiotics were tested at . and mg/kg. acetaminophen at mg/kg was administered min before each antibiotic dose. antibiotic concentrations in serum and middle ear exudate were determined. both antibiotics significantly reduced the number of culture-positive ears and colony counts, with serum concentrations over the mic of the microorganism for ]/ % of the dosing interval. antibiotic concentrations in middle ear exudate were almost identical in animals receiving and not receiving acetaminophen. clinical and microbiological efficacy was correlated with antibiotic concentrations in middle ear exudate ]/ . times the mic of the microorganism, for both antibiotics. both antibiotics demonstrated efficacy in the treatment of pneumococcal aom, with the same rate of ome. acetaminophen, concomitantly administered, did not interfere the efficacy of the two antibiotics tested and did not prevent the evolution of aom to ome. parra a a , ponte c a , cenjor c b , garcía-olmos m a , giménez mj c , aguilar l c , soriano f a . a fundación jiménez díaz, medical microbiology, madrid, spain , b fundación jiménez díaz, otorrinolaryngology, madrid, spain , c glaxosmithkline, medical department, madrid, spain a gerbil model of otitis media with effusion (ome) induced by haemophilus influenzae (amoxicillin/clavulanate-a/c-and erythromycin-ery-mics of / . and mg/l, respectively) was used to evaluate the efficacy of a/c ( / and / mg/kg) and ery ( and mg/kg). antibiotics were administered subcutaneously h post-middle ear inoculation, and continued t.i.d for h, with or without acetaminophen (ap), at mg/kg, administered min before each antibiotic dose. antibiotic concentrations in serum and middle ear (me) were measured by bioassay. me samples for colony counting were collected on day . a/c reduced (p / . ) positive me samples and colony counts versus untreated controls or ery: me positive cultures of % for controls, % for a/c , % for a/c , % for a/c '/ap, % for ery , % for ery and % for ery '/ap. this was due to a/c (but not ery) concentrations in me exceeding . times the mic despite the higher percentage of antibiotic penetration of ery versus a/c ( versus / %). animals receiving ap showed less polymorphonuclear cells and more bacteria in me than those receiving only antibiotics, suggesting that the anti-inflamatory drug diminish the phagocytes and therefore, the efficiency in bacterial clearance. amoxycillin treatment for acute otitis media caused by penicillinresistant streptococcus pneumoniae . a pharmacodynamic analysis pm parra a a , ponte c a , cenjor c b , garcía-calvo g a , giménez mj c , aguilar l c , soriano methods: a serotype f streptococcus pneumoniae strain exhibiting a mic of amoxycillin of mg/l was used in an experimental model performed in gerbils (meriones unguiculatus ) following previously described procedures. amoxycillin was tested at the following doses: . , . , . , . , . and mg/kg. amoxycillin concentrations in serum and middle ear exudate were determined after drug administration. results: doses of ]/ . mg/kg significantly reduced the number of culture-positive ears, colony counts and otorrhoea (p / . ) as compared with untreated controls or animals treated with doses lower than . mg/kg. doses of ]/ . mg/kg achieved antibiotic concentrations in the middle ear . Á/ . times higher than the mic of the infecting strain and serum concentrations over the mic for Á/ % of the dosing interval. conclusions: amoxycillin at doses achieving serum concentrations similar to those obtained in children after standard doses, obtained therapeutic and microbiological efficacy regardless the susceptibility of the infecting strain. better correlation was found between antibiotic efficacy and antibiotic concentrations in middle ear exudate than between efficacy and serum concentrations, which were suboptimal from the pharmacodynamic perspective. increasing prevalence of amoxycillin Á/clavulanate-resistance among e. coli strains in a hungarian university hospital pm veréb i, vígh a, urbán e, hajdú e, nagy e. department of clinical microbiology, university of szeged, szeged, hungary background: amoxicillin Á/clavulanate resistance (acr) is an emerging problem in escherichia coli as reported from different parts of europe. the aims of the present study were to evaluate statistically the prevalence of acr among e. coli isolates and to investigate the genetic background of the resistance. methods: all e. coli strains isolated between and were screened for acr by kirby Á/bauer disc diffusion method. the resistance to other beta-lactam Á/beta-lactamase inhibitor combinations and to different beta-lactam antibiotics were also tested. selected strains underwent determination of beta-lactamase activity. confirmatory tests for suspected extended spectrum beta-lactamase were performed. pcr testing for tem and shv genes were carried out on plasmids isolated from selected strains. results: in out of e. coli strains ( . %) were found to be resistant to amoxicillin clavulanate (amc). most of the resistant strains ( %) were obtained from the genitourinary tract and no acr isolate was found in blood cultures. in out of isolates ( %) proved to be acr and . % were isolated from blood cultures and . % from the genitourinary tract. thirty-five selected strains were further analysed. thirty-two were also resistant to (sam) and six were further resistant to tzp. quantitative beta-lactamase determination showed increased activity in strains which were partially susceptible to amc. the presence of esbl could be proved only in three acr isolates. this open parallel-group study compared the efficacy and tolerability of cef with cfix mg once daily in the treatment of community acquired uncomplicated uti. seventy-eight female patients were randomized to receive either oral cef or cfix for or days. the efficacy of treatment was evaluated by clinical response (by symptoms of uti dysuria frequency urgency suprapubian pain and by clinical signs) by bacteriologic response and health status measures at baseline and posttherapy. results: the clinical cure (complete resolution of symptoms and signs) rate for patients receiving cef was . % of the evaluable patients and . % of the patients receiving cfix. bacteriologic response (based on the results of urine cultures obtained posttherapy) the pathogen was eradicated in . % for cef . % for cfix. no drug related side effects have been reported in cef and side effects were experienced by . % of the patients receiving cfix. improvement in health status comparing visual scale scores baseline and poststudy to have detected a higher change in average score from to in cef, from to in cfix. wilcoxon improvement value was significant on the rd day of therapy in case of cef and on the th day of therapy in cfix group. in conclusion, the results of this study indicate that cef course is more effective than cfix in producing a favourable clinical outcome and achieving higher bacteriologic eradication rate, furthermore cef was better tolerated. cefepime is a fourth generation cephalosporine that has a broader spectrum of antibacterial activity than the third generation cepfalosporines and is more active in vitro against gram-positive aerobic bacteria. the purpose of this study was to measure cefepime concentrations in plasma, bile fluid and gall bladder tissue in patients undergoing cholecystectomy. thirty patients male, female, mean age: years had data acceptable for analysis and were included in this study. all patients received iv g of cefepime. several hours after administration and at different time intervals, during surgery, samples were obtained from plasma, bile fluid and gall bladder tissue concomitantly. antibiotic levels were measured by an agar diffusion method. the mean delta time was / min. the values for plasma, bile fluid and gall bladder tissue, were . / . , . / . and . / . mg/ml, respectively. the plasma/bile fluid ratio was . / . . there was a significant correlation between plasma and gall bladder tissue concentration (r / . , p / b/ . ). a correlation between bile fluid and plasma cefepime concentration was not observed. the minimum inhibitory concentration (mic) data from previous in vitro studies indicate that the cefepime concentration observed in plasma bile and tissue samples of this study would be adequate against typical biliary tract pathogens. furthermore, these cefepime concentrations correlated well with the favorable clinical outcome reported in previous clinical studies in biliary tract infections. there was also good correlation between delta time and plasma and tissue concentrations and if the dose were given closer to the time of surgery, cefepime concentration would be higher reducing the possibility of an infection. objectives: the use of antibiotics may lead to decreased colonization resistance and increased formation of resistant bacteria. present concept was developed to overcome these untoward effects. methods: b-lactamase of bacillus licheniformis was overproduced in bacillus subtilis . this targeted recombinant b-lactamase enzyme (trbl) was released in the small bowel from a controlled-release formulation. beagles (n / ) were treated bid with either mg/kg ampicillin (i.v.)'/placebo (p.o.), mg/kg ampicillin (i.v.)'/trbl (p.o.) or only placebo (i.v.'/p.o.). stool was collected at days and . samples were cultured for total and main groups of aerobic and anaerobic bacteria and yeast. temperature gradient gel electrophoresis (tgge) was used to separate the ribosomal rna genes. results: ampicillin'/placebo group had clearly decreased counts of both aerobic and anaerobic bacteria during the treatment, whereas those receiving trbl had only minor overall changes and some occasional changes by single species. intravenous ampicillin decreased the fecal similarity percentage to %. the similarity percentage during treatment with ampicillin'/trbl did not differ from that of placebo ( vs. %). conclusions: according to our results the trbl can maintain the large intestinal microflora almost unchanged. these results indicate that trbl is a promising novel approach for overcoming the ecological adverse effects on gut flora caused by b-lactam antibiotic agents. adamis since broad-spectrum â-lactams combined with amikacin are often applied for nosocomial infections, their pharmacokinetic interactions might be interesting. one gram of aztreonam and . g of amikacin were administered intravenously single and in combination in six healthy volunteers. blood samples were collected at regular time intervals and concentrations of antimicrobials were determined by a microbiological assay applying a strain developing resistance to single agent after serial passages. mean concentrations of amikacin in serum when administered alone and in combination with aztreonam were . and . , . and . , . and . , . and . , . and . and and . mg/ml immediately after and . , , , and h after infusion of antimicrobials. respective concentrations of aztreonam were . and . , . and . , . and . , . and . , . and . and . and . mg/ml. aucs for amikacin when administered alone and in combination with aztreonam were . / . and . / . mg h/l, respectively. respective auc for aztreonam were . / . and . / . mg h/l. it is concluded that the co-administration of aztreonam and amikacin results in earlier clearance of aztreonam and in higher levels of amikacin compared to the administration of each single antimicrobial. molecular modelling of b-lactams reveals the structural basis for their inhibition of penicillin-binding proteins, susceptibility to b-lactamases and oral bioavailability pm grail bm, gupta s, payne jw. school of biological sciences, university of wales, bangor, uk b-lactam antibiotics are peptide mimetics that act as suicide substrates for transpeptidase enzymes that cross link bacterial cellwall peptides. for the first time, the structural and electronic features needed for their recognition by transpeptidase have been fully described, using innovative molecular modelling techniques to compare the conformational forms adopted by cell-wall peptides and blactams. comparison of features in the backbone and c-terminal regions of conformers of active b-lactam antibiotics and model cellwall peptides, has allowed definition of the molecular recognition template required for substrate recognition by transpeptidase. these shared structural features allow both to act as substrates and to acylate the active-site serine. however, a significant difference in a critical backbone torsion between the two substrates, provides an explanation for the inability of the enzyme Á/antibiotic complex to undergo the deacylation step that causes inhibition of transpeptidase. on the other hand, b-lactamases appear to have evolved molecular mechanisms that facilitate the deacylation reaction through compensating for the altered structural orientations in b-lactams caused by the different backbone torsion. finally, analysis of the conformer repertoires of blactams for structural features required for substrate uptake by peptide transporters, provides insights into how their structures can be tailored for optimal oral absorption. antimicrobial susceptibility of proteus mirabilis clinical isolates producing extended spectrum beta-lactamases (esbls) pm objectives: the aim of the present study was to determine in vitro susceptibility to antimicrobials of proteus mirabilis isolated from urinary tract infections. methods: we studied the susceptibility profile of esbl positive p. mirabilis strains in three adopted children from india with age range from months to years. esbl was identified using the synergic effect of clavulanate with betalactams (ceftazidime and cefotaxime the in vivo efficacy of amoxicillin (amx) sub-therapeutic doses ( . mg/kg, t.i.d for h, achieving serum levels over the mic of only % of the dosing interval) and concomitant specific serotherapy (single intraperitoneal dose of / diluted hyperimmune serum (hs) obtained from mice immunized with the heat-inactivated strain) was assessed in a pneumococcal sepsis balb/c mouse model. mice (five mice/ treatment group) were intraperitoneally infected with . )/ cfu/ ml of a serotype b penicillin-resistant strain (mic of and mg/l for penicillin and amx, respectively). treatments started h after bacterial inoculation. study groups were: control (k; receiving nonimmune serum (nhs)), amx'/nhs, hs, and amx'/hs. survival rates (%) over time were: purpose of the study: the study was performed to determine the consumption of imipenem and resistance of gram-negative pathogens (pseudomonas aeruginosa , acinetobacter sp., klebsiella sp., escherichia coli , proteus mirabilis , serratia marcescens , enterobacter sp. ) to imipenem. gram-negative pathogens were isolated at the sestre milosrdnice university hospital from zagreb, croatia, in and . the imipenem sensitivity testing was performed by disk diffusion and e -test methods. the consumption of imipenem was expressed in ddd/ hospital days in the same periods. results obtained: imipenem resistance of acinetobacter sp. decreased significantly in the year (p / . ), especially in the first months (p / . ) when the lowest consumption of imipenem was recorded. imipenem resistance of other gram-negative pathogens did not decrease significantly. conclusion reached: comsumption of imipenem might lead to changes in resistance to imipenem among acinetobacter strains. vacheva-dobrevski rs, savov ez. military medical academy, clinical microbiology, sofia, bulgaria purpose: acinetobacter baumanii is becoming increasingly frequent nosocomial pathogen at our hospital, and beta-lactam resistant strains are on the increase, especially among icu isolates. to study the susceptibility of a. baumanii clinical isolates to beta-lactams and to determine the esbl-producing strains during , year. a total gram-negative nonfermenters (gnnf) isolates was investigated by semiautomated mini api system (bio merieux, france). eighty-four a. baumanii non-repeated isolates was studied for esbl-producing by double-disk synergy test (ddt) and atb-blse test (bio merieux, france). mics for beta-lactams were determined by e -test (ab biodisk, sweden). results: a. baumanii (n / ) showed a multidrug resistance. the isolates were resistant to cefotaxime ( %), cefoxitin ( %), ceftazidime ( %), amoxicillin/clavulanate ( %), piperacillin ( %), aztreonam ( %), imipenem ( %). the ( %) of investigated a. baumanii expressed esbl activity and originated more frequently from icu ( %). esbls producing strains were isolated from endotracheal aspirate ( %), surgery wounds ( %), blood culture ( . %). conclusions: in general resistance levels were higher in clinical isolates a. baumanii to beta-lactams. the ddt seems to be a practical method for esbl-screening; atb-blse method is more sensitive. our study display to be the first report of esbl-producing a. baumanii strains from our country. carbapenems seems to be the most active agents against a. baumanii . salmonella infantis , strain , was isolated from a newborn baby at wassila bourguiba maternity in tunis. it exhibited high resistance to penicillins, extended-spectrum cephalosporines (cefotaxime, ceftriaxone, ceftazidime, cefpirome) and aztreonam but remained susceptible to cefoxitine and imipenem. involvement and characterization of enzymatic mechanism in b-lactam resistance were investigated in strain . isoelectricfocusing revealed that this strain produced a b-lactamase of pi . this enzyme had a broad-substrate profile, hydrolyzing amoxicillin, ampicillin, ticarcillin, cephaloridine, cefuroxime, cefotaxime, ceftriaxone, cefpirome and ceftazidime. the highest specific activity was observed with ampicillin. cefotaxime was hydrolyzed the most efficiently of the extended-spectum cephalosporines. the pi extended-spectrum b-lactamase (esbl) was inhibited by clavulanic acid and sulbactam. no inhibition of the esbl was observed with mm edta. thus, no metal ion is involved in hydrolysis for this b-lactamase. resistance due to the production of the pi esbl was transferred with dna plasmid into escherichia coli . on the basis of substrate and inhibition profiles and isoelectric point, the pi esbl was not previously described in s. infantis in tunisia. the presence of such a resistance on a plasmid raises concer for rapid dissemination among bacteria and loss of effectiveness of blactams. poizot-martin i a , enel p b , benhaïm s c , vion-dury f c , dinh t c , drogoul mp c , gastaut ja c . a assistance publique hôpitaux de marseille, cisih sud, pr ja gastaut, marseille, france , b assistance publique hôpitaux de marseille, cellule santé publique dmi , marseille, france , c assistance publique hôpitaux de marseille, cisih sud, marseille, france objective: to assess liver biopsy (lb) practices in a cohort of co-infected hcv and hiv patients followed up in an hiv specialized medical unit. method: transversal study with questionnaire among patients in pre-therapeutic's evaluation with pcr'/ and without lb at months. results: among the patients, ( %) are lost of follow up, ( . %) have had lb, ( . %) have no lb. the characteristics of these patients are: median age / . / years; sex ratio / . , cdc-stage a / . % b / . % c / . %, undetectable viral load / . %, median cd / / , anti-retroviral therapy / . %, hcv-genotype / . %; a / . %; / . %. causes of non-made lb are: ( ) refusal from patients because of biopsy's fear / . %; ( ) contraindications because of hiv infection / . % (clinical events / . % which contraindicate anti-hcv treatment, grade iii thrombocytopenia / . % which contraindicate biopsy, non-adherence to previous hiv follow up / . %); ( ) other / . % (alcoholism / . %, psychiatric/depressive disorders / . %, decompensated cirrhosis / . %). drug use or methadone/buprenorphine treatment are not considered as contraindication. conclusion: one-third of patients are afraid of lb. alcoholism and psychiatric/depressive disorders are the principal contraindications to anti-hcv treatment. it seems important to improve information of patients about lb and to focus on alcohol and psychiatric/depressive disorders management in such population. kashiwagi kk a , furusyo nf a , nakashima hn a , kashiwagi sk b , hayashi jh a . a department of environmental medicine and infectious disease, kyushu university, fukuoka, japan , b national kyushu medical center, fukuoka, japan the purpose of the study: the aim of this prospective study was to explore the effect of htlv-i co-infection on the development of hcc among patients with chronic hcv viremia. a total of consecutive patients with chronic hcv viremia were studied and followed-up over a mean period of . years: ( . %) were infected with htlv-i infection and ( . %) were not. the results obtained the annual hcc development rate was . % in patients co-infected with hcv and htlv-i and . % in patients infected with hcv alone. hcc was significantly higher in ( . %) of the patients co-infected patients than in ( . %) of the patients infected with hcv alone (p b/ . , logrank test). in patients under the age of years, hcc development was significantly higher in seven ( . %) of patients co-infected with hcv and htlv-i than in eight ( . %) of patients with hcv alone (pb/ . , logrank test), whereas there was no significant difference in hcc development between patients over age with or without htlv-i infection ( ( . %) of and ( . %) of , respectively). the conclusion reached htlv-i infection accelerates the development of hcc in chronic hcv patients, especially among patients under the age of years. to analyze hbv genotype-related clinical differences among patients with chronic hbv infection, all patients were serially tested for serum alanine aminotransferase (alt) and hepatitis b e antigen (hbeag) and followed up for a mean . ( . ) year period. genotypes b and c were found in ( . %) and ( . %) of the patients, respectively. hbeag positivity and alt abnormality rates at the start of the observation period were significantly higher in genotype c patients ( . and . %) than in genotype b patients ( . and . %). the annual rate of spontaneous hbeag disappearance in genotype b patients was much higher than in genotype c patients ( . versus . %, respectively). patients with genotype c who were continuously hbeag negative from entry had significantly higher alt abnormality ( . %) than those with genotype b ( . %). interestingly, patients with genotype c who became hbeag negative by interferon treatment had high alt abnormality ( . %). all patients with alt abnormality were serum hbv dna positive. these findings indicate that hbv genotype c patients are more severe liver deterioration because of the delay of hbeag disappearance and continued hbv replication after hbeag disappearance. nossik nn a , nebolsin ve b , zheltukhina ga c , yevstigneeva rp c . a the d.i. ivanovsky institute of virology, viral reproduction, moscow, russian federation , b pparminterprisis co., chemistry, mocow, russian federation , c moscow state academy of fine chemical technology, piptide chemistry, moscow, russian federation objective: to study the effects of 'gamma'-l-glutamylhistamine (glu-ha) derivates on non-specific immunity ('alfa'-ifn, 'gamma'-ifn and nk cell activity) and antiviral activity on the experimental influenza and herpes virus infections in mice. the glu-ya and its derivate glu-ii were synthesized by peptide chemistry techniques. the glu-ha and glu-ii was administered i.p. . and . mg/kg before and after influenza virus (type a/aichi) and showed a protective effect even at the high infective dose ( ld ) */the rate of protection / Á/ / % in the positive/control group. they were not very effective in the protection of herpes simplex virus encephalitis in mice. the model of the physico-emotional stress in mice was used to investigate the ifn system and nk cell activity. the production of ifns and nk cell activity of splenocytes decreased in h after the stress and back to normal level in Á/ days. it was shown that glu-ha and glu-ii can protect or substantially prevent the decrease in nk cell activity and ifns synthesis in post-stress period (so normally did not induce the ifns' synthesis). conclusions: the glu-ha and glu-ii showed antiviral effect against influenza virus infection in mice. the immunomodulating activity and ability to normalize the ifn synthesis and nk cell activity depressed the post-stress period and probably play an essential role in the antiviral activity. no dose adjustment of an anti-influenza prodrug oseltamivir is required in patients with hepatic impairment pm oo c a , snell pr b , liu b a , martin d b , simkins t b , small i b , ward p b . a hoffmann-la roche inc., global development, nutley, usa , b roche products ltd., global development, welwyn garden city, uk background: oseltamivir (ose; ro - , tamiflu † ) is an oral ethyl ester prodrug of its active metabolite oseltamivir carboxylate (oc: ro - ), a potent and selective neuraminidase inhibitor of the influenza virus. the purpose of the study is to evaluate the need for ose dosage adjustment in hepatic impaired patients (hi). method: healthy volunteers (hv) versus hi (child-pugh score Á/ ) [matched on the basis of age ( / years), gender and weight ( / %)] were compared. each subject received mg ose. results: based on c max (ng/ml) and auc inf (ng h/ml) analysed using nominal times, ls mean ratios and % ci between hi and hv were similar. ose* values in hi were marginally elevated but not sufficiently to require dose adjustment. the aim of this study is to investigate the influence of molecular structure of macrocyclic pyridinophanes and their analogs on antiinfluenza and antiherpetic activity of these compounds. we used d-qsar approaches on the basis of simple representation of molecular structure. such representation for biologically active substances allows the description of the spatial structure of compounds with the complete stereochemical information. it determines spatial structures either promoting or interfering of the concrete biological activity. it is easy to realize the molecular design of compounds with the given level of activity with the help of the combinations of simplexes. statistic characteristics for qsar of partial least-squares models are satisfactory (r / . Á/ . ; cvr / . Á/ . ). the molecular fragments that increase the antiviral activity were defined and will be demonstrated. this information was used for design and directed synthesis of several novel antiviral agents with predicted high anti-influenza or antiherpetic activities. predicted activities were confirmed experimentally. d-qsar approaches are useful for development of antiviral compounds. this work was partially supported by intas foundation (grant intas - ). lozitsky vp. ukrainian mechnikov research anti-plague institute, chemotherapy, odessa, ukraine the purpose of this study was to research the anti-influenza activity of proteolytic inhibitor e-aca. it prevents the enhancement of proteolysis during the interaction of virions with cell membranes and decreases penetration of virions into cells. e-aca brings down proteolytic cleavage of ha-precursor to ha- and ha-polypeptides and reduces the infectious virus harvest. it shows the prophylactic and therapeutic action during the experimental influenza reducing the enhancement of alkaline proteases activity in lungs after infection. e-aca promotes the intensification of specific antibodies production and cell immunity, prevents vessels' permeability and hemorrhagic phenomena, decreases the destruction of bronchi's epithelium. it reduces the duration of intoxication, catarrhal instances and hyperthermia in sick children. e-aca improves the indexes of immunity, non-specific resistance and decreases the rate of bacterial complications. application of e-aca for treatment influenza and other arvi in children is recommended in ukraine on the base of results of our researches. the higher effects demonstrated as a result of combine usage of e-aca with specific ig, or deitiforin, or unithyol, or ribavirin. in our opinion, the study of effectiveness of e-aca combine application with inhibitors of influenza na is the perspective direction of anti-influenza researches development. we should we treat immediately all varicella patients with acyclovir if the patient is older than years pm during past years in institute for infectious and tropical diseases in belgrade, immunocompetent varicella patients were treated and cured. among them were older than years ( . %). x-rays were performed in all patients. diagnosis of pneumonia was made in patients ( . %), but in ( . %) patients older than years. varicella is a benign, self-limited disease, if it strikes early, i.e. preschool, school children and teenagers. at that time there is no need for specific therapy. but in neonates, immunocompetent adults and in all immunocompromised patients it can be difficult and life-threatening disease. in immunocompetent adult population pneumonia is a very serious, sometimes fatal complication. knowing the pathophysiology of primary varicella Á/zoster infection, specific therapy with acyclovir should be started immediately after making the diagnosis in patients older than years, without waiting for x-ray proof of pneumonia. brivudin compared to acyclovir for the treatment of herpes zoster: effects on acute disease and posttherapeutic pain pm objective: comparison of efficacy and safety of brivudin )/ mg and acyclovir )/ mg, both for days, in the treatment of herpes zoster. methods: randomised, double-blind study on immunocompetent patients ]/ years (brivudin: n / , acyclovir: n / ). a subgroup of patients ]/ years (brivudin: n / , acyclovir: n / ) was examined for the occurrence of posttherapeutic pain in a poststudy survey. posttherapeutic pain was defined as any zoster-associated pain, regardless of intensity, after the end of acute zoster. results: brivudin was superior to acyclovir in reducing time to last occurrence of new vesicles (rr(itt): . [ . Á/ . ], p / . ). the advantage of brivudin was more pronounced in patients ]/ years (rr(itt): . , [ . Á/ . ], p / . ). incidence of posttherapeutic pain was significantly lower with brivudin ( . %) than with acyclovir ( . %, p / . ). duration of pain was comparable in both treatment groups (rr: . , [ . Á/ . ], p / . ). potentially treatment-related adverse events occurred in . % of the brivudin recipients and in % of the acyclovir recipients. conclusions: brivudin mg once daily for days is superior to standard acyclovir in stopping viral replication in acute herpes zoster. in patients ]/ years, brivudin is more effective than acyclovir in reducing the risk of developing posttherapeutic pain. brivudin is as well tolerated as acyclovir. varadinova t a , genova p a , garcia-raso a b , terron a b , fiol j b , badenas f b . a laboratory of virology, sofia university, sofia, bulgaria , b chemistry, universitat de les balears, palma de mallorca, spain we have published that cu(ii) complexes of acyclovir (acv) are active against hsv infection (mbd, ) . here we present data on the activity of acv complexes of ni(ii), cd(ii), co(ii) and ag(i) against resistant to acv hsv strain r- in comparison with the effect against acv sensitive strain victoria. selectivity indexes (si) compared to that of acv were indicative for activity. the following data were obtained: (i) was times less selective inhibitor of strain r- than of strain victoria; (ii) under the action of [cd(acv)cl ], [ni(acv) (h o) ]cl ×/ acv and [ni(acv)(no )] ×/ h o was up to % higher than that in the control; (ii) was times less selective inhibitor than acv; (iv) si of was two times higher for strain r- and five times lower for strain victoria then that of acv. these data show that the selectivity of acv against resistant hsv strains can increase when acv is bond to a proper metal ion. methods: an antiviral activity against herpes simplex virus of the type i (hsv-i/leningrad/ / ) and variant hsv- (vvt/ / r) resistant to acyclovir was determined using commonly accepted method. viruses were grown on a continuous culture. maximal toxic dose was determined by the administration of compounds orally ( mg/kg) or intraabdominally ( mg/kg) to white mice that had mass Á/ g. condition of the animals was controlled during h. mice pneumonia model was used for the testing activity in vivo. results: derivatives tested have activity against hsv- and hsv- resistant to acyclovir. maximum protection of the cells up to % was reached at concentration of compounds Á/ mg/kg. tested compounds have low toxicity and animals did not die after intraabdominal and after per oral administration of the substances. using these compounds led to essential relief of diseases in animals. the number and square of virus specific areas of inflammation in lung was decreased to compare with control untreated group. tested compounds protected animals similar to acyclovir that was used as control. conclusion: derivatives of carboalkoxysulfanilic acids are active against hsv in vitro and in vivo and act on the acyclovir resistant variant viruses. markiewicz r a , szepietowski jc b . a jelfa s.a., medical department, jelenia gora, poland , b department of dermatology, university of medicine, wroclaw, poland background: denotivir is a -benzoamino- ?-chloro- -methyl- isothiazolecarboxanilide anti-inflammatory agent with antiviral and immunomodulatory activities. it possesses also mild antibacterial and antifungal action. the purpose of the study: the aim of this presentation is to give an overview of recent studies demonstrating denotivir efficacy in herpetic infections. the results obtained: in vitro studies revealed that denotivir in the doses below its cytotoxicity (about um) significantly inhibited (by Á/ %). herpes simplex virus (hsv)- and hsv- replication in fibroblast and kidney cell cultures. moreover, it was showed that denotivir in the dose of mg/ml markedly inactivated hsv- after min incubation in c. in giunea pigs research, % denotivir in % dmso appeared to be superior to % dmso alone and untreated groups in the therapy of animal skin infected by hsv- . there was no huge difference in eythema and oedema scorings between studied groups, however in the group treated with denotivir, in contrast to others, no vesicles developed. several clinical studies showed usefulness of denotivir in controlling herpetic infections in dermatology, ophthalmology and otolaryngology. in the majority of studies within few hours after the drug application itch and pain relief was noted and within Á/ days the vesicular lesions were dried up. the conclusion reached: in conclusion, denotivir is an effective antiherpetic agent. this study was conducted on cows affected with teat papillomatosis. in the first step, each cow was located on one of three groups. the first group contained four cows from to years that were treated with fig tree (ficus carica) latex. the second group contained four cows from . to years that were treated with a % solution of salicylic acid, and the third group contained four cows as control. in group one and two following treatment with fig tree latex and salicylic acid, superficial necrosis begun from day and all of the warts disappeared by day . in the control group, after day , there were no changes in number of lesions, but some of them were larger than first observation. on day , one of the marked warts disappeared and on day another wart was disappeared but six were present until day . comparison of effects of salicylic acid and fig latex showed similar effects in treatment of udder papillomatosis in cow. laboratory markers of skeletal muscle toxicity in hiv-infected patients: a cross-sectional case-control survey of frequency, potential correlation with antiretroviral therapy, clinical significance, and outcome pm manfredi r, motta r, patrono d, calza l, chiodo f, boni p. to assess skeletal muscle toxicity among Â/ hiv-infected outpatients (p), the p who had ]/ altered cpk assay ( !/ u/l) between may and november , were compared with p randomly selected among those who had ]/ laboratory exams in this -month interval, in a : case-control study. among the p with altered cpk levels only six were females, and received antiretrovirals. the overall frequency of altered cpk among all p who underwent ]/ laboratory workouts in months was . %. cpk alteration was transient in p, with values ranging from to (mean . / . ) u/l, but was recognized ]/ times in Á/ months in p ( %), of them showing concomitant high aldolase levels ( . Á/ . u/l). a myopathy or a rhabdomyolisis were recognized in four p only; a myositis was confirmed in one p by histopathology. in a multivariate logistic regression analysis, when excluding the unexpected prevalence of the male gender (p b/ . ), no significant difference emerged between p and controls as to age, risk for hiv infection, iv drug use, duration of hiv infection, prior anti-hiv therapy and its length, selected drug combinations, administered nucleoside analogues,hiv disease stage, mean cd '/ count and hiv viremia, signs and duration of lipodystrophy, increased glucose, triglyceride and cholesterol levels, and other therapies. muscle abnormalities, though frequently asymptomatic, are underestimated hiv disease complications, and the role of metabolic (i.e. mitochondrial) alterations, deserves investigation. poor efficacy of non-nucleoside reverse transcriptase inhibitor (nnrti)based salvage haart in hiv-infected patients heavily pre-treated with all other classes of antiretroviral compounds pm manfredi r, calza l, chiodo f. infectious diseases, university of bologna, bologna, italy poorly comparable literature series show conflicting results of nnrti-based rescue haart: Á/ % rate of virologic success. to assess the response to a Á/ -drug rescue haart including a nnrti, patients (p) treated with nucleoside analogues (na) and protease inhibitors (pi) for !/ and !/ months, respectively but naïve to nnrti, with a viremia !/ copies/ml, were prospectively followed during Á/ years, provided that they ensured a !/ % adherence. efavirenz was used in p, nevirapine in , and delavirdine in two. most p ( . %) had an early laboratory improvement, but mean peak viral load decrease was . log, and a significant reduction vs baseline (p b/ . ) lasted months only. a mean % increase of zenith cd count was obtained (p b/ . ), but only . % of p remained !/ cells/ml year after switch to nnrti. in a multivariate analysis, the concurrent introduction of novel pi(s) ( p) and/or different na(s) ( p) acted favorably until the th month of follow-up (p b/ . ), while genotypic mutations conferring nnrti cross-resistance, usually associated with a broad resistance profile, predicted failure in all p (p b/ . ), and the response did not vary according to duration and type of prior therapy, and selected nnrti. a deep salvage nnrtibased haart has a poor and transient virologic outcome also in nnrti-naïve p, while a more evident and sustained immunologic response is expected. p who can introduce novel pi/na and have no mutations impairing nnrti activity are entitled to a better outcome. fatal lactic acidosis without elevation of liver-enzymes during the treatment with stavudine, didanosine and efavirenz: a case report pm winzer r, langmann p, väth t, zilly m, klinker h. medizinische poliklinik der universität würzburg, schwerpunkt hepatologie/infektiologie, ürzburg, germany nucleoside reverse transcriptase inhibitors (nrtis) cause various side effects, many of which are thought to be due to their effects on mitochondria. a -year-old hiv positive (hiv rna: copies/ml, cd cell count: /ml), obese (body-mass-index: . ), therapy-naïve female patient, who after months of well tolerated and effective antiretroviral therapy (stavudine, didanosine, efavirenz), had slight gastrointestinal discomfort and suddenly developed a lactic acidosis (arterial-ph . [ . Á/ . she died days later despite intensive care (continuous venovenous haemodiafiltration, sodium-bicarbonate infusion, high doses of vitamins, respiration). the pathologic examination showed an enlarged liver ( g) with yellowish appearance and pasty consistency, which microscopically appeared as a massive macro-and microvesicular fatty degeneration, and only slight signs of terminal pancreatitis. this reported case gives evidence that a massive lactate acidosis may develop without previously disarranged laboratory parameters for liver or pancreatic function. a fatal outcome may evolve without further accompanying-illnesses. efficacy and tolerability of atorvastatin in the treatment of hypercholesterolemia in hiv-infected patients receiving haart pm calza l, manfredi r, chiodo f. division of infectious diseases, university of bologna, bologna, italy introduction: significant increases in plasma triglyceride and cholesterol levels have been reported in patients treated with haart, and prolonged metabolic imbalances could significantly act on the longterm prognosis and outcome of hiv-infected persons. patients and methods: fourteen hiv-infected patients on pi-based haart since at least months and presenting hypercholesterolemia ( !/ mg/dl) of at least -month duration and unresponsive to a hypolipidemic diet and physical exercise, have been treated with a single daily dose of atorvastatin ( mg) for months. results: one patient was ecluded from evaluation due to early dropout. ongoing antiretroviral treatment included ritonavir in four cases, indinavir in four, nelfinavir in three, and saquinavir hard-gel in two. at the close of -month follow-up of atorvastatin therapy, a decrease of total cholesterol level of . % versus respective baseline value was observed; eight out of patients reached normal values for cholesterol. mild gastroenteric symptoms were found in only one of the treated patients, while no skeletal muscle and liver toxicity has been observed. discussion: in our study, pharmacological treatment with atorvastatin proved certainly effective in the management of diet-resistant hypercholesterolemia, and was associated with a favourable tolerability and adherence profile. the effect of combination antiretroviral therapy regimens on hiv- proviral dna level in peripheral blood mononuclear cells (pbmcs) was examined in hiv- -positive patients, using endpoint dilution pcr and serially cloning and sequencing of the gag region of hiv- . the major clone was defined as the most numerous of analyzed clones, and observation periods ranged from to months (mean, . / . months). in five patients (one with primary-stage hiv- infection) receiving three antiretroviral drugs, hiv- rna levels reduced to undetectable (i.e. b/ copies/ml). hiv- proviral dna levels and the number of major clones reduced in four of these patients. hiv- rna levels reduced, but remained detectable, in five other patients. in the two remaining patients (both receiving two rather than three antiretroviral drugs) hiv- rna levels increased. these results suggested that the population of the major clones may be affected when hiv- rna levels reduce following combination regimens of antiretroviral therapy. saquinavir hard gel (shg) as a part of a spontaneous Á/ -month deintensification anti-hiv regimen following successful highly active antiretroviral therapy (haart) pm manfredi r, calza l, chiodo f. infectious diseases, university of bologna, bologna, italy the induction-maintenance concept was poorly studied in hiv'/ patients (p), and shg was never assessed after prolonged response to potent protease inhibitors (pi)-based haart. shg-naïve p who refused indinavir, ritonavir, or nelfinavir-based haart after achieving long-term viral suppression, and resorted to shg'/ nucleoside analogues (na), were followed prospectively. in . % of the p assessed for Á/ months, ]/ na was changed. prior haart was interrupted after . / . months, due to adverse events ( p), or p's request ( p), while a viremia b/ copies/ml was present since . / . months. a viremia of Á/ hiv-rna copies/ml was maintained in p ( . %), while a higher viral load occurred in p after . / . months, and was related to a pre-haart viremia !/ / ml, a more frequent !/ % recovery of cd count, mutations of codons Á/ , and failure to change na (p b/ . Á/ . ). a cd drop !/ %/ cells/ml was found after . / . months in only eight p, who also had virologic failure: immunologic deterioration was earlier and deeper when na were not changed (p b/ . ). all the p who introduced shg'/novel na after a successful !/ -month induction with a potent pi-based haart had a stable Á/ -month outcome. a suboptimal haart including the less effective but better tolerated shg may be effective for !/ year, especially when novel na are introduced, and specific mutations are absent. despite a lower potency, drugs with a good safety and compliance profile may be recovered for simplified regimens. objective: to evaluate efficacy of antiretroviral therapy (art) with two or three drugs in the nervous 'reservoir'. patients: thirteen acute neurological and art naive aids patients underwent a paired and simultaneous sample from plasma and cerebrospinal fluid (csf) for a quantitative detection of hiv- rna (amplicor roche) before art. all patients underwent a ct and/or mr of the brain to perform a diagnosis. all of them had an hiv related neurological acute inflammatory disease. after diagnosis all patients received art: / received two nrti and / received haart including two nrti and one protease inhibitor. all patients underwent a paired and simultaneous follow-up from plasma and csf during the nd month of treatment. results: in all patients baseline levels of hiv-rna were higher (p b/ . ) in the plasma (log . '/ . ) than in the csf (log . '/ . ). the / patients who received dual therapy had undetectable levels (cut-off copies/ml) of viral rna at the follow-up in csf, but not in plasma: three of these seven patients had a detectable plasma hiv- rna. all / patients with haart had undetectable hiv- rna both in plasma and in csf at the follow up. conclusions: dual nrti therapy is rapidly effective in csf (because of an high penetration of drugs through a more permeable blood Á/brain barrier and lower hiv rna baseline levels) but not in plasma. haart is rapidly and equally effective both in csf and plasma. there are no reports of fulminant and fatal hepatic failure after the start of highly active antiretroviral therapy (haart) in an hiv subject without chronic viral hepatitis. case report: a -year-old naive aids woman with clinical symptoms due by a pcp was observed. baseline alt was increased ( . m.n.v.) because of a mild hepatosteatosis and a silent cholelithiasis. serology for hbv, hdv and hcv was negative; igg anti-hav, anti-ebv, anti-cmv and anti-hsv were present. hiv- rna was . log , cd '/ count was /ml. during the pcp treatment with cotrimoxazole alt values increased ( !/ m.n.v.); nevertheless, she completed the treatment. liver enzymes returned to the pre-treatment values over several days. then she started haart with stavudine, lamivudine and efavirenz. after days the patient showed an efavirenz-related skin rush that resolved within days, without treatment discontinuation. fourteen days after the start of haart jaundice appeared. laboratory revealed severe alt increase ( !/ m.n.v.) and hyperbilirubinemia ( mg/dl) and she died because of an acute liver failure syndrome within few days. an haart efavirenzbased regimen can result highly hepatotoxic when given in presence of a hepatosteatosis, of a recent hepatotoxicity caused by a nonantiretroviral treatment and of a previous idiosyncratic reaction to efavirenz. our experience with bulgarian herbal extracts for improving the general condition of hiv-positive patients pm methods: we used a combination of bulgarian herbal extracts and treated six patients, divided in two groups: three with symptomatic and three with asymptomatic hiv-infection. the all three patients with asymptomatic hiv-infection were treated only with herbal extracts, another three patients with symptomatic hiv-infection were treated with combination of herbal extracts and anti-retroviral therapy. the general status of patients has been evaluated by both subjective and objective surveillance. the immunologic monitoring has been performed by absolute count of cd '/ lymphocytes. results: all patients have shown an obvious improvement in their general condition: high spirit and working capacity, good appetite and sleep, a restoration of body weight. the number of cd '/ lymphocytes has been lightly increased or constant. conclusion: the combination of bulgarian herbal extracts has shown significant positive effect on the general condition and improve the quality of life. antifungal activity of in vitro and in vivo combinations of voriconazole with -fluorocytosine and amphotericin b against candida and cryptococcus spp pm hitchcock ca, andrews rj, lewis bgh, pye gw, oliver gp, troke pf. pfizer global research and development, department of discovery biology, sandwich, uk purpose: the present study was designed to determine whether the activity of voriconazole (vor), a novel triazole, was reduced against candidal and cryptococcal infections by the addition of standard antifungal agents, amphotericin b (amb) and -fluorocytosine ( -fc). vor was tested in combination with standard antifungal agents both in vitro, using a checkerboard mic determination test, and in vivo in immune normal guinea pig models of fungal infections. the results indicate that the efficacy of vor against candida albicans and c. neoformans was not antagonised by amb or -fc in vitro. furthermore, in guinea pig models of systemic candidiasis and intracranial cryptococcosis, no antagonism was observed between the lower doses of vor and either amb or -fc on the basis of reductions in tissue fungal loads. at the highest doses of vor, both amb and -fc showed some antagonism, but the combinations were still effective in significantly reducing fungal tissue loads compared with vehicle-treated control animals. conclusion: these results suggest that vor may be used in combination with standard antifungal agents, and future studies to elucidate the clinical potential of vor combination therapies in the management of candida and cryptococcus infections are warranted. itraconazole in the treatment of pityriasis versicolor pm tiodorovic j, jovanovic d, binic i, nikolic lj. faculty of medicine, clinic of dermatovenerology, nis, serbia, yugoslavia a comparison of two short-term dose schedules with itraconazole was carried out in patients with pityriasis versicolor. the patients were divided in two groups. each group consisted of patients who completed the therapy and controls. the clinical diagnosis was confirmed mycologically, by direct microscopic examination. the first group received mg of itraconazole daily for days. the second group received mg daily for days. the patients were controlled clinically and mycologically and days after the initiation of treatment. erythema, scaling and pruritus was evaluated clinically. clinically and mycologically cured patients accepted as cured. the cure rate were % in the first group and % in the second group at day . the effects of these two groups are similar. none of the patients reported side-effects. fungal urinary infections: emerging species, antifungal susceptibility trends and antibody response pm badawi he a , kamel ai b , fam ns a , el-sayed me a , elian sae c . a theodor bilharz medical research institute (tbmri ), microbiology, giza, egypt , b theodor bilharz medical research institute (tbmri ), urosurgery, giza, egypt , c faculty of medicine, medical microbiology and immunology, cairo university, cairo, egypt objectives: to assess the role of candida species in patients with urinary tract infections (utis) with or without schistosomiasis and/or cancer bladder, to compare chromogenic; chromagar (cma), biggy agar; morphologic (corn meal, rice agar-tween ) media and biochemical candifast test for identification of candida species. susceptibility to antifungal agents using e -test and candifast and the performance of elisa test for detection of anticandida antibodies (igm and igg) in serum were evaluated. results: c. albicans was the most frequent ( . %) species responsible for fungal utis. however, non-albicans species, c. glabrata ( . %), c. tropicalis ( %) and c. krusei ( . %) were also isolated. rice agar-tween was found to be cheap, available and sufficient to make a final identification ( %). cma could not identify c. glabrata . biggy agar could not adequately differentiate candida species. candifast biochemical identification showed low sensitivity of . %. e -test on sabouraud dextrose agar (sda) is simple method for mics determination and could detect s-dd strains in case of azoles. conclusion: the emergence of non-albicans species such as c. glabrata , c. tropicalis and c. krusei have contributed to complicated utis. this necessitates accurate isolation and identification of candida to the species level. morphology on rice agar-tween and antifungal susceptibility using e -test on sda is a simle rapid scheme for routine identification of clinically important yeasts. purpose: classification of allergic fungal rhinosinusitis (afr) is based on the immunologic relationship of the host to the fungus. afr must be differentiated from other fungal rhinosinusitis infections, which include acute invasive, chronic invasive, fungal balls and saprophytic colonization. although many cases of fungal rhinosinusitis is caused by species of aspergillis , dermatiaceous moulds have become an emerging pathogen in immunocompetent individuals. results: our case study involved a year male suffering from facial pain, headache, postnasal drip and loss of smell. he was hiv negative and a nonsmoker. the following laboratory tests were performed: ige- . ( . Á/ . ) iu/ml iga- . ( . Á/ . ) g/l igm- . ( . Á/ . ) g/l allergen specific ige for alternaria */ . ( . Á/ . ) ku/l fbc-normal except eosinophils slightly raised . ( . Á/ . ))/ / l. ct scans indicated fungus proliferation, bone erosion and extension of disease into adjacent anatomic area. sinus tissue following debridement was sent for microscopy and culture. hyphae was microscopically observed and cultures yielded two dermatiaceous fungi, bipolaris spp and alternaria spp . conclusion: it is important to differentiate these two species from curvularia , helminthosporum , drechelria and exserohilum . knowledge of these dermatiaceous fungi is important in directing appropriate antifungal therapy and selecting the correct antigens for postsurgical immunotherapy after initial debridement and irrigation. antifungal activity of in vitro and in vivo combinations of voriconazole with -fluorocytosine and amphotericin b against aspergillus fumigatus pm hitchcock ca, andrews rj, lewis bgh, pye gw, oliver gp, troke pf. pfizer global research and development, department of discovery biology, sandwich, uk purpose: a key requisite for a new antifungal drug is to demonstrate that it is devoid of significant antagonism in combination with other agents. combinations of the new triazole, voriconazole (vor), and standard antifungal agents ( -fluorocytosine or amphotericin b; -fc or amb) were tested against aspergillus fumigatus in vitro and in guinea pig models of infections to confirm that antifungal activity was not antagonised by using combination therapies. vor was studied in combination with amb or -fc in vitro, using a checkerboard mic determination test, and in vivo, using immune normal and immunocompromised guinea pig models of systemic aspergillosis. results: the results indicate that the potency of vor was not antagonised by amb or -fc in vivo; indeed, at lower concentrations of vor, significant improvements in reducing fungal burden in both in vivo models were achieved by the addition of amb. in vitro, no antagonism was found between vor and amb, although -fc had a significant antagonistic effect on vor activity. conclusion: these results from in vitro and in vivo models of aspergillosis suggest that vor may be used in combination with standard antifungal agents and, therefore, justify further examinations of vor combination therapies in a clinical setting. in vitro activity of caspofungin compared to that of amphotericin b, fluconazole, and itraconazole against candida species pm arikan s, sancak b, hascelik g. department of microbiology and clinical microbiology, hacettepe university medical school, ankara, turkey purpose: to evaluate the in vitro activity of caspofungin against various candida spp. and particularly against isolates with decreased amphotericin b, fluconazole, and itraconazole susceptibilities. methods: susceptibility tests were done by nccls m a microdilution guidelines for clinical candida strains. the mics (mg/ml) were read at and h. results: caspofungin mics at h are shown in the table. mics at h were similar to h readings. expectedly, no evidence of crossresistance was detected between caspofungin and other drugs tested. caspofungin was similarly active against fluconazole-or itraconazolesusceptible and resistant isolates. conclusions: ( ) caspofungin is active in vitro against all candida spp. tested. ( ) caspofungin mics are slightly higher for c. parapsilosis compared to other species. ( ) its activity against fluconazole-and itraconazole-resistant isolates is noteworthy. ( ) validation of these data require clinical investigations. oropharyngeal microbiological samples of bmt patients were evaluated. weekly cultures (days (/ , and '/ ) revealed presence of fungi in patients ( . %): in four ( %) patients before bmt only, in ( %) after bmt only, and in ( . %) both before and after bmt. in one patient candida norvegensis was isolated from the throat, buccal and palatal surfaces. three c. albicans , two c. krusei , and three c. norvegensis from four patients were chosen to comper their antifungal sensitivities and extracellular virulence factors. using fungitest method we determined the sensitivities of these isolates to flucytosine, amphotericin b, miconazole, ketoconazole and fluconazole. the fluconazole sensitivities were also determined by the e -test. on the basis of the fungitest data the three c. norvegensis isolates were sensitive to flucytosine, amphotericin b, and also to ketoconazole. in case of fluconazole and miconazole they proved to be susceptible dependent upon dose. the mic fluconazole values determined by the e -test for the three c. norvegensis isolates were , ]/ and ]/ mg/ml, respectively. the oropharyngeal isolates of c. norvegensis produced high amounts of extracellular aspartic protease and phospholipase similarly to c. albicans strains. these enzymes may contribute to the pathogenesis of this new emerging candida species. in vitro activities of antifungal and antiseptic agents against rhodotorula sp pm preney l, théraud m, guiguen c, gangneux jp. laboratory parasitologie-mycologie, chu de rennes, france purpose of the study: rhodotorula species are common saprophyte yeasts widespread in nature. since the last years, they have been implicated in several severe infections, especially in immunocompromised patients, and various antifungal therapies were used. however, only limited data are available on the susceptibility of rhodotorula sp. to antifungal and antiseptic agents. material and methods: in this work, we evaluated the in vitro activities of eight antifungal agents against strains of rhodotorula ( strains of r. rubra and nine strains of r. glutinis using atb fungus system (biomerieux) and etest strips (ab-biodisk). beside, the effect of eight antiseptic agents was assessed on a suspension of r. rubra . the quantification of yeasts after exposure to antiseptic agents was performed by subculturings using a microtitration method in well plates. results and discussion: all strains tested were susceptible to amphotericin b, fc, and nystatin. twenty-nine out of strains were susceptible to ketoconazole, out of were intermediate to econazole. all strains were resistant to fluconazole (cmi!/ mg/ml) and itraconazole (cmi!/ mg/ml), and out of were resistant to miconazole, suggesting that antifungal therapy must be adapted when rhodotorula yeasts are implicated in invasive infection. beside, min exposure to sodium hypochlorite , chlorhexidine . % or ecodiol (isopropyl alcohol'/alkylamin) showed fungicidal activities. susceptibility testing of aspergillus fumigatus and emerging aspergillus pathogens by a modification of the nccls m -p method pm logotheti m a , kapsanaki-gotsi e b , velegraki a a , zagoura d b . a department of microbiology, mycology reference laboratory, medical school, university of athens, athens, greece , b biology department, section ecology and systematics, university of athens, athens, greece aspergillosis in high risk groups of patients is still associated with high mortality rate ( Á/ %). aspergillus fumigatus is the primary pathogen, while other opportunistic aspergillus species are emerging. amphotericin b (ab), itraconazole (it), voriconazole (vo) and terbinafine (te) minimum inhibitory concentrations (mic) were determined by modifying the nccls m -p microdilution method. stock drug solutions were prepared in rpmi , dimethyl sulfoxide (dmso), and polyethylene glycol (peg ). inocula, of the a. fumigatus group ( ), a. flavus group ( ) ( ) and the m -p quality control strains were prepared according to, and by modifying, the nccls guidelines. plates were incubated at and c and read at and h. peg effectively dissolved it and vo, while either dmso or peg dissolved te. low and c Á/ h ab, it, vo and te mics ( . Á/ . mg/l) were recorded. a. terreus ( ) and a. parasiticus ( ) were resistant to ab. certain clinical isolates demonstrate clinical and in vitro resistance. standardization of susceptibility testing would offer reliable assistance in selecting and monitoring antifungal therapy. otag f, aslan, g, ozturk c. microbiology department, faculty of medicine, mersin university, mersin, turkey rates of opportunistic fungal infections have risen markedly. because some of these species have potential resistance to antifungal agents, rapid presumptive species level identification is crucial in allowing for directed antifungal therapy. in this study, isolated yeasts from the clinical specimens were identified by atb id c (biomerieux, france). the number of identified yeasts were, respectively; ( %) candida albicans , six ( %) c. glabrata , five ( . %) c. tropicalis , three ( . %) c. parapsilosis , two ( . %) c. krusei , two ( . %) c. kefyr , one ( . %) c. guillermondii , one ( . %) c. dubliniensis . twenty-one of strains were investigated for antifungal sensitivities by atb fungus kit (biomerieux, france). the results are as follows: % sensitivity was detected to myconasol, % to flusitozin, nystatin and econasol, % to amphtericin b and ketokonazol. it is important to achieve empirik treatment of the opportunistic candida infections and the following of resistance to antifungals. shakhmatov da, strelchenco, ov. novosibirsk state medical academy, dermatovenerology, novosibirsk, russian federation at the present stage in russia with a background of a high case rate of syphilis, it becomes necessary to exclude biological false positive serological tests. because the serodiagnosis of syphilis has significant limitations, the direct detection of t. pallidum in suspect blood may serve as an alternate diagnostic strategy. polymerase chain reaction (pcr) has been the most widely used amplification method. the study of patients receiving examination related and treatment for syphilis in std clinic and persons directed from other hospitals where routine serologic examination revealed doubtful results. pcr reaction was carried out with nested primer pairs based on the dna sequence of the Á/ and Á/ kda gene of t. pallidum . pcr was utilized with whole blood. a complex of serological tests: fta-abs and tit was used as the &rdqup; gold standard''. as a result the sensitivity of pcr was . % and specificity was . %. selective comparison of pcr results with vdrl, the fta-abs and treponemal immobilisation test (tit) has shown concurrence . %. in conclusion, the preliminary results of pcr in whole blood in syphilis detection revealed its high sensitivity and specificity; possibility to obtain rapid results in unclear cases. chlamydia pneumoniae (cp) is an atypical pathogen whit intracellular location, whose eradication is very difficult. in the past years it has been objects of many studies that lead to the demonstration of a relationship between its presence and the development of widespread multifactorial pathologies such as atherosclerosis and asthma. the lack of its eradication can become an important clinical and social problem. the study objective is the comprehension of pathogen Á/host interaction mechanism, to characterize therapeutics protocols that cold lead to complete eradication of cp from organism. the research had been principally made on the studying the molecular mechanisms that are at the root of pathogen permanence inside host cell. using proliferation and apoptosis tests we underlined a different behaviour of infected cells towards control cells. in presence of p ( mg/ml), i.e. a peptide that can inhibit the proliferation and induce apoptosis in vitro inhibiting nf-kb, uninfected cells proliferation decreased of % in comparison whit the controls, while the one of infected decreased only of about %. moreover, using various apoptosis-inducers, the infected cells showing apoptosis were about % while the uninfected were about %. the caspace iii activity increased significantly in uninfected cells. in conclusion, cp could delay its elimination from the host inhibiting the apoptosis via nf-kb activation. hryniewiecki t a , gzyl a b , rawczynska-englert i a , a department of acquired valvular heart disease, national institute of cardiology, warsaw, poland , b department of sera and vaccines, national institute of hygiene, warsaw, poland infective endocarditis (ie) frequently causes problems in diagnosis, especially where blood cultures are negative and with fungal etiology (also as a fungal superinfection in bacterial ie). the purpose of the study: the purpose of the study was to evaluate the usefulness of broad-range fungal pcr in diagnosis of fungal superinfection of bacterial ie. twenty-five blood samples were taken for analysis from patients with infective endocarditis. ie was diagnosed according to duke criteria including positive blood cultures. suspicion of fungal superinfection was established on serological investigation in five patients, confirmed by blood culture in two patients. control group consisted of patients without infection. dna was isolated using the commercially available s.n.a.p. kit. amplification products were analyzed by gel electrophoresis stained with ethidium bromide. the results obtained: fungal dna was found in two patients with fungal superinfection of bacterial ie confirmed by culture. in the remaining patients with ie and controls no fungal dna was found. the conclusion reached: broad-range fungal pcr is a fast and inexpensive tool for the detection of fungal dna, but it is more prone to contamination than species-specific pcr. the method may be valuable in the identification of fungal superinfection of bacterial ie or diagnosis of fungal ie. rivanera d, lilli d, lozzi ma, piunno m, mancini c. microbiology, science and public health, rome, italy aim: the aim of this study was to evaluate the eia method for detection of antibody to ttv virus (ttv) and to investigate the anti-tt virus prevalence in patients with hepatitis b (hbv) virus, hepatitis c (hcv) virus, in group of 'high risk'subjects to hepatitis and in healthy subjects. the elisa methods (nuclear laser vienna lab) using ttv s and ns antigens: orf ( aa) and orf ( aa) was applied to detect anti-ttv; the serological screening was performed from samples to italian subjects. results: the positive rates of anti-ttv antibodies were . % in patients with hepatitis b Á/c and . % in 'high risk' hepatitis patients. the anti-ttv was also found in . % in healthy people. conclusions: the anti-ttv were detected in all groups studied, however, its positive rate was similar in patients with hepatitis b Á/c and in 'high risk' hepatitis respect to heathly people. our results shown that tt virus is frequent in italy both in patients infected by others transmitted viruses and in general population. the positivity found in healthy adults included in our studies suggests that the virus might be transmitted non-parenterally. the study of pattern of antibody to ttv may be an infectious marker of ttv similar to that of anti-hcv. a stress test on a miniaturized identification system designed for neisseria and haemophilus pm rich m a , bannatyne rm a , memish za b . a king fahad national guard hospital, division of microbiology, riyadh, saudi arabia , b king fahad national guard hospital, infection prevention and control, riyadh, saudi arabia we report an incident that occurred in our laboratory when the bbl crystal identification system for neisseria and haemophilus was used to identify a haemophilus-like-organism. the numerical profile generated was not in the system database. conventional biochemical tests subsequently revealed an identification of brucella melitensis , a common isolate in our area. as a result of this revelation we subjected this system to a mini 'stress-test' with a collection of isolates of b. melitensis . two numerical profiles were obtained, and , neither of which are listed in the system database. brucella species have been misidentified as moraxella species, moraxella phenylpyruvica , and as haemophilus influenzae biotype iv in various identification systems. two cases of laboratory-acquired brucellosis have been attributed to misidentification. to its credit the bbl crystal identification system for neisseria and haemophilus neither generates a profile number with a misidentified organism nor assigns a confidence level. instead it properly directs the user to resort to conventional methods to secure an identification. if further studies on additional brucella isolates and strains from different geographical sources confirm the unique biochemical profiles identified here, it may be worthwhile to incorporate these into the database where they would be of considerable assistance in areas where brucellosis is widespread. cloning and characterization of aflmp in aspergillus flavus pm chong tk, woo pcy, leung asp, yuen ky. the university of hong kong, microbiology, hong kong, hong kong purpose of the study: to clone and characterize an antigenic protein for serodiagnosis of infection caused by aspergillus flavus which is the commonest aspergillus species causing aspergilloma (ao) and invasive aspergillosis (ia) in asia. result obtained: we cloned the aflmp gene, which encodes the first antigenic cell wall protein in a. flavus . aflmp codes for a protein, aflmp p, of amino acid residues, with sequence features that are present in mp p and afmp p, the antigenic cell wall mannoprotein in penicillium marneffei and aspergillus fumigatus that we described previously. it contains a serine-and threonine-rich region for o glycosylation, a signal peptide, and a putative glycosylphosphatidylinositol attachment signal sequence. specific anti-aflmp p antibody was generated with recombinant aflmp p protein purified from escherichia coli to allow further characterization of aflmp p. indirect immunofluorescent staining indicated that aflmp p is present in the cell walls of the hyphae and conidia of a. flavus . furthermore, it was observed that patients with ao and ia due to a. flavus develop a specific antibody response against aflmp p. conclusion reached: this suggested that the recombinant protein and its antibody may be useful for serodiagnosis in patients with ao or ia, and the protein may represent a good cell surface target for host humoral immunitiy. grape purpose: to investigate the basis for increasing resistance to trimethoprim and sulphamethoxazole. methods: pcr screening for integrons of clinical urinary tract isolates was performed. isolates were tested for resistance to antibiotics. integrons in isolates were sequenced. results: integrons of class were found in isolates and class integrons were found in . eight isolates in the study were resistant to five antibiotics or more and not shown to carry any integron. nineteen of isolates resistant to trimethoprim did not carry integrons. only one of these isolates was shown to carry sul and is thus probably also carrying an integron. none of the isolates were shown to carry dfr , one of five trimethoprim resistance genes known to exist outside integrons. three isolates were resistant to sulphonamides but were not shown to carry neither sul nor sul . only dfr and aad gene cassettes were found in the sequenced integrons. conclusions: resistance to trimethoprim in of trimethoprim resistant isolates is mediated by genes not detectable, as in the case with three sulphonamide resistant isolates. sequenced integrons that contain dfr genes do not carry any gene cassettes mediating resistance to modern antibiotics. unusual diagnosis tool for an unusual presentation of alveolar echinococcosis: report of two cases of local progression after an animal bite pm bardonnet k, bart jm, loiseau j, gérard a, estavoyer jm, heyd b, badet jm, dubiez a, piarroux r, bresson-hadni s. who collaborating centre for prevention and treatment of human echinococcosis, university of franche-comté, besançon, france introduction: the classical human contamination route for alveolar echinococcosis (ae) is ingestion of eggs. two exceptional human cases are reported with extensive local evolution of ae after a bite. case no. : between and , a patient underwent surgery seven times for a muscle growing tumour which developed after a bite. the diagnosis of muscle ae was assessed on histopathological examination. in , serological tests were in accordance with echinococcus sp infection. case no. : in , a man presented 'cat-scratch fever' with a right supraclavicular tumefaction following a cat bite. between and , five recurrences occurred. different surgical explorations indicated multiple abscesses of the cervical muscles. in , serological tests were in favour of echinococcus sp infection and the pathologist described a parasitic wall suggesting hydatidosis, but specific pcr from histological samples prompted the diagnosis of ae. conclusion: in these exceptional observations, the liver which is the most usual location of ae was lesion-free. the chronic inflammatory ae lesions have developed in the local lymphatic chain area of the bite site. to perform diagnosis in these very unusual forms of ae, it is necessary to add unusual tests such as specific pcr to classical tests. antibiotic resistance in foodborne salmonella is an emerging public health concern. integrons are now recognized as the main genetic vehicles of antibiotic resistance in gram-negative bacteria, including in salmonella . the purpose of the present study was to investigate the presence of class i integrons in resistant isolates of several serotypes of salmonella isolated from poultry products and to determine their association with multidrug-resistance phenotypes. a total of isolates of salmonella belonging to seven different serotypes were tested. the most frequent multiresistant phenotype, found alone or together with other resistances, was to streptomycin and tetracycline. all but seven were resistant to three or more antimicrobial agents, including quinolones and amoxicillin. pcr analysis with the ?cs and ?cs primers detected the presence of class i integrons of . kb in one isolate, with the multiresistant phenotype: amoxicillin, chloramphenicol, streptomycin, trimethoprim-sulphametoxazol and tetracycline. our findings suggest that the uncontrolled use of the antimicrobial agents in food animals may have contributed to the development of the pattern of resistance observed in salmonella isolates. also the presence of integrons in low prevalent human salmonella serotypes but associated with food animals underscores the public health problem of antibiotic resistance acquisition and spread. prevalence and antimicrobial resistance of campylobacter jejuni and c. coli isolated from broilers and pigs in france pm avrain l a , humbert f b , sanders p c , kempf i a . a afssa, umb, ploufragan, france , b afssa, hqpap, ploufragan, france , c afssa, lermvd, fougères, france in , caeca from standard, export or free-range broilers and in , fecal samples from pigs, were collected in french slaughterhouses. prevalence of campylobacter jejuni and c. coli strains was . % in standard, . % in export and % in free-range broilers. in standard and export productions, the most often isolated species was c. jejuni , whereas c. coli was predominant in free-range production. . % samples collected from pigs contained c. coli . the sensitivity of strains to ampicillin, nalidixic acid, enrofloxacin (broilers) or ciprofloxacin (pigs), tetracycline, erythromycin and gentamicin was tested by an agar dilution method. in broilers, the percentages of resistant strains were, respectively , , , , . and % for c. jejuni and , , , , and % for c. coli . in pigs the percentages of resistant c. coli were, respectively , , , , and %. in broiler production, significant differences between distributions of species or percentages of resistant strains were observed according to type of production or administrated antimicrobials. the enzyme dhps (dihydropteroate synthase) participates in the folate synthesis pathway, and is well recognized as the target for sulphonamides. the enzyme preceding dhps in this pathway, pppk (dihydropterin pyrophosphokinase), is another interesting candidate drug target. the metabolic role of pppk is to provide one of the substrates for dhps. earlier studies have suggested that pppk and dhps enzymes need to have physical contact with each other for full enzyme activity. studies of potential interactions between the enzymes have been initiated. so far, indication of a weak interaction has been detected in gelfiltration experiments and the two-hybrid system. to confirm these results, we are currently developing a method to study substrate channeling, as interfering with such interactions could lead to impaired growth and thus be used as inhibitory drugs. we have also cloned and sequenced the operons coding for the enzymes in the folate biosynthesis from different clinical isolates of streptococcus pyogenes . comparisons revealed some isolates with a mosaic structure in the operon, suggesting that horizontal transfer of genetic material has occurred. multi-resistance gene cluster on a plasmid in a clinical isolate of e. faecium pm werner g, hildebrandt b, klare i, witte w. department of nosocomial infections, robert koch institute, wernigerode branch, germany purpose: strain uw was isolated from an urine sample of a patient with a permanent catheter. the purpose of our study was to identify and localize the resistance determinants in this isolate. results: isolate uw was resistant to the following antibiotics: penicillin, ampicillin, gentamicin (high-level), streptomycin (highlevel), erythromycin, clindamycin, vancomycin, teicoplanin, ciprofloxacin, moxifloxacin, nourseothricin, rifampicin, and fusidic acid (lowlevel, mic / mg/l); but showed susceptibilities to oxytetracycline, phosphomycin, chloramphenicol, trimethoprim/sulfamethoxazol, linezolid, and quinupristin/dalfopristin. hybridization, pcr and sequencing experiments localized a cluster consisting of several resistance genes in a composite element on a plasmid. the cluster included genes and transposons tn (vana) Á/tn (ermb) Á/tn (aade Á/ sat Á/apha- ). the plasmid itself was not transferable in filter-matings into a fusidic acid high-level resistant enterococcus faecium recipient while selecting either for erythromycin or vancomycin resistances. however, after transposing a tn -related determinant into uw , determinants became mobilizable with the help of the conjugative transposon. transconjugants were, besides others, high-level resistant to fusidic acid, but susceptible to penicillin and ampicillin. pfge of transconjugants demonstrated a pattern almost identical to the recipient but clearly different from the donor. conclusion: resistance genes in e. faecium could be arranged in a cluster and are mobile via mobilizable/transferable plasmids. lilli d, rivanera d, barbacini ig, lozzi ma, mancini c. department of science and public health, university la sapienza, microbiology, rome, italy aim: hepatitis g virus (hgv), a new rna virus that is parenterally trasmitted has frequentley been found in patients with chronic hepatitis c infection but its role in chronic liver desease is unknown. the aim of this study was to determine the prevalence of hgv infection in patients infected with hcv. ninety-eight patients infected with hcv were evaluated for the presence of hgv rna. the hcv genotypes distribution was genotype b, genotype a, genotype a and four genotype c/ d. hcv rna and hgv rna were detected by rt-nested pcr. results: infection with hepatitis g virus was detected in ( . %) patients and ( . %) were hgv rna negative. none of our patients with genotypes a and c/ d results hgv rna positive. prevalence of hgv infection was % in patients infected with hcv genotype b and . % with genotype a. conclusions: infection with hgv occurred frequently ( . %) in this sample of patients with chronic hepatitis c. we observed a height prevalence of hcv/hgv coinfection in patients infected with hcv genotype a. this association with hcv genotype a was indipendent of the source of infection, infact some of our patients have not history of intravenous drug use. characterization of extended-spectrum beta-lactamase (esbl)mediated resistance in salmonella spp. from durban, south africa pm moodley p a , essack s b , gajee k a , sturm w a . a department of medical microbiology, nelson r. mandela school of medicine, school of infection, university of natal, durban, south africa , b school of pharmacy and pharmacology, university of durban westville, durban, south africa background: gastroenteritis is a common condition among the paediatric population presenting to king edward viii hospital in durban, south africa. from july , we noticed that the susceptibility of the salmonella spp. isolated from stool samples among these children were resistant to multiple antibiotics. aim: to characterize the phenotype of the resistance mechanisms involved. methods: minimum inhibitory concentrations (mics) of ampicillin, azithromycin, ciprofloxacin, cefepime, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefoxitin, chloramphenicol, cotrimoxazole and gentamicin were determined by means of the agar dilution method. isolates were subjected to the e -test for extended-spectrum betalactamase (esbl) production. isoelectric focusing was performed as a preliminary step in enzyme characterization. results and conclusion: thirty isolates of multiresistant salmonella spp. were obtained. antibiogram typing revealed six different resistance phenotypes. all isolates depicted ceftazidime/ceftazidime Á/clavulanate ratio of !/ and were considered putative esbl-producers. isolates expressed Á/ beta-lactamases each with pi values ranging between and . indicative of tem-, shv-and/or ctx-m-related esbls. nine isolates expressed two beta-lactamases each and two isolates expressed three beta-lactamases each. there was evidence of the simultaneous expression of both tem-and shv-derived esbls as well as the simultaneous expression of multiple tem-or shv-derived esbls in single isolates, a phenomenon reported in esbl-positive klebsiella pneumoniae isolated at the same hospital. neutrophils exhibit reduced chemiluminescence response to serum opsonized klebsiella pneumoniae producing extended spectrum b-lactamases (esbl) pm objective: to investigate the ability of esbl and non-esblproducing klebsiella pneumoniae isolates treated with human serum to induce a chemiluminescence response in neutrophils. methods: oxidative burst induced by the interaction of esbl (n / ) and non-esbl-producing (n / ) klebsiella pneumoniae isolates with neutrophils from healthy individuals was monitored by measuring the chemiluminescence response (cl). pooled sera from healthy individuals served as source of complement for pretreatment of the bacteria. cl responses triggered by serum treated zymosan served as positive control. the serum opsonized klebsiella strains were arbitrarily graded as high (h) and low (l) inducers of cl when the cl response induced by the bacteria was cl b/ and !/ %, respectively, of that induced by opsonized zymosan. results: out of non-esbl-producing klebsiella isolates, . % induced high cl response in neutrophils whereas only % of esbl-producing klebsiella isolates did so (pb/ . ). conclusions: strains harboring the esbl plasmid were more virulent than non-esbl-producing strains by virtue of their higher tendency to escape serum-dependent recognition by neutrophils. osiris */an automated system for susceptibility testing in agar diffusion technique pm chegrani f, kolbert m, shah pm. universitätsklinik frankfurt, zentrum der inneren medizin med iii schwerpunkt infektiologie, frankfurt am main, germany objective: osiris measured zone sizes were compared to manually measured inhibition zones using round (rp) and mm mueller hinton square agarplates (sqp). variations of / mm in zone size measurements were defined as tolerable. 'very major errors' (vme) were defined as classification of a resistant organism as sensitive by osiris. thirty thousand two hundred and ninety-eight single measurements testing antibiotics on staphylococci and enterobacteriaceae were done according to the din recommendations. results: vancomycin, rifampicin, gentamicin gave the best results on rp with a concordance of , and %. vancomycin, rifampicin, teicoplanin performed best with , , % on sqp testing staphylococci . worst results on rp gave cefuroxim ( . %) and fosfomycin ( . %), on sqp fosfomycin ( . %), ofloxacin ( . %). for enterobacteriaceae amikacin ( %), gentamicin ( %), ciprofloxacin ( %) performed best on rp; worst nalidixinacid ( . %), piperacillin ( . %). concordance on sqp amikacin ( %), cefotaxim ( %), gentamicin ( %), nitrofurantoin ( . %), cotrimoxazol ( %). very major errors were seen in b/ % of all test performed. interpretation: osiris is a rapid and reliable system for susceptibility testing with round and square agarplates and has an excellent expert system. altindis m a , aktepe oc a , kocagoz t b . a kocatepe university school of medicine, microbiology, afyon, turkey , b diomed inc. tr, istanbul, turkey dio-bacit, in a two section plate, that contains % sheep blood agar on one side and sheep blood agar with bacitracin ( mg/ml) was compared for its efficiency in identification of group a beta hemolytic streptococcus (gabs) with other two different growth plates, one containing % sheep blood agar with bacitracin (b) and the other containing b-sxt. we used latex-agglutination for this comparision. throat specimens obtained from cases were inoculated to dio-bacit plates, first to one side with % sheep blood agar and to the other side with b. after an overnight inoculation at c, colonies with beta hemolysis an % sheep blood agar but no growth with b, were inoculated to % sheep blood agar again and antibiogram identification discs containing . u b and . and . mg sxt (oxoid, uk) were placed onto the plate and incubated overnight at c. after that, colonies with beta hemolysis were defined as b-sensitive while colonies resistant to sxt were defined to be gabs. all colonies are serologically classified by latex-agglutination (oxoid, uk). seventy-one ( . %) inoculations revealed growth of gabs at dio-bacit plates. after inoculating these colonies to % sheep blood agar, of them were found to be sensitive to b, while were found to be sensitive to b but resistant to sxt and of them were defined as gabs by latex test. when compared with latex-agglutination test, we found dio-bacit method's sensitivity and spesificity to be and . %, respectively. method: agar diffusion technique as recommended by din was used to determine izs (read using aura and manually) for staphylococci and enterobacteriaceae . variations in automated measured zone sizes of / mm to the manual readings were considered to be within acceptable range. results: six thousand and fifty-two zone sizes were determined for staphylococci and for enterobacteriaceae . mha displayed tendency to smaller zone sizes in automated readings than isa, as well in staphylococci and enterobacteriaceae . on the other side automated readings presented on isa more precise results than mha. overall less major discrepancies ( b/ mm) were found on isa. izs were generally smaller on mha. the tables below show differences in manually and automated measured zone sizes on different media and species. we discovered seven more cases of resistance in the case of metronidazole. we did not have such experience with clarithromycin. conclusion: our results show that e -test is comparable to ad for clarithromycin, but for metronidazole our findings confirm nccls recommendantion. classical ad is time consuming for every day use in the laboratory. the use of screening agar plate with mg/ml of metronidazole to detect possible resistance could be the solution. rokosz a a , sawicka-grzelak a a , meszaros j b , luczak m a . a department of medical microbiology, the university medical school, warsaw, poland , b department of bacteriology, state institute of hygiene, warsaw, poland purpose: to identify esbl-positive strains and to compare two methods applied for the detection of extended-spectrum beta-lactamases (esbls). methods: two hundred and sixty strains of gram-negative rods were cultured from clinical specimens from hospitalized patients. identification of strains was performed in the automatic atb system (biomerieux, france). these strains were identified as esbl-positive on the basis of the double-disc synergy test (ddst according to jarlier et al., ) results. all strains were also determined using a novel method of esbl detection (dd, diagnostic disc) according to appleton ( ) . two discs were applied in this test: cpd (cefpodoxime) and cd (cefpodoxime/clavulanic acid) (oxoid, england). results: consistent results of two methods (ddst and dd) were obtained in the case of from among of examined strains ( . %). consistent results concerned out of strains of enteric rods ( . %) and only five from among other strains (mostly nonfermenting rods). conclusions: the novel method of esbl-producers detection (dd) is more objective and easier for interpretation than the double-disc synergy test (ddst). diagnostic disc test should be used as the basic one or to confirm the results of ddst in difficult cases. assessment of e -test for determining penicillin resistance in pneumococci pm sener b, yeniþehirli g, ercis s, hasçelik g. department of clinical microbiology, hacettepe university medical faculty, ankara, turkey there is a greater need for susceptibility testing methods that distinguish between susceptible and resistant pneumococci. an alternative method could be the e -test, which is compared with the reference agar dilution method in this study. penicillin susceptibility of a total of pneumococci was determined by e -test and agar dilution methods. streptococcus pneumoniae atcc and enterococcus faecalis atcc were used as controls. the results were given in the effect of anoxic conditions on the minimum inhibitory concentration of metronidazole in helicobacter pylori pm de la obra sanz p, lomas e, roman jl, alarcon t, lopez-brea m. the objective of this study was to determine the effect of incubation under anoxic conditions on the metronidazole resistance of helicobacter pylori . methods: a total of clinical isolates were used in this study. mics were determined by an agar dilution method using mueller-hinton agar plus % lysed horse blood. three plates series contained twofold dilutions of metronidazole from to . mg/l were prepared. the first one was incubated under microaerophilic conditions (oxoid) for days; second and third series were incubated anaerobically (anaerobic system, oxoid) for and h, respectively, and were then transferred to the microaerophilic enviroment up to complete days of incubation. results: with microaerophilic incubation, of strains were resistant (mic and mic were and , respectively). with h anaerobic preincubation, four of strains were resistant (mic and mic were . and , respectively). with h anaerobic preincubation, of strains was resistant (mic and mic were . and , respectively). conclusions: anaerobic preincubations causes an increase in sensitivity to metronidazole, the extent of which was dependent on the length of the anaerobic period. methods: the susceptibility to antibiotics was performed by microdilution method according to nccls guidelines. the production of b-lactamase was tested by nitrocefin sticks (oxoid). results: the mics /mics (mg/ml) appeared, respectively: ampicillin / , amoxicillin/clavulanic . / . , cefaclor / , ceftriazone . / . , erythromycin . / . , azithromycin / . / . , clarithromycin . / . , ciprofloxacin . / . , imipenem / . / . , tetracycline / . / / . , trimethoprim/sulfamethoxazole . / . . b-lactamase was detected in . % of the strains. conclusions: ( ) m. catarrhalis isolates were uniformly susceptible to all tested antimicrobials except ampicillin. ( ) the production of blactamase was responsible for ampicillin resistance ( . %). ( ) m. catarrhalis strains had almost the same behavior 'in vitro' to the tested microlides (erythromycin, azithromycin, clarythromycin). rokosz a, sawicka-grzelak a, luczak m. department of medical microbiology, the university medical school, warsaw, poland purpose: to isolate, identify and determine the drug-susceptibility of fungal strains cultured from fecal samples routinely submitted for detection of clostridium difficile and its toxins in cases of antibioticassociated diarrhea (aad). methods: one hundred fecal samples from hospitalized patients were examined (may Á/october ). c. difficile toxins a/b were detected directly in stools with c. difficile tox a/b ii test (techlab † , usa). fecal specimens were inoculated on ccca and candida id (biomerieux, france) media. c. difficile and fungi were identified with standard microbiological procedures. susceptibility of fungal strains to anti-fungal agents was determined (atb fungus, biomerieux, france). results: c. difficile toxins were detected in and c. difficile strains were isolated from of examined specimens. sixty-two fungal strains of genera were cultured from stool samples ( c. albicans isolates). massive fungal growths were observed on primary plates in all cases. fifty-five fungal strains were susceptible to nystatin, -to fluorocytosine, -to amphotericin b, -to ketoconazole, -to miconazole and -to econazole. conclusions: in some cases of antibiotic-associated diarrhea fungal strains are responsible for symptoms of this disease. certain persons having aad should be treated with anti-fungal agents. results: a total of isolates ( . %) were penicillin nonsusceptible (intermediate and resistant) and ( . %) were erythromycin non-susceptible. non-susceptibility to both antibiotics was found in ( . %). conclusions: if penicillin administration eliminates all penicillin susceptible strains, the prevalence of penicillin non-susceptible strains will increase as well as the erythromycin non-susceptible ones. this means that the proportion of erythromycin non-susceptible strains should increase from . to . %. at the same time, if erythromycin eliminate all susceptible strains to this antibiotic, the prevalence of penicillin non-susceptible strains would increase from the initial . to . %. these data can explain the co-selection results observed in different surveillance studies. antimicrobial susceptibility and capsular types/groups of streptococcus pneumoniae isolates causing pneumococcal diseases in bulgaria pm setchanova l a , gergova r a , ioneva m b , sredkova v c . a department of microbiology, medical university, sofia, bulgaria , b department of microbiology, ii city hospital-sofia, sofia, bulgaria , c department of microbiology, faculty of medicine, pleven, bulgaria a prospective study of pneumococcal infections was performed in cooperation with five clinical microbiology laboratories in bulgaria. mics values to antimicrobials and serotype/serogroup distribution were determined for strains of streptococcus pneumoniae . pneumococci were isolated from patients with systemic or respiratory infections. the incidence of penicillin g-intermediate and penicillin gresistant isolate was . and . %, respectively. the rates of resistance to other antimicrobials were: cefotaxime/ceftriaxone */ . %; erythromycin */ . %; clindamycin */ . %; tetracycline */ %; chloramphenicol */ . %; trimethoprim/sulfamothoxazole */ %; ciprofloxacin */ . %; rifampin */ . %. the s. pneumoniae isolates belonged to capsular types/groups. the most common serotypes/serogroups in bulgaria are , , , , , , we aimed to determine the pneumococcal antibiotic resistance rates and the serotypes of those resistant isolates in our hospital. the mic values of isolates (year Á/ ) were determined by agar dilution method. serotyping was performed by using pooled antisera of the pneumo-test. the results were as follows (n / ). objectives: to asses the antimicrobial susceptibility of clinical isolates of pseudomonas aeruginosa obtained from to and to monitor trends in antimicrobial resistance. methods: mics were determined by microdilution testing according to nccls. the antibiotics tested were: ceftazidime (caz), aztreonam (atm), imipenem (imp), gentamicin (cn), tobramycin (tb), amikacin (ak) and ciprofloxacin (cip). results: a total of isolates were included. urine was the most common site of isolation for outpatients isolates ( . %) while for hospitalized patients respiratory samples were the most frequent ( . %). susceptibility to antibiotics was: % caz, . % atm, % imp, . % cn, . % tb, . % ak and . % cip. comparison of susceptibility data through Á/ showed that the increase in the resistance rate was significative for caz ( . vs . %), atm ( . vs %), cn ( vs %), tb ( . vs . %), ak ( . vs . %) and cip ( . vs %). significant differences were found under the following circumstances: isolates from intensive care units and from inpatients were significatively more resistant to caz, atm and imp. isolates from respiratory samples were more resistant to caz and atm and isolates from urine samples were more resistant to cip. conclusions: although the antimicrobial susceptibility level has been decreasing p. aeruginosa isolates still show good susceptibility percentages for all antibiotics tested. antimicrobial susceptibility testing of clinical isolates of bordetella pertussis : report on isolates from rouen, france pm lemee l a , nouvellon m a , caron f b , lemeland jf a . a chu rouen, bacteriologie, rouen, france , b chu rouen, maladies infectieuses et tropicales, rouen, france reports of an increased clinical incidence of pertussis and the development of resistance by bordetella pertussis to erythromycin prompted the collection and antimicrobial susceptibility testing of recent clinical isolates from patients, who were hospitalized in rouen between and . mics of nine antimicrobial agents (erythromycin, josamycin, spiramycin, roxithromycin, ketolide hmr , cotrimoxazole, ciprofloxacin, rifampicin and amoxicillin) were measured by agar dilution method on mueller-hinton agar containing % horse blood. mbcs of erythromycin and rifampicin were also determined against four isolates of b. pertussis . all isolates were fully susceptible to the nine antimicrobial agents tested. mics (mcg/ml) were . for erythromycin, ketolide hmr and ciprofloxacin, . for josamycin, . for spiramycin, roxithromycin and rifampicin, . / . for cotrimoxazole, and for amoxicillin. mbcs (mcg/ml) were . Á/ . for eyrthromycin and . Á/ for rifampicin. in conclusion, our isolates of b. pertussis remain extremely susceptible to all antimicrobial agents tested, especially macrolides. no resistance was detected. finally, if erythromycin remains the molecule of choice, other macrolides (c and c ) also confirm their good in-vitro activity. in addition, the good in-vitro potency of rifampicin, together with its great diffusion within the respiratory tract, suggests that rifampicin has potential clinical efficacy in pertussis too. the emergence of streptococcus pneumoniae (sp) with diminished susceptibility to penicillin g (psdp) suggests the use of other antibiotics such as newer fluoroquinolones (fq). the resistance phenotypes of consecutive pneumococcal strains isolated from patients of four hospitals (observatoire régional des pneumocoques du nord-pas de calais) were studied: strains were susceptible to penicillin g and were psdp. reference strains provided from the centre national de réfeacute;rence des pneumocoques were added to the study. the activity of pefloxacin, ciprofloxacin, norfloxacin, sparfloxacin, levofloxacin and moxifloxacin was studied. reserpine was used to detect the efflux phenotype. methods used were performed according to the recommendations of the comité de l'antibiogramme de la société française de microbiologie. for each strain, the resistance phenotype to fq was deduced by comparison of mics or diameters obtained with those obtained with the reference strains of known phenotypes. fq resistance phenotypes were not correlated to blactam agent susceptibilities. wild type phenotype was observed among . and . % of the susceptible and psdp strains, respectively. a 'wild efflux' mechanism, deduced by addition of reserpine to norfloxacin, represented the predominant phenotype. it was detected among sp susceptible to penicillin g ( . %) as well as among psdp ( . %). the aim of this study was to determine macrolide resistance phenotypes of sp isolated in three french departments (alpes maritimes, doubs, nord) from nasopharyngeal aspirates of children aged months to years attending a dcc. a random sample of children attending randomly selected dccs was obtained during three periods (spring, autumn and winter ) in each department ( children attending dccs and children sampled). analysis of macrolide susceptibility of sp strains was performed using the ca-sfm method. out of strains, . % had decreased susceptibility to penicillin (spdp) and . % were resistant to erythromycin. the triple disk diffusion method (erythromycin (e), clindamycin (cl) and spiramycin) was used to determine resistance phenotypes. macrolide resistance is a well known phenomenon in france and is confirmed by our study. these results show that the constitutive phenotype is predominant as in other parts of europe and the frequency of efflux mechanism is lower than that observed in the usa and canada. developing antibiotic resistance surveillance of helicobacter pylori in england and wales pm elviss nc, owen rj. central public health laboratory, laboratory of enteric pathogens, london, uk purpose: helicobacter pylori antibiotic resistance is a key contributing factor in Â/ % of infected patients failing drug treatment. our aim was to survey rates of primary in-vitro resistance at different locations, and links to disease severity. antral gastric biopsies/cultures were received from phls in chelmsford, mid-essex ( isolates Á/ ); london ( isolates Á/ ); and bangor, north wales ( isolates Á/ ). susceptibilities to metronidazole (mtz), clarithromycin (cla), tetracycline (tet) and amoxicillin (amx) were tested by disc diffusion and also by e -test for cla and mtz. results: overall resistance rates ( isolates) were % for mtz and % for cla. all were susceptible to amx and tet. dual resistance rate was %. breakdown by location showed some marked differences. mtz resistance was highest in london ( %) compared to % in chelmsford and % in bangor. by contrast cla rates were % for london, and about % for bangor and chelmsford. in london, the majority of mtz resistant isolates were from non-uk borne individuals ( % non-uk vs % uk). comparison of duodenal ulcer-associated isolates with those from non-ulcer patients indicated similar rates of mtz resistance ( %). conclusion: resistance rates may vary significantly between locations depending on the local population with non-uk birth being a key risk factor for primary resistance with a mtz resistant strain. local resistance rates should be taken into account in test and treat strategies. potrykus j, benetkiewicz m, wegrzyn g. department of molecular biology, university of gdansk, gdansk, poland purpose of the study : because of their ability to extrude a wide range of compounds, multidrug efflux pumps have recently become an important issue in combating bacterial infections. acrab-tolc is the major efflux system of escherichia coli . we investigated the effect of acra on plasmid-borne and intrinsic chloramphenicol, tetracycline and ampicillin resistance. results and conclusions: recently, we reported a chloramphenicol sensitivity of e. coli mutant expressing cat , the chloramphenicol resistance gene. the strain was shown to bear a nonsense mutation in the acra gene. our studies indicate that this mutation is, at least in part, responsible for the observed chloramphenicol sensitivity phenotype. the mutation seems also to influence the strain's susceptibility to ampicillin and teta (c )-mediated (plasmid-borne) tetracycline resistance. although the teta(c) protein retained its biological function, there was a considerable growth impairment of the mutant strain when cultured in tetracycline containing medium. deletion of the acrab locus prevented any growth in the presence of tetracycline. upon the addition of ampicillin, the mutant underwent lysis more rapidly than the control strain. such was also observed in acrab deletion derivatives of other e. coli strains. we are trying to elucidate the role of the acra gene product in the phenomena described above. existence of efflux pumps in wild type isolates of drug-resistance bacteria pm raja ray rr. medical microbiology and parasitology, calcutta university, kolkata, india efflux pumps possessed by the bacterial cells of different kinds of bacteria had presented as a newer mode of drug resistance in many organisms. the capacity of bacterial cells to cause outward flow of noxious agents was known, however, for a considerable time with respect to tetracycline. recently, interest in the efflux pump system has brought to light some previously ill-understood mechanisms of drug resistance, involving noxious agents, toxins or poisons. we have found high level of resistance in pseudomonads towards cetrimide and other germicides for which no definite chromosomal/plasmid-mediated genes/mechanisms could be identified. likewise, occurrence of nonantibiotic sensitive vibrios, staphylococci and pseudomonads in the background of their high level of resistance to most of the common antibiotics suggest a mechanism of interference with the efflux pump, which accounts for such sensitivity in such cases. involvement of multiple resistance of marine isolates of v. parahaemolyticus to numerous clinically used antibiotics to which they have never been exposed also suggests a possible role of efflux pumps in determining such resistance */that these can simultaneously develop against multiple marine toxins/poisons and other noxious agents. interaction between oxacillin and glycopeptides in a teicoplanin-resistant mutant of staphylococcus epidermidis with reduced susceptibility to vancomycin pm greco aa, ben hassen a. laboratory service of national bone-marrow transplant center, tunis, tunisia we selected a laboratory-generated mutant of staphylococcus epidermidis capable of growing in the presence of mg/l of teicoplanin ( b tm ), from a methicillin-resistant (mic!/ mg/l), teicoplanin-sensitive (mic mg/l) and vancomycin-sensitive (mic mg/l) clinical isolate of s. epidermidis ( b so). in a previous work, we studied the different phenotypic characteristics acquired by the teicoplanin-resistant mutant b tm ( th interdisciplinary meeting on anti-infectious chemotherapy, december , poster sessions, /p ). in this work, we examined the interaction between oxacillin and glycopeptides against this teicoplanin-resistant mutant of s. epidermidis with reduced susceptibility to vancomycin. to study the combined antibiotic activity of oxacillin and glycopeptides, we used different methods: a modified disk diffusion test, the e -test, time-kill assays and population analysis profiles. the synergistic activity of glycopeptides in combination with oxacillin against the teicoplaninresistant mutant b tm was demonstrated with a bactericidal effect. no synergy was seen against the parental strain b so. moreover, the synergy between glycopeptides and oxacillin occurred with suppression of the subpopulation with the highest level of glycopeptides resistance. we concluded that combination of glycopeptides and oxacillin may be a possible alternative in the treatment of infections caused by methicillin-resistant, teicoplanin-resistant s. epidermidis . compositional changes in microcosm biofilms induced by application of minocycline: a preliminary study pm the aim of the study was to observe the effect of application of minocycline upon microcosm dental plaques. the plaques were cultivated in a constant departmenth film fermentor (cdff), which produces biofilms under conditions mimicking those present in vivo. the composition of the biofilms was determined by viable counting on selective and non-selective media. the proportion of antibiotic resistant genera within the biofilm was determined by viable counts utilising media containing minocycline ( mg/ml). before commencing antibiotic pulsing, the biofilms had a total viable anaerobic count of . )/ cfu per biofilm, with negligible ( cfu/biofilm) minocycline-resistant bacteria. however, h after introduction of the antibiotic, the total count had been reduced to . )/ cfu/biofilm whilst the number of minocycline-resistant bacteria had risen to . )/ cfu/biofilm. at the final sampling time point ( h) the total viable anaerobic count was . )/ cfu/biofilm whilst the number of minocycline-resistant bacteria was . )/ cfu/biofilm. hence, there is a very low basal level of inherent resistance to minocycline within microcosm dental plaques, but this increases considerably once the biofilms are exposed to minocycline. mechanism of resistance to aminoglycosides (amg) e. coli isolated from children with community-acquired urinary tract infections (cau-tis) pm methods: during the Á/ years nine centers took part in the study. the mics of antimicrobials were determined by the agar dilution method as described in the nccls guidelines. results: a total of consecutive urine isolates from children aged month to years with cauti were collected. the most frequently isolated species from children with cauti was e. coli ( . %), followed by klebsiella spp. ( . %) and proteus spp. ( . %). results of the in vitro susceptibility testing of e. coli to amg are shown in table below. resistance of the strains was conditioned on production of amg-modifying enzymes. there has been found following phenotypes among resistance strains: gentamicin Á/ tobramycin Á/netilmicin ( . % */aac( )-v and . % */aac( )-iv enzymes) and gentamicin Á/tobramycin ( . %, due to ant( ƒ) enzyme). conclusion: amikacin is most active amg against e. coli . resistance to gentamicin and netilmicin was mainly determined by production of aac( )-v enzyme. effect of b-lactamase inhibitors (b-l-i) on the evolution of resistance (r) to b-lactams (b-l) in gram the b-lactams antimicrobials still are the most frequently used. among the bacteria responsible of high resistance to b-lactams are gramnegative rods; its most frequent mechanism is the production of b-lactamase. the use of b-l-i has reversed partially this mechanism of resistance. we expect changes in the frequencies of r using b-lƒci after more than years. since , the venezuelan group of bacterial resistance, with health institution in the country; analyse and publish data on bacterial resistance of isolates from patients with bacterial infection coming from hospitals. it was used diffusion disk, according nccls. the software program whonet (world health organization net) was used. we follow the trends of r of gram-negative rods to b-l alone and with b-l-i during the decade Á/ . statistical analyses were made by evaluating the differences among percentages of resistance between the two series (p / . ). results and discussion: the difference in r between b-l and b-l/b-l-i are: ( ) piperacillin, piperacillin/tazobactam: between and % of r for most isolated, except for escherichia coli ( %) and serratia spp. ( %); ( ) ampicilin, ampicilin/sulbactam: between and %; ( ) cefoperazone, cefoperazone/sulbactam: between and %. how is expected gramnegative rods resistance to b-lactams with a b-l-i is lower than the b-lactam alone; furthermore the difference between both series, grows higher with time. these results are relevant and they were not expected, since b-l-i have been shown to be b-lactamase inductors. trends in the resistance (r) to b-lactams and others antimicrobials in p. aeruginosa in venezuelan medical centres. nosocomial (nos) and communitarian resistance pm in order to approach the infection produced by resistant bacteria, it is convenient to consider the hospital and the community as two separate ecosystems. the hospital ecosystem has special relevance in the infection and r of gramnegative aerobic bacilli. today, they are the main responsible of nos infection, with special reference to pseudomonas aeruginosa . infection by resistant bacteria is a world wide problem, specially related to nos. since , the venezuelan group of bacterial resistance, with health institution in the country; identify, analyse and publish data on bacterial r to antimicrobials: b-lactams, quinolones and aminoglicosides of isolates from patients with bacterial infection coming from hospitals and the community. it was used diffusion disk, according nccls. the software program whonet (world health organiza-tion net) was used. statistical significance (p / . ) was determined by application of the x technique. we show significant differences in the r of p. aeruginosa nos and communitarian (highest differences: piperacilina / %, tobra / %). we also established significant differences between the r arising in public hospitals and private hospitals (highest differences: ceftazidime / %, amika / %). we show the tendency in decreasing of frequency of r since ; this is more evident in private hospitals (b-lactam and aminoglicosides). new antimicrobials and new mechanism of action, and in the future the new technology will solve today's problem. however, the most important tools we have today are prevention and antimicrobials, and we must make them suitable. susceptibility to antibiotics of enterobacter cloacae and citrobacter freundii from drinking water pm quintera sm, sousa jc, peixe l. department of microbiology, faculty of pharmacy, university of oporto, oporto, portugal the increased use of antimicrobials in farming, together with the practice of raw sewage discharge into receiving waters, has resulted in a significant increase in the number of antibiotic resistant bacteria present in aquatic environment. our objective was to determine the antimicrobial susceptibility, with focus on b-lactam resistance, among enterobacteriaceae strains isolated from raw drinking water samples. several isolates (n / ) of enterobacter cloacae and citrobacter freundii obtained from drinking waters were screened for antibiotic susceptibility patterns, using the agar diffusion technique, according to nccls's procedures. only % of e. cloacae strains, as well as % of c. freundii strains show resistance to amoxicillin and amoxicillin/ clavulanic acid. a reduced incidence of resistance to several others antibiotics was also observed. the obtained results suggest that strains isolated from raw drinking water have greater susceptibility to antimicrobial agents than pathogenic strains from hospital or outpatients infections. the 'natural' antimicrobial resistance phenotypes, usually described for c. freundii and e. cloacae , only seem to apply to strains isolated from human infections. notwithstanding the high susceptibility of the tested isolates to b-lactams, the role of environmental bacteria as a reservoir of resistance genes justify its periodical monitoring as a valid index for resistance spreading. a snapshot of the soil. using bacterial communities for tracing the evolution of metal-resistance pm quintera sm a , sousa jc a , peixe l a , monteiro nm b . a department of microbiology, faculty of pharmacy, university of oporto, oporto, portugal , b department of zoology and anthropology, faculty of sciences, university of oporto, oporto, portugal it is well known that pathogenic bacteria, specially those resistant to antimicrobial agents and heavy metals poses public health risks of great concern, and its detection, namely in soils is generally related to pollution. in this study, the heavy metal resistance patterns of the microflora isolated from polluted (dump area) and unpolluted soil environments were examined. the plate growth covering percentage in the soil samples was determined using mueller-hinton plates supplemented with different heavy metal (al '/, cd '/, cu '/, pb '/, hg '/ and zn '/) concentrations. parallelly, using icp-aes, it was possible to ascertain the real heavy metal concentration for each soil sample. we found that the percentage of plate growth covering from the used samples was closely linked to the level of chemical pollution measured for each location. moreover, using anova, we found significant differences between locations. the dump site showed the highest tolerance to all the tested metals (newman Á/keuls test). this pattern of results was consistent when using the data from the icp-aes. furthermore, it was possible to observe that pseudomonas spp., with a relatively high mic for the studied metals, might become a relevant model for both public health issues and eco-toxicological studies. biochemical characteristics of environmental isolates of listeria monocytogenes pm moshtaghi h a , garg sr b , mandokhot uv b . a shahrekord university, food hygiene, shahrekord, islamic republic of iran , b haryana agricultural university, food hygiene, hisar, india purpose: the investigations were carried out to study the biochemical reactions of listeria monocytogenes isolated from different sources in the environment. results: a total of isolates of l. monocytogenes were obtained from samples of agricultural soil, faecal matter of animals and sewage. all the isolates were gram-positive, small rods, catalase positive, oxidase negative, motile with tumbling motility in hanging drop at Á/ c, aerobic, facultative anaerobic, fermentative and produced acid from glucose. all the isolates of l. monocytogenes were beta haemolytic and positive for camp reaction with staphylococcus aureus . all the isolates were negative for phenyl alanine deaminase, ornithine decarboxylase, lysine decarboxylase, malonate utilization and beta galactosidase tests. these were also negative for acid production from arabinose, d-xylose, mannitol, soluble starch and sucrose but acid was produced in rhamnose, salicin, and trehalose. hydrogen sulfide production was recorded in tripticase soy broth with lead acetate paper strips but negative with triple sugar iron agar. all the isolates were found to hydrolyse aesculin. out of isolates of l. monocytogenes only two produced acid from lactose. in serotyping all the isolates were serotype b. conclusion: we can conclude that l. monocytogenes serotype b at least in fermentation of lactose shows different reactions. methods: the samples were pre-enriched in bhi broth with and without vancomycin ( mg/l) and then plated onto m-enterococcus agar with and without antibiotics: vancomycin ( mg/l), gentamicin ( mg/l), kanamycin ( mg/l), and streptomycin ( mg/l). representative colonies of each morphology were isolated and identified as enterococcus sp as previous described. pcr was used to identify e. faecium and e. faecalis and to characterise vancomycin resistant genotype. api strep was also used in the identification. susceptibility testing to antibiotics was performed by an agar dilution method (nccls). results: three hundred and fifty-three enterococci were isolated from of a total of faecal samples ( %, n / / ). the majority of enterococci were identified as e. faecium , e. faecalis and enterococcus sp. resistance to almost all antibiotics studied was observed: vancomycin */ . %; teicoplanin */ . ; ampicillin */ . %; tetracyclin */ . ; erythromycin */ . %; ciprofloxacin */ . %; chloramphenicol */ . %; gentamicin */ . %; streptomycin */ . %; kanamycin */ . %; linezolid */ %. the vancomycin resistant enterococci presented a vana genotype. conclusion: resistance to several common antibiotics used in therapy was observed among enterococci isolated from healthy human from community. many of these isolates presented multi-resistance. of concern is the presence of vana genotype among these populations that may constitute a reservoir of vancomycin resistant genes. antimicrobial resistance in tetracycline-resistant oral bacteria pm mercury release from dental amalgam may select for mercuryresistant oral bacteria. mercury resistance is often associated with multiple antibiotic resistances. the aims of this study were to determine whether tetracycline-resistant oral bacteria from children with and without amalgam fillings were also resistant to: (a) mercury; and (b) multiple antibiotics. tetracycline-resistant organisms were isolated on iso-sensitest/blood agar containing tetracycline ( mg/ml). the mic of hgcl and several antibiotics were determined using agar dilution (bsac). one hundred and three organisms were isolated from patients without amalgam. ninety-one were streptococcus species, seven neisseria species, three veillonella dispar and two rothia species. fifty-seven percent exhibited resistance to at least one antibiotic, % were mercury-resistant, % were penicillin-resistant, % were ampicillin-resistant and % erythromycin-resistant. fiftytwo organisms were isolated from patients with amalgam. forty-five were streptococcus species, five neisseria species, one v. dispar and one staphylococcus aureus . sixty-three percent exhibited resistance to at least one antibiotic, % were mercury-resistant, % penicillinresistant, % were ampicillin-resistant and % showed erythromycin-resistance. statistically, the results showed that in tetracyclineresistant organisms, the presence of dental amalgam did not affect the level of resistance to mercury or to the antibiotics tested. conway-wallace hl a , mullany p a , bedi r b , wilson m a . a eastman dental institute, university college london, microbiology, london, uk , b eastman dental institute, university college london, transcultural oral health, london, uk the purpose of this study: to determine the prevalence of antibioticresistant oral bacteria in children who had not received antibiotics during the months prior to sampling. plaque samples were obtained from children aged Á/ years and plated onto media containing: penicillin, ampicillin, tetracycline, erythromycin and vancomycin. resistant isolates were enumerated, sub-cultured and frozen for subsequent identification. the process was repeated and months later. the results obtained: bacteria resistant to each of the antibiotics were present in all of the children at each sampling time (except in the case of ampicillin and penicillin at months). the proportion of antibiotic-resistant bacteria in the oral microflora ranged from ]/ . (erythromycin) to / . % (ampicillin). the proportions of bacteria resistant to a particular antibiotic remained reasonably constant over the -month sampling period. in only two cases (penicillin and ampicillin) was there a statistically significant change in the proportions of resistant bacteria at different time periods. the conclusion reached: the results of the study have revealed that bacteria resistant to a wide range of antibiotics may be isolated from children who have not been administered these agents during the months prior to sampling. furthermore, in many cases the proportion of bacteria resistant to a particular antibiotic remains constant over a -month period. antimicrobial use in the intensive care unit: results of a pharmacoepidemiological study in italy pm periti p. e.i.f.t. srl, firenze, italy a retrospective survey of antimicrobial chemotherapy use in intensive care units in italy was carried out in using a computerized questionnaire under the auspices of the journal of chemotherapy. of the icus contacted, . % replied, being mainly general or post-surgical and pediatric units having a mean of beds, nine doctors and nurses. the antimicrobial agents used in these wards were almost always polychemotherapy with prevalent use of beta-lactams, aminoglycosides and glycopeptides or as empirical treatment during the first h after hospital admission. the continual use of medium-high dose combinational antimicrobial chemotherapy was justified by microbiological testing, which revealed that more than one-third of bacterial pathogens were resistant. approximately, % of gram-positive bacteria were methicillin-resistant, whereas about % of gram-negative strains were resistant to at least one of the tested antibiotics. forty percent of the responding icus furnished microbiological testing data, of which three quarters indicated the incidence of chemoresistance of the isolated strains. fungal infections were less frequent than bacterial, the most commonly isolated agent being candida spp. in conclusion, the sample of icus examined showed adequate and reasonable use of antimicrobial agents, with heavy reliance on medium-high dose combination therapy due to the elevated incidence of resistant isolates found. plasma concentrations (p), urinary excretion (u) and bactericidal activity of gatifloxacin (gat) mg versus ciprofloxacin (cip) mg in healthy volunteers after a single oral dose pm boy d a , kinzig-schippers m b , sö rgel f b , well naber kg a . a hospital st. elisabeth, urologic clinic, straubing, germany , b institute for biomedical and pharmaceutical research, ibmp, nürnberg-heroldsberg, germany twelve volunteers received a single oral dose of mg gat versus mg cip to assess p up to h, u (by hplc), and urinary bactericidal titers (ubt) in eight intervals up to h. the mean pmax of gat/cip was . / . mg. the ucum (mean) for gat/cip was . / . %. the ubts, i.e. the highest twofold dilution of urine still bactericidal, were determined for nine uropathogens and one reference strain */mics (mg/ml) (microdilution) for gat/cip: escherichia coli atcc ( . / . ); e. coli ( . / . ); klebsiella pneumoniae ( . / . ); proteus mirabilis ( . / . ); pseudomonas aeruginosa ( / . ); s. saprophyticus ( . / . ); two strains of s. aureus ( . / . ); two strains of e. faecalis ( . / and / ). the median ubts measured within the first h for gatifloxacin were between : and : for the five gram-negative strains (incl. p. aeruginosa ) and between : and : for the five gram-positive strains. the median ubts for ciprofloxacin were between : and : for the gramnegative strains (incl. p. aeruginosa ) and between : . and : for the five gram-positive strains. for the ubts up to h, gat was significantly superior to ciprofloxacin in all gram-positive strains, not different in the two e. coli strains, and inferior in the klebsiella , proteus and pseudomonas strains. for the ubts at Á/ h, gat was generally superior to cip, but showed no difference in the proteus and pseudomonas strains. gat showed overall comparable urinary bactericidal activity as cip. this is in agreement with a clinical study performed previously. malaria is one of the most prevalent endemic infectious disease affecting humans. in bichat hospital cases of malaria acute illness were reported during . among them, patients were hospitalised and intravenously treated by quinine. this retrospective study consisted of comparing the therapeutic drug monitoring (tdm) of quinine distinguishing, respectively and patients cured in infectious medical department (imd) and intensive care unit (icu) where a standardised quinine regimen was established ( and % malaria attacks, respectively). in icu, the treatment consisted of an infused loading dose mg/kg/ h of quinine diluted in % glucose followed by mg/kg/day. plasma quinine maximal concentrations were assessed after selective liquid Á/liquid extraction and spectrofluorometry detection. statistical analysis was performed using t -test. results showed that patients had comparable weight ( . / . and . / . kg) but quinine doses and plasma concentrations were significantly different in icu and imd, respectively ( . / . versus . / . mg/kg/day, pb/ . and . / . versus . / . mg/l, p b/ . ). in icu and imd, respectively: and % were in the therapeutic range ( Á/ mg/l) with and % below the requested therapeutic concentration ( mg/l) and and % above the limit of toxicity ( mg/l) conveying the importance of tdm in intravenous quinine treatment to avoid infra-therapeutic or toxic concentrations. simultaneous central nervous system distribution using microdialysis and pharmacokinetic Á/pharmacodynamic modelling of the electroencephalogram effect of norfloxacin in rats pm chenel m, marchand s, dupuis a, bouquet s, couet w. university of pharmacy, pharmacology, poitiers, france purpose: to investigate the epileptogenic activity of norfloxacin by a pharmacokinetic Á/pharmacodynamic (pk Á/pd) modelling approach and to assess the contribution of distributional processes across the blood Á/brain barrier (bbb) to the delayed effect. methods: rats (n / ) received an iv bolus dose of norfloxacin ( mg/kg). convulsant effect was quantified by electroencephalogram (eeg) recording during h post-dose. arterial blood samples were collected for drug assays in plasma. unbound norfloxacin concentrations were monitored in brain extracellular fluid (ecf) using microdialysis with in vivo calibration of the probes by retrodialysis with ciprofloxacin. results: the eeg effect reached its maximum between and min post-dose. a pk/pd effect compartment model was successfully fitted to these data. the relationship between effect and concentration at the effect site was best described by a spline function. norfloxacin concentrations in brain ecf were relatively low compared to plasma levels (ecf/plasma areas under curve (auc) ratio equal to . / . %), but central distribution was rapid. therefore, the effect versus brain ecf concentrations curves still exhibited a marked hysterisis. conclusion: the delay observed between plasma concentrations and norfloxacin convulsant effect cannot be explained by a slow distribution of norfloxacin across the bbb. pagoulatou a a , kanellakopoulou k b , vafiadou m a , kostakopoulos th c , kastriotis i b , giamarellou h c . a department of anesthesia, sismanoglio general hospital, greece , b th department of internal medicine, athens medical school, athens, greece , c department of urology, athens medical school, athens, greece csf kinetics of van and fu were studied in patients who underwent short urological surgery under spinal anesthesia. patients were excluded if they were already receiving an antibiotic or were suffering from renal and hepatic dysfunction. van was administered at g over h infusion. serum and csf samples were collected post-dose and the mean serum levels were as follows: min Á/ h: . mg/ml (five patients), Á/ h: . mg/ml (five patients), Á/ h: . mg/ml (six patients), Á/ h: . mg/ml (six patients) and Á/ h: . mg/ml (seven patients). fu was administered at mg dose over h infusion. serum and csf samples were taken post-dose and the mean serum concentrations were found as follows: Á/ min: . mg/ml (six patients), min Á/ h: . mg/ml (six patients), Á/ h: . mg/ml (five patients), Á/ h: . mg/ml (six patients), Á/ h: . mg/ml (five patients). in csf, both van and fu were undetectable. it is concluded that in the absence of meningeal inflammation van and fu do not penetrate (with the applied microbiological assay) the csf barrier. comparison of the pharmacology of intravenous and orally given moxifloxacin in an in-vitro model pm wiegand i, pfeil e, wiedemann b. university of bonn, pharmaceutical microbiology, bonn, germany purpose: the intravenous form (iv) of mg moxifloxacin (mox), one of the newer fluoroquinolones, has been recently approved by the fda. during the iv treatment higher peak serum concentrations are achieved in comparison to the oral administration (po) of the same dose. the antibacterial activity of fluoroquinolones is concentration dependent. we therefore simulated human pharmacokinetics of single po and iv dosages of mg mox in an in-vitro model using six different gram-negative and -positive pathogens to elucidate the different effect of these two dosing schedules. results: the comparison of the pharmacological parameter auc/ mic shows an increase ( table ) that could predict an enhanced antibacterial effect. however, the analysis of the killing curves with the following parameters, ka.max (maximal killing activity) and aac (area above the killing curve between and h), reveals no major difference between the po and iv dosage. conclusion: the serum concentration after oral administration is already sufficiently high to show the optimal bactericidal effect of mox that can only be slightly increased by higher peak concentrations and higher auc/mic ratios. thus the concentration dependence is not linear but ends already at concentrations achievable by oral dosing and documents that auc/mic calculations cannot easily be translated into dosing schedules. background : bacteria growing in vivo multiply much more slowly than in vitro. whether the bactericidal activity of quinolones may be affected by an increase in generation time (g) was studied in batch cultures. methods: by limiting the nutrient supply, generation times were lengthened from approximately . to . h up to . h. alternatively, the quinolones were added to the bacterial cultures during the lag-, exponential-and stationary phase. recent clinical isolates of escherichia coli were exposed to multiples of the mics of ciprofloxacin or norfloxacin. the 'killing rates' were calculated in analogy to the growth rate. results: the bactericidal activity of the quinolones tested against e. coli was minimally influenced by the reduced generation time. ciprofloxacin concentrations of ]/ )/mic eliminated the test strains within / h from the test system if added during the lag or exponential growth phase; four times higher concentrations were needed to reduce cfus by % within h, if added during the stationary phase. norfloxacin was significantly less active. conclusion: in contrast to norfloxacin, the bactericidal activity of ciprofloxacin is minimally affected by the generation time or growth phase of the bacteria. wiegand i, pfeil e, wiedemann b. university of bonn, pharmaceutical microbiology, bonn, germany purpose: moxifloxacin (mox) is one of the newer fluoroquinolones, now available for parenteral application. the pharmacology of an intravenous once-daily dose (od) of mg mox was determined with five gram-negative and -positive pathogens (streptococcus pyogenes , streptococcus pneumoniae , moraxella catarrhalis , escherichia coli , and klebsiella pneumoniae ). a twice-daily dose (bid) of mg mox was simulated with the gram-positive species in order to increase the bactericidal effect. results: to determine the efficacy, killing curves were analyzed, and following parameters were calculated: ka.max: maximal killing activity [log cfu]; ka. conclusion: an intravenous once-daily dose of mox is active against all tested pathogens. the gram-negative species are rapidly killed (ka. h similar to ka.max). there is no pronounced initial effect on the two gram-positive species but a general slow reduction in the viable cell count (ka.max is reached after h). the efficacy of mox (measured as aac and ka.max) on s. pyogenes and s. pneumoniae is to some extent increased after the second dose. however, the analysis of the killing curves reveals no major difference between od and bid. even the od nearly gives the maximal bacterical activity of mox against gram-positive pathogens. objectives: to evaluate the dose proportionality of amoxicillin and to compare the respective pk/pd parameters of two dosage regimens. methods: the dose proportionality of amoxicillin was evaluated using linear regression of mean auc -inf and c max data of different bioequivalence studies (n / volunteers) performed with formulations containing various amounts of amoxicillin alone or in the combination with clavulanic acid. the volunteers received a single oral dose in the range of Á/ mg. amoxicillin plasma concentrations were determined by hplc/uv or lc/ms/ms methods. time above mic (tmic) expressed in% of dosing interval was calculated with three target mic values ( . , . and . mg/l) for mg hourly and g -hourly dosage regimens. results: the absorption of amoxicillin (auc -inf ) showed a linear dependence with a correlation coefficient of . . the correlation coefficient of the linear regression for the cmax dependence on the actual dose was . . the respective tmic for both dosage regimens were very similar, with largely overlapping confidence intervals, supporting a pd breakpoint of mg/l for the g -hourly regimen (tmic ]/ mg/l: . %, % ci . , . %). conclusion: this analysis shows the dose proportionality of amoxicillin over the dosage range of Á/ mg and supports the pharmacodynamic rationale for a g bid dosage regimen. piperacillin/tazobactam concentration profile after high dose administration pattern in nosocomial pneumonias due to mecanical ventilation pm pedeboscq s a , gruson d b , bassoua v a , hilbert g b , pometan jp a . a st. andré hospital, pharmacy, bordeaux, france , b pellegrin hospital, reanimation, bordeaux, france the piperacillin (p)/tazobactam (t) antibacterial spectrum covers the largest part of bacteria responsible for pneumonias due to mechanical ventilation. but, due to important bacterial inoculum and pharmacokinetic parameter modifications in intensive care patients, high doses of beta-lactamines seem to be necessary to obtain antibiotic concentrations above suspected bacteria's mic (minimal inhibitory concentration) . this led us to compare, in patients with pneumonia due to mechanical ventilation, two intermittent administration patterns: g three times a day (usual pattern) versus g four times a day (high dose pattern). this study is carried out in collaboration with intensive care unit, bacteriological department and pharmacy where antibiotic concentrations are determined. twenty-three takings of blood are executed within a h period, in addition to two bronchial secretion samples. concerning p seric concentrations, the high dose pattern seems to be more adapted because of relatively high residual concentrations ( !/ mg/ml). three hours after each injection, t seric concentrations are lower than the mg/ml activity threshold. first and second day residual bronchial concentrations of p seem to be sufficient although t concentrations are below activity threshold. these results are to be correlated with the mic determined by the bacteriological department, and only this correlation will make us able to conclude the better efficacy of the high dose pattern in intensive care patients. anti-inflammatory drugs interference in absorption and tissue penetration of amoxycillin pm del fiol fs a , menon sz b , caramez th b , celotto tf b , lopes ras b . a university of sorocaba, pharmacology, sorocaba, brazil , b school of pharmacy, university of sorocaba, sorocaba, brazil antibiotics and anti-inflammatories are frequently associated in clinical practice. there is some concern about the quantity of antibiotic that reaches the infection sites, which may be reduced in the presence of an anti-inflammatory drug. the purpose of the present study was to analyse how steroids (dexamethasone (dexa)) and aines (celecoxib (cele)) influence on the penetration of amoxicillin to inflamed tissues. thirty female rats (rattus norvegicus ) were used with surgically implanted pvc sponges on their backs to form granulomatous tissue. one week later the animals were divided into three groups. one group received only amox ( mg/kg), another received amox ( mg/kg) plus cele ( . mg/kg) and the last received amox ( mg/kg) plus dexa ( . mg/kg). one hour later the animals were sacrificed and the concentration of amoxicillin in the serum and tissue investigated. there was no difference among the groups in the quantity absorbed (amox / . / . mg/ml; amox'/cele / . / . mg/ml and amox'/dexa / . / . mg/ml). there was a reduction in the tissue concentration of amoxicillin (p b/ . tukey-kramer) for the group that received the drug with dexamethasone. for the other groups, there was no difference in the tissue concentration of amoxicillin. the results indicated that in inflamed tissue, a significant reduction of antibiotic penetration was induced by sinultaneous dexamethasone therapy. prediction of the optimal amoxicillin dose regimen based on coupling of pharmacokinetic data and bactericidal activity pm background: given its short half-life, amoxicillin (amx) should be administered at least three times a day to patients with acute exacerbations of chronic bronchitis, in order to achieve serum concentrations well above the mic of the responsible pathogen. however, several authors have recommended twice-daily administration of a higher dose for a shorter period. we assessed the relationship between amx sputum concentrations and antibacterial activity following two treatment schedules in healthy volunteers. subjects and methods: twelve healthy volunteers were randomized to receive amx for days at a dose of either g bd or mg bd. serum and sputum were collected every day, h after the morning administration, and again days after the last dose. amx concentrations were determined by hplc with fluorometric detection. sputum killing activity was determined against haemophilus influenzae , streptococcus pneumoniae and moraxella catarrhalis . results: mean serum concentrations measured h after the morning administration were . ( mg bd) and . mg/l ( g bd), and were above the mics of the three microrganisms. in contrast, sputum concentrations were always below . mg/l. in terms of sputum killing activity, g bd was more effective than mg bd against s. pneumoniae and m. catarrhalis , whereas no sputum samples were active on h. influenzae . conclusion: the optimal amoxicillin treatment schedule cannot be established on the basis of serum pharmacokinetics only. galmiche h, louchahi k, tod m, drugeon h, giroud jp, rouveix b. service de pharmacologie clinique, hopital cochin, paris, crepit , hopital avicenne, bobigny, service de microbiologie, hopital laennec, nantes, france background: cysteine-based mucolytics are commonly used in combination with antibiotics to treat patients with acute exacerbations of chronic bronchitis (aecb). they are also used to allow in vitro mic determination in sputum specimens. we conducted an in vitro and ex-vivo compatibility study designed to detect a possible interaction between mucolytics and antibiotics. methods: serial samples of bronchial secretions were collected from aecb patients and from healthy volunteers who received g of amoxicillin twice a day for days. two mucolytics were used to fluidify sputum specimens: , -dihydroxy- , -dithiolbutan (digest-eur † ) and acetylcysteine ( % solution). amoxicillin was assayed using a chromatographic system with fluorometric detection. each sample was also tested in a microbiological assay. results: amoxicillin could not be detected in the presence of the mucolytic agents. conclusions: this mucolytic Á/amoxicillin interaction may be explained by amoxicillin fixation to fluidified mucoproteins, and should be taken into account when assessing antibiotic efficacy in vivo. del fiol fs a , ferro c b , albuquerques et b . a university of sorocaba, pharmacology, sorocaba, brazil , b uniso, school of pharmacology, sorocaba, brazil physicians frequently recommend that macrolides should be administered with milk to decrease the discomfort they cause. thus the objective of this study was to verify the interference of milk in the absorption and distribution of erythromycin (eryt); clarithromycin (clar); roxithromycin (roxi) and azithromycin (azit). forty female rats (rattus norvegicus ) were used with surgically implanted pvc sponges on their backs for granulomatous tissue formation. one week later the animals were divided into groups that received the drugs eryt, clar, roxi and azit with and without milk ( . ml/kg [ca'/'/] / . mg/ml). the animals were sacrificed and the serum and tissue concentration of the drugs was investigated. there was no reduction (pb/ . tukey-kramer) in the serum and tissue concentration in the presence of milk for azit and clar. there was a % reduction for roxi in the serum concentration in the presence of milk ( . / . and . / . mg/ml), but no alteration in the tissue concentration. there was a % reduction for eryt (p b/ . ), in the serum concentration in the presence of milk ( . / . and . / . mg/ml) and a % reduction in the tissue concentration. the milk decreased the effectiveness of treatments with erythromycin and roxithromycin and the bioavailabilities of this macrolides were affected by co-administration with milk. del fiol fs a , souza gp b , duzzi mr b . a university of sorocaba, pharmacology, sorocaba, brazil , b uniso, school of pharmacology, sorocaba, brazil the degree to which tetracyclines are absorbed differs greatly. this absorption is impaired by the concurrent ingestion of divalent and trivalent cations. thus the objective of this study was to investigate the interference of milk in the absorption and distribution of tetracycline (tetr), oxytetracycline (oxyt), minocycline (mino) and doxycycline (doxy). forty female rats (rattus norvegicus ) were used with surgically implanted pvc sponges on their back for granulomatous tissue formation. one week later the animals were divided into groups that received the drugs: tetr; oxyt; mino; and doxy with and without milk ( . ml/kg [ca'/'/] / . mg/ml). the animals were sacrificed and the drug concentrations in the serum and tissue were determined. there was no reduction (pb/ . tukey-kramer) in the serum and tissue concentrations in the presence of milk for mino. there was a % reduction (p b/ . ) for doxy in the serum concentration in the presence of milk ( . / . and . / . mg/ml) and % in the tissue concentration. for oxyt, there was a reduction of % (pb/ . ) in the serum concentration in the presence of milk ( . / . and . / . mg/ml) and % in the tissue concentration. the tetr results show a . % reduction (p b/ . ) in the serum concentration in the presence of milk ( . / . and . / . mg/ml) and % in the tissue concentration. milk decreased tetracycline bioavailability and effectiveness. isotopic studies with oxine labelled platelet. platelet kinetics in thrombocytopenic malaria patients pm introduction : thrombocytopenia is a common feature in human malaria ( ). excessive splenic platelet pooling has been suggested to play a role in uncomplicated cases of malaria, but a moderately shortened platelet life span during the period with decreasing parasitaemia seems the most plausible cause of the frequently observed thrombocytopenia ( , ). consumption coagulopathy, eventually manifested as disseminated intravascular coagulation, has been described in malaria ( ). in uncomplicated malaria, however disseminated intravascular coagulation is rarely found ( ). results: in malaria patients the sequestration was not different to normal. platelet half-life was reduced in patients with p. falciparum malaria to Á/ h (normal Â/ days). in one patient with p. vivax malaria platelet half live was . h. conclusion: no significant differences in the sequestration of platelets when compared to healthy individuals could be detected by in-labelled platelet scintigraphy. especially, no enhanced splenic sequestration, as previously expected, was the cause of the thrombocytopenia. therefore, other mechanisms than sequestration are responsible for the dramatically reduced life span of the platelets during acute malaria. zaharanka ag, rozhdestvensky da. vitebsk state medical university, vitebsk, belarus aim: the studying of chromatingeterogenic test (ct) results in sperm of subjects taking doxycycline (d) and some macrolides (erythromycine (e), jozamycine (j), and azytromycine (a)) in moderate therapeutic doses. methods: forty healthy volunteers ( Á/ years) were studied. daily dose of d was . ; e was administered in dose . four times per day days; j */ . before meals twice daily days; a */ . before meals once daily days. ct for evaluation of dna condition in human spermatozoids was performed before treatment (twice), on the th and th days of treatment, as well as after and months after treatment course completing. results: ct data analysis revealed that the mean amount of defective spermato-zoids before treatment was . '/ . %. by the th day of d treatment the index of de-natured dna was . '/ . % (pb/ . ), by the th day */ . '/ . % (pb/ . ). one and months after the d treatment course the amount of generative cells with denatured dna was . '/ . and . '/ . %, respectively (p b/ . in both case). under e treatment the amount of defective spermatozoids changed as . '/ . ( th day), . '/ . ( th day), . '/ . (after month), and . '/ . % (after months) (pb/ . in any case). under a using the ct results at the same control points were . '/ . , . '/ . , . '/ . , . '/ . % (pb/ . in any case); and under j treatment */ . '/ . , . '/ . , . '/ . , . '/ . %, respectively (p !/ . in any case). conclusions: the data obtained permit to conclude that d demonstrates the high level of toxicity to male generative cells. this effect preserves during months after the course of d treatment. objective: to study the effect of aggressive isolation and decontamination measures to control an outbreak of multi-resistant acinetobacter baumanii (mr-ab) in an icu. the outbreak: the index case was transferred from a mediterranean hospital, directly into an open-plan -bedded icu, with severe injuries to his head and thorax. he died shortly after admission. sputum, bronchoalveolar lavage fluid, blood cultures and a chest drain swab grew mr-ab, resistant to ampicillin, co-amoxiclav, aztreonam, amikacin, ceftazidime, cefotaxime, cefuroxime, ciprofloxacin, gentamicin, meropenem, piptazobactam, tobramycin and sensitive only to colistin. within days, mr-ab was isolated from two further icu patients. all isolates demonstrated identical antimicrobial susceptibility profiles. the icu was closed to admissions and thoroughly cleaned. all patients were isolated and their contacts screened. the icu was reopened, however, mr-ab was isolated from a fourth patient. this patient was isolated, the icu closed, for a second time, thoroughly cleaned, and all contacts isolated until discharge. all subsequent patients screened were negative for mr-ab conclusion: this illustrates the importance of aggressive isolation measures and thorough supervised cleaning in control of an outbreak, and the need to screen patients for resistant bacteria before admission to the intensive care unit in a general hospital. extended spectrum beta-lactamase-positive bacteria isolated in neonatal intensive care unit pm sandorcinova z a , siegfried l a , kmetova m a , viragova s b . a institute of medical microbiology, faculty of medicine, university of p.j. safarik, kosice, slovakia , b hospital, kosice-saca, neonatal intensive care unit, kosice, slovakia extended-spectrum beta-lactamases hydrolyse all penicilins, cephalosporins, including third-generation cephalosporins and aztreonam. esbl are predominantly produced by klebsiella spp. but may be presented in other enterobacteriaceae, too. the aim of present study was to investigate the occurrence of esbl-producing bacteria isolated from patients hospitalized at the neonatal intensive care units (icu). fifty escherichia coli and klebsiella spp. were isolated from rectum of patients hospitalized at the neonatal icu. the mics of antimicrobial agents were determined by the standard agar plate dilution method according to the nccls guidelines. for screening of esbl production we investigated strains showing reduced susceptibility (mic equal and/or more than ml/l) to at least one of third generation cephalosporins. esbl production was detected by double disk synergy test (ddst), e -test for esbl, and pcr employing specific primers for the presence of blashv and blatem genes. by using ddst and e -test, among e. coli isolates, an expression of esbl was detected in the three by the former method, while among klebsiella spp. isolates, a production of esbl was found in the two by the latter method. in esbl-positive e. coli strains the presence of blatem genes fragments was detected while in esbl-positive klebsiella spp. genes encoding for shv-type beta-lactamases were found. isolation of staphylococci from wound swabs and their susceptibility to antibiotics pm markov mij, shopovski e, despotovski v, angelevski a, nikolovski b. military hospital, microbiology, skopje, the former yugoslav republic, macedonia purpose: to determine percent of staphylococci from wound swabs and to establish their susceptibility to antibiotics. material and method: the wound swabs have been evaluated with standards microbiological techniques. bacteria have been identified with strips from the 'atb expression' system. the susceptibility testing has been performed with strips with dilution technique, read by the same system. results: during the last years ( Á/ ), a total of wound swabs have been evaluated in the military hospital in skopje. positive bacterial finding have been determined in ( %) swabs with isolated bacterial species, from which ( . ) were staphylococci: staphylococcus aureus ( . %) isolations ( methycillin resistant s. aureus ); s. epidermidis ( . %); s. haemolyticus ( . %); s. hominis ( . %); s. chromogenes and s. lugdunensis nine ( . %); s. intermedius , s. lentus , s. sciuri and s. warneri all with seven ( . %) isolations. the susceptibility of s. aureus was to: penicillin %, ampicillin %, amoksicillin/clavulonic acid %, ceftazidime %, gentamicin %, tetracycline's %, erythromycin %, lincomycin %, ciprofloksacin %, cotrimoxazole %, vancomycin %, fusidic acid %, cefixime %, and azitromicin %. conclusion: in our study most frequently isolated bacteria from the wound swabs were staphylococci, especially s. aureus . susceptibility, except for the penicillin ( %), was high to other antibiotics. the study went on from january to december . at maribor teaching hospital, staphylococcus aureus isolates were collected. in , ( %) and in , ( . %) were mrsa. mrsa were recovered from routine clinical material and from surveillance swabs (nose, throat, skin). for isolation, conventional culture media were used and for surveillance swabs mrsa-screening plate (manitol salt agar with % oxacillin) and trypticase soy broth with . % nacl were added. s. aureus was identified by catalase, dna-se and tube-coagulase test. antibiotic susceptibility was determined by the disk-diffusion method according to ncci guidelines. all mrsa isolates were tested for sensitivity to the following antimicrobials: gentamicin, netilmicin, ciprofloxacin, erythromycin, chloramphenicol, tetracycline, cotrimoxazol, vancomycin and clindamycin. it was found that all mrsa isolates were sensitive to vancomycin and partially or totally resistant to the rest. there were no important differences between the years and . our mrsa isolates were completely ( %) susceptible to vancomycin, but resistant to the other antimicrobials in use to some extent. although the monitoring of mrsa susceptibility to antimicrobials once a year did not show any important change in antimicrobial resistance, the periodical monitoring of mrsa susceptibility to antimicrobials and revaluation of current treatment regimens of mrsa infections is necessary. staphylococcus aureus strains with reduced susceptibility to vancomycin among clinical isolates in university hospital in warsaw pm the visa and especially h-visa are very difficult to be found in the routine laboratory. in our investigations we examined of s. aureus strains isolated and stored in our laboratory for several last years ( Á/ ) . most strains were isolated in , and some in . for all staphylococcal strains mrsa as well as mssa the mics of vancomycin were performed by the standard dilution method. among strains isolated in the last year three strains were recognized as visa (mic values were mg/l). the frequency of visa was . %. in the aim of founding the h-visa strains the population analysis was used. for this analysis all strains growing on the concentration mg/l of vancomycin from the inoculum were chosen. it was strains, but only of them were recognized as h-visa. the frequency of h-visa among investigated strains was about %. most but not all of the h-visa and all visa strains were methicillin resistant. in vitro activity of vancomycin, teicoplanin and oxacillin against staphylococci isolated from patients of surgical intensive care unit pm kucukates e, karayel n, kansiz e. institute of cardiology, university of istanbul, istanbul, turkey objectives: oxacillin-resistant staphylococci have emerged as a major infection control problem in our hospital. the aim of this study was to evaluate the in vitro activity of vancomycin, teicoplanin and oxacillin against staphylococci. material and methods: this study was performed between january and december , at university of istanbul, institute of cardiology. the antimicrobial susceptibilities of staphylococci isolates for vancomycin, teicoplanin and oxacillin have been investigated by e -test according to nccls guidelines. results: fifty-five ( . %) of clinical isolates were staphylococcus aureus . one hundred and twenty-four ( . %) of clinical isolates were coagulase negative staphylococci (cns). none of staphylococci isolates were resistant to vancomycin. but three of cns isolates were intermediate and six of cns isolates were resistant to teicoplanin. twenty-eight ( . %) of s. aureus were resistant to oxacillin. ninety ( . %) of cns isolates were also resistant to methicillin. conclusions: nosocomial staphylococcal infections, especially in intensive care units increase day by day. staphylococcal infections are a major problem in many hospitals. according to our experiences the rate of oxacillin resistant staphylococci isolates in our hospital has also increased. methicillin-resistant staphylococcus aureus (mrsa) is a clinically significant pathogen because mrsa is resistant to many kinds of antibiotics and causes nosocomial infections around the world. the antiseptics are used for prevention of infections by mrsa. antisepticresistant mrsa strains have been isolated from clinical specimens. antiseptic resistance genes confer resistance to many kinds of drugs structurally and the resistance mechanism is the energy-dependent drug efflux system. in addition, the fluoroquinolone (fq)-resistance gene, nora , confers also resistance to many kinds of antiseptics. we studied the relation of the susceptibility to antiseptics and fqs of mrsa strains isolated in japan. a total of strains of mrsa were isolated from hospitals in japan from to . acriflavin (af), acrinol, benzethonium chloride, benzalkonium chloride and chlorhexidine digluconate were used as the antiseptics. norfloxacin and sparfloxacin were also used in this experiment. the mic was determined by agar double-dilution method as recommended by the nccls. about % of mrsa showed resistance to af (mic: !/ ug/ml). no strain was resistant to a specific antiseptic. fq-susceptible strains were susceptible to all antiseptics. this study showed that antiseptic-resistant mrsa are widely spread at hospitals in japan. the drug of choice in treatment of serious infections caused by mrsa was still vancomycin, however sometimes failures were observed, especially in monotherapy. some conflicting are present in literature about an effect of combined action of vancomycin and betalactams. in the present work, the common effect of vancomycin and methicillin against chosen staphylococcus aureus strains was examined. the investigated strains were characterized as visa, h-visa and clones obtained from h-visa in population analysis. two methods were performed: e -tests with methicillin and vancomycin placed on the media supplemented with the second antibiotic and the chessboard micro-analysis with increasing concentrations of both antibiotics. the fic indexes were calculated for different combinations of concentrations. on the basis of the fic indexes it was shown that the simultaneous action of vancomycin and methicillin was synergistic in all examined strains visa and h-visa, but only in appropriate concentrations. in different combinations the observed effect was addition or indifference. antagonism was never observed. the synergistic effect was not observed in the case of standard s. aureus strain sensitive to methicillin. supplementation of media with % of nacl substantially decreased the observed effect. incidence of antibiotic resistance in staphylococcus aureus strains in hungary with special reference to mrsa pm ghidán Á , maró di c, csukás z, kamotsay k, szabó d, ostorházi e, rozgonyi f. institute of medical microbiology, semmelweis university, budapest, hungary between january and december , a total of staphylococcus aureus strains isolated from patients admitted to the clinics of the semmelweis university were examined for antibiotic sensitivity with the disc diffusion test. resistance to individual antimicrobials were as follows: penicillin %, oxacillin %, erythromycin %, ciprofloxacin %, amikacin %, netilmicin %, tobramycin %, gentamicin %, clindamycin %, mupirocin %, tetracyclines %, chloramphenicol %, teicoplanin % and vancomycin %. all mrsa were b-lactamase producer. they showed coresistance to erythromycin ( %), ciproflxacin ( %), amikacin ( %), netilmicin ( %) and mupirocin ( %). multiple resistant mrsa strains to mupirocin'/tetracyclines'/chloramphenicol amounted to . %. triple resistance to oxacillin'/ciprofloxacin'/netilmicin was %. the detection of meca gene by pcr in randomly chosen mrsa qualified with mg oxacillin disc resulted in only % meca positivity indicating that the traditional disc diffusion test overestimates the frequency of mrsa strains particularly in such an environment where the usage of penicillins and cephalosporins is so liberal as in hungary. consequently, the selective pressure for blactam-resistance and b-lactamase induction exists everywhere. this conclusion is coherent with the relatively low frequency of multiple resistant mrsa strains and urge the need of a routinely available genetic method to apply for mrsa detection. objectives: the main objectives of this study were to monitor antibiotic resistance, identify new/emerging resistance mechanisms at an early stage, prevent their dissemination, early detection and prevent the outbreaks. methods: our laboratory used antibiotic disc sensitivity testing methodology (nccls ) . zone sizes were measured objectively using a biomic automated radius zone reader. results: throughout years (january till december ) we have surveyed organisms collected from outpatient departments ( , . %), radio-oncology department ( , . %), medical department ( , . %), obg department ( , . %), surgical-oncology non icu department ( , . %), icu department ( , . %). from ( %) strains of enterobacteriaceae ( . %) were resistant to th generation fluoroquinolone and ( . %) strains were esbl positive. from ( %) strains of staphylococcus aureus were only five ( . %) strains resistant to methicilin (mrsa). we collected ( %) strains of enterococci, whereabout only two ( . %) were resistant to glycopeptides (vre). from ( %) strains of pesudomonas aeruginosa , ( . %) were resistant to aminoglycosides. conclusions: national restrictive antibiotic policy hand in hand with local hospital antibiotic policy and regular rotation of antibiotics used in prevention and treatment on all departments is leading in our case in positive situation in antibiotic resistance in comparing with other slovakian and european centers. antimicrobial resistance of nosocomial strains of staphylococcus aureus pm dekhnich av, stratchounski ls, edelstain ia, narezkina ad. institute of antimicrobial chemotherapy, smolensk, russian federation purpose: to determine the antimicrobial resistance of staphylococcus aureus causing nosocomial infections in smolensk regional hospital. results: a total of s. aureus strains isolated during Á/ were studied. antimicrobials tested included oxacillin (oxa), erythromycin (ery), clindamycin (cli), gentamicin (gen), vancomycin (van), linezolid (lnz), tetracycline (tet), chloramphenicol (chl), rifampicin (rif), fusidic acid (fus), trimethoprim/sulfamethoxazole (ts), ciprofloxacin (cip), mupirocin (mup), quinupristin/dalfopristin (qd). susceptibility testing and its interpretation were performed by agar dilution according to nccls guidelines where applicable. results are presented in the conclusions: the most active antimicrobials were vancomycin, linezolid, quinupristin/dalfopristin, fusidic acid, mupirocin, followed by co-trimoxazole, rifampicin. beta-lactams, macrolides, lincosamydes, tetracyclines and chloramphenicol should not be used for the treatment of nosocomial s. aureus infections. we investigated all staphylococcal infections within years among neonates hospitalized for infection in the neonatal icu in a tertiary neonatal referral center. univariate analysis, to assess risk factors for neonates infected with staphylococcus aureus ( ) vs. without s. aureus ( ) was performed. from the total number of cases, in cases s. aureus was isolated from various samples; in cases from blood cultures, in cases from urine, in cases from eye swabs and in cases from gastric content (no significant differences in comparison with control group). colonization with s. aureus , was a predictor of infection: nasal swabs, throat swabs, ear swabs, skin swabs and umbilical swabs were significantly more commonly observed in neonates infected with s. aureus , than with other infections. etiological analysis showed that co-pathogens escherichia coli and viridans streptococci were significantly more frequently associated with neonatal infection caused by s. aureus , in comparison to other organisms. according to localization of infection site, conjunctivitis and thrush stomatitis was the commonest s. aureus neonatal infections. outcome was similar to other infections and without any significant differences between both groups. mortality was similar to other infections, probably because: initial therapy in our centre contains an antistaphylococcaly active agent (cefuroxime or cefotaxime plus aminoglycosides). morozova ot, semina na. laboratory of hospital infections, central research institute of epidemiology, moscow, russian federation purpose is to study the role of enterococcus spp. in the aetiology of nosocomial infections among the patients of the childrens clinical hospital and susceptibility of these strains to antibiotics. methods: the strains of enterococci were isolated from patients with hospital infections in Á/ . results: the aetiological structure of enterococcus -infections showed the predominance of skin and soft tissue infections ( . %), urinary tract infections ( . %), bloodstream infection ( . %), pneumoniae ( . %), infection of central nervous system, gastrointestinal tract, eye, surgical wound infections were of rare incidence ( Á/ . %). various nosological forms of infections were caused more often by e. faecalis than e. faecium ( . , . %). the antibiotic resistance to ampicillin and other beta-lactams occured in % of e. faecium isolates, but all strains of e. faecalis were susceptible to these drugs. high-level gentamicin resistance demonstrated e. faecalis isolates */ . %, e. faecium */ %; and high-level streptomycin resistance showed e. faecalis */ . %, e. faecium */ . %. all the e. faecalis were active against fluoroquinolones, but e. faecium were resistant in . %. there were no vancomycin resistant enterococci. conclusion: e. faecalis predominated in the aetiological structure of nosocomial infections due to enterococcus spp. antibiotic resistance patterns for two species of enterococci were different, all the strans were susceptible to vancomycin. evaluation of antimicrobial resistance of enterococcus spp. experience of years ( Á/ ) pm lopez-barba j, jesus de la calle i, solino-ocañ a i, rodríguez-iglesias m, perez-ramos s. microbiology laboratory, puerto real university hospital, cádiz, spain objective: determination of quantitative changes in antimicrobial resistance of enterococcus isolated from clinically significant not urinary samples of patients remitted to the laboratory of microbiology during a years period ( Á/ ) . material: the period of the study was comprised between and . the samples has been processed for the isolation of enterococcus following conventional methods. were isolated enterococci strains. the identification and susceptibility to antibiotics have been performed in automated system microscan(c) dade-behring(c) through panels combo cgp. the data were processed by the statistical system statgraphics plus . . results: of the enterococcus , have been identified e. faecalis and e. faecium . the resistance is shown in table . conclusions: the resistance to va and tei of e. faecalis remains through last years ( Á/ %). the high resistance to erythromycin and tetracilin ( !/ %) and the resistance ( Á/ %) to quinolones, antibiotics all of them used in community-acquired infections justify the susceptibility testing to the clinical strains isolated of this group of microorganism. in e. faecium the antimicrobial resistances was high and increasingly to imipenem, meropenem, erythromycin and quinolones. characteristics of strains e. faecium colonizing the neutropenic patients pm abbassi ms, achour w, gréco a, ben hassen a. laboratory of bone marrow transplant center, tunis, tunisia digestive colonization by enterococcus faecium in the neutropenic patients under gut decontamination is important. seventeen multiresistant strains of e. faecium isolated from stools of seven neutropenic patients were the target of an epidemiological analysis through the determination of the mics of amoxicillin, gentamicin, vancomycin, the transferability gentamicin resistance to the recipient strain e. faecalis jh - by filter-mating assay, analysis of plasmid profiles of e. faecium -strain and of transconjugants and the amplification by pcr of the gene aac( ?)-aph( ??) coding for the bifunctional enzyme by using primer m who gives a fragment of kb. among the seventeen strains, eleven had the same antibiotype a , had a gentamicin mic!/ mg/l. the mic of the amoxicillin was of mg/l. all the strains were sensitive to vancomycin. ten strains harbored a plasmid of kb transfered at a frequency of . Á/ , also found in gentamicin-resistant transconjugants. however, strains belong to nine distinguished plasmids profiles. all high-level gentamicin resistant-strains had a positive pcr amplification of the aac ( ?)-aph ( ƒ) gene. the features of the studied strains establish their endogen origin, specific for every patient, sharing only high-level resistance to gentamicin. gut decontamination treatment with gentamicin enhance either the spread and the preservation of easy-transferable plasmid carrying genetic transposable element. frequency and antibiotic resistance of bacteria isolated from patients suffering infectious complications following the implantation of prosthetic devices pm kristó f k, rozgonyi f. institute of medical microbiology, semmelweis university, budapest, hungary for patients with indwelling joint prosthesis, early recognition and prompt therapy for infection in any location may be critical to reduce the risk of seeding the joint implant heamatogenously. a year period ( ) a total of swabs of aspiration from patients with infectious complications following the implantation of prosthetic devices were cultured. cultivation and identification of the strains were performed by conventional methods and by vitek system (biomȇrieux) and susceptibility testing by disc diffusion. potentional pathogens were recovered in cases ( . %). gram positive cocci, in particular staphylococcus spp. proved to be the most commonly isolated bacteria. coagulase-negative staphylococcus (cns) was isolated more frequently ( %), followed by s. aureus ( %), enterococcus faecalis and e. faecium ( %), gram-negatives ( %), anaerob isolates ( . %). resistance to individual antimicrobials of s. aureus and cns were as follows: methicillin and %, clindamycin . and . %, fluoroquinolones and %. mupirocin resistant strains of s. aureus were not found, while . % were among the cns strains. our results could be essential for the rational selection of treatment at our orthopedic wards. results: in the analysed period the percentage of isolated enterococcus sp. strains among all non-repetitive clinical isolates in , and was . , . and %, respectively. cultured strains were identified as e. faecalis, e. faecium, e. gallinarum and e. avium . the most prevalent was e. faecium strains, isolated with a frequency of , and %, respectively. vancomycin-resistant strains were all identified as e. faecium and in they comprised % of all isolates of this species. conclusions: ( ) the frequency of isolation of enterococcus sp. in blood cultures of haematological patients remained relatively stable in Á/ . ( ) the predominant enterococcal species isolated from these patients was e. faecium . ( ) in we recorded for the first time an emergence of vancomycin-resistant e. faecium , which comprised % of all isolates of this species. kalai s, ben hassen a, achour w, greco a. laboratory of microbiology, national bone marrow transplantation center, tunis, tunisia from april to june , non-repeated strains of pseudomonas aeruginosa were isolated from immunocompromised patients. thirty-six percent of strains were isolated from abscess, % from blood culture and % from urine. susceptibility to antibiotic was studied by the routine disk diffusion method (ca-sfm). mics were determined using agar dilution to antibiotics ( b-lactams, four aminosides and two fluoroquinolones). serotyping of the different trains was performed using antisera to the international antigenic typing systems serotypes. the study showed % of resistance to c cochin port royal hospital, service de gynecologie-obstetrique site st vincent-de-paul, paris, france , d cochin port royal hospital, cclin, paris, france aims: to determinate risk markers of an outbreak of postpartum endometritis due to group a streptococcus . design: a case-control study using data collected with a structured form. setting: the cases of postpartum endometritis were diagnosed in the department of obstetric of the paris hospital network during days (december Á/january ). the group of controls consisted of women delivered in the same department during the same period. participants: cases (n / ) and controls (n / ). findings: cases had smoked more often during pregnancy ( vs. %; p / . ) and received more often immunosuppressive treatment than controls ( vs. %; p / . ). instrumental delivery has been needed more often for cases than controls ( vs. %; p / . ). cases had been hospitalized after delivery in a ward z of the department more often than controls ( vs. %; p / . ). they had been examined after delivery more often by a midwife x ( vs. %; p / . ) and a nurse y has provided care to cases and not to controls ( vs. %; p / . ). conclusion: smoking, receiving immunosuppressive treatment during pregnancy, and instrumental delivery were significantly associated with postpartum endometritis (pb/ %). a midwife and a nurse might be involved in the transmission of the infection. petoukhova i a , sokolova e a , dmitrieva n a , nummaev b b . a laboratory microbiology, cancer research center of russia, moscow, russian federation , b department of oncogynecology, cancer research centre, moscow, russian federation the aim of the study was to assess efficacy of perioperative ap. total pts were included. two hundred and one pts with cervical cancer (cc) undergone extensive hysterectomy, pts with cancer of vulva (cv)-extensive vulvoectomy, pts with ovarian cancer (oc) Á/ extensive/combined operations. fifty-one pts (group ) received ap with amoxicillin/clavulanate (am/cl) . g iv min prior to operation, then . g iv thrice per day for Á/ days. fifty pts (group ) received cefotaxime (ctx) g iv min prior to operation, then g four times per day for Á/ days'/metronidazole (mtz) mg two times per day for the same period. one hundred and forty pts were retrospective control (they received ii Á/iii generation cephalosporins or linkosamides only after operation). the rate of swi in pts with cc, cv and oc was . , , %, respectively; dwi */ . , and %, respectively; uti */ , , . %, respectively. the ap with am/cl was more effective compared to ctx'/mtz (swi */ vs %, respectively, pb/ . , dwi */ . vs %, respectively, p b/ . ). the rate of postoperative uti was equivalent in two groups ( vs %, p /n.s.). thus, ap with am/cl is preferrable option in extensive operations in og pts. fifty-eight patients were randomized into two groups. group , a treatment consisting of patients and group , consisting of patients as a control. the patients were at the age of / . and had had different surgical interventions with general anaesthesia from to h and accompanying copd ( %). artificial pulmonary ventilation was used in cases. in the early post-surgery period the patients of group were administered inhalation therapy, including ipratopium of bromide in the combination with fenoterol (atrovent, berodual) and ambrocsol (lazolvan) through a nebulizer. the inhalation therapy was not administered to the patients of group . under the influence of the inhalation therapy pulmonary ventilation and respiratory metabolism was restored faster in all the resuscitation patients (in group */by the end of the first h, in group */on the rd Á/ th day). the percent rate of pef was . '/ . and . '/ . , respectively. artificial pulmonary ventilation ended in . and . h, respectively. the time of the patients' stay in the resuscitation department was . days in group and . days in group . by the end of the st week pneumonia developed in one patient from group and in eight patients in group . aerosol therapy application accelerates medication delivery to the respiratory tracts, increases the local activity and effects good prophylaxis for surgical hospital pneumonia. variation in ethiology of early and late onset ventilator associated pneumonia pm nikolopoulos j, daganou m, michailidou m, karabela e, kavada k, retsou s, antoniadou a, rasidakis a. department of respiratory abstracts s failure and icu, sotiria general and chest disease hospital, athens, greece purpose: to compare the distribution of causative microorganisms, their susceptibility to antibiotics and outcome of 'early' and 'late' vap in a greek icu. methods and results: retrospective study of mechanical ventilated (mv) patients (pts) with early and late vaps during a -month period. diagnosis of vap was made by clinical, radiographic criteria and quantitative cultures of bronchial secretions. vap was diagnosed in pts ( %) out of consecutive admissions in icu. all pts before the development of vap received antibiotics. three episodes of vap ( . %) were developed before the th day of mv (early vap) and were caused: ( ) by multi-resistant acinetobacter; and ( ) by antibiotic-susceptible pseudomonas aeroginosa . in this group one pt died from septic shock related to vap and two pts survived. fourteen pts ( . %) developed vap after the th day of mv (late vap). five cases were caused by multi-resistant p. aeroginosa , two cases by mrsa, two cases by multi-resistant acinetobacter, two cases by susceptible to antibiotics klebsiella pneumoniae , and three were polymicrobial and caused by multi-resistant microorganisms (mrsa and gnb). four pts died ( . %) from septic shock related to vap, five pts ( %) died because of another cause and five pts ( %) survived. conclusions: early and late onset episodes of vap were caused by 'potentially drug-resistant bacteria'. p. aeroginosa as a cause of early vap was susceptible. mortality attributed to early and late vap was similar. antibiotic prophylaxis in oncological and major reconstructive orthopaedic surgery pm de biase p, ciampalini l, astone a, capanna r. azienda ospedaliera careggi, oncological and reconstructive centre, aoc, florence, italy during last year patients scheduled for oncological surgery or major reconstructive procedures were randomised to either vancomycin or teicoplanin prophylaxis. prophylaxis was performed with either vancomycin g i.v. twice daily or teicoplanin once daily i.v. two hundred patients were included. four patients did not agree the study protocol and were excluded. we treated patients with teicoplanin and patients with vancomycin. out of the patients were operated for oncological disease, while the remaining underwent major orthopaedic procedures. we experienced cases of red man syndrome, and five cases of moderate hypotension. five patients had postoperative complications: two deep venous thrombosis, one pulmonary embolism, two postoperative haematoma. in five patients we observed a wound dehiscence; two of these patients showed clinical sign of ssi and microbiological examinations were positive for mrsa. one patient recovered from infection with medical therapy, while the other patient showed a local tumour recurrence and was amputated at the thigh. at last surgery infection was still present clinical and at microbiological examination. in conclusion we had an infection rate of . % which is comparable to the infection rate of a 'clean' surgery in patients with normal risk of infection. teicoplanin showed lower toxicity, has a longer half-life and has a simpler way of infusion and it is our current choice in high risk surgery. injuries with contaminated sharp articles in health care workers in general hospital celje, slovenia pm lesnicar g, sibanc b. department of infectious diseases, medical center celje, celje, slovenia in a prospective study carried out from january till june , we registered subcutaneous injuries with sharp objects, mostly in nurses and cleaning service workers. in % of cases the incident occurred outside the hospital, in persons who were not medical workers. in cases the injury causing object was a needle that had been used in known patients, of which were hepatitis b positive. fifty-five ( . %) of the injured health workers had been previously vaccinated against hepatitis b; the protective antibodies to hepatitis b in the blood were found in / ( . %) health workers only, while the tests for antibodies to hepatitis c and hiv were negative in all cases. following the incident, the majority of the injured persons, i.e. , were vaccinated against hepatitis b, while persons ( . %) also received passive prophylaxis with human immunoglobulin against hepatitis b. none of the injured persons have developed the disease or showed evidence of sero-conversion. in the year the general as well as specific preventive measures practised in our hospital became more rigorous. thus, approximately % of our health workers at risk have already been vaccinated against hepatitis b. to improve measures preventing dissemination of multidrug-resistant bacteria (mrb), a cross-sectional survey ( ) was conducted to analyse healthcare workers' (hcws) isolation precaution knowledge for mrb infection at investigation and outpatient departments excluding four declaring not to be involved in care to mrb patients (emergency, obstetrics, nuclear medicine, and bacteriology). two hundred and eight hcws answered ( % of the paramedical staff, % of the physicians). thirty-three percent of them reported they do not know frequently or always the patient mrb status. they ( %) wish mrb status to be mentioned on the test form or on the advice request letter. mrb patient visit or test was appropriately timed in % answers. gowns ( %) or masks ( %) use were not systematically reported. other hcws ( %) reported better isolation precaution knowledge than physicians ( %) and nurses ( %) than investigation assistants ( %). physicians declared lower compliance with use of gowns, gloves or draw-sheets than other hcws. they had also lower education in isolation precautions and were less interested in education programs. this study suggests the necessity to improve mbr infection information. physicians and investigation assistants seem to be insufficiently aware of hospital infection control. therefore, education strategies targeted at physicians and investigation assistants working at outpatient and investigation departments should be developed. outbreak of clostridium difficile -associated diarrhoea in infectious disease department: risk factors and hygiene measures assessment pm henoun loukili n, martin m, remy v, hansmann y, christmann d. hôpitaux universitaires de strasbourg, maladies infectieuses et tropicales, strasbourg, france (shock)'/ * (bedridden status)'/ * (age !/ years)'/ * (previous antibiotic treatment) and points (women) / * (shock)'/ * (bedridden status)'/ * (age !/ years)'/ * (immunosuppression). the vast majority of patients ( and % of males and females, respectively) could be classified in the subgroups with lower scores (six points or less) which had a very limited risk of death ( Á/ . and Á/ . % for men and women, respectively), whereas for patients in the highest score subgroup ( points or more), the risk was % for men and % for women. conclusion: risk stratification of patients with ap is possible from simple clinical variables available on admission. procalcitonin (pct) and c-reactive protein (crp) for differentiation of systemic inflammatory response syndrome (sirs), sepsis and severe sepsis pm lupse m a , ursu l b , slavcovici a a , carstina d a . a clinical department, teaching hospital of infectious diseases, cluj-napoca, romania , b laboratory department, teaching hospital of infectious diseases, cluj-napoca, romania objectives: to evaluate the value of pct in the differentiation of patients with sirs, sepsis, severe sepsis and bacteremia in comparison to crp. design: prospective study including patients who meet criteria for sirs, sepsis or severe sepsis (consensus conference of the accp/ sccm) admitted over -month period. patients and method: a total of patients were included: eight with sirs, with sepsis and with severe sepsis. sixteen from patients had bacteremia. pct and crp were evaluated in the first h after admission: pct by brahms pct-q test and crp by turbidimetric assay. the sensitivity, specificity, predictive value of different cutoff points for crp and pct were determined. results: with a cut off point of . ng/ml for pct and . mg/dl for crp sensitivity and specificity for sepsis were %, respectively % (ppv . , npv . ) and %, respectively % (ppv . , npv ). a cutoff point of ng/ml for pct accurately predict severe sepsis (sensitivity %, specificity %, ppv ). a pct level of at least ng/ml was a good predictor for bacteremia (sensitivity %, specificity %, ppv . and npv ). conclusion: pct is a good discriminating marker to characterize the level of inflammation caused by infection and can predict bacteremia . giamarellou h a , aoun a b , klastersky j b , anagnostopoulos n c , galani l c , grecka p c , panaretou e c , papageorgiou e c , repoussis p c , syrseloudis pct has been considered as a useful diagnostic marker in neutropenic patients with bacteremia and/or severe sepsis (giamarellos-bourboulis ej et al. clin infect dis ; : ) . in an attempt to define its value in the diagnosis of localized infections in neutropenic hosts, daily determinations of pct and of c-reactive protein (crp) were performed before and after the onset of fever in subjects male and female aged . / . years with various haematologic malignancies (aml , nhl , mds , all ) developing neutropenia ( b/ pmns/mm ) after chemotherapy. thirty-three patients were presented with fever of unknown origin (fuo) and with localized bacterial infections (lbi; pneumonia , acute pyelonephritis , soft tissue infections , acute pharyngitis ). pct was determined by an immunoluminometric assay and crp by nephelometry. it is concluded that febrile neutropenia followed by a localized bacterial infections is accompanied by significantly higher levels of pct than in case of fuo ( . / . vs . / . ng/ml). similar differences are not observed with crp, which lacks the appropriate specificity. our study included patients who were categorized as having proven ( ), probable ( ), or possible ( ) systemic fungosis according to eortc criteria; showed no sign of infection, and were used as controls. blood samples were received on the st, rd, and th day from the onset of signs of a fungal infection, and then twice a week. pct levels were determined by an immunochemioluminent assay, and candida and aspergillus antigen levels by elisa. in only five patients pct indicated early signs of infection, albeit at barely detectable limits. six patients, however, showed significantly increasing titres preceding time of death. positive antigens titres were observed only in patients who had proven or probable systemic fungosis. only half of the control group had negative antigen titres; a high rate of false negatives was also observed. both pct and antigens titres increased in parallel in / patients with unfavorable outcome. pct and antigens titres cannot reliably indicate early diagnosis of systemic fungal infections although may be used as a prognostic tool of severity. lactulose, a factor that decreases endotoxaemia, in obstructive jaundice? pm koutelidakis im a , papaziogas v a , makris i a , giamarellos-bourboulis ej b , giamarellou h b , papaziogas t a . a thessaloniki med school, nd surgical clinic, thessaloniki, greece , b th department internal medicine, athens medical school, athens, greece bacterial translocation is a process implicated in the pathogenesis of spontaneous peritonitis. in order to evaluate the impact of lactulose administration on systemic endotoxaemia, obstructive jaundice was induced in rabbits by common bile duct ligation. animals were divided into two groups, group a of five rabbits not receiving lactulose and group b of six rabbits, which received . ml/kg of lactulose orally by an oral catheter. blood was collected daily, before and after operation for a total duration of four days. samples were applied for culture and for determination of endotoxins (lps) by the lal qcl- assay. concentrations of lps (mean /sd) of group a were . / . , . / . , . / . and . / . eu/ml on the st, nd, rd and th day, respectively. respective concentrations of lps (mean /sd) of group b were . / . , . / . , . / . and . / . . all blood cultures were sterile in both groups. differences activity of linezolid against nosocomial strains of staphylococcus aureus in russia: results of multicentre study pm were included in the study. antimicrobial susceptibility testing was performed by agar dilution method in accordance with the nccls recommendations. all tested strains including mrsa strains ( . % of all strains) were found to be susceptible to linezolid with the mic ranged from . to mg/l. both mic and mic were mg/l. conclusions: linezolid had excellent in vitro activity that was not affected by resistance to other classes of antimicrobials susceptibility to antiseptics of mrsa isolated in japan during Á % to piperacillin, % to ceftazidime, % to cefepime, % to imipenem, % to amikacin and % to ciprofloxacin. fiftythree percent of p. aeruginosa strains were multiresistant ( strains) and were isolated in patients. wild phenotype to b-lactams was observed in % of strains. the most frequent b-lactams resistance phenotypes were: cephalosporinase over production ( %) and penicillinase ( %). imipenem, ceftazidime and piperacillin-tazobactam were the most active b-lactams (mic of . and mg/l, respectively) these results showed high rates of antibiotic resistance and predominance of o serotype in multiresistant strains compared to the o serotype in europe. infectious complications sustained by stenotrophomonas (xanthomonas ) maltophilia in hiv at present, very limited informations are available about s. maltophilia infections in the setting of hiv disease. patients and methods: a retrospective survey of clinical and microbiological records of hiv-infected patients referring to out tertiary care centre between and was performed, in order to identify all episodes of s. maltophilia infections, and analyze its epidemiological, clinical, and microbiological variables. results: sixty-one episodes of s. maltophilia infection were observed in patients: sepsis/bacteraemia in cases ( . %), lower airways infection in five, urinary tract infection in four, pharyngitis in two, lymphadenitis and liver abscess in one case each. forty-seven out of episodes of s. maltophilia infections ( %) occurred as nosocomial disease, generally in association with advanced immunodeficiency, neutropenia, instrumentation, and prior antimicrobial therapy. bacterial isolates showed an elevated resistance profile against many betalactam compounds, aztreonam, imipenem, and aminoglycosides. conclusion: s. maltophilia represents an emerging opportunistic pathogen in hiv-infected patients extended spectrum beta-lactamases producing germs in intensive care units pm university of medicine and pharmacy 'victor babes ', microbiology, timisoara, romania injury and complications lasted months, demanded for surgical procedures and total cost was comparison of different methods for detection of extended spectrum beta lactamases (esbls) and their genetic relatedness among enterobacteriaceae clinical isolates in a research medical institute pm methods: one hundred out of isolates that were screened positive for esbls were tested with double disk synergy test (ddst), three dimensional test (tdt), e -test-esbl and vitek-esbl test. pulsed field gel electrophoresis (pfge) analysis was applied to esbls; five klebsiella pneumoniae and eight escherichia coli . results: revealed the prevalence of esbls in . % of clinical isolates. the sensitivities of the ddst, tdt, e -test and vitek were , , . and . %, respectively. in the ddst, aztreonam was the most sensitive indicator ( . %). pfge demonstrated that % of k. pneumoniae were derived from a single clone whereas . % of e. coli isolates were derived from two different clones. non-clonal origin was demonstrated in % of k. pneumoniae and . % of e. coli . conclusion: there is an increased prevalence of esbls. the ddst is the most sensitive, practical and cost effective diagnostic method reliable for routine use in our laboratory. both clonal spread and plasmid dissemination contributed to the concurrent nosocomial outbreaks caused by esbl-producing k severe nosocomial infections due to stenotrophomonas maltophilia pm the teaching hospital of infectious diseases total og pts after extensive hysterectomy ( pts), extensive vulvoectomy ( pts) and extensive/combined operations for ovarian cancer ( pts) were analysed. ic developed in pts. one hundred and sixtyseven pts had no ic. twenty-eight of rf analysed were independent rf of ic. most important included: age !/ years (p / . ), grade Á/ obesity (p / . ), diabetes mellitus (p / . ), diagnosis of cervical cancer (p / . ), history of pre-cancer of vulva postpartum endometritis due to group a streptococcus : a case-control study pm unite operationnelle d 'hygiene all isolates were sensitive to vancomycin. among gram-negative bacteria klebsiella spp. was isolated in . % of cases, acinetobacter baumanii in . %, enterobacter spp. in . %, providencia spp. in . %. of the klebsiella spp. isolates % were resistant to amikacin, % to cephalosporins, % to piperacillin/ tazobactam. all were sensitive to imipenem. of the a. baumanii isolates % were resistant to amikacin, aztreonam, cefoperazone, cefotaxime, ceftriaxone, piperacillin; % to ampicillin-sulbactam, % to ceftazidime, and % sensitivity to imipenem antimicrobial activity of selected pharmacopoeial antiseptics analysed according to european standards pm european committee for standardisation approved several european standards (en), describing test methods establishing, whether an antiseptic has or does not have a bactericidal or fungicidal activity under the laboratory conditions defined by en. the aim of the study was to investigate, if some chemical compounds in concentrations recommended by polish pharmacopoeia for skin disinfection, comply european standards requirements. methods: basic bactericidal (en ) and fungicidal (en ) activity were investigated as well as bactericidal activity of products for hygienic and surgical handrub and hand wash used in human medicine (pren ). all methods and used neutralizers were validated. standard strains: staphylococcus aureus , pseudomonas aeruginosa , escherichia coli , e. hirae , candida albicans and a. niger were used, when en standards were evaluated. results: ethanol, izopropanol and n -propanol caused viable microbial count reduction required by ens in pharmacopoeial concentrations the purpose of the study: we collected bacteriological samples from adult and neonate patients who were admitted in intensive care units (icu) . the aim was to observe the colonization status with microbes that may have a nosocomial potential and to establish circulating phenotypes in icus. the results obtained from a total of samples strains of gram negative bacteria (enterobacteriaceae family) were isolated. fourteen strains showed extended spectrum beta-lactamases (esbl) phenotype (eight strains of klebsiella pneumoniae , three of escherichia coli , two of klebsiella ornithynolitica , one of klebsiella oxytoca ). we used both disc diffusion test (extended antibiotic susceptibility test and synergy test to visualize 'champagne stopper' pattern) and mini api † system.the conclusion reached: we put in evidence a massive colonization with germs that may have a nosocomial potential especially microbes that produce esbl ( . % from all enterobacteriaceae isolated) which implies a rational policy in prescribing antibiotics in hospitals from western part of romania.carbapenem activity against nosocomial gram-negative rods pm sawicka-grzelak a a , rokosz a a , meszaros j b , luczak m a . a department of medical microbiology, university medical school, warsaw, poland , b department of general and transplantation surgery, university medical school, warsaw, poland purpose: to determine a susceptibility of nosocomial gramnegative rods to carbapenems.methods: two hundred strains of gram-negative rods were cultured from clinical specimens from hospitalized patients (july Á/november ). identification of strains was performed in the automatic atb system (biomerieux, france). susceptibility of strains to carbapenems: imipenem and meropenem was determined with disc diffusion method according to nccls recommendations. esbl-producing strains were detected with double-disc synergy test (ddst according to jarlier et al., ) or a novel method of esbl detection (dd, diagnostic disc) according to appleton ( ) . two discs were applied in this test: with cefpodoxime (cpd) and with cefpodoxime/clavulanic acid (cd ) (oxoid, england) .results: one hundred and ten strains of enteric rods and strains of non-fermenting rods were cultured. twenty eight ( %) esblpositive strains were detected. carbapenems were active against % of enteric rods. the percentage of non-fermenting rods susceptible to imipenem was and to meropenem */ .conclusions: carbapenems: imipenem and meropenem demonstrated high activity against clinical strains of enteric rods. however, the antibiotics were less active against nosocomial strains of nonfermenting rods.inhaled antibiotics against multiresistant bacteria in bronchial secretions of icu patients: a preliminary report pm horianopoulou m a , kanellopoulou m b , paraskevopoulos i a , valakis k a , kyriakidis a a , lambropoulos s a . a intensive care unit, sismanoglio general hospital, athens, greece , b department of microbiology, sismanoglio general hospital, athens, greece purpose: the aim of this study was to assess the effectiveness of aerosolized ampicillin/sulbactam, ceftazidime and colistin, in icu patients with multiresistant acinetobacter baumannii or pseudomonas aeruginosa colonization of the respiratory tract.methods: fifty-three intubated, mechanically ventilated patients participated in the study. multiresistant a. baumannii , sensitive only to ampicillin/sulbactam, or p. aeruginosa , sensitive to ceftazidime or colistin, were isolated from the bronchial secretions ( Á/ cfu/ ml). all patients were subsequently treated with intravenous ampicillin/sulbactam, ceftazidime or colistin, whereas of them were also given the same antibiotic in aerosolized form.results: a decrease in the number of colonies by Á/ cfu/ml was observed, following Á/ days of combined treatment with both intravenous and inhaled antibiotic. none of the patients developed vap. in the patients who only received the antibiotic intravenously, the decrease ranged from zero to cfu/ml, after days of treatment. two of patients developed vap.conclusions: our results suggest that the administration of aerosolized antibiotics represents an effective means of preventing ventilator-associated pneumonia caused by a. baumanni and p. aeruginosa . introduction: pseudomonas aeruginosa is an important nosocomial pathogen. resistance to certain beta-lactam antimicrobial agents among p. aeruginosa is increasing. despite the development of new antibiotics multiresistant strains of p. aeruginosa represent an important therapeutic problem. the aim of this study was to investigate the activity of imipenem, amikacin, piperacillin, ciprofloxacin, ceftazidime, against clinical isolates of p. aeruginosa . methods: a total of isolates by tracheal aspiration from hospitalized patients, admitted to intensive care units were identified as p. aeruginosa using an algorithm that included: gram stain, pigment, oxidaze ('/ ,) and gram negative identifications microscan walkaway- (dade behring) were used according to the manufactures instructions. minium inhibitory concentrations were determined using walkaway, interpretation based on ncclsm -s , january ' .results: the respiratory tract was the single site of isolation for this study. the best activity was showed by imipenem %, followed by amikacin %, piperacillin, pip/tazobactam, ciprofloxacin had the same sensitivity %.conclusion: a high level resistance to antibiotics was observed to p. aeruginosa isolated from tracheal aspiration. carbapenems seem to be the most active against p. aeruginosa in this study. materials and methods: clinical samples were collected from patients admitted to this hospital. only one isolate per patient was included. antimicrobial susceptibility testing was performed as recommended by the nccls. all bacterial isolates were tested by dd and ad to provide a comparison of both test results. very major error was considered when the strains were resistant (r) by ad and susceptible (s) by dd and major error when s by ad and r by dd. categories of s and r were stablised using the breakpoints suggested by mensura ( ) . colistin r strains was typed by rep-pcr.results: among the strains included in this study ( . %) were s to colistin and five ( . %) were colstin r by ad, of this five colistin r strains four ( . %) were s to colistin by dd and one was r by both methods. all r isolates were similar by rep-pcr.conclusions: most of the ad colistin resistant strains were s when tested by dd indicating that this method is not useful to determine the resistance to colistin. rep-pcr patterns show that the spread of a colistin r clone seems to be involved. methods: gnb were isolated from per-operative biopsies (pob) and/ or from articular punction (ap). patients (pts) received cfp, g bid'/ ofl, mg tid or cip, mg bid intravenously for days, followed by a prolonged oral fq monotherapy. cure was defined as: resolution of all clinical signs of infection, normalization of the biological inflammatory profile at the end of treatment (eot) and absence of infection at the same site during the post-treatment followup period (ptfu).results: all of the studied patients [mean age / years] had hospital acquired bji. seventeen/ had an infected orthopedic device (prosthetic joints / , other orthopedic prosthetic devices / ). culture of pob and ap yielded to pseudomonas sp. ( ), enterobacter cloacae ( ), others ( ). vancomycin was added for six pts co-infected by gnb-mrsa. nineteen/ pts underwent a surgical intervention (debridement / , removal-replacement / , amputation / ). after ptfu period of months (range Á/ ), the overall success rate was / ( . %) without serious adverse events.conclusion: cfp Á/fq combination was safe and efficient in the treatment of hypercase gnb, bji.treatment of posttraumatic mrsa osteomyelitis of the femur with longterm cotrimoxazole */a case report pm the authors report a case of posttraumatic osteomyelitis of the femur caused by methicillin-resistant staphylococcus aureus (mrsa), following the shot injury. relapses of the infection occured in months interval and were treated by revision, debridement, lavage and vancomycin. because of laboratory signs of renal insufficiency vancomycin became contraindicated for treatment of the third relapse of infection and the different approach was employed: classic open treatment of bone infection sec. orr was combined with a long-term administration of high-dose cotrimoxazole. the patient was given cotrimoxazole mg daily divided in four doses ( mg/kg/ h) for months, then for gastrointestinal complaints with lowered dose of g daily for next months. the wound completely healed. during months after the final surgery there was no relaps of infection, but the atrophic pseudoarthrosis of the femur resulted. the patient can walk with a rigid orthesis and two crutches. the whole treatment of the objective: to present a variety of severe nosocomial infections due to stenotrophomonas maltophilia in patients hospitalized in tertiary medical units from cluj.results: during the last year nine strains of s. maltophilia obtained from patients with severe infections and hospitalized in different wards were isolated. all but one were considered nosocomial infections: four cases of pneumonia, one urinary tract infection, three cases of surgical wound infections and one case of endocarditis under surgical treatment. the cases of pneumonia were either primary occurring in a granulocytopenic patient with leukemia or secondary in patients that underwent surgical treatment. in the case of endocarditis the ethiology was established after surgery from the damaged valve in a negative hemoculture patient with a poor outcome under medical treatment. in all cases of surgical wound infection bacteremia occurred diagnosed on clinical basis in the presence of severe sepsis or hematogenous dissemination in the lung. the urinary tract infection occurred in a patient after urinary surgery and having a catheter in place. the immediate evolution was favorable in all cases but treatment was difficult due to the highly resistant strains and to underling diseases.conclusions: s. maltophilia should be considered in nosocomial severe infections and prophylaxis by interrupting environmental transmission has to be promoted. sawicka-grzelak a, rokosz a, luczak m. department of medical microbiology, university medical school, warsaw, poland purpose: to identify and determine the drug-susceptibility of esblpositive strains isolated from urine samples.methods: seven hundred and twelve strains of gram-negative rods were cultured from urine samples from hospitalized patients during months (july Á/november ). identification and susceptibility were performed in the automatic atb system (biomerieux, france) using id e, id gn and atb ur strips. esbl-activity was detected with double-disc synergy test (ddst according to jarlier et al., ) or using a novel method of esbl detection (dd, diagnostic disc) according to appleton ( ) . two discs were applied in this test: with cefpodoxime (cpd) and with cefpodoxime/clavulanic acid (cd ) (oxoid, england).results: five hundred and ninety-five strains ( . %) belonging to enterobacteriaceae family, strains ( . %) of non-fermenting rods and two strains ( . %) of other gram-negative rods were isolated. eighty-two esbl-producing strains ( . % of all strains) were detected. fifty-nine esbl-positive strains were susceptible to nitrofurantoin, -to norfloxacin and ciprofloxacin and -to fosfomycin.conclusions: esbl-positive strains were detected most frequently among enteric rods ( strains). nitrofurantoin and quinolones were the most active in vitro antibacterial agents against examined esblpositive uropathogens. results: the mechanisms of resistance were evaluated phenotypically using different aminoglycosides. a total of aminoglycoside resistant gram-negative strains were studied. one hundred fifty-eight strains were collected in Á/ , in and in . the resistant profiles were determined: enterobacteriaceae */ ; pseudomonas aeruginosa */ ; acinetobacter spp. */ . the most frequently phenotypes were gt (gentamicin, tobramycin) */ % and gtnet (gentamicin, tobramycin, netilmicin) */ %. the gt phenotype due to production ant( ƒ)-i enzyme, the gtnet Á/aac( )-v ( strains), aac( )-iv */one strain and aac( ƒ)-i */one strain. the resistance to amikacin in % strains was due to production aac( ?)-i ( %) and aph( ?)-vi ( %). the most of examined strains were simultaneously resistant to kanamycin and neomycin caused by production of aph( ?)-i ( %). only seven strains were resistant to all aminoglycosides due to impermeability of outer membrane. no substantial differences were observed between years.conclusions: the main mechanism of aminoglycoside resistance is fermentative modification. the high rate to gentamicin and tobramycin was due to production of ant( ƒ)-i and aac( )-v. amikacin and isepamicin were the most active aminoglycosides against gramnegative nosocomial isolates.the incidence of clostridium difficile associated diarrhoea (cdad) increased in our department from january to june .objective: to confirm the out break of cdad, to identify the risk factors and assess the effectiveness of the measures implemented for controlling this outbreak.methods: cdc definitions were used to identify the cases. the scope of the outbreak was defined. cdad incidences during the outbreak period and during the same period in were compared. risk factors (reduced mobility, antibiotic treatments . . .) were studied for patients whom length of hospital stay (lhs) was more than days. contact precautions and environmental cleaning with clona implemented were assessed.results: seventeen episodes of cdad were identified. sex ratio: . , mean age / . , mean lhs / days, mean delay for cdad occurring / days. one hundred and fifty-two patients involved in the study of risk factors. relative risk (r.r.) evaluated were: blactams (r.r. / . , ic %: . Á/ . ), reduced mobility (r.r. / . , ic %: . Á/ . ). incidence of cdad was less than two cases per days of hospitalisation after june .conclusion: we confirmed the outbreak of cdad in our department b-lactams and reduced mobility were identified as risk factors for cdad. measures implemented to control the outbreak were effectiveness.positive heart transport fluid cultures associated with severe infections in heart transplant recipients pm at the mount sinai hospital in new york city heart transplants were performed between and june . cultures were routinely performed on all heart transplant transport fluids. culture data was available for of these patients. in total / ( . %) were positive for bacteria, fungi or both. the organisms isolated included coagulase negative staphylococci ( ), pseudomonas aeruginosa ( ), staphylococcus aureus ( ), acinetobacter baumanii ( ), serratia mercescens ( ), enterobacter cloacae ( ), escherichia coli ( ), proteus mirabilus ( ), enterococcus faecalis ( ), viridans streptococci ( ), and fungi (aspergillus fumigatus ( ), penicillium species ( ), and rhodotorula rubra ( ). two heart transplant recipients had two organisms isolated from the transport fluid. isolation of resistant gram-negative bacilli in the transport fluid was associated with significant infection in / patients ( %) with the same organism. the observed infections were pneumonia secondary to e. cloacae , sternal wound infection secondary to p. aeruginosa , and bacteremia secondary to p. aeruginosa . it appears prudent to provide prophylaxis against resistant gram negative bacilli to prevent infections. zacharof ak, flevaris c, petrogianopoulos c, karachalios g, vroulis j, chartzoulakis g, drakogiorgos g, loizidou a, svoukas g. nd department of internal medicine, hellenic red cross hospital, athens, greece objective: we studied the trends of nosocomial bloodstream infection and calculated the population-attributable risk for death among hospitalized patients. methods: we perform a -year retrospective study for all patients (n / ), admitted to our department between and .results: between and , a total of patients developed episodes of nosocomial bloodstream infection. the crude infection rates increased linearly from . to . per discharges ( . Á/ . episodes per patient-days) during the -year study period. increases in the infection rates were due to gram-positive cocci, yeasts and essentially explained by infections caused by coagulasenegative staphylococci, staphylococcus aureus , enterococci, and candida species, respectively. although the crude mortality in patients with nosocomial bloodstream infections decreased from % in to % in , the in-hospital population-attributable mortality among infected patients increased from . deaths per discharges in to . per discharges in . the etiologic fraction or the proportion of deaths in patients with bloodstream infection to all deaths occurring in the hospital increased from . % in to . % in .conclusions: the incidence and the population-attributable risk for death among patients experiencing nosocomial bloodstream infections increased progressively during the last years in our department.ventilator-associated pneumonia before and after intensive care unit temporary closure pm results: we compared the incidence, causative organisms and mortality of vap in two different time periods. period june to december . period june to december . between those two periods the icu remained closed for months because of reconstruction works.period : sixty-seven consecutive patients (pts) were studied with bronchial secretions cultures at least days after mechanical ventilation (mv) initiation. the vap was diagnosed by clinical, radiological and microbiological criteria in pts ( %). causative organisms included: pseudomonas aeruginosa , acinetobacter , staphylococcus aureus , klebsiella pneum. , enterobacter . in three cases vap was proved polymicrobial. fourteen ( ) episodes of vap ( %) were developed after days mv (late vap) and were attributed to multiresistant microorganisms. mortality of vap was %.period : among consecutive pts, vap was diagnosed in ( %). causative organisms included: acinetobacter , p. aeruginosa , s. aureus , k. pneumoniae , escherichia coli . five ( ) cases were polymicrobial and cases were 'late vap' ( %). causative microorganisms had similar patterns of sensitivity to antibiotics (compared to period one). mortality of vap was %.conclusion: temporary icu closure had no significant influence on the incidence, distribution of causative organisms, their sensitivities to antibiotics and mortality of the vap. efstathiou sp a , pefanis av a , tsioulos di a , tsiakou ag a , zacharos id a , kanavaki s b , mountokalakis td a . a third university department of medicine, sotiria general hospital, athens, greece , b microbiology laboratory, sotiria general hospital, athens, greecepurpose: the aim of this study was to derive a scoring system for the prediction of outcome in adult patients with acute pyelonephritis (ap) severe enough to need hospitalization. therefore, the charts of patients ( men, median age years) were reviewed.results: logistic regression analysis identified in both sexes four independent correlates of in-hospital mortality, the coefficients of which divided by . and rounded to the nearest interval, resulted in the following integer-based scoring system: points (men) / * between concentrations of lps of the two groups were statistically significant on the nd and the th day (p b/ . ). it is concluded that the administration of lactulose may decrease systemic endotoxaemia in the field of obstructive jaundice.nosocomial infections: a prevalence study in the island of crete pm doukakis s a , tzimis l b , perogambrakis g a , kalloniatou m a , christodoulakis n a , evaggelopoulos a a , koutsoumba d a , kastanakis s a . a first medical department, 'saint george ' general hospital, chania, greece , b pharmacy department, 'saint george ' general hospital, chania, greeceprevalence surveillance is a rapid and inexpensive mode to estimate the problem of hospital-acquired infections (hais). to study the problem of nosocomial infections in our hospital, a prevalence study was made from our team in . the study included patients (the total number of hospitalized patients at the time of the study). from these patients were males ( . %) and females ( . %). one hundred and ninety-one patients ( . %) belonged in the groups of age between and years. fifty-seven patients had a urine catheter ( . %). one hundred and fifty-five/ patients ( %) received antibiotics and from these patients received one antibiotic and the remaining patients two or more. a nosocomial infection was found in patients and consequently the prevalence of hais was . %. among these, urinary tract infections were six ( . %), lower respiratory tract infections were three ( . %), surgical site infections were three ( . %), and bloodstream infections was one ( . %). the incidence of multiresistant bacteria was primarily enterococcus spp and secondary, pseudomonas aeruginosa , enterobacter spp, klebsiella pneumoniae , escherirchia coli , staphylococcus aureus , enterobacter cloacae . unfortunately prophylactic chemotherapy of long duration was found despite the suggestions of the infection control committee. regarding age the highest incidence of hais occurred in the third age group. bagirova ns, dmitrieva n. laboratory of microbiology, cancer research center of russia, moscow, russian federation objectives: to determine the pathogens and susceptibility to antimicrobials.methods: blood samples were collected from adult pts ( Á/ ). the bacteraemic episodes were classified according to the definitions of the cdc. laboratory detection of bacteraemia and fungaemia was performed according to cumitech b (blood cultures iii, ). susceptibility testing was performed by disk diffusion method (nccls).results: the total number of blood samples */ , -positive ( . % episodes of significant bacteraemias). bsi was confirmed microbiologically in of febrile pts ( . %). the most frequent pathogens were gram('/) cocci ( . %) (p b/ . ), gram((/) bacilli */ . %, fungi */ . %. coagulase-negative staphylococci (cns) represented . %, staphylococcus aureus . %, streptococcus spp. . %, enterococcus spp. . %, enterobacteriaceae . %, pseudomonas aeruginosa . %, other non-fermenting */ . %, yeast . %, mould . %, anaerobes . %. one hundred percent cns were resistant to penicillin, . % to oxacillin, . % to clindamycin, . % to cefazolin, . % to ceftazidime, . % to ciprofloxacin, . % to gentamicin, and no isolate was resistant to vancomycin. the predominant pathogens in all types of hm were gram('/) cocci (mainly cns). all gram('/) microorganisms were sensitive to vancomycin. katashinsky o a , opriatova t b , tchuev p c . a state clinical hospital, anaesteziology, odessa, ukraine , b state clinical hospital, bacteriology, odessa, ukraine , c medical university, anaesteziology, odessa, ukrainethis investigation was carried out in odessa state clinical hospital during Á/ . of the patients with post-operation complications, % of gram-negative cultures were sensitive to ceftazidime and % to amikacin. sixty-nine percent of gram-positive cultures were resistant to penicillin g, but they were sensitive to vancomycin and nitrofurantoin in and % of cases, respectively. sixty percent of isolates of pseudomonas aeruginosa were sensitive to ceftazidime and % to amikacin. rates of resistance to carbenicillin and gentamicin were and %, respectively. one hundred and fortythree isolates of escherichia coli were studied and % of them were resistant to ampicillin % to cephalothin and % to tetracycline. of the isolates tested against ciprofloxacin, all were sensitive. one hundred and eight isolates of staphylococcus aureus were studied and they were resistant only to penicillin g ( %). staphylococcus aureus was sensitive to erythromycin ( %), tetracycline ( %), oxacillin ( %) and vancomycin ( %). all isolates enterococcus faecalis were sensitive to nitrofurantoin and % to ciprofloxacin. the majority of s. aureus and e. faecalis isolates were susceptible to most other antibiotics, but the majority of e. coli isolates were resistant to the studied antibiotics expect ciprofloxacin.campylobacter foetus bacteraemia in an immunocompromised patient: a case report pm monno r a , ierardi e b , rendina m b , ceci g a , luzzi i c , de vito d a , rizzo g a , francavilla a b . a department of internal medicine and public health, university of bari, bari, italy , b department of emergency and organ transplantation, university of bari, bari, italy , c istituto superiore di sanità, rome, italy a -year-old woman was admitted for recurrent fever. the patient underwent a liver transplantation and splenectomy in . she had followed immunosuppressive therapy until when tacrolimus was added for chronic rejection. in non-hodgkin lymphoma was diagnosed and chemotherapy was started. six months later because of the presence of two metastatic encephalic foci affecting the optic chiasm, a new chemotherapy course was started with the regression of lesions. in january she was treated with steroid recycle and cyclosporine Á/azathioprine Á/prednisone reintroduction. fever occurred after months and cytomegalovirus (cmv) infection was diagnosed. treatment with ganciclovir was started with clinical remission. in november cmv infection recurred and blood cultures were positive for a bacterium that was identified as campylobacter fetus . the patient was successfully treated with intravenous ciprofloxacin. bacteremia frequently occurs in cancer patients. bacteremia due to c. fetus are rare, occurring mainly in immunocompromised patients. c. fetus expresses a proteinaceous surface layer that confers serum resistance. in our patients steroid and immunosuppression may have contributed to the development of lymphoma. all of these factors and chemotherapy have contributed to cmv infection and all have made the patient susceptible to bacteremia with this infrequently found bacterium. the clinical microbiologist should be aware of this infection in immunocompromised host. minenko sv, dmitrieva nv, sokolova en, ptushkin vv. bone marrow transplantation department, n.n. blokhin cancer research center, moscow, russian federation c'/a is the standard regimen as empirical therapy for febrile neutropenia (fn). activity of c against g'/ bacteria and g(/ bacteria, producing chromosomally-mediated b-lactamases (e.g. ampc) is suboptimal. cep is active against a broad range of g'/ and g(/, including ampc producing bacteria. the purpose of the study was to compare the efficacy of two regimens in the treatment of fn.methods: patients with fn received either cep ( g/ h) or c ( g/ h) plus amikacin ( mg/kg/day) or netilmicin ( mg/kg/day). data were collected prospectively.results: a total of pts with episodes ( / ) of fn were included. fifteen/ in cep group and / in c'/a group. the median duration of neutropenia grade , distribution of age, sex and underlying disease were comparable in both arms. mdi was in and %, cdi in and % fuo in and % in fep and c'/a groups correspondingly. response to the initial empirical regimen according to ihs criteria was in % of cep and . % of c'/a groups (p / . ). modification of therapy with a change of cep or c to carbapenem took place in and % of cep and c'/a groups (p / . ). no patient in either treatment group died due to the presenting infection. tolerability of cep was good and no laboratory abnormalities took place. transient elevation of serum creatinin level was observed in two patients c'/a group.conclusions: cep monotherapy is as effective as c'/a combination in the treatment of patients with fever and granulocytopenia purpose of the study: retrospectively, we analysed patients with intraabdominal infection for aetiology, risk factors, and outcome from hospitals in slovak republic within year (march Á/march ). results: in this group significantly more frequent were older patients ( !/ years) with cancer ( vs. %, p b/ . ). acinetobacter spp. ( vs. %, p b/ . ) and enterobacteriaceae ( vs. %, pb/ . ) were predictive for monoinfection. pre-treated patients with other antibiotics had inferior prognosis and more risk factors: permanent urinary catheter ( vs. %, pb/ . ), ventilation or intubation ( vs. %, pb/ . ) and polymicrobial infection ( vs. %, pb/ . ). the risk factors with poor prognosis were enterobacteriaceae ( vs. %, pb/ . ), diabetes mellitus as underlying disease ( vs. %, p b/ . ) and uraemia ( vs. %, p b/ . ). surprisingly, negative prognostic factor was also non-effective previous antibiotic therapy. failed patients died significantly more frequently patients due to underlying disease. cefoperazone/sulbactam was shown to be useful, effective and well tolerated also in one group of patients with % efficacy of treatment, and it belongs to a group of antibiotics suitable for treatment of nosocomial infections.