key: cord- -mtpbzgr authors: haynes, alice; khardori, nancy title: current practices for infection prevention in the hospital settings date: - - journal: hospital infection prevention doi: . / - - - - _ sha: doc_id: cord_uid: mtpbzgr the principles and practices aimed at prevention and control of hospital-acquired infections are directed at various links in the chain of transmission. they include the following: ( ) to contain or eliminate the reservoirs of agents and/or to curtail the persistence of agents in a specific setting, ( ) to protect the host against disease caused by microorganisms, and ( ) to interrupt the transmission of infection. interventions to modify environmental reservoirs are aimed at interrupting the transmission for these inanimate environmental sources. the barriers, e.g., masks, were used to keep the smells and “contagion” away even before the germ theory of disease was conceived. the appropriate barriers now include gloves, gowns, and eye protection for blood/body fluid–borne infections and high-filtration masks for infections transmitted by droplet nuclei. the most important and effective nosocomial infection control intervention remains the routine washing of hands before, between, and after patient contact in healthcare settings. this chapter focuses on the interruption of transmission of infectious agents in the hospital setting by standard precautions recommended for all patients and “isolation” of patients using precautions based on known methods of transmission. the principles and practices aimed at prevention and control of hospital-acquired infections are directed at various links in the chain of transmission. they include the following: ( ) to contain or eliminate the reservoirs of agents and/or to curtail the persistence of agents in a specifi c setting, ( ) to protect the host against disease caused by microorganisms, and ( ) to interrupt the transmission of infection. interventions to modify environmental reservoirs are aimed at interrupting the transmission for these inanimate environmental sources. the barriers, e.g., masks, were used to keep the smells and "contagion" away even before the germ theory of disease was conceived. the appropriate barriers now include gloves, gowns, and eye protection for blood/body fl uid-borne infections and high-fi ltration masks for infections transmitted by droplet nuclei. the most important and effective nosocomial infection control intervention remains the routine washing of hands before, between, and after patient contact in healthcare settings. this chapter focuses on the interruption of transmission of infectious agents in the hospital setting by standard precautions recommended for all patients and "isolation" of patients using precautions based on known methods of transmission. historically, hospital construction before featured open wards where cross infection was common and mortality rates were high in urban hospitals [ ] . based on the observations during the crimean war, florence nightingale advocated small pavilion -type wards joined by open-air corridors [ ] . she also emphasized the importance of asepsis and a clean environment. the germ theory of disease was accepted in the us hospitals in late s leading to decrease in overcrowding and increase in antisepsis. individual and group isolation was used by "communicable disease" hospitals as early as [ ] . general hospitals began to isolate patients with communicable diseases in individual rooms with the use of separate utensils and disinfectant by the turn of the century [ ] . the theory of communicability by contact rather than airborne spread for most diseases was promoted in france [ ] . this allowed patients with communicable diseases to be housed in general wards with separation by wire screens. in addition to separating the patient from others, the barrier served as a reminder for hospital staff to wear gowns and wash hands. this is how the trend of caring for patient with communicable disease in the general hospitals rather than isolation/fever hospitals started in the united states. in the early twentieth century, it was demonstrated that fumi-gation had no effect on the secondary cases emphasizing the role of persons rather than things as spreaders of disease [ , ] . the concept of cohorting, allowing patients with communicable diseases to be housed in the same room as other patients, was fi rst applied in the providence city hospital [ ] . the barrier techniques needed for each patient were put on a card placed on the patient's bed. the development of infection control programs in the us hospitals was prompted by the emergence of staphylococcus aureus as a hospital pathogen in the late s. the fi rst edition of american hospital association's manual in presented a simple barrier precautions scheme for patients with communicable diseases and listed the need for gloves, gowns, masks, and visitor screening [ ] . the cdc, while conducting nosocomial outbreak investigations in the s, recognized the need for standardized policies for isolating hospitalized patients with communicable diseases [ ] . the fi rst cdc isolation recommendations were published in [ ] . this manual listed seven categories of isolation: strict isolation, respiratory isolation, enteric precautions, wound and skin precautions, discharge precautions, blood precautions, and protective isolation. many of the practices described in the manual are applicable to any hospitalized patient. application of poor techniques when handling uninfected patients can only result in sense of false security. updates to the cdc manual were made in and . in , substantial changes were made to the recommendations including the use of the word "guidelines." the cdc series guidelines for the prevention and control of nosocomial infections that has followed is now the state of the art in infection control practices. these guidelines have accepted and customized for medical management of bioterrorism threats [ ] . in , the centers for disease control and prevention (cdc) introduced universal precautions (up) to hospitals for the protection of healthcare personnel as a response to the emergence of hiv/aids. another initiative, body substance isolation, soon followed. the cdc recognized there was confusion created by universal precautions and body substance isolation, so in , they published new guidelines with a two-tiered method, standard precautions and transmission-based precautions. the cdc, in cooperation with the healthcare infection control practices advisory committee (hicpac), established standard precautions to address the prevention of the spread of infectious agents in healthcare settings and are the result of combining the key components from universal precautions and body substance isolation along with the understanding that all blood and body fl uids, except sweat, are potentially infectious, and inanimate objects are potentially contaminated with infectious agents, therefore are capable of being reservoirs in the chain of transmission of infectious agents [ , ] . does the term, "standard," downplay the role and signifi cance of these precautions? absolutely not, the message is that this is the expected way to prevent the spread of disease and applies to every encounter between patients and healthcare providers. standard precautions group together infection prevention practices consisting of the use of personal protective equipment (ppe), such as gowns, gloves, masks, goggles or face shields, and the performance of hand hygiene, washing hands with soap and water, especially when they are visibly soiled, or using an alcohol-based hand sanitizer. the basic premise for these practices is the need to anticipate a potential source of exposure, and take precautions by donning the appropriate barrier that will provide protection. for example, gloves should be worn when contact with blood, body fl uid, or contaminated surfaces are likely. when the risk of being splashed by a potentially infectious substance exists, a mask and eye protection should be worn. a gown may be worn to protect clothing as well. care should be taken when handling soiled linen and patient care equipment to reduce contamination of the environment with infectious agents. standard precautions have been found to be an effective means of preventing the transmission of infectious agents in all healthcare settings. the centers for disease control and prevention recommend that standard precautions be implemented for all patient encounters, whether the risk of transmitting an infectious agent is suspected or has been confi rmed; all patients are to be thought of as potentially able to transmit. another component of standard precautions is the potential contamination of items in the patient's environment and appropriate measures to reduce the risk from inanimate sources. when handling or having direct contact with patient care equipment or other items in a patient's environment that potentially have been exposed to infectious agents, gloves should be worn followed by performing hand hygiene after removing gloves. when it is not practical to dedicate equipment to individual patients, proper cleaning and disinfecting or sterilizing is recommended before use on another patient. standard precautions were originally established to protect healthcare personnel by reducing their risk of exposure to infectious agents. but in recent years, the importance of the protection of the patient has been recognized. the need for changes and reinforcement of proper infection control practices, as part of the practice of standard precautions, was identifi ed as the result of outbreak investigations. from those investigations came the recommendations for respiratory etiquette/cough etiquette, safe injection practices, and donning a mask during lumbar puncture procedures. respiratory etiquette/cough etiquette is a practice that was implemented to reduce the spread of respiratory illnesses. during the sars outbreak in , emergency departments needed a way to control transmission of the disease, and putting a mask on a patient who has symptoms of a respiratory illness such as cough, increased production of respiratory secretions, and fever at the fi rst stage of encounter in a healthcare facility has been shown to be effective. healthcare facilities are expected to have masks, tissues, a waste receptacle, and hand hygiene products available with signage to explain their use at points of entry into the facility and in waiting areas. patients should be taught to use a tissue to cover their cough or sneeze, discard the tissue in a wastebasket, and wash their hands to reduce the risk of spreading infection. the need to address injection practices was recognized in response to hepatitis b and c outbreak investigations that were caused by the use of poor technique during the administration of medications by injection. used needles reinserted into a multidose vial or bag of saline and administration of intravenous injections to multiple patients using a single needle/syringe were two of the major breaks in infection control practices that were found to have led to the outbreaks. the need to educate healthcare personnel resulted in the establishment of "the one & only campaign," meaning one needle, one syringe, and only one time use for one patient. safe injection practices dictate that used needles never be recapped, removed from disposable syringes, bent, broken or manipulated by hand, and are disposed of in punctureresistant containers to prevent sharps injuries. wearing a mask to protect the patient has become a part of performing a lumbar puncture procedure after several patients were found to have acquired meningitis following a myelogram. the expectation is that a mask will be worn whenever a catheter in placed or an injection administered into the spinal or epidural space. in addition to standard precautions, transmission-based precautions are implemented when more restrictive measures are needed to decrease the risk of the spread of infection. the precautions taken to contain the known or suspected infectious agents are determined by their mode of transmission. a patient suspected of having, known to have, or in the case of multidrug-resistant organisms, when a patient has a history of infection or colonization and there is a risk of transmission to others, the need to isolate the patient is important for the protection of others. there are three types of transmission-based precautions: contact, droplet, and airborne. contact precautions are implemented when acquisition of a pathogen can occur by touching or coming in direct contact with a patient or the articles in the patient's environment. illnesses spread by respiratory droplets are prevented from transmission by droplet precautions. these infectious agents can be spread by being expelled in respiratory secretions during coughing, sneezing, or talking, but because the particles are large, they drop to the ground within - ft of the patient and do not pose a threat for those at a greater distance. there are some respiratory illnesses that require airborne precautions. airborne precautions require a room with special air handling capability. negative pressure is established in the room, so that the particles, known to remain fl oating in the air for extended periods of time, can be ventilated to the outside or forced through an hepa fi ltration system before the air is returned to circulate in the facility. contact precautions require that a gown and gloves be worn to protect the healthcare worker while performing patient care activities. it is recommended that the gown and gloves be put on prior to entering the room. this combination of ppe can also impact the safety of other patients that are being cared for by the same healthcare worker and may potentially be exposed to pathogens that can be transported to them on the caregiver's clothing. hand hygiene is a key component of contact precautions. hands should be washed with soap and water, or an alcohol-based hand sanitizer product used, prior to putting ppe on and after removing it. examples of illnesses requiring contact precautions • when patient is known or suspected to have an illness transmitted by direct contact with the patient or by contact with articles in the patient's environment all multidrug-resistant organisms gastrointestinal, respiratory, skin, or wound infections or colonization with multidrugresistant bacteria judged by the infection control program, based on current state, regional, or national recommendations, to be of special clinical and epidemiologic signifi cance special contact precautions may be necessary for patients infected with a spore-forming organism. clostridium diffi cile infection (cdi), norovirus, or any organism that is resistant to the usual hospital cleaners and disinfectants require different means to reduce the risk of transmission of disease. • hand washing with soap and water before and after contact with the patient, scrubbing to create slight friction to mechanically mobilize any organism that may be on the hands, and rinsing well to fl ush the organism off the skin. • meticulous cleaning of room with an epaapproved, hospital grade cleaner, followed by disinfecting with a : bleach solution, especially frequently touched surfaces. • use dedicated or disposable equipment. droplet precautions should be implemented when caring for a patient with a respiratory infection or when there is risk of exposure to respiratory secretions or contact with mucous membranes. placing the patient in a private room is preferred, but when a single-patient room is not available, an assessment of risk to other patients should be done before placing an infectious patient with others. if it is necessary to place multiple patients in the same room, separating them by three or more feet and having a privacy curtain drawn between them is important. teaching patients to practice respiratory etiquette can also help reduce the transmission of infectious agents. • hand hygiene. • private room preferred, but not required; patients with the same disease can be placed in the same room. • surgical/procedural mask is worn by care providers and put on before entering the room. a patient requiring airborne isolation precautions should be placed in a room capable of supporting negative pressure airfl ow. the air should be vented outside or fi ltered before being circulated in the facility. the air pressure in the room should be tested daily while it is occupied with a confi rmed or suspected infectious patient. all healthcare providers wear an n- respirator on entry to the room. if a room capable of providing negative pressure is not available, the patient may be placed in a single-patient room and wear a surgical/procedural mask as tolerated, until an airborne illness isolation room is available. strict isolation was introduced in as one of the seven categories of isolation precautions. it continued to be included as a category through the revision when the precautions became more disease-specifi c and was practiced until the guideline for universal precautions was published. isolation practices at that time were simple and required little decision making by the healthcare team members. the isolation category for patients with infections transmissible by more than one route is a combination of above-described categories, e.g., a combination of contact and airborne precautions for varicella. the practice of quarantine is used to prevent the potential spread of disease when it is suspected that a person who is currently well may have been exposed to a communicable disease. by law, a person can be held, separated from others, or confi ned to their home to wait out an illness's incubation period to determine if they become ill it is obvious that for a hospital to just say that they have and follow the cdc guidelines for prevention of transmission of infectious agents is rather bureaucratic and simplistic. the actual implementation is absolutely dependent on behavioral changes needed to support improvements in the areas of personal hygiene, specifically in the washing of hands between tasks in preparation of food, caring for children, and caring for the sick in the hospital and non-hospital settings. in the hospital setting, risks of transmission to other patients especially those with serious comorbidities and immunocompromising conditions are associated with morbidity, mortality, and cost. it is not uncommon to see healthcare workers using personal protective equipment inappropriately. for example, if a gown is not worn and tied properly, it actually be falling on top of the patient and other surfaces and become more likely to pick and transmit microorganisms. if it is not disposed properly, fl ows out of containers, the organisms can be aerosolized and transmitted in more than one way. it is the responsibility of everyone not just a few infection preventionists in the hospital to understand the principles and implement the practices of infection prevention. the practices the healthcare providers believe which protect them and their families are more likely to be adhered to. in this regard, the signifi cance of basic hand hygiene principles seems to be least valued and understood. on the other hand, they can be overzealous about isolation precautions in a given patient based on profi ling and misconceptions leading to their isolation from care. unfortunately, this collateral damage has not received much attention. it is fair to say that as healthcare providers of all types, we have not reached a balanced and fully understood level in infection prevention practices years after they were first formalized. one of the major reasons is the fact that during formative medical school years, the teaching of basic and applied sciences like microbiology is de-emphasized, and getting into the glamorous realm of clinical medicine very early is encouraged at the cost of learning fundamentals. resource constrained settings cannot justify to deviate from the guidelines necessary to prevent hai. the abovementioned measures have been spelled out in simple language to help implementation in letter and spirit. two centuries of american medicine aseptic fever nursing communicable disease nursing. garden city: medical examination publishing the sources and modes of infection ancient concepts of transmission. communicable disease control options for isolation precautions isolation techniques for use in hospitals. dhew publication no. (phs)* - united states army medical institute of infectious diseases. medical management of biological casualties handbook guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings key: cord- -x uatd j authors: breban, romulus title: role of environmental persistence in pathogen transmission: a mathematical modeling approach date: - - journal: j math biol doi: . /s - - - sha: doc_id: cord_uid: x uatd j although diseases such as influenza, tuberculosis and sars are transmitted through an environmentally mediated mechanism, most modeling work on these topics is based on the concepts of infectious contact and direct transmission. in this paper we use a paradigm model to show that environmental transmission appears like direct transmission in the case where the pathogen persists little time in the environment. furthermore, we formulate conditions for the validity of this modeling approximation and we illustrate them numerically for the cases of cholera and influenza. according to our results based on recently published parameter estimates, the direct transmission approximation fails for both cholera and influenza. while environmental transmission is typically chosen over direct transmission in modeling cholera, this is not the case for influenza. modeling infectious diseases that are environmentally transmitted is a field of growing interest. in short, environmental transmission is the process by which a pathogen is passed from an infected to a susceptible individual through the environment. infected individuals shed pathogen particles in the environment where the pathogen persists r. breban (b) unité d'epidémiologie des maladies emergentes, institut pasteur, paris, france e-mail: romulus.breban@pasteur.fr depending on temperature, humidity, acidity, etc. the pathogen is then harvested by susceptible individuals that become infected depending on the ingested dose. this mechanism is in contrast to direct transmission which postulates that the pathogen is acquired through an infectious contact with an infected individual. pathogens persist on fomites (rusin et al. ; reynolds et al. ) , in water (pepper et al. ) and aerosols (gralton et al. ). environmental transmission is empirically recognized as an important transmission pathway for humans viruses [e.g., gastroenteritis (d'souza et al. ) ], animal viruses [e.g., rabbit haemorrhagic disease (henning et al. ) ], water-borne pathogens [e.g., cholera (king et al. ; pascual et al. ) , avian cholera (blanchong et al. )], bacteria [e.g., tetanus (roper et al. ) , salmonella (xiao et al. ), epizootics of plague (webb et al. )], prions [e.g., chronic wasting disease (miller et al. ) , bovine spongiform encephalopathy (anderson et al. ) ] and zoonotic pathogens [e.g., nipah and hendra viral diseases (field et al. ) ]. notably, environmental transmission is the preferred mechanism modeled for the transmission of cholera (codeço ; codeço et al. ; jensen et al. ; pascual et al. ; king et al. ). it has also been included, together with direct transmission, in modeling transmission of avian influenza in aquatic wild birds (breban et al. , roche et al. ; rohani et al. ). li et al. ( ) have opened the discussion on the modeling principles of environmental transmission, addressing the topic from a very general perspective. using a paradigmatic mathematical model, they demonstrated that environmental transmission appears like direct transmission in certain situations where the density of the pathogens in the environment remains approximately constant. notably, li et al. ( ) and spicknall et al. ( ) emphasized that environmental transmission is empirically recognized as mediating the spread of human respiratory diseases such as tuberculosis, sars and influenza. however, most of the modeling work on these diseases uses a direct transmission mechanism, despite difficulties in defining the notion of infectious contact. the direct transmission incidence term is typically defined based on the principle of proportional mixing between susceptible and infected individuals. relaxing this principle by using complex contact networks between individuals still relies on the notion of infectious contact. since direct transmission is widely used in the modeling of environmentally transmitted diseases, it is important to study in what circumstances direct transmission represents a good approximation of environmental transmission. the purpose of this paper is to show that environmental transmission may be approximated by direct transmission in the case where the pathogen persists little time in the environment. we write the environmental transmission term as an expansion in the persistence time. the first order represents the well-known direct transmission term. using the second order of the expansion, we formulate conditions for the validity of this modeling approximation and we illustrate them numerically for the cases of cholera and influenza. using published parameter estimates, we find that the validity conditions do not hold and the approximation is violated in both cases. we generalize the s i model with environmental transmission proposed by codeço ( ) , leaving the environmental transmission term broadly specified by several unrestrictive axioms. the equations of our model are where s, i and v represent the number of susceptible individuals, infected individuals and pathogens in the environment. the parameters /γ , /η and ω are the recovery period, the persistence time of the pathogen and the rate at which pathogen is shed by infected individuals; π is the susceptible inflow, μ is the natural death rate of individuals and ρ represents the contact rate with the environment. all variables and parameters are positively defined. the environmental transmission rate is modeled by the term ρ s f (v ). the function f : [ , ∞) → [ , ] represents the probability that an individual is infected when exposed to a population of v pathogens in the environment. it is empirically characterized by id , the quantity of pathogen which gives % probability of infection. previous work (codeço ; codeço et al. ; jensen et al. ; pascual et al. ; king et al. ; breban et al. breban et al. , roche et al. ; rohani et al. ; dennis et al. ) has used either a negative exponential or a rectangular hyperbola for the analytic forms of f (·), where α and κ are constants that relate to id (i.e., α = log e /id and κ = id ). however, currently available data on environmental transmission are too scarce to select an analytical form for f (·) on the basis of empirical evidence. hence, we leave the function f (·) unspecified and we only make use of properties that derive from its biological meaning. we thus postulate the following furthermore, for technical reasons, we require note that properties and yield f the model has a unique disease-free state (s dfs , i dfs , v dfs ) = (π/μ, , ). all other equilibria have nonzero values for the number of pathogens and infected individuals; they are called endemic states, denoted by (s * , i * , v * ). their components are as follows. v * is a positive solution of the equation where v c ≡ (ω/η)π/(μ + γ ). note that v c represents the amount of the pathogen established in the environmental reservoir in the very extreme case where the inflow of infected individuals equals the inflow of susceptible individuals, π . hence, v c is independent of the details of the environmental transmission mechanism and represents the maximum amount of pathogen that could be established in the environmental reservoir. given the hyperbolic form of the function g(·) in the right hand side of eq. ( ) and the properties postulated for the function f (·), eq. ( ) has a positive solution (i.e., a solution that can be assigned a biological interpretation) if and only if furthermore, if the solution exists, then it is unique and satisfies < v * < v c . the other components of the endemic equilibria are given by hence, the endemic state is unique. linear stability analysis shows that the disease-free state and the endemic state switch stability through a transcritical bifurcation when if r env > then the endemic state is stable and the disease-free state is unstable while if r env < then the endemic state is unstable [and has non-biological values according to eq. ( )] and the disease-free state is stable [see li et al. ( and breban et al. ( ) for similar results]. note that we may have values of r env around even though η is large because the shedding rate ω or the number of susceptible individuals at the disease-free state s dfs could be large, as well. we are interested in the case where the persistence time of the pathogen in the environment is small. that is, pathogen decay is much faster than all the other processes or time scales of the system. we show that, under these conditions, the environmental transmission mechanism appears like a direct transmission mechanism. we start with formally solving eq. ( ) as which, for t /η, becomes since η is large, the exponential e −ηs defines just a narrow time window in the variable s, [ , /η], where the integrand is significantly different from zero. in this narrow time window, i (t − s) does not change much and can be approximated by its taylor series expansion around i (t) truncated at the first two terms for moments of time much larger than the persistence time of the virus (i.e., t /η), eqs. ( ) and ( ) yield the following expansion up to second order in /η demonstrating that v (t) is small when the persistence time of the virus in the environment is small. using eq. ( ) to replace the derivative d i (t)/dt in eq. ( ), we obtain since, due to properties and , the term is proportional with /η and does not contribute to the second order in the expansion in /η. substituting v (t) as given by eq. ( ) in eqs. ( ) and ( ) and using the expansion of f (v ) in the neighborhood of zero, we arrive at the following approximation of our model where we introduced the notation β ≡ ρω f ( )/η. hence, in the first order in /η, eqs. ( ) and ( ) represent the expected s i model with a direct transmission mechanism of transmissibility β. in addition, we obtained the next order corrections (i.e., second order in /η) to the direct transmission term. we note that our analysis may be difficult to apply to general models with environmental transmission. however, for obtaining results emerging from the first order expansion in the pathogen persistence time (e.g., the direct transmission model and its corresponding transmissibility formula) one may use the slow-fast dynamics formalism, a general technique of singular perturbation theory. see the appendix for the application of this technique to our model example. both correction terms have transparent biological interpretations. the term (μ + γ )/η stands for the fact that a susceptible individual may become infected with pathogen that persisted past the recovery period of the shedder; note that an infectious individual cannot cause infections past their infectious period with a direct transmission mechanism. this term adds transmissibility and becomes important as the persistence time of the pathogen /η becomes larger than the infectious period of the shedder /(μ + γ ). the second correction term requires a slightly more elaborated discussion. first, we define an infectious dose id such that, for amounts of pathogen less than id, the probability of infection is small; hence, f ( id) ≈ . we use the expansion of f ( id) in the neighborhood of zero to estimate id we note that, under weak assumptions, the theory of birth processes demonstrates that f (·) is concave [see breban et al. ( ) , dennis et al. ( ) and references therein]; thus, f ( ) < . (n.b., both f ne (·) and f rh (·) are concave.) therefore, eq. ( ) makes biological sense for many reasonable choices of the function f (·). the resulting id relates to id ; e.g., id = id / log e for f ne (·) and id = id for f rh (·). second, we consider the amount of virus shed by i infectious individuals during the persistence time of the pathogen, ωi /η. if ωi /η < id, then susceptible individuals are protected from infection (as compared to direct transmission) since the pathogen always passes through the environment where it does not accumulate in sufficient amounts to create new infections because it undergoes fast decay. hence, a term like would appear as a negative correction to transmissibility. we have chosen r env = . and γ = years − . the vital dynamics parameters are π = , years − and μ = . years − ; i.e., s df s = , . the rest of the parameters are calculated such that ξ andÎ take the values listed below. (n.b., the amount of pathogen in measured in infectious doses; hence κ = .) we use the conditions that the magnitude of each correction term is much smaller than to establish when environmental transmission may be approximated with a direct transmission term. thus, we obtain and hence, in the paradigm model that we study here, the direct transmission approximation holds if two conditions are satisfied. first, the persistence time of the pathogen is much less than the recovery period of the shedder. second, the number of infected individuals is much less thanÎ . in practical terms, for the second condition to hold for all time,Î should be of the order of s dfs . we illustrate numerical simulations of the paradigm model given by eqs. ( )-( ) for various cases of validity of the conditions ( ) and ( ). where we measure the amount of pathogen in infectious doses id ; hence, κ = . we analyze four cases: case a, both approximation conditions hold; case b, the first condition holds but the second fails; case c, the second condition holds and the first fails; and case d, where neither condition holds. the parameter choices are presented in table and computations of prevalence versus time are illustrated in the corresponding panels of fig. . to maintain some means of comparison between the panels, we fixed r env = . in each case. in case a, the first order expansion in /η (i.e., the direct transmission model illustrated by a thin line) is close to the exact model (thick line) and the second order approximation (dashed line) is even closer. in cases b and d, where ξ ∼ (i.e., η ∼ (μ + γ )), the direct transmission approximation fails since the pathogen a b c d fig. successive orders of approximation for a model with environmental transmission (i.e., f (·) = f rh (·)). a the case where both conditions of the direct transmission approximation hold; ξ and i ∼ s df s . b the case where the first approximation condition fails but the second holds; ξ ∼ , butÎ ∼ s df s . c the case where the first approximation condition holds but the second fails; ξ , butÎ s df s . d the case where both approximation conditions fail; ξ ∼ andÎ s df s persists well in the environment. in case c, where the persistence time of the pathogen is short, the direct transmission approximation works as long as the number of infected individuals does not grow aboveÎ (i.e., a prevalence of ∼ − ). once i >Î , the prevalence curves of the exact model and the direct transmission model differ substantially. the curve of the exact model achieves a maximum in the neighborhood ofÎ , then declines steadily. in contrast, the prevalence curve of the direct transmission model continues to rise significantly higher thanÎ , then declines sharply. the phenomenon of epidemic decline after disease invasion is known as depletion of susceptibles and, in this case, appears less significant for the model with environmental transmission than for its corresponding model with direct transmission. in table , we illustrate the conditions under which the direct transmission approximation holds for cholera (codeço ) and influenza (li et al. ). for each of these diseases, the approximation fails in a different way. for cholera, direct transmission could properly model the infection of tens of thousands of individuals. however, its long persistence time (in aquatic environment) renders ξ comparable to ; the situation is similar to that presented in panel b of fig. . in contrast, influenza viruses persist much less (in air or on fomites); hence, in this case, ξ is significantly less than . however, given that influenza viruses are shed at high rates in the environment, direct li et al. ( ) transmission does not accurately model more than several infections. the situation is similar to that presented in panel c of fig. . although many pathogens are transmitted from person to person through an intermediary environmental reservoir, most modeling work on their epidemic spread is based on the concepts of infectious contact and direct transmission. hence, it is important to study the circumstances where direct transmission represents a good approximation of environmental transmission. in this work, we have shown using a paradigm model that direct transmission holds as an approximation for the environmental transmission mechanism in the case where the persistence time of the pathogen in the environment is short. we derived a second order expansion of the model with environmental transmission in the persistence time of the pathogen. the first order in the expansion is a model possessing the well-known direct transmission mechanism. using the second order of the expansion, we derived two explicit conditions for when the first order approximation holds: ( ) the persistence time of the pathogen is much less than the recovery period of the shedder, and ( ) the number of infected individuals is much less than a certain bound given in terms of model parameters. whenever applicable, the direct transmission approximation has the advantages that it reduces (i) the dimensionality of the model by excluding the dynamics of the pathogen population in the environment and (ii) the number of parameters by combining some of them into the direct transmissibility β. we note that when the direct transmission approximation fails, adding higher order corrections no longer collapses the parameter space. this is readily obvious in the next order correction that we obtained here. using the framework of breban et al. ( ) , the results of this paper could be easily generalized for the case of models describing several strains with perfect strain-transcending cross-immunity. two human diseases have been modeled so far using environmental transmission terms: cholera and influenza. while it appears that there is consensus in modeling cholera using environmental transmission, this is not the case for influenza where most work uses direct transmission. however, according to our results based on the parameters developed by li et al. ( ) and spicknall et al. ( ) , the direct transmission approximation fails for influenza. a large shedding rate and a low persistence time of the virus in the environment causes much virus to decay before reaching susceptible individuals. consequently, the environmental transmission model reveals less depletion of susceptibles than its counterpart having a direct transmission mechanism. our findings may bring insight into recent studies revisiting the role of depletion of susceptibles in influenza epidemiology. theoretical studies using models with direct transmission advocate for the importance of this phenomenon in curbing down the epidemic and public health applications (vardavas et al. ; ballesteros et al. ; chowell et al. ; handel et al. ). however, analyses of epidemic curves find that depletion of susceptibles does not play the expected role in epidemic decline and stress out the potential impact of behavior change during epidemics (caley et al. ; goldstein et al. ). our new results suggest that this discrepancy may be resolved by using models with environmental transmission to describe influenza epidemics. in conclusion, our work discusses environmental transmission in the case where the persistence time of the pathogen in the environment is small. using a paradigm model, we established the conditions under which environmental transmission can be approximated by direct transmission. we found that these conditions are violated for both cholera and influenza. while the case of cholera is fairly well understood, much remains to be investigated about human influenza viruses, given their strain diversity and multitude of parameters driving their environmental persistence. whereṼ (i ) ≡ (ω/η)i. defines the plane (s, i,Ṽ (i )) as a stable slow manifold. a well-established theorem ensures that the dynamics of a slow-fast dynamical system having a stable slow manifold converges to the manifold (fenichel ; sakamoto ; berglund and gentz ) . furthermore, the system is dimensionally reduced (as a first order approximation) to its corresponding slow system evolving within the slow manifold. applying these results to our model, we have that eqs. ( ), ( ) and ( ) provide an approximation of our original model given by eqs. ( )-( ) once t /η. the incidence term ρ s f (Ṽ (i )) can be further rewritten using the approximation f (Ṽ (i )) ≈ f ( )Ṽ (i ) (properties and ) since η is large and thusṼ (i ) is small. we obtain which represents a direct transmission term with transmissibility β = ρω f ( )/η. hence, in the slow system, environmental transmission is approximated by a direct transmission mechanism. transmission dynamics and epidemiology of bse in british cattle influenza a gradual and epochal evolution: insights from simple models noise-induced phenomena in slow-fast dynamical systems: a sample-paths approach persistence of pasteurella multocida in wetlands following avian cholera outbreaks a general multi-strain model with environmental transmission: invasion conditions for the disease-free and endemic states the role of environmental transmission in recurrent avian influenza epidemics quantifying social distancing arising from pandemic influenza comparative estimation of the reproduction number for pandemic influenza from daily case notification data endemic and epidemic dynamics of cholera: the role of the aquatic reservoir a stochastic model for ecological systems with strong nonlinear response to environmental drivers: application to two water-borne diseases allee effects: population growth, critical density, and the chance of extinction persistence of caliciviruses on environmental surfaces and their transfer to food geometric singular perturbation theory for ordinary differential equations the natural history of hendra and nipah viruses reconstructing influenza incidence by deconvolution of daily mortality time series the role of particle size in aerosolised pathogen transmission: a review what is the best control strategy for multiple infectious disease outbreaks? survival of rabbit haemorrhagic disease virus (rhdv) in the environment modeling the role of bacteriophage in the control of cholera outbreaks inapparent infections and cholera dynamics dynamics and control of infections transmitted from person to person through the environment dynamics of prion disease transmission in mule deer cholera and climate: revisiting the quantitative evidence tracking the concentration of heterotrophic plate count bacteria from the source to the consumer's tap occurrence of bacteria and biochemical markers on public surfaces water-borne transmission drives avian influenza dynamics in wild birds: the case of the - epidemics in the camargue area environmental transmission of low pathogenicity avian influenza viruses and its implications for pathogen invasion maternal and neonatal tetanus reduction of faecal coliform, coliform and heterotrophic plate count bacteria in the household kitchen and bathroom by disinfection with hypochlorite cleaners invariant manifolds in singular perturbation problems for ordinary differential equations informing optimal environmental influenza interventions: how the host, agent, and environment alter dominant routes of transmission can influenza epidemics be prevented by voluntary vaccination? classic flea-borne transmission does not drive plague epizootics in prairie dogs dynamics of infection with multiple transmission mechanisms in unmanaged/managed animal populations we thank pejman rohani for pointing us out the work by li et al. ( ) and fruitful discussions. we also thank two anonymous referees for constructive comments and suggestions. the research leading to these results has received partial funding from the european union seventh framework programme [fp / [fp / - under grant agreement no. . we approach the problem through the slow-fast dynamics formalism (fenichel ; sakamoto ; berglund and gentz ) , a technique that belongs to the singular perturbation theory. indeed, in the case where the persistence time of the pathogen is small (i.e., η is large and t is thought as a slow time), v is a fast variable (i.e., |dv /dt| = o(η)) while s and i are slow variables (i.e., |d s/dt| = o( ), |d i /dt| = o( )). however, a direct approach using /η as the only small parameter does not provide the expected outcome: v vanishes in the zeroth order in /η [c.f., eq. ( )] and the resulting slow system has only a disease free state and no epidemic threshold.for pathogen to remain present in the environment when its decay rate is large (i.e., η ) and the number of shedders is small (i.e., i = o( ) during disease invasion), we must also have that shedding rates are large; i.e., ω/η = o( ). hence, the slow system associated to our model is given by d s/dt = π − μs − ρ s f (Ṽ (i )), ( ) d i /dt = ρ s f (Ṽ (i )) − (μ + γ )i, key: cord- - g lio l authors: keesing, felicia; belden, lisa k.; daszak, peter; dobson, andrew; harvell, c. drew; holt, robert d.; hudson, peter; jolles, anna; jones, kate e.; mitchell, charles e.; myers, samuel s.; bogich, tiffany; ostfeld, richard s. title: impacts of biodiversity on the emergence and transmission of infectious diseases date: - - journal: nature doi: . /nature sha: doc_id: cord_uid: g lio l current unprecedented declines in biodiversity reduce the ability of ecological communities to provide many fundamental ecosystem services. here we evaluate evidence that reduced biodiversity affects the transmission of infectious diseases of humans, other animals and plants. in principle, loss of biodiversity could either increase or decrease disease transmission. however, mounting evidence indicates that biodiversity loss frequently increases disease transmission. in contrast, areas of naturally high biodiversity may serve as a source pool for new pathogens. overall, despite many remaining questions, current evidence indicates that preserving intact ecosystems and their endemic biodiversity should generally reduce the prevalence of infectious diseases. supplementary information: the online version of this article (doi: . /nature ) contains supplementary material, which is available to authorized users. i n june , a new organization, the intergovernmental science-policy platform on biodiversity and ecosystem services (ipbes)patterned after the intergovernmental panel on climate change (ipcc)-was established to assess changes to the diversity of life on the earth and how these changes will affect human well-being . human well-being would be adversely affected by biodiversity losses if ecosystems with reduced biodiversity are less able to provide the ecosystem services-such as carbon sequestration, nutrient cycling and resistance to drought-on which humans rely. in recent years, a consensus has emerged that ecosystem functions decline as biodiversity is lost . here we examine how biodiversity affects the transmission and emergence of infectious diseases and evaluate the evidence that reduced disease transmission is an important ecosystem service provided by high biodiversity. biodiversity encompasses the diversity of genes, species and ecosystems. increases in human populations have resulted in an unprecedented and precipitous loss of biodiversity . current extinction rates are estimated to be at least - , times background extinction rates and future extinction rates (over the next years) are estimated to be to times present extinction rates . a large proportion of species in all assessed taxa are currently threatened with extinction ( % of birds, % of mammals, % of amphibians; % of gymnosperms; % of corals ) and the best estimate of population trends of birds, mammals, amphibians, reptiles and fish indicates that since global population sizes have declined by almost % (ref. ) . global and local extinction rates of some taxa, particularly microbes, have not been well characterized. for the many organisms that are symbionts of other organisms, extinction of their hosts can cause their extinction too . collectively, these declines and extinctions are caused by changing the earth's ecosystems to meet growing demands for food, fresh water, fibre, timber and fuel, and by climate change. changes in biodiversity have the potential to affect the risk of infectious disease exposure in plants and animals-including humansbecause infectious diseases by definition involve interactions among species. at a minimum, these species include a host and a pathogen; often many more species are involved, including additional hosts, vectors and other organisms with which these species interact. intriguingly, biodiversity may play a dual role in the emergence and transmission of infectious diseases. on the one hand, high biodiversity may provide a larger potential source of novel pathogens, but on the other hand, biodiversity can reduce further pathogen transmission for both longestablished and newly emerging diseases. we first review the effects of biodiversity on the transmission of established diseases and then turn to disease emergence. transmission of pathogens between species biodiversity loss might affect disease transmission through several mechanisms (box ). if the effect of each species on pathogen transmission were entirely idiosyncratic, one would expect that diversity declines would be equally likely to cause a decrease or an increase in disease transmission in the remaining species. however, in recent years, a consistent picture has emerged-biodiversity loss tends to increase pathogen transmission and disease incidence. this pattern occurs across ecological systems that vary in type of pathogen, host, ecosystem and transmission mode ( table ) . as an example, west nile virus is a mosquito-transmitted virus for which several species of passerine birds act as hosts. three recent studies detected strong correlations between low bird diversity and increased human risk or incidence of west nile encephalitis in the united states - . communities with low avian diversity tend to be dominated by species that amplify the virus, inducing high infection prevalence in mosquitoes and people, while communities with high avian diversity contain many species that are less competent hosts. for hantavirus pulmonary syndrome, a directly transmitted zoonotic disease, correlational and experimental studies have shown that a lower diversity of small mammals increases the prevalence of hantaviruses in their hosts, thereby increasing risk to humans (box ). diversity has a similar effect for plant diseases, with species losses increasing the transmission of two fungal rust pathogens that infect perennial rye grass and other plant species . recent attention has focused on assessing the mechanisms by which reduced biodiversity increases pathogen transmission (box ). biodiversity loss can clearly increase transmission if it reduces predation and competition on reservoir hosts, thereby increasing their density. however, controversy has centred around whether the loss of species can increase transmission in other ways . this is because field studies like those on west nile virus, hantaviruses and rye grass have typically not controlled for changes in host density that can result from changes in 'species richness' (the number of species present in a community, which is a measure of taxonomic diversity). as a consequence, it has been difficult to separate the effects of higher density from those of reduced diversity. recent experiments confirm that increases in disease transmission can occur when species richness declines even if host density stays constant. one of the best examples comes from a study of schistosoma mansoni, a trematode that causes schistosomiasis in humans. the parasite alternately infects snails and humans via free-living infectious stages. host snails were placed in tanks at a constant density either alone or with one or two other species of non-host snails and then exposed to the parasite . in single-species treatments, host snails were % more likely to be infected because parasites in multi-species treatments often ended up in dead-end hosts. increased parasite-host encounter rates caused by reduced diversity are sufficient to increase disease transmission for schistosoma. the loss of species can increase encounter rates between pathogens and hosts, as in the schistosoma example, when the lost species are not hosts for the pathogen. but if the lost species are indeed hosts capable of transmission, this declining diversity could also reduce the total number of hosts, thereby decreasing transmission if all else remains equal , . certainly reductions in the number of hosts can reduce the number of vectors and also their infection prevalence , , but empirical examples are relatively rare, in part because the issue has been neglected, and also because all else rarely remains equal. for example, the loss of hosts can cause compensatory increases in the abundances of other hosts, such that total host abundance changes little relative to total host abundance in more diverse communities. even when total host abundance does decline in less diverse systems, differences in host quality among species can alter simple correlations between host abundance and infection risk . pathogen transmission is not always a function of host density. for example, the number of infectious bites delivered by highly mobile vectors like mosquitoes can be independent of the density of the host population . transmission of directly transmitted pathogens like hantaviruses can also be independent of host density if transmission involves behavioural encounters, for example, aggressive interactions between rodents, and if the frequency of these encounters does not vary much with host density , . in systems like these, the loss of host species can actually increase transmission if the lost hosts are suboptimal for parasite development and reproduction; this is because these suboptimal hosts absorb pathogens but are poor at transmitting them. in sum, reducing biodiversity can increase disease transmission when the lost species are either not hosts for the pathogen or are suboptimal ones. for pathogens for which transmission is a function of host density, loss of diversity is most likely to increase transmission if the loss causes an increase in the density of competent hosts. the number and diversity of examples of pathogens for which species loss leads to increases in total transmission suggests that these conditions are frequently met (table ) . additional studies in other disease systems would better establish the generality of these relationships. the loss of particular species in a community clearly has the potential to increase disease transmission. but does reducing diversity itself increase transmission, or is increased transmission the consequence of the removal of particular species? the answer depends on how species composition changes as richness changes , . for example, if those host species most responsible for amplifying the pathogen tend to persist or even thrive as biodiversity is lost, then disease risk will consistently increase as biodiversity declines. on the other hand, if amplifying species tend to disappear as biodiversity declines, then biodiversity loss will tend to reduce disease risk. these hypothetical possibilities indicate the importance of understanding both the non-random sequences by which species are lost from communities, and whether the species that tend to occur only in more species-rich communities tend to amplify or buffer pathogen transmission. in several case studies, the species most likely to be lost from ecological communities as diversity declines are those most likely to reduce pathogen transmission. in the lyme disease system of eastern north america, for example, the white-footed mouse is simultaneously the most abundant host species, the most competent host for the lyme bacterium, and the highest-quality host for immature tick vectors the loss of biodiversity can affect the transmission of infectious diseases by changing: ( ) the abundance of the host or vector. for plants, seeding experimental fields with plant species that are not hosts for fungal pathogens decreased threefold the pathogen load of species that are hosts, apparently by reducing host density through competition . on the other hand, a greater diversity of host species can sometimes increase pathogen transmission by increasing the abundance of vectors . ( ) the behaviour of the host, vector or parasite. in a more diverse community, one of the parasitic worms that causes schistosomiasis (which infects million people worldwide) is more likely to end up in an unsuitable intermediate host. this can reduce the probability of subsequent infection of humans by - % (ref. ) . for hantavirus in utah, usa, rodent hosts on more diverse plots are more likely to come in contact with heterospecific mammals and less likely to come in contact with conspecifics, reducing the probability of transmission of the virus . in principle, higher diversity could influence behaviours with a resulting increase in disease transmission or could alter the evolutionary dynamics of virulence and transmission pathways. ( ) the condition of the host or vector. in experimental rice fields in china, rice plants in genetically diverse mixtures had drier leaves because the mixture changed microclimatic conditions . as a consequence, infection with rice blast fungus was less prevalent in diverse fields. genetically diverse plantings can also lead to induced resistance in host plants because they are exposed to similar pathogens that are specialists on the other cultivars . for some disease systems (for example, lyme disease), multiple mechanisms operate in concert, leading to a compounding effect of biodiversity loss on increased disease transmission (table ) . . ticks that attempt to feed on virginia opossums are likely to be groomed off and killed. green-andyellow circles show the mean number of ticks per hectare fed by mice or opossums; yellow shading shows the proportion of ticks infected after feeding. blue circles show the mean number of ticks per hectare groomed off and killed. ticks that feed on mice are highly likely to become infected with the bacterium that causes lyme disease, whereas those that feed on opossums are not. case study of hantavirus pulmonary syndrome hantaviruses are a group of negative-stranded rna viruses associated with murid rodents. they can cause severe morbidity and mortality in humans, with case-fatality rates near % (ref. ) . infected rodents shed hantavirus in saliva, urine and faeces; transmission to humans occurs through inhalation of aerosolized excreta as well as through rodent bites . the risk of human exposure increases as the density and infection prevalence of rodent reservoirs increase . in a field study in oregon, usa, the only variable significantly linked to infection prevalence in deer mouse host populations was mammalian species diversity, with the prevalence of the hantavirus sin nombre virus rising from % to % as diversity declined. deer mouse population density was not statistically associated with sin nombre virus infection prevalence, suggesting that high diversity reduced intraspecific encounters rather than host abundance . a study in utah, usa , also found a negative correlation between small-mammal diversity and sin nombre virus infection prevalence in deer mice. as in oregon, high diversity reduced infection prevalence apparently by reducing intraspecific encounters rather than by reducing host density, a result supported by experiments . the conclusions of these studies were supported by an experimental study of hantaviruses in small mammal communities of panamá . in replicated plots, small-mammal diversity was reduced by trapping and removing species that are not hosts for the virus; infection prevalence in hosts was compared on manipulated and unmanipulated plots (box figure) . experimentally reduced small-mammal diversity caused an increase in the density of host species and also in seroconversion rates and seroprevalence within hosts (box figure) . review research (fig. ) . as a consequence, this host species infects a high proportion of the ticks within forest communities. the white-footed mouse is also an ecologically resilient species, present in both species-rich and speciespoor communities . in contrast, virginia opossums are poor hosts for the pathogen, kill the vast majority of ticks that attempt to feed on them, and are absent from many low-diversity forest fragments and degraded forests where mice are abundant , . therefore, as biodiversity is lost, the host with a strong buffering effect-the opossum-disappears, while the host with a strong amplifying effect-the mouse-remains. the primary hosts for the pathogens that cause west nile encephalitis, hantavirus pulmonary syndrome, and bartonellosis also appear to be resilient species that increase in abundance as biodiversity is lost , , . whether an organism's host competence and its resilience to factors that reduce biodiversity are causally related is an unresolved but critical issue. traits that make a host resilient to biodiversity loss may also make them susceptible to pathogen infection and transmission. such a relationship would explain the frequency with which the link between diversity loss and disease transmission has been observed in nature ( table ). for plants, species that are fast-growing and nutrient-rich with relatively high metabolic rates-characteristics of 'weedy' speciescan be more competent hosts for arthropod vectors and plant pathogens than those with less weedy traits . plants with these weedy traits are also more likely to become more abundant when plant diversity declines . consequently, the very species that have traits permitting persistence in degraded and species-poor ecosystems are also more likely to carry high pathogen and vector burdens. a similar pattern may occur in vertebrates-resilience in the face of disturbances that cause biodiversity loss, such as habitat destruction and fragmentation, is facilitated by lifehistory features such as high reproductive output and intrinsic rates of increase . vertebrates with these features tend to invest minimally in some aspects of adaptive immunity [ ] [ ] [ ] ; we hypothesize that this may make them more competent hosts for pathogens and vectors. understanding the interrelationships among pathogen transmission, biodiversity loss and interspecific differences in immune function is an important area for future research. such studies would illuminate how frequently resilient species are also those that increase pathogen transmission, and might provide general rules about the impact of biodiversity loss on disease transmission. could changes in biodiversity within the bodies of organisms also alter pathogen transmission? recent improvements in the ability of researchers to detect unculturable microbial species have allowed documentation of the tremendous diversity of microbes upon and within plants and animals. in human bodies, for example, % of all cells are microbial . a number of studies have begun to show links between diseases and the diversity of an organism's 'microbiome'. changes in the composition of microbiomes are frequently associated with infection and disease. for example, corals suffering from white plague disease have microbial communities distinctly different from those in healthy corals . in humans, bacterial vaginosis results from changes in the composition of the vaginal microbial community , and this in turn increases the risk of hiv infection . although changes in microbial species composition associated with infection are welldocumented, few studies have investigated the effects of changes in diversity itself. in a recent investigation, patients with recurrent episodes of infection caused by the bacterium clostridium difficile had significantly lower diversity of intestinal microbes than did control patients . correlational studies such as these, though intriguing, make it difficult to determine whether changes in microbial communities are the cause or the consequence of infections. but some experimental studies clearly demonstrate that increasing microbial biodiversity can protect against infection. for example, children with a history of ear infections given a mixture of five strains of streptococcus were less likely to develop subsequent infections compared to a control group . similarly, reducing microbial diversity within a host can increase transmission. when mice with persistent infections of c. difficile were treated with antibiotics that reduced the diversity of intestinal microbes, they began shedding c. difficile spores at high rates . in some of these examples, a rich microbial community appears to regulate the abundance of endemic microbial species that can become pathogenic when overly abundant . in other cases, high microbial species diversity can prevent colonization by invasive pathogenic species. for example, the more diverse the microbiome surrounding the roots of wheat plants, the more protected the plants were against invasion by the pathogenic bacterium pseudomonas aeruginosa . similarly, piglets raised in natural environments supporting a high diversity of microbes were more resistant to invasion by pathogenic gut microbes than those raised in more sterile environments . the effects of microbial diversity within and upon host bodies show intriguing similarities to the effects of macroscopic species diversity on disease transmission in aquatic and terrestrial ecosystems. further exploration of these similarities, and particularly the specific mechanisms operating within hosts, is a critical research frontier because changes in microbial diversity might accompany biodiversity loss in their hosts. for pathogens already established within ecological communities, we have shown that biodiversity loss frequently increases the rate of transmission. but what role, if any, does biodiversity have in the processes by which new pathogens emerge? between and , over emerging disease events were identified in humans around the world . concomitantly, other emerging infectious diseases also appeared in wildlife, domesticated animals, and crop and wild plants. emerging infectious diseases include those in which the pathogen has evolved into a new strain within the same host species, for example, through the evolution of drug resistance (methicillin-resistant staphylococcus aureus or mrsa) or switched to new host species (for example, human immunodeficiency virus or hiv, severe acute respiratory syndrome or sars). in some cases, the switch to new host species is accompanied by a change in geographic range (for example, west nile virus in the americas). for pathogens that establish in new species, the emergence process involves multiple steps, including the initial invasion into the new host ('spillover'), the production of transmission stages within the new host, and the establishment of the pathogen in the host population as a whole , . the effect of biodiversity may vary for each of these steps. for the initial invasion, biodiversity may act as a source pool. this hypothesis is supported by surveys of emerging diseases of humans: most are zoonotic-jumping to humans from other vertebrate animals . in one recent analysis, the probability of emergence of pathogens from wildlife to humans was positively correlated with mammalian wildlife species richness when data were corrected for reporting bias . other environmental and socioeconomic factors that bring humans into closer contact with potentially new pathogens (for example, forest clearing for agriculture, wildlife hunting) may also contribute to this pattern. indeed, almost half of the zoonotic diseases that have emerged in humans since resulted from changes in land use, from changes in agricultural or other food production practices, or from wildlife hunting (fig. ) . these human activities increase rates of contact between humans and animals, which may be a critical factor underlying spillover. once spillover of the pathogen into a new host has occurred, high densities of that host species may facilitate pathogen establishment and transmission within the new host . for example, nipah virus spilled over from wild fruit bats to domestic pigs in malaysia; high densities of pigs in local farms appear to have facilitated establishment of pig-to-pig transmission, and the pathogen then spilled over from pigs to humans . such high densities of domesticated species are almost always associated with low biodiversity. in contrast to emergence through host-switching, % of emergence events between and arose through the evolution of drug resistance . for these cases, biodiversity of microbial communities within hosts may have a protective effect; human use of antibiotics is research review thought to select for resistant microbes by eliminating the great diversity of non-resistant microbial strains and species that suppress resistant strains in the absence of antibiotics. investigations using recent advances in microbial detection support this idea , . thus, reduced microbial diversity may be an important underlying cause of the emergence of drug-resistant pathogens; this too requires further investigation. the addition of particular species-for example, natural enemies or competitors-can reduce the impacts of established pathogens. for example, experimental addition of a naturally occurring bacterium, janthinobacterium lividum, to the skin of the endangered frog rana mucosa eliminated frog mortality from experimental infection with chytridiomycosis, which is devastating amphibian populations worldwide . for corals, application of phages isolated from natural communities can control the spread of bacterial infections . the growing interest in 'probiotics' for humans and harvested species provides another example of this approach . more broadly, biodiversity itself seems to protect organisms, including humans, from transmission of infectious diseases in many cases (table ) . preserving biodiversity in these cases, and perhaps generally, may reduce the incidence of established pathogens. to preserve high diversity in nature, conservation scientists have developed robust methods that reflect the key principle that larger areas sustain larger numbers of species . methods of conserving microbial diversity within and upon bodies or in the environment are less well developed, but avoiding the overuse of antimicrobial compounds is essential. critically, future research on the relationship between biodiversity and disease must avoid conflating the effects of biogeographic patterns of biodiversity (for example, higher diversity in lower latitudes) with those of anthropogenic reductions in extant biodiversity, because policy and management options can far more readily affect the latter than the former. for emerging diseases, the observation that a more diverse microbiome within a host suppresses strains that are resistant to antimicrobial compounds suggests that avoiding the over-use of these compounds in medicine and agriculture can prevent the emergence of resistant strains. for pathogens that emerge by switching host species, three management approaches are warranted. first, potential emergence 'hotspots' could be predictable on the basis of land-use change and underlying biodiversity patterns; these areas should be targeted for surveillance of endemic wildlife pathogens that have the potential to jump host species , . second, preserving and protecting intact habitats in these hotspots provides a simple, direct way of reducing human-animal contact and reduces the likelihood of emergence of new pathogens, although methods for achieving reduced contact are not always straightforward . and third, to reduce the probability that pathogens become established and transmissible within a new host population once spillover occurs, the husbandry of high-density monocultures of domestic animals, particularly in areas at high risk of spillover, should be subject both to more intensive surveillance and to measures that reduce contact between wildlife and livestock. managing potential emergence hotspots by attempting to eliminate them is likely to backfire because the species most resilient to habitat destruction and degradation may be those that amplify pathogen transmission. despite many recent advances in our understanding of biodiversity and disease, much remains to be learned. first, we must increase the number of disease systems for which we understand the effects of biodiversity loss on disease transmission across a range of spatial and temporal scales. we must also focus on how to implement specific policies informed by this science. future research, for example, should monitor changes in epidemiology in regions in which conservation measures are imposed compared to reference sites. a major challenge will be to untangle the complex ways in which other global anthropogenic trends-such as climate change, biotic exchange, nutrient pollution, armed conflict and economic collapse-interact with biodiversity loss to influence disease dynamics, and which of these trends have the greatest impacts on human well-being. despite remaining questions, connections between biodiversity and disease are now sufficiently clear to increase the urgency of local, regional, and global efforts to preserve natural ecosystems and the biodiversity they contain. globally, almost half of these diseases resulted from changes in land use, changes in agricultural and other food production practices, or through wildlife hunting, which suggests that contact rates between humans and other animals are an important underlying cause of zoonotic disease emergence. 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article at www.nature.com/nature. correspondence and requests for materials should be addressed to f.k. (keesing@bard.edu). supplementary information is linked to the online version of the paper at www.nature.com/nature. key: cord- -yzwsqlb authors: ray, bisakha; ghedin, elodie; chunara, rumi title: network inference from multimodal data: a review of approaches from infectious disease transmission date: - - journal: j biomed inform doi: . /j.jbi. . . sha: doc_id: cord_uid: yzwsqlb networks inference problems are commonly found in multiple biomedical subfields such as genomics, metagenomics, neuroscience, and epidemiology. networks are useful for representing a wide range of complex interactions ranging from those between molecular biomarkers, neurons, and microbial communities, to those found in human or animal populations. recent technological advances have resulted in an increasing amount of healthcare data in multiple modalities, increasing the preponderance of network inference problems. multi-domain data can now be used to improve the robustness and reliability of recovered networks from unimodal data. for infectious diseases in particular, there is a body of knowledge that has been focused on combining multiple pieces of linked information. combining or analyzing disparate modalities in concert has demonstrated greater insight into disease transmission than could be obtained from any single modality in isolation. this has been particularly helpful in understanding incidence and transmission at early stages of infections that have pandemic potential. novel pieces of linked information in the form of spatial, temporal, and other covariates including high-throughput sequence data, clinical visits, social network information, pharmaceutical prescriptions, and clinical symptoms (reported as free-text data) also encourage further investigation of these methods. the purpose of this review is to provide an in-depth analysis of multimodal infectious disease transmission network inference methods with a specific focus on bayesian inference. we focus on analytical bayesian inference-based methods as this enables recovering multiple parameters simultaneously, for example, not just the disease transmission network, but also parameters of epidemic dynamics. our review studies their assumptions, key inference parameters and limitations, and ultimately provides insights about improving future network inference methods in multiple applications. dynamical systems and their interactions are common across many areas of systems biology, neuroscience, healthcare, and medicine. identifying these interactions is important because they can broaden our understanding of problems ranging from regulatory interactions in biomarkers, to functional connectivity in neurons, to how infectious agents transmit and cause disease in large populations. several methods have been developed to reverse engineer or, identify cause and effect pathways of target variables in these interaction networks from observational data [ ] [ ] [ ] . in genomics, regulatory interactions such as disease phenotype-genotype pairs can be identified by network reverse engineering [ , ] . molecular biomarkers or key drivers identified can then be used as targets for therapeutic drugs and directly benefit patient outcomes. in microbiome studies, network inference is utilized to uncover associations amongst microbes and between microbes and ecosystems or hosts [ , , ] . this can include insights about taxa associations, phylogeny, and evolution of ecosystems. in neuroscience, there is an effort towards recovering brain-connectivity networks from functional magnetic resonance imaging (fmri) and calcium fluorescence time series data [ , ] . identifying structural or functional neuronal pairs illuminates understanding of the structure of the brain, can help better understand animal and human intelligence, and inform treatment of neuronal diseases. infectious disease transmission networks are widely studied in public health. understanding disease transmission in large populations is an important modeling challenge because a better understanding of transmission can help predict who will be affected, and where or when they will be. network interactions can be further refined by considering multiple circulating pathogenic strains in a population along with strain-specific interventions, such as during influenza and cold seasons. thus, network interactions can be used to inform interventional measures in the form of antiviral drugs, vaccinations, quarantine, prophylactic drugs, and workplace or school closings to contain infections in affected areas [ ] [ ] [ ] [ ] . developing robust network inference methods to accurately and coherently map interactions is, therefore, fundamentally important and useful for several biomedical fields. as summarized in fig. , many methods have been used to identify pairwise interactions in genomics, neuroscience [ , ] and microbiome research [ ] including correlation and information gain-based metrics for association, inverse covariance for conditional independence testing, and granger causality for causation from temporal data. further, multimodal data integration methods such as horizontal integration, model-based integration, kernelbased integration, and non-negative matrix factorization have been used to combine information from multiple modalities of 'omics' data such as gene expression, protein expression, somatic mutations, and dna methylation with demographic, diagnoses, and phenotypical clinical data. bayesian inference has been used to analyze changes in gene expression from microarray data as dna measurements can have several unmeasured confounders and thereby incorporate noise and uncertainty [ ] . multi-modal integration can be used for classification tasks, to predict clinical phenotypes such as tumor stage or lymph node status, for clustering of patients into subgroups, and to identify important regulatory modules [ ] [ ] [ ] [ ] [ ] . in neuroscience, not just data integration, but multimodal data fusion has been performed by various methods such as linear regression, structural equation modeling, independent component analysis, principal component analysis, and partial least squares [ ] . multiple modalities such as fmri, electroencephalography, and diffusion tensor imaging (dti) have been jointly analyzed to uncover more details than could be captured by a single imaging technique [ ] . in metagenomics, network inference from microbial data has been performed using methods such as inverse covariance and correlation [ ] . in evolutionary biology, the massive generation of molecular data has enabled bayesian inference of phylogenetic trees using markov chain monte carlo chain (mcmc) techniques [ , ] . in infectious disease transmission network inference, bayesian inference frameworks have been primarily used to integrate data such as dates of pathogen sample collection and symptom report date, pathogen genome sequences, and locations of patients [ ] [ ] [ ] . this problem remains challenging as the data generative processes and scales of heterogeneous modalities may be widely different, transformations applied to separate modalities may not preserve the interactions between modalities, and separately integrated models may not capture interaction effects between modalities [ ] . as evidence mounts regarding the complex combination of biological, environmental, and social factors behind disease, emphasis on the development of advanced modeling and inference methods that incorporate multimodal data into singular frameworks has increased. these methods are becoming more important to consider given that the types of healthcare data available for understanding disease pathology, evolution, and transmission are numerous and growing. for example, internet and mobile connectivity has enabled mobile sensors, point-of-care diagnostics, web logs, and participatory social media data which can provide complementary health information to traditional sources [ , ] . in the era of precision medicine, it becomes especially important to combine clinical information with biomarker and environmental information to recover complex genotype-phenotype maps [ ] [ ] [ ] [ ] . infectious disease networks are one area where the need to bring together data types has long been recognized, specifically to better understand disease transmission. data sources including high-throughput sequencing technologies have enabled genomic data to become more cost effective, offering support for studying transmission by revealing pathways of pathogen introduction and evolution in a population. yet, genomic data in isolation is insufficient to obtain a comprehensive picture of disease in the population. while these data can provide information about pathogen evolution, genetic diversity, and molecular interaction, they do not capture other environmental, spatial, and clinical factors that can affect transmission. for infectious disease surveillance, this information is usually conveyed through epidemiological data, which can be collected in various ways such as in clinical settings from the medical record, or in more recent efforts through web search logs, or participatory surveillance. participatory surveillance data types typically include age, sex, date of symptom onset, and diagnostic information such as severity of symptoms. in clinical settings, epidemiological data are generally collected from patients reporting illness. this can include, for example, age at diagnosis, sex, race, family history, diagnostic information such as severity of symptoms, and phenotypical information such as presence or absence of disease which may not be standardized. highthroughput sequencing of pathogen genomes, along with linked spatial and temporal information, can advance surveillance by increasing granularity and leading to a better understanding of the spread of an infectious disease [ ] . considerable efforts have been made to unify genomic and epidemiologic information from traditional clinical forms into singular statistical frameworks to refine understanding of disease transmission [ ] [ ] [ ] [ ] [ ] [ ] . one approach to design and improve disease transmission models has been to analytically combine multiple, individually weak predictive signals in the form of sparse epidemiological, spatial, pathogen genomic, and temporal data [ , , , , ] . molecular epidemiology is the evolving field wherein the above data types are considered together; epidemiological models are used in concert with pathogen phylogeny and immunodynamics to uncover disease transmission patterns [ ] . pathogen genomic data can capture within-host pathogen diversity (the product of effective population size in a generation and the average pathogen replication time [ , ] ) and dynamics or provide information critical to understanding disease transmission such as evidence of new transmission pathways that cannot be inferred from epidemiological data alone [ , ] . in addition, the remaining possibilities can then be examined using any available epidemiological data. as molecular epidemiology and infectious disease transmission are areas in which network inference methods have been developed for bringing together multimodal data we use this review to investigate the foundational work in this specific field. a summary of data types, relevant questions and purpose of such studies is summarized in fig. , and we further articulate the approaches below. in molecular epidemiology, several approaches have been used to overlay pathogen genomic information on traditionally collected epidemiologic information to recover transmission networks. additional modeling structure is needed in these problems because infectious disease transmission occurs through contact networks of heterogeneous individuals, which may not be captured by compartmental models such as susceptible-infec tious-recovered (sir) and susceptible-latent-infectious-recov ered (slir) models [ ] . as well, for increased utility in epidemiology, there is a necessity to estimate epidemic parameters in addition to the transmission network. unlike other fields wherein recovery of just the topology of the networks is desired, in molecular epidemiology bayesian inference is commonly used to reverse engineer infectious disease transmission networks in addition to estimating epidemic parameters (fig. ). while precise features can be extracted from observed data, there are latent variables not directly measured which must simultaneously be considered to provide a complete picture. thus, bayesian inference methods have been used to simultaneously infer epidemic parameters and structure of the transmission network in a single framework. instead of capturing pairwise interactions, such as correlations or inverse covariance, bayesian inference is capable of considering all nodes and inferring a global network and transmission parameters [ ] . moreover, bayesian inference is capable of modeling noisy, partially sampled realistic outbreak data while incorporating prior information. while this review focuses on infectious disease transmission, network inference methods have implications in many areas. modeling network diffusion and influence, identifying important nodes, link prediction, influence probabilities and community topology and parameter detection are key questions in several fields ranging from genomics to social network analysis [ ] . analogous frameworks can be developed with different modalities of observational genomics or clinical data to model information propagation and capture the influences of nodes, nodes that are more influential than others, and the temporal dynamics of information diffusion. for modeling information spread in such networks, influence and susceptibility of nodes can serve to be analogous to epidemic transmission parameters. however, these modified methods should also account for differences in the method of information propagation in such networks from infectious disease transmission by incorporating constraints in the form of temporal decay of infection, strengths of ties measured from biological domain knowledge, and multiple pathways of information spread. to identify the studies most relevant for this focused review, we queried pubmed. for practicality and relevance, our search, summarized in fig. , was limited to papers from the last ten years. as our review is focused on infectious disease transmission network inference, we started with the keywords 'transmission' and 'epidemiological'. to ensure that we captured studies that incorporate pathogen genomic data, we added the keywords 'genetic', 'genomic' and 'phylogenetic' giving articles total. next, to narrow the results to those that are comprised of a study of multi-modal data, we found that the keywords 'combining' or 'integrating' alongside 'bayesian inference' or 'inference' were comprehensive. these filters yielded and articles in total. we found that some resulting articles focused on outbreak detection, sexually transmitted diseases, laboratory methods, and phylogenetic analysis. also, the focus of several articles was to either overlay information from different modalities or to sequentially analyze them to eliminate unlikely transmission pathways. after a full-text review to exclude these and focus on methodological approaches, articles resulted which use bayesian inference to recover transmission networks from multimodal data for infectious diseases, and which represent the topic of this review. this included bayesian likelihood-based methods for integrating pathogen genomic information with temporal, spatial, and epidemiological characteristics for infectious diseases such as foot and mouth disease (fmd), and respiratory illnesses, including influenza. as incorporating genomic data simultaneously in analytical multimodal frameworks is a relatively novel idea, the literature on this is limited. recent unified platforms have been made available to the community for analysis of outbreaks and storing of outbreak data [ ] . thus, it is essential to review available literature on this novel and burgeoning topic. for validation, we repeated our queries on google scholar. although google scholar generated a much broader range of papers, based on the types of papers indexed, we verified that it also yielded the articles selected from pubmed. we are confident in our choice of articles for review as we have used two separate publications databases. below we summarize the theoretical underpinnings of the likelihood-based framework approaches, inference parameters, and assumptions about each of these studies and articulate the limitations, which can motivate future research. infectious disease transmission study is a rapidly developing field given the recent advent of widely available epidemiological, social contact, social networking and pathogen genomic data. in this section we briefly review multimodal integration methods for combining pathogen genomic data and epidemiological data in a single analysis, for inferring infection transmission trees and epidemic dynamic parameters. advances in genomic technology such as sequences of whole genomes of rna viruses and identifying single nucleotide variations using sensitive mass spectrometry have enabled the tracing of transmission patterns and mutational parameters of the severe acute respiratory syndrome (sars) virus [ ] . in this study, phylogenetic trees were inferred based on phylogenetic analysis using parsimony (paup ⁄ ) using a maximum likelihood criterion [ ] . mutation rate was then inferred based on a model which assumes that the number of mutations observed between an isolate and its fig. . study design and inclusion-exclusion criteria. this is a decision tree showing our searches and selection criteria for both pubmed and google scholar. we focused only on genomic epidemiology methods utilizing bayesian inference for infectious disease transmission. ancestor is proportional to the mutation rate and their temporal difference [ ] . their estimated mutation rate was similar to existing literature on mutation rates of other viral pathogens. phylogenetic reconstruction revealed three major branches in taiwan, hong kong, and china. gardy et al. [ ] analyzed a tuberculosis outbreak in british columbia in using whole-genome pathogen sequences and contact tracing using social network information. epidemiological information collection included completing a social network questionnaire to identify contact patterns, high-risk behaviors such as cocaine and alcohol usage, and possible geographical regions of spread. pathogen genomic data consisted of restriction-fragmentlength polymorphism analysis of tuberculosis isolates. phylogenetic inference of genetic lineage based on single nucleotide polymorphisms from the genomic data was performed. their method demonstrated that transmission information inference such as identifying a possible source patient from contact tracing by epidemiological investigation can be refined by adding ancestral and diversity information from genomic data. in one of the earliest attempts to study genetic sequence data, as well as dates and locations of samples in concert, jombart et al. [ ] proposed a maximal spanning tree graph-based approach that went beyond existing phylogenetic methods. this method was utilized to uncover the spatiotemporal dynamics of the influenza a (h n ) from and to study its worldwide spread. a total of gene sequences of hemagglutinin (ha) and of neuraminidase (na) were obtained from genbank. classical phylogenetic approaches fail to capture the hierarchical relationship between both ancestors and descendants sampled at the same time. using their algorithm called seqtrack [ ] , the authors constructed ancestries in samples based on a maximal-spanning tree. seqtrack [ ] utilizes the fact that in the absence of recombination and reverse mutations, strains will have unique ancestors characterized by the fewest possible mutations, no sample can be the ancestor of a sample which temporally preceded it, and the likelihood of ancestry can be estimated from the genomic differentiation between samples. seqtrack was successful in reconstructing the transmission trees in both completely and incompletely sampled outbreaks unlike phylogenetic approaches, which failed to capture ancestral relationships between the tips of trees. however, this method cannot capture the underlying within-host virus genetic parameters. moreover, mutations generated once can be present in different samples and transmission likelihood based on genetic distance may not be reliable. the above methods exploit information from different modalities separately. recent methodological advancements have seen simultaneous integration of multiple modalities of data in singular bayesian inference frameworks. in the following section we discuss state-of-the-art approaches based on bayesian inference, to reconstruct partially-observed transmission trees and multiple origins of pathogen introduction in a host population [ , , , , ] . we specifically focus on bayesian likelihood-based methods as the methods consider heterogeneous modalities in a single framework and simultaneously infer the transmission network and epidemic parameters such as rate of infection transmission and rate of recovery. infectious disease transmission network inference is one problem area wherein there is a foundational literature of bayesian inference methods; reviewing them together allows understanding and comparison of specific related features across models. methods are summarized in table . in bayesian inference, information recorded before the study is included as a prior in the hypothesis. based on bayes theorem as shown below, this method incorporates prior information and likelihoods from the sample data to compute a posterior probability distribution or, pðhypothesisjdataÞ. the denominator is a normalization constant or, the marginal probability density of the sample data computed over all hypotheses [ ] . the hypothesis for this problem can be expressed in the form of a transmission network over individuals, locations, or farms, parameters such as rate of infectiousness and recovery, or mutation probability of pathogens. the posterior probability distribution can then be estimated as in the equation below. the posterior probability is then a measure that the inferred transmission tree and parameters are correct. it can be extremely difficult to analytically compute the posterior probability distribution as it involves iterating over all possible combinations of branches of such a transmission tree and parameter values. however, it is possible to approximate the posterior probability distribution using mcmc [ ] techniques. in mcmc, a markov chain is constructed which is described by the state space of the parameters of the model and which has the posterior probability distribution as its stationary distribution. for an iteration of the mcmc, a new tree is proposed by stochastically altering the previous tree. the new tree is accepted or rejected based on a probability computed from a metropolis-hastings or gibbs update. the quality of the results from the mcmc approximation can depend on the number of iterations that it is run for, the convergence criterion and the accuracy of the update function [ ] . cottam et al. [ ] developed one of the earliest methods to address this problem studying foot-and-mouth disease (fmd) in twenty farms in the uk. in this study, fmd virus genomes (the fmd virus has a positive strand rna genome and it is a member of the genus aphthovirus in the family picornaviridae) were collected from clinical samples from the infected farms. the samples were chosen so that they could be used to study variation within the outbreak and the time required for accumulation of genetic change, and to study transmission events. total rna was extracted directly from epithelial suspensions, blood, or esophageal suspensions. sanger sequencing was performed on overlapping amplicons covering the genome [ ] . as the rna virus has a high substitution rate, the number of mutations was sufficient to distinguish between different farms. they designed a maximum likelihood-based method incorporating complete genome sequences, date at which infection in a farm was identified, and the date of culling of the animals. the goal was to trace the transmission of fmd in durham county, uk during the outbreak to infer the date of infection of animals and most likely period of their infectiousness. in their approach, they first generated the phylogenies of the viral genomes [ , ] . once the tip of the trees were generated, they constructed possible transmission trees by recursively working backwards to identify a most recent common ancestor (mrca) in the form of a farm and assigned each haplotype to a farm. the likelihood of each tree was then estimated using epidemiological data. their study included assumptions of the mean incubation time prior to being infectious to be five days, the distribution of incubation times to follow a discrete gamma distribution, the most likely date of infection to be the date of reporting minus the date of the oldest reported lesion of the farm minus the mean incubation time, and the farms to be a source of infection immediately after being identified as infected up to the day of culling. spatial dependence in the transmission events was determined from the transmission tree by studying mean transmission distance. [ ] developed a bayesian likelihood-based framework integrating genetic and epidemiological data. this method was tested on an epidemic dataset of poultry farms in an epidemic of avian influenza a (h n ) in the netherlands in consisting of geographical, genomic, and date of culling data. consensus sequences of the ha, na and polymerase pb genes were derived by pooling sequence data from five infected animals for out of the farms analyzed. the likelihood of one farm infecting another increased if the former was not culled at the time of infection of the latter, if they were in geographical proximity, or if the sampled pathogen genomic sequences were related. their model included several assumptions such as non-correlation of genetic distance, time of infection, and geographical distance between host and target farms. the likelihood function was generated as follows: for the temporal component, a farm could infect another if its infection time was before the infection time of the target farm or if the infection time of the latter was between the infection and culling time of the former. if a farm was already culled, its infectiousness decayed exponentially. for the geographical component, two farms could infect each other with likelihood equal to the inverse of the distance between them. this likelihood varied according to a spatial kernel. for the genomic component, probabilities of transitions and transversions, and the presence or absence of a deletion was considered. if there was no missing data, the likelihood function was just a product of independent geographical, genomic, and temporal components. this method also allowed missing data by assuming that all the links to a specific missing data type are in one subtree. mcmc [ ] was performed to sample all possible transmission trees and parameters. marginalizing over a large number of subtrees over all possible values can also prove computationally expensive. mutations were assumed to be fixed in the population before or after an infection, ignoring a molecular clock. in the method by morelli et al. [ ] , the authors developed a likelihood-based function that inferred the transmission trees and infection times of the hosts. the authors assumed that a premise or farm can be infected at a certain time followed by a latency period, a time period from infectiousness to detection, and a time of pathogen collection. this method utilized the fmd dataset from the study by cottam et al. in order to simplify the posterior distribution further, latent variables denoting unobserved pathogens were removed and a pseudo-distribution incorporating the genetic distance between the observed and measured consensus sequences was generated. the posterior distribution corresponded to a pseudo-posterior distribution because the pathogens were sampled at observation time and not infection time. the genetic distance was measured by hamming distance between sequences in isolation without considering the entire genetic network. several assumptions including independence of latency time and infectiousness period were made. in determining the interval from the end-of-latency period to detection, the informative prior was centered on lesion age. this made this inference technique sensitive to veterinary estimates of lesion age. this study considered a single source of viral introduction in the population, which is feasible if the population size considered is small. this technique did not incorporate unobserved sources of infection and assumed all hosts were sampled. the authors also assumed that each host had the same probability of being infected. teunis et al. [ ] developed a bayesian inference framework to infer transmission probability matrices. the authors assumed that likelihood of infection transmission over all observed individuals would be equal to the product of conditional probability distributions between each pair of individuals i and j, and the correspond-ing entry from the transition probability matrix representing any possible transmissions from ancestors to i. the inferred matrices could be utilized to identify network metrics such as number of cases infected by each infected source and transmission patterns could be detected by analyzing pairwise observed cases during an outbreak. the likelihood function could be generated by observed times of onset, genetic distance, and geographical locations. their inferred parameters were the transmission tree and reproductive number. their method was applied to a norovirus outbreak in a university hospital in netherlands. in a method developed by ypma et al. [ ] , the statistical framework for inferring the transmission tree simultaneously generated the phylogenetic tree. this method also utilized the fmd dataset from the study by cottam et al. their approach for generating the joint posterior probability of the transmission tree differed from existing methods in including the simultaneous estimation of the phylogenetic tree and within-host dynamics. the posterior probability distribution defined a sampling space consisting of the transmission tree, epidemiological parameters, and withinhost dynamics which were inferred from the measured epidemiological data and the phylogenetic tree and mutation parameters which were inferred from the pathogen genomic data. the posterior probability distribution was estimated using the mcmc technique. the performance of the method was evaluated by measuring the probability assigned to actual transmission events. the assumptions made were that all infected hosts were observed, time of onset was known, sequences were sampled from a subpopulation of the infected hosts, and a single source/host introduced the infection in the population. in going beyond existing methods, the authors did not assume that events in the phylogenetic tree coincide with actual transmission events. a huge sampling fraction would be necessary to capture such microscale genetic diversity. this method works best when all infected hosts are observed and sampled. mollentze et al. [ ] have used multimodal data in the form of genomic, spatial and temporal information to address the problem of unobserved cases, an existing disease well established in a population, and multiple introductions of pathogens. their method estimated the effective size of the infected population thus being able to provide insight into number of unobserved cases. the authors modified morelli et al.'s method described above by replacing the spatial kernel with a spatial power transmission kernel to accommodate wider variety of transmission. in addition, the substitution model used by morelli et al. was modified by a kimura three parameter model [ ] . this method was applied to a partially-sampled rabies virus dataset from south africa. the separate transmission trees from partially-observed data could be grouped into separate clusters with most transmissions in the under-sampled dataset being indirect transmissions. reconstructions were sensitive to choice of priors for incubation and infectious periods. in a more recent approach to study outbreaks and possible transmission routes, jombart et al. [ ] , in addition to reconstructing the transmission tree, addressed important issues such as inferring possible infection dates, secondary infections, mutation rates, multiple pathways of pathogen introduction, foreign imports, unobserved cases, proportion of infected hosts sampled, and superspreading in a bayesian framework. jombart tested their algorithm outbreaker on the sars outbreak in singapore using known cases of primary and secondary infection [ , , ] . in this study, genome sequences of severe acute respiratory syndrome (sars) were downloaded from genbank and analyzed. their method relies on pathogen genetic sequences and collection dates. similar to their previous approach [ ] , their method assumed mutations to be parameters of transmission events. epidemiological pseudo-likelihood was based on collection dates. genomic pseudo-likelihood was computed based on genetic distances between isolates. this method would benefit from known transmission pathways and mutation rates and is specifically suitable for densely sampled outbreaks. their method assumed generation time-time from primary to secondary infections-and time from infection to collection were available. their method ignored within-host diversity of pathogens. instead of using a strict molecular clock, this method used a generational clock. didelot et al. [ ] developed a framework to examine if wholegenome sequences were enough to capture transmission events. unlike other existing studies, the authors took into account within-host evolution and did not assume that branches in phylogenetic trees correspond to actual transmission events. the generation time corresponds to the time between a host being infected and infecting others. for pathogens with short generation times, genetic diversity may not accrue to a very high degree and one can ignore within-host diversity. however, for diseases with high latency times and ones in which the host remains asymptomatic, there is scope for accumulation of considerable within-host genetic diversity. their method used a timed phylogenetic tree from which a transmission tree is inferred on its own or can be combined with any available epidemiological support. their simulations revealed that considering within-host pathogen generation intervals resulted in more realistic phylogenies between infector and infected. the method was tested on simulated datasets and with a real-world tuberculosis dataset with a known outbreak source with only genomic data and then modified using any available epidemiological data. the latter modified network resembled more the actual transmission activity in having a web-like layout and fewer bidirectional links. their approach would work well for densely sampled outbreaks. some of the most common parameters inferred for infectious disease transmission in these bayesian approaches are the transmission tree between infected individuals or animals, the mutation rates of different pathogens, phylogenetic tree, within-host diversity, latency period, and infection dates [ , , , ] . additional parameters in recent work are reproductive number [ ] , foreign imports, superspreaders, and proportion of infected hosts sampled [ ] . several simplifying assumptions have been made in the reviewed bayesian studies, limiting their applicability across different epidemic situations. in cottam's [ ] approach, the phylogenetic trees generated from the genomic data are weighed by epidemiological factors to limit analysis to possible transmission trees. however, sequential approaches may not be ideal to reconstruct transmission trees and a method that combines all modalities in a single likelihood function may be necessary. ypma et al. [ ] assumed that pathogen mutations emerge in the host population immediately before or following infections. moreover, the approach weighed each data type via their likelihood functions and considers each data type independent of the others, which may not be a realistic assumption. jombart et al. [ ] also inferred ancestral relationships to the most closely sampled ancestor as all ancestors may not be sampled. morelli et al. [ ] assumed flat priors for all model parameters. however, the method was estimated with the prior for the duration from latency to infection centered on the lesion age making the method sensitive to it and to veterinary assessment of infection age. the method developed by mollentze et al. [ ] required knowledge of epidemiology for infection and incubation periods. identifying parents of infected nodes, as proposed by teunis et al., [ ] assumes that all infectious cases were observed which may not be true in realistic, partiallyobserved outbreaks. didelot et al. [ ] developed a framework based on a timed phylogenetic tree, which infers within-host evolutionary dynamics with a constant population size and denselysampled outbreaks. several of these approaches rely on assumptions of denselysampled outbreaks, a single pathogen introduction in the population, single infected index cases, samples capturing the entire outbreak, that all cases comprising the outbreak are observed, existence of single pathogen strains, and all nodes in the transmission network having constant infectiousness and the same rate of transmission. however, in real situations the nodes will have different infectiousness and rate of spreading from animal to animal, or human to human. moreover, the use of clinical data only is nonrepresentative of how infection transmits to a population as it generally only captures the most severely affected cases. our literature review is summarized in table . as large-scale and detailed genomic data becomes more available, analyses of existing bayesian inference methods described in our review will inform their integration in epidemiological and other biomedical research. as more and more quantities of diverse data becomes available, developing bayesian inference frameworks will be the favored tool to integrate information and draw inference about transmission and epidemic parameters simultaneously. the specific focus in this review on the application of network inference in infectious disease transmission enables us to consider and comment on common parameters, data types and assumptions (summarized in table ). novel data sources have increased the resolution of information as well as enabled a closer monitoring and study of interactions; spatial and genomic resolution of the bayesian network-inference studies reviewed are summarized in fig. to illustrate the scope of current methods. further, we have added suggestions for addressing identified challenges in these methods regarding their common assumptions and parameters in table . given the increasing number and types of biomedical data available, we also discuss how models can be augmented to harness added value from these multiple and highergranularity modalities such as minor variant identification from deep sequencing data or community-generated epidemiological data. existing methods are based on pathogen genome sequences which may largely be consensus in nature where the nucleotide or amino acid residue at any given site is the most common residue found at each position of the sequence. other recent approaches have reconstructed epidemic transmission using whole genome sequencing. detailed viral genomic sequence data can help distinguish pathogen variants and thus augment analysis of transmission pathways and host-infectee relationships in the population. highly parallel sequencing technology is now available to study rna and dna genomes at greater depth than was previously possible. using advanced deep sequencing methods, minor variations that describe transmission events can be captured and must also then be represented in models [ , ] . models can also be encumbered with considerable selection bias by being based on clinical or veterinary data representative of a subsample of only the most severely infected hosts who access clinics. existing multi-modal frameworks are designed based on clinical data such as sequences collected from cases of influenza [ , ] or veterinary assessment of fmd [ , ] , which generally represent the most severe cases with access to traditional healthcare institutions and automatically inherit considerable selection bias. models to-date do not consider participatory surveillance data that has become increasingly available via mobile and internet accessibility (e.g. data from web logs, search queries, web survey-based participatory efforts such as goviral with linked symptomatic, immunization, and molecular information [ ] and online social networks and social network questionnaires). another approach to improve the granularity of collected data could be community-generated data. these data can be finegrained and can capture information on a wide range of cases from asymptomatic to mildly infectious to severe. this data can be utilized to incorporate additional transmission parameters of a community which can be more representative of disease transmission. as exemplified in fig. a , community-generated data can be collected at the fine-grained spatial level of households, schools, workplaces, or zip codes and models must then also accommodate these spatial resolutions. studies to-date have also generally depended on available small sample sizes and some are specifically tailored to a specific disease or pathogen such as sars, avian influenza, or fmd [ , , ] . hiseq platform with m. tuberculosis cdc reference sequence and aligned using burrows-wheeler aligner algorithm. sars dna sequences were obtained from genbank and aligned using muscle. for avian influenza, rna consensus sequences of the haemagglutinin, neuriminidase and polymerase pb genes were sequenced. for h n influenza, isolates were typed for hemagglutinin (ha) and neuraminidase (na) genes. methods will have to handle missing data and unobserved and unsampled hosts to be applicable to realistic scenarios. in simpler cases, assumptions of single introductions of infection with single strains being passed between hosts may be adequate. however, robust frameworks will have to consider multiple introductions of pathogens in the host population with multiple circulating strains and co-infections in hosts. in order to be truly useful, frameworks have to address questions regarding rapid mutations of certain pathogens, phylogenetic uncertainty, recombination and reassortment, population stochastics, super spreading, exported cases, multiple introductions of pathogens in a population, within and between-host pathogen evolution, and phenotypic information. methods will also need to scale up to advances in nextgeneration sequencing technology capable of producing large amounts of genomic data inexpensively [ , ] . in the study of infectious diseases, the challenge remains to develop robust statistical frameworks that will take into account the relationship between epidemiological data and phylogeny and utilize that to infer pathogen transmission while taking into account realistic evolutionary times and accumulation of withinhost diversity. moreover, to benefit public health inference methods need to uncover generic transmission patterns, wider range of infections and risks including asymptomatic to mildly infectious cases, clusters and specific environments, and host types. network inference frameworks from the study of infectious diseases can be analogously modified to incorporate diverse forms of multimodal data and model information propagation and interactions in diverse applications such as drug-target pairs and neuronal connectivity or social network analysis. the detailed examination of models, data sources and parameters performed here can inform inference methods in different fields, and bring to light the way that new data sources can augment the approaches. in general, this will enable understanding and interpretation of influence and information propagation by mapping relationships between nodes in other applications. review of multimodal integration methods for transmission network inference a comprehensive assessment of methods for de-novo reverse-engineering of genome-scale regulatory networks sparse and compositionally robust inference of microbial ecological networks model-free reconstruction of excitatory neuronal connectivity from calcium imaging signals dialogue on reverse-engineering assessment and methods molecular ecological network analyses marine bacterial, archaeal and protistan association networks reveal ecological linkages network modelling methods for fmri modeling the worldwide spread of pandemic influenza: baseline case and containment interventions a 'smallworld-like' model for comparing interventions aimed at preventing and controlling influenza pandemics reducing the impact of the next influenza pandemic using household-based public health interventions estimating the impact of school closure on influenza transmission from sentinel data model-free reconstruction of excitatory neuronal connectivity from calcium imaging signals network modelling methods for fmri sparse and compositionally robust inference of microbial ecological networks a bayesian framework for the analysis of microarray expression data: regularized t-test and statistical inferences of gene changes mvda: a multi-view genomic data integration methodology information content and analysis methods for multi-modal high-throughput biomedical data a novel computational framework for simultaneous integration of multiple types of genomic data to identify microrna-gene regulatory modules a kernel-based integration of genome-wide 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zhidong title: modeling heterogeneity in direct infectious disease transmission in a compartmental model date: - - journal: int j environ res public health doi: . /ijerph sha: doc_id: cord_uid: bm z gss mathematical models have been used to understand the transmission dynamics of infectious diseases and to assess the impact of intervention strategies. traditional mathematical models usually assume a homogeneous mixing in the population, which is rarely the case in reality. here, we construct a new transmission function by using as the probability density function a negative binomial distribution, and we develop a compartmental model using it to model the heterogeneity of contact rates in the population. we explore the transmission dynamics of the developed model using numerical simulations with different parameter settings, which characterize different levels of heterogeneity. the results show that when the reproductive number, [formula: see text] , is larger than one, a low level of heterogeneity results in dynamics similar to those predicted by the homogeneous mixing model. as the level of heterogeneity increases, the dynamics become more different. as a test case, we calibrated the model with the case incidence data for severe acute respiratory syndrome (sars) in beijing in , and the estimated parameters demonstrated the effectiveness of the control measures taken during that period. mathematical models play an important role in understanding epidemic spread patterns and designing public health intervention measures [ ] [ ] [ ] [ ] . the traditional deterministic compartmental models usually assume homogeneous mixing, which means that each individual has the same probability of contact with all of the others in the population [ ] . however, there is a growing awareness that this assumption is not the case in reality, because heterogeneity can arise due to many sources [ ] , including age, sex, susceptibility to disease, position in space and the activities and behaviors of individuals, among others [ ] . here, we will focus on the heterogeneity in host contact rates at the population level. in recent years, scientists have developed different approaches to model heterogeneity in host contact rates. first, traditional compartmental models were extended: the infection term of the homogeneous mixing compartmental models was modified [ ] [ ] [ ] . the compartments were further divided into multiple subgroups with similar behavioral characteristics (e.g., risk [ ] ) or demography (e.g., age [ , ] ). second, along with the rapid development in research on complex networks, a large body of literature has examined the effects of the heterogeneous contact structure on disease spread in networks [ , ] . the third type of modeling approach considering heterogeneity is agent-based modeling [ ] [ ] [ ] , which characterizes the heterogeneity in individual attributes and behaviors. additionally, several researchers have attempted to bridge the gap between traditional compartmental models and individual-based models [ ] [ ] [ ] . in this paper, we develop a new compartmental model to incorporate heterogeneous contact rates in disease transmission. first, by combining a poisson distribution and a gamma distribution, we derived a negative binomial distribution (nbd) transmission function, with which we developed a compartmental model. then, we explored the influence of different levels of heterogeneity on the transmission dynamics of infectious diseases using numerical simulations. finally, we calibrated the model with the number of daily cases of severe acute respiratory syndrome (sars) in beijing in , and the estimated parameters show that the control measures taken at that time were effective. the heterogeneity in transmission can be modeled by assuming that the number of contacts among individuals varies from person to person. let x i represent the number of effective contacts (the number of contacts that would be sufficient for transmitting the disease successfully, were it to occur between a susceptible individual and an infectious individual [ , ] ) with infectious individuals of the i-th susceptible person per unit time. assume that x i has a poisson distribution π(θ i ), where θ i is the mean of the number of effective contacts that the i-th susceptible individual makes with infectious individuals per unit time. that θ i are identical means that each individual has an equal chance of effective contact with infectious individuals and an equal chance of being infected, thereby resulting in a traditional homogeneous-mixing model. in reality, however, individuals typically come into contact with only a small, clustered, subpopulation [ ] . therefore, it is reasonable to assume that different individuals have different average effective numbers of contacts in a certain period of time; that is, θ i is itself a random variable. the gamma distribution is a good choice for describing θ i for a variety of reasons: it is bounded on the left at zero (the numbers of contact must be non-negative), is positively skewed (it has non-zero probability of an extremely high number of contacts) and can represent a variety of distribution shapes [ ] . it has been used to describe the expected number of secondary cases caused by a particular infected individual [ ] . therefore, we assume a gamma distribution for θ i , with shape parameter k, rate parameter m (or scale parameter m ) and the following probability distribution function: the conditional distribution of x i given θ i = θ is: we obtain the marginal distribution of x i : this is the probability density function of an nbd with mean k m and variance k( +m) m . then, the probability of a susceptible individual escaping from being infected can be represented by the zero term of the nbd: let the mean of the nbd be equal to the mean of the number of effective contacts of all susceptible individuals with infectious individuals, that is k m = βi n , where β denotes the transmission rate, defined as the per capita rate at which two specific individuals come into effective contact per unit time [ ] ; i denotes the number of infectious individuals; and n denotes the size of the total population. it follows that m = βi kn , and: consider a closed population (without births, deaths and migration into or out of the population). let s t and i t denote the numbers of the susceptible and infectious individuals at time t, respectively. then, the difference equation relating s t and i t at successive time steps t and t + is: here, λ t = − ( + βi t kn ) −k is the risk of a susceptible individual becoming infected between time t and t + . using the relationship between the risk and rate derived in [ ] , risk = − e rate , we obtain the rate at which susceptible individuals become infected at time t: therefore, the rate of change in the number of susceptible individuals can be represented by the differential equation representing: we call k ln( + βi kn ) in the right side of this equation the nbd transmission function. a similar function, k ln( + ap t k ), and its discrete form, ( + ap t k ) −k , were first used in host-parasitoid models, where a denotes the per capita searching efficiency of the parasitoid and p t denotes the number of parasitoids [ , ] . then, they were used in insect-pathogen models [ ] . in [ ] , the author used the transmission function, k ln( + βi k ), to model a possum-tuberculosis (tb) system. the influence of different transmission functions on a simulated pathogen spread was studied in [ ] . because: when k → ∞, the nbd transmission function we derived here approximates the frequency-dependent transmission function of the homogeneous-mixing model. therefore, it can be regarded as a generalized frequency-dependent transmission function [ , ] . similarly, the nbd transmission function used in [ ] can be regarded as a generalized density-dependent transmission function [ , ] . comparing the nbd transmission function with the density-dependent transmission function, βsi, and the frequency-dependent transmission function, βsi n , of the homogeneous-mixing model [ , ] , we obtain one more parameter, k, which is the shape parameter of the gamma distribution (equation ( )). denote the mean of the gamma distribution as µ θ ; then, the variance is µ θ k . setting the mean to be a constant and letting k → ∞, the variance goes to zero, resulting in homogeneous-mixing, just as shown in equation ( ) . in contrast, the variance increases as the value of k decreases, which indicates greater heterogeneity of the contact rates between the susceptible and infectious populations. therefore, the parameter k characterizes the level of heterogeneity. the standard susceptible-exposed-infectious-recovered (seir) model divides the total population into four compartments: susceptible (s, previously unexposed to the pathogen), exposed (e, infected, but not yet infectious), infected (i, infected and infectious) and recovered (r, recovered from infection and acquired lifelong immunity) [ , , ] . the infection process is represented in figure . children are born susceptible to the disease and enter the compartment s. a susceptible individual in compartment s is infected after effective contact with an infectious individual in compartment i and then enters the exposed compartment e. after the latent period ends, the individual enters the compartment i and becomes capable of transmitting the infection. when the infectious period ends, the individual enters the recovered class r and will never be infected again [ , ] . in each compartment, individual death occurs at a constant rate, µ, which is equal to the birth rate. death induced by the disease is not considered here. therefore, the total population size in the model, n, remains unchanged. the seir model and its extension have been used to model many infectious diseases, for example, measles [ ] [ ] [ ] , rubella [ , ] , influenza [ , ] and sars [ , ] , among others. using the nbd transmission function, we set up a new seir model in a closed population, represented by a set of ordinary differential equations: where the parameter α is the rate at which individuals in the exposed category become infectious per unit time, and its reciprocal is the average latent period [ , ] ; the parameter γ is the rate at which infectious individuals recover (become immune) per unit time, and its reciprocal is the average infectious period [ , ] ; and the parameter µ refers to the birth and death rates. based on the next-generation matrix approach [ ] , we derive the basic reproductive number (see appendix a for further details), which is identical to that of the homogeneous-mixing model with a frequency-dependent transmission function [ ] . it is worth noting that it is irrelevant to k, which means that it does not depend on the level of heterogeneity. this can be explained by r being an average quantity, which means that it does not consider the individual variance in infectiousness [ ] . this result is in agreement with the conclusion made using a meta population version of the standard stochastic sir model incorporating spatial heterogeneity [ ] . we now determine the equilibrium states. without much work, we can obtain the disease-free equilibrium (n, , , ). we also derive the approximate size of the infectious compartment at the endemic equilibrium, . this is identical to that of the homogeneous-mixing model with a frequency-dependent transmission function [ ] . similar to r , it does not depend on k. in other words, the contact heterogeneity does not influence the endemic equilibrium, although it does change the dynamics, which we demonstrate using numerical simulations in the next section. using numerical simulations, we explore the influence of the heterogeneity level on the transmission dynamics, characterized by the parameter k. the results show that the infectious curves with fixed β, but different values of k achieve a peak after a period that is almost the same in duration (figure a) . however, the transmission speed and, therefore, the peak size, as well as the dynamics after the peak are very different. a low level of heterogeneity results in dynamics similar to those predicted by the homogeneous-mixing model with a frequency-dependent transmission term, βsi n . this is consistent with the conclusion inferred in equation ( ). as the value of k decreases, that is the level of heterogeneity increases, the dynamics differ increasingly from those predicted by the homogeneous-mixing model. the greatest difference is that at the overall level, the heterogeneity slows the transmission speed and decreases the peak sizes, which means milder disease outbreaks, because in the scenario with a high level of heterogeneity, only a small proportion of susceptible individuals have chances of coming into contact with infectious individuals and becoming infected, which results in a slower increase of the infected population. second, after the peak is attained, the infectious curves do not decline as rapidly as those predicted by the homogeneous-mixing model and the nbd models (equation ( )) with larger values of k (figure a) , and the disease persists over a long term in the population ( figure b ). compared to the homogeneous-mixing model or the nbd models with larger values of k, up to the peak time (almost the same), there are many more individuals who are still susceptible to the disease. a proportion of them come into contact with infectious individuals and become infected, and this process persists for a long period of time. moreover, figure b shows that the endemic sizes of the two scenarios are approximately equal, just as noted in the previous section. in addition, when k drops to a very small value, there will be no disease outbreak, because almost none of the susceptible individuals have any chance of coming into contact with infectious individuals and becoming infected. it is shown that the contact patterns exhibit more heterogeneity than that assumed by homogeneous-mixing models, but they do not appear extremely heterogeneous [ ] . we also simulate the dynamics with a fixed value of k and different values of β. because the dynamics obtained with a large value of k are similar to those of the homogeneous-mixing model with a frequency-dependent transmission term, we only show the results for a relatively small value of k = − (figure ). for larger values of β, the infectious curves reach their peaks earlier, and the peaks are higher than those obtained for smaller values of β. after the peak of the disease outbreak is achieved, the infectious curves decrease slowly and reach endemic equilibrium gradually ( figure b ). additionally, for much smaller values of β, such that r < , there will be no disease outbreak (here, for example, β = . ). the sars disease broke out in the beginning of march in beijing, spread rapidly over the next six weeks and peaked during the third and fourth weeks of april [ ] . in total, confirmed cases were reported during the entire outbreak period (the circle markers shown in figure ; the data were provided by the chinese center for disease control and prevention). prompted by the rapid expansion of the epidemic, on april, the beijing municipal government established a joint sars leading group and deployed task forces to oversee crisis management [ , ] . on april, a larger number of cases was reported, and the chinese government canceled the may day holiday in an effort to reduce the mass movement of people [ ] . multiple measures were taken to control the spread of the disease, including the provision of personal protective equipment and training for healthcare workers [ ] ; introduction of community-based prevention and control through case detection, isolation, quarantine and community mobilization [ ] ; closure of the sites of public entertainment and schools [ ] ; and stopping the entry of all visitors or screening them for fever upon entry to universities and other places [ ] . additionally, a general increase in sars awareness played an important role in controlling the outbreak [ ] . the multiple measures implemented in beijing likely led to the rapid resolution of the sars outbreak [ ] . to evaluate the effectiveness of the control measures taken in beijing at that time, we calibrated the nbd model to the data of the sars daily cases using the globalsearch algorithm in the matlab global optimization toolbox [ , ] and estimated the parameters. we used two different values, k and k , to characterize the different levels of heterogeneity in contact in the population before and after april [ ] . we assumed a fixed value for β for simplicity (in reality, the value of β decreased along with the control strategies [ ] ; we mainly discuss the influence of the other parameter, k). we chose the normalized root mean square error (nrmse) [ ] as the goodness of fit between the model output and the daily case data, as well as the objective function of the calibration procedure. in order to compute the nrmse, we solved the set of differential equations (equation ( )) with unknown parameters α, β, γ and k = k from march to april. the initial conditions were set as follows: s( ) = . × , which was the size of the permanent population in beijing in [ ] ; t = corresponds to march ; e( ) = ; i( ) = , which was the number of daily cases on march ; and r( ) = . then, the output of the model on april was taken as the initial value to solve equation ( ) with parameters α, β, γ and k = k from april to june. finally, the two outputs were combined and used to calculate the goodness of fit to the sars daily case data. the birth and death rate, µ, was assumed to be / year − . in total, there were five unknown parameters to be estimated: k , k , α, β and γ. the starting points of the parameters for the calibration procedure were selected randomly between the bounds of the parameters shown in table . because of the stochasticity of the globalsearchalgorithm [ , ] , the results varied slightly every time. we ran the procedure times. table presents the minimum, maximum, mean and standard variance of the results. the average latent and infectious periods are α = . days and γ = . days, respectively. the much smaller k value indicates that the control measures are extremely effective in controlling the sars transmission in beijing in . this is in agreement with the result in [ ] . figure shows the fitted infectious curves and the daily cases. in this paper, we aimed to study the influence of heterogeneity in the contact rates in disease transmission at the population level. the developed nbd model can be regarded as a generalized homogeneous-mixing model with a frequency-dependent transmission function. our results show that, keeping other conditions identical, the higher is the level of heterogeneity in contact rates, the greater is the difference in the disease dynamics observed from those predicted using the homogeneous-mixing models. it is worthwhile to compare our approach and results to previous approaches and results. to address heterogeneous-mixing within populations, the populations were further divided into multiple subgroups [ ] [ ] [ ] , and used the waifw matrix ("who acquires infection from whom" [ ] ), in which any individual is more likely to come into contact with other individuals from within the same subgroup than those outside. however, in this framework, contact rates within the subgroups are still homogeneous. a different class of approaches for extending the traditional compartmental models to incorporate heterogeneity involves modifying the transmission term; our approach belongs to this class. the work in [ , , ] replaced the bilinear transmission term (si) in the homogeneous compartmental model with a nonlinear term ks p i q , where k, p, q are the "heterogeneity parameters". their results showed that the modified model was capable of predicting the disease transmission patterns in a clustered network [ ] . stroud et al. used a power-law scaling of the new infection rate i(s/n) v , with scaling power v greater than one, to relax the homogeneous-mixing assumption [ ] , and it was demonstrated that this power-law formulation leads to significantly lower predictions of the final epidemic size than the traditional linear formulation. compared to these empirical or semi-empirical modifications [ ] [ ] [ ] ] , the nbd transmission function seems to agree more with the real transmission mechanics, in that it assumes that the mean of the number of effective contacts of the susceptible individuals with infectious individuals per unit time is different from individual to individual, and the choice of the gamma distribution offers multiple advantages (see section . ). in recent years, several network-based models have been developed to study the influence of contact heterogeneity on disease transmission. keeling et al. reviewed multiple types of networks and the statistical and analytical approaches for the spread of infectious diseases [ , ] . in particular, bansal et al. demonstrated that the high-level heterogeneous degree distributions generate an almost immediate expansion phase compared to homogeneous degree distributions, such as the poisson distribution [ , , ] . the nbd-seir model does not exhibit this feature. we suspect that this is because our approach belongs to the mean-field class of approaches and considers a large population at the overall level. in addition, it is possible to approximate the main features of disease spread in networks with compartmental models using an appropriate construction. the work in [ ] used r as a fundamental parameter to formulate a mean-field type model, which can implicitly capture some important effects of heterogeneous-mixing in contact networks. the work in [ , ] applied "edge-based compartmental modeling" (ebcm), which focuses on the status of a random partner rather than a random individual, to capture the heterogeneous contact rates in disease transmission. although it incorporates the heterogeneous contact rates in disease transmission in a tractable manner, the nbd model has some weaknesses. first, the parameter k characterizes the level of heterogeneity, which is difficult to measure directly, and this can be overcome by using contact tracing data. second, some features cannot be recovered by the nbd model. in future research, it will be interesting to incorporate other factors that influence transmission dynamics, such as the migration of populations, seasonality and vaccinations, among others. using the probability density function for the negative binomial distribution, we constructed a nbd transmission function and further developed a compartmental model for direct infectious disease. the developed model considers the heterogeneity of contact rates in the population. the simulation results show that, at the population level, the dynamics vary widely according to the level of heterogeneity in contact rates. once r > , a low level of heterogeneity results in dynamics similar to those predicted by the homogeneous mixing models. keeping other conditions identical, as the level of heterogeneity increases, the transmission speed becomes more and more slowly, the peak size becomes smaller and smaller. these results have implications for developing interventions, such as isolation, targeted vaccination, among others. individuals: x = (e, i, s, r). here, the infected compartments are e and i, yielding m = . then, we decompose the components of the differential equations into f , in which f i is the rate of appearance of new infections in compartment i, and v , in which v i is the rate of transfer of individuals into and out of compartment i by all other means: the disease-free equilibrium (dfe) for this model is x = ( , , n, ). then, giving: this is called the next-generation matrix for the model [ ] . finally, the basic reproductive number, r , is calculated using the spectral ratio: because the total population size n is a constant and r = n − s − e − i, the last equation in equation ( ) is redundant. to find the endemic equilibrium, we set the right side of the other three equations to zero. then, s and e can be represented by i: s = µn µ + k ln( + βi kn ) , e = γ + µ α substituting them into k ln( + βi kn )s − (α + µ)e = and after some algebraic manipulation, we obtain: obviously, it is difficult and even impossible to find an explicit solution. we find an approximate solution using the first-degree taylor polynomial of ln( + x) near x = , that is ln( + x) ≈ x. it follows that, we obtain the approximate solution for i: where r is given in equation ( ). infectious diseases of humans: dynamics and control the mathematics of infectious diseases mathematical models of infectious disease transmission modeling infectious diseases in humans and animals models 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airline travel on the geographic spread of pandemic influenza modelling control measures to reduce the impact of pandemic influenza among schoolchildren transmission dynamics and control of severe acute respiratory syndrome spatial dynamics of an epidemic of severe acute respiratory syndrome in an urban area reproduction numbers and sub-threshold endemic equilibria for compartmental models of disease transmission spatial heterogeneity and the persistence of infectious diseases evaluation of control measures implemented in the severe acute respiratory syndrome outbreak in beijing chinese national security: decisionmaking under stress; strategic studies institute of the us army war college (ssi global optimization toolbox scatter search and local nlp solvers: a multistart framework for global optimization goodness of fit between test and reference data frequently asked questions about sars dynamical patterns of epidemic outbreaks in complex heterogeneous networks sir dynamics in random networks with heterogeneous connectivity edge-based compartmental modelling for infectious disease spread incorporating disease and population structure into models of sir disease in contact networks the author for correspondence, jinfeng wang, designed the whole study, and lingcai kong implemented the method and drafted the manuscript. weiguo han and zhidong cao revised the manuscript critically and made constructive suggestions for the interpretation of the results. there was no conflict of interest regarding the submission of this manuscript, and it was approved by all authors for publication. using the next-generation operator approach [ ] , we compute the basic reproductive number r . first, we sort the compartments so that the first m compartments correspond to infected key: cord- -od nnxvg authors: morawska, lidia; tang, julian w.; bahnfleth, william; bluyssen, philomena m.; boerstra, atze; buonanno, giorgio; cao, junji; dancer, stephanie; floto, andres; franchimon, francesco; haworth, charles; hogeling, jaap; isaxon, christina; jimenez, jose l.; kurnitski, jarek; li, yuguo; loomans, marcel; marks, guy; marr, linsey c.; mazzarella, livio; krikor melikov, arsen; miller, shelly; milton, donald k.; nazaroff, william; nielsen, peter v.; noakes, catherine; peccia, jordan; querol, xavier; sekhar, chandra; seppänen, olli; tanabe, shin-ichi; tellier, raymond; wai tham, kwok; wargocki, pawel; wierzbicka, aneta; yao, maosheng title: how can airborne transmission of covid- indoors be minimised? date: - - journal: environ int doi: . /j.envint. . sha: doc_id: cord_uid: od nnxvg abstract during the rapid rise in covid- illnesses and deaths globally, and notwithstanding recommended precautions, questions are voiced about routes of transmission for this pandemic disease. inhaling small airborne droplets is probable as a third route of infection, in addition to more widely recognized transmission via larger respiratory droplets and direct contact with infected people or contaminated surfaces. while uncertainties remain regarding the relative contributions of the different transmission pathways, we argue that existing evidence is sufficiently strong to warrant engineering controls targeting airborne transmission as part of an overall strategy to limit infection risk indoors. appropriate building engineering controls include sufficient and effective ventilation, possibly enhanced by particle filtration and air disinfection, avoiding air recirculation and avoiding overcrowding. often, such measures can be easily implemented and without much cost, but if only they are recognised as significant in contributing to infection control goals. we believe that the use of engineering controls in public buildings, including hospitals, shops, offices, schools, kindergartens, libraries, restaurants, cruise ships, elevators, conference rooms or public transport, in parallel with effective application of other controls (including isolation and quarantine, social distancing and hand hygiene), would be an additional important measure globally to reduce the likelihood of transmission and thereby protect healthcare workers, patients and the general public. during the rapid rise in covid- illnesses and deaths globally, and notwithstanding recommended precautions, questions are voiced about routes of transmission for this pandemic disease. inhaling small airborne droplets is probable as a third route of infection, in addition to more widely recognized transmission via larger respiratory droplets and direct contact with infected people or contaminated surfaces. while uncertainties remain regarding the relative contributions of the different transmission pathways, we argue that existing evidence is sufficiently strong to warrant engineering controls targeting airborne transmission as part of an overall strategy to limit infection risk indoors. appropriate building engineering controls include sufficient and effective ventilation, possibly enhanced by particle filtration and air disinfection, avoiding air recirculation and avoiding overcrowding. often, such measures can be easily implemented and without much cost, but if only they are recognised as significant in contributing to infection control goals. we believe that the use of engineering controls in public buildings, including hospitals, shops, offices, schools, kindergartens, libraries, restaurants, cruise ships, elevators, conference rooms or public transport, in parallel with effective application of other controls (including isolation and quarantine, social distancing and hand hygiene), would be an additional important measure globally to reduce the likelihood of transmission and thereby protect healthcare workers, patients and the general public. the significance of viral transmission via small airborne microdroplets (also commonly referred to as 'aerosols') has been intensely discussed in the context of the sars-cov- /covid- (severe acute respiratory syndrome coronavirus- /coronavirus disease ) pandemic (lewis ; morawska et al. ) . this is one of three commonly accepted modes of viral transmission, the other two being via larger respiratory droplets (which fall close to where they are expired), and direct contact with contaminated surfaces (fomites). especially with the ongoing global shortage of personal protective equipment (mainly surgical masks and n /ffp /ffp respirators) (who c), additional methods to reduce the risk of sars-cov- transmission indoors need to be considered. the need is acute in particular in hospitals and other healthcare facilities managing covid- patients. while evidence for airborne transmission of covid- is currently incomplete, several hospital-based studies have performed air-sampling for sars-cov- , including one published paper (ong et al. ) , one early-release paper (guo et al. ) and papers still in pre-print at the time of writing (chia et al. ; ding et al. ; jiang et al. ; liu et al. ; santarpia et al. ) . four of these studies found several positive samples for sars-cov- genome (rna) in air using polymerase chain reaction (pcr) testing (chia et al. ; jiang et al. ; liu et al. ; santarpia et al. ) , two found very small numbers of positive samples (ding et al. ) , and only one (ong et al. ) found no positive air samples. this evidence at least demonstrates a potential risk for airborne transmission of sars-cov- . in addition, amongst these studies, three also reported some quantitative viral rna data. the singaporean study found positive air samples in of the patient infection isolation rooms, with samples in the - µm and > µm size ranges containing a range of viral loads ( . - . viral rna copies per l of air) (chia et al. ). the study from nebraska, usa found that % of the air samples were positive with a mean viral load of . copies/l, including in patient rooms and the hallway air (santarpia et al. ). in one case, they sampled close to the patient (mean: . copies/l) and at > . m (mean: . copies/l), suggesting some dilution with distance. the highest viral loads were found in personal samplers worn by the sampling team when in the presence of a patient receiving oxygen via nasal cannula (mean: and copies/l), indicating that this treatment may promote the spread of airborne virus. a study in wuhan, china (liu et al. ) provides quantitative data for their small number of positive air samples, with . rna copies/l in a toilet area and . - . copies/l in a room used to remove ppe. more than half the viral rna in these samples was associated with aerosols < . µm. this study also measured deposition through passive aerosol sampling, reporting deposition rates of and rna copies/m per h at samplers located approximately m and m from the patients, respectively (liu et al. ) . whilst this evidence may be deemed to be incomplete at present, more will arise as the covid- pandemic continues. in contrast, the end-stage pathway to infection of the droplet and contact transmission routes has always been assumed to be via self-inoculation into mucous membranes (of the eyes, nose and mouth). surprisingly, no direct confirmatory evidence of this phenomenon has been reported, e.g. where there have been: (i) follow-up of fomite or droplet-contaminated fingers of a host, self-inoculated to the mucous membranes to cause infection, through the related disease incubation period, to the development of disease, and (ii) followed by diagnostic sampling, detection, sequencing and phylogenetic analysis of that pathogen genome to then match the sample pathogen sequence back to that in the original fomite or droplet. it is scientifically incongruous that the level of evidence required to demonstrate airborne transmission is so much higher than for these other transmission modes (morawska et al. ). the infectious agents of several other diseases (tuberculosis, measles, chickenpox) are recognised to be transmissible via the airborne route, either by the short-range (face-to-face, for other respiratory viruses, including sars-cov, mers-cov (middle-east respiratory syndrome coronavirus), respiratory syncytial virus (rsv -a common cause of bronchiolitis in infants) and influenza, both short-range and longer-range airborne transmission are possible, but the predominance of longer range transmission route in various exposure scenarios is difficult to quantify (booth et al. ; kim et al. ; kulkarni et al. ; li et al. ; tellier et al. ) , and may at times be opportunistic (roy et al. ) . a recent mechanistic modelling study showed that short-range airborne transmission dominates exposure during close contact (chen w et al. ) . other studies investigating the transport of human-expired microdroplets and airflow patterns between people also provide substantive support for this transmission route (ai et al. ; li et al. ; liu et al. ) . therefore, in light of this body of evidence for these other respiratory viruses; we believe that sars-cov- should not be treated any differently -with at least the potential for airborne transmission indoors. organization) (who b), continue to place insufficient emphasis on protection from small, virus laden, airborne droplets. other organisations that deal with building environmental control systems, such as rehva (the federation of european heating, ventilation and air conditioning associations) and ashrae (the american society of heating, ventilating, and air-conditioning engineers), have acknowledged the potential airborne hazard indoors and recommended ventilation control measures accordingly (ashrae a; rehva ). infection control specialists also often inquire about the relative contribution of airborne transmission compared to the other transmission modes ('contact' and 'droplet'). multiple studies provide strong evidence for indoor airborne transmission of viruses, particularly in crowded, poorly ventilated environments (coleman et al. ; distasio et al. ; knibbs et al. ; li et al. ; moser et al. ; nishiura et al. ) . however, it is generally difficult to quantitatively compare and conclude which transmission route is the most significant in a given situation. infection may occur via all routes to different degrees depending on the specific exposure circumstances. effective infection control necessitates protection against all potentially important exposure pathways. here, in the face of such uncertainty, we argue that the benefits of an effective ventilation system, possibly enhanced by particle filtration and air disinfection, for contributing to an overall reduction in the indoor airborne infection risk, are obvious (eames et al. ). to maximise protection of the population against the airborne spread of sars-cov- and any other airborne virus-containing small microdroplets, several recommendations are necessary as presented below. these focus on indoor environments, because this is where most transmission occurs (nishiura et al. ) . further, the measures mostly apply to public buildings. in residential houses and apartments, normal practices (e.g. segregating infected individuals, opening windows and doors, and using portable air-cleaning devices when practical) to ensure healthy indoor air, should stay in place at any moment. ventilation airborne protection measures which already exist can be easily enhanced at a relatively low cost to reduce the number of infections and consequently to save lives. the options discussed below should always be implemented in combination with other existing measures (like hand-washing and use of ppe) to reduce infection via other important routes of transmission, as none of them can be completely excluded in any exposure event. the remainder of this article will only cover recommendations for 'engineering level' controls, as described in the traditional infection control hierarchy (figure ) to reduce the environmental risks for airborne transmission. ventilation is the process of providing outdoor air to a space or building by natural or mechanical means (iso ) . it controls how quickly room air is removed and replaced over a period of time. in some cases, it is necessary to remove pollution from outdoor air before bringing it into a building, by using adequate filtration systems. ventilation plays a critical role in removing exhaled virus-laden air, thus lowering the overall concentration and therefore any subsequent dose inhaled by the occupants. appropriate distribution of ventilation (e.g. placement of supply and exhaust vents) ensures that adequate dilution is achieved where and when needed, avoiding the build-up of viral contamination (melikov ; melikov ; thatiparti et al. ; ) . the central guiding principle is to replace contaminated air with clean air, but sometimes local barriers to this process may occur, e.g. where partitions are used or curtains drawn for privacy or medical procedures. if these barriers are in use, secondary or auxiliary measures may be needed to achieve requisite ventilation effectiveness. good ventilation practices are already in place in many hospital settings, as part of everyday and emergency measures to protect against droplet and contact transmission (phiri ) . good ventilation also protects the occupants against airborne transmission. the capacity to increase ventilation rates when needed (such as during the covid- pandemic) may differ, and may be somewhat limited by their original design specifications and implementation. note that many hospitals are naturally ventilated in ward areas, including in some rooms used for critical care. however, if the airflow passage is obstructed (e.g. by closing windows and doors), airborne pathogen concentration can sharply rise leading to an increased risk of airborne transmission and infection (gilkeson et al. a hence, in such environments, with lower ventilation rates intended primarily to control indoor air quality (which may also include some hospital emergency, acute admissions, as 'stay-at-home' lockdown measures are gradually relaxed, much of the population may return to spending increasing amounts of time in inadequately ventilated workplaces, offices, schools and other public buildings, where they may be exposed to a risk of acquiring viral infections by inhalation. in a mechanically ventilated building, ventilation air is typically provided by a heating, ventilating and air conditioning (hvac) system. sometimes, ventilation air is provided by dedicated fans or outdoor air units. shase ). another example is the modification of a hospital ward ventilation system to create a negative pressure isolation ward (miller et al. ). if ventilation is provided using windows openings (aeration) or other means (fixed openings, e.g., natural ventilation), an estimation of the possible outdoor flow rate can be made using cen standard, en - : (cen , or other available references as (aivc ; cibse ) . the outdoor air flow rate that is achieved is strongly dependent on the specific local conditions (opening sizes, relative positions, climatic and weather conditions, etc.) and should be estimated case by case; it can easily range from up to ach or more. for naturally ventilated public buildings, particularly in cold climates, other challenges will arise, but these can also be addressed in order to reduce the risk of airborne infection transmission. it may be necessary to provide additional heating in some buildings to maintain thermal comfort, particularly where the occupants are vulnerable. the recirculation of air is a measure for saving energy, but care must be taken, as it can transport airborne contaminants (including infectious viruses) from one space and distribute them to other spaces connected to the same system, potentially increasing the risk of airborne infection in areas that otherwise would not have been contaminated. this concern has been noted previously in regard to the possible recirculation of biological agents during terrorist attacks that have investigated the effectiveness of eliminating recirculation (e.g. providing % outside air to spaces and exhausting all of it) as a countermeasure following an indoor release of the agent (persily et al. ) . a study modelling the risk of airborne influenza transmission in passenger cars provided also a case against air recirculation in such situations (knibbs et al. ) . particulate filters and disinfection equipment in recirculated air streams can reduce this risk, but they need to be purposely designed to control risk of airborne infection and need regular service to maintain their effectiveness. many systems are designed for filters that are intended to remove larger particles that may affect the functioning of equipment and that are not effective at removing small, sub micrometre or micrometre size particles associated with adverse health effects. filter ratings by test methods, such as ashrae standard . (ashrae ) that give an indication of performance as a function of particle size should be utilized in choosing appropriate filters. where it is not possible, one should try to maximize the oa-level and apply filtering or ultraviolet germicidal irradiation to remove or deactivate potential viral contamination from the recirculated air. in many health care settings, air recirculation is, in most cases not allowed at all, though though recirculation is commonly used in non-hospital settings for improving energy efficiency. at a room (decentral) level, secondary air circulation systems may be installed. one needs to assure that any of such systems also provides ventilation with outdoor air (e.g., induction units). if this is the case, such a system should not be switched off. other systems, which do not have this feature (e.g., split air-conditioning units) should if possible be turned off, to avoid potential transfer of virus through air flows between people. when such a system is needed for cooling then additional ventilation with outdoor air should be secured by regular/periodic ventilation through, e.g., window opening. in environments where it is difficult to improve ventilation, the addition of local air cleaning or disinfection devices, such as germicidal ultraviolet (guv, or uvgi -ultraviolet germicidal irradiation) may offer benefits. under laboratory conditions guv has been shown to be effective against a suite of microorganisms including coronaviruses (walker et al. ), vaccinia (mcdevitt et al. ) and mycobacteria (xu et al. ) , and even influenza (mcdevitt et al. ; mclean ) . several studies show that inactivation decreases with increased humidity for both bacterial (xu et al. ) and viral aerosols (mcdevitt et al. ). darnell et al. ( ) showed that sars-cov- could be inactivated by uv-c, while bedell et al. ( ) showed a uv-c decontamination device could inactivate mers-cov at . m, with almost a log reduction in minutes. there is no data yet for sars-cov- , but the data for other coronaviruses suggest it is highly likely that it is susceptible to uv-c. one application that grew dramatically during the multi-drug resistant tuberculosis outbreaks of the s (young et al. ) , is the 'upper-room' system in which lamps are placed in the upper part of the room, either on the walls or mounted on the ceiling, directing the uv light into the upper zone with louvers and limiting uv exposure in the occupied space (xu et al. ; xu et al. (noakes et al. ) . escombe et al. ( ) showed % reduction in human to guinea pig transmission in a hospital setting, while chamber based studies show the effectiveness of guv against a number of bacterial aerosols (xu et al. ; xu et al. ; yang et al. ). these concur with modelling studies (gilkeson et al. b; noakes et al. ; sung et al. ; yang et al. ) showing that the effectiveness depends on the placement of the lamps relative to the ventilation flow and that addition of a ceiling fan enhances guv effectiveness (xu et al. ; zhu et al. ) . factors that must be considered when evaluating the ability of upper-room guv to kill or inactivate airborne microorganisms include the sensitivity of the microorganisms to guv a zonal infection risk model (noakes et al. ) suggests that an upper-room guv with a plane average irradiance of . w/m at the uv fixtures could be comparable to increasing the ventilation rate from to ach. portable consumer air cleaning devices may be beneficial in smaller rooms, although it should be recognised that such devices must be appropriately sized for the space (miller-leiden et al. ) . there is wide variation in performance of air cleaners depending on air cleaner design and size of room in which it is used (shaughnessy et al. ) . a useful metric for determining performance is the clean air delivery rate, which is equivalent to the volumetric flow rate of particle-free air produced by the air cleaner (foarde ) . kujundzic et al. ( ) reported air cleaners were similarly effective against removing both airborne bacterial and fungal spores from the air at clean air delivery rates of between and m /h corresponding to effective cleaning of between and m room volumes respectively. guv 'in-duct' application within air-conditioning systems and ventilation ducts may also be a practical approach for disinfecting contaminated extracts or in cases where it is not possible to stop recirculation of ventilation flows (kujundzic et al. ). however, these systems are of little benefit against person-to-person transmission when installed in the supply air of once-through systems that do not recirculate air within the space or building. the us centers for disease control has approved both upper-room and in-duct systems for use in controlling tuberculosis transmission as an adjunct to hepa filtration (cdc/niosh ). this measure is self-explanatory in the context of the need to lower the concentration of airborne virus-carrying particles, and reduce the number of people who can be exposed at any time. there is no one specific value for a number of people who could share the same space during pandemics, and this measure should be considered in conjunction with the engineering measures discussed above, and particularly in relation to the ventilation parameters of the space. although the physical distance required to avoid transmission through direct contact dictates the requirements for the floor area per person, the rate of ventilation provided and the efficiency of ventilation are the parameters that control the concentration of virus-laden microdroplets in the air exhaled by the occupants, and will guide decisions on safe occupancy numbers. in a school or a supermarket, for example, if the number of infected students or shoppers is low, and the ventilation rate is high, the risk of airborne transmission can be low. similarly, during an epidemic, reducing the number of people using public or private transport at the same time, e.g. in subway train systems or busses, is part of effective social distancing (knibbs et al. ; stopera et al. ). until effective pharmacological treatments or vaccines are available to reduce the effective reproductive number to less than . and stop the ongoing covid- pandemic, enhanced ventilation may be a key element in limiting the spread of the sars-cov- virus. these are the key ventilation-associated recommendations (see figure ): ) to remind and highlight to building managers and hospital administrators and infection control teams that engineering controls are effective to control and reduce the risks of airborne infection -and sars-cov- has the potential and is likely to be causing some infections by this route. ) to increase the existing ventilation rates (outdoor air change rate) and enhance ventilation effectiveness -using existing systems. ) to eliminate any air-recirculation within the ventilation system so as to just supply fresh (outdoor) air. to supplement existing ventilation with portable air cleaners (with mechanical filtration systems to capture the airborne microdroplets), where there are areas of known air stagnation (which are not well-ventilated with the existing system), or isolate high patient exhaled airborne viral loads (e.g. on covid- cohort patient bays or wards). adequate replacement of the filters in the air cleaners and their maintenance is crucial. to avoid over-crowding, e.g. pupils sitting at every other desk in school classrooms, or customers at every other table in restaurants, or every other seat in public transport, cinemas, etc. if implemented correctly, these recommended building-related measures will lower the overall environmental concentrations of airborne pathogens and thus will reduce the spread of infection by the airborne route. together with other guidance on minimising the risk of contact and droplet transmission (through hand-washing, cleaning of hand-touch sites, and the appropriate use of ppe), these ventilation-related interventions will reduce the airborne infection rates not just for sars-cov- in the current covid- pandemic, but also for other airborne infectious agents. while much of the focus has been on case finding, isolation and quarantine, social distancing and hand hygiene, we emphasise that a parallel reduction in airborne transmission using such engineering controls in hospitals and other public buildings will further protect healthcare workers, patients and the general public. airborne transmission between room occupants during short-term events: measurement and evaluation a guide to energy efficient ventilation. brussels: air infiltration and ventilation centre standard . - method of testing general ventilation air-cleaning devices for removal efficiency by particle size covid- (coronavirus) preparedness resources. american society of heating, ventilating, and air-conditioning engineers position document on airborne infectious diseases, approved by the 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of upper-room air in inactivating airborne bacterial spores and mycobacteria in full-scale studies minimizing the exposure of airborne pathogens by upper-room ultraviolet germicidal irradiation: an experimental and numerical study the resurgence of tuberculosis numerical modeling of indoor environment with a ceiling fan and an upper-room ultraviolet germicidal irradiation system ☐the authors declare the following financial interests/personal relationships which may be considered as potential competing interests key: cord- -xit najq authors: van damme, wim; dahake, ritwik; delamou, alexandre; ingelbeen, brecht; wouters, edwin; vanham, guido; van de pas, remco; dossou, jean-paul; ir, por; abimbola, seye; van der borght, stefaan; narayanan, devadasan; bloom, gerald; van engelgem, ian; ag ahmed, mohamed ali; kiendrébéogo, joël arthur; verdonck, kristien; de brouwere, vincent; bello, kéfilath; kloos, helmut; aaby, peter; kalk, andreas; al-awlaqi, sameh; prashanth, ns; muyembe-tamfum, jean-jacques; mbala, placide; ahuka-mundeke, steve; assefa, yibeltal title: the covid- pandemic: diverse contexts; different epidemics—how and why? date: - - journal: bmj glob health doi: . /bmjgh- - sha: doc_id: cord_uid: xit najq it is very exceptional that a new disease becomes a true pandemic. since its emergence in wuhan, china, in late , severe acute respiratory syndrome coronavirus (sars-cov- ), the virus that causes covid- , has spread to nearly all countries of the world in only a few months. however, in different countries, the covid- epidemic takes variable shapes and forms in how it affects communities. until now, the insights gained on covid- have been largely dominated by the covid- epidemics and the lockdowns in china, europe and the usa. but this variety of global trajectories is little described, analysed or understood. in only a few months, an enormous amount of scientific evidence on sars-cov- and covid- has been uncovered (knowns). but important knowledge gaps remain (unknowns). learning from the variety of ways the covid- epidemic is unfolding across the globe can potentially contribute to solving the covid- puzzle. this paper tries to make sense of this variability—by exploring the important role that context plays in these different covid- epidemics; by comparing covid- epidemics with other respiratory diseases, including other coronaviruses that circulate continuously; and by highlighting the critical unknowns and uncertainties that remain. these unknowns and uncertainties require a deeper understanding of the variable trajectories of covid- . unravelling them will be important for discerning potential future scenarios, such as the first wave in virgin territories still untouched by covid- and for future waves elsewhere. late in , a cluster of acute respiratory disease in wuhan, china, was attributed to a new coronavirus, - later named severe acute respiratory syndrome coronavirus (sars-cov- ). it was soon discovered that the virus is easily transmitted, can cause summary box ► severe acute respiratory syndrome coronavirus (sars-cov- ), the virus that causes covid- , has spread to nearly all countries of the world in only a few months. it is unique that an emerging respiratory virus becomes a pandemic, and can continue human-to-human transmission unabated, probably permanently. ► depending on the context, the trajectory and the impact of the covid- epidemic vary widely across affected countries. this is in fact the case with most infectious diseases. ► despite limited initial knowledge on covid- , most societies have deployed draconian measures, including lockdowns, to contain the virus and mitigate its impact. this had variable success, but invariably with profound socioeconomic collateral effects. ► through research and rapid sharing of its findings, progressively more insights on sars-cov- and covid- have been uncovered (knowns), mainly based on evidence from china, europe and the usa; however, important knowledge gaps remain (unknowns). ► the different covid- epidemics and the responses unfolding in the global south are little described, analysed or understood. insights from these less researched contexts are important for discerning potential future scenarios, not only for the first wave in virgin territories still untouched by covid- , but also for future waves. ► more understanding of lived experiences of people in a variety of contexts is necessary to get a full global picture and allow learning from this variety. ► bmj global health and emerging voices for global health have launched a call for such on-the-ground narratives and analyses on the epidemics of, and responses to, covid- . severe disease and can be quite lethal especially in the elderly and those with comorbidities. [ ] [ ] [ ] [ ] the new human disease is called covid- . soon it became clear that its global spread was unstoppable. even with draconian containment measures, such as strict movement restrictions, the so-called lockdown, it spread, and within a few months reached almost all countries and was declared a pandemic by the who. table summarises key events in the unfolding of the covid- pandemic, from december to may . this progression is quite unique. new human pathogens emerge frequently from an animal host, but most cause only a local outbreak. human-to-human transmission stops at some point, and the virus can only re-emerge as a human pathogen from its animal host. only very rarely does an emerging pathogen become a pandemic. over the past decades, a totally new pathogen emerged, caused serious disease, and spread around the globe continuously only once before: the hiv. it seems increasingly likely that sars-cov- transmission will be continuing. all countries are now facing their own 'covid- epidemic'. in only a few months, the scientific community has started to learn the virus's characteristics and its manifestations in different contexts. but we fail to understand fully why the virus spreads at different speeds and affects populations differently. our main objective is to make sense of those different expressions of the covid- pandemic, to understand why covid- follows variable trajectories in ways that are often quite different from the collective image created by the mediatisation of the dramatic covid- epidemics in densely populated areas. we start by exploring the role of context, followed by a brief summary of what is already known at the time of writing about sars-cov- and covid- . we then bmj global health compare these knowns with what is known of some other viral respiratory pathogens and identify the critical unknowns. we also discuss the coping strategies and collective strategies implemented to contain and mitigate the effect of the epidemic. we finally look ahead to potential future scenarios. the unfolding covid- pandemic: importance of context initially, human-to-human transmission was documented in family/friends clusters. [ ] [ ] [ ] [ ] [ ] [ ] progressively, it became clear that superspreading events, typically during social gatherings such as parties, religious services, weddings, sports events and carnival celebrations, have played an important role. [ ] [ ] [ ] [ ] dense transmission has also been documented in hospitals and nursing homes possibly through aerosols. sars-cov- has spread around the world through international travellers. the timing of the introduction of sars-cov- has largely depended on the intensity of connections with locations with ongoing covid- epidemics; thus, it reached big urban centres first and, within these, often the most affluent groups. from there, the virus has spread at variable speeds to other population groups. as of may , the most explosive covid- epidemics observed have been in densely populated areas in temperate climates in relatively affluent countries. the covid- pandemic and the lockdowns have been covered intensively in the media and have shaped our collective image of the covid- epidemic, both in the general public and in the scientific community. the covid- epidemic has spread more slowly and less intensively in rural areas, in africa and the indian subcontinent, and the rural areas of low and lower-middle income countries (lics/lmics). not only the media but also the scientific community has paid much less attention to these realities, emerging later and spreading more slowly. the dominant thinking has been that it is only a question of time before dramatic epidemics occur everywhere. this thinking, spread globally by international public health networks, has been substantiated by predictive mathematical models based largely on data from the epidemics of the global north. however, what has been observed elsewhere is quite different although not necessarily less consequential. the effects of the covid- epidemic manifest in peculiar ways in each context. in the early stages of the covid- epidemic in sub-saharan africa, the virus first affected the urban elites with international connections. from there, it was seeded to other sections of the society more slowly. in contrast, the collateral effects of a lockdown, even partial in many cases, are mostly felt by the urban poor, as 'stay home' orders abruptly intensify hardship for those earning their daily living in the informal urban economy. governments of lics/lmics lack the budgetary space to grant generous benefit packages to counter the socioeconomic consequences. international agencies are very thinly spread, as the pandemic has been concurrent everywhere. donor countries have focused mainly on their own covid- epidemics. the epidemic is thus playing out differently in different contexts. many factors might explain sars-cov- transmission dynamics. climate, population structure, social practices, pre-existing immunity and many other variables that have been explored are summarised in table . although all these variables probably play some role, many uncertainties remain. it is difficult to assess how much these variables influence transmission in different contexts. it is even more difficult to assess how they interact and change over time and influence transmission among different social groups, resulting in the peculiar covid- epidemic in any particular context. we do not attempt to give a complete overview of viruses but select only those viruses that emerged recently and caused epidemics such as ebola, that have obvious similarities in transmission patterns such as influenza and measles, or that are closely related such as other coronaviruses. respiratory viruses such as severe acute respiratory syndrome coronavirus (sars-cov), middle east respiratory syndrome coronavirus (mers-cov) and avian influenza a and also ebola have originated from animal hosts and caused human diseases (table ) . these viruses do not continuously circulate from human to human. they create an outbreak only when there is interspecies cross-over transmission, most frequently from bats to another animal host. the first human case of a disease from an emerging viral pathogen, the 'index case' or 'patient zero', is invariably someone in close contact with the originating animal host or an intermediary animal host. if this contact occurs in a remote rural community, the spread is usually slow, at low intensity, and could fade out before the pathogen gets a chance to spread to another community. the spread can suddenly intensify if seeded in a densely populated community, frequently in a particular context such as a hospital or during a social event, often referred to as a superspreading event. when the spread reaches a city, it can become a major outbreak, from where it can spread further; this happened with sars-cov in hong kong in and with ebola in conakry, freetown and monrovia in - . but at some stage human-to-human transmission is interrupted and the outbreak stops. only very exceptionally can a new viral pathogen sustain continuous human-to-human transmission. other viral diseases such as measles and influenza are 'old' diseases; they have been studied in great depth. what can we learn from them? measles and influenza: the importance of context it is thought that measles emerged thousands of years ago in the middle east. it is assumed that a cross-over occurred from the rinderpest virus, to become the human measles virus. measles has since spread around the globe in continuous human-to-human transmission. when measles, along with other viruses such as smallpox and influenza, was introduced in the americas by european conquerors, it contributed to a massive die-off of up to % of the original population. the transmission dynamics of sars-cov- can be compared with influenza. influenza typically causes yearly epidemics in temperate climates during winter with less seasonal patterns in tropical or subtropical regions. in hotter climates, such as in sub-saharan africa or south and southeast asia, it is transmitted year round, often not identified as influenza. such different epidemic patterns of influenza are still incompletely understood but thought to be associated with temperature and humidity and human behavioural factors such as indoor crowding. but, in contrast to sars-cov- , the influenza virus is not new. influenza is a very old disease, certainly circulating for several centuries. it has infected most human beings living on the planet already, many of them several times, leaving some immunity but no durable protection. the virus also mutates, giving rise to a new dominant strain every influenza season. influenza is every year a slightly different virus (due to antigenic drift as a result of progressive mutations) with major differences every few decades (antigenic shift as a result of recombination with novel strains). one such antigenic shift resulted in the h n 'spanish' influenza pandemic, which had an estimated case fatality rate (cfr) of %- %, killing millions. box summarises some key facts about h n , including factors thought to be associated with its high cfr. a major difference between covid- and influenza is that sars-cov- is a new pathogen and influenza is not. at the time of writing (may ), sars-cov- has triggered an immune response in over million confirmed infections (and probably in many more), definitely too few to create anything close to herd immunity. calculations using an estimated reproductive number (r ) for sars-cov- suggest that herd immunity would require at least % of the population to have protective immunity (see box ). like covid- , measles and influenza have different epidemic patterns in different contexts. this also is the case for cholera, tuberculosis, hiv/aids and most infectious diseases. the difference in patterns is most pronounced and so is easily understood with vectorborne and water-borne diseases. epidemic patterns are also different for air-borne infections, although they are less easily understood. transmission of respiratory viruses is influenced by factors related to the virus and box pandemic h n influenza, - ► the h n virus probably infected one-third of the world's population at that time (or ~ million people). ► the pandemic had three waves in quick succession; the second wave, in , was worse than the first wave. ► high mortality, especially in younger persons ( - years; ~ % of total deaths) in the pandemic, may have been due to antibody-dependent enhancement and 'cytokine storms'. another possible explanation is that older persons had some protective cross-immunity from previous influenza outbreaks while younger persons did not. ► h n continued to circulate along with seasonal influenza viruses, often recombining to produce more severe local outbreaks, including other pandemics between and , giving it the nickname 'mother of all pandemics'. ► the original h n strain was replaced by a(h n )pdm virus that resulted from an antigenic shift and caused the h n influenza pandemic. ► the h n virus originated in pigs in central mexico in march and was responsible for an estimated deaths worldwide with an estimated cfr< . %. ► during the pandemic, mortality was much lower than in the pandemic. higher mortality in persons younger than years was related to cytokine storms. a role of protective crossimmunity from previous influenza strains in older persons has been suggested. ► after august , the a(h n )pdm virus appeared to have integrated with circulating strains of influenza and continues to cause localised seasonal influenza outbreaks worldwide. box on the use of mathematical models during epidemics a dominant way of studying the transmission dynamics of an infectious disease such as covid- , and predicting the amplitude and peak of the epidemic in a population (city, province, country) and analysing the effect of control measures is using mathematical models. based on available data and several assumptions, a model attempts to predict the course of the epidemic, the expected number of infections, clinical cases and deaths over time. critical is the effective reproductive number (rt). when rt > , the number of cases in a population increases; when rt < , the number of cases decreases. a relatively simple and widely used model is the susceptible-exposed-infectious-recovered model, as used in the two papers recently published in bmj global health on covid- in africa. there are many more types of models, with varying degrees of complexity. the use of such models has strengths and limitations. building a mathematical model implies trade-offs between accuracy, transparency, flexibility and timeliness. a difficulty, in general, is that the parameters on which the model is based, the so-called assumptions are frequently uncertain (table ) and predictions can vary widely if any of the parameters are modestly different. this uncertainty is captured in a sensitivity analysis, leading to various possible quantitative outcomes, usually expressed as a range of plausible possibilities, between 'worst-case' and 'best-case' scenarios. with a new disease such as covid- , certainly at the start of the outbreak, the parameters had to be based on very limited data from a particular context. however, many variables can widely differ across communities as they critically depend on contextual factors (table ) . in mathematical models, all such uncertainties and unknowns are somehow hidden in the complex formulae of the model, as a quasi 'black box'. few people have the knowledge and skill to 'open up the black box'. as uncertainties in covid- are large, the range of possibilities produced by a model is wide, with the worst-case scenario typically predicting catastrophic numbers of cases and deaths. such predictions are often misunderstood by journalists, practitioners and policy-makers, with worst-case estimates getting the most attention, not specifying the huge uncertainties. bmj global health the human host but also by factors related to the natural and human environment (table ) . however, we are quite unable to explain fully which factor has which influence, how these factors vary among different social groups and how interdependent or isolated they are. we are certainly unable to fully model all these variables mathematically to explain the epidemic pattern across a variety of different contexts. too many variables and their interrelations are difficult to quantify, and when all these factors change over time while the pathogen continues to spread in diverse societies, the complexity becomes daunting. understanding transmission dynamics is a bit less daunting for measles, as several variables are well known and rather constant across individuals and contexts. the natural transmission pattern of measles, before the introduction of vaccines, has been well described. measles is mostly a childhood disease, but this is not the case in very remote communities, where measles transmission had been interrupted for extended periods (such as the faroe islands). measles affected all age groups when reaching new territories, causing dramatic first-wave epidemics, a phenomenon called 'virgin soil epidemic'. the latest stages of the global dissemination of measles have been well documented, including in australia, the fiji islands and the arctic countries, where such virgin soil epidemics occurred in the th and the mid- th centuries. fortunately, measles infection creates robust protective immunity and after a first wave becomes a typical childhood disease, affecting only those without any prior immunity. human-to-human transmission of measles virus in a community stops when the virus cannot find new susceptible human hosts and the so-called herd immunity is reached. but transmission of measles continues elsewhere on the planet from where it can be reintroduced a few years later when the population without protective immunity has grown large enough to allow human-to-human transmission again. the epidemic patterns of measles are easily understood as measles is highly infectious, creates disease in almost every infected person and leaves lifelong natural immunity. measles circulation, prior to vaccination, was continuous only in large urban areas with high birth rates. everywhere else reintroduction occurred typically every - ► genetic stability or variability (affecting the potential of long-lasting immunity). ► viral load determines the incubation period with the formula high load ->short incubation period ->high severity. human host ► human susceptibility to the virus; transfer of parental immunity to newborns. ► route and efficiency of human-to-human transmission. ► presence and capacity of asymptomatic carriers to transmit the virus. ► immunity created after infection, its robustness and how long-lasting it is. ► severity and duration of the disease: proportion symptomatic, lethality (cfr). ► pathogenicity and disease spectrum; disease pattern according to age and comorbidities, and related potential to spread. natural environment ► temperature, humidity and seasonal changes in climate affecting the stability and transmission potential of the virus and human susceptibility. ► increasing extreme weather conditions such as droughts and severe storms, as well as global climate change may also affect transmission patterns. ► air pollution may also play a role in the transmission and stability of the virus. human environment/social geography ► demographic variables such as population density, age structure and household composition. ► mixing patterns within households, including bed sleeping patterns, related to housing conditions and hygiene practices. ► house construction with solid walls or permeable walls (thatched walls, straw mats). ► mixing patterns among households related to settlement patterns: social networks, urban-rural differences, working conditions, religious practices and commuting patterns. ► variables related to built environments, road infrastructure and socioeconomic conditions. ► mobility between communities, including international travel. ► crowding institutions: for example, elderly homes, extended families, boarding schools, child institutions, seclusion during tribal ceremonies, hospitals, nursing homes, military barracks and prisons. cfr, case fatality rate. years but sometimes only after or years in isolated rural communities (such as among nomadic groups in the sahel), causing epidemics among all those without acquired immunity and having lost maternal antibodies. these diverse patterns of measles epidemics have been fundamentally changed by variable coverage of measles vaccination. they can still help us make sense of the diversity of covid- epidemics being observed in . measles illustrates convincingly that the transmission pattern of a respiratory virus is strongly influenced by the demographic composition, density and mixing pattern of the population and the connectedness to big urban centres. measles transmission is continuous only in some large urban areas. it presents in short epidemics everywhere else with variable periodicity. this transmission pattern may well be a bit similar for covid- . but it took thousands of years for measles to reach all human communities while sars-cov- spread to all countries in only a few months, despite measles being much more transmissible than sars-cov- . factors such as increased air travel and more dense community structures play bigger roles for sars-cov- than they did for measles. comparison with other pathogenic coronaviruses sars-cov- has many close relatives. six other human coronaviruses (hcovs) are known to infect humans. sars-cov and mers-cov (causing sars and mers, respectively) are very rare and do not continuously circulate among humans. the other four (hcov- e, hcov-oc , hcov-hku and hcov-nl ) cause the common cold or diarrhoea and continuously circulate and mutate frequently. they can cause disease in the same person repeatedly. the typical coronavirus remains localised to the epithelium of the upper respiratory tract, causes mild disease and elicits a poor immune response, hence the high rate of reinfection (in contrast to sars-cov and mers-cov, which go deeper into the lungs and hence are relatively less contagious). there is no cross-immunity between hcov- e and hcov-oc , and new strains arise continually by mutation selection. coping strategies and collective strategies how a virus spreads and its disease progresses depend not only on the variables described above (table ) but also on the human reactions deployed when people are confronted with a disease outbreak or the threat of an outbreak. all these variables combined result in what unfolds as 'the epidemic' and the diverse ways it affects communities. what a population experiences during an epidemic is not fully characterised by the numbers of known infections and deaths at the scale of a country. such numbers hide regional and local differences, especially in large and diverse countries. the epidemic reaches the different geographical areas of a country at different moments and with different intensities. it affects different communities in variable ways, influencing how these communities perceive it and react to it. what constitutes a local covid- epidemic is thus also characterised by the perceptions and the reactions it triggers in the different sections of the society. even before the virus reaches a community, the threat of an epidemic already causes fear, stress and anxiety. consequently, the threat or arrival of the epidemic also triggers responses, early or late, with various degrees of intensity and effectiveness. the response to an epidemic can be divided into individual and household actions (coping strategies), and collectively organised strategies (collective strategies). coping strategies are the actions people and families take when disease threatens and sickness occurs, including the ways they try to protect themselves from contagion. collective strategies are voluntary or mandated measures deployed by organised communities and public authorities in response to an epidemic. these include, among others, isolation of the sick or the healthy, implementation of hygiene practices and physical distancing measures. they can also include mobility restrictions such as quarantine and cordon sanitaire. coping strategies and collective strategies also include treatment of the sick, which critically depends on the availability and effectiveness of diagnostic and therapeutic tools, and performance of the health system. collective strategies also include research being deployed to further scientific insight and the development of diagnostic and therapeutic tools, potentially including a vaccine. implementation of these measures depends not only on resources available but also on the understanding and interpretation of the disease by both the scientific community and the community at large, influenced by the information people receive from scientists, public authorities and the media. this information is interpreted within belief systems and influenced by rumours, increasingly so over social media, including waves of fake news, recently labelled 'infodemics'. coping strategies and collective strategies start immediately, while there are still many unknowns and uncertainties. progressively, as the pandemic unfolds and scientists interpret observations in the laboratory, in the clinic, and in society, more insights are gained and inform the response. table lists measures recommended by the who for preventing transmission and slowing down the covid- epidemic. - 'lockdown' first employed in early in wuhan, china, is the label often given to the bundle of containment and mitigation measures promoted or imposed by public authorities, although the specific measures may vary greatly between countries. in china, lockdown was very strictly applied and enforced. it clearly had an impact, resulting in total interruption of transmission locally. this list or catalogue of measures is quite comprehensive; it includes all measures that at first sight seem to reduce transmission opportunities for a respiratory virus. however, knowledge is lacking about the effectiveness of each measure in different contexts. as a global health bmj global health agency, the who recommends a 'generic catalogue' of measures from which all countries can select an appropriate mix at any one time depending on the phase of the epidemic, categorised in four transmission scenarios (no cases, first cases, first clusters, and community transmission). however, under pressure to act and with little time to consider variable options, public authorities often adopted as 'blueprint' with limited consideration for the socioeconomic context. the initial lockdown in china thus much inspired the collective strategies elsewhere. this has been referred to as 'global mimicry', : the response is somehow partly 'copy/paste' from measures observed previously (strong path dependency). some epidemiologists in northern europe (including the uk, sweden and the netherlands ) pleaded against strict containment measures and proposed that building up herd immunity against sars-cov- might be wiser. towards early april , it became increasingly clear that reaching herd immunity in the short term was illusive. most countries thus backed off from the herd immunity approach to combating covid- and implemented lockdowns. the intensity of the lockdowns has been variable, ranging from very strict ('chinese, wuhan style'), over intermediary ('french/italian/new york city style' and 'hong kong style'), to relaxed ('swedish style'), or piecemeal. the effectiveness of lockdowns largely depends on at what stage of the epidemic they are started, and how intensively they are applied. this is quite variable across countries, depending on the understanding and motivation of the population and their perceived risk ('willingness to adhere'), on the trust they have in government advice ('willingness to comply'), and on the degree of enforcement by public authorities. the feasibility for different population groups to follow these measures depends largely on their socioeconomic and living conditions. it is obviously more difficult for people living in crowded shacks in urban slums to practise physical distancing measures and strict hand hygiene when water is scarce than for people living in wealthier parts of a city. collateral effects of the response every intervention against the covid- epidemic has a certain degree of effect and comes at a cost with collateral effects. each collective strategy ( ) has intended and unintended consequences (some are more or less desirable); ( ) is more or less feasible and/or acceptable in a given context and for certain subgroups in that society; ( ) has a cost, not only in financial terms but in many other ways, such as restrictions on movement and behaviour, stress, uncertainty and others. these costs are more or less acceptable, depending on the perception of the risk and many societal factors; ( ) can be implemented with more or less intensity; and ( ) can be enforced more or less vigorously. the balance between benefit and cost is crucial in judging whether measures are appropriate, which is very context specific. furthermore, benefits and costs are also related to the positionality from which they are analysed: benefits for whom and costs borne by whom? more wealthy societies with strong social safety nets can afford increased temporary unemployment. this is much more consequential in poorer countries, where large proportions of the population live precarious lives and where public authorities cannot implement generous mitigation measures at scale. the adherence to hygiene and distancing measures depends not only on living conditions but also on risk perception and cultural norms. mass masking has been readily accepted in some asian countries, where it was already broadly practised even before the covid- bmj global health epidemic. it remains more controversial in western societies, some of which even have legal bans on veiling in public places. lockdowns are unprecedented and have triggered intensive public debate. not surprisingly, the impact of lighter lockdowns on the transmission is much less impressive; they decrease transmission but do not stop it. quite rapidly, the justification for lockdowns shifted from stopping transmission to 'flattening the curve'. also, once a lockdown is started, rationalised, explained and enforced, it is difficult to decide when to stop it. exit scenarios, usually some form of progressive relaxation, are implemented with the knowledge that transmission will be facilitated again. what we already know the available information on sars-cov- and the spectrum of covid- disease is summarised in tables and . it is increasingly becoming clear that most transmission happens indoors and that superspreading events trigger intensive dissemination. the virology and immunology of sars-cov- / covid- are being studied intensively. this is critical not only to understand what will potentially happen in future waves but also for the development of a vaccine. some scientists and companies are very upbeat about the possibility of producing a vaccine in record time. having a vaccine is one thing, but how effective it is, is quite another. as acquired immunity after a natural infection is probably not very robust (table ), it will also be challenging to trigger robust immunity with a vaccine, but perhaps it is not impossible. many questions remain, some of which are summarised in table . regarding the severity of covid- , initial fears of very high mortality have also lessened. it has progressively become clear that many infections remain asymptomatic, that severe disease is rare in children and young adults, and that mortality is heavily concentrated in the very old and those with comorbidities. table summarises a fuller overview of the present state of knowledge regarding covid- . with covid- epidemics unfolding rapidly, several of the variables in the transmission of sars-cov- and the disease spectrum of covid- could be quantified. this allows for mathematical modelling. several models have been quickly developed, leading to predictions of the speed of transmission and the burden of covid- (box ). predictive models developed by the imperial college ; the center for disease dynamics, economics & policy and johns hopkins university ; the institute for health metrics and evaluation ; harvard university ; and the who, including an 'african model', are a few that are influencing containment strategies around the world. although the covid- pandemic triggered unprecedented research efforts globally, with over scientific papers published between january and april , there are still critical unknowns and many uncertainties. tables and summarise many of the knowns, but their relative importance or weight is not clear. for instance, the virus can spread via droplets, hands, aerosols, fomites and possibly through the environment. however, the relative importance of these in various contexts is much less clear. these factors undoubtedly vary between settings, whether in hospitals, in elderly homes, or at mass events. the weight of the variables also probably differs between the seeding and initial spread in a community and the spread when it suddenly amplifies and intensifies. the importance of each variable probably also depends on climatic conditions, not only outdoors, but also on microclimates indoors, influenced by ventilation and air conditioning and built environments. we summarise the critical unknowns in table along some elements to consider in addressing the unknowns and thoughts on their importance. uncertainty remains, leading to controversy and directly influencing the choice of containment measures. controversy continues regarding when and where lockdown or more selective measures are equally effective with lower societal effects. relationship between the dose of the initial infectious inoculum, transmission dynamics and severity of the covid- disease new evidence is being discovered rapidly. some evidence comes from field observations and ecological studies; other evidence results from scientific experiments or observations in the laboratory and the clinic. sense-making by combining insights from different observations and through the lens of various disciplines can lead to hypotheses that can be tested and verified or refuted. one such hypothesis is that there is a relationship between the dose of virus in the infectious inoculum and the severity of covid- disease. several intriguing observations in the current pandemic could be (partially) explained by such a relationship. we develop this hypothesis in box , as an example of possible further research, to create new insight which may influence control strategies. this viral inoculum theory is consistent with many observations from the early stages of the covid- pandemic, but it is not easy to test scientifically. as covid- is a new disease, we should make a distinction between ( ) the current - 'virgin soil pandemic' caused by sars-cov- , specifically in how it will further spread around the globe in the first wave, and ( ) the potential future transmission in subsequent waves. in some countries, transmission will continue at lower levels. in other countries, such as china, the virus bmj global health may have been eliminated but can be reintroduced in identical or mutated form. for the current first wave, using influenza and the common cold as reasonable comparisons, it is possible that the major epidemics, as witnessed in wuhan, northern italy, or new york, will typically occur in temperate climates in the winter season. some predict that such epidemics will last between and weeks (but this is just a plausible and reasonable comparison in analogy with seasonal influenza). it is possible that in hotter climates the transmission may become continuous, year round at lower levels. it is increasingly clear that hot climate does not exclude superspreading events as observed in guayaquil, ecuador and in various cities in brazil. ventilation, air-conditioning and crowded places may still create favourable environments for intensive transmission. it is also quite possible that the more difficult spread of sars-cov- in such climates may, in certain table knowns, uncertainties and unknowns about severe acute respiratory syndrome coronavirus (sars-cov- ), as of may origin of sars-cov- ► most probably from bats via intermediate animal hosts to index case. all subsequent cases resulted from human-to-human transmission. transmission ► mainly through respiratory droplets from infected persons ; by hands, after contamination at nose, mouth or eyes; also through air on exposure to sneezing or coughing from an infected person at close distance. ► through aerosols, while singing/talking loudly in congregations, groups, parties, karaoke, and so on, especially in poorly ventilated spaces. ► through fomites. ► possibly via faecal-oral route ; detection in sewage. [ ] [ ] [ ] ► related to peak in upper respiratory tract viral load prior to symptom onset in presymptomatic (paucisymptomatic) persons. ► transmission dynamics in asymptomatic persons not fully elucidated although viral shedding occurs. influence of climate and/or air pollution on transmission ► influence of climate on the capacity of the virus to survive outside human body (in air, in droplets, on surfaces, etc.) and to spread has been speculative. ► may spread more readily in milder/colder climate ; although variability of the reproductive number could not be explained by temperature or humidity. ► existing levels of air pollution may play a role; air pollutants, such as particulate matter, nitrogen dioxide and carbon monoxide, are likely a factor facilitating longevity of virus particles. ► elevated exposure to common particulate matter can alter host immunity to respiratory viral infections. immunity-protective antibodies ► igm and iga antibody response - days after onset of symptoms, does not depend on clinical severity, correlates with virus neutralisation; igg is observed ~ days after onset of symptoms, may or may not correspond to protective immunity. whether antibody response is long lasting has remained unclear. ► rechallenge in rhesus macaques showed immunity post primary infection. how protective immunity after first infection is against subsequent infection with an identical or mutated strain has been uncertain. ► incidental reports showed recovered persons positive by real-time pcr, later attributed to testing errors. seroprevalence to sars-cov- ► reported estimates for seroprevalence range between . % and . % ; differences in timing of the serosurvey, the use of assay kits with varying sensitivity/specificity, and different methods for detection may contribute to this large variation. ► seemingly high seroprevalence may be due to cross-reactive epitopes between sars-cov- and other hcovs. ► whether seroprevalence implies immune protection is unclear, yet, some countries have considered use of 'immunity passports'. ► for herd immunity to be effectively achieved, an estimated seroprevalence of % of the population will be required. other studies estimate between . % and % seroprevalence in different countries. communities, be compensated for by human factors such as higher population density, closer human contacts and lesser hygiene (as, for instance, exist in urban slums in mega cities in low income countries). how all this plays out in sub-saharan africa, in its slums and remote areas, is still largely unknown. with sars-cov- , transmission scenarios are mainly based on mathematical models despite their serious limitations (box ). as the virus continues to circulate, it will progressively be less of a 'new disease' during subsequent waves. the immunity caused by the first epidemic will influence how the virus spreads and causes disease. whether later waves will become progressively milder or worse, as observed in the - spanish influenza, is a matter of intense speculation. both views seem plausible and the two are not necessarily mutually exclusive. indeed, immunity should be defined on two levels: individual immunity and herd immunity. individual immunity will dictate how mild or severe the disease will be in subsequent infections. herd immunity could be defined in different communities/regions/ disease spectrum ► many different estimates: ► initially, it was estimated that among infected, % remained asymptomatic, %- % had mild/moderate disease, %- % had severe disease, and %- % became critically ill. - ► very variable estimates for remaining totally asymptomatic (estimated %- % [ ] [ ] [ ] [ ] ). ► what determines that an infection remains asymptomatic? ► quasi-absence of disease in children: why? case fatality rate (cfr) ► initial estimates cfr: %- %; comparisons: influenza . %; common cold: %; sars: %- %; mers: %. ► calculated infection fatality rates (cifr) and calculated cfr (ccfr) on the princess diamond were . % and . %, respectively (for all ages combined), and projected cifr and ccfr for china were between . %- . % and . %- . %, respectively. in gangelt, germany: ccfr of . %. ► cfr is influenced significantly by age; male sex; comorbidities; body mass index and/or fitness; and adequacy of supportive treatment, mainly oxygen therapy. if a vaccine is developed? ► what type of vaccine will it be (live/non-live, classic killed, dna, or recombinant)? ► will it need special manufacture and transport conditions (such as cold chain)? ► how robust will be vaccine-acquired immunity? after how many doses? ► how protective will it be against infection? ► for how long will vaccine-acquired immunity last? and hence: how often will the vaccine have to be administered? only once? or yearly? ► will there be any adverse effects? acquired immunity is not very strong; hence, what is the consequence regarding herd immunity? ► to achieve herd immunity, how efficient will the vaccine need to be? ► what proportion of the population (critical population) will need to be vaccinated? ► how long will it take to effectively vaccinate the critical population? ► will vaccination be acceptable in the population? or will vaccine hesitancy reduce uptake? what are the socioeconomic implications? ► which countries will get the vaccine first (implications for lics/lmics)? ► how expensive will the vaccine be? ► will vaccination be made mandatory, especially for international travel? the various degrees of societal disruption and the collateral effects on other essential health services (eg, reluctance to use health services for other health problems, because of 'corona fear'). our growing knowledge may enable us to progressively improve our response. learning from the variety of ways the covid- epidemic is unfolding across the globe provides important 'ecological evidence' and creates insights into its epidemiology and impacts. until now, the insights gained on covid- have been largely dominated by the covid- epidemics in the global north. more understanding of lived experiences of people in a variety of contexts, where the epidemic is spreading more slowly and with different impacts, is necessary to get a full global picture and allow learning from this variety. this is an important missing piece of the covid- puzzle. bmj global health and emerging voices for global health have launched a call (https:// blogs. bmj. com/ bmjgh/ / / / from-models-to-narratives-andback-a-call-for-on-the-ground-analyses-of-covid- spread-and-response-in-africa/) for such on-the-ground narratives and analyses of the spread of and response to covid- , local narratives and analyses that will hopefully help to further enrich our understanding of how and why the covid- pandemic continues to unfold in multiple local epidemics along diverse trajectories around the globe. table some critical unknowns in sars-cov- transmission which transmission patterns will occur and will human-to-human transmission continue permanently? ► seasonal transmission in temperate climate? ► continuous tides, with ups and downs? ► the experience from china and some other countries showed that 'local elimination' is possible but risk of reintroduction remains. ► increasingly unlikely that elimination everywhere is possible. this will strongly depend on: how strong will the acquired immunity after a first infection with sars-cov- be and how long will it last? ► evidence of acquired immunity against subsequent infections has been limited. ► measurable antibodies have been observed in most persons who have recovered from covid- , and research in animal models has suggested limited possibility of reinfection. ► it is still unclear as to how robust the immunity is and how long it will last. ► debate on use, practicality and ethics of 'immunity passports' for those recovered from covid- has been ongoing. how stable is the virus (mutation) and do the different clades seen worldwide have any effect on the transmission potential/severity of the disease? ► if the virus mutates quickly and different strains develop, then antibodydependent enhancement might be an important risk, as in dengue with its four different strains. if so, then in subsequent waves progressively more severe cases could occur. ► this has been reported for the spanish influenza, where the second and third waves were characterised by a more severe disease pattern. what is the role of children in transmission? ► children have quasi-universally presented less severe disease. however, their susceptibility to infection remains unclear, with large heterogeneity reported between studies. ► their role in transmission has remained unclear, but evidence points to a more modest role in transmission than adults. how significant are asymptomatic carriers in transmission? ► there have been several reports of asymptomatic transmission and estimates based on modelling. ► increasing consensus that asymptomatic carriers play an important role in transmission. box relationship between the dose of the initial infectious inoculum, transmission dynamics and severity of the covid- disease hypothesis: the dose of the virus in the initial inoculum may be a missing link between the variation observed in the transmission dynamics and the spectrum of the covid- disease. it is plausible that: ► viral dose in inoculum is related to severity of disease. ► severity of disease is related to viral shedding and transmission potential. this hypothesis plays out potentially at three levels: ► at individual level: a person infected with a small dose of viral inoculum will on average develop milder disease than a person infected with a high viral inoculum and vice versa. ► at cluster level: a person with asymptomatic infection or mild disease will on average spread lower doses of virus in droplets and aerosols and is less likely to transmit disease; when the person transmits, the newly infected person is more likely to have milder disease than if infected by a severely ill person, who spreads on an average higher doses of virus. this causes clusters and chains of milder cases or of more severe cases. ► at community level: in certain contexts, such as dense urban centres in moderate climates during the season when people live mostly indoors, the potential for intensive transmission and explosive outbreaks is high, especially during indoor superspreading events. in other contexts, such as in rural areas or in regions with hot and humid climate where people live mostly outdoors, intensive transmission and explosive outbreaks are less likely. outbreak of pneumonia of unknown etiology in wuhan, china: the mystery and the miracle new-type coronavirus causes pneumonia in wuhan: expert a novel coronavirus from patients with pneumonia in china coronaviridae study group of the international committee on taxonomy of viruses. the species severe acute respiratory syndrome-related coronavirus: classifying -ncov and 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isn't mutating quickly, suggesting a vaccine would offer lasting protection. the washington post genomic epidemiology of novel coronavirus implications of test characteristics and population seroprevalence on 'immune passport' strategies systematic review of covid- in children shows milder cases and a better prognosis than adults susceptibility to and transmission of covid- amongst children and adolescents compared with adults: a systematic review and meta-analysis presumed asymptomatic carrier transmission of covid- transmission of -ncov infection from an asymptomatic contact in germany acknowledgements we would like to thank johan leeuwenburg, piet kager, and luc bonneux for useful comments on a previous draft, the teams of the riposte corona, inrb, kinshasa and the belgian embassy in kinshasa for welcoming and hosting wvd during his unscheduled extended stay in kinshasa during the lockdown, march-june . we are thankful to mrs. ann byers for editing the manuscript at short notice. funding the authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.competing interests none declared. provenance and peer review not commissioned; externally peer reviewed. open access this is an open access article distributed in accordance with the creative commons attribution non commercial (cc by-nc . ) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. see: http:// creativecommons. org/ licenses/ by-nc/ . /. key: cord- -nquov i authors: murphy, f.a. title: epidemiology of human and animal viral diseases date: - - journal: encyclopedia of virology doi: . /b - - . - sha: doc_id: cord_uid: nquov i viral disease epidemiology is the study of the determinants, dynamics, and distribution of viral diseases in populations. the risk of infection or disease in a population is determined by characteristics of the virus, the host, and the host population, as well as behavioral, environmental, and ecological factors that affect virus transmission from one host to another. viral disease epidemiology has come to have a major role in clarifying the etiologic role of particular viruses and viral variants as the cause of specific diseases, in improving our understanding of the overall nature of specific viral diseases, and in determining factors affecting host susceptibility and immunity, in unraveling modes of transmission, in clarifying the interaction of viruses with environmental determinants of disease, in determining the safety, efficacy, and utility of vaccines and antiviral drugs, and especially in alerting and directing disease prevention and control actions. information on incidence, prevalence, and morbidity and mortality rates contributes directly to the establishment of priorities for prevention and control programs, whether this involves vaccine or drug development and delivery, environmental and hygienic improvements, enhancement of nutritional status, personal or community behavior, agricultural and food processing enhancements, reservoir host and vector control, and international cooperation and communication. evs, they encode other types of defense molecules. among these are the inhibitor of apoptosis (iap) genes. the iap of amev has been well characterized and functionally inhibits apoptosis. a related amev gene that functions to inhibit apoptosis is a homolog of the baculovirus pan-caspase inhibitor, p . another novel protein expressed by amev is a cu-zn superoxide dismutase (sod) . although a number of the orthopoxviruses encode genes with homology to this class of sods, neither the vv or myxoma virus proteins are functional in that capacity, although they are present within the virion. the sod expressed by amev is functional as an sod but is not essential for virus growth in culture. the deletion of the sod gene from amev appears to have no effect on the growth of the virus in gypsy moth larvae. it is clear that this large subfamily of the family poxviridae provides a wealth of possible information about the basic mechanisms of the poxvirus lifecycle. there appear to be a number of interesting variations on the molecular details which define this overall family of viruses. there are clear similarities to the vertebrate poxviruses in virion morphology, double-stranded dna genome, cytoplasmic life cycle, and rna expression. yet the differences between the cvs and evs are significant and represent an area of research that has not been fully explored. the data that have been obtained from genomic sequencing has been essential to identifying some of the different proteins that are present in the evs, as well as identifying potentially missing homologs of vv proteins. it is important to note that there are large differences at the dna level between the two sequenced evs, indicating that there is probably a wide variety of unique features within the evs as a group. as more sequence information becomes available, the diversity of this family of viruses may become more evident. direct contact transmission involves actual physical contact between an infected subject and a susceptible subject (e.g., kissing, biting, coitus). epidemic major increase in disease incidence affecting either a large number of humans or animals or spreading over a large area. epidemiology the study of the determinants, dynamics, and distribution of diseases in populations. fomite an inanimate object that may be contaminated with virus and become the vehicle for transmission. herd immunity the immune status of a population that affects viral transmission rates. often used in describing the elimination of a virus from a population when there are too few susceptible hosts remaining to sustain a transmission chain. horizontal transmission the transfer of infectious virus from one human or animal to another by any means other than vertical transmission. iatrogenic transmission transmission via health care procedures, materials, and workers (e.g., physicians, nurses, dentists, veterinarians). incidence rate (or attack rate) a measure of the occurrence of infection or disease in a population over time -it refers to the proportion of a population contracting a particular disease during a specified period. mathematical model (epidemiological) a means to convey quantitative information about a host-virus interaction, such as an epidemic or an emerging disease episode, by the construction of a set of predictive mathematical algorithms. nosocomial transmission pertains to infections acquired while a patient, human or animal, is in hospital. prevalence rate the ratio, at a particular point in time, of the number of cases currently present in the population divided by the number of subjects in the population at risk; it is a snapshot of the occurrence of infection or disease at a given time. species jumping (or host range extension) referring to a virus that derives from an ancient reservoir life cycle in animals, but has subsequently established a new life cycle in humans or a different animal species and no longer uses, the original animal reservoir. transmission the process by which a pathogen is shed from one host and infects the next. vector-borne transmission involves the bites of arthropod vectors (e.g., mosquitoes, ticks, sandflies). vertical or transplacental transmission occurs from mother to fetus prior to or during parturition, either across the placenta, when the fetus passes through the birth canal, or via colostrum and milk. vertical transmission transmission of virus from parent to progeny through the genome, sperm, or ovum or extracellularly (e.g., through colostrum or across the placenta). zoonosis disease which is naturally transmitted to humans from an ongoing reservoir life cycle in animals or arthropods, without the permanent establishment of a new life cycle in humans. viral disease epidemiology is the study of the determinants, dynamics, and distribution of viral diseases in populations. the risk of infection or disease in a population is determined by characteristics of the virus, the host, and the host population, as well as behavioral, environmental, and ecological factors that affect virus transmission from one host to another. epidemiology attempts to meld these factors into a unified whole. the depiction of the interaction of factors favoring the emergence of a viral disease (figure ) , called 'the convergence model', is taken from the us institute of medicine study, microbial threats to health, emergence, detection and response (national academy press, ) . at the center is a box representing the convergence of factors leading to 'the black box', reflecting the reality that many unknown interactions are important virologically and epidemiologically. the foundations of epidemiology predate the microbiological and virological sciences, starting with hippocrates, the greek physician and father of medicine, who in the fourth century bc made important epidemiologic observations on infectious diseases. john snow is called the father of modern epidemiology because he developed excellent quantitative methods while studying the source of a cholera outbreak at the broad street pump in london in . snow was followed by william farr, who in the s advanced the use of vital statistics and clarified many of the principles of risk assessment and retrospective and prospective studies. their vision is reflected in the fast-changing science of epidemiology which is now supported by advanced computer technology, sophisticated statistical methods, and very sensitive and specific diagnostic systems. by introducing quantitative measurements of disease trends, epidemiology has come to have a major role in improving our understanding of the overall nature of disease and in alerting and directing disease control activities. epidemiology is also effective in ( ) clarifying the role of particular viruses and viral variants as the cause of disease, ( ) clarifying the interaction of viruses with environmental determinants of disease, ( ) determining factors affecting host susceptibility, ( ) unraveling modes of transmission, and ( ) field testing of vaccines and antiviral drugs. the comparison of disease experience between populations is expressed in the form of 'rates'. the terms 'incidence rate' and 'prevalence rate' are used to describe quantitatively the frequency of occurrence of infection or disease in populations. 'incidence rate' (also called attack rate) is defined as the ratio of new cases occurring in a population to the size of the population during a specified period of time. prevalence rate is the ratio of the total number of cases occurring in a population to the size of the population during a specified period of time. 'seroprevalence rate' relates to the occurrence of antibody to a particular virus in a population. because viral antibodies, especially neutralizing antibodies, often last a lifetime, seroprevalence rates usually represent cumulative experience with the virus. the term 'case-fatality rate' is used to indicate the percentage of subjects with a particular disease that die from the disease. all these rates may be affected by various attributes that distinguish one individual from another: age, sex, genetic constitution, immune status, pregnancy, nutritional status, and various behavioral and medical care and patient management parameters. the most widely applicable attribute is age, which may encompass immune status as well as various physiological variables. a viral disease is characterized as 'endemic' when there are multiple or continuous chains of transmission resulting in continuous occurrence of disease in a population over a period of time. 'epidemics' are peaks in disease incidence that exceed the endemic baseline or expected rate of disease. the size of the peak required to constitute an epidemic is arbitrary and is related to the background endemic rate and the anxiety that the disease arouses (e.g., a few cases of rabies is regarded as an epidemic, whereas a few cases of influenza is not). a 'pandemic' is a worldwide epidemic. a proper description of an outbreak of disease or an epidemic must include the parameters of 'person (or subjects in the case of animals), place, and time'. such descriptive information is a necessary first step in describing the occurrence, distribution, course, threat, and anticipated action response to the initial recognition of a cluster of cases of disease. much of the initial investigation called for rests in common sense, observational acuity, and an insightful 'index of suspicion'. much of the initial investigation has been termed 'shoe-leather epidemiology'. the trigger for such initial investigation is most often an astute clinician (physician or veterinarian) or an astute pathologist. there are two basic analytic techniques used to investigate relationships between cause and effect and to evaluate risk factors of disease. these are the 'case-control study' and the 'cohort study'. in the case-control study, investigation starts after the disease has occurred -it is a retrospective study, going back in time to determine causative events. although this kind of study does not require the creation of new data or records, it does require careful selection of the control group, matched to the test group so as to avoid bias. the retrospective case-control study lends itself to quick analysis and is relatively inexpensive to carry out. in the cohort study, the prospective study, investigation entails the gathering of new data to identify cause-effect relationships. this kind of study is expensive and does not lend itself to quick analysis as groups must be followed until disease is observed. however, when cohort studies are successful, proof of cause-effect relationship is often incontrovertible. the term 'molecular epidemiology' is used to denote the use of any of a large number of molecular biological methods in support of epidemiologic investigations. for example, with herpesviruses, restriction endonuclease mapping has provided a means of identification of unique viral genotypes -in an epidemiologic study recognized as the first based upon viral molecular characterization, the source of herpes simplex virus causing disease in a hospital newborn nursery was traced to one persistently infected nurse rather than any of several other possible shedders. with rotaviruses and bluetongue viruses, polyacrylamide gel electrophoresis of the segmented viral rna has been used epidemiologically, for example, to unravel outbreaks involving multiple viral variants. panels of monoclonal antibodies have been used to distinguish virus variants for epidemiologic purposes; they have been particularly useful in elucidating host-range and geographic variants of rabies virus. today, partial sequencing has become the most commonly used molecular epidemiologic methodology; partial sequencing of poliovirus isolates recovered from patients indicates whether they are wild type (even local or introduced wild type), attenuated vaccine type, or a vaccine type that has reacquired neurovirulence during human passage. partial sequencing of foot-and-mouth disease viruses can offer the same kind of geographic information of virus movement as has proved so useful in polio control and eradication programs, but because of political sensitivities in some countries a robust international reference laboratory system has not been established that could provide the same kind of practical disease control information as has been the case with polio. thus, with many human and animal viruses molecular epidemiologic studies are flourishing, but more such studies should lead to international reference laboratory systems to guide prevention and control actions. such studies are developing rapidly today to deal with the threat of a human pandemic of avian influenza, but there are many more viral diseases, especially animal diseases, in need of this kind of development. one of the landmarks in the history of infectious diseases was the development of the henle-koch postulates which established the evidence required to prove a causal relationship between a particular infectious agent and a particular disease. these simple postulates were originally drawn up for bacteria, but were revised in by rivers and again in by evans in attempts to accommodate the special problem of proving disease causation by viruses ( table ) . in many cases, virologists have had to rely on indirect evidence, 'guilt by association', with associations based on epidemiologic data and patterns of serologic positivity in populations. today, many aspects of epidemiologic investigation play roles, especially in trying to distinguish an etiological, rather than coincidental or opportunistic relationship between a virus and a given disease. for example, early in the investigation of human acquired immunodeficiency syndrome (aids), before its etiology was established, many kinds of viruses were being isolated from patients and many candidate etiologic agents were being advanced. prediction that the etiologic agent would turn out to be a member of the family retroviridae was based upon years of veterinary research on animal retroviruses and animal retroviral diseases. this prediction was based upon recognition of common biologic and pathogenetic characteristics of aids and animal retroviral diseases. this prediction guided many of the early experiments to find the etiologic agent of aids; later, after human immunodeficiency virus (hiv ) was discovered, its morphological similarity to equine infectious anemia virus, a prototypic member of the genus lentivirus, family retroviridae, was the key to unraveling confusion over the fact that the human virus killed host lymphocytes rather than transforming them as typical oncogenic retroviruses would do. ever since, this essence of comparative medicine has been guiding hiv/ aids research in many areas, including drug design, diagnostics, and vaccine development. hiv/aids epidemiologic research has often been intertwined with research on the several simian immunodeficiency viruses (sivs). seroepidemiology is useful in public health and animal health investigations and in research to determine the prevalence or incidence of particular infections, to evaluate control and immunization programs, and to assess past history when a 'new' virus is discovered. when paired serum specimens are obtained from individuals several weeks apart, the initial appearance of antibody in the second specimen or a rise in antibody titer indicates recent infection. similarly, the presence of specific immunoglobulin m (igm) antibody in single serum samples, indicating recent infection, may be used in seroepidemiologic studies. correlation of serologic tests with clinical observations makes it possible to determine the ratio of clinical to subclinical infections. because of advanced diagnostic/serologic methods, sentinel studies can yield many valuable data in timely fashion about impending disease risks. for example, sentinel chicken flocks are set out for the early detection of the presence of arboviruses such as west nile virus in the united states. these flocks are bled and tested weekly for the presence of virus or antiviral antibody; they provide an early warning of the levels of virus amplification that occur before epidemics. the immunogenicity, potency, safety, and efficacy of vaccines are first studied in laboratory animals, followed by small-scale closed trials, and finally in large-scale open trials. such studies employ epidemiologic methods, rather like those of the cohort (prospective) study. in most cases, there is no alternative way to evaluate new vaccines, and the design of trials has now been developed so that they yield maximum information with minimum risk and acceptable cost. viruses survive in nature only if they are able to be transmitted from one host to another, whether of the same or another species. transmission cycles require virus entry into the body, replication, and shedding with subsequent spread to another host. portals of virus entry into the body include the skin, respiratory tract, intestinal tract, oropharynx, urogenital tract, and conjunctiva. in some cases, viruses use a particular portal of entry because of particular environmental or host-behavior factors and in other cases because of specific viral ligands and host-cell receptors. in many cases, disruption of normal host-defense mechanisms leads to entry that might otherwise be thwarted; for example, papillomaviruses may enter the deep layers of the skin via abrasions, acid-labile coronaviruses may enter the intestine protected by the buffering capacity of milk, and influenza viruses may enter the lower respiratory tract because a drug has dampened cilial action of the respiratory epithelium. the exit of virus from an infected host is just as important as entry in maintaining its transmission cycle. all portals used by viruses to gain entry are used for exit. the table criteria for disease causation: a unified concept appropriate for viruses as causative agents of disease, based on the henle-koch postulates, and modified by a. s. evans important elements in virus shedding are virus yield (from the standpoint of the virus, the more shedding the better) and timeliness of yield (again, the earlier the shedding the better). viruses that cause persistent infections often employ remarkable means to avoid host inflammatory and immune responses so as to continue shedding. for example, the epidemiologically important shedding of herpes simplex viruses and that perpetuates the viruses in populations requires recrudescence of persistent ganglionic infection, centrifugal viral genomic transit to peripheral nerve endings, and productive infection of mucosal epithelium, all in the face of established host immunity. virus transmission may be 'horizontal' or 'vertical'. the vast majority of transmission is horizontal, that is, between individuals within the population at risk. modes of horizontal transmission of viruses can be characterized as direct contact, indirect contact, common vehicle, airborne, vector-borne, iatrogenic, and nosocomial. vertical or transplacental transmission occurs between the mother and her fetus or newborn. some viruses are transmitted in nature via several modes, others exclusively via one mode (see table ). 'direct contact transmission' involves actual physical contact between an infected subject and a susceptible subject (e.g., kissing, epstein-barr virus, the cause of mononucleosis, biting (e.g., rabies); coitus (sexually transmitted viral diseases)). indirect contact transmission occurs via 'fomites', such as shared eating utensils, improperly sterilized surgical equipment, or improperly sterilized non-disposable syringes and needles. 'common vehicle transmission' pertains to fecal contamination of food and water supplies (e.g., norovirus diarrhea). common vehicle transmission commonly results in epidemic disease. 'airborne transmission' typically results in respiratory infections (and less typically in intestinal infections), but these infections may also be transmitted by direct and indirect contact. airborne transmission occurs via large droplets and via very small droplet nuclei (aerosols) emitted from infected persons during coughing or sneezing (e.g., influenza) or from environmental sources. large droplets (> mm in diameter) settle quickly, but droplet nuclei evaporate forming dry particles (< mm in diameter) which remain suspended in the air for extended periods. droplets may travel only a meter or so while droplet nuclei may travel over much longer distances. 'vector-borne transmission' involves the bites of arthropod vectors (e.g., mosquitoes, ticks, and sandflies). 'iatrogenic transmission' involves health care procedures, materials, and workers (e.g., physicians, nurses, dentists, and veterinarians). 'nosocomial transmission' pertains to infections acquired while a patient, human or animal, is in hospital. 'vertical or transplacental transmission' occurs from mother to fetus prior to or during parturition. certain retroviruses are vertically transmitted in animals via the integration of viral dna directly into the dna of the germline of the fertilized egg. other viruses are transmitted to the fetus across the placenta; yet others are transmitted when the fetus passes through the birth canal. another vertical transmission route is via colostrum and milk. vertical transmission of a virus may or may not be associated with 'congenital disease' (i.e., disease that is present at birth) which may be lethal (and the cause of abortion or stillbirth) or the cause of congenital abnormalities. the herpesviruses, especially cytomegaloviruses, and rubella virus cause important congenital diseases in humans, and pestiviruses, such as bovine viral diarrhea virus, in animals. enteric infections are most often transmitted by direct contact and by fomites in a 'fecal-oral cycle' that may include fecal contamination of food and water supplies; diarrheic feces may also splash to give rise to aerosols (droplets and droplet nuclei). respiratory infections are most often transmitted by the airborne route or by indirect contact via fomites in a 'respiratory cycle', that is, virus is shed in respiratory secretions and enters its next host through the nares during inhalation. the respiratory cycle is responsible for the most explosive patterns of epidemic disease in humans and all domestic animal species. perpetuation of a virus in nature depends upon the maintenance of serial infections, that is, a chain of transmission; the occurrence of disease is neither required nor necessarily advantageous. infection without recognizable disease is called 'subclinical' or 'clinically inapparent'. overall, subclinical infections are much more common than those that result in disease. their relative frequency accounts for the difficulty of tracing chains of transmission, even with the help of laboratory diagnostics. although clinical cases may be somewhat more productive sources of virus than subclinical infections, because the latter do not restrict the movement of the infected host, they can be most important as sources of viral dissemination. in most acute infections, whether clinically apparent or not, virus is shed in highest titers during the late stages of the incubation period, before the influence of the host-immune response takes effect. persistent infections, whether or not they are associated with episodes of clinical disease, also play an important role in the perpetuation of many viruses in nature. for example, prolonged virus shedding can reintroduce virus into a population of susceptibles all of which have been born since the last clinically apparent episode of infection. this is important in the survival of rubella virus in some isolated populations. sometimes the persistence of infection, the production of disease, and the transmission of virus are dissociated; for example, togavirus and arenavirus infections may have little adverse effect on their reservoir hosts (arthropods, birds, and rodents), but transmission may be very efficient. on the other hand, the persistence of infection in the central nervous system, as with measles virus in subacute sclerosing panencephalitis (sspe), is of no epidemiological significance, since no infectious virus is shed from this site. the virulence of the infecting virus may directly affect the probability of its transmission. the classic example of this is rabbit myxomatosis. in australia, mosquito-borne transmission of myxoma virus was found to be most effective when infected rabbits maintained highly infectious skin lesions for several days before death. highly virulent strains of the virus were found to kill rabbits so quickly that transmission did not occur, and naturally attenuated strains were found to produce minimal lesions that healed quickly and did not permit transmission. virus strains at either extreme of this virulence spectrum were found not to survive in nature, but virus strains of intermediate virulence have circulated for many years. with most viruses, endemic or epidemic transmission leads to a level of immunity in the host population that affects or even interrupts further transmission. the 'herd immunity' effect is countered in some cases by viral antigenic variation. for example, influenza viruses undergo genetic variations ('shift' and 'drift') such that persons immune to previously circulating virus strains are susceptible to new strains. assessing these genetic changes is the main objective of laboratory-based surveillance programs, which in turn are the basis for decisions on the formulation of each year's influenza vaccine. it is self-evident that the long-term survival of a virus requires that it be continuously transmitted from one host to another. in general, for rapidly and efficiently transmitted viruses such as many respiratory viruses, local survival of the virus requires that the susceptible host population be very large. a virus may disappear from a population because it exhausts its potential supply of susceptible hosts as they acquire immunity to reinfection with the same virus. depending on duration of immunity and the pattern of virus shedding, the 'critical population size' varies considerably with different viruses and with different host species. the most precise data on the importance of population size in acute nonpersistent infections come from studies of measles. persistence of measles virus in a population depends upon a continuous supply of susceptible children. analyses of the incidence of measles in large cities and in island communities have shown that a population of about half a million persons is needed to ensure a large enough annual input of new susceptible hosts, by birth or immigration, to maintain measles virus in the population. because infection depends on respiratory transmission, the duration of epidemics of measles is correlated inversely with population density. if a population is dispersed over a large area, the rate of spread is reduced and the epidemic may last longer, so that the number of susceptible persons needed to maintain transmission chains is reduced. on the other hand, in such a situation a break in the transmission chain is much more likely. when a large proportion of the population is initially susceptible, the intensity of the epidemic builds up very quickly and attack rates are almost % ('virginsoil epidemic'). on the other hand, when measles vaccination programs are implemented properly the virus disappears completely from the regional population. because most viruses are host-restricted, most viral infections are maintained in nature within populations of the same or related species. however, there are a number of viruses that may have multiple hosts and spread naturally between several different species of vertebrate host, for example, rabies and eastern equine encephalitis viruses. the term 'zoonosis' is used to describe multiple-host infections that are transmissible from animals to man. the zoonoses, whether involving domestic or wild animals or arthropods, usually represent important problems only under conditions where humans are engaged in activities involving close contact with animals or exposure to arthropods. many viral zoonoses are caused by arboviruses. arboviruses have two classes of hosts, vertebrate and invertebrate. over arboviruses are known, of which about cause disease in humans and in domestic animals; some of these are transmitted by ticks, some by mosquitoes, and yet others by phlebotomine flies (sandflies) or culicoides spp. (midges). arthropod transmission may be 'mechanical', where the arthropod acts as a 'flying pin', or more commonly, 'biological', involving replication of the virus in the arthropod vector. the arthropod vector acquires virus by feeding on the blood of a viremic person or animal. replication of the ingested virus, initially in the arthropod's gut, and its spread to the salivary glands takes several days; the interval varies with different viruses and is influenced by ambient temperature. virions in the salivary secretions of the vector are injected into human or animal hosts during subsequent blood meals. most arboviruses have localized natural habitats in which specific receptive arthropod and vertebrate hosts are involved in the viral life cycle. vertebrate reservoir hosts are usually wild mammals or birds; humans are rarely involved in primary transmission cycles, although the exceptions to this generalization are important (e.g., venezuelan equine encephalitis, yellow fever, and dengue viruses). humans are in most cases infected incidentally, for example, by the geographic extension of a reservoir vertebrate host and/or a vector arthropod. ecological changes produced by human activities disturb natural arbovirus life cycles and have been incriminated in the geographic spread or increased prevalence of arbovirus diseases. from the time of william farr, who studied epidemic disease problems in the s, mathematicians have been interested in 'epidemic curves' and secular trends in the incidence of infectious diseases. with the development of computer-based mathematical modeling techniques, there has been a resurgence of interest in the population dynamics of infectious diseases. there has also been a resurgence in controversies surrounding the use of models; critics say 'for every model there is an equal and opposite model'. so, the proof of the value of models lies in their practical application, and in recent years there have been more and more successes. for example, when for counterterrorism reasons universal smallpox vaccination was being considered, models that showed that vaccine could be used effectively after rapid detection of a terrorism incident led to a decision to stockpile, but not widely use vaccine. as another example, when a foot-and-mouth disease epidemic raged in the united kingdom in , a model showed that only the most vigorous stamping-out campaign could get ahead of the movement of the virus across the country. the model, seeming eminently logical now, importantly provided the kind of veracity and political will needed to accelerate the stamping-out campaign. models may be used to determine ( ) patterns of disease transmission, ( ) critical population sizes to support the continuous transmission of viruses with short and long incubation periods, ( ) the dynamics of endemicity of viruses that become persistent in their hosts, and ( ) the variables in age-dependent viral pathogenicity. computer modeling also provides useful insights into the effectiveness of disease control programs. much attention has been given to modeling the future of the aids epidemic in the united states and the rest of the world. such models usually start with historical data on the introduction of the etiologic virus, hiv , proceed to the present stage of the epidemic where the disease has become well established in many countries and in fewer countries subject to prevention and treatment strategies, and then proceed to project its course into the future. during the first years of the aids epidemic in the united states, african countries, and then in asian countries, most models underestimated developing trends; more recently models have become more accurately predictive -but in many places more and more sobering. knowledge of the epidemiology and modes of transmission of infectious diseases is critical to the development and implementation of prevention and control strategies. data on incidence, prevalence, and mortality contribute directly to the establishment of priorities for prevention and control programs while knowledge of viral characteristics and modes of transmission are used in deciding prevention strategies focusing on vaccine development and delivery, environmental improvements, enhancement of nutritional status, improvement in personal hygiene, and behavioral changes. see also: disease surveillance; viral pathogenesis; zoonoses. prevalence of the disease is significantly higher in subjects exposed to the putative virus than in those not so exposed. . incidence of the disease is significantly higher in subjects exposed to the putative virus than in those not so exposed temporally, the onset of disease follows exposure to the putative virus, always following an incubation period a regular pattern of clinical signs follows exposure to the putative virus, presenting a graded response, often from mild to severe a measurable host-immune response, such as an antibody response and/or a cell-mediated response, follows exposure to the putative virus experimental reproduction of the disease follows deliberate exposure of animals to the putative virus, but nonexposed control animals remain disease free. deliberate exposure may be in the laboratory or in the field, as with sentinel animals elimination of the putative virus and/or its vector decreases the incidence of the disease prevention or modification of infection, via immunization or drugs, decreases the incidence of the disease control of communicable diseases manual, th edn mandell, douglas, and bennett's principles and practice of infectious diseases the epidemiology of viral infections veterinary virology fields virology evolution of viral diseases virus dynamics: mathematical principles of immunology and virology emerging microbial threats to health in the st century. institute of medicine/ national academy of sciences microbial threads to health, emergence, detection and response veterinary epidemiology general features all rights reserved. the lymphocryptoviruses (lcvs) present in old world nonhuman primates, including ebv-like viruses of chimpanzees and rhesus monkeys. these viruses share homologous sequences and genetic organization, and infect the b lymphocytes of their host species, resulting in the establishment of latent infection in vivo and transformation key: cord- -yn bbkdh authors: kohanski, michael a.; lo, l. james; waring, michael s. title: review of indoor aerosol generation, transport, and control in the context of covid‐ date: - - journal: int forum allergy rhinol doi: . /alr. sha: doc_id: cord_uid: yn bbkdh the coronavirus disease‐ (covid‐ ) pandemic has heightened the awareness of aerosol generation by human expiratory events and their potential role in viral respiratory disease transmission. concerns over high severe acute respiratory syndrome‒coronavirus‐ (sars‐cov‐ ) viral burden of mucosal surfaces has raised questions about the aerosol‐generating potential and dangers of many otorhinolaryngologic procedures. however, the risks of aerosol generation and associated viral transmission by droplet or airborne routes for many otorhinolaryngology procedures are largely unknown. indoor aerosol and droplet viral respiratory transmission risk is influenced by factors: ( ) aerosol or droplet properties; ( ) indoor airflow; ( ) virus‐specific factors; and ( ) host‐specific factors. herein we elaborate on known aerosol vs droplet properties, indoor airflow, and aerosol‐generating events to provide context for risks of aerosol infectious transmission. we also provide simple but typically effective measures for mitigating the spread and inhalation of viral aerosols in indoor settings. understanding principles of infectious transmission, aerosol and droplet generation, as well as concepts of indoor airflow, will assist in the integration of new data on sars‐cov‐ transmission and activities that can generate aerosol to best inform on the need for escalation or de‐escalation from current societal and institutional guidelines for protection during aerosol‐generating procedures. the coronavirus disease-covid-pandemic has heightened the awareness of aerosol generation by human expiratory events and their potential role in viral respiratory disease transmission concerns over high severe acute respiratory syndrome-coronavirus-sars-cov-viral burden of mucosal surfaces has raised questions about the aerosol-generating potential and dangers of many otorhinolaryngologic procedures however the risks of aerosol generation and associated viral transmission by droplet or airborne routes for many otorhinolaryngology procedures are largely unknown indoor aerosol and droplet viral respiratory transmission risk is influenced by factors aerosol or droplet properties indoor airflow virus-specific factors and host-specific factors herein we elaborate on known aerosol vs droplet properties indoor airflow and aerosol-generating events to provide context for risks of aerosol infectious transmission we also provide simple but typically effective measures for mitigating the spread and inhalation of viral aerosols in indoor settings understanding principles of infectious transmission aerosol and droplet generation as well as concepts of indoor airflow will assist in the integration of new data on sars-cov-transmission and activities that can generate aerosol to best inform on the need for escala-many otorhinolaryngology procedures involve instrumentation of respiratory mucosal surfaces and proximity to a patient's airway for a period ranging from minutes to hours, and there has been concern that many of these procedures may be aerosol-generating procedures (agps) that increase the risk of contracting covid- due to inhalation of airborne droplets or aerosols. [ ] [ ] [ ] [ ] [ ] the lack of studies within the otorhinolaryngology field assessing the aerosol-generating potential of procedures involving mucosal surfaces pre-covid- made it challenging to understand in an evidence-based fashion the potential risks of sars-cov- transmission associated with instrumentation of the upper airway; that is, whether these procedures may be infectious agps. at the early stages of the pandemic, based on the risks of exposure to high viral load mucosal surfaces, , as well as on the lack of any immunity to sars-cov- and of any vaccines or effective treatments, an array of practice changes to protect health-care workers and patients were recommended and instituted for otorhinolaryngology procedures involving upper airway mucosal surfaces. , [ ] [ ] [ ] [ ] [ ] [ ] respiratory disease transmission can occur through contact (touching a contaminated surface followed by self-inoculation of the eyes, nose, or mouth), droplet figure . three possible mechanisms of respiratory pathogen transmission. transmission can occur through self-inoculation after contact with droplets that settle on surfaces, direct deposition/inspiration of infectious droplets in the mouth or nose and deposition on the eyes, as well as through airborne transmission with inhalation of aerosols. short range (< to meters) aerosol transmission can be difficult to separate from droplet transmission and long-range transmission for viral respiratory pathogens, including influenza and coronaviruses, remains controversial. (inhalation in nasal/upper airway or direct inoculation of eyes, nose, or mouth), or aerosol transmission (inhalation into upper or lower airway) (fig. ) . , in addition, airborne respiratory pathogen transmission is ill-defined with proposed definitions of short-range droplet (< or meters) vs long-range aerosol transmission. when considering modes of transmission for sars-cov- , it is important to recognize that airborne transmission remains controversial as a significant or common mode of transmission for viral respiratory diseases, such as influenza, severe acute respiratory syndrome (sars), and middle east respiratory syndrome (mers). - sars-cov- and sars-cov- both target the surface receptor angiotensinconverting enzyme- (ace- ) in humans as a means of entry, , and ace- is expressed on type ii pneumocytes in the lung , and ciliated cells of nasal mucosa, , suggesting that there is a biologically plausible mechanism for an airborne route of transmission. observational studies and models are emerging suggesting airborne transmission of sars-cov- can occur. [ ] [ ] [ ] indoor airborne viral respiratory transmission risk is influenced by factors: ( ) aerosol and droplet properties; ( ) indoor airflow; ( ) virus-specific factors; and ( ) hostspecific factors. herein we elaborate on known aerosol vs droplet properties, aerosol-generating events, and concepts of indoor airflow. combining principles of these elements with those of infectious transmission can inform simple yet typically effective measures for mitigating the concentration, distribution, and inhalation of viral aerosols in indoor settings. an aerosol is "a suspension of fine solid particles or liquid droplets in air or another gas," and an aerosol can be usefully envisioned as a particle that follows the streamlines of the flowing gas (indoor air in our case) in which it resides. yet, this definition does not fully encompass the wide range of airborne particle behaviors, which depend on particle size. the dominant method of classifying particle behavior is by size based on diameter, typically in micrometers (μm). generally, indoor aerosols exist as particles of diameter size of subnanometer to several hundred micrometers, and they may be most broadly defined as ultrafine (< . μm), fine ( . - . μm), or coarse (> . μm). although droplets are often discussed in some communities as distinct from aerosols, both are airborne particulate matter cast on a continuum of size. the definition of droplet is nebulous, and droplets have been variously defined as having diameters of > , > , or > μm. however, this distinction has utility, as droplets should be thought of as particles that fall out of the air rapidly while aerosols do not and remain airborne indoors. thus, characterization of the size of the particle is crucial for calculating particle deposition on surfaces, where particles above ∼ μm in size are more likely to fall out of airflow streams and settle or impact onto surfaces (fig. ) . because a droplet is often a large particle consisting mostly of water, with an associated aerosol-size nucleus (ie, a droplet nucleus), evaporation kinetics driven by conditions such as relative humidity, air temperature, and velocity determine a droplet critical size below which the droplet rapidly evaporates to form an aerosol with an appreciable indoor air lifetime and above which evaporation kinetics are slow enough that the droplet quickly settles out of the air. aerosol and droplet descriptions and divisions are based on characteristic behaviors of particles from modeling and experimental data, but they do not account for the infectious composition of the particles. often, descriptions of aerosol regarding infectious disease transmission have followed similar paradigms-with divisions based on particle size that can be inhaled into different respiratory regions ( fig. ) . , , to date, sars-cov- viral rna has been detected predominantly in the > -μm-diameter range, with the majority of viral rna detected in aerosols > μm in hospitals with large outbreaks of covid- . this study, in conjunction with particle lung deposition models (fig. ) , suggests that a preponderance of viral-laden infectious particles may deposit in the nasal airway. single coronavirus. (b) as particle size decreases, airborne suspension time increases-particles > to µm have suspension times on the order of seconds and are considered droplets, whereas particles with smaller diameter remain airborne much longer and are considered aerosol. for context, the time for a particle to fall meter due to gravity can be calculated using its terminal settling velocity, and particles of , , , and . µm will settle a distance of meter in . seconds, . minutes, . hours, and days, respectively. particle settling is important when the suspension time is less than the indoor air residence time, which is how long air resides indoors before being exhausted and replaced by fresh ventilation air. the suspension time is defined as amount of time for a particle of a given size to settle meter with no air flow, as depicted by the black line. the influence of the number of achs is depicted; that is, particles with a suspension time of > . hour will be less likely to deposit on surfaces and will be cleared from a room with ≥ achs, and those with suspension times > hour will behave similarly when there is ≥ ach. although ultrafine and smaller fine aerosols never appreciably settle due to gravity on surfaces indoors, they do deposit effectually on indoor surfaces by the brownian diffusion mechanism. note that the graph represents suspension times and indoor air times for well-mixed environments, and does not include impact of local airflow, source proximity, or evaporation. ach = air changes per hour. aerosol emissions from breathing, talking, coughing, singing, and sneezing with regard to aerosol-or droplet-generating expiratory actions, it is important to consider both the quantity and size range of emitted particles, as well as the velocity of the generating or initial carrying event that impact the transport of particles (especially droplets). breathing, talking, coughing, and sneezing generate aerosols and/or droplets, and aerosol generation with these actions is not uniform, with a high degree of variability from individual to individual. [ ] [ ] [ ] [ ] [ ] in addition, aerosol generation in those with viral respiratory infections may be increased when compared with healthy individuals. with the exception of sneezing, which emits large droplets with central tendencies of particles at tens or hundreds of micrometers, studies have reported that these events generate more submicrometer than supermicrometer particles, that there is high variability among test subjects, and that the order of least-producing actions is breathing followed by talking and then coughing. moreover, newer work has demonstrated that speech generates hundreds or thousands of sub-and supermicrometer particles per second, and that emission rates correlate with the loudness of the speech. singing and sustained vocalization also have increased emission rates, , and singing in close proximity in an enclosed space was recently linked with a large documented cluster of covid- cases associated with a choir practice highlighting the concern for airborne transmission. aerosol-generating procedures the us centers for disease control and prevention (cdc) defines "aerosol-generating procedures" (agps) as procedures with the potential to generate infectious respiratory particles at higher concentrations than breathing, coughing, sneezing, or talking (table ) , or procedures that create uncontrolled respiratory secretions. , as also noted by the cdc, the list of agps is both limited in accuracy and completeness. the limited data on airborne transmission risks with most commonly performed medical procedures involving mucosal surfaces has made it challenging to arrive at a unified consensus defining otolaryngology procedures that are agps. the current cdc list of infectious agps includes some otolaryngology-associated procedures, among them open suctioning of airways, intubation, and bronchoscopy. recent work examining endonasal procedures and mastoidectomy has demonstrated droplet dispersion with high-speed endonasal drilling and drilling of the mastoid, respectively. aerosols in the to -μm-diameter range were observed after nasal endoscopy, endonasal electrocautery, or high-speed endonasal drilling. most procedures listed as agps have limited or no data characterizing particle size-resolved emission rates, resulting characteristics of indoor particle transport, or quantification of infectious agents recoverable from emitted aerosol. aerosol transport in buildings has been well researched and the physics of particle movement in indoor environments is understood. [ ] [ ] [ ] [ ] [ ] in a room setting, particle emission from the mouth or nose is influenced by its initial velocity. a sneeze, for example, can generate an extremely high velocity initially (∼ m/s), but it will quickly dissipate over a short distance (∼ m/s after . meter), whereas talking generates a lower velocity at ∼ m/s, with the initial airflow field likely dissipating completely within meter from the mouth. because the majority of generated particles are < μm for all but sneezing, larger diameter droplets will fall to a surface quickly, but, for an aerosol without appreciable settling, the bulk indoor airflow governs its movement as the initial velocity dissipates. in the indoor environment, bulk airflow is impacted largely by forces: the first is the movement from thermal buoyancy of equipment and occupants; and the other is the forced-air movement of the heating, ventilation, and air-conditioning (hvac) system. for aerosols, these mechanisms greatly increase the distance exhaled particles can spread indoors. , an hvac system conditions and distributes air around a building using various amounts of recirculated and ventilation (fresh outdoor) air, and an aerosol emission can be transported from its point of origin to the entire hvac zone or building due to the recirculation, although the concentration will diminish due to dilution and filtration. in one documented example from guangzhou, china, li et al observed that, in a poorly ventilated space, the transmission of sars-cov- could be traced to localized airflow, highlighting the importance of indoor local airflow patterns for covid- transmission. transmission of a respiratory viral pathogen requires exposure to and successful inoculation with an infectious titer of virus. opportunistic aerosol transmission due to local airflow between an aerosol source and susceptible host is an area of concern and controversy due to challenges in clearly delineating this mode of transmission from droplet transmission. nevertheless, proximity to an aerosol or droplet source increases the risk of exposure and successful viral transmission, particularly as the distance between particle source (eg, airway during an expiratory event) and susceptible host decreases to < meter, a typical situation during both physical examination and any otolaryngology procedure. guidelines for use of eye protection do not currently delineate between protective goggles or face shields; however, we advocate for use of face shields as they provide additional protection beyond shielding the eyes. face shields are effective at preventing early exposure to coughor sneeze-generated aerosols by intercepting droplets and high-velocity airborne particles before impacting on a face mask or respirator. face-shield efficacy is reduced as time increases after the expiratory event as aerosol particles are able to "slip" around the face shield when particle transport associated with bulk airflow takes over. at this point, the role of an effective face mask or respirator becomes critical. of note, current clinical data is not clear cut on the efficacy of n masks over surgical masks in preventing disease transmission [ ] [ ] [ ] ; however, a recent analysis has suggested that n masks are likely more effective than surgical masks at reducing coronavirus-associated disease transmission. although long-range viral respiratory pathogen aerosol transmission is controversial and has not been definitively established as a common mechanism of sars-cov- transmission to date, principles associated with bulk airflow can be used to help minimize risks of aerosol transmission. reducing infectious aerosols can be achieved by increasing the building ventilation (dilution) rate and using higher efficiency filtration. hospital-based clinic rooms require a minimum of air changes per hour (achs) and operating rooms (ors) a minimum of ach, of which at a minimum (in the or only) are air changes with outdoor air, whereas, according to the american society for heating, refrigeration, and air-conditioning engineers (ashrae), outpatient care facilities should have about achs. the risk of aerosol transmission is likely highest in clinic settings, particularly office-building-based practices and older or repurposed buildings with poor ventilation or older hvac systems with no or lower efficiency filtration. indoor air dilution to reduce aerosol exposure is the key strategy that ashrae recommends for building protection during the pandemic reopening phase, advocating for increasing ventilation air intake in buildings to achs, roughly to times higher than the minimum ventilation standard in offices or similar building types. at achs, the outdoor air dilution is able to remove about % of the contaminants indoors within hour, assuming the space is well mixed. hvac systems should be operated to increase ventilation (outdoor) air as much as the system constraints allow for optimization of these dilutional effects. whenever possible, opening windows can increase crossflow and is also a simple and effective option for enhancing dilution and decreasing concentrations of indoor-emitted aerosol. hvac systems in buildings usually employ intentional particle filtration, which will further diminish aerosol concentrations. properly installed, the most efficient filter typically used (merv ) can remove > % of the . -to -μm-size range of particles. knowledge of the hvac zones (what nonclinic rooms are connected to airflow from clinic rooms) may help inform how best to approach and optimize enhanced filtration that can remove aerosols and reduce risks of circulating infectious aerosols within an hvac zone. strongly increasing ventilation air and filtration may not be possible with all systems due to increased system strain or the configuration or age of the hvac system. especially in these, but in our opinion possibly all situations, there is a role for portable air cleaners with high clean air delivery rates (cadrs) to reduce aerosol concentrations in a room, such as a stand-alone hepa filter with a high flow rate. [ ] [ ] [ ] the cadr is the effective flow rate of particle-free air supplied by the device. the impact a portable air cleaner will have in a room can be determined by dividing the cadr by the room volume. for example, a unit with a cadr of ft /min will effectively add achs in terms of particle removal for a room that is ∼ ft (eg, for a room of ft × ft × . ft; cadr = ft /min × min/h = , ft /h; impact = cadr/volume = , ft /h/ ft = h − is equivalent to achs). the risk of long-range aerosol transmission in an or setting meeting current federal guidelines for ach is likely minimized due to aerosol exhaust, dilution, and filtration. in this type of setting, the key transport mechanism for potential aerosol transmission relies on duration of exposure to local airflow within an or between the emitter and a given target. because aerosols move with bulk air, specific airflow design strategies can be used to control or mitigate exposure to pathogens indoors. awareness of the location of the air-handling vents and the general direction of airflow may be helpful in orienting patient positioning to maximize airborne particle movement away from the healthcare provider. however, given the complexity of assessing and modeling airflows, impacts of such changes to risks of infectious airborne transmission will likely need to be assessed on a case-by-case basis. the risk of long-range airborne transmission of sars-cov- remains controversial; however, the nature of an otolaryngology practice makes it plausible that the proximity to a patient's airway during elements of the physical examination and some otorhinolaryngologic procedures carries a risk of opportunistic aerosol transmission due to short-term viral exposure at a high concentration or cumulative viral exposure over time. awareness of local airflow patterns within a clinical space can help orient patient positioning to enhance aerosol movement away from the provider. the grim reality is that the true measure of protection will be tracking covid- among health-care workers at high risk for droplet and aerosol exposure, which will be challenging to separate from ongoing community spread. by combining enhanced hvac or portable air-cleaner filtration with increased ventilation, clinic spaces can be prepared to better protect occupants from possible aerosol transmission. these actions will narrow the key transport mechanism for potential aerosol transmission to rely on local air movement between the emitter and a given target, which is a mechanism that can be mitigated with the use of face shields and respirators. this approach can improve overall clinical safety and allow clinics to remain operational as regional surges in cases occur. as we learn more about covid- transmission, understanding the principles of infectious transmission, airborne particle and droplet generation, and concepts of indoor airflow will help us to make informed and rational decisions on escalation or de-escalation of our current 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inhibitor angiotensin-converting enzyme is a functional receptor for the sars coronavirus tissue distribution of ace protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis sars-cov- reverse genetics reveals a variable infection gradient in the respiratory tract sars-cov- entry factors are highly expressed in nasal epithelial cells together with innate immune genes high sars-cov- attack rate following exposure at a choir practice evidence for probable aerosol transmission of sars-cov- in a poorly ventilated restaurant identifying airborne transmission as the dominant route for the spread of covid- aerosol technology: properties, behavior, and measurement of airborne particles indoor particle dynamics how far droplets can move in indoor environmentsrevisiting the wells evaporation-falling curve aerosol transmission of infectious disease detection of air and surface contamination by sars-cov- in hospital rooms of infected patients airflow and particle transport in the human respiratory system origin of exhaled breath particles from healthy and human rhinovirus-infected subjects inhaling to mitigate exhaled bioaerosols the size and concentration of droplets generated by coughing in human subjects size distribution of exhaled particles in the range from . to . μm characteristics of exhaled particle production in healthy volunteers: possible implications for infectious disease transmission characterizations of particle size distribution of the droplets exhaled by sneeze the size distribution of droplets in the exhaled breath of healthy human subjects the airborne lifetime of small speech droplets and their potential importance in sars-cov- transmission aerosol emission and superemission during human speech increase with voice loudness modality of human expired aerosol size distributions singing and the dissemination of tuberculosis which procedures are considered aerosol generating procedures in healthcare settings? aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review endonasal instrumentation and aerosolization risk in the era of covid- : simulation, literature review, and proposed mitigation strategies demonstration and mitigation of aerosol and particle dispersion during mastoidectomy relevant to the covid- era airborne aerosol generation during endonasal procedures in the era of covid- : risks and recommendations. otolaryngol head neck surg indoor particles: a review the measurement and simulation of indoor air flow indoor air quality and its effects on humans-a review of challenges and developments in the last years indoor particle dynamics particle tracking velocimetry for indoor airflow field: a review airflow dynamics of human jets: sneezing and breathingpotential sources of infectious aerosols characterization of expiration air jets and droplet size distributions immediately at the mouth opening characterizing exhaled airflow from breathing and talking cfd modeling and measurement of aerosol particle distributions in ventilated multizone rooms numerical modeling of exhaled droplet nuclei dispersion and mixing in indoor environments experimental measurements and numerical simulations of particle transport and distribution in ventilated rooms physical distancing, face masks, and eye protection to prevent personto-person transmission of sars-cov- and covid- : a systematic review and meta-analysis efficacy of face shields against cough aerosol droplets from a cough simulator n respirators vs medical masks for preventing influenza among health care personnel: a randomized clinical trial effectiveness of n respirators versus surgical masks in protecting health care workers from acute respiratory infection: a systematic review and meta-analysis surgical mask vs n respirator for preventing influenza among health care workers: a randomized trial environmental infection control guidelines: appendix b refrigeration, and air-conditioning engineers. ashrae position document on infectious aerosols american society for heating, refrigeration, and air-conditioning engineers. ventilation for acceptable indoor air quality. standard - air filters and air cleaners: rostrum by the american academy of allergy, asthma & immunology indoor allergen committee using air purifier as a supplementary protective measure in dental clinics during the covid- pandemic what is an effective portable air cleaning device? a review ultrafine particle removal and generatin by portable air cleaners particle transport and deposition: basic physics of particle kinetics modeling indoor particle deposition from turbulent flow onto smooth surfaces aerosol deposition in health and disease airborne transmission of communicable infection-the elusive pathway key: cord- -fkdep cp authors: thompson, robin n.; hollingsworth, t. déirdre; isham, valerie; arribas-bel, daniel; ashby, ben; britton, tom; challenor, peter; chappell, lauren h. k.; clapham, hannah; cunniffe, nik j.; dawid, a. philip; donnelly, christl a.; eggo, rosalind m.; funk, sebastian; gilbert, nigel; glendinning, paul; gog, julia r.; hart, william s.; heesterbeek, hans; house, thomas; keeling, matt; kiss, istván z.; kretzschmar, mirjam e.; lloyd, alun l.; mcbryde, emma s.; mccaw, james m.; mckinley, trevelyan j.; miller, joel c.; morris, martina; o'neill, philip d.; parag, kris v.; pearson, carl a. b.; pellis, lorenzo; pulliam, juliet r. c.; ross, joshua v.; tomba, gianpaolo scalia; silverman, bernard w.; struchiner, claudio j.; tildesley, michael j.; trapman, pieter; webb, cerian r.; mollison, denis; restif, olivier title: key questions for modelling covid- exit strategies date: - - journal: proc biol sci doi: . /rspb. . sha: doc_id: cord_uid: fkdep cp combinations of intense non-pharmaceutical interventions (lockdowns) were introduced worldwide to reduce sars-cov- transmission. many governments have begun to implement exit strategies that relax restrictions while attempting to control the risk of a surge in cases. mathematical modelling has played a central role in guiding interventions, but the challenge of designing optimal exit strategies in the face of ongoing transmission is unprecedented. here, we report discussions from the isaac newton institute ‘models for an exit strategy’ workshop ( – may ). a diverse community of modellers who are providing evidence to governments worldwide were asked to identify the main questions that, if answered, would allow for more accurate predictions of the effects of different exit strategies. based on these questions, we propose a roadmap to facilitate the development of reliable models to guide exit strategies. this roadmap requires a global collaborative effort from the scientific community and policymakers, and has three parts: (i) improve estimation of key epidemiological parameters; (ii) understand sources of heterogeneity in populations; and (iii) focus on requirements for data collection, particularly in low-to-middle-income countries. this will provide important information for planning exit strategies that balance socio-economic benefits with public health. as of august , the coronavirus disease (covid- ) pandemic has been responsible for more than million reported cases worldwide, including over deaths. mathematical modelling is playing an important role in guiding interventions to reduce the spread of severe acute respiratory syndrome coronavirus (sars-cov- ). although the impact of the virus has varied significantly across the world, and different countries have taken different approaches to counter the pandemic, many national governments introduced packages of intense non-pharmaceutical interventions (npis), informally known as 'lockdowns'. although the socio-economic costs (e.g. job losses and long-term mental health effects) are yet to be assessed fully, public health measures have led to substantial reductions in transmission [ ] [ ] [ ] . data from countries such as sweden and japan, where epidemic waves peaked without strict lockdowns, will be useful for comparing approaches and conducting retrospective cost-benefit analyses. as case numbers have either stabilized or declined in many countries, attention has turned to strategies that allow restrictions to be lifted [ , ] in order to alleviate the economic, social and other health costs of lockdowns. however, in countries with active transmission still occurring, daily disease incidence could increase again quickly, while countries that have suppressed community transmission face the risk of transmission reestablishing due to reintroductions. in the absence of a vaccine or sufficient herd immunity to reduce transmission substantially, covid- exit strategies pose unprecedented challenges to policymakers and the scientific community. given our limited knowledge, and the fact that entire packages of interventions were often introduced in quick succession as case numbers increased, it is challenging to estimate the effects of removing individual measures directly and modelling remains of paramount importance. we report discussions from the 'models for an exit strategy' workshop ( ) ( ) ( ) ( ) ( ) may ) that took place online as part of the isaac newton institute's 'infectious dynamics of pandemics' programme. we outline progress to date and open questions in modelling exit strategies that arose during discussions at the workshop. most participants were working actively on covid- at the time of the workshop, often with the aim of providing evidence to governments, public health authorities and the general public to support the pandemic response. after four months of intense model development and data analysis, the workshop gave participants a chance to take stock and openly share their views of the main challenges they are facing. a range of countries was represented, providing a unique forum to discuss the different epidemic dynamics and policies around the world. although the main focus was on epidemiological models, the interplay with other disciplines formed an integral part of the discussion. the purpose of this article is twofold: to highlight key knowledge gaps hindering current predictions and projections, and to provide a roadmap for modellers and other scientists towards solutions. given that sars-cov- is a newly discovered virus, the evidence base is changing rapidly. to conduct a systematic review, we asked the large group of researchers at the workshop for their expert opinions on the most important open questions, and relevant literature, that will enable exit strategies to be planned with more precision. by inviting contributions from representatives of different countries and areas of expertise (including social scientists, immunologists, epidemic modellers and others), and discussing the expert views raised at the workshop in detail, we sought to reduce geographical and disciplinary biases. all evidence is summarized here in a policy-neutral manner. the questions in this article have been grouped as follows. first, we discuss outstanding questions for modelling exit strategies that are related to key epidemiological quantities, such as royalsocietypublishing.org/journal/rspb proc. r. soc. b : the reproduction number and herd immunity fraction. we then identify different sources of heterogeneity underlying sars-cov- transmission and control, and consider how differences between hosts and populations across the world should be included in models. finally, we discuss current challenges relating to data requirements, focusing on the data that are needed to resolve current knowledge gaps and how uncertainty in modelling outputs can be communicated to policymakers and the wider public. in each case, we outline the most relevant issues, summarize expert knowledge and propose specific steps towards the development of evidencebased exit strategies. this leads to a roadmap for future research (figure ) made up of three key steps: (i) improve estimation of epidemiological parameters using outbreak data from different countries; (ii) understand heterogeneities within and between populations that affect virus transmission and interventions; and (iii) focus on data needs, particularly data collection and methods for planning exit strategies in low-to-middle-income countries (lmics) where data are often lacking. this roadmap is not a linear process: improved understanding of each aspect will help to inform other requirements. for example, a clearer understanding of the model resolution required for accurate forecasting ( § a) will inform the data that need to be collected ( § ), and vice versa. if this roadmap can be followed, it will be possible to predict the likely effects of different potential exit strategies with increased precision. this is of clear benefit to global health, allowing exit strategies to be chosen that permit interventions to be relaxed while limiting the risk of substantial further transmission. (a) how can viral transmissibility be assessed more accurately? the time-dependent reproduction number, r(t) or r t , has emerged as the main quantity used to assess the transmissibility of sars-cov- in real time [ ] [ ] [ ] [ ] [ ] . in a population with active virus transmission, the value of r(t) represents the expected number of secondary cases generated by someone infected at time t. if this quantity is, and remains below, one, then an ongoing outbreak will eventually fade out. although easy to understand intuitively, estimating r(t) from case reports (as opposed to, for example, observing r(t) in known or inferred transmission trees [ ] ) requires the use of mathematical models. as factors such as contact rates between infectious and susceptible individuals change during an outbreak in response to public health advice or movement restrictions, the value of r(t) has been found to respond rapidly. for example, across the uk, country-wide and regional estimates of r(t) dropped from approximately . - in mid-march [ , ] to below one after lockdown was introduced [ , ] . one of the criteria for relaxing the lockdown was for the reproduction number to decrease to 'manageable levels' [ ] . monitoring r(t), as well as case numbers, as individual components of the lockdown are relaxed is critical for understanding whether or not the outbreak remains under control [ ] . several mathematical and statistical methods for estimating temporal changes in the reproduction number have been proposed. two popular approaches are the wallinga-teunis method [ ] and the cori method [ , ] . these methods use case notification data along with an estimate of the serial interval distribution (the times between successive cases in a transmission chain) to infer the value of r(t). other approaches exist (e.g. based on compartmental epidemiological models [ ] ), including those that can be used alongside different data (e.g. time series of deaths [ , , ] or phylogenetic data [ ] [ ] [ ] [ ] ). despite this extensive theoretical framework, practical challenges remain. reproduction number estimates often rely on case notification data that are subject to delays between case onset and being recorded. available data, therefore, do not include up-to-date knowledge of current numbers of infections, an issue that can be addressed using 'nowcasting' models [ , , ] . the serial interval represents the period between symptom onset times in a transmission chain, rather than between times at which cases are recorded. time series of symptom onset dates, or even infection dates (to be used with estimates of the generation interval when inferring r(t)), can be estimated from case notification data using latent variable methods [ , ] or methods such as the richardson-lucy deconvolution technique [ , ] . the richardson-lucy approach has previously been applied to infer incidence curves from time series of deaths [ ] . these methods, as well as others that account for reporting delays [ figure . research roadmap to facilitate the development of reliable models to guide exit strategies. three key steps are required: (i) improve estimates of epidemiological parameters (such as the reproduction number and herd immunity fraction) using data from different countries ( § a-d); (ii) understand heterogeneities within and between populations that affect virus transmission and interventions ( § a-d); and (iii) focus on data requirements for predicting the effects of individual interventions, particularly-but not exclusively-in data-limited settings such as lmics ( § a-c). work in these areas must be conducted concurrently; feedback will arise from the results of the proposed research that will be useful for shaping next steps across the different topics. (online version in colour.) royalsocietypublishing.org/journal/rspb proc. r. soc. b : useful avenues to improve the practical estimation of r(t). further, changes in testing practice (or capacity to conduct tests) lead to temporal changes in case numbers that cannot be distinguished easily from changes in transmission. understanding how accurately and how quickly changes in r(t) can be inferred in real time given these challenges is crucial. another way to assess temporal changes in r(t), without requiring nowcasting, is by observing people's transmissionrelevant behaviour directly, e.g. through contact surveys or mobility data [ ] . these methods come with their own limitations: because these surveys do not usually collect data on infections, care must be taken in using them to understand and predict ongoing changes in transmission. other outstanding challenges in assessing variations in r(t) include the decrease in accuracy when case numbers are low, and the requirement to account for temporal changes in the serial interval or generation time distribution of the disease [ , ] . when there are few cases (such as in the 'tail' of an epidemic- § d), there is little information with which to assess virus transmissibility. methods for estimating r(t) based on the assumption that transmissibility is constant within fixed time periods can be applied with windows of long duration (thereby including more case notification data with which to estimate r(t)) [ , ] . however, this comes at the cost of a loss of sensitivity to temporal variations in transmissibility. consequently, when case numbers are low, the methods described above for tracking transmission-relevant behaviour directly are particularly useful. in those scenarios, the 'transmission potential' might be more important than realized transmission [ ] . the effect of population heterogeneity on reproduction number estimates requires further investigation, as current estimates of r(t) tend to be calculated for whole populations (e.g. countries or regions). understanding the characteristics of constituent groups contributing to this value is important to target interventions effectively [ , ] . for this, data on infections within and between different subpopulations (e.g. infections in care homes and in the wider population) are needed. as well as between subpopulations, it is also necessary to ensure that estimates of r(t) account for heterogeneity in transmission between different infectious hosts. such heterogeneity alters the effectiveness of different control measures, and, therefore, the predicted disease dynamics when interventions are relaxed. for a range of diseases, a rule of thumb that around % of infected individuals are the sources of % of infections has been proposed [ , ] . this is supported by recent evidence for covid- , which suggests significant individual-level variation in sars-cov- transmission [ ] with some transmission events leading to large numbers of new infections. finally, it is well documented that presymptomatic individuals (and, to a lesser extent, asymptomatic infected individuals-i.e. those who never develop symptoms) can transmit sars-cov- [ , ] . for that reason, negative serial intervals may occur when an infected host displays covid- symptoms before the person who infected them [ , ] . although methods for estimating r(t) with negative serial intervals exist [ , ] , their inclusion in publicly available software for estimating r(t) should be a priority. increasing the accuracy of estimates of r(t), and supplementing these estimates with other quantities (e.g. estimated epidemic growth rates [ ] ), is of clear importance. as lockdowns are relaxed, this will permit a fast determination of whether or not removed interventions are leading to a surge in cases. (b) what is the herd immunity threshold and when might we reach it? herd immunity refers to the accumulation of sufficient immunity in a population through infection and/or vaccination to prevent further substantial outbreaks. it is a major factor in determining exit strategies, but data are still very limited. dynamically, the threshold at which herd immunity is achieved is the point at which r(t) ( § a) falls below one for an otherwise uncontrolled epidemic, resulting in a negative epidemic growth rate. however, reaching the herd immunity threshold does not mean that the epidemic is over or that there is no risk of further infections. great care must be taken in communicating this concept to the public, to ensure continued adherence to public health measures. crucially, whether immunity is gained naturally through infection or through random or targeted vaccination affects the herd immunity threshold, which also depends critically on the immunological characteristics of the pathogen. since sars-cov- is a new virus, its immunological characteristics-notably the duration and extent to which prior infection confers protection against future infection, and how these vary across the populationare currently unknown [ ] . lockdown measures have impacted contact structures and hence the accumulation of immunity in the population, and are likely to have led to significant heterogeneity in acquired immunity (e.g. by age, location, workplace). knowing the extent and distribution of immunity in the population will help guide exit strategies. as interventions are lifted, whether or not r(t) remains below one depends on the current level of immunity in the population as well as the specific exit strategy followed. a simple illustration is to treat r(t) as a deflation of the original (basic) reproduction number (r , which is assumed to be greater than one): where i(t) is the immunity level in the community at time t and p(t) is the overall reduction factor from the control measures that are in place. if i(t) . À =r , then r(t) remains below one even when all interventions are lifted: herd immunity is achieved. however, recent results [ , ] show that, for heterogeneous populations, herd immunity occurs at a lower immunity level than À =r . the threshold À =r assumes random vaccination, with immunity distributed uniformly in the community. when immunity is obtained from disease exposure, the more socially active individuals in the population are over-represented in cases from the early stages of the epidemic. as a result, the virus preferentially infects individuals with higher numbers of contacts, thereby acting like a well-targeted vaccine. this reduces the herd immunity threshold. however, the extent to which heterogeneity in behaviour lowers the threshold for covid- is currently unknown. we highlight three key challenges for determining the herd immunity threshold for covid- , and hence for understanding the impact of implementing or lifting control measures in different populations. first, most of the quantities for calculating the threshold are not known precisely and require careful investigation. for example, determining the immunity level royalsocietypublishing.org/journal/rspb proc. r. soc. b : in a community is far from trivial for a number of reasons: antibody tests may have variable sensitivity and specificity; it is currently unclear whether or not individuals with mild or no symptoms acquire immunity or test seropositive; the duration of immunity is unknown. second, estimation of r , despite receiving significant attention at the start of the pandemic, still needs to be refined within and between countries as issues with early case reports come to light. third, as discussed in § , sars-cov- does not spread uniformly through populations [ ] . an improved understanding of the main transmission routes, and which communities are most influential, will help to determine how much lower diseaseinduced herd immunity is compared to the classical threshold to summarize, it is vital to obtain more accurate estimates of the current immunity levels in different countries and regions, and to understand how population heterogeneity affects transmission and the accumulation of immunity. quantitative information about current and past infections are key inputs to formulate exit strategies, monitor the progression of epidemics and identify social and demographic sources of transmission heterogeneities. seroprevalence surveys provide a direct way to estimate the fraction of the population that has been exposed to the virus but has not been detected by regular surveillance mechanisms [ ] . given the possibility of mild or asymptomatic infections, which are not typically included in laboratory-confirmed cases, seroprevalence surveys could be particularly useful for tracking the covid- pandemic [ ] . contacts between pathogens and hosts that elicit an immune response can be revealed by the presence of antibodies. typically, a rising concentration of immunoglobulin m (igm) precedes an increase in the concentration of immunoglobulin g (igg). however, for infections by sars-cov- , there is increasing evidence that igg and igm appear concurrently [ ] . most serological assays used for understanding viral transmission measure igg. interpretation of a positive result depends on detailed knowledge of immune response dynamics and its epidemiological correspondence to the developmental stage of the pathogen, for example, the presence of virus shedding [ , ] . serological surveys are common practice in infectious disease epidemiology and have been used to estimate the prevalence of carriers of antibodies, force of infection and reproduction numbers [ ] , and in certain circumstances (e.g. for measles) to infer population immunity to a pathogen [ ] . unfortunately, a single serological survey only provides information about the number of individuals who are seropositive at the time of the survey (as well as information about the individuals tested, such as their ages [ ] ). although information about temporal changes in infections can be obtained by conducting multiple surveys longitudinally [ , ] , the precise timings of infections remain unknown. available tests vary in sensitivity and specificity, which can impact the accuracy of model predictions if seropositivity is used to assess the proportion of individuals protected from infection or disease. propagation of uncertainty due to the sensitivity and specificity of the testing procedures and epidemiological interpretation of the immune response are areas that require attention. the possible presence of immunologically silent individuals, as implied by studies of covid- showing that - % of symptomatically infected people have few or no detectable antibodies [ ] , adds to the known sources of uncertainty. many compartmental modelling studies have used data on deaths as the main reliable dataset for model fitting. the extent to which seroprevalence data could provide an additional useful input for model calibration, and help in formulating exit strategies, has yet to be ascertained. with the caveats above, one-off or regular assessments of population seroprevalence could be helpful in understanding sars-cov- transmission in different locations. (d) is global eradication of sars-cov- a realistic possibility? when r is greater than one, an emerging outbreak will either grow to infect a substantial proportion of the population or become extinct before it is able to do so [ ] [ ] [ ] [ ] [ ] . if instead r is less than one, the outbreak will almost certainly become extinct before a substantial proportion of the population is infected. if new susceptible individuals are introduced into the population (for example, new susceptible individuals are born), it is possible that the disease will persist after its first wave and become endemic [ ] . these theoretical results can be extended to populations with household and network structure [ , ] and scenarios in which r is very close to one [ ] . epidemiological theory and data from different diseases indicate that extinction can be a slow process, often involving a long 'tail' of cases with significant random fluctuations (electronic supplementary material, figure s ). long epidemic tails can be driven by spatial heterogeneities, such as differences in weather in different countries (potentially allowing an outbreak to persist by surviving in different locations at different times of year) and varying access to treatment in different locations. regions or countries that eradicate sars-cov- successfully might experience reimportations from elsewhere [ , ] , for example, the reimportation of the virus to new zealand from the uk in june . at the global scale, smallpox is the only previously endemic human disease to have been eradicated, and extinction took many decades of vaccination. the prevalence and incidence of polio and measles have been reduced substantially through vaccination but both diseases persist. the foot and mouth disease outbreak in the uk and the sars pandemic were new epidemics that were driven extinct without vaccination before they became endemic, but both exhibited long tails before eradication was achieved. the - ebola epidemic in west africa was eliminated (with vaccination at the end of the epidemic [ ] ), but eradication took some time with flare ups occurring in different countries [ , ] . past experience, therefore, raises the possibility that sars-cov- may not be driven to complete extinction in the near future, even if a vaccine is developed and vaccination campaigns are implemented. as exemplified by the ebola outbreak in the democratic republic of the congo that has only recently been declared over [ ] , there is an additional challenge of assessing whether the virus really is extinct rather than persisting in individuals who do not report disease [ ] . sars-cov- could become endemic, persisting in populations with limited access to healthcare or circulating in seasonal outbreaks. appropriate royalsocietypublishing.org/journal/rspb proc. r. soc. b : communication of these scenarios to the public and policymakers-particularly the possibility that sars-cov- may never be eradicated-is essential. (a) how much resolution is needed when modelling human heterogeneities? a common challenge faced by epidemic modellers is the tension between making models more complex (and possibly, therefore, seeming more realistic to stakeholders) and maintaining simplicity (for scientific parsimony when data are sparse and for expediency when predictions are required at short notice) [ ] . how to strike the correct balance is not a settled question, especially given the increasing amount of available data on human demography and behaviour. indeed, outputs of multiple models with different levels of complexity can provide useful and complementary information. many sources of heterogeneity between individuals (and between populations) exist, including the strong skew of severe covid- outcomes towards the elderly and individuals from specific groups. we focus on two sources of heterogeneity in human populations that must be considered when modelling exit strategies: spatial contact structure and health vulnerabilities. there has been considerable success in modelling local contact structure, both in terms of spatial heterogeneity (distinguishing local and long-distance contacts) and in local mixing structures such as households and workplaces. however, challenges include tracking transmission and assessing changes when contact networks are altered. in spatial models with only a small number of near-neighbour contacts, the number of new infections grows slowly; each generation of infected individuals is only slightly larger than the previous one. as a result, in those models, r(t) cannot significantly exceed its threshold value of one [ ] . by contrast, models accounting for transmission within closely interacting groups explicitly contain a mechanism that has a multiplier effect on the value of r(t) [ ] . another challenge is the spatio-temporal structure of human populations: the spatial distribution of individuals is important, but longdistance contacts make populations more connected than in simple percolation-type spatial models [ ] . clustering and pair approximation models can capture some aspects of spatial heterogeneities [ ] , which can result in exponential rather than linear growth in case numbers [ ] . while models can include almost any kind of spatial stratification, ensuring that model outputs are meaningful for exit strategy planning relies on calibration with data. this brings in challenges of merging multiple data types with different stratification levels. for example, case notification data may be aggregated at a regional level within a country, while mobility data from past surveys might be available at finer scales within regions. another challenge is to determine the appropriate scale at which to introduce or lift interventions. although measures are usually directed at whole populations within relevant administrative units (country-wide or smaller), more effective interventions and exit strategies may target specific parts of the population [ ] . here, modelling can be helpful to account for operational costs and imperfect implementation that will offset expected epidemiological gains. the structure of host vulnerability to disease is generally reported via risk factors, including age, sex and ethnicity [ , ] . from a modelling perspective, a number of open questions exist. to what extent does heterogeneous vulnerability at an individual level affect the impact of exit strategies beyond the reporting of potential outcomes? where host vulnerability is an issue, is it necessary to account for considerations other than reported risk factors, as these may be proxies for underlying causes? once communicated to the public, modelling results could create behavioural feedback that might help or hinder exit strategies; some sensitivity analyses would be useful. as with the questions around spatial heterogeneity, modelling variations in host vulnerability could improve proposed exit strategies, and modelling can be used to explore how these are targeted and communicated [ ] . finally, heterogeneities in space and vulnerabilities may interact; modelling these may reveal surprises that can be explored further. (b) what are the roles of networks and households in sars-cov- transmission? npis reduce the opportunity for transmission by breaking up contact networks (closing workplaces and schools, preventing large gatherings), reducing the chance of transmission where links cannot be broken (wearing masks, sneeze barriers) and identifying infected individuals (temperature checks [ ] , diagnostic testing [ ] ). network models [ , ] aim to split pathogen transmission into opportunity (number of contacts) and transmission probability, using data that can be measured directly (through devices such as mobility tracking and contact diaries) and indirectly (through traffic flow and co-occurrence studies). this brings new issues: for example, are observed networks missing key transmission routes, such as indirect contact via contaminated surfaces, or including contacts that are low risk [ ] ? how we measure and interpret contact networks depends on the geographical and social scales of interest (e.g. wider community spread or closed populations such as prisons and care homes; or subpopulations such as workplaces and schools) and the timescales over which the networks are used to understand or predict transmission. in reality, individuals belong to households, children attend schools and adults mix in workplaces as well as in social contexts. this has led to the development of household models [ , [ ] [ ] [ ] [ ] , multilayer networks [ ] , bipartite networks [ , ] and networks that are geographically and socially embedded to reflect location and travel habits [ ] . these tools can play a key role in understanding and monitoring transmission, and exploring scenarios, at the point of exiting a lockdown: in particular, they can inform whether or not, and how quickly, households or local networks merge to form larger and possibly denser contact networks in which local outbreaks can emerge. regional variations and socio-economic factors can also be explored. contact tracing, followed by isolation or treatment of infected contacts, is a well-established method of disease control. the structure of the contact network is important in determining whether or not contact tracing will be successful. for example, contact tracing in clustered networks is known to be most effective [ , ] , since an infected contact can be royalsocietypublishing.org/journal/rspb proc. r. soc. b : traced from multiple different sources. knowledge of the contact network enhances understanding of the correlation structure that emerges as a result of the epidemic. the first wave of an epidemic will typically infect many of the highly connected nodes and will move slowly to less connected parts of the network, leaving behind islands of susceptible and recovered individuals. this can lead to a correlated structure of susceptible and recovered nodes that may make the networks less vulnerable to later epidemic waves [ ] , and has implications for herd immunity ( § b). in heterogeneous populations, relatively few very wellconnected people can be major hubs for transmission. such individuals are often referred to as super-spreaders [ , ] and some theoretical approaches to controlling epidemics are based on targeting them [ ] . however, particularly for respiratory diseases, whether specific individuals can be classified as potential super-spreaders, or instead whether any infected individual has the potential to generate super-spreading events, is debated [ , , ] . as control policies are gradually lifted, the disrupted contact network will start to form again. understanding how proxies for social networks (which can be measured in near real time using mobility data, electronic sensors or trackers) relate to transmission requires careful consideration. using observed contacts to predict virus spread might be successful if these quantities are heavily correlated, but one aim of npis should be at least a partial decoupling of the two, so that society can reopen but transmission remains controlled. currently, a key empirical and theoretical challenge is to understand how households are connected and how this is affected by school opening ( § c). an important area for further research is to improve our understanding of the role of within-household transmission in the covid- pandemic. in particular, do sustained infection chains within households lead to amplification of infection rates between households despite lockdowns aimed at minimizing between-household transmission? even for well-studied household models, development of methods accommodating time-varying parameters such as variable adherence to household-based policies and/or compensatory behaviour would be valuable. it would be useful to compare interventions and de-escalation procedures in different countries to gain insight into: regional variations in contact and transmission networks; the role of different household structures in transmission and the severity of outcomes (accounting for different household sizes and agestructures); the cost-effectiveness of different policies, such as household-based isolation and quarantine in the uk compared to out-of-household quarantine in australia and hong kong. first few x (ffx) studies [ , ] , now adopted in several countries, provide the opportunity not only to improve our understanding of critical epidemiological characteristics (such as incubation periods, generation intervals and the roles of asymptomatic and presymptomatic transmission) but also to make many of these comparisons. a widely implemented early intervention was school closure, which is frequently used during influenza pandemics [ , ] . further, playgrounds were closed and social distancing has kept children separated. however, the role of children in sars-cov- transmission is unclear. early signs from wuhan (china), echoed elsewhere, showed many fewer cases in under s than expected. there are three aspects of the role of children in transmission: (i) susceptibility; (ii) infectiousness once infected; and (iii) propensity to develop disease if infected [ , ] . evidence for age-dependent susceptibility and infectiousness is mixed, with infectiousness the more difficult to quantify. however, evidence is emerging of lower susceptibility to infection in children compared to adults [ ] , although the mechanism underlying this is unknown and it may not be generalizable to all settings. once infected, children appear to have a milder course of infection, and it has been suggested that children have a higher probability of a fully subclinical course of infection. reopening schools is of clear importance both in ensuring equal access to education and enabling carers to return to work. however, the transmission risk within schools and the potential impact on community transmission needs to be understood so that policymakers can balance the potential benefits and harms. as schools begin to reopen, there are major knowledge gaps that prevent clear answers. the most pressing question is the extent to which school restarting will affect population-level transmission, characterized by r(t) ( § a). clearer quantification of the role of children could have come from analysing the effects of school closures in different countries in february and march, but closures generally coincided with other interventions and so it has proved difficult to unpick the effects of individual measures [ ] . almost all schools in sweden stayed open to under- s (with the exception of one school that closed for two weeks [ ] ), and schools in some other countries are beginning to reopen with social distancing measures in place, providing a potential opportunity to understand within-school transmission more clearly. models can also inform the design of studies to generate the data required to answer key questions. the effect of opening schools on r(t) also depends on other changes in the community. children, teachers and support staff are members of households; lifting restrictions may affect all members. modelling school reopening must account for all changes in contacts of household members [ ] , noting that the impact on r(t) may depend on the other interventions in place at that time. the relative risk of restarting different school years (or universities) does not affect the population r(t) straightforwardly, since older children tend to live with adults who are older (compared to younger children), and households with older individuals are at greater risk of severe outcomes. thus, decisions about which age groups return to school first and how they are grouped at school must balance the risks of transmission between children, transmission to and between their teachers, and transmission to and within the households of the children and teachers. return to school affects the number of physical contacts of teachers and support staff. schools will not be the same environments as prior to lockdown, since physical distancing measures will be in place. these include smaller classes and changes in layout, plus increased hygiene measures. some children and teachers may be less likely to return to school because of underlying health conditions and if there is transmission within schools, there may be absenteeism following infection. models must, therefore, consider the different effects on transmission of pre-and post-lockdown school royalsocietypublishing.org/journal/rspb proc. r. soc. b : environments. post-lockdown, with social distancing in place in the wider community, reopening schools could link subcommunities of the population together, and models can be used to estimate the wider effects on population transmission as well as within schools. these estimates are likely to play a central role in decisions surrounding when and how to reopen schools. (d) the pandemic is social: how can we model that? while the effects of population structure and heterogeneities can be approximated in standard compartmental epidemiological models [ , , ] , such models can become highly complex and cumbersome to specify and solve as more heterogeneities are introduced. an alternative approach is agent-based modelling. agent-based models (abm) allow complex systems such as societies to be represented, using virtual agents programmed to have behavioural and individual characteristics (age, sex, ethnicity, income, employment status, etc.) as well as the capacity to interact with other agents [ ] . in addition, abm can include societal-level factors such as the influence of social media, regulations and laws, and community norms. in more sophisticated abm, agents can anticipate and react to scenarios, and learn by trial and error or by imitation. abm can represent systems in which there are feedbacks, tipping points, the emergence of higher-level properties from the actions of individual agents, adaptation and multiple scales of organization-all features of the covid- pandemic and societal reactions to it. while abm arise from a different tradition, they can incorporate the insights of compartmental models; for example, agents must transition through disease states (or compartments) such that the mean transition rates correspond to those in compartmental models. however, building an abm that represents a population on a national scale is a huge challenge and is unlikely be accomplished in a timescale useful for the current pandemic. abm often include many parameters, leading to challenges of model parametrization and a requirement for careful uncertainty quantification and sensitivity analyses to different inputs. on the other hand, useful abm do not have to be all-encompassing. there are already several models that illustrate the effects of policies such as social distancing on small simulated populations. these models can be very helpful as 'thought experiments' to identify the potential effects of candidate policies such as school re-opening and restrictions on long-distance travel, as well as the consequences of non-compliance with government edicts. there are two areas where long-term action should be taken. first, more data about people's ordinary behaviour are required: what individuals do each day (through timeuse diaries), whom they meet ( possibly through mobile phone data, if consent can be obtained) and how they understand and act on government regulation, social media influences and broadcast information [ ] . second, a large, modular abm should be built that represents heterogeneities in populations and that is properly calibrated as a social 'digital twin' of our own society, with which we can carry out virtual policy experiments. had these developments occurred before, they would have been useful currently. as a result, if these are addressed now, they will aid the planning of future exit strategies. (a) what are the additional challenges of data-limited settings? in most countries, criteria for ending covid- lockdowns rely on tracking trends in numbers of confirmed cases and deaths, and assessments of transmissibility ( § a). this section focuses on the relaxation of interventions in lmics, although many issues apply everywhere. perhaps surprisingly, concerns relating to data availability and reliability (e.g. lack of clarity about sampling frames) remain worldwide. other difficulties have also been experienced in many countries throughout the pandemic (e.g. shortages of vital supplies, perhaps due in developed countries to previous emphasis on healthcare system efficiency rather than pandemic preparedness [ ] ). data about the covid- pandemic and about the general population and context can be unreliable or lacking globally. however, due to limited healthcare access and utilization, there can be fewer opportunities for diagnosis and subsequent confirmation of cases in lmics compared to other settings, unless there are active programmes [ ] . distrust can make monitoring programmes difficult, and complicate control activities like test-trace-isolate campaigns [ , ] . other options for monitoring-such as assessing excess disease from general reporting of acute respiratory infections or influenza-like illness-require historical baselines that may not exist [ , ] . in general, while many lmics will have a well-served fraction of the population, dense peri-urban and informal settlements are typically outside that population and may rapidly become a primary concern for transmission [ ] . since confirmed case numbers in these populations are unlikely to provide an accurate representation of the underlying epidemic, reliance on alternative data such as clinically diagnosed cases may be necessary to understand the epidemic trajectory. some tools for rapid assessment of mortality in countries where the numbers of covid- -related deaths are hard to track are starting to become available [ ] . in settings where additional data collection is not affordable, models may provide a clearer picture by incorporating available metadata, such as testing and reporting rates through time, sample backlogs and suspected covid- cases based on syndromic surveillance. by identifying the most informative data, modelling could encourage countries to share available data more widely. for example, burial reports and death certificates may be available, and these data can provide information on the demographics that influence the infection fatality rate. these can in turn reveal potential covid- deaths classified as other causes and hence missing from covid- attributed death notifications. in addition to the challenges in understanding the pandemic in these settings, metrics on health system capacity (including resources such as beds and ventilators), as needed to set targets for control, are often poorly documented [ ] . furthermore, the economic hardships and competing health priorities in low-resource settings change the objectives of lifting restrictions-for example, hunger due to loss of jobs and changes in access to routine healthcare (e.g. hiv services and childhood vaccinations) as a result of lockdown have the potential to cost many lives in themselves, both in the short and long term [ , ] . this must be accounted for when deciding how to relax covid- interventions. royalsocietypublishing.org/journal/rspb proc. r. soc. b : we have identified three key challenges for epidemic modellers to help guide exit strategies in data-limited settings: (i) explore policy responses that are robust to missing information; (ii) conduct value-of-information analyses to prioritize additional data collection; and (iii) develop methods that use metadata to interpret epidemiological patterns. in general, supporting lmics calls for creativity in the data that are used to parametrize models and in the response activities that are undertaken. some lmics have managed the covid- pandemic successfully so far (e.g. vietnam, as well as trinidad and tobago [ ] ). however, additional support in lmics is required and warrants special attention. if interventions are relaxed too soon, fragile healthcare systems may be overwhelmed. if instead they are relaxed too late, socio-economic consequences can be particularly severe. (b) which data should be collected as countries emerge from lockdown, and why? identifying the effects of the different components of lockdown is important to understand how-and in which order-interventions should be released. the impact of previous measures must be understood both to inform policy in real time and to ensure that lessons can be learnt. all models require information to make their predictions relevant. data from pcr tests for the presence of active virus and serological tests for antibodies, together with data on covid- -related deaths, are freely available via a number of internet sites (e.g. [ ] ). however, metadata associated with testing protocols (e.g. reason for testing, type of test, breakdowns by age and underlying health conditions) and the definition of covid- -related death, which are needed to quantify sources of potential bias and parametrize models correctly, are often unavailable. data from individuals likely to have been exposed to the virus (e.g. within households of known infected individuals), but who may or may not have contracted it themselves, are also useful for model parametrization [ ] . new sources of data range from tracking data from mobile phones [ ] to social media surveys [ ] and details of interactions with public health providers [ ] . although potentially valuable, these data sources bring with them biases that are not always understood. these types of data are also often subject to data protection and/or costly fees, meaning that they are not readily available to all scientists. mixing patterns by age were reasonably well-characterized before the current pandemic [ , ] ( particularly for adults of different ages) and have been used extensively in existing models. however, there are gaps in these data and uncertainty in the impacts that different interventions have had on mixing. predictive models for policy tend to make broad assumptions about the effects of elements of social distancing [ ] , although results of studies that attempt to estimate effects in a more data-driven way are beginning to emerge [ ] . the future success of modelling to understand when controls should be relaxed or tightened depends critically on whether, and how accurately as well as how quickly, the effects of different elements of lockdown can be parametrized. given the many differences in lockdown implementation between countries, cross-country comparisons offer an opportunity to estimate the effects on transmission of each component of lockdown [ ] . however, there are many challenges in comparing sars-cov- dynamics in different countries. alongside variability in the timing, type and impact of interventions, the numbers of importations from elsewhere will vary [ , ] . underlying differences in mixing, behavioural changes in response to the pandemic, household structures, occupations and distributions of ages and comorbidities are likely to be important but uncertain drivers of transmission patterns. a current research target is to understand the role of weather and climate in sars-cov- transmission and severity [ ] . many analyses across and within countries highlight potential correlations between environmental variables and transmission [ ] [ ] [ ] [ ] [ ] [ ] , although sometimes by applying ecological niche modelling frameworks that may be ill-suited for modelling a rapidly spreading pathogen [ ] [ ] [ ] . assessments of the interactions between weather and viral transmissibility are facilitated by the availability of extensive datasets describing weather patterns, such as the european centre for medium-range weather forecasts era dataset [ ] and simulations of the community earth system model that can be used to estimate the past, present and future values of meteorological variables worldwide [ ] . temperature, humidity and precipitation are likely to affect the survival of sars-cov- outside the body, and prevailing weather conditions could, in theory, tip r(t) above or below one. however, the effects of these factors on transmission have not been established conclusively, and the impact of seasonality on short-or long-term sars-cov- dynamics is likely to depend on other factors including the timing and impact of interventions, and the dynamics of immunity [ , ] . it is hard to separate the effect of the weather on virus survival from other factors including behavioural changes in different seasons [ ] . the challenge of disentangling the impact of variations in weather on transmission from other epidemiological drivers in different locations is, therefore, a complex open problem. in seeking to understand and compare covid- data from different countries, there is a need to coordinate the design of epidemiological studies, involving longitudinal data collection and case-control studies. this will help enable models to track the progress of the epidemic and the impacts of control policies internationally. it will also allow more refined conclusions than those that follow from population data alone. countries with substantial epidemiological modelling expertise should support epidemiologists elsewhere with standardized protocols for collecting data and using models to inform policy. there is a need to share models to be used 'in the field'. collectively, these efforts will ensure that models are parametrized as realistically as possible for particular settings. in turn, as interventions are relaxed, this will allow us to detect the earliest possible reliable signatures of a resurgence in cases, leading to an unambiguous characterization of when it is necessary for interventions to be reintroduced. (c) how should model and parameter uncertainty be communicated? sars-cov- transmission models have played a crucial role in shaping policies in different countries, and their predictions have been a regular feature of media coverage of the pandemic [ , ] . understandably, both policymakers and journalists generally prefer single 'best guess' figures from models, rather than a range of plausible values. however, the ranges of outputs that modellers provide include important information about the variety of possible scenarios and guard royalsocietypublishing.org/journal/rspb proc. r. soc. b : against over-interpretation of model results. not displaying information about uncertainty can convey a false confidence in predictions. it is critical that modellers present uncertainty in a way that is understandable and useful for policymakers and the public [ ] . there are numerous and often inextricable ways in which uncertainty enters the modelling process. model assumptions inevitably vary according to judgements regarding which features are included [ , ] and which datasets are used to inform the model [ ] . within any model, ranges of parameter values can be considered to allow for uncertainty about clinical characteristics of covid- (e.g. the infectious period and case fatality rate) [ ] . alternative initial conditions (e.g. numbers and locations of imported cases seeding national outbreaks, or levels of population susceptibility) can be considered. in modelling exit strategies, when surges in cases starting from small numbers may occur and where predictions will depend on characterizing epidemiological parameters as accurately as possible, stochastic models may be of particular importance. not all the uncertainty arising from such stochasticity will be reduced by collecting more data; it is inherent to the process. where models have been developed for similar purposes, formal methods of comparison can be applied, but in epidemiological modelling, models often have been developed to address different questions, possibly involving 'what-if?' scenarios, in which case only qualitative comparisons can be made. the ideal outcome is when different models generate similar conclusions, demonstrating robustness to the detailed assumptions. where there is a narrowly defined requirement, such as short-term predictions of cases and deaths, more tractable tools for comparing the outputs from different models in real time would be valuable. one possible approach is to assess the models' past predictive performance [ , ] . ensemble estimates, most commonly applied for forecasting disease trajectories, allow multiple models' predictions to be combined [ , ] . the assessment of past performance can then be used to weight models in the ensemble. such approaches typically lead to improved point and variance estimates. to deal with parameter uncertainty, a common approach is to perform sensitivity analyses in which model parameters are repeatedly sampled from a range of plausible values, and the resulting model predictions compared; both classical and bayesian statistical approaches can be employed [ ] [ ] [ ] . methods of uncertainty quantification provide a framework in which uncertainties in model structure, epidemiological parameters and data can be considered together. in practice, there is usually only a limited number of policies that can be implemented. an important question is often whether or not the optimal policy can be identified given the uncertainties we have described, and decision analyses can be helpful for this [ , ] . in summary, communication of uncertainty to policymakers and the general public is challenging. different levels of detail may be required for different audiences. there are many subtleties: for instance, almost any epidemic model can provide an acceptable fit to data in the early phase of an outbreak, since most models predict exponential growth. this can induce an artificial belief that the model must be based on sensible underlying assumptions, and the true uncertainty about such assumptions has vanished. clear presentation of data is critical. it is important not simply to present data on the numbers of cases, but also on the numbers of individuals who have been tested. clear statements of the individual values used to calculate quantities such as the case fatality rate are vital, so that studies can be interpreted and compared correctly [ , ] . going forwards, improved communication of uncertainty is essential as models are used to predict the effects of different exit strategies. we have highlighted ongoing challenges in modelling the covid- pandemic, and uncertainties faced devising lockdown exit strategies. it is important, however, to put these issues into context: at the start of , sars-cov- was unknown, and its pandemic potential only became apparent at the end of january. the speed with which the scientific and public health communities came together and the openness in sharing data, methods and analyses are unprecedented. at very short notice, epidemic modellers mobilized a substantial workforce-mostly on a voluntary basis-and state-of-the-art computational models. far from the rough-and-ready tools sometimes depicted in the media, the modelling effort deployed since january is a collective and multi-pronged effort benefitting from years of experience of epidemic modelling, combined with long-term engagement with public health agencies and policymakers. drawing on this collective expertise, the virtual workshop convened in mid-may by the isaac newton institute generated a clear overview of the steps needed to improve and validate the scientific advice to guide lockdown exit strategies. importantly, the roadmap outlined in this paper is meant to be feasible within the lifetime of the pandemic. infectious disease epidemiology does not have the luxury of waiting for all data to become available before models must be developed. as discussed here, the solution lies in using diverse and flexible modelling frameworks that can be revised and improved iteratively as more data become available. equally important is the ability to assess the data critically and bring together evidence from multiple fields: numbers of cases and deaths reported by regional or national authorities only represent a single source of data, and expert knowledge is even required to interpret these data correctly. in this spirit, our first recommendation is to improve estimates of key epidemiological parameters. this requires close collaboration between modellers and the individuals and organizations that collect epidemic data, so that the caveats and assumptions on each side are clearly presented and understood. that is a key message from the first section of this study, in which the relevance of theoretical concepts and model parameters in the real world was demonstrated: far from ignoring the complexity of the pandemic, models draw from different sources of expertise to make sense of imperfect observations. by acknowledging the simplifying assumptions of models, we can assess the models' relative impacts and validate or replace them as new evidence becomes available. our second recommendation is to seek to understand important sources of heterogeneity that appear to be driving the pandemic and its response to interventions. agent-based modelling represents one possible framework for modelling complex dynamics, but standard epidemic models can also be extended to include age groups or any other relevant strata in the population as well as spatial structure. network royalsocietypublishing.org/journal/rspb proc. r. soc. b : models provide computationally efficient approaches to capture different types of epidemiological and social interactions. importantly, many modelling frameworks provide avenues for collaboration with other fields, such as the social sciences. our third and final recommendation regards the need to focus on data requirements, particularly (although not exclusively) in resource-limited settings such as lmics. understanding the data required for accurate predictions in different countries requires close communication between modellers and governments, public health authorities and the general public. while this pandemic casts a light on social inequalities between and within countries, modellers have a crucial role to play in sharing knowledge and expertise with those who need it most. during the pandemic so far, countries that might be considered similar in many respects have often differed in their policies; either in the choice or the timing of restrictions imposed on their respective populations. models are important for drawing reliable inferences from global comparisons of the relative impacts of different interventions. all too often, national death tolls have been used for political purposes in the media, attributing the apparent success or failure of particular countries to specific policies without presenting any convincing evidence. modellers must work closely with policymakers, journalists and social scientists to improve the communication of rapidly changing scientific knowledge while conveying the multiple sources of uncertainty in a meaningful way. we are now moving into a stage of the covid- pandemic in which data collection and novel research to inform the modelling issues discussed here are both possible and essential for global health. these are international challenges that require an international collaborative response from diverse scientific communities, which we hope that this article will stimulate. this is of critical importance, not only to tackle this pandemic but also to improve the response to future epidemics of emerging infectious diseases. data accessibility. data sharing is not applicable to this manuscript as no new data were created or analysed in this study. the effect of control strategies to reduce social mixing on outcomes of the 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harnessing multiple models for outbreak management control fast or control smart: when should invading pathogens be controlled? accurate quantification of uncertainty in epidemic parameter estimates and predictions using stochastic compartmental models fitting dynamic models to epidemic outbreaks with quantified uncertainty: a primer for parameter uncertainty, identifiability, and forecasts infectious disease pandemic planning and response: incorporating decision analysis improving the evidence base for decision making during a pandemic: the example of influenza a/h n potential biases in estimating absolute and relative case-fatality risks during outbreaks estimates of the severity of coronavirus disease : a model-based analysis acknowledgements. thanks to the isaac newton institute for mathematical sciences, cambridge (www.newton.ac.uk), for support during the virtual 'infectious dynamics of pandemics' programme. this work was undertaken in part as a contribution to the 'rapid assistance in modelling the pandemic' initiative coordinated by the royal society. thanks to sam abbott for helpful comments about the manuscript. key: cord- -nzigx k authors: lipinski, tom; ahmad, darem; serey, nicolas; jouhara, hussam title: review of ventilation strategies to reduce the risk of disease transmission in high occupancy buildings date: - - journal: nan doi: . /j.ijft. . sha: doc_id: cord_uid: nzigx k an unforeseen pandemic is facing the world caused by a corona virus known as sars-cov- . numerous measures are being put in place to try and reduce the spread of this deadly disease, with the most effective response to the outbreak being mass quarantines, a public health technique borrowed from the middle ages. the widely accepted main transmission mechanism is through droplet borne pathways. however, many researchers and studies are considering that this virus can also spread via the airborne route and remain for up to three hours in the air. this is leading to questions as to whether enough is being done regarding ventilation to reduce the risk of the spread of this or other diseases that may be air borne. ventilation and air conditioning systems are the main focus when it comes to the transmission of such deadly pathogens and should be appropriately designed and operated. this paper reviews and critically evaluates the current ventilation strategies used in buildings to assess the state of the art and elaborates if there is room for further development, especially for high occupancy buildings, to reduce or eradicate the risk of pathogen transmission and adapt ventilation measures to new threats posed by pandemics. an unprecedented viral disease has brought our globe to a halt, impacting most of mankind's activities. at the time of writing, more than , people are dead worldwide, the global economy is on the verge of an unprecedented depression, with the covid- pandemic still raging and a second wave predicted as inevitable. covid- belongs to the group of coronavirus, also known as severe acute respiratory syndrome corona virus (sars-cov- ) [ ] . this virus has already surpassed the number of infections of two other epidemics in this century [ ] . current measures introduced worldwide, and designed to control the spread of the virus include lockdowns, selfisolation, social distancing, use of face masks and the recommendation to wash hands as frequently as possible, [ ] . n masks have been recommended by who and have been known to help prevent infected individuals from spreading the virus if not necessarily preventing healthy individuals from contracting it from others [ ] , [ ] . covid- is one of the most contagious viruses that mankind has experienced, spreading across most of china in only days [ ] , then worldwide within a couple of months. the widely accepted mechanism of covid- transmission is by droplet and contact methods as backed-up by the who, but the possible air transmission route has been broadly documented by new scientific research [ ] and the who is not ruling out this possibility. as individuals are infected with the respiratory disease, the rate of expiratory events increases which in turn increases the generation and dispersion of droplets containing the virus. such expiratory events include not only coughing and sneezing but also talking [ ] . considering how fast this disease has spread across the world, many researchers [ ] state that an additional mode of transmission, nuclei borne by air droplets, plays an important role in the spread of this virus. flow dynamics of air particles can be complex and include turbulent jets, droplet evaporation, airmucous interaction and particle sedimentation amongst others [ ] . these flow dynamics and particle interaction with air is at the core of transmission of the covid- virus. as mentioned previously, a variety of physical containment methods have been introduced, such as wearing the recommended personal protective equipment (ppe) and improving personal hygiene. however, since the vast majority of infections occur indoors [ ] , it has been noted that ventilation strategies can play a vital role in controlling or at least reducing the risk of respiratory infections [ ] . droplet nuclei are fine air particles that remain airborne for a considerable length of time. any air particles below micrometres are classified as being able to be airborne. sars-cov- is yet to be officially classified as an airborne disease by the who, however, a weight of emerging evidence is being established for aerosol driven infections [ ] [ ] [ ] [ ] . the chartered institution of building services engineers, cibse, recently provided guidance on using ventilation as a way of diluting airborne pathogens. it is stated that: "there is good evidence that demonstrates room occupants are more at risk of catching an illness in a poorly ventilated room than in a well-ventilated room." besides this, new evidence that has been found shows high rates of infection in poorly ventilated spaces [ ] . since sars-cov- has spread around the world at an unprecedented pace, infecting millions of people, and further aerosol driven infections are highly likely to emerge, ventilation plays a key role in efforts to limit the transmission rate of this and other diseases. this paper will discuss the factors affecting air particle properties in-terms of flow dynamics and critically analyse current ventilation strategies and mechanisms and identify areas for improvement in the search for the reduction of indoor infections. thoughtful modifications to the built environment -to how schools, offices or health-care facilities are designed, operated and maintained -could help curb the spread of infectious disease, reducing the toll of future outbreaks as well as the current covid- pandemic. this section will review the current state-of-the-art covering characteristics of respiratory particles, the ability of viruses to spread as well as the mechanisms for airborne transmission and how current ventilation strategies can affect the risk of transmission. respiratory particles are formed during any respiratory activity such as coughing, sneezing, talking and breathing. once the particles are released into the surroundings, the mechanisms in-which they flow and settle depend on the fluid dynamics of the particles and the conditions in the vicinity. fluid dynamics can characterise the evaporation rate of the particles which allows the determination of the prevalence of small droplets and nuclei droplet transport [ ] . covid- belongs to the betacovs pathogen group and has an approximate diameter of - nm. the shape of the virus can be spherical or ellipsoidal [ ] . particle trajectories depend primarily on their size and the balance of various forces acting on the particle in the air. gravitational and aerodynamic forces are the two primary forces acting on such particles, where the latter force dictates the flow behaviour of the particle. figure shows the trajectories for particles of various sizes ranging from . µm to µm [ ] . figure : trajectories of particles with various sizes [ ] . stokes law explains the frictional force relation exerted on spherical objects with very small reynolds numbers in viscous fluid. to help explain the trajectories of air particles, the aerodynamic drag coefficient (cd), shown in equation of a spherical particle relative to reynolds number, shown in equation , is not constant. reynolds number is a ratio between inertial and viscous forces that originate from interactions between a body and a fluid. the equation for reynolds number is shown below. where fd is the aerodynamic drag force, and a is the frontal area. using reynolds equation, for natural ventilation systems with air velocity of . m/s and a particle size of nm, the reynolds number is calculated at . . this shows that for such air flow environment, the flow is laminar whereby the viscous forces prevail. therefore, drag coefficient for viscous non-separated flow around a sphere can be defined by equation . however, this equation implies that drag force is proportional to the diameter which is not entirely accurate. the resistance coefficient may decrease with increasing diameter, but the drag force increases linearly with the diameter. however, since the gravitational force increases with the mass, it increases with diameter cubed, thus, more rapidly than the drag force as the diameter increases. therefore, larger particles have the tendency to settle [ ] . this phenomenon helps to explain why smaller particles are more likely to be airborne. the drag coefficient for a sphere as a function of reynolds number can be plotted to show the influence of changing flow regime on the drag coefficient. this is shown in figure , whereby a sphere exhibits a reduction in drag coefficient until the flow regime becomes turbulent causing a sudden dip. furthermore, when the boundary layer on the leading surface becomes turbulent, the separation occurs farther round the sphere and the drag coefficient decreases. a rough surface, such as on a golf ball, promotes an earlier transition to turbulence. the numbers on figure refer to various flow regimes and their corresponding changes in the drag coefficient. flow regime on the figure refers to stokes flow and steady separated flow, whereby the reynolds number is less than which is typical for fluid velocities are very slow and the viscosities are very high. flow regime on the figure refers to separated, unsteady flow, whereby a laminar flow boundary is formed upstream of the separation and producing vortex street. flow regime refers to separated unsteady flow with a laminar boundary layer at the upstream side and chaotic turbulent wake downstream of the sphere. regime refers to a turbulent boundary layer [ ] . a graph of aerodynamic drag coefficient against reynolds number [ ] . various parameters affect the transmission of droplet borne infections, including density, initial velocity and the size distribution of the droplets that are released during respiratory activities, as well as indoor air velocity and direction. many research studies have been carried out to measure these characteristics [ ] . sneezing is the respiratory activity that ejects the most droplets, in the range of or more. the droplets from sneezing have initial velocities in the range of m/s. other respiratory activities release droplets at a significantly lower density and lower initial velocities. table shows the droplet densities and velocities for the common respiratory activities. the terminal velocity at which any spherical particle settles due to gravity in a fluid can be explained by stokes' law for fine particle size and newton's law for coarse particles. both equations have been shown below. where = gravitational acceleration = density of solid and fluid respectively d = particle diameter = drag coefficient μ = fluid viscosity the terminal velocity equations shown above have been used to generate graphical representations of the expected particle speeds at various conditions as shown below in figure . since covid- has an approximate diameter of - nm [ ] , stokes' law applies for ventilation in buildings whereby the air flow exhibits a laminar behaviour. figure shows that at very small diameter particles of less than . µm, the terminal velocity is almost negligible which further amplifies the fact that if covid- was proven to be airborne then the virus and its potent materials could be airborne for long durations especially if enclosed environments are not ventilated adequately. a mathematical model by c.p cummins et al. shows that particles with a diameter smaller than µm (stoke's number ≤ . × − ) are almost unaffected by the gravity and air extraction is very efficient at removing these fine particles [ ] . this is explained by the major impact of the drag forces on the particle's movement for this diameter. the settling velocity calculated by stokes' law (equation ) is proportional with the diameter squared. particle terminal velocities remain elusive due to a vast number of factors, such as droplet diameter, droplet density, contributing to this phenomenon and primarily due to the difficulty in making measurements of such parameters [ , , ]. pathogen transmission can occur through different routes: direct contact, indirect contact, droplet borne or airborne such as shown in figure [ ] [ ] [ ] . the direct contact route covers any contact between a contagious person and a susceptible person: touching, kissing, sexual contact, contact with skin lesions or oral secretion. this route is well documented and outside the scope for this paper. in the indirect contact transmission mode, the contagious person touches or expels contaminated droplets containing infectious organisms which settle on an inanimate object, such as a doorknob or an elevator button, called "fomite". the person being infected touches this fomite and then an area where the pathogen can enter the body such as the eyes, nose, or mouth [ ] . droplet transmission can occur when infective large droplets expelled from a contagious person reach an uninfected person. airborne transmission occurs when very small particles ( - µm in diameter) or small droplets evaporating to a small enough size [ ] , are expelled by coughing, sneezing, speaking, or breathing. these droplets are small enough to remain airborne for long periods of time (up to several hours), until they are inhaled by or land on the uninfected person. airborne transmission is not yet widely accepted for various transmissible respiratory diseases. in the case of sars-cov- , the world health organisation only recognizes the risk for airborne transmission under certain medical procedures producing large amounts of infective respiratory particles [ , , [ ] [ ] [ ] . there is now growing pressure on the who from the scientific community to relax the dogmatic and outdated division between aerosols and small droplets and acknowledge the mounting evidence for the indoor spreading of the covid- infection through the air [ ] . in the case of sars-cov- and mers-cov, retrospection on the different outbreaks and multiple studies make a strong case for the route as an opportunistic transmission, meaning that the virus will transmit preferably through other routes but can potentially infect by means of respiratory particles when conditions are met. another factor explaining the elusive validation of airborne transmission is the dilution of small particles after they are emitted. indeed, people standing farther away from a contagious emitter see an exponentially decreasing concentration of droplet nuclei. the potential transmission over larger distances are by nature more difficult to identify especially in the context of an outbreak or a pandemic when the sources are multiple. furthermore, when the transmission happens close to an identified source, the transmission is indiscernible from that due to droplets or indirect transmission [ , ] . in order for viruses to be transmitted through the airborne route, some conditions must be satisfied: the virus must be able to remain viable outside of the host, withstand the external conditions and be transported to a susceptible area of a new host. the effect of evaporation, light, humidity and temperature on the concentration and virality (capacity to infect and reproduce) of the pathogen need to be further researched to make conclusions on the threat level of the airborne route [ ] . there are already multiple pathogens for which the airborne route is acknowledged. such viruses including adenovirus, influenza, measles, meningococcal disease, mumps, pertussis, parvovirus b , respiratory syncitial virus, rubella, tuberculosis and varicella, can spread by droplet nuclei [ ] . measles and tuberculosis for example are proven to be preferentially airborne transmitted diseases [ ] . but the fact that these diseases have been controlled with widely available drugs and vaccines resulted in a decrease in research effort into airborne transmission mechanisms. recent sars-cov- and mers-cov outbreak have given a new impetus to research on this subject. indeed, sars-cov- is thought to be transmissible by direct, indirect, and droplet contact, the amoy garden case identifies a strong possibility of airborne transmission. during the outbreak, the virus spread from a faulty dried-out bathroom drainage system and rose to a extraction fan, then was carried by the wind into the adjacent building infecting several occupants [ , , , , , ] . ribonucleic acid, rna, and even viable viruses have been detected in aerosols in healthcare facilities for some respiratory viruses such as seasonal and avian influenzas virus, mers-cov and respiratory syncytial virus [ ] . in the case of mers-cov, samples taken in hospitals and isolation wards in south korea confirmed the airborne transmission. some patients of the same ward were infected, even though they were standing more than two meters away from the source. air samples and surrounding areas, including regularly disinfected accessible and inaccessible surfaces, were all contaminated by mers-cov [ ] . this experimental data challenges the previously recognized transmission routes, acknowledging the high possibility of airborne transmission as an opportunistic route at close range and even long range when the conditions were favourable and concentrations at the source were high. sars-cov- shares the same modes of transmission as the sars cov- and, although the viability and virality of an air sample has not been proven at the time of writing, it cannot be ruled out. the airborne route, being opportunistic [ ] , is by its nature difficult to interpret. air samples take time before being tested after which the concentration might be too low, through dilution, to establish with confidence the presence of viable virus on droplet nuclei. rna detection is also not usually enough to interpret the risk of airborne transmission [ ] . a number of studies indicate airborne or droplet borne transmission [ ] , and to the authors' knowledge, there is no study yet demonstrating the lack of infection in a situation where only airborne transmission is permitted (and with particles in high concentration). this would be the only definitive way to disprove the mode of transmission [ ] . recent superspreading events also support the argument for airborne transmission. during a choir rehearsal in mount vernon (washington), although precautionary care was taken to suppress direct contacts and keep distance between the singers, out of the participants caught the disease [ ] and at least two people were reported to have died [ ] . the aerosol stability of sars-cov- was recently tested in laboratory conditions. a three-jet collison nebulizer created contaminated aerosols (< µm) fed into a goldberg drum. in this environment, the sars-cov- remained viable with a half-life between . and . hours ( % credible interval . to . h) as shown in figure . the researchers compared the results with sars-cov- and found similar half-life results ( % credible interval . to . h). the reduction in infectious concentration (titer) during the -hour long tests was from . to . tcid (fifty-percent tissue culture infective dose) per litre of air for sars-cov- . this reduction was similar to that observed with sars-cov- , from . to . tcid per litre of air [ ] . in order to better understand how to combat airborne transmission, one must understand the relation between the particle emission and deposition mechanisms. droplets can be generated from different places in the respiratory tract of the infected person with various resulting diameters. once deposited on the uninfected individual they then infect the conjunctiva or mucous membranes in the upper respiratory tract of the new host [ , , ] . small particles can be generated during speech in the alveoli of the lungs and vocal cord vibration by a fluid film burst mechanism [ , ] . it was reported that vocalization emits times more particles than breathing, and some speech super-emitters can (for reasons unclear yet) expel times more particles than average [ ] . this could be an explanation to the mount vernon choir outbreak: the higher concentration of infected particles added to the need for extra deep breathing required for singing facilitates airborne transmission. coughing and sneezing also generate large numbers of particles, the majority of which are inhalable (< μm in size): . - . % for coughing and . % for sneezing. furthermore, between . - . % of cough expelled particles and . % of particles produced by sneezing were under μm in diameter [ ] . these smaller particles penetrate deeper and can deposit further in the respiratory tract. generally, particles above µm do not reach the alveoli whereas particles above µm deposit in the upper respiratory tract as shown in figure [ , , , , , ] . [ ] . transmission that occurs in the lower respiratory tract, shown in figure due to smaller particles potentially leads to aggravated symptoms and a higher mortality rate, whereas deposition in the upper respiratory track by larger aerosols necessitates a larger number of viruses for the host to develop symptoms [ ] . this is due to the fact that the nasal and tracheobronchial regions have an additional defence system. the nasal tracts are covered by a mucus layer that entraps deposited particulates. the continuous movement of cilia pushes the captive infected particles up to the gastrointestinal track where they cannot infect the host [ , ] . research studies have shown that small particles still present a substantial risk of infection [ ] , and it was reported that for some respiratory diseases, a single virus can cause illness. in the case of sars-cov- , a minimum required viral load has not yet been confirmed [ , , ] . once the virus finds a susceptible cell, it can infect individuals through binding its pike proteins to the cell wall then uses the cell to replicate before bursting it. thereafter, it releases more viruses that can either contaminate other cells, be destroyed by the immune system or be expelled from the body and potentially transmit to a new host [ ] . studies have shown that that the ensuing incubation period is on average . days, but can range from to days [ ] . the virus remains detectable for a median of days [ , ] . a critical specificity of sars-cov- is the serial interval (or the time lapse) between an infection of a host and the transmission to a susceptible uninfected person. an average of . days, with a % credible interval between . and . days, and median of . days, with credible interval between . and . days, were reported [ ] . the small-time delay and possible overlap between the end of the incubation period and the secondary infection shows that pre-symptomatic transmission is very likely. it is believed that the infectiousness starts . days before the first symptoms of the disease and peaks when the symptoms are starting [ , ] . this would be the major cause of the rapid spread of the pandemic. the speed of the spread is represented by the basic reproduction, ro, number which is the average number of susceptible persons infected by a single host [ ] . for sars-cov- ro is estimated to range between . to . (mean, . ; median, . ) [ ] . furthermore, the ro is rapidly evolving and other studies have found values of ro between and before intervention to limit the spread [ ] . the basic reproduction number corresponding to pre-symptomatic transmissions alone is estimated to be . , with % credible interval between . and . . a ro value superior to means the virus will spread exponentially, indicating these transmissions are almost sufficient to sustain the pandemic [ ] . at the beginning of the wuhan outbreak, the contribution of pre-symptomatic cases accounted for % of all infections, with % for asymptomatic cases, and it is now widely accepted that seemingly healthy people can spread the virus, though uncertainty remains over how much they have contributed to the pandemic. though estimates vary, models using data from hong kong, singapore and china suggest that to percent of spreading occurs when people have no symptoms [ , , ] . as the body starts to build antibodies against the virus, the concentration begins to decrease, and the infectiousness of the disease declines significantly after days [ ] . when a significant portion of the population stops being susceptible to the virus, the ro falls below and the number of new infections drops below the sustaining rate. this can be achieved through vaccination or by building immunity after recovering from the disease -thus the state of herd immunity may be achieved [ ] . although mutation from the virus and decay of the immune system memory could still pose a challenge to achieving this goal. in order to supress or slow the progression of the pandemic, efforts must be made to reduce ro. precautionary measures must consider the entire population since pre-symptomatic and asymptomatic transmissions are a critical factor in the spread of sars-cov- . if the virus can spread from seemingly healthy carriers or people who had not yet developed symptoms, the publicawareness campaigns, airport screening and 'stay-home-if-you're sick' policies might not stop it. more targeted measures are required including a considered re-design of indoor environments, especially aspects handling the air buildings' ventilation systems [ ] . both the airborne and or droplet borne routes cannot be ignored. pre-symptomatic and asymptomatic hosts do not cough or sneeze extensively [ , , ] . when doctors in wuhan, china, where the new virus first emerged, studied early cases, they concluded that percent of patients had most likely contracted the disease in the hospital [ ] . therefore, the hypothesis stating that infection through small particles plays a more important role in the transmission along with the direct and indirect (fomites) routes can be used. thus, ventilation plays an important role in reducing the risk of transmission through dilution and removal of the infected particles within the indoor environment [ ] . preparedness to fight airborne disease is essential and sars-cov- offers the chance to research and apply mitigating ventilation solutions which could prove life-saving now and in the future when another virulent and deadly pandemic arises [ ] . ashrae standard . : defines acceptable indoor air quality as "air in which there are no known contaminants at harmful concentrations, as determined by cognizant authorities, and with which a substantial majority ( % or more) of the people exposed do not express dissatisfaction". [ ] if airborne infectious particles are to be counted as harmful even in small concentrations, as explained in the previous section, either the amount of fresh air supplied to a room needs to be dramatically increased or the ventilation strategy needs to be reconsidered to protect the occupants. this paper focuses on high occupancy buildings such as schools or office spaces where the occupants are static most of the time. current standards already have predetermined values to meet the acceptable indoor air quality. for example, the ashrae standards dictate a minimum ventilation rate of l/s per person or . l/s.m in educational facilities. for office buildings, the minimum values are . l/s per person or . l/s.m [ ] . having said that, due to variability in ventilation methodologies, similar ventilation rates may translate to significantly different indoor transmission outcomes. fresh air can be provided in a number of ways, relying on many different technologies and having different extraction, dilution and air distribution effectiveness. the british standards bs en - : defines basic types of ventilation systems: [ ] . system type fan assisted air volume flow in only one direction. this system is balanced by air transfer devices within the building envelope. fan assisted system operates in supply and exhaust directions. bidirectional ventilation system natural ventilation relies on natural driving forces. natural ventilation system hybrid systems rely on natural and mechanical mechanisms. any combination of the ventilation mechanisms can be used depending on the situation. several factors play a role after a ventilation solution is selected that affect the final system performance and indoor air quality. the poor initial design of a selected ventilation solution could be due to various reasons such as error in sizing, reduced performance due to lack of maintenance, lack of operator knowledge or the intentional reduced use in order to save energy or reduce noise and all can be detrimental to the occupants' health. several studies have demonstrated that in classrooms, the ventilation rates have often failed to reach the minimum standard required. the peak co concentration, which can be used as an indicator of the ventilation rate in occupied spaces, often exceeded the recommended levels. in a study, the reported co measurements in several thousand classrooms has shown that all classroom averages exceeded ppm ( . %) which is an indicator of a ventilation rate lower than l/s/person at default occupancy. in many instances, the average co levels were above ppm with peak concentrations between and ppm [ ] . this discrepancy between the building standards and reality demonstrated the need for a thorough reconsideration of ventilation design and ventilation systems specified in high occupancy buildings well before the impact of coronavirus. in the light of sars-cov- pandemic there is an even more desperate need to address the ventilation design and effectiveness. improved ventilation has been noted to deliver a positive health impact with a noticeable reduction in illnesses and absences. in particular, reduced respiratory health effects, such as mucosal and allergy symptoms are significantly reduced with increased ventilation rates [ ] . a study based on californian schools demonstrated that an increase in the ventilation rate by l/s/person resulted in a . % reduction in illness related absences [ ] . poor ventilation has also been linked to many adverse health effects: transmission of infectious diseases, acute respiratory symptoms and impaired cognition performance [ ] [ ] [ ] . it expresses the dilution of the said pollutant as a function of the ventilation rate effectiveness which can be engineered to suit the room, occupant type, and the risk at hand. in the case of infected particles, the recommendations from rehva, the federation of european heating, ventilation and air conditioning associations, are to supply as much outside air as possible. according to rehva, mechanical ventilation should be activated more often ( / when possible with lower rates during quiet times) and at least to start ventilating before and after busy hours while the density of occupancy needs to be decreased when possible this will increase the distance between people and lower the pollutant emission rate. with or without mechanical ventilation, window airing should be used to boost the air exchange rate. toilet windows on the other hand need to remain closed and mechanical extraction activated at all times to create negative pressure and prevent contaminated particles from entering other parts of the building though doors or by an unforeseen route through nearby open windows [ ] . prior to covid- , densely packed open-plan offices were already suspected of making employees sick [ ] . viruses and other pathogens are not the typical pollutants and even small and temporary exposure has been proven to lead to infections. studies of viral infections spread through indoor spaces document clearly that mechanically induced, mixing airflow can pose a greater risk of infection spread as it pushes turbulent air deep into rooms, possibly picking up infected droplets along the way [ ] . further research by the university of oregon demonstrated how air conditioning or hybrid ventilation can spread the pathogens much farther than feet, even when the host is positioned a long distance from the fan driven system [ , ] . it appears that it is not just the rate of supply of fresh air that needs to be considered but also the air flow dynamics and air distribution pathways through occupied spaces that urgently need review, which include the type of airflow, velocity, its turbulence and its direction. keeping indoor environments virus-free plays a key part in reducing or slowing the transmission of various airborne infections. since viruses have an approximate diameter of nm, they can be easily carried by aerosol droplets in the air and linger afloat for many minutes and sometimes hours. an inappropriate or inadequate ventilation strategy can dramatically increase the risk of disease transmission. a research study conducted by a team of scientists at the defence science and technology laboratory on the aerosol survival of sars-cov- in artificial saliva and tissue culture media and high humidity found that covid- could be transmitted via airborne droplets in addition to physical contact with droplets deposited onto surfaces [ ] . the study used the sars-cov- england variant which was suspended in the air using tissue culture media at medium and high relative humidity, - % and - %. the outcome of the study has shown that the virus was still detectable after minutes. taking the above-mentioned publications into account, ventilation and comfort strategies have been categorised by airflow characteristics and their potential impact on pathogen spread through occupied spaces in the next section. considering the dynamics of droplet and aerosol spread indoors, various ventilation and air conditioning strategies can be grouped into three main categories:  recirculating ventilation (frequently called mixing or hybrid ventilation) and conditioning systems that either move the indoor air around (typical split ac or vrf system or even a ceiling fan) or mix indoor air with outdoor air before pumping it into the room (such as hybrid or 'heat recycling' ventilation systems that have been lately installed in many schools). this ventilation method generally produces turbulent air flows with stale air either partly or fully recirculated back into the affected rooms.  mixing ventilation systems that are designed to distribute fresh air throughout the occupied space ensuring all occupants experience similar air quality, with air supplied through specific ventilation outlets or diffusers. they are predominantly mechanical systems such as large, centralised air handling units (ahu) or smaller, localised mechanical ventilation systems with heat recovery (mvhr). this ventilation method generally produces turbulent, mixing air flows within rooms.  displacement ventilation systems that remove contaminated indoor air and supply fresh outside air in a predominantly even, buoyancy assisted fashion, effectively displacing it with no or little disruption. they are primarily passive systems such as natural ventilation cowls, façade louvres or automatically opening windows. this ventilation method generally produces a laminar airflow within rooms (outside of very windy conditions). typical ventilation measures are listed and grouped in the table below, complete with a brief description: building integrated measures designed to displace stale air and supply fresh air using buoyancy including elements such as windows, passive stacks or solar chimneys. natural ventilation systems natural ventilation products or systems utilising buoyancy in their operation including roof cowls, wall mounted iaq responsive louvres or iaq controlled window openers. the recirculating approach has been popular choice for new schools in recent years for both ventilation and comfort provision, mainly due to its low capital cost and simplicity. some recirculating systems are used for ventilation with the recirculated stale air mixed with fresh, outside air, in order to increase the temperature of the air supplied to the classroom, necessary to reduce discomfort in absence of a heat exchanger. the diagram, shown in figure , illustrates the concept of hybrid ventilation: the mixed, partly recirculated, air is fan driven in such a way as to reach far into the classroom up to m from the system and to supply enough fresh air, mixed with stale air for comfort, to maintain co levels below an average of ppm. as this requires fresh air flows rate in a range of l/s, when combined with stale air it may reach a volume flow rate of l/s or higher which, considering the small size of the air diffusers, can generate substantial air velocities in occupied spaces -leading to high air turbulence. according to a recent study and modelling conducted by the university of oregon, this type of airflow has the potential for high spread of coronavirus infected droplets within densely occupied spaces, even with just one person exhaling the virus droplets [ , ] . apart from the recirculation itself, the transmission appears to be facilitated by the type and velocity of turbulent airflow designed to reach deep into the occupied space as shown in figure . this covers most of the air conditioning systems used commercially with the mode of operation similar to the hybrid ventilation systems mentioned above with the exception of containing no fresh air in its supply path -all is constantly recirculated. air is pulled into the system from the room, conditioned, either cooled or heated, and then supplied back into the room at high enough velocity to reach to the end of the occupied space. since the systems are designed to ensure that conditioned air gets to every area of the room, providing comfort, the pathogens picked up by the circulating air can travel much further than m [ , , ] . a typical ac airflow can be illustrated by the computational fluid dynamics picture in figure : ceiling fan is another recirculating comfort system and is designed to either reduce air stratification in the room, bringing the warm air down from the ceiling, or to introduce enough air movement to cool the occupants through wind chill effect. both actions are designed to improve comfort while displacing the need for more power-hungry ac or excess space heating. as it can be seen in the cfd snapshot in figure , ceiling fans also ensure that air within the room is fully mixed. as much as there can be various iterations of the above approach, the unifying factor is that ceiling fans continuously mix air within spaces where they serve, such as classrooms, lecture theatres or offices. consequently, any contaminated droplets and aerosols sneezed, coughed or exhaled can travel significant distances within the rooms and reach occupants who are much farther away from the infected host than metres [ ] . the research carried out by jaakkola et al. [ ] shows the importance of the introduction of fresh air into any occupied room, with recirculation of the air posing a significant risk with many of the air borne diseases not just being carried from person to person by the airflow but also entering the ventilation system itself, possibly being trapped in the air filter. however, many of the pathogens may escape filters causing further infections and droplets can be carried for long distances across spaces by fan induced turbulent airflow without having to enter the recirculating system. since the vast majority of air conditioners in high occupancy buildings utilise air recirculation, it raises the question over their safety and indicates the need for further research into such comfort, ventilation and indoor air quality provision so that the occupant safety can be improved, especially in the light of the covid- pandemic [ ] . air handling units are generally located in the basement or lower floors of a building such as office blocks (us) or on top of the building (uk). ahus are tasked to supply hundreds of m of air per second across the whole building and generally dehumidify, heat and cool the incoming fresh air as required. the air is supplied through floor or ceiling grills generating positive pressure within the building, it then moves across the ventilated space mixing with existing, stale air along the way and is exhausted through various building fabric openings, exhaust ducts or atria created for that purpose as shown in figure . in some cases, buildings can utilise a hybrid solution combining both natural ventilation principles (even natural free cooling) and mechanical assistance. figure : typical ahu ventilation arrangement with supply ducts located in ceiling voids [ ] . a cfd study of a simplified room, with one simulated occupant, using a positive pressure mixing ventilation system can be seen in figure . however, as the fresh air is supplied, a significant degree of mixing will occur within the occupied space. the general design of ahu ductwork, as well as deep floor plan offices exacerbate the fan induced mixing throughout occupied spaces leading to increased risk of long-distance droplet movement. these balanced ventilation systems are generally localised and mounted within the ceiling void of the room or classroom they serve, extracting air from the occupied space, passing it through the air to air heat exchanger to recover the heat and warm up the incoming fresh air, as shown in figure . as much as both air flows are channelled through the same box, there is generally no mixing between the two paths. these systems allow for higher thermal efficiencies due to heat recovery but with an electrical penalty of two fans running constantly. a typical classroom mvhr ventilation arrangement can be seen in figure constructed through simulation software, whereby an air plume generated by supply airflow in façade mounted mvhr system. mvhr systems have been documented to deliver adequate indoor air quality as well as expected comfort levels. their design is to deliver fresh, tempered air to every area of the ventilated space, as it can be seen on a cfd of the façade mounded mvhr below, which, in case of the risk of infection, appears to have similar airflow flow characteristics as recirculating ventilation modelled by the university of oregon. more turbulent air flow at higher velocity is much more likely to mix with existing air and carry larger droplets further into the room, possibly spreading virus contaminated droplets around the room and leading to a higher risk of infection spread. as this is specific to air delivery design rather than the system characteristics, it may be possible to reduce the risk of infection by a careful redesign of the ductwork, its size as well as inlet and outlet location and sizing. it may also be theoretically possible to use mvhr as displacement ventilation in some cases if a complete change of installation design is possible. as much as this is an important area for further research, specific ventilation ductwork design or ventilation design guidance are outside the scope of this paper. piv is very similar in its airflow characteristics to positive pressure air handling units described beforehand with the main difference being the local placement of the fan powered unit or system. the unit supplies the air into an occupied area with enough velocity to evenly distribute it throughout the space. due to its design, it has similar air mixing characteristics as ahus. although mechanical ventilation usually comes with better controllability, it can increase both capital and operating costs which are some of the drawbacks. the need for higher maintenance and the loss of performance when not effectively managed also need to be factored in. it was demonstrated that the severity of symptoms associated with sick building syndromes can be linked with the cleanness of the air filters and hvac system. the occupants' symptoms were recorded by questionnaire before and after cleaning a part of the hvac system and changing the filters. in the renovated section, the severity of the symptoms decreased while they remained identical in the untouched section. when using dirty filters, which is often the case in many high occupancy buildings equipped with such mechanical ventilation, the emissions from the used filters were found to increase with the outdoor airflow rate. increasing the ventilation did not improved the air quality, while raising the operation costs [ ] . the main difference between mixing and displacement ventilation can be seen in figure . as much as the risk of recirculation is significantly lower or negligible within the ductwork, virus contaminated droplets can still be carried for long distances across occupied spaces by fan induced turbulent airflow. it may be theoretically possible, however, to design the air distribution ductwork and room diffusers in such a way as to reduce in-room mixing and thus the risk of airflow induced infection spread. furthermore, there is even a possibility of adapting existing building services with covid- specific office floor alterations. further research into the possible development of such comfort, ventilation and indoor air quality provision is urgently needed so that designers, engineers and facilities managers can ensure occupant safety, especially in the light of the covid- pandemic. displacement ventilation systems can be broadly divided into mechanical and natural. mechanical displacement systems can service the entire building, often using a simplified version of air handling units with centralised extract systems or with specific rooms, office floors or classrooms using localised extract systems. continuous extract ventilation is more frequently used in domestic buildings and is currently used predominantly in bathroom areas in high occupancy buildings. natural displacement ventilation approaches can include whole building integrated systems, room specific systems, ventilation products, such as passive ventilation cowls or specific wall integrated louvres. they can also rely on windows, either automated or manually operated, in which case they may be placed at the opposing ends of the room and at different heights with the exhaust located at a high level close to the ceiling, providing maximum displacement ventilation benefit. brief examples of each approach are listed below: conventionally, the most economical way to provide ventilation was to rely on natural forces acting on air, taking advantage of atmospheric pressure differentials such as wind pressure moving air sideways or making use of the buoyancy of warmer air moving upwards. figure the warmed stale air floats to the exhaust opening faster while drawing air from all connected floors, increasing the ventilation rate [ ] . even though natural ventilation methods, including operable windows that are either manual or automatic, are one of the simplest methods of providing ventilation they frequently suffered the most from drawbacks such as bad design and implementation. main design issues included calculating full window area as an opening, which in reality is often less than / th of the window, locating windows in the wrong area or at the wrong height. as much as varied height cross ventilation can be effective, a row of short windows at mid height will generate almost no air movement, no solar shading and window related overheating, cold draughts, noise, incompatibility with interiors such as blinds or with the user behaviour. the study by the university of oregon [ , ] observed that natural ventilation with a plentiful supply of fresh air dilutes and removes contaminated air much more effectively than fan driven, recirculated air movement, significantly reducing the risk of infection, as shown in figure . however, ventilation design that requires the stale air to move across the entire floor plan, or through common areas such as hallways and staircases before being exhausted from the building, is understandably more likely to spread infection than when the stale air is exhausted at the source, directly to the outside. considering the research conducted so far, if designed and implemented appropriately, natural ventilation measures, or a combination of localised mechanical exhaust and large cross section natural inlets, can provide an adequate displacement ventilation solution, significantly reducing the risk of infection. [ ] . a frequently quoted drawback of natural ventilation measures is the perceived lack of control and dependence on external factors such as wind speed and air temperature to provide fresh air. moreover, the need to reduce the internal airflow resistance and maintain large openings and air pathways in large, building-integrated natural solutions reduces the possibilities for noise dampening or provision of adequate temperature management. in noisy, hot or cold environments, this ventilation strategy is often rejected in favour of mechanical ventilation solutions which are simpler to design and do not require familiarity with building physics. as opposed to building integrated ventilation methods or measures such as opening windows, the natural ventilation systems are products that can include roof mounted cowls and/or façade integrated elements. they can be designed or sized specifically for the application, be it a classroom or a sports hall. the systems rely on either the roof cowls to both supply fresh and extract stale air or on façade elements entirely, in which case, they would be placed at the top and bottom of each space to maximise the stack effect. some natural ventilation products can include heat recovery or comfort cooling. most of these systems can ensure displacement ventilation with little contaminated air mixing, as long as used with appropriate internal air dividers, as illustrated in figure . various examples are listed below: roof mounted natural ventilation systems: these have been available for many decades and successfully used in schools and other low-rise high occupancy buildings. their use has declined in recent years due to comparatively higher capital costs than simple mixing systems and the lack of a heat recovery function, although overall energy consumption is reduced due to the lack of fans and the associated electricity use and heat recovery systems have recently become available. these systems are available from several uk manufacturers. roof mounted natural ventilation systems with heat recovery: these are relatively new additions to the natural ventilation product range, even though the addition of heat recovery to natural ventilation has been researched considerably with several academic publications considering heat transfer with heat pipes or thermal wheels in order to improve natural ventilation whilst saving energy. their operation is broadly similar to the standard roof cowl systems in terms of air movement, and can also include façade integrated ventilation for boost, with the addition of heat recovery capability which reduces ventilation related heat loss, further increasing energy efficiency. an example of this mechanism is shown in figure : ventive windhive (natural ventilation with heat recovery) systems. figure . numerous academic papers covered the use of natural ventilation systems, both with and without heat recovery, and demonstrated that, when appropriately sized and designed, they work very effectively [ ] [ ] [ ] . façade mounted natural ventilation systems, these could be stand alone or have additional heating: these are generally automatically actuated façade openings with a room matching grille on the inside and a weather louvre on the outside, located at both high and low level in the room. depending on co concentrations, one or both dampers would open automatically to provide the required, buoyancy driven airflow. in some cases, these systems may include a heating coil, to reduce the cold drafts that could be generated during winter in the absence of a heat recovery function. if required, they can also include a bank of acoustic attenuators to reduce external noise transfer to the indoors as shown in figure . intelligent façade mounted systems with heat pump: latest technology developments include the addition of a heat pump to façade mounted natural ventilation systems to provide both the heat recovery feature. this feature is implemented by transferring heat from the exhaust vent to the supply vent with the help from a low power compressor as well as heat pump driven summer cooling as shown in figure . the general operation is the same as for the twin façade system noted above -fresh air is supplied at low level with the exhaust mounted at high level. however, unlike the above, the incoming air is tempered to improve occupant comfort using the exhausted air energyeither warmed in winter or cooled in the summer. the usual electrical consumption of the compressor is, in part, offset by the reduced electrical consumption due to the absence of fans. the other potential benefit of the system is that the summer cooling tends to boost natural ventilation by heating the exhaust air above the ambient temperature enabling the natural ventilation equipment to maintain adequate air flows all year round. a school in grong in norway implemented hybrid bidirectional ventilation, shown in figure , for the provision of the required indoor air quality based on a balance between supply and exhaust air. underground ducts connect the basement of the building to the wind tower. the mechanism in which this ventilation strategy works relies on air entering the tower further down the school field either naturally or using a fan, depending on the available buoyancy. the air is then driven under the school through a duct entering the rooms through the lower level then rising due to buoyancy, leaving the building through the chimney-like stack. the ventilation rate for each room is controlled by the degree of opening of the exhaust damper and the optional extraction fan. this type of system is simple mechanically, and offers fresh air either naturally, during winter, or using fans when buoyancy is too weak to drive the airflow, with compressor driven heat recovery that utilises a centralised concept for ventilation [ ] . [ ] . a study in a school in new-zealand highlights the positive effects of a better ventilation strategy on airborne particles. two adjacent classrooms were monitored and compared, one with continuous mechanical extraction ventilation solutions and the other where the occupants were relied on to open windows. the levels of inorganic airborne particles were monitored to show how they were removed from the breathing space. the first room was equipped with a unidirectional ventilation system consisting of a fan assisted solar roof prototype with a double-layer roof made of a polycarbonate layer over a steel corrugated north-facing roof, where outdoor air was passed between the two layers, while the other classroom had no specific ventilation system with manually operable windows as the only means of ventilation. the goal of the study was to assess the air quality and the effect of ventilation on reducing respiratory and cardiovascular diseases associated with poor air quality. air samples were measured to identify the number of inorganic particles sizing under μm. the exhaled airborne particle concentration and dilution provided by the ventilation system follow the same trend, since, at this size, aerodynamic forces prevail over gravitational forces as explained in section . . the ventilated system provided . l/s of tempered outside air, or approximately . air change per hour, for a classroom volume of m . the unidirectional ventilation system reduced the average co concentrations by %, from ppm to ppm, and average moisture content by %, from . g of water per kg of dry air to . g of water per kg of dry air. the actively ventilated classroom had on average a % lower concentration of airborne particles sizing under μm than the unventilated classroom as shown in figure [ ] . [ ] . displacement ventilation systems, such as natural ventilation, naturally assisted extraction ventilation and continuous mechanical extraction ventilation, appear to be the most promising ventilation solution in terms of reducing the spread of viruses and other pathogens indoors this is mainly due to the lower air flow velocity, non-turbulent air flow characteristics and a much lower likelihood of air mixing occurring within the ventilated spaces. this observation is investigated further using computational fluid dynamics in the next section. two of the above listed displacement ventilation systems have been selected for further analysis of room specific airflow dynamics and its potential impact on exhaled droplet and pathogen distribution through occupied spaces to assess their impact on the potential spread of infection: ) roof mounted natural ventilation with heat recovery and ) the façade mounted naturally intelligent ventilation system with heat pump. due to their similarity to each group of the natural ventilation systems mentioned above, we consider the results of the cfd modelling to be representative across the roof mounted and façade natural ventilation range. both of the selected systems appear thermally and physically well designed to be able to passively ventilate occupied spaces whilst recovering heat through either passive or active methods, using wind speed, wind pressure and air buoyancy to drive the air flow. under normal circumstances, a natural ventilation strategy has many benefits over mechanical or fan-powered systems, including lower carbon emissions, reduced operating costs, and ease of installation. according to the research mentioned above, it also appears to have measurable advantages when it comes to reducing the risk of infection spread indoors -this is further investigated below. to aid in the assessment of expected airflow and classroom comfort levels achieved in-situ for two displacement systems, a computational fluid dynamics study has been carried out. the cfd study aims to quantify the steady state performance within a school classroom for the following two natural ventilation systems with heat recovery: ventive windhive and ventive active. the overall ventilation performance will be quantified in terms of the simulated co concentration levels within the classroom alongside more specific modelling results of the temperature and, most importantly, air velocity and airflow characteristics. the global setting for the analysis of the two ventilation systems is that of a fully enclosed classroom, with dimensions h x d x w (mm), where: h is height, d is depth and w is width. the classroom is occupied by seated students with corresponding chairs and tables as shown in figure for the ventive windhive system. to enable a true representation of the natural ventilation system's working environment an additional region is included to represent the outside ambient with dimensions , h x , d x , w (mm). although the two ventilation systems will be modelled in the same working environment, the configuration and set-up of each unit is different, and therefore each will be presented separately for clarity. the windhive system, shown in figure , is a roof-mounted unit, with the indoor diffuser located at an arbitrary central location such that it is not positioned directly above any person. the ventive active system, shown in figure , has a different buoyancy driving set-up utilising the external wall of the classroom with the supply unit located no more than mm from the floor level and the extract unit located at the top of the room (preferably . m from the finished floor level or higher). following the finalisation of the geometry an idealised room specific d model of each set-up was created using cad software before being imported into star-ccm+ v . . to help reduce the computational expense of the simulations in terms of mesh and physics several modelling assumptions were made, these are listed below:  simplified geometry for the children and desks to act as the sole obstacles in the classroom  u value of . w/m /k applied to the walls to account for an average heat flux  each child assumed to act as a heat source producing w (equating to a total heat source of w)  wind, solar gain and equipment loads including lighting and airtightness are ignored  grill losses located on the invent active and passive are accounted for through specification of a porous medium with an effective opening of % and a porous inertial (α) and viscous (β) resistance of . and . m/s, respectively  to achieve a realistic outside ambient a small constant velocity field ([ . ] m/s) is active across the length of the domain, in order to account for natural wind and to help initiate a flow solution. this is adopted also for the additional ambient region within the invent passive simulation to account for the open window.  ambient and initial temperature field is equal to °c  initial classroom co level is set at ppm whilst the ambient/environment is equal to ppm  each child is presumed to provide a co release rate of . m /h equating to a bulk class co supply of . m /h the aim is to complete two independent cfd simulations, one for each of the natural ventilation systems. each simulation will operate with a multi-component gas as the working fluid, separated such that the co and other components of air are modelled independently. the chosen software package for all simulations is that of the commercial cfd package, starccm+ v . , supplied by siemens. this is a well validated cfd code that is widely used throughout both industry and academia. to provide a solution domain suitable for the cfd solver the d model must be discretised into a series of smaller fluid volumes by successively splitting nominally hexahedral cells until a desired cell size is achieved. the accuracy of a given simulation is largely controlled by the size and quality of the cells and therefore a number of refinement regions in areas of interest were created. it should also be noted that a grid independent solution is achievable, at this point further reduction of the cells will only account for a higher computational cost instead of improved accuracy. all meshes presented here have been generated using a trimmed cell mesh with local refinement regions and prism layers to account for the near wall effects. each mesh is illustrated below with the total number of cells for each specified. the total number of cells used for the windhive model is . million. an image of the mesh for windhive is shown in figure . the total number of cells used for the invent active model is . million. an image of the mesh for windhive is shown in figure . figure shows the velocity scenes for the two cases for vertical and horizontal cross-sections. for both systems it can be seen that the greatest flow speeds are experienced at the inlet and outlet locations, with both the ventive windhive and ventive active showing the greatest velocities regarding the inlet stream. it also provides a top down projection of a m velocity slice, directly inline with the heads of the seated students. this image shows more clearly the locations and magnitude of the incoming air stream of the windhive. it must be noted that the ventive active's inlet is below this point. table indicates the mass and volume flow rates calculated at the inlets and outlets of the two respective systems. the greatest flow rate is provided by the windhive ( l/s) even without the wall purge opening whilst the active is somewhat lower in the fully passive operation mode ( l/s). the stated flow rates relate to values of . l/s (ventive windhive), and . l/s (ventive active) per person with reference to children and teacher. an important factor aiding in achieving a desired level of co within a room is the total rate of air change in one hour. based on a classroom area of m the estimated number of air changes per hour for the two configurations (based on the inlet flow rates provided in table ) are calculated as: • windhive = . air changes per hour • ventive active = . air changes per hour stagnation regions are possible for such systems according to the model whereby figure shows the velocity profiles. however, people within such environment tend to stand up and move around slightly which will induce further air movement within the stagnated air regions. the cen report cr ventilation for buildings states that if seated occupants are the only source of pollution then the co concertation should be below ppm for category a, ppm for category b and for category c, where the outdoor ambient level is quoted as ppm. category a represents a high level of expectation, recommended for fragile and sensitive persons like young children, elderly, sick or handicapped persons. category b is the normal level of expectation that should be considered for new buildings or renovations. category c represents moderate level of expectation that may be used for existing buildings [ ] . expectedly the windhive configuration provides the most air changes over a given period due to its higher flow rates, and this correlates to a more favourable mass fraction of co , as shown in figure figure . although it should be noted that despite having a lower rate of air change, the ventive active reduces the levels of co comparably to the windhive. both these systems appear to be able to maintain the initial co conditions through the regular exchange and circulation of air throughout the room. the distinct airflow profiles of both natural ventilation systems shown above are of great interest in relation to spread of coronavirus and other pathogens indoors. the supplied fresh air is observed to distribute evenly at low level (well below the breathing, and especially exhaling, area) at a higher volume but lower velocity than fan induced ventilation (thus is much less likely to pick up heavier droplets already dropping to the floor) while the stale air appears to move steadily upwards before being exhausted out of the building, with no observed mixing indoors. this, in combination with the low observed co levels (which are a good proxy for contaminated, exhaled air) as well as the prior research listed above (where, unlike mechanical and recirculating ventilation, the cloud of droplets and particles is not pushed around the room but instead travels in a fairly direct line from window to the exhaust vent, resulting in fewer people being exposed to it), indicates that natural ventilation has a much lower risk of spreading the droplet and aerosol borne infection indoors than other ventilation methods. this displacement and stacking effect in interesting also since it protects the occupant regardless of the configuration off the room: for example, younger children often sit around large table instead of rows. by moving the stale air upward the concentration at the breathing level is reduced as well as the infection risk. airborne disease transmission is highly contagious in enclosed environments and especially in buildings with inadequate or inappropriate ventilation systems. the theory shows that small droplets of less than µm in diameter have the potential to remain in the air for hours since their terminal velocities would be at mm/s, depending on various characteristics and conditions at the time. with the unprecedented pandemic of the covid- spreading through the society at an extremely fast pace, many academics and industry professionals are raising the question of whether the current ventilation strategies are outdated and inadequate for such contagious diseases. even though the widely accepted mechanism of sars-cov- transmission to the date of writing this article has been through droplet borne pathways, the who is accepting the possibility that the deadly virus could be transmitted through the air. many research studies have shown that with appropriate ventilation, the risk of transmission is greatly reduced, further emphasizing the need for research into and adaptation of current ventilation methodologies. furthermore, an insufficient ventilation rate and inappropriate ventilation strategy (mixing of in-room or recycled air, poor mechanical ventilation maintenance) have been linked to degraded health outcomes for the users of high occupancy buildings. this includes facilitated airborne transmission of diseases, sick building syndrome, increased sickness absence and reduced cognition. this paper has reviewed widely used ventilation strategies adopted in high occupancy buildings such as schools and offices. the currently accepted approach to reducing airborne disease transmission recommended by various industry associations (ashrae, cibse) as well as the world health organisation is to increase the ventilation rate using plentiful fresh air to dilute the contaminant to a safe level. in many schools and other high occupancy buildings, the target ventilation rates are rarely met. the benefits of better health and attendance and resultant economic outcomes largely outweighed the capital investment of installing, renovating, or retrofitting appropriate ventilation solutions, even before the covid- pandemic. as can be seen above, the most commonly used ventilation approaches are inadequate when it comes to lowering airborne transmission risks. different strategies were reviewed with cfd examples to consider their impact on the pathogen propagation indoors. it seems beyond doubt that recirculating ventilation strategies should be avoided as they limit and prevent the dilution of harmful particles while also facilitating the distribution of stale, possibly contaminated air throughout occupied spaces. as the occupancy of the room increases (expressed in time and number of people), so does the exposure. mixing ventilation approaches are also disadvantageous as they may increase the range of infectious particles within the room and the range of sizes of particle that can sustainably remain airborne. displacement ventilation with a generously sized natural inlet is preferred as it can move stale, contaminated air directly to the exhaust of the room in a laminar fashion whilst the concentration of small droplets and airborne particles in the indoor air is significantly reduced. the mode of ventilation can be achieved by either fully natural ventilation or natural supply with a mechanical extraction strategy. natural displacement ventilation offers many other advantages such as reduced power consumption and low maintenance costs. on the other hand, some natural ventilation systems may lack controllability or a heat recovery, both of which can be addressed through careful system selection (ensuring sensor-based responses as well as automatic actuators for the supply and exhaust openings) and good design practice. mechanical solutions have an energy consumption penalty due to the use of fans and may require larger capital investment and maintenance costs. if balanced mechanical systems are to be considered, a significant, research based, re-design effort is required with larger ductwork and openings to avoid high air velocity and in-room mixing ventilation dynamics which currently can defeat the purpose of ventilation by increasing the concentrations and the range of the infectious particles. it has also been demonstrated that the use of filters can prove detrimental when not properly maintained and regularly cleaned or changed. on the other hand, the use of mouth and nose covering, such as ply masks for example, directly impact the quantity of droplets and particles emitted by the occupants in the indoor volume. in practice, the constant use of these masks can reduce the comfort level of the occupants and may be difficult to enforce in high occupancy buildings since it relies on the cooperation of each individual and following procedures. whereas, the implementation of a natural displacement ventilation systems passively offers an additional form of transmission risk reduction. two ventive natural displacement ventilation systems were chosen for study using cfd simulations. the large air volume combined with low airflow speed allow sufficient quantities of fresh air to be supplied into the space, distributing evenly through the bottom of the room and gradually displacing the stale air to the top of the space thanks to the buoyancy-driven stack effect. the advantages of this type of ventilation strategy is that it can significantly reduce the risk of airborne disease transmission. it provides large volume ventilation at low air speed, which facilitates a stratification effect. this stratification effect along with the appropriate placement of air inlets and outlets allow a natural and almost universal upward flow of air to the top of the room and out through the appropriate exhaust vents. this restricts the horizontal movement of airborne particles which contain pathogens that are produced when infected individuals breath, speak or cough, capturing the smaller droplets to migrate almost upwards, while allowing larger droplets to fall out of breathable level air, vastly reducing the risk of disease transmission via indoor air. the large volume of fresh air supplied into rooms lowers the concentration of other contaminants in the room and increases the iaq to desired levels. as an added benefit, in both closely studied systems, the heat recovery capability and dynamic, connected controls both increase comfort levels, making the high air refresh rate more bearable for occupants, and enable remote adaptation of ventilation provision, which improves the response of facilities managers to risk levels. building services of high occupancy buildings must be better adapted as a matter of urgency to facilitate the reduction of disease transmission resulting from inappropriate or inadequate ventilation. the covid- pandemic has exposed areas requiring urgent development to protect both our health, wellbeing and the economy by providing safe indoor environments for employees or students. this paper has demonstrated possible routes for indoor disease transmission, the mechanisms in which diseases can spread, facilitated by conventional ventilation systems, the gaps in current knowledge and technologies and areas of interest for future research and development. although many cases of disease transmission can be reduced by social distancing or wearing the recommended ppe, the air surrounding us indoors requires much better management to safely remove air borne pathogens. many of the current ventilation strategies that rely on centralised air distribution and ceiling level supply or recirculation can provide the optimum conditions for rapid disease spread in high occupancy buildings. on the other hand, displacement ventilation strategies, such as the natural ventilation or naturally assisted ventilation explored above, can provide an effective starting point for reclaiming our 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transmission indoor airflow simulation inside lecture room: a cfd approach cfd modeling approach for turbomachinery using mrf model | learncax air recirculation and sick building syndrome: a blinded crossover trial grounding hvac motor shafts: protecting bearings and lowering repair costs -construction canada mixing ventilation i simscale mechanical ventilation simulation and optimization with sav systems ventilation filters and indoor air quality: a review of research from the international centre for indoor environment and energy, indoor air sustainable ventilation strategies in buildings: cfd research performance of a natural ventilation system with heat recovery in uk classrooms: an experimental study makris-makridis, s. consultant, passive ventilation with heat recovery in an urban school: performance in use performance of a natural ventilation system with heat recovery in uk classrooms: an experimental study towards sustainable, energyefficient and healthy ventilation strategies in buildings: a review the effect of ventilation on air particulate matter in school classrooms on the definition of ventilation requirements in iaq standards -a method based on emission rates of pollutants on the definition of ventilation requirements in iaq standards -a method based on emission rates of pollutants rua luis reis santos key: cord- -iw bzy m authors: kraemer, m. u. g.; perkins, t. a.; cummings, d. a. t.; zakar, r.; hay, s. i.; smith, d. l.; reiner, r. c. title: big city, small world: density, contact rates, and transmission of dengue across pakistan date: - - journal: j r soc interface doi: . /rsif. . sha: doc_id: cord_uid: iw bzy m macroscopic descriptions of populations commonly assume that encounters between individuals are well mixed; i.e. each individual has an equal chance of coming into contact with any other individual. relaxing this assumption can be challenging though, due to the difficulty of acquiring detailed knowledge about the non-random nature of encounters. here, we fitted a mathematical model of dengue virus transmission to spatial time-series data from pakistan and compared maximum-likelihood estimates of ‘mixing parameters’ when disaggregating data across an urban–rural gradient. we show that dynamics across this gradient are subject not only to differing transmission intensities but also to differing strengths of nonlinearity due to differences in mixing. accounting for differences in mobility by incorporating two fine-scale, density-dependent covariate layers eliminates differences in mixing but results in a doubling of the estimated transmission potential of the large urban district of lahore. we furthermore show that neglecting spatial variation in mixing can lead to substantial underestimates of the level of effort needed to control a pathogen with vaccines or other interventions. we complement this analysis with estimates of the relationships between dengue transmission intensity and other putative environmental drivers thereof. the transmission dynamics of all infectious diseases depend on a few basic but key determinants: the availability of susceptible and infectious hosts, contacts between them and the potential for transmission upon contact. susceptibility is shaped primarily by historical patterns of transmission, the natural history of the pathogen, the host's immune response and host demography [ ] . what constitutes an epidemiologically significant contact depends on the pathogen's mode of transmission [ ] , and structure in contact patterns can be influenced by transportation networks and the spatial scale of transmission [ ] , by host heterogeneities such as age [ ] , and dynamically in response to the pathogen's influence on host behaviour [ ] . whether transmission actually occurs during contact between susceptible and infectious hosts often depends heavily on environmental conditions [ ] [ ] [ ] . disentangling the relative roles of these factors in driving patterns of disease incidence and prevalence is a difficult but central & the authors. published by the royal society under the terms of the creative commons attribution pursuit in infectious disease epidemiology, and mathematical models that capture the biology of how these mechanisms interact represent an indispensible tool in this pursuit [ ] . the time-series susceptible-infected-recovered (tsir) model was developed by finkenstädt & grenfell [ ] to offer an accurate and straightforward way to statistically connect mechanistic models of infectious disease transmission with time-series data. among other features, tsir models readily account for inhomogeneous mixing in a phenomenological way by allowing for rates of contact between susceptible and infectious hosts to depend on their densities nonlinearly. although this is a simple feature that can be incorporated into any model based on mass-action assumptions-indeed, earlier applications pertained to inhomogeneous mixing in predator-prey systems [ ] -the 'mixing parameters' that determine the extent of this nonlinearity have primarily been fitted to empirical data in applications of the tsir model to measles, cholera, rubella and dengue [ ] [ ] [ ] [ ] . applied to discrete-time models such as the tsir, mixing parameters also have an interpretation as corrections for approximating a truly continuous-time process with a discrete-time model [ , ] . in no application of the tsir model to date has the potential for variation in these parameters been assessed, leaving the extent to which inhomogeneity of mixing varies across space and time as an open question in the study of infectious disease dynamics. there are a number of reasons why mixing might vary in time or space. seasonal variation in mixing might arise because of travel associated with labour [ ] , religious events [ ] or vacation [ ] , or because of the timing of school openings in the case of influenza [ ] . spatial variation in mixing could arise because of cultural differences at geographical scales [ , , ] , because of variation in the density and quality of roads [ ] , or because of variation in human densities and myriad-associated factors [ , ] . for vector-borne diseases, variation in mixing is amplified even further by variation in vector densities [ ] , which effectively mediate contact between susceptible and infectious hosts. dengue is a mosquito-borne viral disease with a strong potential for spatial variation in mixing [ , ] . the dominant vectors of dengue viruses (aedes spp.) thrive in areas where they are able to associate with humans, as humans provide not only a preferred source of blood but also water containers that the mosquitoes use for egg laying and for larval and pupal development [ ] . two additional aspects of aedes ecology-limited dispersal distance of the mosquito [ ] and daytime biting [ ] -imply that human movement should be the primary means by which the viruses spread spatially [ ] . indeed, analyses of dengue transmission dynamics at a variety of scales have strongly supported this hypothesis [ ] [ ] [ ] [ ] . to the extent that human movement in dense urban environments is more well mixed than elsewhere, there are likely to be differences in the extent of inhomogeneous mixing in peri-urban and rural areas. this is also presumably the case for directly transmitted pathogens, but with a potentially even stronger discrepancy for dengue due to the urban-rural gradient in mosquito densities. to assess the potential for spatial variation in the inhomogeneity of mixing as it pertains dengue transmission, we performed an analysis of district-level time series of dengue transmission in the punjab province of pakistan using a tsir model with separate mixing parameters for urban and rural districts. we likewise made estimates of the relationships between density-independent transmission potential and putative drivers thereof, such as temperature, to allow for the relative roles of extrinsic and intrinsic factors to be teased apart. finally, we performed mathematical analyses of the fitted model to assess the significance of spatial variation in mixing inhomogeneity for how time-series data are interpreted and used to guide control efforts. we obtained daily dengue case data aggregated at hospital level from punjab province provided by the health department punjab, pakistan, between and . in total, suspected and confirmed dengue cases were reported in hospitals. all hospitals were subsequently geo-located using 'google maps' (http://www.maps.google.com) similar to methods described here [ ] . hospitals that could not be identified were removed from the database. the hospitals were then assigned to a district within punjab, pakistan by their spatial location. a total of cases alone were reported from the year , which affected almost the entire province. many more cases occurred in lahore ( ) compared to all other districts ( ) (table ). a breakdown per year and each province is provided in electronic supplementary material, table s , and additional information about collection can be found in the electronic supplementary material, appendix. no information on dengue serotypes were available. however, the predominant serotype circulating in punjab province, pakistan is that of denv- [ ] . environmental conditions are instrumental in defining the risk of transmission of dengue [ ] . transmission is limited by the availability of a competent disease vector. due to a lack of resources and political instability, no comprehensive nationwide entomological surveys have been performed in pakistan. therefore, we use a probabilistic model to infer the probability of occurrence of aedes aegypti and aedes albopictus in pakistan derived from a globally comprehensive dataset containing more than records for each species (figure a,b). in short, a boosted regression tree model was applied that predicts a continuous spatial surface of mosquito occurrence from a fitted relationship between the distribution of these mosquitoes and their environmental drivers. a detailed description of the occurrence database and modelling outputs are available here [ , , ] . such model outputs have proved useful in identifying areas of risk of transmission of dengue as well as malaria [ , , ] . other important environmental conditions defining the risk of transmission of dengue are temperature, water availability and vegetation cover [ ] . to account for such variation, raster layers of daytime land surface temperature were processed from the mod a satellite, gap-filled to remove missing values, and then averaged to a monthly temporal resolution for all years [ ] . the density of vegetation coverage has been shown to be associated with vector abundance [ ] . moreover, vegetation indices are useful proxies for precipitation and may be used to derive the presence of standing water buckets that are habitats for the aedes mosquitos [ ] . the same method was again applied to derive the enhanced vegetation index (evi) from the mod a satellite to produce -day and monthly pixel-based estimates for - (figure g) [ ] . due to the inherent delay between rainfall and daily temperature influencing mosquito population dynamics and those mosquitoes contributing to an increase in denv transmission, we consider both, the influence of the current temperature, vegetation indices and precipitation, data on current transmission as well as the values of those covariates the time step before (figure f ). we used population count estimates on a m resolution that were subsequently aggregated up to match all other raster layers to a  km resolution for the year (http://www.worldpop.org) (figure e). in a follow-up analysis to our primary investigation into the climatological drivers of dengue transmission, we included several density-based covariates. we derived a weighted accessibility metric that includes both, population density and urban accessibility, a metric commonly used to derive relative movement patterns [ , ] . this map shows a friction surface, i.e. the time needed to travel through a specific pixel (figure d). we also used an urban, peri-urban and rural classification scheme to quantify patterns of urbanicity based on a globally available grid [ ] (figure c). all covariates and case data were aggregated and averaged (where appropriate) to a district level. following finkenstädt & grenfell [ ] , we assume a general transmission model of where i t,i is the number of infected and infectious individuals and s t,i the number of susceptible individuals, at time t in district i, n i is the population of district i, and b t,i is the covariate driven contact rate. we assume each individual to be susceptible as the epidemic is the first large dengue outbreak. the mixing parameter for the ith district is given by a i ; when a i is equal to , the population has homogeneous mixing where values less than one can either indicate inhomogeneous mixing or a need to correct for the discretization of the continuous-time process. b t , i was fitted using covariates shown in figure . finally, the error terms e t,i are assumed to be independent and identically log-normally distributed random variables. the term b t,i is fit using generalized additive model regression [ - ] . the time-varying climatological covariates are all fit as a smooth spline, while all other covariates enter b t,i linearly. for example, if covariate x and x are time varying and x and x are temporally constant, then we fit b as where s are smooths. additionally, unexplained seasonal variation is accounted for using a -month periodic smooth spline. model selection was performed using backwards selection. two base models were investigated. first, a climate-only model was created using only the climatological and environmental suitability covariates. second, a 'full' model using the densitydependent covariates as well as the climatological covariates were combined into a single model which was then subjected to backwards selection. for both models, the mixing coefficient was initially set equal for each district and once a final model was arrived upon, the mixing coefficient for lahore was allowed to vary separately from the other coefficients. all model fitting was conducted using r [ ] and the 'mgcv' package [ ] . models are fit by maximizing the restricted maximum likelihood [ ] to reduce bias and over-fitting of the smooth splines. the model source code and processing of covariates will be made available in line with previous projects [ ] . to explore the potential significance of spatial variation in mixing parameters, we conducted an analysis to probe the inherent mathematical trade-off between the mixing parameter a and the density-independent transmission coefficient b. specifically, to answer the question, what difference in local transmission would be necessary to account for a difference in mixing while achieving identical transmission dynamics. to explore this, we used equation ( . ) to establish: we then examined how variation in l and a a affected the left-hand side of equation ( . ) and likewise the critical proportion of the population to control in order to effect pathogen elimination, which, under our model, is p c ¼ ( /b). the majority of cases were clustered in lahore, the capital of punjab province. ongoing transmission appeared to be focal in three (vehari, rawalpindi and lahore) districts and to have spread through infective 'sparks' to smaller more rural provinces. to disentangle the different aspects of dengue dynamics and their drivers, we used a model containing only the climatological covariates and performed backwards model selection until each covariate in the model was significant at a % level. this resulted in a model that explained . % of the deviance and that had an adjusted r of . . among the yearly averaged covariates, evi and precipitation remained in the model, as well as the derived a. albopictus range map ( p ¼ .  , . , and .  , respectively). interestingly, when we substituted the derived a. aegypti map for the a. albopictus map, the deviance explained changed very little to . %. for climatological covariates that were fit as smooth splines, temperature, lagged temperature and evi remained in the model (figure , p-value of . , . and . with effective degrees of freedom . , . and . , respectively). there was a significant amount of periodic variation unexplained by the climatological covariates alone, as the 'seasonality' covariate was retained by the model selection algorithm (figure , p ¼ . ). the estimated median values for r per district were clustered around (mean ¼ . ), and their geographical distribution indicated a clear trend towards districts with larger populations ( figure ) . finally, the mixing coefficient was significantly lower than (a ¼ . , % ci ¼ ( . , . ), p ¼ .  ). to understand these differences, the final model was then compared to a nested model in which the coefficient for lahore was allowed to vary independently of all other districts. deviance explained increased to % and adjusted r increased to . . further, the mixing coefficient for lahore (a ¼ . ) was significantly larger than the mixing coefficient for the other districts (a ¼ . , p ¼ . ) (electronic supplementary material, figure s ). the median r for lahore was estimated at . , the highest among all districts. to assess the extent to which the variation in mixing coefficients could be explained by other covariates, we considered the possibility that movement accounted for the differences in the mixing coefficients between lahore and the other districts. the density-dependent covariates (described earlier) were then added to the full model and backwards selection was performed again. the resulting model explained . % of the deviance, had an adjusted r of . and was superior to the final climatological model based on aic ( . versus . ). yearly averaged evi, normalized difference vegetation index and precipitation were all significant ( p ¼ .  , . and . , respectively). again, the derived a. albopictus map was significant ( p ¼ . ). for climatological covariates fit as smooth splines, only temperature and lagged temperature were found to be significant (figure b, p ¼ .  and . , and effective degrees of freedom . and . , respectively), and there was still a significant 'seasonality' effect (figure b, p ¼ .  , effective degrees of freedom . ). the best-fit mixing coefficient was a ¼ . , barely lower than the mixing coefficient for non-lahore districts in the climatological model. the estimated median r again clustered around (mean ¼ . ), and again the r for lahore was largest, but in this model it was considerably larger than in the climatological model (lahore r ¼ . , figure b ). full details of the best-fit model parameters are shown in electronic supplementary material, table s -s . two of the density-dependent covariates remained in the model: the urban map ( p ¼ . ) and the weighted access map ( p ¼  ). when the nested model that allowed lahore's mixing coefficient to vary was fitted, there was no significant difference between the two mixing coefficients ( p % ). given a difference in estimates of the mixing parameters between lahore and elsewhere of . , we analysed equation our results point to considerable spatial heterogeneity in the inhomogeneity of mixing and the strength of an associated figure . model outputs using a backwards model selection procedure in the model using climatological variables (a, i -iv), and including the density-dependent variables (b, i -iv). every subplot shows the predictions of the model for the indicated parameter carrying across the indicated range and every other parameter set to their mean. figure (b, iv) shows the differences in the transmission coefficient from lahore (green) and all other districts (red). rsif.royalsocietypublishing.org j. r. soc. interface : nonlinearity in transmission along an urban -rural gradient. this regional variability in mixing has direct implications for estimates of the basic reproductive number of dengue in our study region and elsewhere. although the potential for such bias in estimates of the basic reproductive number has been shown in a theoretical context [ , ] , we provide quantitative estimates of the extent of this problem by interfacing models with a rich spatio-temporal dataset. our results have implications for estimates of population-level parameters not only for dengue but also for other infectious diseases [ , - ] and possibly even more broadly in ecology [ ] . our analysis revealed significant differences in the inhomogeneity of mixing between urban and rural settings and found that a population-weighted urban accessibility metric was able to account for differences in mixing between these settings. mixing is presumably influenced directly by human behaviour and has been shown to be highly unpredictable, largely dependent on the local context and the spatial and temporal scale [ ] . in this study, however, we could show that the density-dependent covariate we considered was able to capture the influence of these behavioural effects on a district level. once differences in the inhomogeneity of mixing were accounted for, estimated r values indicated considerably larger differences between transmission potential in lahore and all other districts. synchronizing more accurate geo-referenced data would allow for the assessment of the extent to which the relationship between 'mixing parameters' and urban accessibility is dependent on the spatial scale at which data are aggregated [ , ] . in the case of dengue, this has been limited specifically by the availability of high-resolution data [ ] . complementing such an analysis with measurement of social contact patterns could be important for exploring this relationship in even more detail [ , , ] and could be informed by mathematical models that explored this relationship previously for other diseases [ , ] . another encouraging result from our analysis was the finding that large-scale mosquito suitability surfaces helped capture the environmental determinants of dengue transmission [ ] . intervention strategies are contingent on both understanding key environmental drivers of transmission and the dynamics of ongoing human-to-human transmission, particularly in outbreak situations [ ] . environmental drivers such as seasonal fluctuations in rainfall, temperature, vegetation coverage or mosquito abundance will help guide surveillance and control efforts targeted mostly towards the mosquito vector and its ecology [ ] . once infection occurs, an important and unresolved question for dengue is how to best optimize the delivery of intervention strategies to reduce disease incidence, which is largely determined by r . our analysis shows that the interaction between mixing parameters and force of infection has potentially large implications for optimizing targeted intervention, particularly in countries where transmission is high and resources are scarce [ ] . in fact, this may be even more important in areas of low transmission where incidence appears to be rsif.royalsocietypublishing.org j. r. soc. interface : more focal [ ] . again, however, more attention is needed to determine the spatial and temporal resolution of appropriate intervention strategies and the effects of key covariates and model parameters [ ] . empirical understanding of the spatial scale that is most appropriate for carrying out large-scale interventions remains unknown. once transmission has occurred in one place, understanding not only spatial heterogeneity in transmission dynamics but also their subsequent spread in mechanistic stochastic models would help to empirically determine the propagation of the disease [ ] . interest in spatial spread dynamics has risen with increasing importation of dengue into heretofore non-endemic areas due to travel and trade continentally and internationally [ ] . exploration of the case data in pakistan that we analysed here suggests that the virus spreads along major transport routes from lahore to karachi and north to rawalpindi. using results presented here on mixing coefficients and environmental drivers will help pinpoint areas of major risk of importation more accurately, especially in the case of recurring epidemics. we explored the consequences of a spatially differentiated mixing coefficient in the context of transmission potential within this analysis. using the fitted relationships of the environmental drivers of transmission and r will enable future analyses and comparisons between diseases and geographical regions. in this context, it will be instrumental to integrate a variety of movement and social network models with the evidence presented here to infer more accurately how the geographical spread of dengue is determined. unifying the epidemiological and evolutionary 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drivers of autochthonous transmission of chikungunya virus in its invasion of the americas chikungunya on the move geographical and socioeconomic inequalities in women and children's nutritional status in pakistan in : an analysis of data from a nationally representative survey revealing the microscale spatial signature of dengue transmission and immunity in an urban population travelling waves and spatial hierarchies in measles epidemics dengue and dengue vectors in the who european region: past, present, and scenarios for the future acknowledgements. the authors thank the who punjab office, health department punjab and pid for providing the epidemiological data, and all participants that helped collect the data. competing interests. we declare we have no competing interests. funding. m.u.g.k. acknowledges funding from the german academic key: cord- -fb rtmx authors: joseph, maxwell b.; mihaljevic, joseph r.; arellano, ana lisette; kueneman, jordan g.; preston, daniel l.; cross, paul c.; johnson, pieter t. j. title: taming wildlife disease: bridging the gap between science and management date: - - journal: j appl ecol doi: . / - . sha: doc_id: cord_uid: fb rtmx . parasites and pathogens of wildlife can threaten biodiversity, infect humans and domestic animals, and cause significant economic losses, providing incentives to manage wildlife diseases. recent insights from disease ecology have helped transform our understanding of infectious disease dynamics and yielded new strategies to better manage wildlife diseases. simultaneously, wildlife disease management (wdm) presents opportunities for large‐scale empirical tests of disease ecology theory in diverse natural systems. . to assess whether the potential complementarity between wdm and disease ecology theory has been realized, we evaluate the extent to which specific concepts in disease ecology theory have been explicitly applied in peer‐reviewed wdm literature. . while only half of wdm articles published in the past decade incorporated disease ecology theory, theory has been incorporated with increasing frequency over the past years. contrary to expectations, articles authored by academics were no more likely to apply disease ecology theory, but articles that explain unsuccessful management often do so in terms of theory. . some theoretical concepts such as density‐dependent transmission have been commonly applied, whereas emerging concepts such as pathogen evolutionary responses to management, biodiversity–disease relationships and within‐host parasite interactions have not yet been fully integrated as management considerations. . synthesis and applications. theory‐based disease management can meet the needs of both academics and managers by testing disease ecology theory and improving disease interventions. theoretical concepts that have received limited attention to date in wildlife disease management could provide a basis for improving management and advancing disease ecology in the future. population density decreased due to disease, contact rates would become too low for transmission to continue; thus, pathogens would be extirpated before host populations (anderson & may ) . however, disease-induced declines and extinctions of wildlife resulting from small population sizes, reservoir hosts, host switching and heterogeneity in contact rates, susceptibility and transmission within and among populations have forced a re-evaluation of this perspective (de castro & bolker ) . for example, when contact rates among individuals do not depend on host density, pathogens are more likely to drive populations to extinction because transmission continues as host populations are reduced, as seen with tasmanian devil sarcophilus harrisii (boitard ) facial tumour disease where transmission appears to be related to mating behaviours (mccallum ) . white nose syndrome in bats also seems to be more likely to cause extinctions owing to social behaviours in which hosts cluster in hibernacula, reducing the correlation between contact rates and population densities (langwig et al. ) . in recent decades, wildlife disease management (wdm) has been increasingly used to conserve threatened wildlife populations (deem, karesh & weisman ) . for example, wdm has controlled outbreaks of feline leukaemia in critically endangered iberian lynxes lynx pardinus (temminck ) and rabies in endangered ethiopian wolves canis simensis (r€ uppell ), both of which are associated with domestic animal disease reservoirs (haydon et al. ; l opez et al. ). despite the wealth of empirical wdm research, management outcomes can be difficult to predict because system-specific information is lacking for novel pathogens and many theoretical concepts in disease ecology (see table for a subset) have not been widely tested in the field, leading to uncertainty in their generality. this is unlike other environmental management disciplines such as fisheries ecology, which has effectively used theoretical models to predict yields, manage harvest timing and limits and design reserves (e.g. gerber et al. ) . indeed, theoretical applications in fisheries ecology have also produced insights into density-dependent population dynamics, metapopulation theory and the evolution of life-history table . selected theoretical concepts in disease ecology: theoretical concepts in disease ecology theory that apply to wildlife disease management, some direct management implications and a theoretical reference for each concept theoretical concepts management applications selected references host population regulation by disease disease reductions may increase host abundance and/or survival anderson & may ( ) trade-offs between transmission and virulence artificial stocking may increase virulence, and culling may reduce or increase virulence depending on pathogen life-history, culling selectivity and transmission dynamics frank ( ) seasonal drivers of disease emergence and dynamics intervention timing and frequency matters; control efforts can target transmission peaks altizer et al. ( ) pathogen interactions within hosts managing one pathogen alters the transmission and virulence of other pathogens fenton ( ) multi-host species disease dynamics reservoir hosts can drive the extinction of alternate hosts; rates of interspecific transmission may be inferred by managing one host species; management may need to target multiple host species dobson & foufopoulos ( ) spread of disease in spatially structured hosts corridor vaccination can reduce disease in metapopulations; movement controls are unlikely to work for chronic infections keeling & eames ( ) transmission increases with host density host density reductions may reduce disease transmission, and density thresholds for disease persistence may exist anderson & may ( ) transmission increases with disease prevalence independent of host density transmission associated with sexual interactions is more likely to cause host extinction, and non-selective culling may not reduce transmission getz & pickering ( ) predation as a regulator of host population and disease predator conservation may reduce disease in prey populations packer et al. ( ) community composition, diversity and disease risk biodiversity loss and community disassembly may increase disease as predators and less-competent hosts are extirpated, depending on community composition and transmission dynamics keesing, holt & ostfeld ( ) environmental reservoirs and indirect transmission duration of disease control must scale with the environmental persistence; host extinction is more likely joh et al. ( ) individual-level variation and superspreading heterogeneity in individual resistance and infectiousness within a host population can lead to 'superspreaders' that account for a large portion of transmission; management can target superspreaders lloyd-smith et al. ( ) strategies (frank & leggett ) . in this review, we assess the extent to which a similar union between theory and practice has been achieved in wdm. we use a quantitative, case-based approach to provide a critical retrospective of wdm over the last four decades to: (i) quantify how frequently specific theoretical concepts from disease ecology have been applied in the literature, (ii) identify prevailing management objectives, groups and reported outcomes and (iii) assess taxonomic biases in wdm literature. we then present methodological and conceptual opportunities to facilitate the newly emerging synthesis of disease ecology and management, drawing from environmental management and biomedicine to outline steps towards more cost-effective, efficacious and informative wdm. this synthesis aims to facilitate the development of a more predictive framework for disease interventions while simultaneously building empirical support for understanding of disease processes across systems. we compiled wdm case studies using a systematic, twostep search process with specific criteria for inclusion in our review. in the first stage, we searched titles and abstracts of records included in isi web of science using specific terms [(wild*) and (disease* or infect* or pathogen* or parasit*) and (manage* or conserv*)] to capture breadth in published wdm records. additionally, we searched for case studies in grey literature using the following online resources: national wildlife health center, wildpro, national biological information infrastructure wildlife disease information node, u.s. government printing office and the u. s. fish and wildlife service. no case studies identified in the grey literature met our criteria that were independent of cases identified in the scientific literature. case studies were also identified using previous review papers and books (lafferty & gerber ; wobeser ; hudson et al. ; wobeser ; ostfeld, keesing & eviner ) . we conducted a follow-up search with isi web of knowledge to capture subject depth for each managed disease or pathogen identified in the first step, using a search string that included all pathogen and disease names along with terms related to management interventions: (e.g. (rabi* or lyssavir*) and (vaccin* or treat* or manag* or control* or preval* or incidence or cull*) and (wild* or free-ranging or free ranging). the initial web of science search returned articles dating back to , but our disease-specific search strings often returned results dating back to the s or earlier. historical accounts of wdm are probably under-represented in the literature available online, and those returned by our search strings were often less readily accessible than recently published articles. as a result, the cases reviewed here primarily represent recently published cases of wdm. the publication dates of included cases range from to , and % of the cases included in our review were published after . for each article that met our criteria, we recorded (i) pathogen and host characteristics, (ii) management motivations, strategies and outcomes and (iii) whether and how disease ecology theory was incorporated in each article that satisfied our criteria. we only included cases that provided quantitative data on disease in a population or area (number of cases, seroprevalence, prevalence, incidence, etc.). when multiple records were encountered for a single management event, we used the most recent record (as of spring ). cases that only described disease management in humans, livestock or plants were excluded. finally, we only included studies that described management of diseases in populations (operationally defined as groups of > individual) of free-ranging wildlife. incorporation of disease ecology theory was defined broadly as the explicit use or discussion of theoretical concepts relating to transmission dynamics, host population regulation by disease, pathogen evolution, host or pathogen community effects on transmission, spatial heterogeneity in disease dynamics, life stage-or age-specific disease dynamics, endemic vs. epidemic disease states and herd immunity (see table for a list of specific concepts used to define theory in the literature search). four broad management objectives were identified, including conservation of a host species, prevention of disease transmission to humans, prevention of disease transmission to livestock and basic research. studies falling into our basic research category were usually an attempt to better understand the system, determine the extent of the disease problem or provide insight into future management opportunities. to investigate differences in theory application and objectives among managing groups, we also classified author affiliations for each paper as academic, governmental, private or some combination thereof. university or university laboratory affiliations were considered academic, and we used the same criteria for governmental and private affiliation. mixed author affiliations (e.g. academic and governmental) were recorded for individual authors and for papers with multiple authors with different affiliations. we characterized management outcomes by recording whether the disease was eradicated, and if not, whether there were changes in the prevalence, incidence or intensity of disease. ideally, these changes could be quantified and compared across disease systems, but in many cases, inconsistent reporting of results and a lack of pre-management or control data complicate meaningful quantitative comparisons of effect sizes across studies. finally, we considered whether the original management objective was attained using the following categories: 'apparent success', meaning that there was no unmanaged control population or area to compare to the treated area; 'partial success', meaning that at least some of the management objectives were reported as fulfilled; and 'success,' for cases that had controls and reported fulfilment of all management objectives. while management outcomes are rarely clear-cut in this practice, this simplified classification system facilitated coarse comparisons across disease systems and among management studies with variable monitoring time-scales. in total, scientific articles among the identified from the search strings satisfied our criteria (see appendix s and table s in supporting information). many ( %) cases consisted of collaborations between government agencies and academic researchers (fig. ) . conservation motivated % of management that involved private groups, whereas basic research was only conducted when academics were involved. overall, host conservation was the most common objective ( % of cases), while reducing disease risk to humans and domestic animals were the next most common objectives ( % and % of cases, respectively; fig. ). disease ecology theory as defined above has only recently been incorporated consistently into wdm literature (fig. a) . some theoretical concepts such as density dependence in transmission were frequently applied, while others such as pathogen evolution and the role of predators and biodiversity in regulating disease were not (fig. , table ). unexpectedly, papers authored by academics were not more likely to incorporate theory (fisher's exact test, p = Á ). management outcomes were related to theory incorporation (fisher's exact test, p = Á ). the three papers that reported disease increases following intervention explained their results in terms of disease ecology theory, providing insights into transmission and optimal control strategies (e.g. cross et al. ; fig b) . however, there was no relationship between management objective attainment and theory incorporation (fisher's exact test, p = Á ). nevertheless, some counter-intuitive but successful management distribution of management outcomes according to whether disease ecology theory was incorporated. reductions and increases refer to changes in prevalence, incidence, infection intensity or diseaseinduced mortality; eradication refers to local rather than global eradication. programmes clearly benefited from theory. for example, control of classical swine fever in wild boar sus scrofa (linnaeus ), is often hampered by stage-dependent transmission dynamics. susceptible piglets are hard to target with baited vaccines and act as disease reservoirs. by allowing an epidemic to peak such that most adults are immune, then culling only piglets, swiss academics and governmental groups successfully eradicated the disease from a -km region near the italian border (schnyder et al. ) . reductions in prevalence, incidence or infection intensity were reported in % of cases, with vaccination and host treatment as the most commonly applied intervention strategies (fig. b) . ninety-four percentage of cases reported management in terrestrial systems, with % and % of cases reporting management in freshwater and marine systems, respectively. the majority ( %) of reported management efforts were directed towards mammals, with birds and fish representing % and % of cases, respectively. however, mammals are less speciose and less threatened by disease than amphibians (vi e, hilton-taylor & stuart ), for which we found no published wdm records. taxonomic bias could arise because vaccines and drugs are developed primarily to protect human, livestock or poultry health. relatively few cases ( %) reported a failure to meet management objectives, possibly due to negative publication bias. collectively, our analyses indicate that while academics and government agencies collaborate to manage wildlife diseases, collaborations do not necessarily lead to an integration of disease ecology theory with management. density-dependent transmission was often assumed to justify control efforts, but other theoretical concepts were rarely applied (fig. ). data quality issues and potential publication biases currently hinder the application of metaanalytical techniques for wdm, and there is a paucity of published records on non-mammalian management. overcoming challenges to theory-based management while collaboration alone may not necessarily lead to an integration of disease ecology theory and wdm, it should provide a starting point for such integration. academics and managers have unique needs, constraints and knowledge-seeking behaviour that challenge such collaborations. for instance, untreated control areas or pre-treatment data can be unavailable or even unethical in wdm, but are critical for experiments in disease ecology. while academics may design field experiments to test and refine theoretical models, managers need practical, effective and uncontroversial management strategies that succeed in particular systems. such strategies may not be easily identified in the literature from model systems, which managers may be unable to access. modelling wildlife disease systems requires decisions about model complexity. in our experience, theoreticians prefer simpler, more general models that may be applicable to many systems. these models are easier to parameterize and analyse, and the resulting papers are likely to have a wider academic audience. on the other hand, simple models are easily discarded by managers because they lack system-specific detail. this tension is likely to continue, but we recommend additional flexibility on both sides. in particular, managers should appreciate that the addition of modelling details that are only weakly supported by data may not lead to better predictions. meanwhile, theoreticians may develop general models that bear little resemblance to any biological system. furthermore, individuals may be most interested in a particular suite of theoretical concepts, but a narrow approach can impede management by ignoring the full range of phenomena relevant to producing desired management outcomes (driscoll & lindenmayer ) . thus, academics and managers are challenged to take a broad view that incorporates relevant theoretical concepts and an appropriate amount of biological realism, which may require collaboration among researchers with different areas of expertise (driscoll & lindenmayer ) . unfortunately, such large collaborative efforts may bring a loss of autonomy at odds with academic or governmental bureaucracy. a diverse body of literature addresses the gap between academics and environmental managers and provides examples of successful strategies for integration. for instance, international symposia have improved information transfer in invasion biology (shaw, wilson & richardson ) . social networking, joint appointments, interinstitutional sabbaticals, fellowships, concise reporting table , and their application in the literature was included in this review, showing that some concepts such as densitydependent transmission are well represented, while others were less frequently (or not at all) applied. of relevant science to managers and targeted calls for research proposals by managers can all help to foster cooperation (gibbons et al. ) . interdisciplinary working groups for particular management issues can ensure that the needs of multiple stakeholders are considered together when organizing such activities (gibbons et al. ) . groups such as the wildlife disease association and applied journals including the journal of wildlife diseases have encouraged interdisciplinary collaboration, and a broader recognition of the complementarity between disease ecology theory and wdm can provide the impetus for expanding interdisciplinary work in this important field. theory can help address unprecedented management challenges and can be refined in the process. disease outbreaks are often caused by novel pathogens or the appearance of known pathogens in new hosts. often, details of host-pathogen interactions are unknown. by combining limited information with general principles of disease ecology (table ) theory is often refined by evaluating competing hypotheses. therefore, adaptive management is one way to integrate theory and management, especially if multiple management hypotheses can be tested (holling ) . differentiation among competing hypotheses is synonymous with identifying optimal management in this framework. thus, monitoring the effects of disease interventions on prevalence, virulence and host vital rates can help to estimate model parameters including transmission and recovery rates and help in evaluating management outcomes. when agencies have limited flexibility in decisionmaking, thus precluding adaptive management, the best available theoretical and system-specific knowledge can at least produce a 'best guess' management strategy (gregory, ohlson & arvai ) . failed management is still valuable in this framework because outcomes can be compared to predictions from competing models of disease dynamics that can be selectively eliminated, as with tasmanian devil facial tumour disease (mcdonald-madden et al. ). this approach produces mechanistic insights that might be missed if management strategies are characterized simply as effective or ineffective based on management outcomes. if many groups apply adaptive management separately in similar systems without communicating, generalities that benefit management and disease ecology may remain elusive. systematic reviews, invaluable to biomedicine, can help establish which interventions are effective and explain heterogeneity in effectiveness with a standardized meta-analytic approach. guidelines for systematic reviews in environmental management exist, but have not been applied in wdm (sensu pullin & stewart ) . our metadata indicate that this may be due to a lack of data quality and quantity. simple recommendations to facilitate the production of data suitable in quality for systematic review include: (i) establishing unmanaged control areas and/or baseline data, (ii) achieving replication, (iii) reporting precision for estimates of model parameters, prevalence and effect size, (iv) publishing and mechanistically explaining failed management and (v) reporting the spatiotemporal extent of management. data quantity may be lacking because of publication biases and a lack of incentives for managers to publish when working independently. this latter issue is minor if collaborations involve academics, but even motivated scientists may have difficulty publishing if management has no effect. however, management failures are as important to report in the literature as successes for systematic reviews and meta-analyses. an evaluation of the applicability of a theoretical concept in a particular case will rely on comparisons of observed data with explicit predictions from theoretical models, which can often be derived through mathematical modelling. theoretical concepts can be explicitly built into systemspecific mathematical models to identify and evaluate management strategies, as exemplified in a modern wdm challenge: chronic wasting disease (cwd). in , the state of wisconsin began culling white-tailed deer odocoileus virginianus (zimmermann ) and lengthened the hunting season in an attempt to eradicate cwd. these efforts were mandated despite uncertainty over transmission dynamics, the environmental persistence of prions that cause cwd and the time of cwd arrival to the state (bartelt, pardee & thiede ) . five years later, prevalence was still slowly increasing (heisey et al. ) . as this epidemic has unfolded, several models have been used to describe the dynamics of cwd (gross & miller ; wasserberg et al. ; wild et al. ) . simple models of cwd do not tend to produce plausible results. purely density-dependent transmission models predict increases in prevalence that are too rapid, while frequencydependent transmission models predict rapid host extinction or epidemics that are very slow to develop (on the order of centuries). modelling indirect transmission via environmental contamination results in a wider range of outcomes and produces several patterns observed in the field including a slow disease progression with prevalences of over % and significant host population reduction without rapid extinction (almberg et al. ) . recent analyses did not provide much support for models with variable increases in transmission over models with variable starting prevalence, suggesting that host density effects may be relatively weak in this system (heisey et al. ) . taken together, these results suggest that managers would have to reduce deer densities to extremely low levels, probably for decades, at which point other stakeholders such as hunters may wonder whether it is worse to have a lower deer density due to disease impacts or disease control efforts. disease ecology theory is not a 'silver bullet' for solving management problems. indeed, some have pointed out that application of theory under certain circumstances can lead to poor management (driscoll & lindenmayer ) . misapplication of theory at an inappropriate scale, or in a system that does not meet necessary assumptions, could cause undesired consequences. for instance, an assumption of broad-scale culling as a disease management intervention is that pathogen transmissions scale positively with host population density. however, density-dependent changes in social behaviour can alter dispersal patterns that violate this assumption, increasing transmission, as seen with bovine tuberculosis (tb) in cattle and european badgers meles meles (linnaeus ) (woodroffe et al. ) . work in the badger-tb system has refined our understanding of the effects of culling on social animals. however, one could argue that if culling-induced dispersal had been discovered in another disease system, the unintended increase in tb transmission to cattle following badger culling might have been avoided. unfortunately, had this been the case, the applicability of the social perturbation-transmission increase phenomenon to the badger-tb system would have remained uncertain. this underscores the value of moving beyond a case studydominated paradigm, towards a rigorous and empirically verified contingency-based understanding of theory applicability to disease management. such a framework could test and refine theoretical concepts that have shown promise in model systems, but have been infrequently applied in the wdm literature (fig. ) . what are the future directions for wdm? recent advances in disease ecology based on co-infection provide new ways to reduce disease susceptibility and transmission. for example, in african buffalo syncerus caffer (sparrman ), gastrointestinal nematodes reduce individual resistance to mycobacterium tuberculosis, which causes bovine tb, because of cross-regulatory immune responses to micro-and macroparasites (ezenwa et al. ) . hence, deworming drugs may increase resistance to tb and improve tb vaccination efficacy, raising the possibility that tb could be managed indirectly through nematode control (elias, akuffo & britton ; ezenwa et al. ) . management involving immunological trade-offs could improve general understanding of immune-mediated parasite interactions. for instance, interventions aimed at helminth parasites, which accounted for % of cases in our review, are predicted to differentially affect microparasite transmission depending on recovery rates and virulence (ezenwa & jolles ) . these predictions could be evaluated opportunistically by monitoring non-target pathogens. similarly, management in systems with co-infecting parasites could be used to understand virulence evolution in response to changing co-infection dynamics (alizon & van baalen ) . there is increasing recognition that microbial symbiosis can play a role in host health. using mutualistic microbes to control disease, a technique known as probiotics therapy, has benefitted aquaculture, agriculture and human medicine. for example, addition of bacillus and pseudomonas bacteria controls pathogenic vibrio that infect prawns, salmon and crabs in aquaculture (irianto & austin ; panigrahi & azad ) . bifidobacterium and lactobacillus can ameliorate escherichia coli infection in pig farms (zani et al. ; shu, qu & gill ) . in humans, probiotics can treat diarrhoea caused by clostridium difficile infection and antibiotic therapy (mcfarland ; rohde, bartolini & jones ). probiotics may prove useful for wdm. frogs with certain skin bacteria may be less susceptible to population extirpation caused by chytridiomycosis, a fungal disease that implicated global amphibian declines (lam et al. ) . experimental augmentation of skin bacteria reduces mortality of susceptible amphibians in captivity, and field experiments are underway to determine whether probiotics can prevent extirpations in nature (harris et al. ; rex ) . probiotics can also reduce vector populations. for instance, laboratory-reared mosquitoes with a maternally heritable probiotic that disrupts dengue fever virus transmission can locally replace wild mosquito populations and reduce dengue fever risk (hoffmann et al. ) . the successful use of probiotics depends on an understanding of microbial ecology, especially with respect to long-term probiotic maintenance in a host or environment. risks associated with introducing non-native microbes may be ameliorated by isolating probiotic agents from native hosts. as data accumulate, it will be important to evaluate whether the risks of probiotics outweigh those associated with antibiotic treatment in terms of antibiotic or probiotic resistance and pathogen virulence evolution. finally, linking these within-host processes to among-host processes (e.g. microbial community structure and transmission) is an important frontier for wdm and disease ecology. optimal management strategies depend on the degree to which transmission is driven by host population density and the amount of individual and population heterogeneity in contact or transmission rates. host population size, aggregation patterns and contact rates can be altered through hunting, artificial feeding, predator and scavenger conservation, fertility control, culling, translocation of individuals, artificial stocking, movement barriers, etc. understanding the functional form of the relationships among host contacts, density and transmission in real systems is critical to predicting the impacts of such interventions. therefore, field manipulations will play a crucial role in refining our mechanistic understanding of disease transmission. optimal management strategies are not static; contact rates, host abundance and demography can change naturally over time, in response to disease and due to management. for example, group sizes and contact rates may remain constant for highly social species despite management-induced population reduction. reservoir hosts may increase disease risk for other species if infected individuals maintain high fitness via increased reproductive output (fecundity compensation, for example, schwanz ) . fertility control of such reservoir hosts may protect other species that are less tolerant to infection. lastly, if transmission peaks in a short time period, perhaps due to breeding or a pulsed influx of juveniles (altizer et al. ) , management may be applied optimally in a narrow time interval. brucellosis in the elk (cervus elaphus linnaeus ) populations of the greater yellowstone ecosystem of wyoming illustrates how management can capitalize on temporal transmission dynamics. every year, wildlife managers provide supplemental feed to elk at sites in the region. contrary to theoretical predictions, elk abundance at each feeding site is uncorrelated with brucellosis seroprevalence (cross et al. ), but locally, host contact rates correlate positively with elk density (creech et al. ) . these seemingly contradictory findings are explained by variation and interaction between transmission and host density over time, which suggests that brucellosis seroprevalence may be reduced by shortening the length of the feeding season in early spring when transmission is highest (maichak et al. ). this option is appealing because vaccination has had limited, if any, effect (cross et al. ) , and a testand-remove programme, although effective, is financially prohibitive to implement across a broad region. establishing contact networks for a variety of disease systems across a range of densities and over time will help to identify life-history traits, social structures and other species characteristics that predictably influence transmission. taken together, these population-level tools can advance general understanding of transmission dynamics and optimize the application of disease control strategies. community-level interactions including predation and competition can influence disease management outcomes. predation on hosts can increase or decrease disease prevalence and the likelihood of epidemics depending upon predator selectivity, as well as behavioural and demographic effects on host populations that influence transmission and disease susceptibility (packer et al. ; holt & roy ) . interspecific competition can also influence host background mortality and thus the net effect of disease in a population (bowers & turner ) . unintended consequences when managing predators or competitors may be of less concern if coupled with ongoing management such as predator restoration and invasive species control. interspecific transmission of generalist parasites is hard to quantify, but attempts to control generalist parasites in one host species can reveal the extent to which other hosts contribute to transmission. for example, tsao et al. ( ) vaccinated white-footed mice peromyscus leucopus (rafinesque ) in southern connecticut to reduce the prevalence of borrelia burgdorferi, the bacterium that causes lyme disease. based on the strains of b. burgdorferi found in ticks in vaccinated plots, and the relationships between mouse density and tick infection prevalence, the authors concluded that other host species contributed more to tick b. burgdorferi infections than previously thought. thus, vaccination would have to target multiple host species to be effective. contact prevention between wildlife and livestock also provides an opportunity to prevent disease spillover, and when linked with monitoring of both wildlife and domestic populations, can be used to estimate relative rates of within-and among-species transmission. novel management strategies may target ultimate causes of disease emergence once they have been identified. for instance, lyme disease risk in the north-eastern united states increases with habitat fragmentation, which leads to extirpations of (i) predators and competitors that limit white-footed mouse abundance and (ii) less-competent hosts for b. burgdorferi and ticks (ostfeld & logiudice ) . in this system, biodiversity conservation might be an option for proactive wdm. management interventions that recognize and target community-or ecosystem-level processes are rare, but in some cases may more directly address disease threats than focusing solely on individuals or populations. a black box? common wdm interventions have evolutionary consequences that remain largely unexplored. in contrast, a vast literature in the biomedical sciences describes the effects of vaccination on the evolution of human pathogens. generally, (i) some pathogens tend to evolve vaccine resistance, (ii) imperfect vaccines that confer partial immunity select for increased virulence, and (iii) live attenuated vaccines can revert to virulence if inadequately distributed (anderson, crombie & grenfell ; gandon & day ; mackinnon, gandon & read ) . together, these observations provide strong incentives for an 'all or nothing' approach to vaccine-laden bait distribution programmes, which may jeopardize long-term success if low-coverage field trials using vaccines of limited or unknown efficacy precede full distribution of an effective vaccine. selective culling (analogous to selective predation) whereby managers remove infected individuals from the population to prevent disease spread may also have unintended consequences. it can select for increased virulence, because there are relatively more susceptible hosts available for the pathogen, and pathogens must transmit to susceptible hosts faster to avoid being culled along with their hosts (choo, williams & day ) . in many cases, selective culls are based on serological tests that do not discriminate between recovered and infectious individuals. removal of recovered individuals may actually result in more explosive epidemics later on due to a reduction in herd immunity (ebinger et al. ) . experiments and genetic analyses of wildlife pathogens that are often treated by vaccination or culling could reveal the extent to which these concerns are realized. aside from developing new vaccines, these risks may be mitigated if management capitalizes on immune-mediated parasite interactions, employ probiotic approaches and consider population-and community-level management interventions. the use of multiple strategies (seen in % of our case studies) may provide one means with which to avoid problems such as antibiotic or vaccine resistance resulting from the overuse of any one strategy. a more complete integration of disease ecology with wdm can benefit both disciplines. management provides unique opportunities to test disease ecology theory while building system-specific understanding. by evaluating management outcomes in terms of theory, managers can better identify effective strategies even in the face of management failures. we have presented specific recommendations, methodological tools and conceptual approaches to achieve a stronger integration of theory and practice, which we hope will facilitate the development of a strong predictive framework for wdm. the generality of this framework is currently limited by the lack of theoretical and taxonomic breadth of coverage. however, these biases are beginning to be addressed, and disease ecology theory is being integrated with wdm with increasing frequency. by continuing to incorporate ecological and evolutionary ideas in the development and evaluation of management actions, disease ecology and wdm are likely to continue to advance towards a more unified body of theory and evidence. multiple infections, immune dynamics, and the evolution of virulence modeling routes of chronic wasting disease transmission: environmental prion persistence promotes deer population decline and extinction seasonality and the dynamics of infectious diseases the epidemiology of mumps 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mule deer: disease dynamics and control skin microbes on frogs prevent morbidity and mortality caused by a lethal skin fungus low-coverage vaccination strategies for the conservation of endangered species linking process to pattern: estimating spatiotemporal dynamics of a wildlife epidemic from cross-sectional data successful establishment of wolbachia in aedes populations to suppress dengue transmission adaptive environmental assessment and management, st edn predation can increase the prevalence of infectious disease the ecology of wildlife diseases, st edn probiotics in aquaculture dynamics of indirectly transmitted infectious diseases with immunological threshold global trends in emerging infectious diseases networks and epidemic models dynamics of the uk foot and mouth epidemic: stochastic dispersal in a heterogeneous landscape effects of species diversity on disease risk good medicine for conservation biology: the intersection of epidemiology and conservation theory proportion of individuals with anti-batrachochytrium dendrobatidis skin bacteria is associated with population persistence in the frog rana muscosa sociality, density-dependence and microclimates determine the persistence of populations suffering from a novel fungal disease, white-nose syndrome should we expect population thresholds for wildlife disease? management measures to control a feline leukemia virus outbreak in the endangered iberian lynx virulence evolution in response to vaccination: the case of malaria effects of management, behavior, and scavenging on risk of brucellosis transmission in elk of western wyoming disease and the dynamics of extinction active adaptive conservation of threatened species in the face of uncertainty meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of clostridium difficile disease infectious disease ecology: effects of ecosystems on disease and of disease on ecosystems community disassembly, biodiversity loss, and the erosion of an ecosystem service keeping the herds healthy and alert: implications of predator control for infectious disease microbial intervention for better fish health in aquaculture: the indian scenario guidelines for systematic review in conservation and environmental management scientist at work: toiling to save a threatened frog the use of probiotics in the prevention and treatment of antibiotic-associated diarrhea with special interest in clostridium difficile-associated diarrhea epidemiology and control of an outbreak of classical swine fever in wild boar in switzerland. the veterinary record persistent effects of maternal parasitic infection on offspring fitness: implications for adaptive reproductive strategies when parasitized initiating dialogue between scientists and managers of biological invasions probiotic treatment using bifidobacterium lactis hn reduces weanling diarrhea associated with rotavirus and escherichia coli infection in a piglet model an ecological approach to preventing human infection: vaccinating wild mouse reservoirs intervenes in the lyme disease cycle wildlife in a changing world. an analysis of the iucn red list of threatened species host culling as an adaptive management tool for chronic wasting disease in white-tailed deer: a modelling study the role of predation in disease control: a comparison of selective and nonselective removal on prion disease dynamics in deer disease management strategies for wildlife. revue scientifique et technique de l'office international des epizooties disease in wild animals: investigation and management culling and cattle controls influence tuberculosis risk for badgers effect of probiotic cenbiot on the control of diarrhea and feed efficiency in pigs we thank y.p. springer, v.j. mckenzie, s.h. paull, s.a. orlofske, s. ellis, t.j. zelikova, the cu disease discussion group and the johnson lab for insightful comments. any use of trade, product or firm names is for descriptive purposes only and does not imply endorsement by the u.s. government. a.l.a., d.l.p., j.g.k., j.r.m. and m.b.j. were supported by the nsf graduate research fellowship program. p.c.c.'s work was supported by u.s.g.s. and the nsf/nih ecology of infectious disease program deb- , and some ideas stem from working groups sponsored by the nih/dhs-funded rapidd program. p.t.j.j. was supported by a fellowship from the david and lucile packard foundation and grants from the national science foundation (deb- , ) and the morris animal foundation. the authors have no conflict of interests with regard to this research or its funding. additional supporting information may be found in the online version of this article.appendix s . references for reviewed articles. table s . metadata from reviewed articles. key: cord- -ioemd ij authors: tellier, raymond; li, yuguo; cowling, benjamin j.; tang, julian w. title: recognition of aerosol transmission of infectious agents: a commentary date: - - journal: bmc infect dis doi: . /s - - -y sha: doc_id: cord_uid: ioemd ij although short-range large-droplet transmission is possible for most respiratory infectious agents, deciding on whether the same agent is also airborne has a potentially huge impact on the types (and costs) of infection control interventions that are required. the concept and definition of aerosols is also discussed, as is the concept of large droplet transmission, and airborne transmission which is meant by most authors to be synonymous with aerosol transmission, although some use the term to mean either large droplet or aerosol transmission. however, these terms are often used confusingly when discussing specific infection control interventions for individual pathogens that are accepted to be mostly transmitted by the airborne (aerosol) route (e.g. tuberculosis, measles and chickenpox). it is therefore important to clarify such terminology, where a particular intervention, like the type of personal protective equipment (ppe) to be used, is deemed adequate to intervene for this potential mode of transmission, i.e. at an n rather than surgical mask level requirement. with this in mind, this review considers the commonly used term of ‘aerosol transmission’ in the context of some infectious agents that are well-recognized to be transmissible via the airborne route. it also discusses other agents, like influenza virus, where the potential for airborne transmission is much more dependent on various host, viral and environmental factors, and where its potential for aerosol transmission may be underestimated. the classification of an infectious agent as airborne and therefore 'aerosol-transmissible' has significant implications for how healthcare workers (hcws) need to manage patients infected with such agents and what sort of personal protective equipment (ppe) they will need to wear. such ppe is usually more costly for airborne agents (i.e. aerosol-transmissible) than for those that are only transmitted by large droplets or direct contact because of two key properties of aerosols: a) their propensity to follow air flows, which requires a tight seal of the ppe around the airways, and b) for bioaerosols, their small size, which calls for an enhanced filtering capacity. several recent articles and/or guidance, based on clinical and epidemiological data, have highlighted the potential for aerosol transmission for middle-east respiratory syndro me-associated coronavirus (mers-cov) [ , ] and ebola virus [ , ] . some responses to the latter have attempted to put these theoretical risks in a more practical light [ ] , and this nicely illustrates the quandary of how to classify such emerging or re-emerging pathogens into either the large droplet (short-range) versus airborne (short and possibly long-range) transmission categories. however, this delineation is not black and white, as there is also the potential for pathogens under both classifications to be potentially transmitted by aerosols between people at close range (i.e. within m). strictly speaking, 'aerosols' refer to particles in suspension in a gas, such as small droplets in air. there have been numerous publications classifying droplets using particle sizes over the years [ ] [ ] [ ] [ ] [ ] [ ] . for example it is generally accepted that: i) small particles of < - μm aerodynamic diameter that follow airflow streamlines are potentially capable of short and long range transmission; particles of < μm readily penetrates the airways all the way down to the alveolar space, and particles of < μm readily penetrates below the glottis ( ) ii) large droplets of diameters > μm refer to those that follow a more ballistic trajectory (i.e. falling mostly under the influence of gravity), where the droplets are too large to follow inhalation airflow streamlines. for these particle sizes, for example, surgical masks would be effective, as they will act as a direct physical barrier to droplets of this size that are too large to be inhaled into the respiratory tract around the sides of the mask (which are not close-fitting); iii) 'intermediate particles' of diameters - μm, will share some properties of both small and large droplets, to some extent, but settle more quickly than particles < μm and potentially carry a smaller infectious dose than large (> μm) droplets. ' aerosols' would also include 'droplet nuclei' which are small particles with an aerodynamic diameter of μm or less, typically produced through the process of rapid desiccation of exhaled respiratory droplets [ , ] . however, in some situations, such as where there are strong ambient air cross-flows, for example, larger droplets can behave like aerosols with the potential to transmit infection via this route (see next section below). several properties can be inferred from this, for example the penetration of the lower respiratory tract (lrt), as at greater than μm diameter, penetration below the glottis rapidly diminishes, as does any potential for initiating an infection at that site. similarly, any such potential for depositing and initiating an lrt infection is less likely above a droplet diameter of μm, as such large particles will probably impact onto respiratory epithelial mucosal surfaces or be trapped by cilia before reaching the lrt [ ] . the infectious diseases society of america (idsa) has proposed a scheme that is essentially equivalent [ ] , defining "respirable particles" as having a diameter of μm or less; and "inspirable particles" as having a diameter between μm and μm, nearly all of which are deposited in the upper airways. some authors have proposed the term "fine aerosols", consisting of particles of μm or less, but this has been in part dictated by constraints from measurement instruments [ ] . several authors lump together transmission by either large droplets or aerosol-sized particles as "airborne transmission" [ ] , or use "aerosol transmission" to describe pathogens that can cause disease via inspirable particles of any size [ ] . however, we think that it is important to maintain a distinction between particles of < μm and larger particles, because of their significant qualitative differences including suspension time, penetration of different regions of the airways and requirements for different ppe. in this commentary, we use the common convention of "airborne transmission" to mean transmission by aerosol-size particles of < μm. if the infected patients produce infectious droplets of varying sizes by breathing, coughing or sneezing, transmission between individuals by both short-range large droplets and airborne small droplet nuclei are both possible, depending on the distance from the patient source. figure illustrates these potential routes of short and long-range airborne transmission, as well as the downstream settling of such droplets onto surfaces (fomites). from such fomites, they may be touched and transported by hands to be self-inoculated into mucosal membranes e.g. in the eyes, nose and mouth) to cause infection, depending on the survival characteristics of individual pathogens on such surfaces, and the susceptibility (related to available, compatible cell receptors) of the different exposed tissues to infection by these pathogens. for example, when the infectious dose (the number of infectious agents required to cause disease) of an organism is low, and where large numbers of pathogen-laden droplets are produced in crowded conditions with poor ventilation (in hospital waiting rooms, in lecture theatres, on public transport, etc.), explosive outbreaks can still occur, even with pathogens whose airborne transmission capacity is controversial, e.g. the spread of influenza in a grounded plane where multiple secondary cases were observed in the absence of any ventilation [ ] . the more mechanistic approaches (i.e. arguing from the more fundamental physical and dynamic behavior of small versus larger particle and droplet sizes in the absence of any biological interactions) to classifying which pathogens are likely to transmit via the airborne route have been published in various ways over the years [ ] [ ] [ ] [ ] [ ] [ ] , but may have to be considered in combination with epidemiological and environmental data to make a convincing argument about the potential for the airborne transmissibility of any particular agentand the number of possible potential exposure scenarios is virtually unlimited). one should note that "aerosol" is essentially a relative and not an absolute term. a larger droplet can remain airborne for longer if ambient airflows can sustain this suspension for longer, e.g. in some strong cross-flow or natural ventilation environments, where ventilation-induced airflows can propagate suspended pathogens effectively enough to cause infection at a considerable distance away from the source. one of the standard rules (stoke's law) applied in engineering calculations to estimate the suspension times of droplets falling under gravity with air resistance, was derived assuming several conditions including that the ambient air is still [ ] [ ] [ ] [ ] [ ] . so actual suspension times will be far higher where there are significant cross-flows, which is often the case in healthcare environments, e.g. with doors opening, bed and equipment movement, and people walking back and forth, constantly. conversely, suspension times, even for smaller droplet nuclei, can be greatly reduced if they encounter a significant downdraft (e.g. if they pass under a ceiling supply vent). in addition, the degree of airway penetration, for different particle sizes, also depends on the flow rate. in the field of dentistry and orthopedics, where high-powered electric tools are used, even bloodborne viruses (such as human immunodeficiency virus -hiv, hepatitis b and hepatitis b viruses) can become airborne when they are contained in high velocity blood splatter generated by these instruments [ , ] . yet, whether they can cause efficient transmission via this route is more debatable. this illustrates another point, that although some pathogens can be airborne in certain situations, they may not necessarily transmit infection and cause disease via this route. here 'expiration' also includes normal breathing exhalation, as well as coughing and/or sneezing airflows. airborne droplets can then settle on surfaces (fomites) from where they can be touched and carried on hands leading to further self-inoculation routes of transmission outline over time, for a pathogen with a truly predominant airborne transmission route, eventually sufficient numbers of published studies will demonstrate its true nature [ ] . if there are ongoing contradictory findings in multiple studies (as with influenza virus), it may be more likely that the various transmission routes (direct/indirect contact, short-range droplet, long-, and even shortrange airborne droplet nuclei) may predominate in different settings [ , ] , making the airborne route for that particular pathogen more of an opportunistic pathway, rather than the norm [ ] . several examples may make this clearer. the selected pathogens and supporting literature summarized below are for illustrative purposes only, to demonstrate how specific studies have impacted the way we consider such infectious agents as potentially airborne and 'aerosol-transmissible'. it is not intended to be a systematic review, but rather to show how our thinking may change with additional studies on each pathogen, and how the acceptance of "aerosol transmission" for different pathogens did not always followed a consistent approach. chickenpox chickenpox is a febrile, vesicular rash illness caused by varicella zoster virus (vzv), a lipid-enveloped, double-stranded dna virus, and a member of the herpesviridae family. for chickenpox, the evidence appears to be mainly epidemiological and clinical, though this has appeared to be sufficient to classify varicella zoster virus (vzv) as an airborne agent. studies on vzv have shown that the virus is clearly able to travel long distances (i.e. up to tens of meters away from the index case, to spread between isolation rooms and other ward areas connected by corridors, or within a household) to cause secondary infections and/or settle elsewhere in the environment [ ] [ ] [ ] . in addition, tang et al. [ ] showed that airborne vzv could leak out of isolation rooms transported by induced environmental airflows to infect a susceptible hcw, most likely via the direct inhalation route. measles (also known as rubeola) is a febrile, rash illness caused by the measles virus, a lipid-enveloped, singlestranded, negative-sense rna virus, and a member of the paramyxoviridae family. for measles several studies examined a more mechanistic airflow dynamical explanation (i.e. based upon the fundamental physics and behaviour of airborne particles) for the main transmission route involved in several measles outbreaks [ ] , including that of riley and colleagues who used the concept of 'quanta' of infection [ ] . later, two other outbreaks in outpatient clinics included retrospective airflow dynamics analysis, providing more evidence for the transmissibility of measles via the airborne route [ , ] . tuberculosis is a localized or systemic, but most often respiratory bacterial illness caused by mycobacteria belonging to the mycobacterium tuberculosis complex. for tuberculosis (tb), definitive experimental evidence of airborne transmission being necessary and sufficient to cause disease was provided in a series of guinea-pig experiments [ , ] , which has been repeated more recently in a slightly different clinical context [ ] . numerous other outbreak reports have confirmed the transmissibility of tb via the airborne route [ ] [ ] [ ] , and interventions specifically targeting the airborne transmission route have proven effective in reducing tb transmission [ ] . smallpox is a now eradicated, febrile, vesicular rash and disseminated illness, caused by a complex, doublestranded dna orthopoxvirus (poxviridae family), which can present clinically in two forms, as variola major or variola minor. for smallpox, a recent comprehensive, retrospective analysis of the literature by milton has suggested an important contribution of the airborne transmission route for this infection [ ] . although various air-sampling and animal transmission studies were also reviewed, milton also emphasized clinical epidemiological studies where non-airborne transmission routes alone could not account for all the observed smallpox cases. at least one well-documented hospital outbreak, involving cases of smallpox, could only be explained by assuming the aerosol spread of the virus from the index case, over several floors. retrospective smoke tracer experiments further demonstrated that airborne virus could easily spread to patients on different floors via open windows and connecting corridors and stairwells in a pattern roughly replicating the location of cases [ ] . for sars-cov, several thorough epidemiological studies that include retrospective airflow tracer investigations are consistent with the hypothesis of an airborne transmission route [ ] [ ] [ ] . air-sampling studies have also demonstrated the presence of sars-cov nucleic acid (rna) in air, though they did not test viability using viral culture [ ] . although several studies compared and contrasted sars and mers from clinical and epidemiological angles [ ] [ ] [ ] , the predominant transmission mode was not discussed in detail, if at all. several other studies do mention the potential for airborne transmission, when comparing potential routes of infection, but mainly in relation to super-spreading events or "aerosolizing procedures"such as broncho-alveolar lavage, and/or a potential route to take into consideration for precautionary infection control measures [ ] [ ] [ ] . however, from the various published studies, for both mers and sars, it is arguable that a proportion of transmission occurs through the airborne route, although this may vary in different situations (e.g. depending on host, and environmental factors). the contribution from asymptomatic cases is also uncertain [ ] . for both sars and mers, lrt samples offer the best diagnostic yield, often in the absence of any detectable virus in upper respiratory tract (urt) samples [ ] [ ] [ ] . furthermore, infected, symptomatic patients tend to develop severe lrt infections rather than urt disease. both of these aspects indicate that this is an airborne agent that has to penetrate directly into the lrt to preferentially replicate there before causing disease. for mers-cov specifically, a recent study demonstrated the absence of expression of dipeptidyl peptidase (dpp ), the identified receptor used by the virus, in the cells of the human urt. the search for an alternate receptor was negative [ ] . thus, the human urt would seem little or non-permissive for mers-cov replication, indicating that successful infection can only result from the penetration into the lrt via direct inhalation of appropriately sized 'droplet nuclei'-like' particles. this makes any mers-cov transmission leading to mers disease conditional on the presence of virus-containing droplets small enough to be inhaled into the lrt where the virus can replicate. influenza is a seasonal, often febrile respiratory illness, caused by several species of influenza viruses. these are lipid-enveloped, single-stranded, negative-sense, segmented rna viruses belonging to the orthomyxoviridae family. currently, influenza is the only common seasonal respiratory virus for which licensed antiviral drugs and vaccines are available. for human influenza viruses, the question of airborne versus large droplet transmission is perhaps most controversial [ ] [ ] [ ] [ ] . in experimental inoculation experiments on human volunteers, aerosolized influenza viruses are infectious at a dose much lower than by nasal instillation [ ] . the likely answer is that both routes are possible and that the importance and significance of each route will vary in different situations [ , , ] . for example, tighter control of the environment may reduce or prevent airborne transmission by: ) isolating infectious patients in a single-bed, negative pressure isolation room [ ] ; ) controlling environmental relative humidity to reduce airborne influenza survival [ ] ; ) reducing exposure from aerosols produced by patients through coughing, sneezing or breathing with the use of personal protective equipment (wearing a mask) on the patient (to reduce source emission) and/or the healthcare worker (to reduce recipient exposure) [ ] ; ) carefully controlling the use and exposure to any respiratory assist devices (high-flow oxygen masks, nebulizers) by only allowing their use in designated, containment areas or rooms [ ] . the airflows being expelled from the side vents of oxygen masks and nebulisers will contain a mixture of patient exhaled air (which could be carrying airborne pathogens) and incoming high flow oxygen or air carrying nebulized drugs. these vented airflows could then act as potential sources of airborne pathogens. numerous studies have shown the emission of influenza rna from the exhaled breath of naturally influenzainfected human subjects [ ] [ ] [ ] [ ] [ ] and have detected influenza rna in environmental air [ ] [ ] [ ] . more recently, some of these studies have shown the absence of [ ] , or significantly reduced numbers of viable viruses in air-samples with high influenza rna levels (as tested by pcr) [ , , ] . the low number of infectious particles detected is currently difficult to interpret as culture methods are inherently less sensitive than molecular methods such as pcr, and the actual operation of airsampling itself, through shear-stress related damage to the virions, also causes a drop in infectivity in the collected samples. this may lead to underestimates of the amount of live virus in these environmental aerosols. an additional variable to consider is that some animal studies have reported that different strains of influenza virus may vary widely in their capacity for aerosol transmission [ ] . in some earlier articles that discuss the predominant mode of influenza virus transmission [ ] [ ] [ ] [ ] [ ] , these same questions are addressed with mixed conclusions. most of the evidence described to support their views was more clinical and epidemiological, and included some animal and human volunteer studies, rather than physical and mechanistic. yet, this mixed picture of transmission in different circumstances is probably the most realistic. it is noteworthy that several infections currently accepted as airborne-transmitted, such as measles, chickenpox or tb present, in their classical form, an unmistakable and pathognomonic clinical picture. in contrast the clinical picture of influenza virus infection has a large overlap with that of other respiratory viruses, and mixed outbreaks have been documented [ ] . thus, a prevalent misconception in the field has been to study 'respiratory viruses' as a group. however, given that these viruses belong to different genera and families, have different chemical and physical properties and differing viral characteristics, it is unwise and inaccurate to assume that any conclusions about one virus can be applied to another, e.g. in a cochrane review of published studies on interventions to reduce the spread of respiratory viruses, there were actually only two studies specifically about influenza viruses [ ] . as the authors themselves pointed out, no conclusion specific to influenza viruses was possible. while many airborne infections are highly contagious, this is not, strictly speaking, part of the definition. even so, the lower contagiousness of influenza compared to, say, measles has been invoked as an argument against a significant contribution of airborne transmission. yet, it should be noted that a feature of influenza virus infections is that the incubation time (typically - days) is much shorter than its duration of shedding. this allows for the possibility that a susceptible person will be exposed during an outbreak to several different infectious cases belonging to more than one generation in the outbreak. this multiple exposure and telescoping of generations may result in an underestimate of influenza virus transmissibility, as fewer secondary cases will be assigned to a known index case, when in fact the number of secondary cases per index could be much higher. for example, it is known that in some settings a single index case can infect a large number of people, e.g. in an outbreak on an alaska airlines flight [ ] . ebola is a viral hemorrhagic fever associated with a very high mortality, caused by the ebola viruses; these are enveloped single-strand, negative-sense rna viruses comprising five species within the family filoviridae. four ebola species have been implicated in human diseases; the most widespread outbreak, also the most recent, was caused by ebola zaire in west africa in - . the transmission of ebola viruses has been reviewed in depth by osterholm et al. ( ) . these authors noted the broad tissue tropism, as well as the high viral load reached during illness and the low infectious dose, from which it appears inescapable that more than one mode of transmission is possible. regarding aerosol transmission, concerns are raised by several documented instances of transmission of ebola zaire in laboratory settings between animals without direct contact [ , ] (also reviewed in [ ] ). experimental infections of rhesus monkeys by ebola zaire using aerosol infection has been shown to be highly effective [ , ] and this experimental procedure has in fact been used as infectious challenge in ebola vaccine studies [ , ] . rhesus monkeys infected by aerosol exposure reliably developed disseminated, fatal infection essentially similar to that caused by parenteral infection with the addition of involvement of the respiratory tract. autopsies showed pathological findings in the respiratory tract and respiratory lymphoid system in animals infected by the aerosol route that are not found in animals infected parenterally [ , ] . such respiratory pathological lesions have not been reported in human autopsies of ebola cases, but as noted by osterholm et al. [ ] , there have been few human autopsies of ebola cases, arguably too few to confidently rule out any possibility of disease acquired by the aerosol route. the precautionary principle would therefore dictate that aerosol precautions be used for the care of infected patients, and especially considering that infection of the respiratory tract in such patients is not necessary to create an aerosol hazard: ebola viruses reach a very high titer in blood or other bodily fluids during the illness [ , ] and aerosolization of blood or other fluids would create a significant airborne transmission hazard. in summary, despite the various mechanistic arguments about which organisms can be potentially airborne and therefore aerosol-transmissible, ultimately, the main deciding factor appears to be how many studies using various differing approaches: empirical (clinical, epidemiological), and/or experimental (e.g. using animal models), and/or mechanistic (using airflow tracers and air-sampling) methods, reach the same consensus opinion. over time, the scientific community will eventually form an impression of the predominant transmission route for that specific agent, even if the conclusion is one of mixed transmission routes, with different routes predominating depending on the specific situations. this is the case for influenza viruses, and is likely the most realistic. some bacterial and viral infections that have more than one mode of transmission are also anisotropic, like anthrax, plague, tularemia and smallpox: the severity of the disease varies depending on the mode of transmission [ , ] . older experimental infection experiments on volunteers suggest that this is the case for influenza, with transmission by aerosols being associated with a more severe illness [ , ] , and some more recent field observations are consistent with this concept [ ] . for anisotropic agents, even if a mode of transmission (e.g. aerosols) accounts for only a minority of cases, interruption 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challenge with ebolavirus protection of nonhuman primates against two species of ebola virus infection with a single complex adenovirus vector rapid diagnosis of ebola hemorrhagic fever by reverse transcription-pcr in an outbreak setting an assessment of patient viral load as a predictor of outcome a case of severe ebola virus infection complicated by gramnegative septicemia clinical recognition and management of patients exposed to biological warfare agents attenuated influenza produced by experimental intranasal inoculation none. none required. all studies cited/discussed are already published and in the public domainsome require the relevant journal subscriptions for access. please note that the views expressed here are solely those of the authors and are not representative of the institutions to which they are affiliated. authors' contributions jwt, rt, bjc developed the original concept and outline of the article; yl contributed the figures and some additional related text; all authors critically reviewed the final version of the manuscript. all authors read and approved the final manuscript.ethics approval and consent to participate not required. no individual patient information is included. only previously published papers are discussed. not applicable. none of the authors have any competing interests to declare. key: cord- -bv udg k authors: lawrence, robert m. title: chapter transmission of infectious diseases through breast milk and breastfeeding date: - - journal: breastfeeding doi: . /b - - - - . - sha: doc_id: cord_uid: bv udg k nan a large body of evidence clearly demonstrates the protective effects of breastfeeding and documents the transmission of specific infections to infants through breast milk. the fear and anxiety that arise with the occurrence of any infectious disease are even greater in the situation of the breastfeeding mother-infant dyad. uncertainty and lack of knowledge often lead to proscribing against breastfeeding out of fear, which then deprives the infant of the potential protective, nutritional, and emotional benefits of breastfeeding exactly at the time when they are most needed (see the discussion of immunologic benefits of human milk in chapter ). decisions concerning breastfeeding in a mother with an infectious illness should balance the potential benefits of breastfeeding versus the known or estimated risk for the infant acquiring a clinically significant infection via breastfeeding and the potential severity of the infection. documenting transmission of infection from mother to infant by breastfeeding requires not only the exclusion of other possible mechanisms of transmission but also the demonstration of the infectious agent in the breast milk and a subsequent clinically significant infection in an infant that was caused by a plausible infectious process. the first step is to establish the occurrence of a specific infection (clinically or immunologically evident) in a mother and demonstrate the persistence of the infectious agent such that it could be transmitted to the infant. isolation or identification of the infectious agent from the colostrum, breast milk, or an infectious lesion of the breast is important but not necessarily proof of transmission to an infant. epidemiologic evidence of transmission must be considered, including identifying characteristics of the organism that relate an isolate from an infant to the maternal isolate. infectious organisms can reach the breast milk either by secretion in the fluid or cellular components of breast milk or by contamination of the milk at the time of or after expression. a reasonable mechanism of infection via breast milk should be evident and proved through either animal or human studies. demonstration of a subclinical or clinically evident infection in an infant should follow these outlined steps. exclusion of other possible mechanisms of transmission (exposure to mother or other persons/ animals via airborne, droplet, arthropod, or vector modes of transmission or through direct contact with other infectious fluids) would complete the confirmation of transmission of infection via breastfeeding. it is essential to exclude prenatal or perinatal transmission of infection to a fetus/infant, but doing this can often be difficult. clinical case reports or studies confirming the isolation of an infectious agent from the milk are important. to determine a reasonable estimate of the risk for infection via breast milk, larger epidemiologic studies are needed that compare infection rates in breastfed infants versus formula-fed infants, robert m. lawrence addressing the issues just identified. timing of breastfeeding is important relative to the timing of maternal infection and to the presence of a pathogen in colostrum or breast milk. the duration of breastfeeding is another important variable to consider in the estimate of risk because shedding of a pathogen in breast milk may be intermittent. these considerations are only some of the variables to be taken into account, in general, to assess the risk for transmission of an infectious agent from mother to infant via breast milk or breastfeeding. efforts to prove transmission of infection in a particular maternal-infant dyad can be just as difficult and must consider many of the same factors. this chapter focuses on a discussion of specific, clinically relevant, infectious agents and diseases, with reasonable estimates of the risk for infection to infants from breastfeeding. the basic tenet concerning breastfeeding and infection is that breastfeeding is rarely contraindicated in maternal infection. the few exceptions relate to specific infectious agents with strong evidence of transmission and to the association of an infant' s illness with significant morbidity and mortality. the risk or benefit of breastfeeding relative to immunization of a mother or infant is discussed for certain microorganisms. appendix d addresses drugs in breast milk and includes table d- , on antiinfective agents, and chapter reviews how breastfeeding may protect against infection. chapter addresses specific concerns relating to banked breast milk and includes standards developed by the human milk banking association of north america to guide the appropriate handling of banked human milk relative to possible infectious agents. isolation precautions have undergone some revisions in terminology and conceptualization. understanding that the transmission of microorganisms can occur with a known infection and with unrecognized sources of infection, recommendations have been made for standard precautions to be applied to all patients to protect health care workers from potentially infectious body fluids. additionally, precautions based on the predominant modes of transmission have been recommended to protect against infection through the airborne route, direct contact, or contact with droplets. although these precautions are intended to be used in clinical situations to protect health care workers, they may be applied in certain situations to the mother-infant dyad to prevent transmission of infectious agents from one to the other or to other hospitalized mothers and infants. these precautions are useful most often when a mother and infant are still hospitalized. the use of such precautions within the home is not meant to limit breastfeeding. they are intended to allow breastfeeding in the majority of cases and to facilitate the continuation of breastfeeding with some additional safeguards in certain situations, after short temporary periods of stopping breastfeeding, and when to safely use expressed breast milk (see appendix f). standard precautions include preventing contact with blood, all body fluids, secretions and excretions, nonintact skin, and mucous membranes by ( ) careful handwashing before and after every patient contact; ( ) use of gloves when touching body fluids, nonintact skin, or mucous membranes or any items contaminated with body fluids (linens, equipment, devices, etc.); ( ) use of nonsterile gowns to prevent contact of clothing with body fluids; ( ) use of masks, eye protection, or face shields when splashing with body fluids is possible; and ( ) appropriate disposal of these materials. standard precautions should be applied to all patients regardless of actual or perceived risks. the centers for disease control and prevention (cdc) does not consider breast milk a body fluid with infectious risks and thus these policies do not apply to breast milk. (see section on misadministration of breast milk later in this chapter as a possible exception to this concept.) in considering breastfeeding infant-mother dyads and standard precautions, body fluids other than breast milk should be avoided, and only in specified situations should breast milk also be avoided. in general, clothing or a gown for the mother and bandages, if necessary, should prevent direct contact with nonintact skin or secretions. avoiding infant contact with maternal mucous membranes requires mothers to be aware of and understand the risks and to make a conscious effort to avoid this type of contact. the use of gloves, gowns, and masks on infants for protection is neither practical nor appropriate. the recommendations concerning the appropriateness of breastfeeding and breast milk are addressed for specific infectious agents throughout this chapter. human immunodeficiency virus (hiv) infection is an example of one infection that can be prevented by the use of standard precautions, including avoiding breast milk and breastfeeding. the recommendations concerning breastfeeding and hiv and the various variables and considerations involved are discussed later. airborne precautions are intended to prevent transmission via droplet nuclei (dried respiratory particles smaller than mcm that contain microorganisms and can remain suspended in the air for long periods) or dust particles containing microorganisms. airborne precautions include the use of a private room with negative-air-pressure ventilation and masks at all times. in the case of pulmonary tuberculosis (tb), respiratory protective devices (requiring personal fitting and seal testing before use) should be worn. airborne precautions are recommended with measles, varicella or disseminated zoster, and tb. breastfeeding in the presence of these maternal infections is prohibited for the infectious period. this is to protect against airborne transmission of the infection from the mother and to allow the infant to be fed the mother' s expressed breast milk by another individual. the exception to allowing breast milk would be local involvement of the breast by varicella-zoster lesions or mycobacterium tuberculosis, such that the milk becomes contaminated by the infectious agent. transmission via droplets occurs when an individual produces droplets that travel only a short distance in the air and then contact a new host's eyes, nose, mouth, or skin. the common mechanisms for producing droplets include coughing, sneezing, talking (singing or yelling), suctioning, intubation, nasogastric tube placement, and bronchoscopy. in addition to standard precautions applied to all patients, droplet precautions include the use of a private room (preferred) and a mask if within feet ( . m) of the patient. droplet precautions are recommended for adenovirus, diphtheria, respiratory infections, haemophilus influenzae, neisseria meningitidis or invasive infection, influenza, mumps, mycoplasma, parvovirus, pertussis, plague (pneumonic), rubella, and streptococcal pharyngitis, pneumonia, or scarlet fever. the institution of droplet precautions with a breastfeeding mother who has these infections should be specified for each particular infection. this may require some period of separation for the infant and mother (for duration of the illness, for short-term or complete treatment of the mother, for the infectious period) with use of expressed breast milk for nutrition in the interim. prophylactic treatment of the infant, maternal use of a mask during breastfeeding or close contact combined with meticulous handwashing, and the mother's avoidance of touching her mucous membranes may be adequate and reasonable for certain infections. contact precautions are meant to prevent transmission of infection via direct contact (contact between the body surfaces of one individual with another) and indirect contact (contact of a susceptible host with an object contaminated with microorganisms from another individual). contact precautions include cohorting or a private room, gloves and gowns at all times, and handwashing after removal of gown and gloves. contact precautions are recommended for a long list of infections, such as diarrhea in diapered or incontinent patients with clostridium difficile infection, escherichia coli o :h , shigella, rotavirus, hepatitis a, respiratory illness with parainfluenza virus or respiratory syncytial virus (rsv), multidrug-resistant (mdr) bacteria (e.g., enterococci, staphylococci, gramnegative organisms), enteroviral infections, cutaneous diphtheria, impetigo, herpes simplex virus (hsv) infection, herpes zoster (disseminated or in immunocompromised individuals), pediculosis, scabies, staphylococcus aureus skin infection, viral hemorrhagic fevers (e.g., ebola, lassa), conjunctivitis and abscesses, cellulitis, or decubitus that cannot be contained by dressings. for a breastfeeding infant-mother dyad, implementation of precautions for each of these infections in a mother requires meticulous attention to gowning and handwashing by the mother and a specialized plan for each situation. each of these transmission-based precautions can be used together for organisms or illnesses that can be transmitted by more than one route. they should always be used in conjunction with standard precautions, which are recommended for all patients. the red book: report of the committee on infectious diseases by the american academy of pediatrics (aap) remains an excellent resource for infection control guidelines and recommendations to prevent transmission in specific situations and infections. routine culturing of breast milk or culturing breast milk to screen for infectious agents is not recommended except when the milk is intended as donor milk to another mother' s child directly or through human milk banks. see chapter for specific bacterial count standards for raw donor milk and for pasteurization of donor milk. breastfeeding and the expression of or pumping of breast milk (referred to as expressed breast milk) for later use are not sterile activities. in general expressed breast milk should not contain large numbers of microorganisms (less than for raw milk and less than for milk to be pasteurized), nor should it contain potential pathogens such as s. aureus, β-hemolytic streptococci, pseudomonas species, proteus species, or streptococcus faecalis or faecium. few studies have examined "routine" culturing of milk and the significance of specific bacterial colony counts relative to illness in infants. the studies have been primarily concerned with premature or low-birth-weight (lbw) infants who remain hospitalized and are commonly fed via enteral tubes. a study from canada tested samples of milk for use in preterm infants. the study did not identify any adverse events in the infants attributed to organisms growing in the milk samples, and routine bacteriological testing of expressed breast milk was not recommended. a study from chicago examined gram-negative bacilli in the milk used in premature infants. samples were tested before feeding and from the nasogastric tubes during feeding. milk samples from before feeding were less likely to contain gram-negative bacilli ( %) than milk samples from the nasogastric tubing ( %). feeding intolerance was observed when there were more than colony-forming units per milliliter (cfu/ml), and episodes of sepsis were identified when the bacterial counts in the milk were greater than or equal to cfu/ml. this study recommended the routine bacteriologic testing of expressed breast milk. another study from arkansas focused on contamination of feeding tubes during administration of expressed breast milk or formula. ten infants in the neonatal intensive care unit (nicu) were exposed to greater than gram-negative bacteria in their feeding tubes. the three infants who were fed expressed breast milk with contamination at greater than organisms remained well, but the seven formula-fed infants with high levels of bacterial contamination in the feeding tubes developed necrotizing enterocolitis. the gram-negative bacteria with high level contamination in the feeding tubes were either enterobacter or klebsiella in all cases. many nicus consider to cfu/ml as the significant bacterial count for gram-negative bacilli in breast milk that places premature and lbw infants at greater risk for infection. even less data are available concerning specific bacterial colony counts for gram-positive organisms and the risk to the infant. generally less than gram-positive organisms per ml of milk is considered acceptable, with only case reports and no controlled trials to support this cutoff. when the presence of an infectious illness in an infant and/or the breastfeeding mother' s breast when breast milk is seriously considered as a possible mechanism of transmission to the infant, culturing breast milk to identify the organism may be warranted and useful. more important than hurrying to culture breast milk is the careful instruction of mothers on the proper technique for collecting expressed breast milk, storing it, and cleaning the collection unit. the reinforcement of proper technique from time to time, especially when a question of contamination arises, is equally important. many small reports comment on the contamination of breast milk with different collection methods. relative comparisons suggest decreasing contamination of expressed breast milk when collected by the following methods; drip milk, hand pumped milk, manual expression, modern electric pumped milk. one group from malaysia published results showing no difference in contamination between milk collected by electric pump versus manual expression when collected in the hospital. expressed breast milk collected at home by breast pump had higher rates of contamination with staphylococci and gram-negative bacteria. discussion continues about the need to discard the first few milliliters of milk to lower bacteria numbers in expressed breast milk without any evidence to suggest if this is truly necessary. , no evidence shows that cleansing the breast with anything other than tap water decreases the bacterial counts in cultured expressed breast milk. if an infant is directly breastfeeding, collecting milk for culture by manual expression and trying to obtain a "midstream" sample (as is done with "midstream" urine collection for culture) is appropriate. if an infant is being fed expressed breast milk, collecting and culturing the milk at different points during collection (utilizing the same technique the mother uses [manual expression, hand pump, or electric pump]) and administration is appropriate. this might include a sample from immediately after collection, another of stored expressed breast milk, and a sample of milk from the most recent infant feeding at the time the decision to culture is made. please see box - for the basic steps in culturing expressed breast milk. interpretation of such culture results can be difficult and should involve a pediatric infectious disease expert, a microbiologist, and hospital epidemiologist. additional organism identification is often required, utilizing antibiogram patterns or molecular fingerprinting by various techniques to correlate a bacterial isolate from breast milk with an isolate causing disease in infant or mother. misadministration of breast milk, also known as misappropriation, breast milk exposure, and accidental ingestion of breast milk, and other terms, is a medical-legal issue when it occurs in a hospital. this scenario occurs when one infant receives breast milk from another mother by mistake. this occurrence can be very distressing to the families (recipient patient, recipient parent, and donor mother) and medical staff involved. the actual risk for transmission of an infectious agent to an infant via a single ingestion of expressed breast milk (the most common occurrence) from another mother is exceedingly low. in this scenario, the cdc recommends treating this as an accidental exposure to a body fluid, which could be infectious. bacterial, fungal, or parasitic infection from the one exposure is highly unlikely. the concern is about viral pathogens, known to be blood-borne pathogens, which have been identified in breast milk and include but are not limited to hepatitis b virus (hbv), hepatitis c virus (hcv), cytomegalovirus (cmv), west nile virus, human t-cell lymphotropic virus (htlv), and hiv. most hospitals have protocols for managing the situation from both the infection control/prevention and the medical-legal perspectives. these protocols advise informing both families about what occurred, discussing the theoretical risks of harm from the exposure, and reviewing test results and/ or recommending testing to determine the infectious status of each mother relative to the above mentioned viruses. hcv is not a contraindication to breastfeeding and west nile virus infection in lactating women is rare. , neither infection has a documented effective form of prevention or acute treatment. testing either mother (donor or of recipient infant) for these agents is not warranted. prenatal testing for hiv is more commonplace throughout the world. the incidence of hiv among women of childbearing age is low, although it varies significantly by geographic location, and the hospital or locale-specific incidence would be important to know to estimate risk. most women and medical staff are aware that hiv can be transmitted by breastfeeding; therefore breast milk from hiv-positive women is rarely if ever stored in hospitals. the risk for transmission of hiv via breastfeeding is due to the volume of feedings over months (estimated at to feedings in the first months of life) compared with the small "dose of exposure" from one or two "accidental feedings." transmission of hiv from a single breast milk exposure has never been documented. immunologic components in breast milk, along with time and cold of storage, inactivate the hiv in expressed breast milk. for these reasons, the risk for transmission of hiv via expressed breast milk consumed by another child is thought to be extremely low. htlv-i/ii infection in childbearing women is uncommon except in certain geographic regions (japan, africa, the caribbean, and south america). transmission of htlv via breast milk does occur and, like hiv, appears to be related to the volume and duration of breastfeeding. limiting the duration of breastfeeding is effective in decreasing transmission. , , freezing and thawing expressed breast milk decreases the infectivity of htlv-i. in areas of low prevalence, a positive test in a mother should be suspected to be a false positive test, and retesting with both antibody and polymerase chain reaction (pcr) testing should be performed. for these reasons the transmission of htlv-i/ii via accidental expressed breast milk exposure is thought to be extremely low. although the majority of women are cmv positive by childbearing age and cmv transmission occurs via breastfeeding, the risk for cmv in a full-term infant is low. premature or lbw infants are at greater risk for developing disease with cmv infection. freezing expressed breast milk (at − ° c) for to days significantly decreases the infectivity of cmv. here again the risk for cmv transmission from a single accidental exposure to cmv-positive expressed breast milk is extremely low. with a discussion of theoretical risk should be a discussion of possible preventive interventions, such as vaccination or antimicrobial postexposure prophylaxis. if donor mothers are positive for hbv, it is appropriate to give recipient infants hepatitis b virus immunoglobulin (hbig) and hbv vaccines if they have not already received them. if a box - . culturing breast milk . wash hands as per routine. . wash breast with warm tap water and a clean washcloth. . manually express breast milk ("midstream" collection is not required) or attach breast pump flange (previously cleaned as per routine) for collection and collect milk. . place a to ml sample of expressed breast milk in a sterile container with a nonleakable top. . deliver to the labatory in less than hour or refrigerate at ° c until delivery. before sending samples to the viral lab or for nucleic acid/ po lymerase chain reaction (pcr) testing, confirm that the laboratory will accept and process the sample as requested and that the appropriate collection container and prelaboratory management of the specimen are utilized. it may also be appropriate to consult a pediatric infectious disease specialist. additional important components of the hospital-based protocols for managing accidental expressed breast milk exposure include ongoing psychosocial support for the families and staff, documentation of medical discussions with the families, investigative steps, consents and interventions, and the demonstration of ongoing infection control efforts to prevent additional events of misadministration of breast milk. microorganisms produce a whole spectrum of clinical illnesses affecting mothers and infants. many situations carry the risk for transmission of the involved organism from a mother to the infant, or vice versa; in general, however, infants are at greater risk because of such factors as inoculum size and immature immune response. as always, an infection must be accurately diagnosed in a timely manner. empiric therapy and initial infection control precautions should begin promptly based on the clinical symptoms and the most likely etiologic agents. when dealing with a maternal infection, clarifying the possible modes of transmission and estimating the relative risk for transmission to the infant are essential first steps to decision-making about isolating a mother from her infant and the appropriateness of continuing breastfeeding or providing expressed breast milk. breastfeeding infrequently is contraindicated in specific maternal infections. often the question of isolation and interruption of breastfeeding arises when symptoms of fever, pain, inflammation, or other manifestations of illness first develop in a mother and the diagnosis is still in doubt. a clinical judgment must be made based on the site of infection, probable organisms involved, possible or actual mechanisms of transmission of these organisms to the infant, estimated virulence of the organism, and likely susceptibility of the infant. additionally, by the time the illness is clearly recognized or diagnosed in a mother, the infant has already been exposed. given the dynamic nature of the immunologic benefits of breast milk, continuation of breastfeeding at the time of diagnosis or illness in a mother can provide the infant protection rather than continued exposure in most illnesses. stopping breastfeeding is rarely necessary. many situations associated with maternal fever do not require separation of mother and infant, such as engorgement of the breasts, atelectasis, localized nonsuppurative phlebitis, or urinary tract infections. appendix f lists a number of clinical syndromes, conditions, and organisms that require infection control precautions in hospitals. this appendix also includes short lists of possible etiologic agents for these conditions and appropriate precautions and recommendations concerning breastfeeding for different scenarios or organisms. this chapter considers specific infectious agents that are common, clinically significant, or of particular interest. bacillus anthracis, a gram-positive, spore-forming rod, causes zoonotic disease worldwide. human infection typically occurs due to contact with animals or their products. three forms of human disease occur: cutaneous anthrax (the most common), inhalation anthrax, and gastrointestinal (gi) disease (rare). person-to-person transmission can occur as a result of discharge from cutaneous lesions, but no evidence of human-to-human transmission of inhalational anthrax is available. no evidence of transmission of anthrax via breast milk exists. standard contact isolation is appropriate for hospitalized patients or patients with draining skin lesions. the issue of anthrax as a biologic weapon has exaggerated its importance as a cause of human disease. the primary concerns regarding anthrax and breastfeeding are antimicrobial therapy or prophylaxis in breastfeeding mothers and the possibility that infant and mother were exposed by intentional aerosolization of anthrax spores. the cdc published recommendations for treatment and prophylaxis in infants, children, and breastfeeding mothers. the recommendations include the use of ciprofloxacin, doxycycline, amoxicillin, and several other agents without discontinuing breastfeeding. little available is information on ciprofloxacin and doxycycline in breast milk for prolonged periods of therapy or prophylaxis ( days) and possible effects on infants' teeth and bone/cartilage growth during that time period. depending on the clinical situation and sensitivity testing of the identified anthrax strain, other agents can be substituted to complete the -day course. the cdc has approved the use of ciprofloxacin and doxycycline for breastfeeding women for short courses of therapy (less than several weeks). simultaneous exposure of infant and mother could occur from primary aerosolization or from spores "contaminating" the local environment. in either case decontamination of the mother-infant dyad' s environment should be considered. breastfeeding can continue during a mother' s therapy for anthrax as long as she is physically well. open cutaneous lesions should be carefully covered and, depending on the situation, simultaneous prophylaxis for the infant may be appropriate. considerable justifiable concern has been expressed because of the reports of sudden infant death from botulism. infant botulism is distinguished from food-borne botulism from improperly preserved food containing the toxin and from wound botulism from spores entering the wound. infant botulism occurs when the spores of clostridium botulinum germinate and multiply in the gut and produce the botulinal toxin in the gi tract. the toxin binds presynaptically at the neuromuscular junction, preventing acetylcholine release. the clinical picture is a descending, symmetric flaccid paralysis. not every individual who has c. botulinum identified in the stool experiences a clinical illness. the age of infants seems to relate to their susceptibility to illness. the illness is mainly in children younger than months of age; the youngest patient described in the literature was days old. most children become ill between weeks and months of age. the onset of illness seems to occur earlier in formula-fed infants compared with breastfed infants. when a previously healthy infant younger than months of age develops constipation, then weakness and difficulty sucking, swallowing, crying, or breathing, botulism is a likely diagnosis. the organisms should be looked for in the stools, and electromyography may or may not be helpful. in a group reviewed by arnon et al, of patients hospitalized in california were still being nursed at onset of the illness. a beneficial effect of human milk was observed in the difference in the mean age at onset, with breastfed infants being twice as old as formula-fed infants with the disease. the breastfed infants' symptoms were milder. breastfed infants receiving iron supplements developed the disease earlier than those who were breastfed but unsupplemented. of the cases of sudden infant death from botulism, no infants were breastfed within weeks of death. all were receiving iron-fortified formulas. in most cases, no specific food source of c. botulinum can be identified, but honey is the food most often implicated, and corn syrup has been implicated in infants older than months of age. honey may contain botulism spores, which can germinate in the infant gut. however, botulin toxin has not been identified in honey. it has been recommended that honey not be given to infants younger than months of age. this includes putting honey on a mother' s nipples to initiate an infant' s interest in suckling. arnon reviewed the first years of infant botulism monitoring worldwide. the disease has been reported from of the states in the united states and from eight countries on four continents. the relationship to breastfeeding and human milk is unclear. in general the acid stools (ph . to . ) of human milk fed infants encourage bifidobacterium species. few facultative anaerobic bacteria, or clostridia, existing as spores, are present in breastfed infants. in contrast, formula-fed infants have stool phs ranging from . to . , with few bifidobacteria, primarily gram-negative bacteria, especially coliforms and bacteroides species. c. botulinum growth and toxin production decrease with declining ph and usually stops below ph . . breast milk also contains additional protective immunologic components, which purportedly have activity against botulinum toxin. the relationship between the introduction of solid foods or weaning in both formula-fed and breastfed infants and the onset of botulism remains unclear. for a breastfed infant, the introduction of solid food may cause a major change in the gut with a rapid rise in the growth of enterobacteria and enterococci followed by progressive colonization by bacteroides species, clostridia, and anaerobic streptococci. feeding solids to formula-fed infants minimally changes the gut flora as these organisms already predominate. although more hospitalized infants have been breastfed, sudden-death victims are younger and have been formula fed, which supports the concept of immunologic protection in the gut of a breastfed infant. much work remains to understand this disease. clinically, constipation, weakness, and hypotonicity in a previously healthy child constitute botulism until ruled out, especially with recent dietary changes. at this time, no reason exists to suspect breastfeeding as a risk for infant botulism, and some evidence suggests a possible protective effect from breastfeeding. breastfeeding should continue if botulism is suspected in mother or infant. brucella melitensis has been isolated in the milk of animals. foods and animals represent the primary sources of infection in humans. brucellosis demonstrates a broad spectrum of illness in humans, from subclinical to subacute to chronic illness with nonspecific signs of weakness, fever, malaise, body aches, fatigue, sweats, arthralgia, and lymphadenitis. in areas where the disease is enzootic, childhood illness has been described more frequently. the clinical manifestations in children are similar to those in adults. infection can occur during pregnancy, leading to abortion (infrequently), and can produce transplacental spread, causing neonatal infection (rarely). the transmission of b. melitensis through breast milk has been implicated in neonatal infection. , there have been eight cases of brucellosis in infants that were possibly associated with breastfeeding, but brucella was not isolated from the breast milk in any of those cases.* one case of brucellosis in an infant caused by breast milk transmission, with b. melitensis isolated from the breast milk, before antibiotic treatment was given to the mother has been documented. additionally, brucella melitensis has been cultured from women with breast lumps and abscesses. only one of six women described in this report was lactating at the time of diagnosis, and no information about the infant was given. brucellosis mastitis or abscess should be considered in women presenting with appropriate symptoms and occupational exposure to animals, contact with domestic animals in their environment, or exposure to animal milk or milk products (especially unpasteurized products). the breast inflammation tends to be granulomatous in nature (without caseation) and is often associated with axillary adenopathy; occasionally systemic illness in the woman is evident. treatment of brucellosis mastitis or abscess should be treated with surgery or fine needle aspiration as indicated and to weeks of combination antibiotic therapy with two or three medications. temporary interruption of breastfeeding with breast pumping and discarding the milk to continue stimulation of milk production is appropriate. breastfeeding should then continue after an initial period of to hours of therapy in the mother. acceptable medications for treating the mother while continuing breastfeeding include gentamicin, streptomycin, tetracycline, doxycycline, trimethoprim-sulfamethoxazole, and rifampin (see appendix d). chlamydial infection is the most frequent sexually transmitted disease (std) in the united states and is a frequent cause of conjunctivitis and pneumonitis in an infant from perinatal infection. the major determinant of whether chlamydial infection occurs in a newborn is the prevalence rate of chlamydial infection of the cervix. chlamydial immunoglobulin a (iga) has been found in colostrum and breast milk in a small number of postpartum women who were seropositive for chlamydia. no information is available on the role of milk antibodies in protection against infection in infants. it is not believed that chlamydia is transmitted via breast milk. use of erythromycin or tetracycline to treat mothers and oral erythromycin and ophthalmic preparations of tetracyclines, erythromycin, or sulfonamides to treat suspected infection in infants are appropriate during continued breastfeeding. separating infants from mothers with chlamydial infections or stopping breastfeeding is not indicated. simultaneous treatment of mothers and infants may be appropriate in some situations. corynebacterium diphtheriae causes several forms of clinical disease, including membranous nasopharyngitis, obstructive laryngotracheitis, and cutaneous infection. complications can include airway obstruction from membrane formation and toxinmediated central nervous system (cns) disease or myocarditis. the overall incidence of diphtheria has declined even though immunization does not prevent infection but does prevent severe disease from toxin production. fewer than five cases are reported annually in the united states. transmission occurs via droplets or direct contact with contaminated secretions from the nose, throat, eye, or skin. infection occurs in individuals whether they have been immunized or not, but infection in those not immunized is more severe and prolonged. as long as the skin of the breast is not involved, no risk for transmission exists via breast milk. no toxin-mediated disease from toxin transmitted through breast milk has been reported in an infant. breastfeeding, along with chemoprophylaxis and immunization of affected infants, is appropriate in the absence of cutaneous breast involvement (see appendix f). maternal infection with neisseria gonorrhoeae can produce a large spectrum of illness ranging from uncomplicated vulvovaginitis, proctitis, pharyngitis, conjunctivitis, or more severe and invasive disease, including pelvic inflammatory disease, meningitis, endocarditis, or disseminated gonococcal infection. the risk for transmission from mother to infant occurs mainly during delivery in the passage through the infected birth canal and occasionally from postpartum contact with the mother (or her partner). risk for transmission from breast milk is negligible, and n. gonorrhoeae does not seem to cause local infection of the breasts. infection in neonates is most often ophthalmia neonatorum and less often a scalp abscess or disseminated infection. mothers with presumed or documented gonorrhea should be reevaluated for other stds, especially chlamydia trachomatis and syphilis, because some therapies for gonorrhea are not adequate for either of these infections. with the definitive identification of gonorrhea in a mother, empiric therapy should begin immediately, and the mother should be separated from the infant until completion of hours of adequate therapy. treatment of the mother with ceftriaxone, cefixime, penicillin, or erythromycin is without significant risk to the infant. single-dose treatment with spectinomycin, ciprofloxacin, ofloxacin, or azithromycin has not been adequately studied but presumably would be safe for the infant given the -hour separation and a delay in breastfeeding without giving the infant the expressed breast milk (pump and discard). doxycycline use in a nursing mother is not routinely recommended. careful preventive therapy for ophthalmia neonatorum should be provided, and close observation of the infant should continue for to days, the usual incubation period. empiric or definitive therapy against n. gonorrhoeae may be necessary depending on an infant' s clinical status and should be chosen on the basis of the maternal isolate' s sensitivity pattern. the mother should not handle other infants until after hours of adequate therapy, and the infant should be separated from the rest of the nursery population, with or without breastfeeding. haemophilus influenzae type b can cause severe invasive disease such as meningitis, sinusitis, pneumonia, epiglottitis, septic arthritis, pericarditis, and bacteremia. shock can also occur. because the increased utilization of the h. influenzae type b conjugate vaccines, invasive disease caused by haemophilus has decreased dramatically, more than %, in the united states. most invasive disease occurs in children months to years of age. older children and adults rarely experience severe disease but do serve as sources of infection for young children. children younger than months of age seem to be protected because of passively acquired antibodies from the mothers, and some additional benefits may be received from breast milk. transmission occurs through contact with respiratory secretions, and droplet precautions are protective. no evidence suggests transmission through breast milk or breastfeeding. evidence supports that breast milk limits the colonization of h. influenzae in the throat. in the rare case of maternal infection, an inadequately immunized infant in a household is an indication to provide rifampin prophylaxis and close observation for all household contacts, including the breastfeeding infant. expressed breast milk can be given to an infant during the -hour separation after the mother' s initiation of antimicrobial therapy, or if the mother' s illness prevents breastfeeding, it can be reinitiated when the mother is able (see appendix f). although uncommon in the united states, leprosy occurs throughout the world. this chronic disease presents with a spectrum of symptoms depending on the tissues involved (typically the skin, peripheral nerves, and mucous membranes of the upper respiratory tract) and the cellular immune response to the causative organism, mycobacterium leprae. transmission occurs through long-term contact with individuals with untreated or multibacillary (large numbers of organisms in the tissues) disease. leprosy is not a contraindication to breastfeeding, according to jeliffe and jeliffe. the importance of breastfeeding and urgency of treatment are recognized by experts who treat infants and mothers early and simultaneously. no mother-infant contact is permitted except to breastfeed. dapsone, rifampin, and clofazimine are typically and safely used for infant and mother regardless of the method of feeding (see appendix d). listeriosis is a relatively uncommon infection that can have a broad range of manifestations. in immunocompetent individuals, including pregnant women, the infection can vary from being asymptomatic to presenting as an influenza-like illness, occasionally with gi symptoms or back pain. severe disease occurs more frequently in immunodeficient individuals or infants infected in the perinatal period (pneumonia, sepsis, meningitis, granulomatosis infantisepticum). although listeriosis during pregnancy may manifest as mild disease in a mother and is often difficult to recognize and diagnose, it is typically associated with stillbirth, abortion, and premature delivery. it is thought that transmission occurs through the transplacental hematogenous route, infecting the amniotic fluid, although ascending infection from the genital tract may occur. early and effective treatment of a woman can prevent fetal infection and sequelae. , neonatal infection occurs as either early-or late-onset infection from transplacental spread late in pregnancy, ascending infection during labor and delivery, infection during passage through the birth canal, or, rarely, during postnatal exposure. no evidence in the literature suggests that listeria is transmitted through breast milk. treatment of the mother with ampicillin, penicillin, or trimethoprim-sulfamethoxazole is not a contraindication to breastfeeding as long as the mother is well enough. expressed colostrum or breast milk also can be given if the infant is able to feed orally. the management of lactation and feeding in neonatal listeriosis is conducted supportively, as it is in any situation in which an infant is extremely ill, beginning feeding with expressed breast milk or directly breastfeeding as soon as reasonable. n. meningitidis most often causes severe invasive infections, including meningococcemia or meningitis often associated with fever and a rash and progressing to purpura, disseminated intravascular coagulation, shock, coma, and death. transmission occurs via respiratory droplets. spread can occur from an infected, ill individual or from an asymptomatic carrier. droplet precautions are recommended until hours after initiation of effective therapy. despite the frequent occurrence of bacteremia, no evidence indicates breast involvement or transmission through breast milk. the risk for maternal infection to an infant after birth is from droplet exposure and exists whether the infant is breastfeeding or bottle feeding. in either case the exposed infant should receive chemoprophylaxis with rifampin, mg/kg/dose every hours for days ( mg/kg/dose for infants younger than month of age), or ceftriaxone, mg intramuscularly (im) once, for children younger than years of age. close observation of the infant should continue for days, and breastfeeding during and after prophylaxis is appropriate. the severity of maternal illness may prevent breastfeeding, but it can continue if the mother is able, after the mother and infant have been receiving antibiotics for hours. a period of separation from the index case for the first hours of effective therapy is recommended; expressed breast milk can be given during this period. respiratory illness caused by bordetella pertussis evolves in three stages: catarrhal (nasal discharge, congestion, increasing cough), paroxysmal (severe paroxysms of cough sometimes ending in an inspiratory whoop, i.e., whooping cough), and convalescent (gradual improvement in symptoms). transmission is via respiratory droplets. the greatest risk for transmission occurs in the catarrhal phase, often before the diagnosis of pertussis. the nasopharyngeal culture usually becomes negative after days of antibiotic therapy. chemoprophylaxis for all household contacts is routinely recommended. no evidence indicates transmission through breast milk, with similar risk to breastfed and bottle-fed infants. in the case of maternal infection with pertussis, chemoprophylaxis for all household contacts, regardless of age or immunization status, is indicated. in addition to chemoprophylaxis of the infant, close observation and subsequent immunization (in infants older than weeks of age) are appropriate. despite chemoprophylaxis, droplet precautions and separation of mother and infant during the first days of effective maternal antibiotic therapy are recommended. expressed breast milk can be provided to the infant during this period. staphylococcal infection in neonates can be caused by either s. aureus or coagulase-negative staphylococci (most often s. epidermidis) and can manifest in a wide range of illnesses. localized infection can be impetigo, pustulosis in neonates, cellulitis, or wound infection, and invasive or suppurative disease includes sepsis, pneumonia, osteomyelitis, arthritis, and endocarditis. s. aureus requires only a small inoculum ( to organisms) to produce colonization in newborns, most often of the nasal mucosa and umbilicus. by the fifth day of life, % to % of the infants in the nursery will be colonized with s. aureus. the organism is easily transmitted to others from mother, infant, family, or health care personnel through direct contact. outbreaks in nurseries were common in the past. mothers, infants, health care workers, and even contaminated, unpasteurized, banked breast milk were sources of infection. , careful use of antibiotics, changes in nursery layout and procedures, standard precautions, and cohorting as needed decreased the spread of s. aureus in nurseries. now the occurrence of methicillin-resistant s. aureus (mrsa) is again a common problem, requiring cohorting, occasionally epidemiologic investigation, and careful infection control intervention. there are numerous reports of mrsa outbreaks in nicus.* the significance of colonization with staphylococcus and the factors leading to development of disease in individual patients are not clear. the morbidity and mortality related to s. aureus infection in neonates is well described. , , management of such outbreaks has been reviewed. , little has been written about the role of breastfeeding in colonization with s. aureus in nicus, wellbaby nurseries, or at home. mrsa is an important pathogen worldwide. community-acquired mrsa is different from hospital-acquired mrsa. community-acquired mrsa is usually defined as occurring in an individual without the common predisposing variables associated with hospital-acquired mrsa, lacking a mdr phenotype (common with hospital-acquired mrsa), frequently carrying multiple exotoxin virulence factors (such as panton-valentine leukocidin toxin), as well as carrying the smaller type iv staphylococcal cassette cartridge for the meca gene on a chromosome (hospital-acquired mrsa carries types i-iii staphylococcal cassette cartridge) and as being molecularly distinct from the common nosocomial strains of hospital-acquired mrsa. community-acquired mrsa is most commonly associated with skin and soft tissue infections and necrotizing pneumonia and less frequently associated with endocarditis, bacteremia, necrotizing fasciitis, myositis, osteomyelitis, or parapneumonic effusions. community-acquired mrsa is so common, it is now being observed in hospital outbreaks. , , , community-acquired mrsa transmission to infants via breast milk has been reported. , , , , premature or small-forgestational-age infants are more susceptible to and at increased risk for significant morbidity and mortality due to mrsa due in part to prolonged hospitalization, multiple courses of antibiotics, invasive procedures, and intravenous (iv) lines, their relative immune deficiency due to prematurity and illness, and altered gi tract due to different flora and decreased gastric acidity. therefore colonization with mrsa may pose a greater risk to infants in nicus in the long run. full-term infants develop pustulosis, cellulitis, and soft tissue infections, but rarely has invasive disease been reported. , , fortunov et al from texas reported infections in term or late-preterm previously well infants including with pustulosis, with celluliltis or abscesses, and invasive infections. family history of soft tissue skin infections and male sex were the only variables associated with risk for infection; cesarean delivery, breastfeeding, and circumcision were not. nguyen et al reported mrsa infections in a well-infant nursery from california. the eleven cases were all in full-term boys with pustularvesicular lesions in the groin. the infections were associated with longer length of stay, lidocaine injection use in infants, maternal age older than years, and circumcision. breastfeeding was not an associated risk factor for mrsa infection. the question of the role of circumcision in mrsa outbreaks was addressed by van howe and robson. they reported that circumcised boys are at greater risk for staphylococcal colonization and infection. others report that s. aureus carriage in infants (and subsequent infection) is most likely affected by multiple variables including infant factors (antibiotics, surgical procedures [circumcision being the most common], duration of hospital stay as a newborn), maternal factors (previous colonization, previous antibiotic usage, mode of delivery, length of stay), and environmental factors (mrsa in the family or hospital, nursery stay versus rooming-in, hand hygiene).* gerber et al from the chicago area published a consensus statement for the management of mrsa outbreaks in the nicu. the recommendations, which were strongly supported by experimental, clinical, and epidemiologic data, included using a waterless, alcohol-based hand hygiene product, monitoring and enforcing hand hygiene, placing mrsa-positive infants in contact precautions with cohorting if possible, using gloves and gowns for direct contact and masks for aerosolgenerating procedures, cohorting nurses for care of mrsa-positive infants when possible, periodic screening of infants for mrsa using nares or nasopharyngeal cultures, clarifying the mrsa status of infants being transferred into the nicu, limiting overcrowding, and maintaining ongoing instruction and monitoring of health care workers in their compliance with infection control and hand hygiene procedures. evaluation of the outbreak could include screening of health care workers and environmental surfaces to corroborate epidemiologic data and laboratory molecular analysis of the mrsa strains if indicated epidemiologically. the use of mupirocin or other decolonizing procedures should be determined on an individual basis for each nicu. s. aureus is the most common cause of mastitis in lactating women. , , , recurrence or persistence of symptoms of mastitis is a well described occurrence and an important issue in the management of mastitis. communityacquired mrsa has been associated with mastitis as well. pasteurization, s. aureus was not detected in any of the samples of expressed breast milk. colonization of one infant with mrsa was identified, but no mrsa infections were identified in any of the hospitalized infants in the nicu during the months of the study. novak et al identified mrsa in of samples ( %) of expressed fresh-frozen milk from different donors from five brazilian milk banks. only of the samples were positive with high-level bacterial counts of mrsa: greater than , cfu/ml. these were the only samples that would not have been acceptable by bacteriological criteria according to brazilian or american criteria for raw milk use. they did not investigate other epidemiologic data to identify possible variables associated with low or high level contamination of expressed breast milk with mrsa. management of an infant and/or mother with mrsa infection relative to breastfeeding or use of breast milk should be based on the severity of disease and whether the infant is premature, lbw, very-lowbirth-weight (vlbw), previously ill, or full term. full-term infants who themselves or their mothers develop mild to moderate infections (impetigo, pustulosis, cellulitis/abscess, mastitis/breast abscess, or soft tissue infection) can continue breast feeding after a short period of interruption ( to hours). during this time, pumping to maintain the milk supply should be supported, an initial evaluation for other evidence of infection should be done in the maternalinfant dyad, the infected child and/or mother should be placed on "commonly" effective therapy for the mrsa infection, and ongoing observation for clinical disease should continue. the mother and infant can "room-in" together in the hospital, if necessary, with standard and contact precautions. culturing the breast milk is not necessary. empiric therapy for the infant may be chosen based on medical concerns for the infant and the known sensitivity testing of the mrsa isolate. appropriate antibiotic choices include short-term use of azithromycin (erythromycin use during infancy [less than weeks of age], or breastfeeding associated with an increased risk for hypertrophic pyloric stenosis), sulfamethoxazoletrimethoprim (in the absence of g pd deficiency and older than days of age), clindamycin, and perhaps linezolid for mild to moderate infections. infants in nicus (premature, lbw, vlbw, and/ or previously ill), who themselves or their mothers have a mrsa infection, should have the breast milk cultured and suspend breastfeeding or receiving breast milk from their mother until the breast milk is shown to be culture negative for mrsa. the infant should be treated as indicated for their infection or empirically treated if symptomatic (with pending culture results) and closely observed for development of new signs or symptoms of infection. pumping to maintain the milk supply and the use of banked breast milk are appropriate. the infant should be placed on contact precautions, in addition to the routine standard precautions. the infant can be cohorted with other mrsa-positive infants with nursing care cohorted as well. for the mother with mrsa infection, she should be instructed concerning hand hygiene, the careful collection, handling, and storage of breast milk, contact precautions to be used with her infant, and the avoidance of contact with any other infants. the mother can receive several possible antibiotics for mrsa that are compatible with breastfeeding when used for a short period. if the mother remains clinically well, including without evidence of mastitis, but her breast milk is positive for mrsa greater than cfu/ml, empiric therapy to diminish or eradicate colonization would be appropriate. various regimens have been proposed to "eradicate" mrsa colonization, but none have been proven to be highly efficacious. these regimens usually include systemic antibiotics with one or two medications (rifampin added as the second medication), nasal mupirocin to the nares twice daily for to weeks with routine hygiene, with or without the usage of hexachlorophene (or similar topical agent or cleanser) for bathing during the to week treatment period. there is no clear information concerning the efficacy of using similar colonization eradication regimens for other household members or pets in preventing recolonization of the mother or infant. before reintroducing the use of the mother' s breast milk to the infant at least two to three negative breast milk cultures should be obtained after completion of therapy. routine screening of breast milk provided by mothers for their infants in nicus for the presence of mrsa is not indicated in the absence of mrsa illness in the maternal-infant dyad, an mrsa outbreak in nicus, or a high frequency of mrsa infection in a specific nicu. one case of staphylococcal scalded skin syndrome was reported by katzman and wald in an infant breastfed by a mother with a lesion on her areola that did not respond to ampicillin therapy for days. subsequently the infant developed conjunctivitis with s. aureus, which produced an exfoliative toxin, and a confluent erythematous rash without mucous membrane involvement or nikolsky sign. no attempt to identify the exfoliative toxin in the breast milk was made, and the breast milk was not cultured for s. aureus. the child responded to iv therapy with nafcillin. this emphasizes the importance of evaluating mother and infant at the time of a suspected infection and the need for continued observation of the infant for evidence of a pyogenic infection or toxin-mediated disease, especially with maternal mastitis or breast lesions. this case also raises the issue of when and how infants and their mothers become colonized with s. aureus and what factors lead to infection and illness in each. the concern is that staphylococcus can be easily transmitted through skin to skin contact, colonization readily occurs, and potentially serious illness can occur later, long after colonization. in the case of staphylococcal scalded skin syndrome or toxic shock syndrome (tss), the primary site of infection can be insignificant (e.g., conjunctivitis, infection of a circumcision, or simple pustulosis), but a clinically significant amount of toxin can be produced and lead to serious disease. toxic shock syndrome can result from s. aureus or streptococcus pyogenes infection and probably from a variety of antigens produced by other organisms. tss- has been identified as a "superantigen" that affects the t lymphocytes and other components of the immune response, producing an unregulated and excessive immune response and resulting in an overwhelming systemic clinical response. tss has been reported in association with vaginal delivery, cesarean delivery, mastitis, and other local infections in mothers. mortality rate in the mother may be as high as %. the case definition of staphylococcal tss includes meeting all four major criteria: fever greater than . ° c, rash (diffuse macular erythroderma), hypotension, and desquamation (associated with subepidermal separation seen on skin biopsy). the definition also includes involvement of three or more organ systems (gi, muscular, mucous membrane, renal, hepatic, hematologic, or central nervous system); negative titers for rocky mountain spotted fever, leptospirosis, and rubeola; and lack of isolation of s. pyogenes from any source or s. aureus from the cerebrospinal fluid (csf). a similar case definition has been proposed for streptococcal tss. aggressive empiric antibiotic therapy against staphylococci and streptococci and careful supportive therapy are essential to decreasing illness and death. oxacillin, nafcillin, first-generation cephalosporins, clindamycin, erythromycin, and vancomycin are acceptable antibiotics, even for a breastfeeding mother. the severity of illness in the mother may preclude breastfeeding, but it can be reinitiated when the mother is improving and wants to restart. standard precautions, but allowing breastfeeding, are recommended. staphylococcal enterotoxin f has been identified in breast milk specimens collected on days , , and from a mother who developed tss at hours postpartum. s. aureus that produced staphylococcal enterotoxin f was isolated from the mother' s vagina but not from breast milk. infant and mother lacked significant antibody against staphylococcal enterotoxin f in their sera. the infant remained healthy after days of follow-up. staphylococcal enterotoxin f is pepsin inactivated at ph . and therefore is probably destroyed in the stomach environment, presenting little or no risk to the breastfeeding infant. breastfeeding can continue if the mother is able. coagulase-negative staphylococcal infection (the predominant isolate is staphylococcus epidermidis) produces minimal disease in healthy, full-term infants but is a significant problem in hospitalized or premature infants. factors associated with increased risk for this infection include prematurity, high colonization rates in specific nurseries, invasive therapies (e.g., iv lines, chest tubes, intubation), and antibiotic use. illness produced by coagulasenegative staphylococci can be invasive and severe in high-risk neonates, but rarely in mothers. there are reports of necrotizing enterocolitis associated with coagulase-negative staphylococcus. at weeks of age, for infants still in the nursery, s. epidermidis is a frequent colonizing organism at multiple sites, with colonization rates as high as % to %. serious infections with coagulase-negative staphylococci (e.g., abscesses, iv line infection, bacteremia/sepsis, endocarditis, osteomyelitis) require effective iv therapy. many strains are resistant to penicillin and the semisynthetic penicillins, so sensitivity testing is essential. empiric or definitive therapy may require treatment with vancomycin, gentamicin, rifampin, teicoplanin, linezolid, or combinations of these for synergistic activity. transmission of infection in association with breastfeeding appears to be no more common than with bottle feeding. as with s. aureus infection control includes contact and standard precautions. occasionally, during presumed outbreaks, careful epidemiologic surveillance may be required, including cohorting, limiting overcrowding and understaffing, surveillance cultures of infants and nursery personnel, reemphasis of meticulous infection control techniques for all individuals entering the nursery, and, rarely, removal of colonized personnel from direct infant contact. s. epidermidis has been identified as part of fecal microbiota of breastfed infants. s. epidermidis has also been identified in the breast milk of women with clinical evidence of mastitis. nevertheless, s. epidermidis is rarely associated with infection in full-term infants. conceivably breast milk for premature infants could be a source of s. epidermidis colonization in the nicus. the other factors associated with hospitalization in a nicu noted previously presumably play a significant role in both colonization and infection in premature infants. the benefits of early full human milk feeding potentially outweigh the risk for colonization with s. epidermidis via breast milk. ongoing education and assistance should be provided to mothers about the careful collection, storage, and delivery of human breast milk for their premature infants. s. pyogenes (β-hemolytic group a streptococcus [gas]) is a common cause of skin and throat infections in children, producing pharyngitis, cellulitis, and impetigo. illnesses produced by gas can be classified in three categories: ( ) impetigo, cellulitis, or pharyngitis without invasion or complication; ( ) severe invasive infection with bacteremia, necrotizing fasciitis, myositis, or systemic illness (e.g., streptococcal tss); and ( ) autoimmune-mediated phenomena, including acute rheumatic fever and acute glomerulonephritis. gas can also cause puerperal sepsis, endometritis, and neonatal omphalitis. significant morbidity and mortality rates are associated with invasive gas infection; mortality rate is % to %, with almost half the survivors requiring extensive tissue débridement or amputation. infants are not at risk for the autoimmune sequelae of gas (rheumatic fever or poststreptococcal glomerulonephritis). transmission is through direct contact (rarely indirect contact) and droplet spread. outbreaks of gas in the nursery are rare, unlike with staphylococcal infections. either mother or infant can be initially colonized with gas and transmit it to the other. in the situation of maternal illness (extensive cellulitis, necrotizing fasciitis, myositis, pneumonia, tss, mastitis), it is appropriate to separate mother and infant until effective therapy (penicillin, ampicillin, cephalosporins, erythromycin) has been given for at least hours. breastfeeding should also be suspended and may resume after hours of therapy for the mother. group b streptococcus (gbs, streptococcus agalactiae) is a significant cause of perinatal bacterial infection. in parturient women, infection can lead to asymptomatic bacteriuria, urinary tract infection (often associated with premature birth), endometritis, or amnionitis. in infants, infection usually occurs between birth and months of age ( to cases per live births). it is routinely classified by the time of onset of illness in the infant: early onset ( to days, majority less than hours) and late onset ( to days, generally less than weeks). infants may develop sepsis, pneumonia, meningitis, osteomyelitis, arthritis, or cellulitis. early-onset gbs disease is often fulminant, presenting as sepsis or pneumonia with respiratory failure; three quarters of neonatal disease is early onset. type iii is the most common serotype causing disease. transmission is believed to occur in utero and during delivery. colonization rates of mothers and infants vary between % and %. postpartum transmission is thought to be uncommon, although it has been documented. risk factors for early-onset gbs disease include delivery before weeks' gestation, rupture of membranes for longer than hours before delivery, intrapartum fever, heavy maternal colonization with gbs, or low concentrations of anti-gbs capsular antibody in maternal sera. the common occurrence of severe gbs disease before hours of age in neonates has lead to prevention strategies. revised guidelines developed by the aap committees on infectious diseases and on the fetus and newborn have tried to combine various variables for increased risk for gbs infection (prenatal colonization with gbs, obstetric and neonatal risk factors for early-onset disease) and provide intrapartum prophylaxis to those at high risk ( figure - ) the utilization of these guidelines and intrapartum prophylaxis across the united states has decreased the incidence of early-onset disease by approximately %. in , the incidence of early-onset disease was . cases per live births. late-onset gbs disease is thought to be the result of transmission during delivery or in the postnatal period from maternal, hospital, or community sources. dillon et al demonstrated that of infants with late-onset disease were colonized at birth, but the source of colonization was unidentified in the others. gardner et al showed that only . % of children who were culture negative for gbs at discharge from the hospital had acquired gbs by months of age. anthony et al noted that many infants are colonized with gbs, but the actual attack rate for gbs disease is low and difficult to predict. acquisition of gbs through breast milk or breastfeeding is uncommon. cases of late-onset gbs disease associated with gbs in the maternal milk have been reported. , , , , some of the mothers had bilateral mastitis, at least one had delayed evidence of unilateral mastitis, and the others were asymptomatic. it was not clear when colonization of the infants occurred or when infection or disease began in the infants. the authors discussed the possibility that the infants were originally colonized during delivery, subsequently colonized the mothers' breasts during breastfeeding, and then became reinfected at a later time. butter and demoor showed that infants initially colonized on their heads at birth had gbs cultured from their throat, nose, or umbilicus days later. whenever they cultured gbs from the nipples of mothers, the authors also found it in the nose or throat of the infants. byrne et al presented a review of gbs disease associated with breastfeeding and made recommendations to decrease the risk for transmission of gbs to infants via breastfeeding or breast milk. some of their recommendations included confirming appropriate collection and processing procedures for gbs cultures in medical facilities to decrease false-negative cultures, reviewing proper hygiene for pumping, collection, and storage of expressed breast milk with mothers, reviewing the signs and symptoms of mastitis with mothers, and utilizing banked human milk as needed instead of mother' s milk. when a breastfed infant develops late-onset gbs disease, it is appropriate to culture the milk. (see discussion of culturing breast milk earlier in this chapter.) consider treatment of the mother to prevent reinfection if the milk is culture positive for gbs (greater than cfu/ml), with or without clinical evidence of mastitis in the mother. withholding the mother' s milk until it is confirmed to be culture negative for a pathogen is appropriate and should be accompanied by providing ongoing support and instruction to the mother concerning pumping and maintaining her milk supply. serial culturing of expressed breast milk after treatment of the mother for gbs disease or colonization would be appropriate to insure the ongoing absence of a pathogen in the expressed breast milk. there are reports of reinfection of the infant from breast milk. , eradication of gbs mucosal colonization in the infant or the mother may be difficult. some authors have recommended using rifampin prophylactically in both the mother and infant at the end of treatment to eradicate mucosal colonization. (see chapter for management of mastitis in the mother.) a mother or infant colonized or infected with gbs should be managed with standard precautions while in the hospital. ongoing close evaluation of the infant for infection or illness and empiric therapy for gbs in the infant are appropriate until the child has remained well and cultures are subsequently negative at hours. occasionally, epidemiologic investigation in the hospital will utilize culturing medical staff and family members to detect a source of late-onset gbs disease in the nursery. this can be useful when more than one case of late-onset disease is detected with the same serotype. cohorting in such a situation may be appropriate. selective prophylactic therapy for colonized infants to eradicate colonization may be considered, but unlike gas or staphylococcus infection, gbs infection in nurseries has not been reported to cause outbreaks. no data support screening all breastfeeding mothers and their expressed breast cbc including wbc count with differential and blood culture. applies only to penicillin, ampicillin, or cefazolin and assumes recommended dosing regimens. a healthy-appearing infant who was ≥ weeks' gestation at delivery and whose mother received ≥ hours of iap before delivery may be discharged home after hours if other discharge criteria have been met and a person able to comply fully with instructions for home observation will be present. if any one of these conditions is not met, the infant should be observed in the hospital for at least hours and until criteria for discharge are achieved. milk for gbs as a reasonable method for protecting against spread of gbs infection via expressed breast milk. selective culturing of expressed breast milk may be appropriate in certain situations. the face of tuberculosis (tb) is changing throughout the world. in the united states the incidence of tb rose during through and has been declining since then. increased rates of tb were noted in adults between and years of age, and because these are the primary childbearing years, the risk for transmission to children increased. tb during pregnancy has always been a significant concern for patients and physicians alike. it is now clear that the course and prognosis of tb in pregnancy are less affected by the pregnancy and more determined by the location and extent of disease, as defined primarily by chest radiograph, and by the susceptibility of the individual patient. untreated tb in pregnancy is associated with maternal and infant mortality rates of % to %. effective therapy is crucial to the clinical outcome in both pregnant and nonpregnant women. tb during pregnancy rarely results in congenital tb. any individual in a high-risk group for tb should be screened with a tuberculin skin test (tst). no contraindication or altered responsiveness to the tst exists during pregnancy or breastfeeding. interpretation of the tst should follow the most recent guidelines, using different sizes of induration in different-risk populations as cutoffs for a positive test, as proposed by the cdc. figure - outlines the evaluation and treatment of a pregnant woman with a positive tst. treatment of active tb should begin as soon as the diagnosis is made, regardless of the fetus' gestational age, because the risk for disease to mother and fetus clearly outweighs the risks of treatment. isoniazid, rifampin, and ethambutol have been used safely in all three trimesters. isoniazid and pyridoxine therapy during breastfeeding is safe, although the risk for hepatotoxicity in the mother may be a concern during the first months postpartum. congenital tb is extremely rare if one considers that to million cases of tb occur each year worldwide and that less than cases of congenital tb have been reported in the literature. as with other infectious diseases presenting in the perinatal period, distinguishing congenital infection from perinatal or postnatal tb in infants can be difficult. postnatal tb infection in infancy typically presents with severe disease and extrapulmonary extension (meningitis, lymphadenopathy, and bone, liver, spleen involvement). airborne transmission of tb to infants is the major mode of postnatal infection because of close and prolonged exposure in enclosed spaces, especially in their own household, to any adult with infectious pulmonary tb. potential infectious sources could be the mother or any adult caregiver, such as babysitters, day care workers, relatives, friends, neighbors, and even health care workers. the suspicion of tb infection or disease in a household with possible exposure of an infant is a highly anxiety-provoking situation ( figure - ). although protection of an infant from infection is foremost in everyone' s mind, separation of the infant from the mother should be avoided when reasonable. every situation is unique, and the best approach will vary according to the specifics of the case and accepted principles of tb management. the first step in caring for the potentially exposed infant is to determine accurately the true tb status of the suspected case (mother or household contact). this prompt evaluation should include a complete history (previous tb infection or disease, previous or ongoing tb treatment, tst status, symptoms suggestive of active tb, results of most recent chest radiograph, sputum smears, or cultures), physical examination, a tst if indicated, a new chest radiograph, and mycobacterial cultures and smears of any suspected sites of infection. all household contacts should be evaluated promptly, including history and tst with further evaluation as indicated. continued risk to the infant can occur from infectious household contacts who have not been effectively evaluated and treated. an infant should be separated temporarily from the suspected source if symptoms suggest active disease or a recent tst documents conversion, and separation should continue until the results of the chest radiograph are seen. because of considerable variability in the course of illness and the concomitant infectious period, debate continues without adequate data about the appropriate period of separation. this should be individualized given the specific situation. hiv testing and assessment of the risk for mdr tb should be done in every case of active tb. sensitivity testing should be done on every mycobacterium tuberculosis isolate. table - summarizes the management of the newborn infant whose mother (or other household contact) has tb. initiation of prophylactic isoniazid therapy in the infant has been demonstrated to be effective in preventing tb infection and disease in the infant. therefore continued separation of infant and mother is unnecessary after therapy in both mother and child has begun. the real risk to an infant requiring separation is from airborne transmission. separation of the infant from a mother with active pulmonary tb is appropriate, regardless of the method of feeding. however, in many parts of the world, after therapy in the mother and prophylaxis with isoniazid in the infant has begun, the infant and mother are not separated. with or without separation, the mother and infant should continue to be closely observed throughout the course of maternal therapy to ensure good compliance with medication by both mother and infant and to identify, early on, any symptoms in the infant suggestive of tb. tuberculous mastitis occurs rarely in the united states but does occur in other parts of the world* and can lead to infection in infants, frequently involving the tonsils. a mother usually has a single breast mass and associated axillary lymph node swelling and infrequently develops a draining sinus. tb of the breast can also present as a painless mass or edema. involvement of the breast can occur with or without evidence of disease at other sites. evaluation of extent of disease is appropriate, including lesion cultures by needle aspiration, biopsy, or wedge resection and milk cultures. therapy should be with multiple anti-tb medications, but surgery should supplement this, as needed, to remove extensive necrotic tissue or a persistently draining sinus. neither breastfeeding nor breast milk feeding should be done until the lesion is healed, usually weeks or more. continued anti-tb therapy for months in the mother and isoniazid for the infant for to months is indicated. in the absence of tuberculous breast infection in the mother, transmission of tb through breast milk has not been documented. thus even though temporary separation of infant and mother may occur pending complete evaluation and initiation of adequate therapy in the mother and prophylactic isoniazid therapy ( mg/kg/day as a single daily dose) in the infant, breast milk can be expressed and given to the infant during the short separation. breastfeeding can safely continue whether the mother, infant, or both are receiving anti-tb therapy. anti-tb medications (isoniazid, rifampin, pyrazinamide, aminoglycosides, ethambutol, ethionamide, p-aminosalicylic acid) have been safely used in infancy, and therefore the presence of these medications in smaller amounts in breast milk is not a contraindication to breastfeeding. although conflicting, reports indicate that breastfeeding by tst-positive mothers does influence infants' responses to bacille calmette-guérin notes: further workup should always include evaluation of tb status of all other household (or close) contacts by tuberculin skin testing (tst), review of symptoms, physical examination, and chest x-ray (cxr). sputum smears and cultures should be done as indicated. separation should occur until interpretation of cxr film confirms absence of active disease, or, with active disease, separation should continue until individual is no longer considered infectious: three negative consecutive sputum smears, adequate ongoing empiric therapy, and decreased fever, cough, and sputum production. separation means in a different house or location, not simply separate rooms in a household. duration of separation should be individualized for each case in consultation with tb specialist. this assumes no evidence of breast involvement, suspected tb mastitis, or lesion (except in status , when breast involvement is considered). risk to infant is via aerosolized bacteria in sputum from the lung. expressed breast milk can be given even if separation of mother and infant is advised. tst positive, no symptoms or physical findings suggestive of tb, negative cxr film. prophylactic therapy: isoniazid mg/kg/day, maximum mg for months; pyridoxine to mg/day for months. empiric therapy: standard three-or four-drug regimens for months, and treatment should continue for total of months with isoniazid and rifampin when organism is shown to be sensitive. suspected multidrug-resistant (mdr) tb requires consultation with tb specialist to select optimum empiric regimen and for ongoing monitoring of therapy and clinical response. vaccine, the tst, and perhaps the m. tuberculosis bacillus. despite efforts to identify either a soluble substance or specific cell fractions (gamma/delta t cells) in colostrum and breast milk that affect infants' immune responsiveness, no unified theory explains the various reported changes and no evidence has identified a consistent, clinically significant effect. , , , viral infections arboviruses arboviruses were originally a large collection of viruses grouped together because of the common mode of transmission through arthropods. they have now been reclassified into several different families: bunyaviridae, togaviridae, flaviviridae, reoviridae, and others. they include more than human pathogens. these organisms primarily produce either cns infections (encephalitis, meningoencephalitis) or undifferentiated illnesses associated with fever and rash, severe hemorrhagic manifestations, and involvement of other organs (hepatitis, myalgia, polyarthritis). infection with this array of viruses may also be asymptomatic and subclinical, although how often this occurs is uncertain. some of the notable human pathogens include bunyaviridae (california serogroup viruses), hantavirus, hantaan virus, phlebovirus (rift valley fever), nairovirus (crimean-congo hemorrhagic fever), alphavirus (western, eastern, and venezuelan equine encephalomyelitis viruses, chikungunya virus), flavivirus (st. louis encephalitis virus, japanese encephalitis virus, dengue viruses, yellow fever virus, tick-borne encephalitis viruses), and orbivirus (colorado tick fever). other than for crimean-congo hemorrhagic fever and for reported cases of colorado tick fever associated with transfusion, direct person-to-person spread has rarely been described. recent outbreaks of chikungunya virus infection in reunion island and in india described infection in young infants probably secondary to vertical spread from mother to infant transplacentally. , , a few cases of early fetal deaths were associated with infection in pregnant women. the cases of vertical transmission occurred with near-term infection in the mothers, and the infants developed illness within to days of delivery. , no evidence for transmission via breast milk or breastfeeding is available. little evidence indicates that these organisms can be transmitted through breast milk. the exceptions to this include evidence of transmission of two flaviviruses via breast milk, west nile virus, and yellow fever vaccine virus. standard precautions are generally sufficient. with any of these infections in a breastfeeding mother, the severity of the illness may determine the mother' s ability to continue breastfeeding. providing the infant with expressed breast milk is acceptable. (see the discussion of west nile virus and yellow fever vaccine virus later in this chapter.) in general, treatment for these illnesses is supportive. however, ribavirin appears to decrease the severity of and mortality from hantavirus pulmonary syndrome, hemorrhagic fever with renal failure, and crimean-congo hemorrhagic fever. ribavirin has been described as teratogenic in various animal species and is contraindicated in pregnant women. no information is available concerning ribavirin in breast milk, with little information available on the use of iv or oral ribavirin in infants. arenaviruses are single-stranded ribonucleic acid (rna) viruses that infect rodents and are acquired by humans through the rodents. the six major human pathogens in this group are ( ) lymphocytic sensitivity testing should be done on any positive culture. isoniazid mg/kg/day for to months depending on mother's or contact's status; repeat tst at months and obtain normal cxr in infant before stopping isoniazid. before beginning therapy, workup of infant for congenital or active tb may be appropriate. this workup should be determined by clinical status of infant and suspected potential risk, and may include tst after weeks of age, with cxr, complete blood count, and erythrocyte sedimentation rate, liver function tests, cerebrospinal fluid analysis, gastric aspirates, sonography/computed tomography of liver/spleen, and chest if congenital tb is suspected. breastfeeding is proscribed when separation of mother and infant is indicated because of risk for aerosolized transmission of bacteria. expressed breast milk given to infant via bottle is acceptable in absence of mastitis or breast lesions. consult with tb specialist about mdr tb. empiric therapy will be chosen based on the most recent culture sensitivities of index patient or perhaps suspected source case, if known, as well as medication toxicities and other factors. tb mastitis usually involves a single breast with associated axillary lymph node swelling and, infrequently, a draining sinus tract. it can also present as a painless mass or edema of breast. with suspected mastitis or breast lesion caused by tb, even breast milk is contraindicated until lesion or mastitis heals, usually weeks or more. patient has a documented, recent tst conversion but has not been completely evaluated. evaluation should begin and cxr done and evaluated in less than hours to minimize separation of this person from infant. further workup should proceed as indicated by symptoms, physical findings, and cxr results. choriomeningitis virus, ( ) lassa fever virus, ( ) junin virus (argentine hemorrhagic fever), ( ) machupo virus (bolivian hemorrhagic fever), ( ) guanarito virus (venezuelan hemorrhagic fever), and ( ) sabia virus. the geographic distribution of these viruses and the illness they cause are determined by the living range of the host rodent (reservoir). the exact mechanism of transmission to humans is unknown and hotly debated. , , direct contact and aerosolization of rodent excretions and secretions are probable mechanisms. lymphocytic choriomeningitis virus is well recognized in europe, the americas, and other areas. perinatal maternal infection can lead to severe disease in the newborn, but no evidence suggests transmission through breast milk. , standard precautions with breastfeeding are appropriate. lassa fever (west africa) and argentine hemorrhagic fever (argentine pampas) are usually more severe illnesses with dramatic bleeding and involvement of other organs, including the brain. these fevers more frequently lead to shock and death than do the forms of hemorrhagic fever caused by the other viruses in this group. person-to-person spread of lassa fever is believed to be common, and transmission within households does occur. this may relate to prolonged viremia and excretion of the virus in the urine of humans for up to days. the possibility of persistent virus in human urine, semen, and blood after infection exists for each of the arenaviruses. the possibility of airborne transmission is undecided. current recommendations by the cdc are to use contact precautions for the duration of the illness in situations of suspected viral hemorrhagic fever. no substantial information describes the infectivity of various body fluids, including breast milk, for these different viral hemorrhagic fevers. considering the severity of the illness in mothers and the risk to the infants, it is reasonable to avoid breastfeeding in these situations if alternative forms of infant nutrition can be provided. as more information becomes available, reassessment of these recommendations is advisable. a vaccine is in clinical trials in endemic areas for junin virus and argentine hemorrhagic fever. preliminary studies suggest it is effective, but data are still being accumulated concerning the vaccine' s use in children and pregnant or breastfeeding women. cytomegalovirus (cmv) is one of the human herpesviruses. congenital infection of infants, postnatal infection of premature infants, and infection of immunodeficient individuals represent the most serious forms of this infection in children. the time at which the virus infects the fetus or infant and the presence or absence of antibodies against cmv from the mother are important determinants of the severity of infection and the likelihood of significant sequelae (congenital infection syndrome, deafness, chorioretinitis, abnormal neurodevelopment, learning disabilities). about % of all infants are born excreting cmv at birth, and approximately % of these congenitally infected infants will demonstrate evidence of infection at birth (approximately five symptomatic cases per , live births). approximately % of infants born after primary infection in a pregnant woman will manifest at least one sequela of prenatal infection. various studies have detected that % to % of pregnant women have cmv in cervical cultures and that % to % of pregnant women have cmv in their urine. , perinatal infection certainly occurs through contact with virus in these fluids but usually is not associated with clinical illness in fullterm infants. the lack of illness is thought to result from transplacental passive transfer of protective antibodies from the mother. postnatal infection later in infancy occurs via breastfeeding or contact with infected fluids (e.g., saliva, urine) but, again, rarely causes clinical illness in full-term infants. seroepidemiologic studies have documented transmission of infection in infancy, with higher rates of transmission occurring in daycare centers, especially when the prevalence of cmv in the urine and saliva is high. cmv has been identified in the milk of cmv-seropositive women at varying rates ( % to %) using viral cultures or cmv deoxyribonucleic acid (dna) pcr. , , , cmv is more often identified in the breast milk of seropositive mothers than in vaginal fluids, urine, and saliva. the cmv isolation rate from colostrum is lower than that from mature milk. , the reason for the large degree of variability in identification of cmv in breast milk in these studies probably relates to the intermittent nature of reactivation and excretion of the virus in addition to the variability, frequency, and duration of sampling of breast milk in the different studies. some authors have hypothesized that the difference in isolation rates between breast milk and other fluids is caused by viral reactivation in cells (leukocytes or monocytes) in the breast leading to "selective" excretion in breast milk. vochem et al reported that the rate of virolactia was greatest at to weeks postpartum, and yeager et al reported significant virolactia between and weeks postpartum. antibodies (e.g., secretory iga) to cmv are present in breast milk, along with various cytokines and other proteins (e.g., lactoferrin). these may influence virus binding to cells, but they do not prevent transmission of infection.* several studies have documented increased rates of postnatal cmv infection in breastfed infants ( % to %) compared with bottle-fed infants ( % to %) observed through the first year of life , , , in these same studies, full-term infants who acquired cmv infection postnatally were only rarely mildly symptomatic at the time of seroconversion or documented viral excretion. also, no evidence of late sequelae from cmv was found in these infants. postnatal exposure of susceptible infants to cmv, including premature infants without passively acquired maternal antibodies against cmv, infants born to cmv-seronegative mothers, and immunodeficient infants, can cause significant clinical illness (pneumonitis, hepatitis, thrombocytopenia).* in one study of premature infants followed up to months, vochem et al found cmv transmission in of infants ( %) exposed to cmv virolactia and breastfed compared with no infants infected of exposed to breast milk without cmv. no infant was given cmv-seropositive donor milk or blood. five of the infants who developed cmv infection after months of age had mild signs of illness, including transient neutropenia, and only one infant had a short increase in episodes of apnea and a period of thrombocytopenia. five other premature infants with cmv infection before months of age had acute illness, including sepsis-like symptoms, apnea with bradycardia, hepatitis, leukopenia, and prolonged thrombocytopenia. vollmer et al followed premature infants with early postnatal cmv infection acquired through breast milk for to . years to assess neurodevelopment and hearing function. none of the children had sensorineural hearing loss. there was no difference between the cmv-infected children and matched premature control cmv-negative infants in terms of neurologic, speech and language, or motor development. neuberger et al examined the symptoms and neonatal outcome of cmv infection transmitted via human milk in premature infants in a case-control fashion; cmv-infected premature infants were compared with cmv-negative matched premature infants. neutropenia, thrombocytopenia, and cholestasis were associated with cmv infection in these infants. no other serious effects or illnesses were found directly associated with the infection including intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, duration of mechanical ventilation or oxygen therapy, duration of hospital stay or weight, gestational age, or head circumference at the time of discharge. exposure of cmv-seronegative or premature infants to cmv-positive milk (donor or natural mother' s) should be avoided. various methods of inactivating cmv in breast milk have been reported, including holder pasteurization, freezing (− ° c for days), and brief high temperature ( ° c for seconds). , , , , one small, prospective study suggests that freezing breast milk at − °c for hours protects premature infants from cmv infection via breast milk. sharland et al reported on premature infants (less than weeks) who were uninfected at birth and exposed to breast milk from their cmv seropositive mothers. only one of ( %) infants became positive for cmv at days of life, and this infant was clinically asymptomatic. this transmission rate is considerably lower than others reported in the literature. cmvseronegative and leukocyte-depleted blood products were used routinely. banked breast milk was pasteurized and stored at − ° c for various time periods and maternal expressed breast milk was frozen at − ° c before use whenever possible. the infants received breast milk for a median of days (range to days) and they were observed for a median of days (range to days). breast milk samples pre-or postfreezing were not analyzed by pcr or culture for the presence of cytomegalovirus. buxmann et al demonstrated no transmission of cmv in premature infants receiving thawed frozen breast milk until weeks (gestational age + postnatal age) (less than or equal to weeks gestational age) born to mothers who were cmv-igg negative. cmv infection was found in five premature infants of infants born to mothers who were cmv-igg positive and who provided breast milk for their infants. three of the five children remained asymptomatic. one child development a respirator-dependent pneumonia and the second developed an upper respiratory tract infection and thrombocytopenia in association with their cmv infections. yasuda et al reported on preterm infants (median gestational age weeks) demonstrating a peak in cmv dna copies, detected by a real-time pcr assay, in breast milk at to weeks postpartum. thirty of the infants received cmv dna-positive breast milk. three of the had cmv dna detected in their sera, but none of the three had symptoms suggestive of cmv infection. much of the breast milk had been stored at − ° c before feeding, which the authors propose is the probable reason for less transmission in this cohort. lee et al reported on the use of maternal milk frozen at − °c for a minimum of hours before feeding to premature infants in a nicu; infants had cmv-seropositive mothers and infants had cmv-seronegative mothers. two infants developed cmv infection, which was symptomatic. they were both fed frozen thawed milk from cmv-seropositive mothers. others have reported individual cases of cmv infection in premature infants despite freezing and thawing breast milk. , simple freezing and thawing of breast milk does not completely prevent transmission of cmv to premature infants. the efficacy of freezing and thawing breast milk for varying lengths of time to prevent cmv infection in premature infants has not been studied prospectively in a randomized controlled trial. eleven of neonatal units in sweden ( of which have their own milk banks) freeze maternal milk to reduce the risk for cmv transmission to premature infants. a prominent group of neonatologists and pediatric infectious disease experts in california who recognize the significant benefits of providing human milk to premature and lbw infants recommend screening mothers of premature infants for cmv igg at delivery and, when an infant' s mother is cmv igg positive at delivery, using either pasteurized banked human milk or frozen then thawed maternal breast milk for premature infants until they reach the age of weeks. in consideration of the low rates of cmv virolactia in colostrum , and the predominant occurrence of virolactia between and weeks (peak at to weeks) postpartum, , they reasonably propose beginning colostrum and breast milk feedings for all infants until the maternal cmv serologic screening is complete. they appropriately recommend close observation and follow-up of premature infants older than weeks of age for signs, symptoms, and laboratory changes of cmv infection until discharge from the hospital. cmv-seropositive mothers can safely breastfeed their full-term infants because, despite a higher rate of cmv infection than in formula-fed infants observed through the first year of life, infection in this situation is not associated with significant clinical illness or sequelae. dengue viruses (serotypes dengue to ) are flaviviruses associated primarily with febrile illnesses and rash; dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. the mosquito aedes aegypti is the main vector of transmission of dengue virus in countries lying between latitudes degrees north and degrees south. more than . billion people live in areas where transmission occurs; dengue virus infects over million individuals a year and casuses approximately , deaths a year. , although dengue hemorrhagic fever and dengue shock syndrome occur frequently in children younger than year of age, they are infrequently described in infants younger than months of age. there are also differences in the clinical and laboratory findings of dengue virus infection in children compared with adults. boussemart et al reported on two cases of perinatal/prenatal transmission of dengue and discussed eight additional cases in neonates from the literature. prenatal or intrapartum transmission of the same type of dengue as the mother was confirmed by serology, culture, or pcr. phongsamart et al described three additional cases of dengue virus infection late in pregnancy and apparent transmission to two of the three infants with passive acquisition of antibody in the third infant. sirinavin et al reported on cases in the literature of vertical dengue infection, all presenting at less than weeks of age, but no observations or discussion of breast milk or breastfeeding as a potential source of infection were published. watanaveeradej et al presented an additional three cases of dengue infection in infants documenting normal growth and development at follow-up at months of age. it has been postulated that more severe disease associated with dengue disease occurs when an individual has specific igg against the same serotype as the infecting strain in a set concentration, leading to antibody-dependent enhancement of infection. the presence of preexisting dengue serotype specific igg in an infant implies either previous primary infection with the same serotype, passive acquisition of igg from the mother (who had a previous primary infection with the same serotype), or perhaps acquisition of specific igg from breast milk. watanaveeradej et al documented transplacentally transferred antibodies against all four serotypes of dengue virus in % of cord sera at delivery. follow-up of infants documented the loss of antibodies to dengue virus over time with losses of %, %, %, %, and % at , , , , and months of age, respectively. no evidence is available in the literature about more severe disease in breastfed infants compared with formula-fed infants. no interhuman transmission of dengue virus in the absence of the mosquito vector and no evidence of transmission via breast milk are known. only one report of a factor in the lipid portion of breast milk, which inhibits the dengue virus, is available, and no evidence for antibody activity against dengue virus in human breast milk is known. breastfeeding during maternal or infant dengue disease should continue as determined by the mother' s or infant' s severity of illness. epstein-barr virus (ebv) is a common infection in children, adolescents, and young adults. it is usually asymptomatic but most notably causes infectious mononucleosis and has been associated with chronic fatigue syndrome, burkitt lymphoma, and nasopharyngeal carcinoma. because ebv is one of the human herpesviruses, concern has been raised about lifelong latent infection and the potential risk for infection to a fetus and neonate from the mother. primary ebv infection during pregnancy is unusual because few pregnant women are susceptible. , although abortion, premature birth, and congenital infection from ebv are suspected, no distinct group of anomalies is linked to ebv infection in fetus or neonate. also, no virologic evidence of ebv as the cause of abnormalities was found in association with suspected ebv infection. culturing of ebv from various fluids or sites is difficult. the virus is detected by its capacity to transform b lymphocytes into persistent lymphoblastoid cell lines. pcr and dna hybridization studies have detected ebv in the cervix and in breast milk. one study, which identified ebv dna in breast milk cells in more than % of women donating milk to a breast milk bank, demonstrated that only % had antibody to ebv (only igg, no igm). another study examining serologic specimens from breastfed and bottle-fed infants showed similar seroprevalence of ebv at to months of age ( / [ . %] and / [ . %]) in the breastfed and bottle-fed children, respectively. the question of the timing of ebv infection and the subsequent immune response and clinical disease produced requires continued study. differences exist among the clinical syndromes that manifest at different ages. infants and young children are asymptomatic, have illness not recognized as related to ebv, or have mild episodes of illness, including fever, lymphadenopathy, rhinitis and cough, hepatosplenomegaly, or rash. adolescents or young adults who experience primary ebv infection more often demonstrate infectious mononucleosis syndrome or are asymptomatic. chronic fatigue syndrome is more common in adolescents and young adults. burkitt lymphoma, observed primarily in africa, and nasopharyngeal carcinoma, seen in southeast asia, where primary ebv infection usually occurs in young children, are tumors associated with early ebv infection. these tumors are related to "chronic" ebv infection and tend to occur in individuals with persistently high antibody titers to ebv viral capsid antigen and early antigen. the questions of why these tumors occur with much greater frequency in these geographic areas and what cofactors (including altered immune response to infection associated with coinfections, immune escape by ebv leading to malignancy, or increased resistance to apoptosis secondary to ebv gene mutations) may contribute to their development remain unanswered. , it also remains unknown to what degree breast milk could be a source of early ebv infection compared with other sources of ebv infection in an infant' s environment. similar to the situation of postnatal transmission of cmv in immunocompetent infants, clinically significant illness rarely is associated with primary ebv infection in infants. more data concerning the pathogenesis of ebv-associated tumors should be obtained before proscribing against breastfeeding is warranted, especially in areas where these tumors are common but the protective benefits of breastfeeding are high. in areas where burkitt lymphoma and nasopharyngeal carcinoma are uncommon, ebv infection in mother or infant is certainly not a contraindication to breastfeeding. marburg and ebola viruses cause severe and highly fatal hemorrhagic fevers. the illness often presents with nonspecific symptoms (conjunctivitis, frontal headache, malaise, myalgia, bradycardia) and progresses with worsening hemorrhage to shock and subsequent death in % to % of patients. personto-person transmission through direct contact, droplet spread, or airborne spread is the common mode of transmission. however, the animal reservoir or source of these viruses in nature for human infection has not been identified. attack rates in families are % to %. no postexposure interventions have proved useful in preventing spread, and no treatment other than supportive is currently available. a recent report documented the presence of ebola virus in numerous body fluids including in breast milk. one acute breast milk sample on day after the onset of illness and a "convalescent" breast milk sample on day from the same woman were positive for ebola virus by both culture and pcr testing. in the same study, saliva remained virus positive for a mean of days after disease onset, urine was positive for a mean of days, and semen for a mean of days after the onset of disease. no information is available concerning the risk for transmission of these viruses in breast milk or additional risks or benefits from breastfeeding. contact precautions are recommended for marburg virus infections and contact and airborne precautions for ebola virus infection. given the high attack and mortality rates, these precautions should be carefully instituted and breastfeeding not allowed. if any other suitable source of nutrition can be found for an infant, expressed breast milk should also be proscribed for the infant of a mother with either of these infections for at least weeks postrecovery. the diagnosis of hepatitis in a pregnant woman or nursing mother causes significant anxiety. the first issue is determining the etiology of the hepatitis, which then allows for an informed discussion of risk to the fetus/infant. the differential diagnosis of acute hepatitis includes ( ) common causes of hepatitis, such as hepatitis a, b, c, and d; ( ) , igm anti-hbcag, anti-hcv) as the initial diagnostic tests. simultaneous consideration of other etiologies of acute liver dysfunction is appropriate depending on a patient' s history. if the initial diagnostic tests are all negative, subsequent additional testing for anti-hepatitis d virus (hdv), hcv rna, hepatis g virus (hgv) rna, anti-hepatis e virus (hev), or hev rna may be necessary. if initial testing reveals positive hbsag, testing for anti-hdv, hbeag, and hbv dna is appropriate. these additional tests are useful in defining the prognosis for a mother and the risk for infection to an infant. during the diagnostic evaluation, it is appropriate to discuss with the mother or parents the theoretic risk for transmitting infectious agents that cause hepatitis via breastfeeding. the discussion should include an evaluation of the positive and negative effects of suspending or continuing breastfeeding until the exact etiologic diagnosis is determined. the relative risk for transmission of infection to an infant can be estimated and specific preventive measures provided for the infant (table - ) . hepatitis a virus (hav) is usually an acute selflimited infection. the illness is typically mild, and generally subclinical in infants. occasionally, hav infection is prolonged or relapsing, extending to months, and rarely it is fulminant, but hav infection does not lead to chronic infection. the incidence of prematurity after maternal hav infection is increased, but no evidence to date indicates obvious birth defects or a congenital syndrome. , hav infection in premature infants may lead to prolonged viral shedding. transmission is most often person to person (fecal-oral), and transmission in food-borne or water-borne epidemics has been described. transmission via blood products and vertical transmission (mother to infant) are rare. transmission in daycare settings has been clearly described. infection with hav in newborns is uncommon and does not seem to be a significant problem. the usual period of viral shedding and presumed contagiousness lasts to weeks. acute maternal hav infection in the last trimester or in the postpartum period could lead to infection in an infant. symptomatic infection can be prevented by immunoglobulin (ig) administration, and % to % of disease can be prevented by ig administration immune serum globulin within weeks of exposure. hav vaccine can be administered simultaneously with ig without affecting the seroconversion rate to produce rapid and prolonged hav serum antibody levels. transmission of hav via breast milk has been implicated in one case report, but no data exist on the frequency of isolating hav from breast milk. because hav infection in infancy is rare and usually subclinical without chronic disease and because exposure has already occurred by the time the etiologic diagnosis of hepatitis in a mother is made, no reason exists to interrupt breastfeeding with maternal hav infection. the infant should receive ig and hav vaccine, administered simultaneously. hepatitis b virus (hbv) infection leads to a broad spectrum of illness, including asymptomatic seroconversion, nonspecific symptoms (fever, malaise, fatigue), clinical hepatitis with or without jaundice, extrahepatic manifestations (arthritis, rash, renal involvement), fulminant hepatitis, and chronic hbv infection. chronic hbv infection occurs in up to % of infants infected via perinatal and vertical transmission and in % of children infected between to years of age. given the increased risk for significant sequelae from chronic infection (chronic active hepatitis, chronic persistent hepatitis, cirrhosis, primary hepatocellular carcinoma), prevention of hbv infection in infancy is crucial. transmission of hbv is usually through blood or body fluids (stool, semen, saliva, urine, cervical secretions). vertical transmission either transplacentally or perinatally during delivery has been well described throughout the world. vertical transmission rates in areas where hbv is endemic (taiwan and japan) are high, whereas transmission to infants from hbv carrier mothers in other areas where hbv carrier rates are low is uncommon. transmission of hbv to infants occurs in up to % of infants when the mothers are acutely infected immediately before, during, or soon after pregnancy. hbsag is found in breast milk, but transmission by this route is not well documented. beasley and beasley et al demonstrated that although breast milk transmission is possible, seroconversion rates are no different between breastfed and nonbreastfed infants in a long-term follow-up study of hbsag-positive mothers. hill et al followed breastfed infants and formula-fed infants born to women who were chronically hbsag positive. all infants received hepatitis b immunoglobulin at birth and a full series of hepatitis b vaccine. none of the breastfed infants and nine of the formulafed infants were positive for hbsag after completion of the hbv vaccine series. breastfeeding had occurred for a mean of . months (range weeks to year). transmission, when it does happen, probably occurs during labor and delivery. another report from china followed infants born to hbsag-positive women. the infants received appropriate dosing and timing of hbig and hbv vaccine. at year of age, anti-hbs antibody was present in . % of the breastfed infants and . % of the bottle-fed infants. risk factors associated with immunoprophylaxis failure against vertical transmission of hbv include hbeag-seropositive mothers and elevated hbv dna "viral loads" in the mothers. in the aap committee on infectious diseases stated that "that breastfeeding of the infant by a hbsag-positive mother poses no additional risk for acquisition of hbv infection by the infant with appropriate administration of hepatitis b vaccine and hbig." screening of all pregnant women for hbv infection is an essential first step to preventing vertical transmission. universal hbv vaccination at birth and during infancy, with administration of hepatitis b immunoglobulin (hbig) immediately after birth to infants of hbsag-positive mothers, prevents hbv transmission in more than % of cases. breastfeeding by hbsag-positive women is not contraindicated, but immediate administration of hbig and hbv vaccine should occur. two subsequent doses of vaccine should be given at appropriate intervals and dosages for the specific hbv vaccine product. this decreases the small theoretic risk for hbv transmission from breastfeeding to almost zero. when acute peripartum or postpartum hepatitis occurs in a mother and hbv infection is a possibility, with its associated increased risk for transmission to the infant, a discussion with the mother or parents should identify the potential risks and benefits of continuing breastfeeding until the etiology of the hepatitis can be determined. if an appropriate alternative source of nutrition is available for the infant, breast milk should be withheld until the etiology of the hepatitis is identified. hbig and hbv vaccine can be administered to the infant who has not already been immunized or has no documented immunity against hbv. if acute hbv infection is documented in a mother, breastfeeding can continue after immunization has begun. acute infection with hcv can be indistinguishable from hepatitis a or b infection; however, it is typically asymptomatic or mild. hcv infection is the major cause of blood-borne non-a, non-b hepatitis (nanbh). chronic hcv infection is reported to occur % to % of the time regardless of age at time of infection. sequelae of chronic hcv infection are similar to those associated with chronic hbv infection. bortolotti et al the two commonly identified mechanisms of transmission of hcv are transfusions of blood or blood products and iv drug use. however, other routes of transmission exist because hcv infection occurs even in the absence of obvious direct contact with significant amounts of blood. other body fluids contaminated with blood probably serve as sources of infection. transmission through sexual contact occurs infrequently and probably requires additional contributing factors, such as coinfection with other sexually transmitted agents or high viral loads in serum and other body fluids. studies of transmission in households without other risk factors have demonstrated either low rates of transmission or no transmission. the reported rates of vertical transmission vary widely. in mothers with unknown hiv status or known hiv infection, the rates of vertical transmission were % to %, whereas the rates varied between % and % in known hiv-negative mothers. these same studies suggest that maternal coinfection with hiv, hcv genotype, active maternal liver disease, and the serum titer of maternal hcv rna may be associated with increased rates of vertical transmission. , , the correlation between hcv viremia, the hcv viral load in a mother, and vertical transmission of hcv is well documented. , , , the clinical significance and risk for liver disease after vertical transmission of hcv are still unknown. the timing of hcv infection in vertical transmission is also unknown. in utero transmission has been suggested by some studies, whereas intrapartum or postpartum transmission was proposed by ohto et al when they documented the absence of hcv rna in the cord blood of neonates who later became hcv rna positive at to months of age. more recently, gibb et al reported two pieces of data supporting the likelihood of intrapartum transmission as the predominant time of vertical transmission: (a) low sensitivity of pcr for hcv rna testing in the first month of life with a marked increase in sensitivity after that for diagnosing hcv infection in infants and (b) a lower transmission risk for elective cesarean delivery (without prolonged rupture of membranes) compared with vaginal or emergency cesarean delivery. another group, mcmenamin et al, analyzed vertical transmission in mother-infant pairs. the overall vertical transmission rate was . % ( / ), with another infants not tested or lost to follow-up. comparison of the vertical transmission rate was no different for vaginal delivery or emergency cesarean in labor versus planned cesarean ( . % vs. . %). this held true even when mothers had hepatitis c rna detected antenatally ( . % vs. . %). the authors did not support planned cesarean delivery to decrease vertical transmission of hepatitis c infection. no prospective, controlled trials of cesarean versus vaginal delivery and the occurrence of vertical hepatitis c transmission are available. the risk for hcv transmission via breast milk is uncertain. anti-hcv antibody and hcv rna has been demonstrated in colostrum and breast milk, although the levels of hcv rna in milk did not correlate with the titers of hcv rna in serum. , , , nevertheless, transmission of hcv via breastfeeding (and not in utero, intrapartum, or from other postpartum sources) has not been proven in the small number infants studied. transmission rates in breastfed and nonbreastfed infants appear to be similar, but various important factors have not been controlled, such as hcv rna titers in mothers, examination of the milk for hcv rna, exclusive breastfeeding versus exclusive formula feeding versus partial breastfeeding, and duration of breastfeeding.* zanetti et al including infants whose mothers were seropositive for hcv rna. eight infants in that study were infected with hcv, their mothers had both hiv and hcv, and three of these eight infants were infected with both hiv and hcv. the hcv rna levels were significantly higher in the mothers coinfected with hiv compared with those mothers with hcv alone. overall, the risk for hcv infection via breastfeeding is low, the risk for hcv infection appears to be more frequent in association with hiv infection and higher levels of hcv rna in maternal serum, no effective preventive therapies (ig or vaccine) exist, and the risk for chronic hcv infection and subsequent sequelae with any infection is high. it is therefore appropriate to discuss the theoretic risk for breastfeeding in hcv-positive mothers with the mother or parents and to consider proscribing breast milk when appropriate alternative sources of nutrition are available for the infants. hiv infection is a separate contraindication to breastfeeding. additional study is necessary to determine the exact role of breastfeeding in the transmission of hcv, including the quantitative measurement of hcv rna in colostrum and breast milk, the relative risk for hcv transmission in exclusively or partially breastfed infants versus the risk in formulafed infants, and the effect of duration of breastfeeding on transmission. the current position of the cdc is that no data indicate that hcv virus is transmitted through breast milk. therefore breastfeeding by a hcvpositive, hiv-negative mother is not contraindicated. infants born to hcv rna-positive mothers require follow-up through to months of age to determine infants' hcv status, regardless of the mode of infant feeding. infants should be tested for alanine aminotransferase and hcv rna at months and to months of age. alanine aminotransferase and anti-hcv antibody should be tested at to months of age to confirm an infant' s status: uninfected, ongoing hepatitis c infection, or past hcv infection. hepatitis d virus (hdv) is a defective rna virus that causes hepatitis only in persons also infected with hbv. the infection occurs as either an acute coinfection of hbv and hdv or a superinfection of hbv carriers. this "double" infection results in more frequent fulminant hepatitis and chronic hepatitis, which can progress to cirrhosis. the virus uses its own hbv rna (circular, negative-strand rna) with an antigen, hdag, surrounded by the surface antigen of hbv, hbsag. hdv is transmitted in the same way as hbv, especially through the exchange of blood and body fluids. hdv infection is uncommon where the prevalence of hbv is low. in areas where hbv is endemic, the prevalence of hdv is highly variable. hdv is common in tropical africa and south america as well as in greece and italy but is uncommon in the far east and in alaskan inuit despite the endemic occurrence of hbv in these areas. transmission of hdv has been reported to occur from household contacts and, rarely, through vertical transmission. no data are available on transmission of hdv by breastfeeding. hdv infection can be prevented by blocking infection with hbv; therefore hbig and hbv vaccine are the best protection. in addition to hbig and hbv vaccine administration to the infant of a mother infected with both hbv and hdv, discussion with the mother or parents should include the theoretic risk for hbv and hdv transmission through breastfeeding. as with hbv, once hbig and hbv vaccine have been given to the infant, the risk for hbv or hdv infection from breastfeeding is negligible. therefore breastfeeding after an informed discussion with the parents is acceptable. hepatitis e virus (hev) is a cause of sporadic and epidemic, enterically transmitted nanbh, which is typically self-limited and without chronic sequelae. hev is notable for causing high mortality rate in pregnant women. transmission is primarily via the fecal-oral route, commonly via contaminated water or food. high infection rates have been reported in adolescents and young adults (ages to years). tomar reported that % of cases of hev infections in the pediatric population in india manifest as acute hepatitis. maternal-neonatal transmission was documented when the mother developed hepatitis e infection in the third trimester. although hev was demonstrated in breast milk, no transmission via breast milk was confirmed in the report. five cases of transfusion-associated hepatitis e were reported. epidemics are usually related to contamination of water. person-to-person spread is minimal, even in households and day care settings. although ig may be protective, no controlled trials have been done. animal studies suggest that a recombinant subunit vaccine may be feasible. hev infection in infancy is rare, and no data exist on transmission of hev by breastfeeding. no evidence of clinically significant postnatal hev infection in infants or of chronic sequelae in association with hev infection and no documented hev transmission through breast milk is available. currently no contraindication exists to breastfeeding with maternal hev infection. ig has not been shown to be effective in preventing infection, and no vaccine is available for hev. hepatitis g virus (hgv) has recently been confirmed as a cause of nanbh distinct from hepatitis viruses a through e. several closely related genomes of hgv, currently named gbv-a, -b, and -c, appear to be related to hcv, the pestiviruses, and the flaviviruses. epidemiologically, hgv is most often associated with transfusion of blood, although studies have identified nontransfusion-related cases. hgv genomic rna has been detected in some patients with acute and chronic hepatitis and a small number of patients with fulminant hepatitis. gbv-c/hgv has also been found in some patients with inflammatory bile duct lesions, but the pathogenicity of this virus is unconfirmed. hgv rna has been detected in % to % of healthy blood donors in the united states. feucht et al described maternal-to-infant transmission of hgv in three of nine children. two of the three mothers were coinfected with hiv and the third with hcv. none of these infants developed signs of liver disease. neither the timing nor the mode of transmission was clarified. lin et al reported no hgv transmission in three mother-infant pairs after cesarean delivery and discussed transplacental spread via blood as the most likely mode of hgv infection in vertical transmission. wejstal et al reported on perinatal transmission of hgv to of infants born to hgv viremic mothers, identified by pcr. hgv did not appear to cause hepatitis in the children. fischler et al followed eight children born to hgv-positive mothers and found only one to be infected with hgv. that child remained clinically well, while his twin, also born by cesarean delivery and breastfed, remained hgv negative for years of observation. five of the other six children were breastfed for variable periods without evidence of hgv infection. ohto et al examined hgv mother-to-infant transmission. of pregnant japanese women who were screened, were identified as positive for gbv-c/hgv rna by pcr; of infants born to the hgv positive women were shown to be hgv rna positive. reportedly, none of the infants demonstrated a clinical picture of hepatitis, although two infants had persistent mild elevations (less than two times normal) of alanine aminotransferase. the viral load in mothers, who transmitted hgv to their infants, was significantly higher than in nontransmitting mothers. infants born by elective cesarean delivery had a lower rate of infection ( in ) compared with infants born by emergency cesarean delivery ( of ) or born vaginally ( of ) . in this study, hgv infection in breastfed infants was four times more common than in formula-fed infants, but this difference was not statistically significant because only four infants were formula fed. the authors report no correlation between infection rate and duration of breastfeeding was seen. testing of the infants was not done frequently and early enough routinely through the first year of life to determine the timing of infection in these infants. schröter et al reported transmission of hgv to of infants born to hgv rna positive mothers at week of age. none of breast milk samples were positive for gbv-c/hgv rna, and all of the children who were initially negative for hgv rna in serum remained negative at follow-up between to months of age. the foregoing data suggest that transmission is more likely to be vertical, before, or at delivery rather than via breastfeeding. the pathogenicity and the possibility of chronic disease due to hgv infection remain uncertain at this time. insufficient data are available to make a recommendation concerning breastfeeding by hgv-infected mothers. herpes simplex virus types and (hsv- , hsv- ) can cause prenatal, perinatal, and postnatal infections in fetuses and infants. prenatal infection can lead to abortion, prematurity, or a recognized congenital syndrome. perinatal infection is the most common form of infection ( in to live births, to cases per year in the united states) and is often fatal or severely debilitating. the factors that facilitate intrapartum infection and predict the severity of disease have been extensively investigated. postnatal infection is uncommon but can occur from a variety of sources, including oral or genital lesions and secretions in mothers or fathers, hospital workers and home caregivers, and breast lesions in breastfeeding mothers. a number of case reports have documented severe hsv- or hsv- infections in infants associated with hsvpositive breast lesions in the mothers. , , , cases of infants with hsv gingivostomatitis inoculating the mothers' breasts have also been reported. in the absence of breast lesions breastfeeding in hsv-seropositive or culture-positive women is reasonable when accompanied by careful handwashing, covering the lesions, and avoiding fondling or kissing with oral lesions until all lesions are crusted. breastfeeding during maternal therapy with oral or iv acyclovir can continue safely as well. inadequate information exists concerning valacyclovir, famciclovir, ganciclovir, and foscarnet in breast milk to make a recommendation at this time. breastfeeding by women with active herpetic lesions on their breasts should be proscribed until the lesions are dried. treatment of the mothers' breast lesions with topical, oral, and/or iv antiviral preparations may hasten recovery and decrease the length of viral shedding. human herpesvirus (hhv- ) is a cause of exanthema subitum (roseola, roseola infantum) and is associated with febrile seizures. hhv- appears to be most similar to cmv based on genetic analysis. no obvious congenital syndrome of hhv- infection has been identified, although prenatal infection has been reported. seroepidemiologic studies show that most adults have already been infected by hhv- . therefore primary infection during pregnancy is unlikely, but reactivation of latent hhv- infection may be more common. no case of symptomatic hhv- prenatal infection has been reported. the significance of reactivation of hhv- in a pregnant woman and the production of infection and disease in the fetus and infant remains to be determined. primary infection in children occurs most often between and months of age, when maternally acquired passive antibodies against hhv- are waning. febrile illnesses in infants younger than months of age have been described with hhv- infection, but infection before months or after years is uncommon. various studies involving serology and restriction enzyme analysis of hhv- isolates from mother/infant pairs support the idea that postnatal transmission and perhaps perinatal transmission from the mothers are common sources of infection. one study was unable to detect hhv- in breast milk by pcr analysis in samples, although positive control samples seeded with hhv- -infected cells did test positive. given the limited occurrence of clinically significant disease and the absence of sequelae of hhv- infection in infants and children, the almost universal acquisition of infection in early childhood (with or without breastfeeding) and the absence of evidence that breast milk is a source of hhv- infection, breastfeeding can continue in women known to be seropositive for hhv- . human herpesvirus (hhv- ) is closely related to hhv- biologically. primary infection with hhv- occurs primarily in childhood, usually later in life than hhv- infection. the median age of infection is months, with % of children becoming hhv- positive by years of age. seroprevalence of hhv- antibody has been reported to be % to % in adults, and passive antibody is present in almost all newborns. , like hhv- , hhv- infection can be associated with acute febrile illness, febrile seizures, and irritability, but in general it is a milder illness than with hhv- with fewer hospitalizations. virus excretion of hhv- occurs in saliva, and pcr testing of blood cells and saliva are frequently positive in individuals with past infection. congenital infection of hhv- was detected via dna pcr testing in of of cord blood samples ( %), but hhv- was not detected in any of cord blood specimens. hhv- dna was detected by pcr in of breast milk mononuclear cell samples from women who were serum positive for hhv- antibody. in the same study, small differences were seen in the hhv- seropositive rates between breastfed infants and bottle-fed infants at months of age ( . % versus %), at months of age ( % versus . %), and at months of age ( . % versus . %, respectively,). none of these differences were statistically significant. given that, in general, hhv- infection occurs earlier than hhv- infection in most infants and that hhv- is rarely found in breast milk, it seems unlikely that hhv- in breast milk is a common source of infection in infants and children. the infrequent occurrence of significant illness with hhv- infection, with the absence of sequelae except in patients who had transplantation surgery at older ages and the common occurrence of infection in childhood argue, that no reason to proscribe against breastfeeding for hhv- positive women exists. human papillomavirus (hpv) is a dna virus with at least different types. these viruses cause warts, genital dysplasia, cervical carcinoma (types and ), and laryngeal papillomatosis. transmission occurs through direct contact and sexual contact. laryngeal papillomas are thought to result from acquiring the virus in passage through the birth canal. infection in pregnant women or during pregnancy does not lead to an increase in abortions or the risk for prematurity, and no evidence indicates intrauterine infection. hpv is one of the most common viruses in adults and one of the most commonly sexually transmitted infections. diagnosis is usually by histologic examination or dna detection. spontaneous resolution does occur, but therapy for persistent lesions or growths in anatomically problematic locations is appropriate. therapy can be with podophyllum preparations, trichloroacetic acid, cryotherapy, electrocautery, and laser surgery. interferon is being tested in the treatment of laryngeal papillomas, with mixed results. prevention against transmission means limiting direct or sexual contact, but this may not be sufficient because lesions may not be evident and transmission may still occur. rintala et al examined the occurrence of hpv dna in the oral and genital mucosa of infants during the first years of life. hpv dna was identified in % to % of the oral scrape samples and in % to % of the genital scrape samples by pcr. oral hpv infection was acquired by % of children, cleared by %, and persisted in % of children; % of the children were never infected. they did not report on breast milk or breastfeeding in that study. the question of the source of the infection remains undetermined. the breast is a rare site of involvement. hpv types and can immortalize normal breast epithelium in vitro. hpv dna has been detected in breast milk in of ( . %) of milk samples from mothers, collected days postpartum. no attempt was made to correlate the presence of hpv dna in breast milk with the hpv status of an infant or to assess the "viral load" of hpv in breast milk or its presence over the course of lactation. a second study found dna of cutaneous and mucosal hpv types in of human milk samples and of colostrum samples. no reports of hpv lesions of the breast or nipple and documented transmission to an infant secondary to breastfeeding are available. no increased risk for acquiring hpv from breast milk is apparent, and breastfeeding is acceptable. even in the rare occurrence of an hpv lesion of the nipple or breast, no data suggest that breastfeeding or the use of expressed breast milk is contraindicated. measles is another highly communicable childhood illness that can be more severe in neonates and adults. measles is an exanthematous febrile illness following a prodrome of malaise, coryza, conjunctivitis, cough, and often koplik spots in the mouth. the rash usually appears to days after exposure. complications can include pneumonitis, encephalitis, and bacterial superinfection. with the availability of vaccination, measles in pregnancy is rare ( . in , pregnancies), although respiratory complications (primary viral pneumonitis, secondary bacterial pneumonia), hepatitis, or other secondary bacterial infections often lead to more severe disease in these situations. prenatal infection with measles may cause premature delivery without disrupting normal uterine development. no specific group of congenital malformations have been described in association with in utero measles infection, although teratogenic effects of measles infection in pregnant women may rarely manifest in the infants. perinatal measles includes transplacental infection when measles occurs in an infant in the first days of life. infection from extrauterine exposure usually develops after days of life. the severity of illness after suspected transplacental spread of virus to an infant varies from mild to severe and does not seem to vary with the antepartum or postpartum onset of rash in the mother. it is uncertain what role maternal antibodies play in the severity of an infant's disease. more severe disease seems to be associated with severe respiratory illness and bacterial infection. postnatal exposure leading to measles after days of life is generally mild, probably because of passively acquired antibodies from the mother. severe measles in children younger than year of age may occur because of declining passively acquired antibodies and complications of respiratory illness and rare cases of encephalitis. measles virus has not been identified in breast milk, whereas measles-specific antibodies have been documented. infants exposed to mothers with documented measles while breastfeeding should be given immunoglobulin (ig) and isolated from the mother until hours after the onset of rash, which is often only a short period after diagnosis of measles in the mother. the breast milk can be pumped and given to the infant because secretory iga begins to be secreted in breast milk within hours of onset of the exanthem in the mother. table - summarizes management of the hospitalized mother and infant with measles exposure or infection. mumps is an acute transient benign illness with inflammation of the parotid gland and other salivary glands and often involves the pancreas, testicles, and meninges. mumps occurs infrequently in pregnant women ( to cases in , pregnancies) and is generally benign. mumps virus has been isolated from saliva, respiratory secretions, blood, testicular tissue, urine, csf in cases of meningeal involvement, and breast milk. the period of infectivity is believed to be between days before and days after the onset of parotitis, with the usual incubation period being to days. prenatal infection with the mumps virus causes an increase in the number of abortions when infection occurs in the first trimester. a small increase in the number of premature births was noted in one prospective study of maternal mumps infection. no conclusive evidence suggests congenital malformations are associated with prenatal infection, not even with endocardial fibroelastosis, as originally reported in the s. perinatal mumps (transplacentally or postnatally acquired) has rarely if ever been documented. natural mumps virus has been demonstrated to infect the placenta and infect the fetus, and live attenuated vaccine virus has been isolated from the placenta but not from fetal tissue in women vaccinated days before induced abortion. antibodies to mumps do cross the placenta. postnatal mumps in the first year of life is typically benign. no epidemiologic data suggest that mumps infection is more or less common or severe in breastfed infants compared with formula-fed infants. although mumps virus has been identified in breast milk and mastitis is a rare complication of mumps in mature women, no evidence indicates that breast involvement occurs more frequently in lactating women. if mumps occurs in the mother breastfeeding can continue because exposure has already occurred throughout the days before the development of symptoms in the mother and secretory iga in the milk may help to mitigate the symptoms in the infant. human parvovirus b causes a broad range of clinical manifestations, including asymptomatic infection (most frequent manifestation in all ages), erythema infectiosum (fifth disease), arthralgia and arthritis, red blood cell (rbc) aplasia (less often decreased white blood cells or platelets), chronic infection in immunodeficient individuals, and rarely myocarditis, vasculitis, or hemophagocytic syndrome. vertical transmission can lead to severe anemia and immune-mediated hydrops fetalis, which can be treated, if accurately diagnosed, by intrauterine transfusion. inflammation of the liver or cns can be seen in the infant, along with vasculitis. if the child is clinically well at birth, hidden or persistent abnormalities are rarely identified. no evidence indicates that parvovirus b causes an identified pattern of birth defects. postnatal transmission usually occurs person to person via contact with respiratory secretions, saliva, and rarely blood or urine. seroprevalence in children at years of age is less than %, with the peak age of infection occurring during the schoolage years ( % to % of children infected). the majority of infections are asymptomatic or undiagnosed seroconversions. severe disease, such as prolonged aplastic anemia, occurs in individuals with hemoglobinopathies or abnormal rbc maturation. attack rates have been estimated to be % to % in casual contacts but up to % among household contacts. in one study of susceptible pregnant women, the annual seroconversion rate was . %. no reports of transmission to an infant through breastfeeding are available. excretion in breast milk has not been studied because of limitations in culturing techniques. rat parvovirus has been demonstrated in rat milk. the very low seroconversion rate in young children and the absence of chronic or frequent severe disease suggest that the risk for parvovirus infection via breast milk is not significant. the possibility of antibodies against parvovirus or other protective constituents in breast milk has not been studied. breastfeeding by a mother with parvovirus infection is acceptable. poliovirus infections (types , , and ) cause a range of illness, with % to % subclinical, % to % abortive, and % to % manifest as paralytic poliomyelitis. a review by bates from of cases of poliomyelitis in infants younger than month of age demonstrated paralysis or death in more than % and only one child without evidence of even transient paralysis. more than half the cases were ascribed to transmission from the mothers, although no mention was made of breastfeeding. breastfeeding rates at the time were approximately %. prenatal infection with polioviruses does cause an increased incidence of abortion. prematurity and stillbirth apparently occur more frequently in mothers who developed paralytic disease versus inapparent infection. although individual reports of congenital malformations in association with maternal poliomyelitis exist, no epidemiologic data suggest that polioviruses are teratogenic. also, no evidence indicates that live attenuated vaccine poliovirus given during pregnancy is associated with congenital malformations. , perinatal infection has been noted in several case reports of infants infected in utero several days before birth who had severe disease manifesting with neurologic manifestations (paralysis) but without fever, irritability, or vomiting. additional case reports of infection acquired postnatally demonstrate illness more consistent with poliomyelitis of childhood. these cases were more severe and involved paralysis, which may represent reporting bias. no data are available concerning the presence of poliovirus in breast milk, although antibodies to poliovirus types , , and have been documented. in this era of increasing worldwide poliovirus vaccination, the likelihood of prenatal or perinatal poliovirus infection is decreasing. maternal susceptibility to poliovirus should be determined before conception and poliovirus vaccine offered to susceptible women. an analysis of the last great epidemic in italy in was done using a population-based case-control study. in , births, infants were reported with paralytic poliomyelitis. a group of matched control subjects was selected from infants admitted to the hospital at the same time. using the dichotomous variable of never breastfed and partially breastfed, never-breastfed infants were among the cases and among the control group. the authors determined an odds ratio of . , with % confidence interval of . to , demonstrating that the risk for paralytic poliomyelitis was higher in infants never breastfed and lowest among those exclusively breastfed. because by the time the diagnosis of poliomyelitis is made in a breastfeeding mother, the exposure of the infant to poliovirus from maternal secretions has already occurred, and because the breast milk already contains antibodies that may be protective, no reason exists to interrupt breastfeeding. breastfeeding also does not interfere with successful immunization against poliomyelitis with oral or inactivated poliovirus vaccine. the occurrence of human t-cell leukemia virus type i (htlv-i) is endemic in parts of southwestern japan, , , , the caribbean, south america, and sub-saharan africa. htlv-i is associated with adult t-cell leukemia/lymphoma and a chronic condition with progressive neuropathy. the progressive neuropathy is called htlv-i associated myelopathy or tropical spastic paraparesis. other illnesses have been reported in association with htlv-i infection including dermatitis, uveitis, arthritis, sjögren syndrome in adults, and infective dermatitis and persistent lymphadenitis in children. transmission of htlv-i occurs most often through sexual contact, via blood or blood products, and via breast milk. infrequent transmission does occur in utero or at delivery and with casual or household contact. seroprevalence generally increases with age and varies widely in different regions and in populations of different backgrounds. in some areas of japan, seropositivity can be as high as % to %, but in south america, africa, and some caribbean countries the rates are % to %. in latin america seropositive rates can be as high as % to % among female sex workers or attendees to std clinics. in blood donors in europe, the seroprevalence of htlv-i has been reported at . % to . %. the seroprevalence in pregnant women in endemic areas of japan is as high as % to % and in nonendemic areas as low as . % to . %. htlv- is not a major disease in the united states. in studies from europe the seroprevalence in pregnant women has been noted to be up to . %. these pregnant women were primarily of african or caribbean descent. htlv-i antigen has been identified in breast milk of htlv-i positive mothers. another report shows that basal mammary epithelial cells can be infected with htlv-i and can transfer infection to peripheral blood monocytes. human milk from htlv-i positive mothers caused infection in marmosets. , htlv-i infection clearly occurs via breastfeeding and a number of reports document an increased rate of transmission of htlv-i to breastfed infants compared with formula-fed infants.* ando et al , in two separate reports demonstrated a parallel decline in antibodies against htlv-i in both formula-fed and breastfed infants to a nadir at approximately year of age and a subsequent increase in antibodies from to years of age. the percentage of children seropositive at year of age in the breastfed and formula-fed groups, respectively, was . % and . %, at . years of age it was . % and . %, and at years of age it was . % and . %. a smaller group of children followed through to years of age demonstrated no newly infected children after years of age and *references , , , , - , . no loss of antibody in any child who was seropositive at years of age. , transmission of htlv-i infection via breastfeeding is also clearly associated with the duration of breastfeeding. , , , it has been postulated that the persistence of passively acquired antibodies against htlv-i offers some protection through months of life (table - ) . other factors relating to htlv-i transmission via breast milk have been proposed. yoshinaga et al presented data on the htlv-i antigen producing capacity of peripheral blood and breast milk cells and showed an increased mother-to-child transmission rate when the mother' s blood and breast milk produced large numbers of antigen-producing cells in culture. hisada et al reported on mothers and infants in jamaica, demonstrating that a higher maternal provirus level and a higher htlv-i antibody titer were independently associated with htlv-i transmission to the infant. ureta-vidal et al reported an increased seropositivity rate in children of mothers with a high proviral load and elevated maternal htlv-i antibody titers. various interventions have been proposed to decrease htlv-i transmission via breastfeeding. complete avoidance of breastfeeding was shown to be an effective intervention by hino et al , in large population of japanese in nagasaki. avoiding breastfeeding led to an % decrease in transmission. breastfeeding for a shorter duration is another effective alternative. ando et al showed that freezing and thawing breast milk decreased the infectivity of htlv-i. sawada et al demonstrated in a rabbit model that htlv-i immunoglobulin protected against htlv-i transmission via milk. it is reasonable to postulate that any measure that would decrease the maternal provirus load or increase the anti-htlv-i antibodies available to infants might decrease the risk for transmission. the overall prevalence of htlv-i infection during childhood is unknown because the majority of individuals do not manifest illness until much later in life. the timing of htlv-i infection in a breastfeeding population has been difficult to assess because of passively acquired antibodies from the mother and issues related to testing. furnia et al in areas where the prevalence of htlv-i infection (in the united states, canada, or europe) is rare, the likelihood that a single test for antibody against htlv-i would be a false positive test is high compared with the number of true positive tests. repeat testing is warranted in many situations. quantification of the antibody titer and the proviral load is appropriate in a situation when mother-to-child transmission is a concern. a greater risk for progression to disease in later life has not been shown for htlv-i infection through breast milk, but early-life infections are associated with the greatest risk for adult t-cell leukemia. the mother and family should be informed about all these issues. if the risk for lack of breast milk is not too great and formula is readily available and culturally acceptable, then the proscription of breastfeeding, or at least a recommendation to limit the duration of breastfeeding to months or less, is appropriate to limit the risk for htlv-i transmission to the infant. freezing and thawing breast milk before giving it to an infant might be another reasonable intervention to decrease the risk for transmission, although no controlled trials document the efficacy of such an intervention. neither ig nor antiviral agents against htlv-i are available at this time. human t-cell leukemia virus type ii (htlv-ii) is endemic in specific geographic locations, including africa, the americas, the caribbean, and japan. transmission is primarily through intravenous drug use, contaminated blood products, and breastfeeding. sexual transmission occurs but its overall contribution to the prevalence of htlv-ii in different populations remains uncertain. many studies have examined the presence of htlv-i and ii in blood products. pcr testing and selective antibody tests suggest that about half of the htlv seropositivity in blood donors is caused by htlv-ii. htlv-ii has been associated with two chronic neurologic disorders similar to those caused by htlv-i, tropical or spastic ataxia. a connection between htlv-ii and glomerulonephritis, myelopathy, arthritis, t-hairy cell leukemia, and large granulocytic leukemia has been reported. mother-to-child transmission has been demonstrated in both breastfed and formula-fed infants. it appears that the rate of transmission is greater in breastfed infants.* htlv-ii has been detected in breast milk. nyambi et al reported that htlv-ii transmission did correlate with the duration of breastfeeding. the estimated rate of transmission was %. the time to seroconversion (after the initial loss of passively acquired maternal antibodies) for infected infants seemed to range between and years of age. at this time avoidance of breastfeeding and limiting the duration of breastfeeding are the only two possible interventions with evidence of effectiveness for preventing htlv-ii mother-to-child transmission. with the current understanding of retroviruses, it is appropriate in cases of documented htlv-ii maternal infection to recommend avoiding or limiting the duration of breastfeeding and provide alternative nutrition when financially practical and culturally acceptable. mothers should have confirmatory testing for htlv-ii and measurement of the proviral load. infants should be serially tested for antibodies to htlv-ii and have confirmatory testing if seropositive after to months of age. further investigation into the mechanisms of transmission via breast milk and possible interventions to prevent transmission should occur as they have for hiv- and htlv-i. human immunodeficiency virus type (hiv- ) is transmitted through human milk. refraining from breastfeeding is a crucial aspect of preventing perinatal hiv infection in the united states and many other countries. the dilemma is the use of replacement feeding versus breastfeeding in countries where breastfeeding provides infants with significant protection from illness and death due to malnutrition or other infections. the question of the contribution of breastfeeding in mother-to-child hiv- transmission is not a trivial one when one considers the following: . the who estimates that . million people were newly infected with hiv- in , with children younger than years old making up , of that . million. (this number has declined due to increasing access to interventions to prevent mother-to-infant transmission. availability of antiretroviral therapy for prevention of mother-to-child hiv transmission in developing countries in was estimated to reach % of the mothers who needed it.) . breastfeeding contributes an estimated % to % increase in the overall mother-to-child transmission rates, over and above intrauterine and intrapartum transmission, when no specific interventions to prevent transmission via breastfeeding are utilized. . despite a dramatic increase in the number of people receiving antiretroviral therapy in developing countries ( million), this represented only % of the individuals who needed treatment. the evidence of hiv transmission via breastfeeding is irrefutable. multiple publications summarize the current evidence for hiv transmission via breastfeeding in the literature. , , since , case reports have documented hiv transmission via breast milk to children around the world. , , , primary hiv infection in breastfeeding mothers, with the concomitant high viral load, is associated with a particularly high rate of hiv transmission via breast milk. palasanthiran et al estimated that risk at %.large observational studies have demonstrated higher rates of hiv transmission in breastfed infants of mothers with chronic hiv infection compared with formula-fed infants. , , a systematic analysis of published reports estimated the additional risk for perinatal hiv transmission due to breastfeeding to be % ( % confidence interval % to %). more recently published cohort studies similarly attributed additional risk for hiv transmission due to breastfeeding at % to % over and above the risk from prenatal and intrapartum transmission. , , laboratory reports demonstrate the presence of cell-free virus and cell-associated virus in breast milk as well as various immunologic factors that could block or limit infection.* a dose-response relationship has been observed, correlating the hiv viral load in human milk as well as a mother' s plasma viral load with an increased transmission risk for the breastfed infant. , , , many of the potential risk factors associated with human milk transmission of hiv is higher the longer the duration of breastfeeding. , , , , maternal characteristics related to transmission of hiv via human milk include younger maternal age, higher parity, lower cd + counts, higher plasma viral loads, and breast abnormalities (mastitis, abscess, or nipple lesions). characteristics of human milk that relate to a higher risk for transmission include higher viral load in the milk, lower concentrations of antiviral substances (lactoferrin, lysozyme), and lower concentrations of virus-specific cytotoxic t-lymphocytes, levels of various interleukins (il- , il- ), , secretory iga, and igm. mixed breastfeeding is also associated with a higher risk for hiv transmission compared with exclusive breastfeeding. , , the measurable benefits of breast milk versus the relative risk for hiv transmission to the infant due to exclusive breastfeeding (with optimization of other factors to decrease hiv transmission) have been reported in a couple of studies. , the measurable benefits of receiving breast milk versus the relative increased risk for hiv transmission will need to be determined in a prospective fashion in different locales. a number of potential interventions to prevent breastfeeding transmission of hiv- can be utilized (box - ) . the simplest and most effective is the compete avoidance of human milk. this is a practical solution in places like the united states and other countries where replacement feeding as well as other strictly medical interventions are feasible and reasonable, and the risk for not providing breast milk to the infant is negligible. in resourcepoor situations, where the risk for other infections is high without the benefits of breast milk, exclusive breastfeeding is appropriate, with any other reasonable and culturally acceptable interventions to decrease hiv transmission via breast milk. potentially effective interventions include exclusive breastfeeding, early weaning versus breastfeeding for longer durations, education, and support to decrease the likelihood of mastitis or nipple lesions. other possible interventions include treating a mother with antiretroviral therapy for her own health (cd counts less than ) or prophylactically to decrease the human milk viral load, treating an infant prophylactically for a prolonged period of time ( weeks to months) to protect against transmission via breastfeeding, treating the milk itself to decrease the viral load (by pasteurization or other methods), , treating acute conditions in mothers and infants (e.g., mastitis, breast lesions, infant candidiasis), and enhancing an infant' s own defenses via vitamins, immunization, or antiretroviral therapy. some of these may not be feasible in certain settings such as pasteurization or maternal antiretroviral therapy. others may not be culturally acceptable, such as treating expressed breast milk before giving it to an infant or even exclusive breastfeeding. significant data demonstrate the advantage of breastfeeding, even for hiv-infected or hivexposed infants. the complete avoidance of breastfeeding in certain situations may lead to increased risk for illness and death due to other reasons besides hiv transmission. a study from kenya showed improved hiv- -free survival rates in a formula-fed group of children born to hiv-positive mothers, but the breastfed and formula groups had similar mortality rates ( . % versus . %, respectively) and similar incidences of diarrhea and pneumonia in the first years of life. no difference in the two groups was seen in the prevalence of malnutrition, but the breastfed infants had better nutritional status in the first months of life. arpadi et al recommend additional nutritional interventions to complement breastfeeding in this population after months of age. two reports from zambia document the benefit of exclusive breastfeeding for decreasing late hiv transmission and the lower mortality at months in infants who had continued breastfeeding rather than had discontinued breastfeeding at months of age. , in malawi, hiv-infected and hiv-exposed infants who were breastfed (exclusive breastfeeding for months and mixed feeding after that) had lower mortality at months than those who were not breastfed. a report from botswana examined breastfeeding plus infant zidovudine prophylaxis for months versus formula feeding plus infant zidovudine for month; this study showed a decreased risk for vertical transmission with formula feeding, but also increased cumulative mortality for the hiv-infected infants at months of age who were in the formula-fed group. a study from south africa examining the use of vitamin a also demonstrated less morbidity in hiv-infected children who were breastfed than not breastfed. other abstract reports have shown increased morbidity in hiv-infected children due to diarrhea, gastroenteritis, and hospitalization after weaning from breastfeeding. , , , exclusive breastfeeding in most areas of the world is essential to infant health and survival, even in the situation of maternal hiv infection. , , , the duration of exclusive breastfeeding is crucial to decreasing the risk for hiv infection in infants versus the risk for malnutrition and other infections with early weaning. in the mashi study in botswana, thior et al evaluated infants randomized to breastfeeding plus infant zidovudine for months or formula feeding plus month of infant zidovudine. the cumulative infant mortality was significantly higher at months for the formula-fed group but at months it was similar between the two groups. the breastfed infants were more likely to become hiv infected despite the months of zidovudine prophylaxis. becquet et al analyzed data from cote d'ivoire for to ; % of the hivexposed infants were breastfed for a median of months, and % were formula fed and observed for years. no significant difference in the rate of hiv infection was seen in the two groups, and no significant difference between the two groups was seen for morbid events (diarrhea, acute respiratory infections or malnutrition) or hospitalization or death. the authors attributed these good outcomes to effective nutritional counseling and care, access to clean water, and the provision of a safe and continuous supply of breast milk substitute. coovadia et al studied exclusive breastfeeding in the first months of life as an intervention in south africa. of the exclusively breastfed infants, . % at weeks of age and . % at months of age were hiv infected. breastfed infants who also were fed solids or formula milk were more likely to acquire infection than exclusively breastfed infants. the cumulative mortality at months of age was markedly lower for exclusively breastfed infants ( . %) versus . % in the infants receiving mixed feedings. kuhn et al examined the effects of early, abrupt weaning on hiv-free survival of children in zambia. infants were randomly assigned to two different counseling programs that advised either abrupt weaning at months or prolonged breastfeeding. in the weaning intervention group, % of mothers stopped breastfeeding by months compared with a median duration of breastfeeding of months in the control group. the study found no significant difference in hiv-free survival at • women and their health care providers need to be aware of the potential risk for transmission of hiv infection to infants during pregnancy and in the peripartum period and through breast milk. • documented, routine hiv education and routine testing with the consent of women seeking prenatal care are strongly recommended so that each woman knows her hiv status and the methods available both to prevent the acquisition and transmission of hiv and to determine whether breastfeeding is appropriate. • at delivery, education about hiv and testing with the consent of women whose hiv status during pregnancy is unknown are strongly recommended. knowledge of a woman' s hiv status assists in counseling on breastfeeding and helps each woman understand the benefits to herself and her infant of knowing her serostatus and the behaviors that would decrease the likelihood of acquisition and transmission of hiv. • women who are known to have hiv infections must be counseled not to breastfeed or provide their milk for the nutrition of their own or other' s infants. • in general, women who are known to be hiv seronegative should be encouraged to breastfeed. however, women who are hiv seronegative but at particularly high risk for seroconversion (e.g., injection drug users and sexual partners of known hiv-positive persons or active drug users) should be educated about hiv with an individualized recommendation concerning the appropriateness of breastfeeding. in addition, during the perinatal period, information should be provided on the potential risk for transmitting hiv through breast milk and about methods to reduce the risk for acquiring hiv infection. • each woman whose hiv status is unknown should be informed of the potential for hiv-infected women to transmit hiv during the peripartum period and through breast milk and the potential benefits to her and her infant of knowing her hiv status and how hiv is acquired and transmitted. the health care provider needs to make an individualized recommendation to assist the woman in deciding whether to breastfeed. months in the two groups ( . % versus . %). children already infected by months of age had a higher mortality if they were assigned to the early weaning group ( . % versus . %). additional analysis showed that in mothers with less severe hiv disease early weaning was clearly harmful to the infant. arpadi et al studied the growth of hiv-exposed, uninfected children who were exclusively breastfed for months with rapid weaning to replacement foods or exclusively breastfed until months and then continued breastfeeding with complementary foods. weight-for-age z scores dropped markedly in both groups from to months of age but less so in the continued breastfeeding group. length-for-age z score also dropped dramatically, but was not influenced by continued breastfeeding. even in this hiv-exposed, uninfected group of children, additional nutritional interventions are essential to complement breastfeeding beyond months of age. in recent years the discussion around preventing hiv transmission via breastfeeding and in the number of studies examining the important issues have increased. , , the fact that intrapartum and perinatal transmission of hiv from mothers to infants has decreased markedly due to the increased utilization of antiretroviral therapy during pregnancy, delivery, and postnatally for prevention emphasizes the importance of now working harder to decrease breast milk transmission of hiv. in considering different possible interventions to decrease mother-infant hiv transmission, it is crucial to reemphasize the goals of optimizing maternal health and survival and optimizing infant health and survival at the same time. a laboratory report shows that mothers receiving highly active antiretroviral therapy (haart) while breastfeeding do have decreased whole breast milk hiv- viral loads ( / mothers had less than copies/ml) compared with mothers who did not receive haart ( / with less than copies/ml). however, the whole milk hiv- dna load (measured as "undetectable" at less than copies/ cells) was not significantly different in the haart ( of mothers)] and non-haart ( of ) groups. hiv- dna is incorporated into cells found in breast milk. another group showed significantly lower hiv rna levels in the breast milk of women treated with nevirapine, zidovudine, and lamivudine compared with women not receiving antiretroviral therapy. the use of maternal haart seems to decrease hiv- transmission via breastfeeding. one group working in mozambique, malawi, and tanzania working with mother-infants pairs receiving haart as prevention during pregnancy compared one cohort ( mother-infant pairs) who received supplementary formula and water filters for the first months of life with a second cohort ( motherinfant pairs) breastfeeding exclusively and the mothers receiving haart for the first months. the cumulative incidence rate of hiv infection at months of age was . % for the formula-fed infants and . % for breastfed infants. through months of age no apparent additional risk for late postnatal transmission of hiv was observed. the petra study team working in tanzania, south africa, and uganda examined the efficacy of three shortcourse regimens of zidovudine and lamivudine in preventing early and late hiv transmission in this predominantly breastfeeding population. there were four regimens: a, zidovudine and lamivudine starting at weeks' gestation plus intrapartum medication and -days' postpartum treatment; b, same as a without the prepartum component; c, intrapartum zidovudine and lamivudine only; d, placebo. at week the hiv transmission rates were . % in group a, . % in group b, . % in group c, and . % in group d. at months the hiv infection rates were % in group a, % in group b, % in group c, and % in group d. although a measurable decrease in transmission at weeks of age was observed, limited protection was seen at months of age. an observational study from tanzania compared maternal haart for months with exclusive breastfeeding and abrupt weaning at to months of age with a historical control of the same feeding schedule without the postnatal maternal haart. in the treatment group the cumulative hiv transmission was . % at weeks, . % at months, and . % at months of age. the cumulative hiv infection or death rate was . % at months and . % at months of age. the cumulative risk for hiv transmission was . % between and months. the hiv transmission in this treatment group was half the transmission rate in the historical control group. another study in sub-saharan africa with months of maternal haart and exclusive breastfeeding for months demonstrated % hiv-free survival at months of age; the maternal and infant mortality rates for the treated mother-infant pairs were significantly lower than the country' s maternal and infant mortality rates. antiretroviral therapy prophylaxis for infants is another investigated intervention to decrease hiv transmission via breastfeeding. in a study from cote d'ivoire comparing different groups over time, infants received zidovudine (zdv) alone as zdv prophylaxis, a single dose of nevirapine (nvp), and days of zidovudine (zdv) as nvp/ zdv prophylaxis, or a single dose of nevirapine plus zidovudine and lamivudine ( tc) for days as nvp/zdv/ tc prophylaxis. formula feeding (ff) was compared with exclusive shortened breastfeeding (esb) upto months of age and prolonged breastfeeding (pb). the cumulative transmission rates at months were . % in infants in the zdv + pb group, . % in infants in the nvp/zdv + esb group, . %, in the infants in the nvp/zdv +ff group, . % in the infants in the nvp/zdv/ tc + esb group, and . % in the infants in the nvp/zdv/ tc + ff group. kumwenda et al working in malawi demonstrated decreased hiv transmission with breastfeeding and two different infant prophylaxis regimens. at months of age, they observed a . % occurrence of hiv transmission for infants receiving a single dose of nevirapine plus week of zidovudine compared with . % in the group receiving a single dose of nevirapine plus week of zidovudine plus weeks of daily nevirapine, and . % in the group receiving a single dose of nevirapine plus week of zidovudine plus weeks of nevirapine and zidovudine. in the mitra study in tanzania in which the median time of breastfeeding was weeks, the hiv transmission rate at months in the infants who received zidovudine plus tc for week plus tc alone for breastfeeding through months of age was less than % of the transmission rate for those infants receiving only week of zidovudine plus tc. a summary of three trials in ethiopa, india, and uganda compared a single dose of nevirapine at birth for infants with weeks of daily nevirapine in predominantly breastfed infants whose mothers were counselled regarding feeding per the who/ unicef guidelines. at months of infants in the single-dose group and of in the extended-dose group were hiv infected, which was not statistically significant. the authors suggested that a longer course of infant antiretroviral prophylaxis might be more effective. the potential effect of breastfeeding on the hivpositive mother needs to be adequately assessed in relation to the mother's health status. from uganda and zimbabwe mbizvo et al reported no difference in the number of hospital admissions or mortality between hiv-positive and hiv-negative women during pregnancy. in the years after delivery the hiv-positive women had higher hospital admission (approximately two times increased risk) and death rates (relative risk greater than ) than hiv-negative women. chilongozi et al reported on hiv-positive mothers from four sub-saharan sites followed for months. serious adverse events occurred in women ( . %); deaths occurred in the hiv-positive women, and no deaths occurred in hiv-negative women. several studies have examined breastfeeding relative to mothers' health and reported conflicting results. the first study from kenya demonstrated a significantly higher mortality rate in breastfeeding mothers compared with a formula-feeding group in the years after delivery. the hypothesized explanation offered by the authors for this difference was increased metabolic demands, greater weight loss, and nutritional depletion. a second study from south africa showed an overall lower mortality rate in the two groups with no significant difference in mortality rate in the months of observation. kuhn et al reported no difference in mortality at months after delivery between women randomly assigned to a short breastfeeding group ( women, median breastfeeding duration months, % still breastfeeding at months) and a long breastfeeding group ( women, % breastfeeding at months, % breastfeeding at months, median months). the hiv-related mortality rates were high ( . %), but not associated with prolonged lactation. walson et al followed hiv-positive women for to years in kenya. the mortality risk was . % at year and . % at years of follow-up. although less than % of women reported a hospitalization during the years, they experienced various common infections (pneumonia, diarrhea, tb, malaria, stds, urinary tract infections, mastitis). breastfeeding was a significant cofactor for diarrhea and mastitis but not for pneumonia, tb, or hospitalization. in summary, breastfeeding of infants by hiv-positive mothers does lead to an increased risk for hiv infection in the infants. much remains to be understood about the mechanisms of hiv transmission via breast milk and the action and efficacy of different interventions to prevent such transmission. the complete avoidance of breastfeeding is a crucial component for the prevention of perinatal hiv infection in the united states and many other countries. in resource-poor settings, where breastfeeding is the norm and where it provides vital nutritional and infection protective benefits, the who, unicef, and the joint united nations programme on hiv/ aids (unaids) recommend education, counseling, and support for hiv-infected mothers so they can make an informed choice concerning infant feeding. mothers choosing to breastfeed should receive additional education, support, and medical care to minimize the risk for hiv transmission and to optimize their own health status during and after breastfeeding. mothers choosing to use replacement feedings should receive parallel education, support, and medical care for themselves and their infants to minimize the effect of the lack of breastfeeding. good evidence now shows that antiretroviral prophylactic regimens for mothers or infants while continuing breastfeeding does decrease postnatal hiv transmission. early weaning is associated with increased morbidity and mortality. further carefully controlled research is indicated to adequately assess the risks and benefits to infants and mothers of prolonged breastfeeding with antiretroviral prophylaxis for either or both mothers and infants. along with this, hiv testing rates must be improved at the same time as increased availability and access to antenatal care, hiv prevention services, and hiv medical care for everyone must be increased. the availability and free access to antiretroviral medications must also improve. the decision about infant feeding for hivpositive mothers remains a difficult one, but this is slowly changing with increasing options. the goals remain % hiv transmission prevention, optimal maternal health and survival, and long-term infant health and survival. human immunodeficiency virus type (hiv- ) is an rna virus in the nononcogenic, cytopathic lentivirus genus of retroviruses. it is genetically closer to simian immunodeficiency virus than to hiv- . the clinical disease associated with hiv- has similar symptoms to hiv- infection but progresses at a slower rate to severe immunosuppression. hiv- is endemic in western africa and parts of the caribbean and found infrequently in europe and north and south america. , it is transmitted via sexual contact, blood, or blood products and from mother to child. routine testing for hiv- is recommended in blood banks. antibody tests used for hiv- are only % to % sensitive for detecting hiv- . specific testing for hiv- is appropriate whenever clinically or epidemiologically indicated. vertical transmission occurs infrequently. ekpini et al followed a large cohort of west african mothers and infants: hiv- positive women, hiv- positive women, women seropositive for both hiv- and , and hiv seronegative women. a few cases of perinatal hiv- transmission occurred, but no case of late postnatal transmission was observed. it is probable that hiv- transmission via breast milk is less common than with hiv- , but insufficient data support that the risk for transmission is zero. mothers who test positive for hiv- should be tested for hiv- , and guidelines for breastfeeding should follow those for hiv- until additional information is available. rabies virus produces a severe infection with progressive cns symptoms (anxiety, seizures, altered mental status) that ultimately proceeds to death; few reports of survival exist. rabies occurs worldwide except in australia, antarctica, and several island groups. in more than , cases of rabies were reported to the who, a number that is probably a marked underestimate of the actual cases. between and , cases of human rabies were reported in the united states. , postexposure prophylaxis is given to thousands of patients each year. rabies virus is endemic in various animal populations, including raccoons, skunks, foxes, and bats. because of aggressive immunization programs, rabies in domesticated dogs and cats in the united states is uncommon. the virus is found in the saliva and tears and nervous tissue of infected animals. transmission occurs by bites, licking, or simply contact of oral secretions with mucous membranes or nonintact skin. many cases of rabies in humans now lack a history of some obvious contact with a rabid animal. this may be a result of the long incubation period (generally to weeks, but can be up to year, with reports of incubation periods of several years), a lack of symptoms early in an infectious animal, or airborne transmission from bats in enclosed environments (caves, laboratories, houses). person-to-person transmission via bites has not been documented, although it has occurred in corneal transplants. rabies viremia has not been observed in the spread of the virus. no evidence exists indicating transmission through breast milk. in the case of maternal infection with rabies, many scenarios can occur before the onset of progressive, severe cns symptoms. the progression and severity of maternal illness can preclude breastfeeding, but separation of an infant from the mother is appropriate regardless of the mother' s status and method of infant feeding (especially to avoid contact with saliva and tears). breastfeeding should not continue when the mother has symptoms of rabies, and the infant should receive postexposure immunization and close observation. an infant may received expressed breast milk, but the expression must occur without possible contamination with saliva or tears from the mother. depending on the scenario, the nature of a mother' s illness, the possible exposure of an infant to the same source as the mother, and the exposure of a child to the mother, postexposure immunization of an infant may be appropriate. a more common scenario is a mother' s apparent exposure to rabies (without exposure for the infant), necessitating postexposure immunization of the mother with rabies vaccine. in the majority of cases, in the absence of maternal illness, breastfeeding can reasonably continue during the mother' s five-dose immunization series in days. in a rare situation in which apparent exposure of mother and infant to rabies occurs together, postexposure treatment of both mother and infant should be instituted, and breastfeeding can continue. respiratory syncytial virus (rsv) is a common cause of respiratory illness in children and is relatively common in adults, usually producing milder upper respiratory tract infection in adults. no evidence indicates that rsv causes intrauterine infection, adversely affects the fetus, or causes abortion or prematurity. rsv does produce infection in neonates, causing asymptomatic infection, afebrile upper respiratory tract infection, bronchiolitis, pneumonia, and apnea. mortality rate can be high in neonates, especially in premature infants and ill full-term infants, particularly those with preexisting respiratory disease (hyaline membrane disease, bronchopulmonary dysplasia) or cardiac disease associated with pulmonary hypertension. rsv is believed to be transmitted via droplets or direct contact of the conjunctiva, nasal mucosa, or oropharynx with infected respiratory secretions. documentation of rsv infection is rarely made in adults, and spread from a mother or other household contacts probably occurs before a diagnosis can be made. therefore risk for rsv transmission from breast milk is probably insignificant compared with transmission via direct or droplet contact in families. in nurseries, however, it is appropriate to make a timely diagnosis of rsv infection in neonates to isolate infants from the others and prevent spread in the nursery. ribavirin is not recommended for routine use. it is infrequently used in patients with potentially life-threatening rsv infection. rsv infection should be suspected in any infant with rhinorrhea, nasal congestion, or unexplained apnea, especially in october through march in temperate climates. prophylaxis against rsv with rsv-specific immunoglobulin iv (rsv-igiv) during this season for infants at highest risk for severe disease is appropriate. debate surrounds the topic of the effect of passively acquired antibodies (in infants from mothers before birth) against rsv on the occurrence and severity of illness in neonates and infants. it appears that a higher level of neutralizing antibody against rsv in neonates decreases the risk for severe rsv disease. , some controversy remains concerning the measurable benefit of breastfeeding for preventing serious rsv disease. , , some studies have shown benefit and others no effect. controlling for possible confounding factors (e.g., smoking, crowded living conditions) in these studies has been difficult. at this point, no reason exists to stop breastfeeding with maternal rsv infection; a potential exists for benefit from nonspecific factors in breast milk against the rsv. infants with rsv infection should breastfeed unless their respiratory status precludes it. rotavirus infections usually result in diarrhea, accompanied by emesis and low-grade fever. in severe infections the clinical course can include dehydration, electrolyte abnormalities, and acidosis and can contribute to malnutrition in developing countries. generally, every child will have at least one episode of rotavirus infection by years of age. in developed countries, rotavirus is often associated with diarrhea requiring hospitalization in children younger than years of age, but rarely associated with death. worldwide rotavirus is the leading cause of diarrhea-related deaths in children younger than years old. estimates suggest that in children younger than years old rotavirus infection leads to more than million occurrences of diarrhea, million hospital admissions, and , deaths each year. fecal-oral transmission is the most common route, but fomites and respiratory spread may also occur. spread of infection occurs most often in homes with young children or in daycare centers and institutions. in hospitalized infants or mothers with rotavirus infection, contact precautions are indicated for the duration of the illness. no evidence indicates prenatal infection from rotavirus, but perinatal or postnatal infection from contact with the mother or others can occur. no case of transmission of rotavirus via breast milk has been documented. breast milk does contain antibodies to rotavirus for up to years. human milk mucin has been demonstrated to inhibit rotavirus replication and prevent experimental gastroenteritis. the mechanisms of rotavirus immunity are not well understood. they are thought to be multifactorial with cell-mediated immunity limiting severity and the course of infection, while humoral immunity protects against subsequent infections. innate and adaptive responses at the level of the mucosa are probably the most important. exclusive breastfeeding may decrease the likelihood of severe rotavirus-related diarrhea by as much as %. , although breastfeeding does not prevent infection with rotavirus, it seems to decrease the severity of rotavirus-induced illness in children younger than years old. , , at least one study suggested that this may represent simply the postponement of severe rotavirus infection until an older age. one study suggested that protection against rotavirus rapidly declines upon discontinuation of breastfeeding. this delay in rotavirus infection until the child is older may be beneficial in that the older child may be able to tolerate the infection or illness with a lower likelihood of becoming dehydrated or malnourished. continuing breastfeeding during an episode of rotavirus illness with or without vomiting is appropriate and often helpful to the infant. no reason to suspend breastfeeding by a mother infected with rotavirus is apparent. two rotavirus vaccines (rotateq and rotarix) have been licensed for use in more than countries, but less than countries have routine immunization programs. additional types of rotavirus vaccines are undergoing study in various countries, specifically examining the efficacy of the vaccines in low and medium income countries. some of the explanations for the slow implementation of an effective vaccine globally include differences in protection with specific vaccines in high income countries compared with low or medium income countries, the unfortunate association with intussusception in the united states, the delayed recognition of the significant rotavirus-related morbidity and mortality, and the cost of the new vaccines. the question of variable efficacy of the specific rotavirus vaccines in developed and developing countries remains an important one. several trials are examining this issue and attempting to address factors such as maternal transplacentally transferred antibodies, breastfeeding practices (especially immediately before immunization with a live oral rotavirus vaccine), stomach acid, micronutrient malnutrition, interfering gut flora, and differences in the epidemiology of rotavirus in different locations. evidence indicates that maternal immunization with rotavirus vaccine can increase both transplacental acquisition of antibodies and secretory iga in breast milk. additionally, oral rotavirus vaccines have been able to stimulate a good serologic response in both formula-fed and breastfed infants, although the antigen titers may need to be modified to create an optimal response in all infants. the actual protective effect of these vaccines in different situations and strategies will require measurement in ongoing prospective studies. congenital rubella infection has been well described, and the contributing variables to infection and severe disease have been elucidated. the primary intervention to prevent congenital rubella has been to establish the existence of maternal immunity to rubella before conception, including immunization with rubella vaccine and reimmunization if indicated. perinatal infection is not clinically significant. postnatal infection occurs infrequently in children younger than year of age because of passively acquired maternal antibodies. the predominant age of infection is to years old, and more than half of those with infections are asymptomatic. postnatal rubella is a self-limited, mild viral infection associated with an evanescent rash, shotty adenopathy, and low-grade transient fever. it most often occurs in the late winter and spring. infants with congenital infection shed the virus for prolonged periods from various sites and may serve as a source of infection throughout the year. contact isolation is appropriate for suspected and proved congenital infection for at least year, including exclusion from day care and avoidance of pregnant women, whereas postnatal rubella infection requires droplet precautions for days after the onset of rash. rubella virus has been isolated from breast milk after natural infection (congenital or postnatal) and after immunization with live attenuated vaccine virus. both iga antibodies and immunoreactive cells against rubella have been identified in breast milk. breastfed infants can acquire vaccine virus infection via milk but are asymptomatic. because postpartum infection with this virus (natural or vaccine) is not associated with clinically significant illness, no reason exists to prevent breastfeeding after congenital infection, postpartum infection with this virus, or maternal immunization with rubella vaccine. severe acute respiratory syndrome (sars) is a term that could be applied to any acute serious respiratory illness caused by or associated with a variety of infections agents; since , however, it has been linked with sars-associated coronavirus (sars-cov). in the global outbreak of to , more than probable cases of sars and more than deaths occurred. more than the actual number of affected individuals or its associated mortality rate (approximately % overall, and closer to % in persons older than years of age), it was what we did not know about this new unusual illness, and the tremendous publicity surrounding it, that made sars such a sensation. we now know the cause of this illness, known as the sars-cov. sars-cov was shown not to be closely related to the previously characterized coronavirus groups. , despite intense international collaboration to study the illness and the virus, many things are not known, such as the degree of infectiousness, the actual period of transmissibility, all the modes of transmission, how many people have an asymptomatic infection compared with those with symptoms or severe illnesses, how to make a rapid diagnosis of confirmed cases, and where it originated. at least cases of probable sars in children have been described in the literature. , , , in general, the illness in children is a mild, nonspecific respiratory illness, but in adolescents and adults it is more likely to progress to severe respiratory distress. it has been reported that children are less likely to transmit sars than adults. the overall clinical course, the radiologic evolution, and the histologic findings of these illness are consistent with the host' s immune response playing a significant role in disease production. five infants were born to mothers with confirmed sars. the infants were born prematurely ( to weeks), presumably due to maternal illness. although two of the five infants had serious abdominal illnesses (other coronaviruses have been associated with reported outbreaks of necrotizing enterocolitis), the presence of sars-cov could not be demonstrated in any of these infants. no evidence of vertical transmission of sars is available. the mode of feeding for any of the reported cases of young children with sars or the infants born to mothers with sars was not mentioned. as with other respiratory viruses predominantly transmitted by droplets, transmission via breast milk is an insignificant mode of transmission, if it occurs at all. the benefits of breastfeeding being what they are, mothers with sars should continue breastfeeding if they are able, or expressed breast milk can be given to an infant until the mother is able to breastfeed. in this era of worry about biologic terrorism, smallpox is an important concern. the concern for infants (breastfed or formula-fed) is direct contact with mothers or household members with smallpox. smallpox is highly contagious in the household setting due to person-to-person spread via droplet nuclei or aerosolization from the oropharynx and direct contact with the rash. additional potential exposures for infants include the release of a smallpox aerosol into the environment by terrorists, contact with a smallpox-contaminated space or the clothes of household members exposed to an aerosol, and infection via contact with a mother' s or a household member' s smallpox vaccination site. these risks are the same for breastfed and formulafed infants. no evidence for transmission of the smallpox virus via breast milk exists. a contact is defined as a person who has been in the same household or had face-to-face contact with a patient with smallpox after the onset of fever. patients do not transmit infection until after progression from the fever stage to the development of the rash. an exposed contact does not need to be isolated from others during the postcontact observation period (usually days) until the person develops fever. temperature should be monitored daily in the exposed contact. personal contact and breastfeeding between mother and infant can continue until the onset of fever, when immediate isolation (at home) should begin. providing expressed breast milk for the infant of a mother with smallpox should be avoided because of the extensive nature of the smallpox rash and the possibility of contamination (from the rash) of the milk during the expression process. no literature documents transmission of the smallpox virus via expressed breast milk. the other issue for breastfeeding infants is the question of maternal vaccination with smallpox in a preexposure event vaccination program. children older than year of age can be safely and reasonably vaccinated with smallpox in the face of a probable smallpox exposure. smallpox vaccination of infants younger than year of age is contraindicated. breastfeeding is listed as a contraindication to vaccination in the preevent vaccination program. it is unknown whether vaccine virus or antibodies are present in breast milk. the risk for infection due to contact or aerosolization of virus from a mother' s smallpox vaccination site is the same for breastfed and formula-fed infants. the advisory committee on immunization practices also does not recommend preevent smallpox vaccination of children younger than years old. a report documents tertiary contact vaccinia in a breastfeeding infant. a united states military person received a primary smallpox vaccination and developed a local reaction at the inoculation site. despite reportedly observing appropriate precautions, the individual' s wife developed vesicles on both areolae (secondary contact vaccinia). subsequently, the breastfeeding infant developed lesions on her philtrum, cheek, and tongue. both the mother and infant remained well and the infections resolved without therapy. culture and pcr testing confirmed vaccinia in both the mother' s and the infant' s lesions. the breast milk was not tested. in a review from to , sepkowitz reported on cases of secondary vaccinia in households. the cdc reported suspected cases of secondary/tertiary vaccinia with of those cases confirmed by culture or pcr. the cases were related to , vaccinated military personnel. this is an incidence of . cases per , vac cinees and . cases per , primary vaccinees. in a separate report on the civilian preevent smallpox vaccination program, , individuals were vaccinated between january and june , and no cases of contact vaccinia were reported. the risk for contact vaccinia is low. the risk is from close or intimate contact. in the above-mentioned case, the risk for the infant was contact with the mother' s breasts, the inadvertent site of her contact vaccinia. breastfed and formulafed infants are equally at risk from close contact in the household of a smallpox vaccinee or a case of secondary vaccinia, and separation from the individual is appropriate in both situations. if the breast of the nursing mother is not involved, expressed breast milk can be given to the infant. tt virus (ttv) is a recently identified virus found in a patient (tt) with posttransfusion hepatitis not associated with the other hepatitis-related viruses a through g. ttv has been described as an unenveloped, circular, single-stranded dna virus. this virus is prevalent in healthy individuals, including healthy blood donors, and has been identified in patients with hepatitis. ttv dna has been detected in infants of ttv-positive and ttvnegative mothers. ohto et al reported no ttv dna was detected in cord blood from infants, and it was detected in only of samples taken at month of age. they noted an increasing prevalence from months ( %) to years ( %), which they ascribed to acquisition via nonparenteral routes. in comparisons of the ttv dna in ttvpositive mothers and their ttv-positive infants, of showed high level nucleotide sequence similarity, and of differed by greater than %. schröter et al reported on ttv dna in breast milk examined retrospectively. notably, ttv dna was detected in of serum samples of infants at week of age, who were born to women viremic for ttv dna. twenty-four women who were negative for ttv dna gave birth to children who were initially negative for ttv dna and remained negative throughout the observation period (mean . months, range to months). ttv dna was detected in % of breast milk samples from ttv viremic women and in none of the breast milk samples from ttv-negative women. no clinical or laboratory evidence of hepatitis was found in the children who were observed to be ttv dna positive during the period of the study. other authors have reported ttv in breast milk detected by pcr. they describe the absence of ttv dna in infants at days and months of age, and of infants were positive for ttv dna at months of age, suggesting the late acquisition of infection via breastfeeding. tt virus is transmitted in utero and is found in breast milk. no evidence of clinical hepatitis in infants related to ttv infection and no evidence for a late chronic hepatitis exist. given the current available information, no reason to proscribe breastfeeding by ttv-positive mothers is compelling. certainly more needs to be understood concerning the chronic nature of this infection and the possible pathogenesis of liver disease. no documented evidence indicates that women with breast cancer have rna of tumor virus in their milk. no correlation between rna-directed dna polymerase activity has been found in women with a family history of breast cancer. rna-directed dna polymerase activity, a reserve transcriptase, is a normal feature of the lactating breast. , , epidemiologic data conflict with the suggestion that the tumor agent is transmitted through the breast milk. the incidence of breast cancer is low among groups who had nursed their infants, including lower economic groups, foreign-born groups, and those in sparsely populated areas. the frequency of breast cancer in mothers and sisters of a woman with breast cancer is two to three times that expected by chance. this could be genetic or environmental. cancer actually is equally common on both sides of the family of an affected woman. if breast milk were the cause, it should be transmitted from mother to daughter. when mother-daughter incidence of cancer was studied, no relationship was found to breastfeeding. sarkar et al reported that human milk, when incubated with mouse mammary tumor virus, caused degradation of the particular morphology and decreased infectivity and reverse transcriptase activity of the virions. they suggest that the significance of this destructive effect of human milk on mouse mammary tumor virus may account for the difficulty in isolating the putative human mammary tumor agent. sanner showed that the inhibitory enzymes in milk can be removed by special sedimentation technique. he ascribes the discrepancies in isolating virus particles in human milk to these factors, which inhibit rna-directed dna po lymerase. the fear of cancer in breastfed female offspring of a woman with breast cancer does not justify avoiding breastfeeding. breastfed women have the same breast cancer experience as nonbreastfed women, and no increase is seen in benign tumors. daughters of breast cancer patients have an increased risk for developing benign and malignant tumors because of their heredity, not because of their breastfeeding history. , unilateral breastfeeding (limited to the right breast) is a custom of tanka women of the fishing villages of hong kong. ing et al investigated the question, "does the unsuckled breast have an altered risk for cancer?" they studied breast cancer data from to . breast cancer occurred equally in the left and the right breasts. comparison of patients who had nursed unilaterally with nulliparous patients and with patients who had borne children but not breastfed indicated a highly significantly increased risk for cancer in the unsuckled breast. the authors conclude that in postmenopausal women who have breastfed unilaterally, the risk for cancer is significantly higher in the unsuckled breast. they thought that breastfeeding may help protect the suckled breast against cancer. others have suggested that tanka women are ethnically a separate people and that left-sided breast cancer may be related to their genetic pool and not to their breastfeeding habits. no mention has been made of other possible influences, such as the impact of their role as "fishermen" or any inherent trauma to the left breast. in , lane-claypon stated that a breast that had never lactated was more liable to become cancerous. nulliparity and absence of breastfeeding had been considered important risk factors for breast cancer. macmahon et al reported in that age at first full-term pregnancy was the compelling factor, and the younger the mother, the less the risk. in a collective review of the etiologic factors in cancer of the breast in humans, papaioannou concludes, "genetic factors, viruses, hormones, psychogenic stress, diet, and other possible factors, probably in that order of importance, contribute to some extent to the development of cancer of the breast." wing concluded in her review on human milk and health that "in view of the complete absence of any studies showing a relationship between breastfeeding and increased risk of breast cancer, the presence of virus-like particles in breast milk should not be a contraindication to breastfeeding." henderson et al gradually, studies have appeared challenging the dogma. brinton et al, mctiernan and thomas, and layde et al showed the clearly protective effects of breastfeeding. another example is a study conducted to clarify whether lactation has a protective role against breast cancer in an asian people, regardless of confounding effects of age at first pregnancy, parity, and closely related factors. in a hospital-based case-control study of women without breast cancer, statistical adjustment for potential confounders and a likelihood ratio test for linear trend were done by unconditional logistic regression. total months of lactation regardless of parity was the discriminator. regardless of age of first pregnancy and parity, lactation had an independent protective effect against breast cancer in japanese women. although breast cancer incidence is influenced by genetics, stress, hormones, and pregnancy, breastfeeding clearly has a protective effect. "there is a reduction in the risk of breast cancer among premenopausal women who have lactated. no reduction in the risk of breast cancer occurred among postmenopausal women with a history of lactation," according to newcombe et al, reporting a multicenter study in . varicella-zoster virus infection (varicella/chickenpox, zoster/shingles) is one of the most communicable diseases of humans, in a class with measles and smallpox. transmission is thought to occur via respiratory droplets and virus from vesicles. varicella in pregnancy is a rare event, although disease can be more severe with varicella pneumonia, and can be fatal. congenital varicella-zoster virus infection occurs infrequently, causing abortion, prematurity, and congenital malformations. a syndrome of malformations has been carefully described with congenital varicella-zoster virus infection, typically involving limb deformity, skin scarring, and nerve damage, including to the eye and brain. perinatal infection can lead to severe infection in infants if maternal rash develops days or less before delivery and within days after delivery. illness in infants usually develops before days of age and is believed to be more severe because of the lack of adequate transfer of antibody from the mother during this period and transplacental spread of virus to the fetus and infant during viremia in the mother. varicella in a mother occurring before days before delivery allows sufficient formation and transplacental transfer of antibodies to the infant to ameliorate disease even if the infant is infected with varicella-zoster virus. mothers who develop varicella rash more than days after delivery are less likely to transfer virus to the infant transplacentally; they pose a risk to the infants from postnatal exposure, which can be diminished by the administration of varicellazoster ig to the infant. postnatal transmission is believed to occur through aerosolized virus from skin lesions or the respiratory tract entering the susceptible infant's respiratory tract. airborne precautions are therefore appropriate in the hospital setting. infants infected with varicella-zoster virus in utero or in the perinatal period (younger than month of age) are more likely to develop zoster (reactivation of latent varicella-zoster virus) during childhood or as young adults. postnatal varicella from nonmaternal exposure can occur but is generally mild when it develops after weeks of age or when a mother has passed on antibodies against varicella-zoster virus via the placenta. severe postnatal varicella does occur in premature infants or infants of varicella-susceptible mothers. when a mother' s immune status relative to varicella-zoster virus is uncertain and measurement of antibodies to varicella-zoster virus in mother or infant cannot be performed promptly (less than hours), administration of vzig or ivig to the infant exposed to varicella or zoster in the postnatal period is indicated. ideally a mother' s varicella status should be known before pregnancy, when varicella virus vaccine could be given if indicated. varicella-zoster virus virus has not been cultured from milk, but varicella-zoster virus dna has been identified in breast milk. antibody against varicella-zoster virus has also been found in breast milk. breast milk from mothers who had received the varicella vaccine in the postpartum period was tested for varicella-zoster virus dna. varicella dna was not detected in any of the breast milk samples from the women, all of whom seroconverted after vaccination. one case of suspected transfer of varicella-zoster virus to an infant via breastfeeding has been reported, but virus may have been transmitted by respiratory droplet or exposure to rash before the mother began antiviral therapy. isolation of an infant from the mother with varicella and interruption of breastfeeding should occur only while the mother remains clinically infectious, regardless of the method of feeding. as soon as the infant has received varicella-zoster ig, expressed breast milk can be given to an infant if no skin lesions involve the breasts. persons with varicella rash are considered noninfectious when no new vesicles have appeared for hours and all lesions have crusted, usually in to days. immunocompetent mothers who develop zoster can continue to breastfeed if the lesions do not involve the breast and can be covered because antibodies against varicella-zoster virus are provided to the infant via the placenta and breast milk and will diminish the severity of disease, even if not preventing it. conservative management in this scenario would include giving an infant varicella-zoster ig as well (see table - ). it is estimated that to asymptomatic cases of west nile infection occur for every febrile illnesses and for every one case of meningoencephalitis associated with west nile virus. west nile fever is usually a mild illness of to days' duration. the symptoms are relatively nonspecific, including malaise, nausea, vomiting, headache, myalgia, lymphadenopathy, and rash. west nile disease is characterized by severe neurologic symptoms (e.g., meningitis, encephalitis, or acute flaccid paralysis, and occasionally optic neuritis, cranial nerve abnormalities, and seizures). children are infrequently sick with west nile virus infection and infants younger than year of age have rarely been reported. the case-fatality rate for in the united states was approximately . %, but has been reported as high as % to % in hospitalized patients. the case-fatality rate for persons older than years of age is considered to be higher, % to % among hospitalized patients in outbreaks in romania and israel. the primary mechanism of transmission is via a mosquito bite. mosquitoes from the genus culex are primary vectors. the bird-mosquito-bird cycle serves to maintain and amplify the virus in the environment. humans and horses are incidental hosts. the pathogenesis of the infection is believed to occur via replication of the virus in the skin and lymph nodes, leading to a primary viremia that seeds secondary sites before a second viremia causes the infection of the cns and other affected organs. , transmission has been reported in rare instances during pregnancy , via organ transplant and percutaneously in laboratory workers. a study of west nile virus infection in pregnancy documented four miscarriages, two elective abortions, and live births. cord blood samples were tested in infants and of were negative for anti-west nile virus igm. three infants had west nile virus infection, which could have been acquired congenitally. three of infants who had congenital malformations might have been caused by maternal west nile virus infection based on timing in pregnancy, but no evidence of west nile virus etiology is conclusive. west nile virus transmission occurs via blood and blood product transfusion, and the incidence has been estimated to be as high as per , donations during epidemics in specific cities. no evidence of direct person-to-person transmission without the mosquito vector has been found. one case of possible west nile virus transmission via breastfeeding has been documented. the mother acquired the virus via packed rbc transfusions after delivery. the second unit of blood she received was associated with other blood products from the same donation causing west nile infection in another transfusion recipient. eight days later the mother had a severe headache and was hospitalized with fever and a csf pleocytosis on day after delivery. the mother' s csf was positive for west nile virus-specific igm antibody. the infant had been breastfed from birth through the second day of hospitalization of the mother. samples of breast milk were west nile virus-specific igg and igm positive on day after delivery and west nile virus-specific igm positive on day . the same milk was west nile virus rna positive by pcr testing on day , but not on day after delivery. the infant tested positive for west nile virus-specific igm in serum at day of age, but remained well without fever. no clear-cut exposure to mosquitoes for the infant were reported. the cord blood and placenta were not available to be tested. igm antibodies can be found in low concentrations in breast milk, but this is not common or as efficient as the transfer of iga, secretory iga, or igg into breast milk. a review of west nile virus illness during the breastfeeding identified six occurrences of breastfeeding during maternal west nile virus illness. five of the six infants had no illness or detectable antibodies to west nile virus in their blood. one infant developed a rash and was otherwise well after maternal west nile virus illness, but was not tested for west nile virus infection. two infants were identified who developed west nile virus illness while breastfeeding, but no preceding west nile virus infection was demonstrated in their mothers. two other breastfeeding infants developed west nile virus-specific antibodies after their mothers acquired west nile virus illness in the last week of pregnancy, but congenital infection could not be ruled out. live virus was not cultured from samples of breast milk from mothers infected with west nile virus during pregnancy, but west nile virus rna was detected in two samples and samples had igm antibodies to west nile virus. the above data suggest that west nile virus infection through breastfeeding is rare. to date evidence of significant disease due to west nile virus infection in young breastfeeding children is lacking. at this time, no reason exists to proscribe breastfeeding in the case of maternal west nile virus infection if a mother is well enough to breastfeed. as with many other maternal viral illnesses, by the time the diagnosis is made in a mother, the infant may have already been exposed during maternal viremia and possible virolactia. the infant can and should continue to receive breast milk for the potential specific and nonspecific antiviral immunologic benefits. yellow fever virus is a flavivirus which is transmitted to humans by infected aedes and haemogogus mosquitos in tropical areas of south america and africa. large outbreaks occur when mosquitos in a populated area become infected from biting viremic humans infected with yellow fever virus. transmission from the mosquitos to other humans occurs after an incubation period in the mosquito of days. direct person-to-person spread has not been reported. illness due to yellow fever virus usually begins after an incubation period of to days, with acute onset of headache, fever, chills, and myalgia. photophobia, back pain, anorexia, vomiting, and restlessness are other common symptoms. the individual is usually viremic for the first days of illness until the fever and other symptoms diminish. liver dysfunction and even failure can develop as can myocardial dysfunction. cns infection is uncommon but symptoms can include seizures and coma. medical care should include intensive supportive care and fluid management. one case of congenital infection after immunization of a pregnant woman with the attenuated vaccine strain has been reported. one of infants whose mothers had inadvertently received the yellow fever virus vaccine during pregnancy developed igm and elevated neutralizing antibodies against the yellow fever virus without any evidence of illness or abnormalities. a more recent study from brazil examined inadvertent yellow fever virus immunization during pregnancy during a mass vaccination campaign in ; pregnant women received the yellow fever virus at a mean of . weeks' gestation, the majority of whom did not know their pregnancy status at the time. seroconversion occurred in . % of the women after at least weeks after vaccination. mild postvaccination illness (headache, fever, or myalgia) was reported by . % of the women. the frequency of malformations, miscarriages, stillbirths, and premature deliveries was similar to that found in the general population. at the -month follow-up point, % of the infants still demonstrated neutralizing antibodies against yellow fever virus, but after months only one child was still seropositive. transmission of the yellow fever vaccine virus through breastfeeding was recently reported from brazil. the mother was immunized during a yellow fever epidemic in a nonendemic area in brazil; days after delivering a healthy female infant ( weeks' gestational age) the mother received the dd yellow fever vaccine, and days later the mother reported headache, malaise, and low-grade fever that persisted for days. the mother continued breastfeeding and did not seek medical care for herself. at days of age the infant became irritable, developed fever, and refused to nurse. the infant developed seizures and subsequent evaluation of the infant demonstrated an abnormal csf and ct of the brain showed bilateral areas of diffuse low density suggestive of inflammation and consistent with encephalitis. yellow fever-specific igm antibodies were identified in the infant' s serum and csf. reverse-transcriptase polymerase chain reaction (rt-pcr) testing of the csf also demonstrated yellow fever virus rna identical to the dd yellow fever vaccine virus. breast milk and maternal serum were not tested for yellow fever virus. yellow fever virus, wild or vaccine type, has not been identified in human breast milk, although another flavivirus, west nile virus, has been detected in milk from a few lactating women with west nile virus infection. (see the section on west nile virus.) yellow fever vaccine-associated neurologic disease occurs at different rates in different age-groups, including . to . cases per infants younger than months of age. the d-derived yellow fever vaccines are contraindicated in infants younger than months of age. since , the advisory committee on immunization practices has recommended, based on theoretical risk, that yellow fever vaccine be avoided in nursing mothers, except when exposure in highrisk yellow fever endemic areas is likely to occur. no case of transmission of yellow fever virus from an infected mother to her infant via breastfeeding or breast milk has been reported. published information on the severity of yellow fever virus infection in infants younger than year of age, potential protection from passively acquired antibodies, or protection from breast milk is limited. no information on a differential risk in breastfed versus formula-fed infants is available. given the well documented method of transmission of yellow fever virus via mosquitos, and the lack of evidence of transmission via breast milk, it makes more sense to protect all infants against mosquito bites than to proscribe breastfeeding, even in the mother infected with yellow fever virus. continued breastfeeding or use of expressed breast milk will depend on a mother's health status and ability to maintain the milk supply while acutely ill. if another source of feeding is readily available then temporarily discarding expressed breast milk for at least days of acute illness in the mother is a reasonable precaution. lyme disease, as with other human illnesses caused by spirochetes, especially syphilis, is characterized by a protean course and distinct phases (stages) of disease. lyme borreliosis was described in europe in the early twentieth century. since the s, tremendous recognition, description, and investigation of lyme disease have occurred in the united states and europe. public concern surrounding this illness is dramatic. lyme disease is a multisystem disease characterized by involvement of the skin, heart, joints, and nervous system (peripheral and central). stages of disease are identified as early localized (erythema migrans, often accompanied by arthralgia, neck stiffness, fever, malaise, and headache), early disseminated (multiple erythema migrans lesions, cranial nerve palsies, meningitis, conjunctivitis, arthralgia, myalgia, headache, fatigue, and, rarely, myocarditis), and late disease (recurrent arthritis, encephalopathy, and neuropathy). the varied manifestations of disease may relate to the degree of spirochetemia, the extent of dissemination to specific tissues, and the host' s immunologic response. the diagnosis of lyme disease is often difficult in part because of the broad spectrum of presentations, inapparent exposure to the tick, and the lack of adequately standardized serologic tests. culture of the spirochete, borrelia burgdorferi, is not readily available. enzyme-linked immunosorbent assay (elisa), immunofluorescent assay, and immunoblot assay are the usual tests. pcr detection of spirochetal dna requires additional testing in clinical situations to clarify and standardize its utility. gardner reviewed infection during pregnancy, summarizing a total of adverse outcomes from cases reported in the literature. the adverse outcomes included miscarriage and stillbirth ( % of cases), perinatal death ( %), congenital anomalies ( %), and both early-and late-onset progressive infection in the infants. silver reviewed published reports and concluded that lyme disease during pregnancy is uncommon, even in endemic areas. although the spirochete can be transmitted transplacentally, a significant immune response in the fetus is often lacking, and the association of lyme infection with congenital abnormalities is weak. , little published information exists on whether b. burgdorferi can be transmitted via breast milk. one report showed the detection of b. burgdorferi dna by pcr in the breast milk of two lactating women with untreated erythema migrans, but no evidence of lyme disease or transmission of the spirochete in the one infant followed for year. no attempt to culture the spirochete was made, so it is not possible to determine if the detectable dna was from viable spirochetes or noninfectious fragments. in that same study of women with untreated erythema migrans who had detectable b. burgdorferi dna in the urine, still had detectable dna in the urine to days after starting treatment, but none had it months after initiating therapy. ziska et al reported on the management of nine cases of lyme disease in women associated with pregnancy; seven of the nine women were symptomatic at conception and six received antibiotics throughout pregnancy. follow-up of the infants showed no transmission of lyme disease, even in the seven infants who had been breastfed. the lack of adequate information on transmission of b. burgdorferi via breast milk cannot be taken as proof that it is not occurring. if one extrapolates from data on syphilis and the treponema pallidum spirochete, it would be prudent to discuss the lack of information on the transmission of b. burgdorferi via breast milk with the mother or parents and to consider withholding breast milk at least until therapy for lyme disease has begun or been completed. if the infection occurred during pregnancy and treatment has already been completed, an infant can breastfeed. if infection occurs postpartum or the diagnosis is made postpartum, infant exposure may have already occurred. again, discussion with the mother or parents about withholding versus continuing breastfeeding is appropriate. after prenatal or postnatal exposure, an infant should be closely observed and empiric therapy considered if the infant develops a rash or symptoms suggestive of lyme borreliosis. treatment of mother and infant with ceftriaxone, penicillin, or amoxicillin is acceptable during breastfeeding relative to the infant' s exposure to these medications. doxycycline should not be administered for more than days while continuing breastfeeding because of possible dental staining in the neonate. continued surveillance for viable organisms in breast milk and evidence of transmission through breastfeeding is recommended. a large body of information is available on various "lyme vaccines" used in dogs, but these vaccines are only partially protective and must be repeated yearly. preliminary information suggests that a vaccine for use in humans safely produces good serologic responses, but protective efficacy has not been demonstrated, and no information exists on its use during pregnancy or breastfeeding. syphilis is the classic example of a spirochetal infection that causes multisystem disease in various stages. both acquired syphilis and congenital syphilis are well-described entities. acquired syphilis is almost always transmitted through direct sexual contact with open lesions of the skin or mucous membranes of individuals infected with the spirochete, treponema pallidum. congenital syphilis occurs by infection across the placenta (placentitis) at any time during the pregnancy or by contact with the spirochete during passage through the birth canal. any stage of disease (primary, secondary, tertiary) in a mother can lead to infection of the fetus, but transmission in association with secondary syphilis approaches %. infection with primary syphilis during pregnancy, without treatment, leads to spontaneous abortion, stillbirth, or perinatal death in % of cases. similar to acquired syphilis, congenital syphilis manifests with moist lesions or secretions from rhinitis (snuffles), condylomata lata, or bullous lesions. these lesions and secretions contain numerous spirochetes and are therefore highly infectious. postnatal infection of an infant can occur through contact with open, moist lesions of the skin or mucous membranes of the mother or other infected individuals. if the mother or infant has potentially infectious lesions, isolation from each other and from other infants and mothers is recommended. if lesions are on the breasts or nipples, breastfeeding or using expressed milk is contraindicated until treatment is complete and the lesions have cleared. spirochetes are rarely identified in open lesions after more than hours of appropriate treatment. penicillin remains the best therapy. evaluation of an infant with suspected syphilis should be based on the mother' s clinical and serologic status, history of adequate therapy in the mother, and the infant' s clinical status. histologic examination of the placenta and umbilical cord, serologic testing of the infant' s blood and csf, complete analysis of the csf, long bone and chest radiographs, liver function tests, and a complete blood cell count are all appropriate given the specific clinical situation. treatment of the infant should follow recommended protocols for suspected, probable, or proven syphilitic infection. no evidence indicates transmission of syphilis via breast milk in the absence of a breast or nipple lesion. when a mother has no suspicious breast lesions, breastfeeding is acceptable as long as appropriate therapy for suspected or proven syphilis is begun in the mother and infant. giardiasis is a localized infection limited to the intestinal tract, causing diarrhea and malabsorption. immunocompetent individuals show no evidence of invasive infection, and no evidence exists that documents fetal infection from maternal infection during pregnancy. giardiasis is rare in children younger than months of age, although neonatal infection from fecal contamination at birth has been described. human milk has an in vivo protective effect against giardia lamblia infection, as documented by work from central africa, where the end of breastfeeding heralds the onset of giardia infection. this has been reaffirmed in undeveloped countries around the world. the protective effect of breast milk has been identified in the milk of noninfected donors. the antiparasitic effect does not result from specific antibodies but rather from lipase enzymatic activity. the lipase acts in the presence of bile salts to destroy the trophozoites as they emerge from their cysts in the gi tract. hernell et al demonstrated that free fatty acids have a marked giardiacidal effect, which supports the conclusion that lipase activity releasing fatty acids is responsible for killing g. lamblia. g. lamblia have also been reported to appear in the mother' s milk, and the parasite has been transmitted to newborns via that route. the exact relationship of breastfeeding to transmission of g. lamblia and the effect on infants continue to be studied, even though symptomatic infection in breastfed infants is rare. one report from the middle east suggests that even partial breastfeeding is protective against infection with intestinal parasites, including cryptosporidium and giardia lamblia. breastfeeding by mothers with giardiasis is problematic mainly because of the medications used for therapy. metronidazole' s safety in infants has not been established, and little information is available on quinacrine hydrochloride and furazolidone in breast milk. paromomycin, a nonabsorbable aminoglycoside, is a reasonable alternative recommended for treatment of pregnant women. breastfeeding by a mother with symptomatic giardiasis is acceptable when consideration is given to the presence of the therapeutic agents in the breast milk. hookworm infection, most often caused by ancylostoma duodenale and necator americanus, is common in children younger than the age of years, and there is at least one report on infantile hookworm disease from china. this publication from the chinese literature reports hundreds of cases of infantile hookworm disease that include the common symptoms of bloody stools, melena, anorexia, listlessness, and edema. anemia, eosinophilia and even leukemoid reactions occur as part of the clinical pictures in young children. they also note at least cases of hookworm diseases in newborn infants younger than month of age. in the discussion of infantile hookworm infection, they note four routes of infection: direct contact with contaminated soil, "sand-stuffed" diapers, contaminated "washed/wet" diapers, and vertical equal to transmammary transmission or transplacental transmission. they postulated that infection of infants before to days of age would most likely be due to transplacental transmission and infection before environmental contact would most likely be due to transmammary transmission. ample evidence is available in veterinary medicine of transmammary spread of helminths. , at least two reports suggest the possibility of transmammary transmission of hookworms in humans. setasuban et al described the prevalence of necator americanus in nursing mothers as % and identified n. americanus in breast milk in one case. nwosu documented positive stool samples for hookworms in of neonates ( %) at to weeks of age in southern nigeria. the majority of neonatal infections were due to ancylostoma duodenale although necator americanus is more prevalent in that area of nigeria. examination of colostral milk did not demonstrate any hookworm larvae. additional epidemiologic work is necessary to determine the potential significance of transmammary spread of helminths in humans, and more careful examination of breast milk as a source of hookworm infection is required before reasonable recommendation are possible. malaria is recognized as a major health problem in many countries. the effect of malaria infection on pregnant and lactating women and thus on the developing fetus, neonate, and growing infant can be significant. the four species of malaria, plasmodium vivax, p. ovale, p. malariae, and p. falciparum, vary in the specific aspects of the disease they produce. p. vivax exists throughout the world, but p. falciparum predominates in the tropics and is most problematic in its chloroquine-resistant form. malaria in the united states is most often seen in individuals traveling from areas where malaria is endemic. the parasite can exist in the blood for weeks, and infection with p. vivax and p. malariae can lead to relapses years later. transmission occurs through the bite of the anopheline mosquito and can occur via transfusion of blood products and transplacentally. congenital malaria is rare but seems to occur more often with p. vivax and p. falciparum. it usually presents in the first days of life (range day to months). it may resemble neonatal sepsis, with fever, anemia, and splenomegaly occurring in the most neonates and hyperbilirubinemia and hepatomegaly in less than half. malaria in infants younger than months of age generally manifests with less severe disease and death than in older children. possible explanations include the effect of less exposure to mosquitoes, passive antibody acquired from the mother, and the high level of fetal hemoglobin in infants at this age. the variations in the infection rates in children younger months of age during the wet and dry seasons support the idea that postnatal infection is more common than congenital infection. no evidence indicates that malaria is transmitted through breast milk. the greatest risk to infants is exposure to the anopheline mosquito infected with malaria. the main issues relative to malaria and breastfeeding are how to protect both mothers and infants effectively from mosquitoes and what drugs for treating malaria in mothers are appropriate during lactation. protection from mosquito bites includes screened-in living areas, mosquito nets while sleeping, protective clothing with or without repellents on the clothes, and community efforts to eradicate the mosquitoes. chloroquine, quinine, and tetracycline are acceptable during breastfeeding. sulfonamides should be avoided in the first month of an infant' s life, but pyrimethamine-sulfadoxine (fansidar) can be used later. mefloquine is not approved for infants or pregnant women. however, the milk/plasma ratio for mefloquine is less than . , there is a large volume of distribution of the drug, high protein binding of the drug limits its presence in breast milk, and the relative importance of breastfeeding in areas where malaria is prevalent shifts the risk/benefit ratio in favor of treatment with mefloquine. the single dose recommended for treatment or the onceweekly dose for prevention allows for continued breastfeeding with discarding of the milk for short periods after a dose ( to hours). maternal plasma levels of primaquine range from to ng/ml, but no information is available on levels in human milk. primaquine is used in children, and once daily dosing in the mother would allow discarding milk with peak levels of drug. therefore breastfeeding during maternal malaria even with treatment is appropriate with specific medications. strongyloides stercoralis is a nematode (roundworm). most infections are asymptomatic, but clinically significant infection in humans can include larval skin invasion, tissue migration, intestinal invasion with abdominal pain and gi symptoms, and a loeffler-like syndrome due to migration to the lungs. immune-compromised individuals can develop dissemination of larvae systemically, causing various clinical symptoms. humans are the principal hosts, but other mammals can serve as reservoirs. infection via the skin by filariform larvae is the most common form of transmission; ingestion is an uncommon occurrence. transmammary transmission of strongyloides species has been described in dogs, ewes, and rats. , , only one report of transmammary passage of strongyloides larvae in humans is available. in infants younger than days of age, % demonstrated the presence of strongyloides fuelleborni on stool examination. the clinical significance of this was not elucidated. strongyloides larvae was identified in only one sample of milk from nursing mothers. in the absence of an understanding of the clinical significance of strongyloides in the stools of young infants, given the lack of exclusion of the most common mechanism of transmission (through the skin) in the single report and the apparent infrequent evidence of these larvae in human milk, it is difficult to make any recommendations concerning breastfeeding and strongyloides. toxoplasmosis is one of the most common infections of humans throughout the world. the infective organism, toxoplasma gondii, is ubiquitous in nature. the prevalence of positive serologic test titers increases with age, indicating past exposure and infection. the cat is the definitive host, although infection occurs in most species of warmblooded animals. postnatal infection with toxoplasmosis is usually asymptomatic. symptomatic infection typically manifests with nonspecific symptoms, including fever, malaise, myalgia, sore throat, lymphadenopathy, rash, hepatosplenomegaly, and occasionally a mononucleosis-like illness. the illness usually resolves without treatment or significant complications. congenital infection or infection in an immunodeficient individual can be persistent and severe, causing significant morbidity and even death. although most infants with congenital infection are asymptomatic at birth, visual abnormalities, learning disabilities, and mental retardation can occur months or years later. the syndrome of congenital toxoplasmosis is clearly defined, with the most severe manifestations involving the cns, including hydrocephalus, cerebral calcifications, microcephaly, chorioretinitis, seizures, or simply isolated ocular involvement. the risk for fetal infection is related to the timing of primary maternal infection, although transmission can occur with preexisting maternal toxoplasmosis. in the last months of pregnancy the protozoan is more readily transmitted to the fetus, but the infection is more likely to be subclinical. early in pregnancy the transmission to a fetus occurs less frequently but does result in severe disease. treatment of documented congenital infection is currently recommended, although duration and optimal regimen have not been determined, and reversal of preexisting sequelae generally does not occur. prevention of infection in susceptible pregnant women is possible by avoiding exposure to cat feces or the organism in the soil. pregnant or lactating women should not change cat litter boxes, but if they must, it should be done daily and while wearing gloves. the oocyst is not infective for the first to hours after passage. mothers can avoid ingestion of the organism by fully cooking meats and carefully washing fruits, vegetables, and food preparation surfaces. in various animal models, t. gondii has been transmitted through the milk to the suckling young. the organism has been isolated from colostrum as well. the newborn animals became asymptomatically infected when nursed by an infected mother whose colostrum contained t. gondii. only one report has identified t. gondii in human milk, and some question surrounds the reliability of that report. transmission during breastfeeding in humans has not been demonstrated. breast milk may contain appropriate antibodies against t. gondii. given the benign nature of postnatal infection, the absence of documented transmission in human breast milk, and the potential antibodies in breast milk, no reason exists to proscribe breastfeeding by a mother known to be infected with toxoplasmosis. trichomonas vaginalis is a flagellated protozoan that can produce vaginitis (see chapter for a discussion of vaginitis) but frequently causes asymptomatic infection in both men and women. the parasite is found in % to % of women in the childbearing years. it is transmitted predominantly by sexual intercourse, but it can be transmitted to the neonate by passage through the birth canal. this parasite often coexists with other stds, especially gonorrhea. infection during pregnancy or while taking oral contraceptives is more difficult to treat. some evidence suggests that infection with and growth of the parasite are enhanced by estrogens or their effect on the vaginal epithelium. no evidence indicates adverse effects on the fetus in association with maternal infection during pregnancy. occasionally female newborns have vaginal discharge during the first weeks of life caused by t. vaginalis. this is thought to be influenced by the effect of maternal estrogen on the infant' s vaginal epithelium and acquisition of the organism during passage through the birth canal. the organism does not seem to cause significant disease in a healthy infant. no documentation exists on transmission of t. vaginalis via breast milk. the difficulty encountered with maternal infection during lactation stems from metronidazole (flagyl), the drug of choice, being contraindicated for infants. case reports describe treatment of neonates with metronidazole without adverse effect. although topical agents containing povidone-iodine (betadine) or sodium lauryl sulfate (trichotine) can be effective when given as douches, creams, or suppositories, metronidazole remains the treatment of choice. the aap advises using metronidazole only with a physician' s discretion and considers its effect on a nursing infant unknown but possibly a concern. the potential concerns are metronidazole' s disulfiram-like effect in association with alcohol, tumorigenicity in animal studies, and leukopenia and neurologic side effects described in adults. on the other hand, metronidazole is given to children beyond the neonatal period to treat serious infections with various other parasites, such as entamoeba histolytica. the current recommendation for lactating women is to try local treatment first, and if these fail, then to try metronidazole. a -g single-dose treatment produces peak levels after hour, and discarding expressed breast milk for the next to hours is recommended. if this treatment also fails, a -g twice-daily regimen for days or a -g single daily dose for to days is recommended, with discarding of breast milk close to the dose and timing of feedings distant from the dose. infants who exclusively breastfeed are presumed at greater risk from exposure to metronidazole than those who are only partially breastfed. candida consists of multiple species. the most common species affecting humans include c. albicans as the dominant agent and c. tropicalis, c. krusei, and c. parapsilosis, as well as many other uncommon species. in general, candida exists as a commensal organism colonizing the oropharynx, gi tract, vagina, and skin without causing disease until some change disrupts the balance between the organism and the host. mild mucocutaneous infection is the most common illness, which can lead to vulvovaginitis, mastitis, or, uncommonly, oral mucositis in a mother, and thrush (oral candidiasis) and candidal diaper rash in an infant. invasive candidal infection occurs infrequently, usually when a person has other illness, impaired resistance to infection (hiv, diabetes mellitus, neutropenia; decreased cell-mediated immunity in premature infants or lbw or vlbw infants), or disrupted normal mucosal and skin barriers and has received antibiotics or corticosteroids. invasive disease can occur through local spread, and may occur more often in the genitourinary tract (urethra, bladder, ureters, kidneys), but usually develops in association with candidemia. the bladder and kidney are more frequently involved, but when dissemination occurs via candidemia, a careful search for other sites of infection should be made (e.g., retina, liver, spleen, lung, meninges). transmission usually occurs from healthy individuals colonized with candida through direct contact with them or through contact with their oral or vaginal secretions. intrauterine infection can occur through ascending infection through the birth canal but is rare. no distinct syndrome of congenital candidal infection exists. most often an infant is infected in passing through the birth canal and remains colonized. postnatal transmission can occur through direct contact with caregivers. the mother and infant serve as an immediate source of recolonization for each other, especially during the direct contact of breastfeeding. for this reason, an infant and breastfeeding mother should be treated simultaneously when treating thrush, vulvovaginitis, diaper candidiasis, or mastitis. colonization with this organism usually occurs in the absence of any clinical evidence of infection. simultaneous treatment should occur even in the absence of any clinical evidence of candida infection or colonization in the apparently uninvolved individual of the breastfeeding dyad. no well-controlled clinical trials define the most appropriate or most effective method(s) of treatment for candidal infection in breastfeeding mother-infant pairs. the list of possible treatment products is extensive and includes many anecdotal and empirical regimens. in the face of this absence of data, brent conducted a survey of members of the academy of breastfeeding medicine concerning the respondents' approach to diagnosis and treatment of thrush in the breastfeeding dyad. most of the respondents relied on the history and physical examination of the infant, but only a third rated the examination of the mother as very important in making a diagnosis. only % reported using laboratory testing to make the diagnosis. twentyone percent of the respondents reported using only oral nystatin for the infant when the mother was asymptomatic. almost half treated the infant and the mother with topical nystatin, and % used oral nystatin for the infant and oral fluconazole for the mother when the mother had breast pain. less than % used oral fluconazole for both infant and mother, and other therapies were used by about % of the respondents. for recurrence of persistence of the thrush, more respondents reported treating the mother or both the infant and mother with fluconazole, and almost a quarter reported using other therapies. considerable discussion of mammary candidosis/candidiasis, the clinical diagnosis of candidal involvement of the breast, the significance of pain with breastfeeding, and the presence or absence of candida albicans in milk samples is ongoing. , , this topic will continue to be debated because additional prospective studies are necessary to clarify specific issues. data are inadequate to make specific recommendations about various clinical situations regarding candida and breastfeeding. clinical practice will vary with experience, especially for the more problematic clinical situations. some general guidelines follow. (see chapter for a discussion of mastitis.) the treatment of mucocutaneous candidiasis should probably begin with a topical agent, such as nystatin, clotrimazole, miconazole, econazole, butaconazole, terconazole, or ciclopirox. treatment should continue for at least weeks, even with obvious improvement in or days. failures most often result from inadequate therapy involving the frequency of application, careful washing and drying before application, or, in the case of diaper candidiasis, decreasing the contact of the skin with moisture. nystatin oral suspension is less effective for the treatment of oral candidiasis in infants, now compared with the past, supposedly due to increasing resistance. gentian violet (diluted to . % to . %) applied to the breast or painted onto an infant' s mouth is being recommended more frequently. other topical preparations have been recommended for the mother' s breast including mupirocin, grapefruit seed extract, or mixtures of mupirocin, betamethasone ointments, and miconazole powder. controlled clinical trials for efficacy and toxicity are not available. when good adherence to the proposed regimen with topical agents fails, or when infant or mother are severely affected by pain and decreased breastfeeding, systemic therapy is appropriate. fluconazole and ketoconazole are the most commonly used systemic agents for oral or diaper candidiasis and vulvovaginitis or mastitis. fluconazole has a better side effect profile than ketoconazole, and more data are available concerning its safe use in children younger than months of age and even neonates and premature infants. , , fluconazole is not currently approved for use in infants younger than months of age. for severe invasive infections in infants, amphotericin b with or without oral flucytosine, iv fluconazole, voriconazole or caspofungin are reasonable choices in different situations. use of itraconazole in infants has not been adequately studied to date. maternal use of fluconazole during breastfeeding is not contraindicated because only a small amount of medicine compared with the usual infant dose reaches the infant through breast milk. amphotericin or caspofungin therapy in mothers is also not contraindicated because these are both poorly absorbed from the gi tract. whenever a mother is treated for candidal mastitis or vulvovaginitis, the infant should be treated simultaneously, at least with nystatin oral suspension as the first choice of medication. any predisposing risk factors for candidal infection in mothers and infants should be reduced or eliminated to improve the chance of rapid, successful treatment and to decrease the likelihood of chronic or recurrent disease. for mothers, such interventions might include decreasing sugar consumption, stopping antibiotic use as soon as possible, and consuming some form of probiotic bacteria, such as acidophilus (in yogurt, milk, or pill form), to reestablish a normal colonizing bacterial flora. for infants, breastfeeding can enhance the growth of specific colonizing bacterial flora such as lactobacillus, which can successfully limit fungal growth. breastfeeding should continue with appropriate support and problem-solving with a professional who is knowledgeable about breastfeeding. hiv- , hiv- , htlv-i, and htlv-ii are the only infectious diseases that are considered absolute contraindications to breastfeeding in developed countries. when the primary route of transmission is via direct contact or respiratory droplets/particles, temporary separation of mother and infant may be appropriate (whether the infant is breastfed or formula fed), but expressed breast milk should be given to the infant for the organism-specific immunologic benefits in the mother' s milk. in most instances, by the time a specific diagnosis of infection is made for a mother, the infant has already been exposed to the organism and providing expressed breast milk to the infant should continue. (refer to appendix f for specific exceptions, such as lassa fever.) regarding antimicrobial therapy for mothers and continued breastfeeding, the majority of the medications commonly used in adults can be used to treat the same infection in infants. the additional amount of medication received by infants via breast milk is usually insignificant. in almost all instances, an appropriate antimicrobial agent for treating mothers that is also compatible with breastfeeding can be chosen. unless the risk to infants for transmission of an infectious agent via breast milk that leads to a clinically significant illness in the infants is documented, breastfeeding should continue. measles antibodies in the breast milk of nursing mothers spectrum of breast tuberculosis respiratory syncytial virus infection among young children with acute respiratory tract infection in iraq probable breast milk borne brucellosis in a young infant breast milk transmission of cytomegalovirus (cmv) infection congenital and perinatal cytomegalovirus infections intrauterine west nile virus: ocular and systemic findings the cloning and clinical implications of hgv and hgbv-c bottle feeding can prevent transmission of htlv-i from mothers to their babies transmission of adult t-cell leukemia retrovirus (htlv-i) from mother to child: comparison of bottle-with breastfed babies effect of freezethawing breast milk on vertical htlv-i transmission from seropositive mothers to children long-term follow up study of vertical htlv-i infection in children breastfed by seropositive mothers long-term followup study of htlv-i infection in bottle-fed children born to seropositive mothers the yeast connection: is candida linked to breastfeeding associated pain? epidemiology of group b streptococcus: maternal and nosocomial sources for acquisition tuberculosis and pregnancy and tuberculous mastitis infant botulism infant botulism: anticipating the second decade protective role of human milk against sudden death from infant botulism growth faltering due to breastfeeding cessation in uninfected children born to hiv-infected mothers in zambia other viral infections of the fetus and newborn protozoan and helminth infections (including pneumocystis carinii) recurrent group b streptococcal disease in infants: who should receive rifampin? methicillin-resistant staphylococcus aureus sccmec type iv: nosocomial transmission and colonisation of healthcare workers in a neonatal intensive care unit stringent precautions are advisable when caring for patients with viral hemorrhagic fevers prevalence of methicillin-resistant staphylococcus aureus in expressed breast milk in a neonatal intensive care unit transmision de brucelosis por lactancia materna: presentacion de dos casos congenital lymphocytic choriomeningitis virus infection in twins poliomyelitis in pregnancy, fetus and newborn assessment of the risk of ebola virus transmission from bodily fluids and fomites transmission of hepatitis by breastfeeding 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prevention: yellow fever vaccine; recommendations of the advisory committee on immunization practices (acip) update: cardiac and other adverse events following civilian smallpox vaccination-united states centers for disease control and prevention: secondary and tertiary transfer of vaccinia virus among u.s. military personnel-united states and worldwide centers for disease control and prevention: a new product (varizig) for post exposure prophylaxis of vericells available under an investigational new drug application expanded access protocol centers for disease control and prevention: communityassociated methicillin-resistant staphylococcus aureus infection among healthy newborns: chicago and los angeles county centers for disease control and prevention: what to do if an infant or child is mistakenly fed another woman' s expressed breast milk prevention: transmission of yellow fever vaccine through breast feeding: brazil take of rhesushuman reassortment tetravalent rotavirus vaccine in 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breast milk for evidence of human herpesvirus by pcr cytomegalovirus infection of breast milk and transmission in infancy late postnatal mother-to-child transmission of hiv- in abidjan listeriosis during pregnancy and in neonates rotavirus infections in young nicaraguan children european collaborative study: children born to women with hiv- infection: natural history and risk of transmission european paediatric hepatitis c virus network: effects of mode of delivery and infant feeding on the risk for motherto-child transmission of hepatitis c virus flora of the umbilical stump: cultures a lipid inhibitor of dengue virus in human colostrum and milk, with a note on the absence of anti-dengue secretory antibody vertical transmission of hepatitis g nonspecific antiviral substances in human milk against arbovirus and murine leukemia virus genetic evidence for mother-to-infant transmission of hepatitis g virus stringent precautions are not advisable when caring for patients with viral hemorrhagic fevers evalution and treatment of community acquired staphylococcus aureus infections in term and late-preterm previously healthy neonates diagnostic value of signs and symptoms of mammary candidosis among lactating women immunity and correlates of protection for rotavirus vaccines rate of inactivation of cytomegalovirus in raw banked milk during storage at degrees c and pasteurisation htlv-i transmission from mother to child detection of human herpesvirus (hhv- ) dna in breast milk by polym erase chain reaction and prevalence of hhv- antibody in breast-fed and bottle-fed children a new endemic focus of human t-lymphotropic virus type ii carriers among orinoco natives in colombia estimating the time of htlv-i infection following mother-to-child transmission in a breast-feeding population in jamaica tertiary contact vaccinia in a breastfeeding infant community acquisition of group b streptococcus by infants of colonized mothers infectious diseases of the fetus and newborn 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case-control study in japan a maternal factor for mother-to-child transmission: viral antigen-producing capacities in culture of peripheral blood and breast milk cells mother-to-infant transmission of hepatitis c virus infectious diseases of the fetus and newborn infant sensitive method for detection of human herpes viruses and in saliva collected in field studies survey of pregnant women with hepatitis a and their neonates postnatal transmission of aids-associated retrovirus from mother to infant disseminated lyme disease and pregnancy. th annual international scientific conference on lyme disease and other tick-borne disorders a. siblings at home have active chickenpox when neonate and mother are ready for discharge from hospital.no no . mother: if she has a history of chickenpox, she may return home. without a history, she should be tested for varicellazoster virus antibody titer.* if test is positive, she may return home. if test is positive, she may return home. if test is negative, varicella-zoster ig † is administered and she is discharged home. . neonate: may be discharged home with mother if mother has history of varicella or is varicella-zoster virus-antibody positive. if mother is susceptible, administer varicella-zoster ig to infant and discharge home or place in protective isolation. b. mother has no history of chickenpox; exposed during period - days antepartum. ‡ ‡if exposure occurred less than days antepartum, mother would not be potentially infectious until at least hours postpartum. §considered noninfectious when no new vesicles have appeared for hours and all lesions have crusted. ¶dosage of acyclovir for pregnant woman is mg/kg/day; for seriously ill infant with varicella, to mg/m /day. elisa, enzyme-linked immunosorbent assay; fama, fluorescent antibody to membrane antigen; la, latex agglutination. key: cord- -swlkjtyo authors: arzt, jonathan; branan, matthew a.; delgado, amy h.; yadav, shankar; moreno-torres, karla i.; tildesley, michael j.; stenfeldt, carolina title: quantitative impacts of incubation phase transmission of foot-and-mouth disease virus date: - - journal: sci rep doi: . /s - - - sha: doc_id: cord_uid: swlkjtyo the current investigation applied a bayesian modeling approach to a unique experimental transmission study to estimate the occurrence of transmission of foot-and-mouth disease (fmd) during the incubation phase amongst group-housed pigs. the primary outcome was that transmission occurred approximately one day prior to development of visible signs of disease (posterior median hours, % ci: . – . ). updated disease state durations were incorporated into a simulation model to examine the importance of addressing preclinical transmission in the face of robust response measures. simulation of fmd outbreaks in the us pig production sector demonstrated that including a preclinical infectious period of one day would result in a % increase in the median number of farms affected ( additional farms and , pigs euthanized) compared to the scenario of no preclinical transmission, assuming suboptimal outbreak response. these findings emphasize the importance of considering transmission of fmd during the incubation phase in modeling and response planning. interventions . the proportion of transmission that occurs during the incubation phase is commonly denoted by theta (θ) , . a low value of θ indicates correspondingly low extent of transmission prior to observation of clinical disease. although a low θ is relatively uncommon, this has been associated with infectious diseases for which control or eradication programs have been highly successful such as smallpox and rinderpest , . at the other end of the spectrum are diseases for which θ is remarkably high, such as hiv/aids, which are notoriously difficult to control . closely related to the concept of θ is the temporal disparity between incubation and latency which represents the period of infectiousness included within the incubation period, defined herein as ω (omega; fig. ). while θ is intrinsically linked to the total length of the infectious period (often difficult to measure), ω can be estimated without having knowledge of the termination of infectiousness. additionally, the basic reproduction number (r ) of a pathogen is frequently cited to project and characterize an infectious disease epidemic. this quantity is defined as the average number of secondary cases generated by a typical primary case during its entire period of infectiousness, in a completely susceptible population and in the absence of control measures , . thus, in addition to aspects intrinsic to the specific host-pathogen combination, r will also be affected by numerous extrinsic factors at the population level. combining estimates for r , θ, and ω provides a robust background for evaluating the importance of preclinical transmission in successful modeling of disease spread and control interventions. this current study focused on investigating the concept of θ and ω for direct contact transmission of a virulent strain of foot-and-mouth disease virus (fmdv) amongst juvenile domestic pigs, and examining the impact of pre-clinical transmission on simulated outbreak size and severity within a us swine production system assuming either optimal or suboptimal response conditions. fmdv is a highly contagious viral pathogen of cloven-hoofed domestic and wild animals (genus: aphthovirus, family: picornaviridae) , . the virus, which is the causative agent of foot-and-mouth disease (fmd), has been associated with multiple major disease epidemics in previously free regions in recent years [ ] [ ] [ ] . given the highly contagious nature of the disease, the ability to predict potential fmd dissemination in a naïve population and assess the effectiveness of control interventions can result in critical improvements in preparedness and emergency response for food animal production systems . however, data-driven modeling is intrinsically and precariously dependent upon the appropriateness of the data used for parameterization. recent work examining incubation phase transmission of fmdv amongst cattle has been inconsistent between two studies suggesting either a high value of θ for dairy cattle or a low value for calves , . in contrast to this, a similar investigation demonstrated the occurrence of substantial transmission of fmdv during the incubation phase in group-housed pigs . this current report provides novel modeling approaches based upon the data obtained from this recent transmission study . the findings presented herein suggest a difference between the duration of the latent-and incubation periods (pre-clinical infectiousness; ω) in fmdv-infected pigs that is statistically significantly greater than , and a resultant θ that is larger than previously suggested in studies of fmdv transmission in cattle. additionally, simulating fmd outbreak scenarios using fixed and incrementally increasing values of ω demonstrated significant influence of incubation phase transmission on the size and duration of fmd outbreaks in us pig production systems, even in the presence of rigorous control strategies. fmdv transmission study. the experimental basis for the analyses presented herein consisted of a transmission study in which groups of naïve pigs were exposed to a group of fmdv-infected "donor pigs" through successive eight hour time periods (fig. ) . successful transmission from donors was determined by confirmed occurrence of fmd in contact-exposed pigs subsequent to exposure. the progression of infection was monitored and quantitated in both donors and contact-exposed pigs through measurements of viral genomic rna in serum and oropharyngeal fluids (opf). in brief, all pigs in the donor group were confirmed to have been infected by needle-free oropharyngeal inoculation with fmdv and were shedding fmdv rna in opf throughout the figure . definitions used to characterize distinct periods of infectious diseases. the latent period (e; green arrow) begins at the time of infection and ends at the onset of the infectious period. (i; red arrow). the incubation period (c; blue arrow) starts at the time of infection and ends at the appearance of clinical signs of disease (purple arrow). the difference between incubation and latency is denoted by ω (omega), and can have either a positive or negative value depending on whether transition to the infectious period occurs before or after appearance of clinical signs. the ratio of transmission occurring during incubation, and transmission occurring through the total infectious period is denoted by θ (theta; not shown). contact transmission trial. viremia in donor pigs was first detected at hours post inoculation (hpi), whereas fever (rectal temperatures > °c) and vesicular lesions were observed simultaneously at hpi ( supplementary fig. s ). there were no transmission events between the donors and contact groups or , which had been exposed to the donor pigs from to hpi, and to hpi, respectively. contrastingly, all pigs in contact groups through , corresponding to exposure from through hpi of the donors, developed clinical fmd (fig. ) . on this basis it was experimentally demonstrated that transmission from donor pigs had occurred at least hours prior to detection of clinical disease . a bayesian model was used to estimate the length of the latent, incubation, and infectious periods of the donor pigs based on data from the transmission trial . the model estimated the latent period to last slightly longer than one day (median hours, % ci - hours) ( table , fig. ). the incubation period was estimated to be approximately days (median hours, % ci: - ), and the total infectious period was estimated to be approximately days (median hours, % ci: - hours). the posterior median latent period was shorter than the prior median latent period (fig. a ). using the prior information, the latent period ended approximately hours after inoculation. by the posterior information, the length of the latent period was updated to last about hours (table ) . thus, the latent period is likely longer than a day and the effect of the observed data was large enough to influence the diffuse prior information (table ; figure . experimental design, fmdv transmission study. seven groups of five pigs each were exposed to five fmdv-infected donor pigs through successive eight hour exposure periods. contact groups were housed in separate isolation rooms before and after exposure to the donor pigs. the time points in the figure represent beginning (green) and end (red) of exposure for each contact group in relation to inoculation of the donor pigs. there was no transmission of infection to contact groups and (exposed from - , and - hours post infection of donors, respectively). all pigs in contact groups through developed clinical fmd after exposure to the donors. , incubation (c), and infectious (i) periods and their means (μ e, μ c, and μ i ) are expressed in terms of hours for a typical member of the donor animal group. parameter estimates for θ are in terms of a proportion, and β is expressed in terms of transmission rate. www.nature.com/scientificreports www.nature.com/scientificreports/ fig. a) . in contrast to this, the durations of the incubation and total infectious periods by posterior distributions were not significantly different from the prior distributions (fig. b,c) . a specific interest of this part of the analysis was to determine the duration of infectiousness during the incubation period (ω) as well as the proportion of transmission that occurred during this subclinical infectious period relative to total transmission (θ). the estimation of θ relies on the length of the total infectious period, which is comprised by both subclinical and clinical phases. assuming a median total infectious period of hours as estimated by the bayesian model, θ was estimated to be . . the duration of the subclinical phase of infectiousness corresponds to the difference between incubation and latent periods, both of which were modeled based upon directly measured experimental data. given the posterior medians of the latent ( hours) and incubation ( hours) periods, the difference between these values indicates a median duration of subclinical infectiousness (ω) of approximately hours ( % ci: . - . hours; table ). estimating the sensitivity of θ to variations in duration of infectious period. theta (θ) represents the fraction of transmission that occurs during the incubation phase in relation to transmission occurring through the total infectious period and is thereby intimately linked to the duration of the total infectious period. yet, no study has effectively measured the duration of infectiousness in fmdv-infected animals experimentally; rather, modeling studies have universally used proxies to generate estimates for this variable. in order to explore the sensitivity of θ to variations of the infectious period, θ was modeled using step-wise increasing durations of infectiousness ranging from to days, while keeping ω at the modeled estimate of . hours. the maximum resultant value of θ, which was based on modeling an infectious period of day was . ( % ci . - . ; supplementary table s ). contrastingly, if modeling a duration of infectiousness of days, the resulting estimate of θ was . ( % ci . - . ; supplementary table s ). as expected, θ varied inversely with duration of infectiousness throughout the sensitivity analysis. because transmission is rarely directly quantified in experimental or field studies, we tested the ability of our bayesian model to characterize transmission using various forms of more commonly available proxy measures for table ) . in order to test the reliability of these proxies to predict transmission, the bayesian model of donor pig infection dynamics was repeated to compare the model outcomes when the onset of infectiousness in donor pigs was defined based on the proxy measures rather than confirmed transmission events (cte-standard). the most noteworthy findings from this approach were the substantial changes in the modeled estimates of the duration of latency and subclinical infectiousness (ω) when defining the onset of infectiousness by either the occurrence of clinical signs of fmd in donor pigs or by any detection of fmdv rna in opf. defining the onset of infectiousness by the occurrence of clinical signs in donors led to a hour discrepancy of latency compared to the cte-standard, with a prolonged latent period of hours ( % ci - hours), and an ω of − . hours (fig. , supplementary table s ) . similarly, detection of (any) fmdv rna in opf as indicator of infectiousness resulted in a shortened latent period lasting only hours ( % ci - hours) and a resultant duration of subclinical infectiousness (ω) of hours ( % ci - hours; fig. , supplementary table s ). defining the onset of infectiousness by detection of fmdv rna in opf above a threshold of . log gcn/ml led to marginally decreased durations of latency and ω, whereas use of the proxy, detection of fmdv in serum led to the closest estimate to the cte-standard (fig. , supplementary table s ). our bayesian modeling of infection dynamics in fmdv-infected pigs estimated the occurrence of a subclinical infectious period (ω) of hours (table ). the practical ramification of this finding is that pigs that are infected with fmdv are capable of transmitting disease for approximately day prior to the development of any visible signs of infection, which could lead to further disease spread through animal movements and indirect contacts before a producer realizes through clinical observation that there is a health problem in the herd. in order to assess the impact of the duration of the subclinical infectious period in fmdv-infected pigs on outbreak size and duration, we performed a series of fmd outbreak simulations with the us national fmd model (interspread plus (isp) version . model software ), which can account for the complex movements and interactions seen in intensive pig production systems. simulations were run on a reduced farm population file composed of , swine operations with different production types and a total of , , pigs, in the eastern united states ( supplementary fig. s ). surveillance and control measures were modeled including passive and active surveillance in zones around infected premises, movement restrictions in the k zone around infected premises, and depopulation of infected premises. under optimal conditions, detection of the index case was based on the onset of clinical signs within the herd and depopulation occurred within to days (depending on herd size) at a rate of farms/day. for the suboptimal response, initial detection was delayed days, and depopulation was delayed days. for both the optimal and suboptimal responses, the duration of subclinical infectiousness was varied from to days, and the effect on outbreak size and duration examined. overall, incremental increases of subclinical infectious period (ω) led to substantial increases in the size and severity of simulated outbreaks under both categories of outbreak responses. when outbreak response conditions were assumed to be optimal, a -day subclinical infectious period (ω = day) as compared to absence of subclinical infectiousness (ω = day), resulted in a % increase of the median number of infected farms, necessitating euthanasia of , more pigs, and an increase of the median outbreak duration from to days ( fig. and supplementary table s ). when the outbreak response was assumed to be suboptimal, the effects of increasing ω were more profound, with a one-day subclinical infectious period resulting in median outbreak size increasing by farms ( %), outbreak duration increasing from days to days, and euthanasia of , additional pigs required ( fig. and supplementary table s ). further increases of ω resulted in corresponding increases in outbreak size and severity, under both optimal and suboptimal outbreak response conditions (fig. ) . specifically, each incremental increase in omega led to a longer duration of the outbreak, with some increments having significant effect. the greatest magnitude of effect that was estimated occurred with a -day subclinical infectious period (ω = day) combined with suboptimal outbreak response which resulted in . % of farms, and . % of all pigs in the population ( , , pigs) becoming infected. numeric values between and , with . increments corresponding to observations of lesions in contact-exposed pigs table . proxy measures used to determine the onset of infectiousness. www.nature.com/scientificreports www.nature.com/scientificreports/ effective control of infectious disease outbreaks is dependent upon rapid identification of infected individuals and mitigation of risks that could otherwise cause widespread dissemination of contagion. in the absence of an outbreak, data-driven mathematical models that can estimate disease spread and the impacts of control interventions can offer valuable insights to enable planning and preparedness . the ultimate goal of such modeling is to guide and assess the effectiveness of control measures to minimize disease impacts, quantitated as morbidity, mortality, economic loss, or other relevant metrics , . the overarching objective of the current investigation was to use detailed data from a carefully executed experimental study of fmdv transmission to model the durations of distinct stages of disease in fmdv-infected pigs, and to highlight the importance of addressing incubation phase (subclinical) transmission in fmd models. in order to explore the concept of disease spread before clinical detection, it was of particular interest to estimate the latent period (time from infection until onset of infectiousness) in relation to the incubation period (time from infection until appearance of clinical signs of disease). the estimated parameters were subsequently used to explore the impact of alterations in the duration of subclinical infectiousness on simulated fmd outbreaks in commercial swine production systems under both optimal and suboptimal response conditions. disease modeling is critically dependent upon input parameters that closely reflect the intrinsic properties of the infectious agent as well as externally variable features of the modeled scenario (e.g. population composition and density, contact networks and patterns, topographical characteristics, meteorological variations and availability of resources) , . the simulations in this current investigation utilized the national fmd model developed by the us department of agriculture to simulate fmd outbreaks within the us pig production system. this the proxy measures consisted of detection of fmdv rna in blood ("viremia"), detection of fmdv shedding in oropharyngeal fluid (opf) either above the assay lower limit detection ("any" shedding), or above a defined threshold of . log fmdv rna copies per ml ("threshold" shedding), or detection of clinical signs of fmd. the duration of latency (a) was underestimated compared to the cte-standard, when using fmdv shedding in opf ("any" or "threshold" shedding) to define the onset of infectiousness. detection of viremia as a proxy of infectiousness led to an estimated latent duration that was close to the cte-standard, whereas defining infectiousness by detection of clinical signs overestimated the duration of latency. the duration of subclinical infectiousness (b) and the proportion of transmission during the incubation phase (c) were underestimated when the onset of infectiousness was based on detection of clinical signs. the estimates based on the remaining four proxy-measures were less dispersed. for both parameters, detection of viremia provided the estimates closest to the cte-standard, whereas detection of fmdv shedding in opf provided slightly higher estimates. www.nature.com/scientificreports www.nature.com/scientificreports/ model is adapted to specific conditions within the us agricultural system, and parameterized to reflect the complex and overlapping outbreak response measures identified in the us national fmd outbreak response plan . additionally, the model is flexible and allows for adjustment of select parameters, as was performed in the current study to explore the effect of preclinical transmission on simulated outbreaks. similar to other disease spread models, this model is built upon assumptions concerning specific characteristics of the us production system for which it was designed. extrapolation of the modeled output should therefore be done with caution. however, under the given circumstances, the outcome of the outbreak simulations included herein serve to emphasize the critical impact that the occurrence of disease transmission during the incubation phase may have on the magnitude of an fmd outbreak. parameters for modeling of disease outbreaks are usually derived from meta-analyses figure . output of fmd outbreak simulations based on increasing durations ( - days) of subclinical infectiousness under optimal and suboptimal outbreak response conditions. ribbon plots for the cumulative number of infected pigs (a) and ridge plots for the epidemic curve (b) when modeled using incrementally increasing durations of subclinical infectiousness (ω) and assuming optimal (left panels) and suboptimal (right panels) outbreak responses. the lower edge, central line, and upper edge of the plots represent th percentile, median, and th percentile, respectively for the specific duration of the subclinical infectiousness (ω). www.nature.com/scientificreports www.nature.com/scientificreports/ of published experimental investigations that were not originally designed to assess disease transmission , . bayesian methods offer an alternative approach to inferring epidemiologic parameters from transmission experiments, which can improve our understanding of the latent and infectious periods , . regardless of the method used, in the absence of data explicitly describing actual disease transmission, different proxy measures must be used to define the transition between distinct stages of disease. the use of proxies often results in the assumption that the onset of infectiousness is defined either by the first evidence of infection in a given individual (pathogen detection), or by the appearance of visible clinical signs of disease. in the current investigation, the proxy measure of high-threshold shedding was interpreted to be the most relevant predictor of transmissibility of fmdv. onset of viremia was also correlated with infectiousness, which is likely due to the role of viremia in causing systemic dissemination and shedding of virus. as demonstrated in this investigation, inappropriate use of proxy measures to define the onset of infectiousness in replacement of actual transmission data can lead to drastic misinterpretations of the transmission potential of infected animals. these misinterpretations may in turn affect fmd outbreak simulations, resulting in underestimation of outbreak size and severity, leading to unrealistic estimates of resource needs and misguided guidance on the appropriate application of control interventions. specifically, underestimating the potential for disease transmission during the incubation phase may lead to wider dissemination of the outbreak than anticipated, and subsequent failure of reactive control interventions such as vaccination. contrastingly, overestimating disease transmission can promote excessively aggressive countermeasures and lead to destruction of large numbers of healthy animals and associated economic losses. this may result in substantial animal welfare issues and added economic losses as products and animals from unaffected farms cannot enter the production chain. appropriately balanced interventions are thus critical to effectively control disease spread while striving to maintain business continuity. the current investigation demonstrated that the modeled onset of infectiousness in fmdv-infected pigs occurred approximately one day prior to appearance of clinical signs of disease, as was consistent with the primary descriptive data from these experiments . this is consistent with earlier work which demonstrated fmd transmission during the incubation phase in pigs, lambs, and cattle . however, one published work contradicts these findings by suggesting that fmd is unlikely to be transmitted before the onset of clinical disease . although there is limited published information on this subject, the consensus of available data suggests that subclinical transmission of fmd does occur, indicating that incubation is longer than latency and the resultant ω is greater than zero. this result was concluded based on the significant disparity between the durations of incubation and latency which indicated a distinct period of subclinical infectiousness that was demonstrated by experimentation and verified by modeling. due to the limited group sizes and ubiquitous infection in groups to which transmission occurred, it was not possible to estimate r in the current investigation. however, previous investigations have estimated the basic reproduction ratio, r , for fmdv within groups of non-vaccinated pigs in experimental settings to be as high as . ( % ci: . - . ) or ( % ci: - ) . the combination of a generally high r for within-group transmission of fmdv in pigs, and a positive value for ω as determined in the current study suggests that the potential for fmdv transmission during the incubation phase should be recognized when modeling fmd outbreak scenarios. our estimate for the proportion of preclinical transmission of fmdv that occurs in pigs was %, falling between values reported for sars (θ < %) and smallpox ( < θ < %) . fraser et al. identified a relationship between r , θ, and the effectiveness of control interventions to bring an outbreak under control. as r and θ increase, control interventions must be highly effective, and multiple interventions are required in order bring the outbreak under control. estimated values of r and θ for fmdv suggest that control of epidemics is dependent on using multiple, highly effective control interventions. interestingly, these results may also suggest that isolation and contact tracing, if conducted nearly perfectly, could eventually be sufficient to prevent epidemic propagation. however, in the absence of significant technological advances, such interventions are unlikely to be implemented perfectly in livestock populations, and the timelines required for disease control could be much longer than when more interventions are enacted simultaneously. the potentially profound consequences of fmdv incursions into regions previously free of fmd can, to a great extent, be attributed to the highly contagious nature of the virus. this was demonstrated in the current study by the maximum impact simulated example of infection of over , , pigs when high ω was combined with a suboptimal outbreak response. although fmdv can be transmitted via a multitude of both direct and indirect routes , movement of infected animals has been identified as the most significant risk for dissemination of infection during the early phase of an outbreak . this current investigation demonstrated the relevance of fmdv transmission during the incubation period in group-housed pigs. furthermore, it was demonstrated that the duration of subclinical infectiousness had significant effects on spread and duration of simulated fmd outbreaks. the data used for modeling of disease stage durations in the current study were derived from experiments in which pigs were infected with one specific fmdv strain, under experimental conditions. the virus strain and host criteria were chosen based upon extensive experience in our laboratory with these conditions and the assumption that the virus and conditions were representative of most virulent fmdvs. it is possible that disease dynamics in the field may differ due to strain-specific variations in virulence, as well as differences in animal age, health status, and housing conditions. thus, it should be emphasized that the modeled output presented herein is based on experimental conditions, and represents our best estimate of what could be expected to occur under natural conditions in the field. the findings presented herein demonstrate the importance of considering and elucidating the intricacies of key epidemiologic parameters, including preclinical infectiousness, the importance of understanding the relationships between proxy measures of disease status and infectiousness, and the subsequent value of incorporating these detailed parameters into disease spread models. additionally, improved understanding of the influence of animal-level disease dynamics upon dissemination of fmd outbreaks may lead to improved approaches to www.nature.com/scientificreports www.nature.com/scientificreports/ surveillance and diagnostic testing to further refine control measures and maximize effectiveness while limiting undesired consequences for the agricultural industries. animal experiment. the data used in this current investigation were derived from an experimental trial designed to evaluate the onset of infectiousness in relation to the appearance of clinical disease in fmdv-infected pigs (fig. ) . a detailed description of the experimental study and clinical findings has been published previously . animal experiments were carried out within bsl -ag facilities at plum island animal disease center, new york. all procedures were carried out in accordance with guidelines specified within the associated experimental protocol (protocol - -r), and were approved by the plum island animal disease center institutional animal care and use committee. in brief, the study included groups of pigs of approximately - weeks of age (~ kg), of which one group was infected with fmdv a cruzeiro through simulated-natural inoculation . the remaining groups of pigs (contact groups - ) were sequentially exposed to the infected donor pigs through hours of successive co-habitation within a designated isolation room (fig. ) . after exposure to the donor pigs, contact-exposed pigs were moved into separate isolation rooms and were monitored for development of fmd. samples collected were oropharyngeal swabs to assess virus shedding and blood samples to measure viremia. clinical examinations and sample collection were done at - hour intervals after exposure. the choice to use fmdv a cruzeiro for these experiments was based upon numerous previous experiments in our laboratory which had demonstrated that this strain was consistently virulent and transmissible in pigs , - . data analysis. definitions. the end of latency for the donor pigs was defined as the beginning of the hour contact exposure period during which the first successful transmission event occurred. it was not possible to attribute transmission events to specific individuals as donors and contact pigs were allowed to move freely within the exposure room. thus, the earliest observed transmission event was used to define the transition from latent to infectious periods for all donor pigs. the end of the incubation period for the donor pigs was determined for each pig individually by the first detection of vesicular lesions, which for all donor pigs coincided with detection of fever (rectal temperature ≥ °c). fmdv shedding was defined by continuous detection of fmdv rna in opf. viremia was defined by detection of fmdv rna in serum. a bayesian model was fitted to the data for the purpose of estimating the length of three distinct periods the donor pigs were expected to traverse: the latent, incubation, and infectious periods. a modeling approach was adapted from that published by charleston et al. . this model describes the relationship among the observed transmission successes and the unobserved latent, incubation, and infectious periods as well as the hyperparameters describing the distribution of those periods in the following way: : start/end time of challenge i of donor j. p ij : probability of successful transmission in challenge i of donor j. β: transmission rate. t ij : time during challenge i for which donor j is infectious. e j : latent period for donor j. c j : incubation period for donor j. i j : infectious period for donor j. μ e , μ c , μ i , σ e , σ c , σ i , ρ ec : hyperparameters for latent, incubation, and infectious period prior distributions (in order; the means for the three periods, the standard deviations for the three periods, and the correlation between the latent and incubation periods). α e , η e , α c , η c , α i , η i : hyperparameters for the means and standard deviations for the latent, incubation, and infectious period prior distributions (in order, the mean and standard deviation for the mean of the prior latent distribution, the mean and standard deviation for the mean of the prior incubation distribution, the mean and standard deviation for the mean of the prior infectious distribution). the likelihood above describes the relationship between the observed transmission event data with the unobserved latent, incubation, and infectious periods, while the prior information (table ) was based on accumulated data from previous investigations carried out under similar conditions [ ] [ ] [ ] [ ] , or were left diffuse in the absence of such information. these sources of information were combined and the posterior distribution over the parameters (latent, incubation, and infectious periods along with the means of the three periods) given the observed data ( ) : | https://doi.org/ . /s - - - www.nature.com/scientificreports www.nature.com/scientificreports/ (the outcomes of the transmission events) was estimated. this distribution is proportional to the product of the likelihood and the joint prior distribution for all of the parameters. as the posterior conditional distributions for at least the latent period, infectious period, and the transmission rate were intractable, a numerical rather than an analytic approach was pursued. the model was coded using just another gibbs sampler (jags) software designed to perform markov chain monte carlo (mcmc) simulations . this version of the model required two sacrifices: the latent and incubation periods could not be jointly lognormal, and the prior hyperparameter variance terms (σ e , σ c, and σ i ) were held fixed due to mcmc chain convergence issues as a result of unidentifiability issues. the result of the former being that the latent and incubation periods are assumed independent a priori. the proportion of infection that occurs prior to onset of clinical disease, denoted as θ, is a function of the quantities estimated by the model described above. using the jags version of the model adapted from charleston et al. and assuming that latent and incubation periods are independent a priori, θ is described in as follows: in addition to θ, we propose herein a distinct parameter (ω; omega) that allows more precise and direct inference about pre-clinical infectiousness to be made regardless of the total duration of the infectious period by representing the disparity between incubation and latency (fig. ) . estimating fluctuations of θ due to variations in duration of infectious period. as total duration of infectiousness was not experimentally evaluated in the current study, information about the length of the infectious period is drawn almost solely from the prior information. in order to evaluate the sensitivity of θ to variations in the total infectious period, θ was estimated as described above, but using incrementally increased integer values of infectious duration ranging from to days. modeling infection dynamics using different proxy measures to determine the onset of infectiousness. four different proxy measures (table ) were evaluated for their ability to predict disease transmission. the outcome of modeling transmission using the defined proxy measures was compared to the standard model, which was based on confirmed transmission of fmdv to contact-exposed pigs (confirmed transmission event (cte) -standard). the four evaluated proxies were defined as follows: (a) detection of fmdv rna in serum, (b) detection of any fmdv rna in opf, (c) detection of fmdv rna in opf above a threshold of . log gcn/ml, which had previously been associated with successful transmission of fmdv (d) clinical signs of fmd. the data were input into a bayesian model via five distinct indicator matrices, one for each measure of transmission, in which the number of rows equaled the number of contact animals-hours-post-inoculation combinations and the number of columns represented the five donor pigs. each entry in the matrices was either a , if the donor animal met the criteria for successful transmission for the given transmission metric (table ) during exposure to the contact animal represented by that row, or a if the donor animal did not meet the criteria for successful transmission given transmission metric at that time. for the cte-standard transmission metric, which was defined by confirmed transmission to contact-exposed pigs, the vector for all donors was identical as the effect of individual donors on contact animal could not be determined as both sets of animals were exposed to one another in groups. simulation modeling of an fmd outbreak using estimated transmission parameters. the objective of the fmd outbreak simulations described herein was to evaluate the effect of altering the duration of the subclinical infectious period (omega; ω) on spread and duration of an outbreak of fmd in a us pig production sector. estimates of disease stage durations were derived from modeling of animal-level infection dynamics ( table ). the originally modeled output consisted of estimates for the durations of latent (e), incubation (c) and infectious (i) periods. the durations of the subclinical infectious period (ω = c − e) and clinical infectious period (i c = i − c) were derived from these outputs. in addition to the baseline scenario (ω = day), five omega values ( day, days, days, days, and days) were subjectively selected to evaluate the effect on altering the duration of the subclinical infectious period on the spread and duration of simulated outbreaks. while choosing different omega values, the durations of latent and clinical infectious periods were kept constant (similar to baseline scenario) except for the scenario in which ω = day of omega where the latent duration was set to days (supplementary table s ). the within-herd (wh) software version . . available through the north american animal disease spread model was used to estimate herd-level parameters based on the modeled animal-level fmd disease stage durations. a spatial microsimulation model called the farm location and agricultural production simulator (flaps) was used to generate a synthetic population file of , farms with , , total pigs representative of pig production systems in the eastern united states (supplementary fig. s ). the us pig farms (with essential attributes for isp such as identification number, herd size, type of farms, and cartesian coordinates) located in the great lake, north east and south east regions were included in the model scenarios. about % (n = , ) of the total pig farms in the united states are located in these regions. amongst these farms, % were commercial farms with a median herd size of pigs (range: to , ) and % were small-scale enterprises with a median herd size of pigs (range: to ). farm-type specific movement parameters and contact rates were assigned to reflect differences in movements between commercial and small-scale enterprises. fmd outbreak simulations were performed using interspread plus (isp) version . model software . the isp www.nature.com/scientificreports www.nature.com/scientificreports/ is a state-transition, stochastic and spatial modeling tool for the simulation of fmd and other similar diseases . twelve fmd outbreak scenarios were developed in isp representing optimal and suboptimal outbreak response conditions for each of distinct values for the duration of subclinical infectiousness: day, day, days, days, days, and days of omega, respectively (supplementary table s ). the unit of interest in the model was the individual farms. fmd epidemics were initiated from single farms. after exposure to fmdv, the susceptible farms were modeled to transit into latent, subclinically infectious, clinically infectious, and depopulated states. the spread of fmdv from an infected to susceptible farms was modeled to occur through direct contact, indirect contact, and local spread (supplementary note). the daily probability of transmission of fmd virus from infected farms to susceptible farm was calculated as the hypergeometric probability of shipping at least one infected animal off of an infected farm given the average herd size, shipment size, and the number of infected animals in a herd on a given day ( supplementary fig. s , supplementary note). once an infected farm was detected, several control strategies were imposed simultaneously as is typically performed in response to outbreaks in fmd-free areas. control strategies included zoning of control areas, tracing of animal movements, animal movement restrictions, depopulation of the infected farms, and surveillances as delineated in the national response plan for fmd (supplementary note). for each of the omega scenarios, two overall control strategies (optimal and suboptimal) were separately simulated. in the optimal control strategy, the detection of infected farms through passive surveillance was modeled to occur just after onset of clinical signs, which was further delayed by days in suboptimal control category. additionally, the delay in depopulation of detected farms was (small farms) to days (big farms) in the optimal control category, which was delayed by more days to represent the suboptimal control. the major outputs parameters were outbreak size (number of infected farms and pigs), epidemic duration (days from onset of infection to end of epidemic), time between onset of infection to detection, and daily new infected farms due to each of the incorporated omega values. the median and interquartile range of outbreak size and epidemic duration were reported. the data analyses were performed using sas (sas institute inc., nc, usa, ) and microsoft excel (microsoft excel, redmond, washington, ). the kruskal-wallis test with bonferroni corrections was performed for multiple group comparisons for the outcomes from various omega values. a p-value of ≤ . % was considered for statistical significance. all data generated or analyzed during this study are included in this published article and its supplementary information files. table . prior distributions and estimates used to model animal level infection dynamics. posterior estimates for the latent (e), incubation (c), and infectious (i) periods, their means (μ e, μ c, and μ i ), and their standard deviations (σ e , σ c , and σ i ) are expressed in terms of hours for a typical member of the donor animal group. parameter estimates for θ are in terms 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review and meta-analysis with application to simulation models a meta-analysis quantifying transmission parameters of fmdv strain o taiwan among non-vaccinated and vaccinated pigs the pathogenesis and diagnosis of foot-and-mouth disease relative risks of the uncontrollable (airborne) spread of fmd by different species infection dynamics of foot-and-mouth disease virus in pigs using two novel simulated-natural inoculation methods early events in the pathogenesis of foot-and-mouth disease in pigs; identification of oropharyngeal tonsils as sites of primary and sustained viral replication detection of foot-and-mouth disease virus rna and capsid protein in lymphoid tissues of convalescent pigs does not indicate existence of a carrier state direct contact transmission of three different foot-and-mouth disease virus strains in swine demonstrates important strain-specific differences american animal disease spread model (naadsm) development team simulating the distribution of individual livestock farms and their populations in the united states: an example using domestic swine (sus scrofa domesticus) farms interspread plus: a spatial and stochastic simulation model of disease in animal populations pauszek are thanked for supporting sample processing and laboratory analyses. c.s. and j.a. conceived and coordinated the study, executed the animal experiments and drafted the manuscript. m.b. performed the bayesian analysis and contributed to data interpretation. k.m. and s.y. performed simulation modeling and contributed to data interpretation. a.d. coordinated and oversaw data analyses and contributed scientific content. m.t. critically reviewed data analyses and contributed scientific content. all authors have reviewed and revised the manuscript and approved the final product. supplementary information accompanies this paper at https://doi.org/ . /s - - - .competing interests: the authors declare no competing interests.publisher's note: springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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 license, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons license 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. to view a copy of this license, visit http://creativecommons.org/licenses/by/ . /. key: cord- - ewz ok authors: kutter, jasmin s; spronken, monique i; fraaij, pieter l; fouchier, ron am; herfst, sander title: transmission routes of respiratory viruses among humans date: - - journal: curr opin virol doi: . /j.coviro. . . sha: doc_id: cord_uid: ewz ok respiratory tract infections can be caused by a wide variety of viruses. airborne transmission via droplets and aerosols enables some of these viruses to spread efficiently among humans, causing outbreaks that are difficult to control. many outbreaks have been investigated retrospectively to study the possible routes of inter-human virus transmission. the results of these studies are often inconclusive and at the same time data from controlled experiments is sparse. therefore, fundamental knowledge on transmission routes that could be used to improve intervention strategies is still missing. we here present an overview of the available data from experimental and observational studies on the transmission routes of respiratory viruses between humans, identify knowledge gaps, and discuss how the available knowledge is currently implemented in isolation guidelines in health care settings. viral respiratory tract infections are a leading cause of morbidity and mortality worldwide, representing an enormous economic and disease burden [ ] . respiratory viruses replicate in the respiratory tract from where they are subsequently shed and transmitted via respiratory secretions. they are classified in different virus families and differ in virulence and target groups. respiratory tract infections may range from asymptomatic to acute live threating disease thereby posing a major health threat to young children, elderly, and immunocompromised people. respiratory viruses spread via three different transmission routes: contact (direct or indirect), droplet and aerosol transmission (table ) [ , ] . contact transmission refers to direct virus transfer from an infected person to a susceptible individual (e.g. via contaminated hands) or indirect virus transfer via intermediate objects (fomites). transmission of virus through the air can occur via droplets or aerosols. the commonly accepted cut-off size between the large droplets and small aerosols is mm, although this varies considerably between studies, ranging up to mm [ ] [ ] [ ] [ ] [ ] . droplets generated during coughing, sneezing or talking do not remain suspended in air and travel less than m before settling on the mucosa of close contacts or environmental surfaces. aerosols have a slow settling velocity, thus they remain suspended in the air longer and can travel further [ , , ] . transmission via each of these three routes is complex and depends on many variables such as environmental factors (e.g. humidity and temperature), crowding of people, but also on host factors such as receptor distribution throughout the respiratory tract. the fact that all these variables affect the different transmission routes of the different respiratory viruses in a dissimilar way, makes it very difficult to investigate them experimentally [ , ] . here, we summarize the evidence from experimental and observational studies on inter-human transmission routes of important respiratory viruses (summarized in table ). a literature search was conducted for each respiratory virus using 'human transmission experiments' and 'transmission (routes)' of the virus of interest as search criteria in pubmed and google scholar. subsequently, the backward snowball method was applied in which additional papers were identified based on the reference list of a paper of interest. as this review focuses on the evidence on inter-human transmission routes, data from animal studies were excluded. in addition, intervention studies, (aircraft) outbreak reports and household studies were excluded if the transmission route was not specifically investigated. the strengths and weaknesses of the different methods employed in transmission studies are summarized in table . finally, we discuss our findings in the light of several available (inter)national guidelines on infection control. our observations underscore the urgent need for new knowledge on respiratory virus transmission routes and the implementation of this knowledge in infection control guidelines to advance intervention strategies for currently circulating and newly emerging viruses and to improve public health. measles is one of the most contagious viral diseases in humans that has been associated with aerosol transmission for a long time [ , , , - , ]. however, it should be noted that mv also replicates systemically, and that there is a role for dead cell debris-associated virus spread via fomites. in the late s and early s, data from retrospective observational studies obtained during outbreaks in pediatric practices, a school, and a sporting event suggested transmission through aerosols [ , - , ] . indeed, those studies showed that most secondary cases never came in direct contact with the index patient and some were never even simultaneously present in the same area as the index case [ , ] . examination of airflow in the pediatricians' offices showed that aerosols were not only dispersed over the entire examination room but also accumulated in the hallway and other areas [ , ] . furthermore, based on the investigation of air circulation in a sport stadium, in which a mv outbreak occurred, authors suggested that mv had been dispersed through the ventilation system [ ] . thus it was concluded that mv can be transmitted via aerosols. although coughing is a common symptom associated with measles disease, index patients were described to cough inter-human transmission of respiratory viruses kutter et al. table commonly accepted respiratory routes of transmission [ ] . superspreaders are individuals who are able to infect a disproportionally large number of susceptible contacts when compared to a typical individual [ ] [ ] [ ] [ ] , which may contribute to the efficient transmission of mv. table overview of the methods to study human-to-human transmission and their respective pro's and con's usually not conclusive on transmission route or relative importance of transmission routes. [ ] [ ] [ ] [ ] outbreak reportaircraft relatively easy to perform outbreak in closed setting retrospective which can result in recall-bias and hard to trace back passenger movements. inconclusive. only reported in case of secondary infections and in these cases infections may also occur before or after the flight. [ , [ ] [ ] [ ] [ ] non-pharmaceutical intervention can help to discriminate between transmission routes if performed properly. usually no controlled environment. difficult to determine ideal time-point of the intervention. risk of drop-out or perseverance. [ , [ ] [ ] [ ] [ ] pharmaceutical intervention characterization of droplet/ aerosol size. can be used in parallel with human studies or outbreaks. can gain information on possible aerosol spread. in a nosocomial setting aerosol-generating procedures can play a major role. frequently only detection by pcr. direct human-to-human transmission is not studied (circumstantial). technical issues (procedure may affect virus viability) or false interpretation. visualize airstream usually performed retrospectively and not during outbreaks [ , ] computational modeling/simulation describes transmission in a greater context. can account for heterogeneity of transmission within a population. human mannequins can be used as replacement for humans theoretical (for mathematical modeling). artificial setting. [ , [ ] [ ] [ ] [ ] [ ] [ ] there is a substantial lack of (experimental) evidence on the transmission routes of piv (types - ) and hmpv. for both viruses, contact and droplet transmission are commonly accepted transmission routes [ ] [ ] [ ] . however, only virus stability on various surfaces has been investigated so far and it has been shown that piv and hmpv are stable on non-absorptive surfaces and can barely be recovered from absorptive surfaces [ - ]. transmission of rsv among humans is thought to occur via droplets and fomites [ , ] . in the s three potential transmission routes of rsv were studied in humans by dividing infected infants and healthy volunteers into three groups, representing: firstly, all transmission routes, secondly, transmission via fomites and finally, airborne transmission by allowing the volunteers to have either, firstly, direct contact with infants (cuddlers), secondly, touching potential fomites (touchers) or finally, sitting next to the infant (sitters). volunteers in the group of the cuddlers and touchers but not the sitters became infected, suggesting that direct contact and droplet transmission were the probable routes for efficient infection of the volunteers and that transmission via aerosols was less likely [ ] . another study on the transmission via fomites showed that rsv could be recovered from countertops for several hours, but only for several minutes from absorptive surfaces such as paper tissue and skin [ ] . later on, in the late s, aintablian et al. detected rsv rna in the air up to m away from a patient's head [ ] . in spite of that, since virus infectivity could not be demonstrated, potential airborne transmission of rsv has been considered negligible and transmission of rsv was thought to occur mainly through contact and droplet transmission. however, in a recent study authors were able to collect aerosols that contained viable virus from the air around rsv infected children [ ] . although the detection of viable virus in the air is by itself not enough to confirm aerosol transmission, the general presumption that rsv exclusively transmits via droplets should be reconsidered and explored further. . in a three-day rhinovirus experiment with healthy volunteers different exposure modes were used to investigate the rhinovirus transmission route: firsrtly, smallparticle exposure (separating donor and recipients by wire mesh), secondly, large particle exposure (encouraging contact, coughing and sneezing while wearing gloves) and finally, direct contact exposure (hand contact followed by self-inoculation). from the results it was concluded that direct contact was the main transmission route [ ] . furthermore, rhinovirus rna was detected in offices by air sampling studies and subsequent sequencing resulted in a matched air-mucus pair [ ] . in a miniature field trail, experimentally infected donors with severe colds participated in a card game with susceptible recipients for hours [ , , ]. a restraining device, preventing touching of the head and face, was used in the aerosol condition and heavily contaminated cards and exaggerated hand-to-face movements in the fomite condition. in these experiments aerosol transmission was suggested [ ] . in general, transmission rates and exposure time varied between studies, which may contribute to the different routes of transmission that were observed. therefore, the donor-hours of exposure was determined using donors with severe rhinovirus infections. at hours of exposure to donors, transmission had occurred to % of the susceptible recipients, though the transmission route itself was not investigated [ ]. due to the severity of the yearly influenza epidemics and the potential of zoonotic influenza a viruses to cause severe outbreaks, there have been many studies on influenza a virus transmission among humans. different kinds of studies, such as air sampling and intervention studies, as well as human challenge studies have been conducted. in addition, transmission events have been described extensively after outbreaks in aircrafts, households and hospital settings. however, until today, results on the relative importance of droplet and aerosol transmission of influenza viruses stay inconclusive and hence, there are many reviews intensively discussing this issue [ , [ ] [ ] [ ] [ ] [ ] [ ] . already in the mid- s human challenge models were used to assess the transmission route of influenza virus [ , - ]. it was shown that illness outcome is dependent on the inoculation route and tends to be milder in intranasally infected volunteers in comparison to inoculation through inhalation [ , ] . furthermore, illness seemed to be milder in experimentally infected volunteers than in naturally infected individuals [ ] . increasing numbers of studies focused on the detection and quantification of influenza viruses contained in droplets and aerosols expelled into the air through breathing, sneezing and coughing of infected individuals the sars outbreak was primarily linked to healthcare settings, with % of the cases linked to hospitals [ ] , most probably caused by aerosol-generating procedures on severely ill patients [ , ] . aerosol-generating procedures like intubation, the use of continuous positivepressure ventilation and drug delivery via nebulizers are likely to produce 'fine infectious droplets', which travel further than droplets from coughs [ ] . additionally, superspreading events contributed to the dispersion of the sars outbreak [ , [ ] [ ] [ ] , particularly in the hotel metropole and the prince of wales hospital in hong kong [ ] . moreover, a link with transmission to healthcare workers was observed when they were in close proximity (< m) to an index patient, suggesting direct contact or droplet transmission [ , , ] . air samples and swabs from frequently touched surfaces in a room occupied by a sars patient tested positive by pcr, although no virus could be cultured from these samples [ ] . in the amoy gardens outbreak fecal droplet transmission was suggested [ , ] . to date, there is little data on the human-to-human mers-cov transmission route [ ] . mers-cov remained stable on non-absorptive for up to hours and for min at c and % relative humidity in aerosols [ ] . mers-cov outbreaks in humans are, like those with sars-cov, primarily linked to healthcare settings, with a link to hospitals in % of the cases [ , , ] and healthcare associated human-to-human transmission was observed [ , ] . superspreader events were shown to play an important role in nosocomial outbreaks [ , ] . virus was isolated from environmental samples in hospital rooms, suggesting direct contact or fomite transmission. moreover, the airborne potential of mers was investigated by air sample analysis [ , ] . viral rna was detected on the inlet of air ventilation equipment [ ] and virus was isolated from air samples and surfaces from inaccessible areas like the ventilator exit, implicating potential aerosol transmission [ ] . human adenoviruses can cause respiratory disease (mainly type - , , and ) [ , ] , conjunctivitis or infantile gastroenteritis (type and ) [ ] . they are a common cause of respiratory illness and pneumonia in children [ , ] , whereas infections are generally asymptomatic in adults [ ] . adenoviruses cause nosocomial outbreaks, especially in pediatric care facilities, where they spread rapidly [ , , ] . moreover, adenovirus type and are responsible for large outbreaks of acute respiratory disease, especially in crowded conditions. this is illustrated by, for example, outbreaks among military recruits for which airborne spread was suggested [ , , ] . it is difficult to eliminate adenovirus from skin, fomites and environmental surfaces [ ] . an outbreak in a mental care facility was probably enhanced by spending the day mainly in a crowded room while sharing cigarettes and soda cans, suggesting indirect fomite spread [ ] . in a study published in , experimental infections with adenovirus administered as aerosols ( . - . mm) or droplets ( mm) to healthy, male inmates, resulted in infection of all volunteers, although the resulting illness resembled a natural infection only in the aerosol group [ ] . during a military training period, increased numbers of adenovirus infections occurred over time, which correlated with an increased detection of pcr-positive air filters. additionally, a correlation between disease and the extent of ventilation was observed, with more ventilation resulting in fewer disease cases [ ] . in a more recent study in military recruits, positive viral dna samples were mainly obtained from pillows, lockers and rifles, although adenovirus dna was also detected in air samples. no consistent correlation between increased positive environmental samples and disease was observed [ ] . studies on the transmission routes of respiratory viruses have been performed since the beginning of the th century [ ] . despite this, the relative importance of transmission routes of respiratory viruses is still unclear, depending on the heterogeneity of many factors like the environment (e.g. temperature and humidity), pathogen and host [ , ] . differences in virus shedding between individuals can contribute to the transmissibility rate, especially in the case of superspreaders [ , ] . in addition, the sars-cov outbreak highlighted the impact of aerosol-generating procedures on the increased risk of human-to-human transmission [ , ] , demonstrating that for these procedures additional containment measures are necessary. inter-human transmission has been studied under many different (experimental) conditions. a summary of the advantages and disadvantages of the different study designs (table ) highlights the difficulty of human transmission experiments. as a consequence, contrasting results have been obtained for many viruses. this is also reflected in table , summarizing the experimental data on inter-human transmission. besides the difficulty of performing studies under well-controlled conditions, another key issue is that often (attenuated) laboratory strains are studied in healthy adults, which does not reflect the natural circumstances and target group and hence influence the outcome of the studies. respiratory viruses are an important cause of nosocomial infections, especially in children. therefore, we consulted the guidelines on infection prevention from national [ ] , european [ ] , american [ , ] and international [ ]) organizations for their information on transmission routes (table ) and associated isolation guidelines (figure ) . unfortunately, terms and definitions of respiratory transmission routes and isolation guidelines are not always used in a uniform way, leaving room for personal interpretation. but more importantly, information on the transmission route does not always reflect the isolation guidelines (e.g. for piv and rhinovirus, figure ) . as a proxy for transmission route, virus stability is often referred to in the guidelines, however, this can only imply a role for indirect contact transmission but is by no means conclusive on the transmission route. inter-human transmission of respiratory viruses kutter et al. precautions such as strict hand hygiene and cough etiquette. it is important to note differences in isolation guidelines between different organizations and the lack of correlation to scientific data. the variation in described transmission routes and associated isolation guidelines among the different organizations underscores the lack of convincing data. well-designed human infection studies could be employed to investigate the role of transmission routes of respiratory viruses among humans [ ] . however, since human transmission experiments are very challenging, animal transmission models can provide an attractive alternative and should be explored and developed for all respiratory viruses. in such experiments, the influence of environmental factors on transmission routes can also be investigated [ ] . however, before extrapolating experimentally generated data to humans, it is important to understand the limitations of these models, and appreciate the heterogeneity of experimental setups employed in laboratories [ ] . furthermore, quantitative data such as viral load in the air can be obtained by air sampling methods in various environments, such as hospital settings. air sampling of viruses is an increasingly used technology in animal and human experiments. however, whereas most studies rely on the detection of viral genome copies, viability assays such as plaque assays or virus titration should be included to gain information on virus infectivity. ultimately, the knowledge gap on inter-human transmission should be filled by developing and performing stateof-the art experiments in a natural setting. combined with animal transmission models and air sampling in different (health care and experimental) settings, these data should result in a thorough scientific understanding of the inter-human transmission routes of respiratory viruses. eventually, this knowledge will help with an evidence-based risk assessment of the different transmission routes to improve existing infection prevention strategies. papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest infection prevention and control of epidemic and pandemic-prone acute respiratory diseases in health care: who interim guidelines guideline for isolation precautions: preventing transmission of infectious agents in health care settings the role of particle size in aerosolised pathogen transmission: a review inactivation of influenza a viruses in the environment and modes of transmission: a critical review influenza virus aerosols in human exhaled breath: particle size, culturability, and effect of surgical masks aerosol transmission of 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infection and control of ventilation in healthcare premises we thank dr. rik de swart, dr. bart haagmans, dr. arno andeweg, and dr. sabrina schreiner for helpful discussions. jk and sh are supported by an nwo vidi grant (contract number ), and ms, rf and sh by niaid/nih contract hhsn c. pf receives funding from the eu fp project prepare (grant number ). the sponsors had no role in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication. key: cord- - zk i qb authors: siegel, jane d.; guzman-cottrill, judith a. title: pediatric healthcare epidemiology date: - - journal: principles and practice of pediatric infectious diseases doi: . /b - - - - . - sha: doc_id: cord_uid: zk i qb nan jane d. siegel the reduction of healthcare-associated infections (hais) is an important component of patient safety programs. five of the hospital national patient safety goals for of the joint commission (formerly the joint commission on accreditation of healthcare organizations) target prevention of hais. hospitals have learned from high-reliability organizations (e.g., the aviation industry) the importance of adopting changes that include the leadership's commitment to achieving zero patient harm, a fully functional culture of safety throughout the organization, and the widespread deployment of highly effective process improvement tools. involvement of new stakeholders for improving patient safety and outcomes related to hais (e.g., children's hospitals' solutions for patient safety, children's hospital association, individual states' mandatory hai public reporting programs, the centers for medicare and medicaid services, the joint commission) has broadened the arena for hai prevention efforts. knowledge of the complexities of prevention and control of hais in children is critical to many different leaders of children's healthcare facilities. one framework for patient safety in children's hospitals that includes infection prevention and control (ipc) was developed by the ohio children's hospital solutions collaborative and demonstrates the effectiveness of hospitalwide collaboration. as more disciplines in healthcare become engaged in prevention of hais as well as antimicrobial stewardship, it is the responsibility of the healthcare epidemiologist and the ipc staff (infection preventionists, healthcare epidemiologists) to educate the facility leadership on the discipline of ipc. ipc for the pediatric population is a unique discipline that requires understanding of various host factors, sources of infection, routes of transmission, behaviors required for care of infants and children, pathogens and their virulence factors, treatments, preventive therapies, and behavioral theory. although the term nosocomial still applies to infections that are acquired in acute care hospitals, the more general term, healthcare-associated infections (hais), is preferred because much care of high-risk patients, including patients with medical devices (e.g., central venous catheters, ventilators, ventricular shunts, peritoneal dialysis catheters), has shifted to ambulatory settings, rehabilitation or chronic care facilities, and the home; thus, the geographic location of acquisition of the infection often cannot be determined. the principles of transmission of infectious agents in healthcare settings and recommendations for prevention are reviewed in the healthcare and infection control practices advisory committee (hicpac) guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings, and in the management of multidrug resistant organisms in healthcare settings, document. as new pathogens emerge, epidemiologists will continue to learn more about preventing transmission; therefore, for such pathogens, the most up-to-date guidance posted on the centers for disease control and prevention (cdc) or the world health organization (who) website should be consulted. the experience treating ebola virus disease (evd) in the united states in is the most recent example of changes in the usual infection prevention paradigm that were required, with emphasis on the hierarchy of controls and donning and doffing of personal protective equipment (ppe) with trained observers. a detailed discussion of hais can be found in chapters and . this chapter focuses on the components of an effective pediatric hospital epidemiology program. unique aspects of hais in children are summarized in the following sections. specific risks and pathogens are addressed in several other chapters in this textbook. intensive care units (icus), oncology services, and gastroenterology services caring for patients with short gut syndrome who are dependent on total parenteral nutrition (and lipids) have the highest rates of bacterial and fungal infection associated with central venous catheters. a newer definition of mucosal barrier injury laboratory-confirmed bloodstream infection (mbi-lcbi) currently is used by the national healthcare safety network (nhsn) of the cdc to distinguish bacteremia that represents translocation of gut microorganisms related to mucosal barrier injury in patients with oncologic conditions, hematopoietic stem cell transplantation (hsct), and intestinal failure from bacteremia associated with central venous catheters. hais can result in substantial morbidity and mortality, as well as lifetime physical, neurologic, and developmental disabilities. host (i.e., intrinsic) factors that make children particularly vulnerable to infection include immaturity of the immune system, congenital abnormalities, and congenital or acquired immunodeficiencies. children with congenital anomalies have a high risk of hai if their unusual anatomic features predispose them to contamination of normally sterile sites. moreover, these children require prolonged and repeated hospitalizations, undergo many complex surgical procedures, and have extended exposure to invasive supportive and monitoring equipment. innate deficiencies of the immune system in prematurely born infants, who may be hospitalized for prolonged periods and exposed to intensive monitoring, supportive therapies, and invasive procedures, contribute to the relatively high rates of infection in the neonatal icu (nicu). all components of the immune system are compromised in neonates, and the degree of deficiency is proportional inversely to gestational age (see chapter ) . the underdeveloped skin of the very low birth weight (< g) infant provides another mode of pathogen entry. populations of immunosuppressed children have expanded with the advent of more intense immunosuppressive therapeutic regimens used for oncologic conditions, hsct, solid-organ transplantation, and rheumatologic conditions and inflammatory bowel disease for which immunosuppressive agents and tumor necrosis factor-α-inhibiting agents (infliximab [remicade] ) and other immune modulators are used. genetic mutations in the genes for the transmembrane conductance regulator (cftr) in children with cystic fibrosis result in thick secretions, chronic endobronchial infections, and gastrointestinal malabsorption. knowledge of the epidemiology of infection of patients with cystic fibrosis and effective methods to prevent patient-to-patient transmission have expanded with the use of newer molecular diagnostic methods, resulting in a update in the infection prevention and control guideline for cystic fibrosis. fortunately, the population of children with perinatally acquired human immunodeficiency virus (hiv) infection and acquired immunodeficiency syndrome (aids) has decreased dramatically since , but new cases of sexually transmitted hiv infection continue to be diagnosed in teens who receive care in children's hospitals. finally, young infants who have not yet been immunized, or immunosuppressed children who do not respond to vaccines or who lose antibody during disease or treatment (e.g., patients with nephrotic syndrome), have increased susceptibility to vaccine-preventable diseases. the source of many hais is the endogenous flora of the patient. an asymptomatically colonizing pathogen can invade a patient's bloodstream or be transmitted to other patients on the hands of healthcare personnel (hcp) or on shared equipment. other important sources of hais in infants and children include the mother in the case of neonates, toys were implicated in an outbreak of multidrug-resistant pseudomonas aeruginosa in a pediatric oncology unit. although the source of most candida hais is the patient's endogenous flora, horizontal transmission, most likely through hcp hands, has been demonstrated in studies using typing by pulsed gel electrophoresis in the nicu and in a pediatric oncology unit. , newer molecular diagnostic methods (e.g., whole genome sequencing) are more sensitive and specific than pulsed gel electrophoresis and have proven to be valuable in identifying outbreaks of a variety of pathogens in both pediatric and adult settings. , droplet. infectious respiratory droplets > µm in diameter are generated from the respiratory tract by coughing, sneezing, or talking or during such procedures as suctioning, intubation, chest physiotherapy, or pulmonary function testing. transmission of infectious agents by the droplet route requires exposure of mucous membranes to large respiratory droplets within to feet ( to m) of the infected person. large respiratory droplets do not remain suspended in the air for prolonged periods, and they settle on environmental surfaces. the dynamics of infectious aerosols can be affected by a variety of factors including characteristics of specific strains of bacteria, temperature, humidity, and number of air exchanges in a room. adenovirus, influenza virus, and rhinovirus are transmitted primarily by the droplet route, whereas rsv is transmitted primarily by the contact route. although influenza virus can be transmitted by the airborne route under unusual conditions of reduced air circulation or low absolute humidity, ample evidence indicates that transmission of influenza is prevented by droplet precautions and, in the care of infants, the addition of contact precautions. airborne. droplet nuclei that arise from desiccation of respiratory droplets and are < µm in diameter and contain infectious agents remain suspended in the air for prolonged periods and travel long distances on air currents. susceptible persons who have not had face-to-face contact or been in the same room as the source person can inhale such infectious particles. m. tuberculosis, varicella-zoster virus (vzv), and rubeola virus are the agents most frequently transmitted by the airborne route. although transmission of m. tuberculosis by the airborne route can occur rarely from an infant or young child with active tuberculosis, the more frequent source is the adult visitor with active pulmonary tuberculosis that has not yet been diagnosed; thus screening of visiting family members is an important component for control of tuberculosis in pediatric healthcare facilities. some agents (e.g., severe acute respiratory syndrome-coronavirus [sars-cov]) can be transmitted as small-particle aerosols under special circumstances of aerosol-generating procedures (e.g., endotracheal intubation, bronchoscopy); therefore, an n or higher respirator is indicated for persons in the same airspace when these procedures are performed, but an airborne infection isolation room (aiir) may not always be required. roy and milton proposed the following classification for aerosol transmission when evaluating routes of sars-cov transmission: . obligate: under natural conditions, disease occurs following transmission of the agent only through small-particle aerosols (e.g., tuberculosis). . preferential: natural infection results from transmission through multiple routes, but small-particle aerosols are the predominant route (e.g., measles, varicella). . opportunistic: agents naturally cause disease through other routes, but under certain environmental conditions they can be transmitted by fine-particle aerosols. this conceptual framework can explain rare occurrences of airborne transmission of agents that are transmitted most frequently by other routes (e.g., smallpox, sars, influenza, noroviruses). concern about airborne transmission of influenza arose during the influenza a (h n ) pandemic. however, the conclusion from all published experiences during the pandemic was that droplet transmission is the usual route of transmission, and surgical masks were noninferior to n respirators in preventing laboratory-confirmed influenza in hcp. , concerns about unknown or possible routes of transmission of agents that can cause severe disease and have no known treatment often result in more extreme prevention strategies. therefore, recommended precautions could change as the epidemiology of emerging agents is defined and these controversial issues are resolved. although no evidence supports airborne transmission of the ebola virus under usual circumstances in the field, the aerosolization of body fluids that contain high titers of ebola virus requires additional protection. invasive monitoring and supportive equipment, blood products, total parenteral nutrition fluids, lipids, infant formula and human milk, hcp, and other contacts, including adult and sibling visitors. maternal infection with neisseria gonorrhoeae, treponema pallidum, hiv, hepatitis b virus, parvovirus b , mycobacterium tuberculosis, herpes simplex virus, or group b streptococcus, or colonization with multidrug-resistant organisms (mdros), pose substantial threats to the neonate. during perinatal care, procedures such as fetal monitoring using scalp electrodes, fetal transfusion and surgical procedures, umbilical cannulation, and circumcision are potential risk factors for infection. intrinsically contaminated powdered formulas and infant formulas prepared in contaminated blenders or improperly stored or handled have resulted in sporadic and epidemic infections in the nursery (e.g., cronobacter [formerly enterobacter] sakazakii), but such infections have become less frequent since the pathogenesis was defined and contamination reduced. human milk that has been contaminated by maternal flora or by organisms transmitted through breast pumps has caused isolated serious infections and epidemics. the risks of neonatal hepatitis, cytomegalovirus (cmv) infection, and hiv infection from human milk warrant further caution for handling and use of banked breast milk. with increasing numbers of procedures being performed by pediatric interventional radiologists, an understanding of appropriate aseptic technique, as well as prevention and management of infectious complications, by interventional radiologists is important. construction, renovation, demolition, and excavation in and near healthcare facilities are important sources of environmental fungi, (e.g., aspergillus spp., agents of mucormycoses, fusarium spp., scedosporium spp., bipolaris spp.). immunocompromised patients and patients in the pediatric icu (picu) and nicu are at greatest risk for fungal infection, and case fatality rates can be ≥ %, especially if diagnosis and treatment are delayed. practices related to care of infants and young children. several practices must be evaluated with respect to the potentially associated risk of infection. a significant association between reduced levels of nurse staffing and appropriately trained nurses has been demonstrated to increase risk of infection in many studies in both children and adults. , , theoretical concerns exist that infection risk also will increase in association with the innovative practices of co-bedding of twins and kangaroo care in the nicu because of increased opportunity for skin-to-skin exposure of multiple-gestation infants to each other and to their mothers, respectively. neither the benefits nor the safety of co-bedding multiple-birth infants in the hospital setting has been demonstrated. overall, the infection risk is reduced with kangaroo care, but transmission of tuberculosis and respiratory syncytial virus (rsv) has occurred in kangaroo mother care units in south africa. parents providing kangaroo care should be monitored for the presence of skin infections. antimicrobial selective pressure. exposure to vancomycin and to thirdgeneration cephalosporins contributes substantially to the increase in infections caused by vancomycin-resistant enterococcus (vre) and multidrug-resistant gram-negative bacilli, including extended spectrum β-lactamase (esbl)-producing organisms and carbapenem-resistant enterobacteriaceae (cre) in children. additionally, exposure to thirdgeneration cephalosporins also is a risk factor for the development of invasive candidiasis in low birth weight infants in the nicu. studies of the human microbiome using culture-independent methods have demonstrated the bacterial community diversity on mucosal surfaces and the profound suppressive effect of antimicrobial agents on the population of protective bacteria, firmicutes, thus increasing the risk of colonization and subsequent invasive disease caused by pathogenic bacteria. the principal modes of transmission of infectious agents are direct and indirect contact, droplet, and airborne. contact. most infectious agents are transmitted by the contact route on the hands of hcp or through shared items; many pathogens can be transmitted by more than route. viruses, bacteria, and candida spp. can be transmitted horizontally. toddlers often share waiting rooms, playrooms, toys, books, and other items and therefore have the potential of transmitting pathogens directly and indirectly to one another. contaminated bath part i understanding, controlling, and preventing infectious diseases (nnis), now nhsn icus. hais caused by mdros are associated with increased length of stay, increased morbidity and mortality, and increased cost, in part because of the delay in initiating effective antimicrobial therapy. , although the prevalence of specific mdros is lower in pediatric institutions, the same principles of target identification and interventions to control mdros apply in all settings. c. difficile is an important pathogen in children, as it is in adults, especially in children receiving chemotherapy. testing for c. difficile in the first year of life is not advised because of the high asymptomatic colonization rate with toxigenic strains in this age group. candida spp. are the third most frequent pathogens associated with bloodstream infections in us nicus. there is considerable center-tocenter variability in both the incidence of invasive candidiasis and the proportion of candida infections caused by candida non-albicans spp., most of which are resistant to fluconazole. risk factors for candida infections include prolonged length of stay in an icu, use of central venous catheters, intralipids, histamine (h )-blocking agents, and exposure to third-generation cephalosporins. gnb and candida spp. are especially important pathogens for hais in patients with intestinal failure who are receiving total parenteral nutrition, and these organisms can cause repeated episodes of sepsis. the incidence of candida infections had increased in incidence in most picus and nicus during the s, but the rate of c. albicans and non-albicans central line-associated bloodstream infections decreased by % in all birth weight categories from to , likely a result of improved infection control practices, antimicrobial stewardship, and use of fluconazole prophylaxis in the very low birth weight preterm infants. the most recently published clinical practice guidelines of the infectious diseases society of america (idsa) recommend the use of oral or intravenous fluconazole prophylaxis in infants weighing < g at birth in nicus with high rates (> %) of invasive candidiasis, based on high quality of evidence to support efficacy and safety. additionally, empiric antifungal therapy in preterm infants of ≤ g birth weight is associated with improved survival rates without adverse outcomes. the staff members of each nicu first must optimize infection control practices and then assess the remaining risk of candida infections. finally, environmental fungi (e.g., aspergillus, fusarium, scedosporium, bipolaris, agents of mucormycosis) are important sources of infection for severely immunocompromised patients; meticulous attention to the conditions of the internal environment of any facility that provides care for severely immunocompromised patients is required, as well as prevention of possible exposure to construction dust in and around healthcare facilities. with the advent of more effective and less toxic antifungal agents and improved outcomes, it is important to identify promptly the infecting agent by obtaining tissue samples and to determine susceptibility to candidate antifungal agents. prevention remains the mainstay of infection control and requires special considerations in children. the goals of ipc are to prevent the transmission of infectious agents among individual patients or groups of patients, visitors, and hcp who care for them. as new pathogens emerge, new strategies for prevention emerge. the experience treating evd in the us in and is the most recent example of changes in the usual infection prevention paradigm that were required, with a renewed emphasis on the tiers of the hierarchy of controls (e.g., engineering, administration, and ppe), donning and doffing of ppe, and use of trained observers. , if prevention cannot always be achieved, the strategy of early diagnosis, treatment, and containment is critical. a series of ipc guidelines have been developed and updated at varying intervals by the hicpac/cdc, idsa, society for healthcare epidemiology of america (shea), american academy of pediatrics, association for professionals in infection control and epidemiology, and others to provide evidence-based and rated recommendations for practices that are associated with reduced rates of hais, especially those infections associated with the use of medical devices and surgical procedures. recommended isolation precautions by infectious agent also can be found in the most recent edition of the red book report of the committee on infectious diseases of the american academy of pediatrics. prevention bundles are groups of to evidence-based "best practices" with respect to a process that individually improve care, but when applied together result in substantially greater reduction in infection transmission of microbes between children and hcp is a risk because of the very close contact that occurs during care of infants and young children and is facilitated by overcrowding, understaffing, and too few appropriately trained nurses in pediatric facilities. , staffing levels and composition are important components of an effective ipc program. hcp rarely are the source of outbreaks of hais caused by bacteria and fungi, but when they are, certain factors are usually present that increase the risk of transmission (e.g., sinusitis, draining otitis externa, respiratory tract infections, dermatitis, onychomycosis, wearing of artificial nails). [ ] [ ] [ ] persons with direct patient contact who were wearing artificial nails have been implicated in outbreaks of p. aeruginosa and esbl-producing klebsiella pneumoniae in nicus; therefore, the use of artificial nails or extenders is prohibited in persons who have direct contact with high-risk patients. several published studies have shown that infected pediatric hcp, including resident physicians, transmitted bordetella pertussis to other patients and can be the source of other vaccine-preventable infections in healthcare. pathogens associated with hais in children differ from those in adults in that respiratory viruses are more frequently associated with transmission in pediatric healthcare facilities. respiratory viruses (e.g., rsv, parainfluenza, adenovirus, human metapneumovirus) have been implicated in outbreaks in high-risk units. as more respiratory viruses and gastrointestinal pathogens are identified by using highly sensitive molecular methods, epidemiologic studies will be required to define further the risk of transmission in healthcare facilities and the clinical significance of positive antigen detection test results. , healthcareassociated outbreaks of varicella, measles, and rotavirus infection now are rare events because of the consistent use of vaccines by children and hcp. the emergence of community-associated mrsa isolates characterized by the unique scc mec type iv element was first observed among infants and children. as rates of colonization with community-associated mrsa at the time of hospital admission increased, so did transmission of community strains, most often usa , within the hospital and especially within the nicu, thus making prevention especially challenging. other mdros (e.g., vre, esbls, and cre, especially k. pneumoniae) have emerged as the most challenging healthcare-associated pathogens in both pediatric and adult settings, and otherwise healthy children in the community can be colonized asymptomatically with these mdros. gnb, including esbl and other multidrug-resistant isolates, are more frequent than mrsa and vre in many picus and nicus. patients who are transferred from chronic care facilities may be colonized with mdr gnb at the time of admission to the picu. trends in targeted mdros are tracked in the national nosocomial infections surveillance system . oversight of occupational health services related to ipc (e.g., assessment of risk and administration of recommended prophylaxis following exposure to infectious agents, tuberculosis screening, influenza and pertussis vaccination, respiratory protection fit testing, administration of other vaccines as indicated during infectious disease crises such as preexposure smallpox vaccine in and pandemic influenza a [h n ] vaccine in ) . preparedness planning for annual influenza outbreaks, pandemic influenza, sars, middle east respiratory syndrome (mers), bioweapons attacks, and evd . adherence monitoring for selected ipc practices . oversight of risk assessment and implementation of preventive measures associated with construction, renovation, and other environmental conditions associated with increased infection risk . participation in antimicrobial stewardship programs, focusing on prevention of transmission of mdros . evaluation of new products and medical devices that could be associated with increased infection risk (e.g., endoscopes, contaminated injectable medications ) and introduction and assessment of performance after implementation of modified products . mandatory public reporting of hai rates in states according to enacted legislation . increased communication with the public and with local public health departments concerning infection control-related issues . participation in local and multicenter reporting and research projects ipc programs must be adequately staffed to perform all the foregoing activities. thus the ratio of infection preventionist to beds that was associated with a % reduction in the rates of nosocomial infection in the study on efficacy of nosocomial infection control (senic) performed in the s no longer is sufficient because the complexity of patient populations and responsibilities have increased. many experts recommend that a ratio of infection preventionist to beds is more appropriate for the current workload, but no study has been performed to confirm the effectiveness of that ratio. no information is available on the number of ipc personnel required outside acute care, but it is clear that persons well trained in ipc must be available for all sites where healthcare is delivered. data collected from a member workforce survey conducted in by the association for professionals in infection control and epidemiology are expected to help determine the optimal number of infection preventionists for different healthcare settings based on the current responsibilities and demographics of infection preventionists. surveillance for hais consists of a systematic method of determining the incidence and distribution of infections acquired by hospitalized patients. the cdc recommends the following: ( ) prospective surveillance on a regular basis by trained infection preventionists, using standardized definitions; ( ) analysis of infection rates using established epidemiologic and statistical methods (e.g., calculation of rates using appropriate denominators that reflect duration of exposure; use of statistical process control charts for trending rates); ( ) regular use of data in decision making; and ( ) employment of an effective and trained healthcare epidemiologist who develops ipc strategies and policies and serves as a liaison with the medical community and administration. [ ] [ ] [ ] the cdc has established a set of standard definitions of hais that have been validated and accepted widely with updates posted on the cdc nhsn website. standardization of surveillance methodology has become especially important with the advent of state legislation for mandatory reporting of hai rates to the public. the nhsn now receives, analyzes, and reports data from > , healthcare facilities in the us. a standardized infection ratio (sir) that takes into account differences in risk among healthcare settings, unit types, procedures, and patient populations has been included in summary reports of hai rates since . the centers for medicare and medicaid services and most states use the nhsn data for public reporting of hai rates on their websites. although much effort has been directed toward making these data understandable and useful to consumers, interpretation of rates. adherence to the individual measures within a bundle is readily measured. bundled practices are used most frequently for prevention of device-or procedure-related hais, but they can be applied to prevention of any type of hai. the importance of certain administrative measures for a successful ipc program has been demonstrated. a white paper published by shea summarizes the necessary infrastructure for an effective ipc program in modern times. the paper addresses the expansion of ipc responsibilities from a relatively narrow focus on acute infectious disease events in the acute care hospital, surveillance, and implementation of recommended isolation precautions to a broader set of activities across the continuum of care requiring team work within and beyond individual facilities, usually including large networks. because ipc comprises one component of the institutional culture of safety, it is critical to obtain support from the senior leadership of healthcare organizations to provide necessary fiscal and human resources for a proactive, successful ipc program. critical elements requiring administrative support include access to the following: ( ) appropriately trained healthcare epidemiologists and ipc personnel; ( ) clinical microbiology laboratory services needed to support infection control outbreak investigations, including ability to perform molecular diagnostic testing; ( ) data-mining programs and information technology specialists; ( ) multidisciplinary programs to ensure judicious use of antimicrobial agents and control of resistance; ( ) development of effective educational information for delivery to hcp, patients, families, and visitors; and ( ) local and state health department resources for preparedness. provision of adequate numbers of well-trained infection preventionists and bedside nursing staff is critical for success. an effective ipc program improves safety of patients and hcp and decreases short-term and long-term morbidity, mortality, and healthcare costs. the ipc committee of a facility establishes policies and procedures to prevent or reduce the incidence and costs associated with hais. this committee should be one of the strongest and most accessible committees in the facility; committee composition should be considered carefully and limited to active, authoritative participants who have well-defined committee responsibilities and who represent major groups within the hospital. the chairperson should be a good communicator with expertise in ipc issues, healthcare epidemiology, and clinical pediatric infectious diseases. important functions of the ipc committee are regular review of ipc policies and development of new policies as needed. annual review of all policies is required by the joint commission and can be accomplished optimally by careful review of a few policies each month. with the advent of unannounced inspections, a constant state of readiness is required. the hospital epidemiologist or medical director of the pediatric ipc department usually is a physician with training in pediatric infectious diseases and dedicated expertise in healthcare epidemiology. in multispecialty medical centers where infants and children comprise a small proportion of patients, pediatric infectious disease experts should be consulted for management of pediatric ipc issues and report to the broader ipc leadership. the skillsets, training, and competencies needed for success as a healthcare epidemiologist were summarized in another white paper published by the shea. certification for healthcare epidemiologists has not yet been developed. infection preventionists are specialized professionals with advanced training, and preferably certification, in ipc. although most infection preventionists are registered nurses, other professionals, including microbiologists, medical technologists, pharmacists, and epidemiologists, are successful in this position. pediatric patients should have infection preventionist services provided by professionals with expertise and training in the care of children. in a large, general hospital, at least infection preventionist should be dedicated to ipc services for children. the responsibilities of infection preventionists have expanded greatly and include the following: . surveillance and ipc in facilities affiliated with primary acute care hospitals (e.g., ambulatory clinics, day-surgery centers, long-term care facilities, rehabilitation centers, home care) in addition to the primary hospital part i understanding, controlling, and preventing infectious diseases according to guidelines, if transmission continues after standardized horizontal interventions have been completely implemented. at this time, no formal recommendation has been made to discontinue routine use of contact precautions for patients with asymptomatic colonization with mrsa or vre in an endemic setting; thus each ipc program must determine practice based on local conditions and follow with close auditing and surveillance for potential adverse outcomes. the microbiology laboratory can provide online culture information about individual patients, outbreaks of infection, antibiograms (antibiotic susceptibility patterns of pathogens summarized periodically), and employee infection data. the laboratory also can assist with surveillance cultures and facilitation of molecular typing of isolates during outbreak investigations. rapid diagnostic testing of clinical specimens for identification of respiratory and gastrointestinal tract viruses and b. pertussis is especially important for pediatric facilities. the ipc division and the microbiology laboratory must communicate daily because even requests for cultures or other diagnostic testing from physicians (e.g., m. tuberculosis, neisseria meningitidis, c. difficile) can identify patients early who are infected, are at high risk of infection, or require isolation. if microbiology laboratory work is outsourced, it is important to ensure that the services needed to support effective icp be available, as delineated in a guideline developed by the idsa and the american society for microbiology. control of unusual infections or outbreaks in the community generally is the responsibility of the local or state public health department; however, the individual facility must be responsible for preventing transmission within that facility. public health agencies can be helpful, particularly in alerting hospitals of community outbreaks so that outpatient and inpatient diagnosis, treatment, necessary isolation, and other preventive measures are implemented promptly to avoid further spread. conversely, designated persons in the hospital must notify public health department personnel of reportable infections to facilitate early diagnosis, treatment, and infection control in the community. benefits of community or regional collaboratives of individual healthcare facilities and local public health departments for prevention of hais, especially those caused by mdros, have been demonstrated, and this collaboration should be encouraged. the rapid increase of mdros is a public health threat. between % and % of antibiotics prescribed in us hospitals are either inappropriate or unnecessary. in , the president's council of advisors on science and technology submitted a -page report to the president on combating antibiotic resistance that raised awareness of antimicrobial resistance to a national level. a national action plan based on this report was released in march , and funding was made available for its implementation. antimicrobial stewardship was defined in a consensus statement by the idsa, shea, and pediatric infectious diseases society in as "coordinated interventions designed to improve and measure the appropriate use of antibiotic agents by promoting the selection of the optimal antibiotic regimen, including dosing, duration and route of administration." antimicrobial stewardship programs are collaborative partnerships among infection preventionists, healthcare epidemiologists, clinical pharmacists, and microbiologists. hospital administrative support for the infrastructure required for ongoing measurement and reporting of antimicrobial use and other related outcome measures, including feedback to prescribers, is a critical component of a successful antimicrobial stewardship program. an antimicrobial stewardship program can optimize clinical outcomes while decreasing unintended consequences of antimicrobial use, including the emergence of resistant organisms. additionally, use of specific antimicrobial agents can alert the ipc program to the presence of potentially infectious patients (e.g., with pulmonary tuberculosis, mdros). national guidelines exist for developing and implementing an institutional antimicrobial stewardship program, including core components for acute care hospitals and for long-term care facilities. , the natinal quality forum and its partners have also developed a playbook that provides additional guidance for implementation of antimicrobial stewardship programs in acute care. the knowledge and skills required for antimicrobial stewardship leaders also have been defined. , these data by the public remains difficult, and more research is needed to optimize methods of data display to the public. new york state is the first state to have published an improvement in process and outcomes of central line-associated bloodstream infection rates in nicus following implementation of a public reporting program. although various surveillance methods are used, the basic goals and elements are similar and include using standardized definitions of infection, finding and collecting cases of hais, tabulating data, using appropriate denominators that reflect duration of risk, analyzing and interpreting the data, reporting important deviations from endemic rates (epidemic, outbreaks) to the bedside care providers and to the facility administrators, implementing appropriate control measures, auditing adherence rates for recommended processes, and assessing efficacy of the control measures. medical centers can use different methods of surveillance, as outlined in box . . most experts agree that a combination of methods enhances surveillance and reliability of data, and some combination of clinical chart review and database retrieval is important. whatever data collection systems are used, validation is required. administrative databases created for the purposes of billing should not be used as the sole source to identify hais because of overestimates and underestimates that result from inaccurate coding of hais. use of software designed specifically for ipc data entry and analysis facilitates real-time tracking of trends and timely intervention when clusters are identified. the ipc team should participate in the development and update of electronic medical record systems for a healthcare organization, to ensure that surveillance needs will be met. controversy has surrounded the role of obtaining active surveillance cultures from all patients admitted to an acute care hospital, especially to an icu, to detect asymptomatic colonization with mrsa or vre and then placing those persons on contact precautions in an endemic setting, a practice referred to as a vertical approach. , more recently published experiences demonstrate the benefits of a horizontal approach to reduce the risk of transmission of a broader variety of pathogens, and a framework for a less restrictive approach has been published. contributing factors to the benefits of the horizontal approach include the following: ( ) widespread implementation of bundled prevention practices, including limiting use of unnecessary medical devices; ( ) improved understanding and more consistent implementation of standard precautions, especially hand hygiene; ( ) establishment of the safety and efficacy of universal decolonization using chlorhexidine bathing in icus , and nicus for infants weighing > g at birth ; ( ) improving environmental cleaning; and ( ) identified the following potential infection control breaches: ( ) use of multidose vials for heparin or saline administration; ( ) poor compliance with hand hygiene before and after patient contacts or after touching a possibly contaminated surface; ( ) failure to change gloves between patient contacts or after contact with a potentially contaminated surface; ( ) failure to disinfect environmental surfaces adequately; ( ) unsafe injection practices; ( ) failure to disinfect shared equipment between patient uses; ( ) lack of a separate area for medication preparation; and ( ) failure to have clean and dirty utility rooms clearly separated. two additions were made to standard precautions in : ( ) respiratory hygiene or cough etiquette for source containment by people with signs and symptoms of respiratory tract infection and ( ) use of a mask by personnel inserting an epidural anesthesia needle or performing a myelogram when prolonged exposure of the puncture site is likely. both components have a strong evidence base. implementation of standard precautions requires the availability of ppe in proximity to all patient care areas. hcp with exudative lesions or weeping dermatitis must avoid direct patient care and handling of patient care equipment. persons having direct patient contact should be able to anticipate exposure incurring risks and steps to take if a highrisk exposure occurs. exposures of concern are as follows: exposures to blood or other potentially infectious material defined as an injury with a contaminated sharp object (e.g., needlestick, scalpel cut); a spill or splash of blood or other potentially infectious material onto nonintact skin (e.g., cuts, hangnails, dermatitis, abrasions, chapped skin) or onto a mucous membrane (e.g., mouth, nose, eye); or blood exposure covering a large area of normal skin. patient-related duties that do not constitute high-risk exposures include handling food trays or furniture, pushing wheelchairs or stretchers, using restrooms or telephones, having personal contact with patients (e.g., giving information, touching intact skin, bathing, giving a back rub, shaking hands), or performing clerical or administrative functions for a patient. if hands or other skin surfaces are exposed to blood or other potentially infectious material, the area should be washed immediately with soap and water for at least seconds and rinsed with running water for at least seconds. for an eye, nose, or mouth splash with blood or body fluids, the area should be irrigated immediately with a large volume of water. if a skin cut, puncture, or lesion is exposed to blood or other potentially infectious material, the area should be washed immediately with soap and water for at least seconds and rinsed with % isopropyl alcohol. any exposure incident should be reported immediately to the occupational health department to determine whether blood samples are required from the source patient and the exposed person and if immediate prophylaxis is indicated. all hcp should know where to find the exposure control plan specific to each place of employment, whom to contact, where to go, and what to do if inadvertently exposed to blood or body fluids. important resources include the occupational health department, the emergency department, and the infection control or hospital epidemiology division. the most important recommendation in any accidental exposure is to seek advice and intervention immediately because the efficacy of recommended prophylactic regimens is improved with shorter intervals after exposure, such as for hepatitis b immune globulin administration after exposure to hepatitis b virus or for antiretroviral therapy after percutaneous exposure to hiv. chemoprophylaxis following exposure to hiv-infected material is most effective if it is initiated as soon as possible, but within hours of exposure. the current guidelines recommend using ≥ drugs for postexposure prophylaxis of hiv independent of the severity of exposure. updates are posted on the cdc website as they are developed. reporting a work-related exposure is required for subsequent medical care and workers' compensation. transmission-based precautions are designed for patients with documented or suspected infection with pathogens for which additional precautions beyond standard precautions are needed to prevent transmission. the categories of transmission-based precautions are contact precautions, droplet precautions, and airborne precautions, and they are based on the likely routes of transmission of specific infectious agents. transmission-based precautions are combined for infectious agents that have more than route of transmission. when used singly or in the effectiveness of antimicrobial stewardship programs in achieving improved patient outcomes is evident in pediatric acute care hospitals, , including the nicu, , in ambulatory settings, and in long-term care facilities. the area of antimicrobial stewardship, however, requires additional research to establish optimal methods in various pediatric specialty populations. one practice from the cdc get smart program that can be implemented by each prescriber in most settings is the antibiotic "time out" that consists of reviewing patient data at to hours of treatment to determine which of the following is indicated: ( ) continue antibiotic treatment; ( ) change to a narrower-spectrum agent; ( ) change from a parenteral to an oral agent; or ( ) shorten or conclude therapy. isolation of patients with potentially transmissible infectious diseases is a strategy proven to prevent transmission of infectious agents in healthcare settings. many published studies, performed in both adult and pediatric settings, provide a strong evidence base for most recommendations for isolation precautions and for limiting outbreaks. however, controversies exist concerning the most clinically and cost-effective measures for preventing certain hais, especially those associated with mdros. as discussed earlier in the section on surveillance, a call has gone out to reconsider recommendations for isolation of patients who are asymptomatically colonized with mrsa or vre, but no definite recommendation has been made by the hicpac/cdc, shea, or association for professionals in infection control and epidemiology. since , the guidelines for isolation developed by cdc have responded to the needs of the evolving us healthcare systems. for example, universal precautions became a required standard in response to the hiv epidemic that emerged in the s and the need to prevent acquisition of bloodborne pathogens (e.g., hiv, hepatitis b and c viruses) by hcp through skin, eye, mucous membrane, or parenteral contact with blood or other potentially infectious materials from persons not known to be or suspected of being infected. universal precautions were modified and have been known as standard precautions since publication of the guideline for isolation. the federal needlestick safety and prevention act, signed into law in november , authorized the occupational safety and health administration's revision of its bloodborne pathogens standard more explicitly to require the use of safety-engineered sharp devices. evidence and recommendations are provided for the prevention of transmission of mdros such as mrsa, vre, visa, vrsa, and gnb. , the components of a protective environment for prevention of environmental fungal infections in hsct recipients are summarized. finally, evidence-based, rated recommendations for administrative measures that are necessary for effective prevention of infection in healthcare settings are provided. the most recent guideline for isolation precautions published in reaffirms standard precautions, a combination of universal precautions and body substance isolation, as the foundation of transmission prevention measures. critical thinking is required for hcp to recognize the importance of body fluids, excretions, and secretions in the transmission of infectious pathogens and take appropriate protective precautions by using ppe (e.g., masks, gowns, gloves, face shields, or goggles) and safety devices when exposure is likely even if an infection is not suspected or known. in addition, these updated guidelines provide recommendations for standard precautions in all settings in which healthcare is delivered (acute care hospitals, ambulatory surgical and medical centers, longterm care facilities, and home health agencies). the components of standard precautions are summarized in table instruct symptomatic persons to cover the mouth or nose when sneezing or coughing; use tissues and dispose in no-touch receptacle; observe hand hygiene after soiling of hands with respiratory secretions; wear a surgical mask if tolerated or maintain spatial separation, > - m ( - feet) if possible a during aerosol-generating procedures on patients with suspected or proven infections transmitted by aerosols (e.g., severe acute respiratory syndrome), wear a fit-tested n or higher respirator in addition to gloves, gown, and face and eye protection. although targeted contact precautions and universal gowning and gloving are effective for preventing transmission of infectious agents, potential adverse effects in patients placed on contact precautions have been described (e.g., depression, fewer visits from the healthcare team, increased rates of hypoglycemia or hyperglycemia, increased falls). additionally, adherence to contact precautions decreases as the number of patients on contact precautions increases. finally, a simulation study demonstrated contamination of hcp skin and clothing during doffing of gowns and gloves ; this study effectively demonstrated the ppe lessons learned during the sars and evd experiences. evidence supports the importance of applying contact precautions only when indicated, obtaining training on the use of ppe, having effective ppe readily available, and practicing consistent and precise use of ppe. table . lists the categories of isolation based on routes of transmission and their necessary components. table . lists precautions by syndromes, to be used when a patient has an infectious disease and the agent is not yet identified. for infectious agents that are more likely to be transmitted by the droplet route (e.g., pandemic influenza), droplet precautions (with use of surgical mask) are appropriate; however, during an aerosol-generating procedure, n or higher respirators are indicated. contaminated environmental surfaces and noncritical medical items have been implicated in transmission of several infectious agents, including vre, c. difficile, acinetobacter spp., mrsa, and rsv in healthcare settings. , , pathogens on surfaces are transferred to the hands of hcp and are then transferred to patients or items to be shared. occupying a room previously occupied by a patient with a key pathogen is a risk factor for acquiring that pathogen during a hospital stay. most often, the failure to follow recommended procedures for cleaning and disinfection contributes more than does the specific pathogen to the environmental reservoir during outbreaks. education of environmental services personnel combined with direct observation and feedback was associated with a persistent decrease in vre acquisition in a medical icu. use of a standardized cleaning checklist and implementation of monitoring for adherence to recommended environmental cleaning practices are important determinants of success. visual markers (e.g., invisible fluorescein powder) and adenosine triphosphate bioluminescence technologies are self-disinfecting surfaces can be created by altering the structure of the surface material or by incorporating a material that has antimicrobial activity. [ ] [ ] [ ] copper has antimicrobial activity against a wide range of organisms including bacteria and fungi. thus, incorporating copper into high-touch surfaces such as toilet seats, bed rails, door handles, or countertops is a novel infection prevention strategy that has been shown to reduce bacterial colony counts compared with control surfaces in healthcare settings. however, no recommendation for routine use has yet been made. disinfection and sterilization as they relate to ipc have been reviewed, and the hicpac/cdc developed comprehensive guidelines in . cleaning is the removal of all foreign material from surfaces and objects. this process is accomplished using soap and enzymatic products. failure to remove all organic material from items before disinfection and sterilization reduces the effectiveness of these processes. disinfection is a process that eliminates all forms of microbial life except the endospore. disinfection usually requires liquid chemicals. disinfection of an inanimate surface or object is affected adversely by the following: the presence of organic matter; a high level of microbial contamination; use of too dilute germicide; inadequate disinfection time; an object that also useful for monitoring effective environmental cleaning and providing immediate feedback to workers. a program of environmental cleaning should be developed collaboratively by the ipc and environmental services departments. certain infectious agents (e.g., rotavirus, noroviruses, c. difficile) can be resistant to some routinely used hospital disinfectants; thus when ongoing transmission occurs despite appropriate cleaning procedures, a : dilution of . % sodium hypochlorite (household bleach) or other special disinfectants are indicated. "no-touch" automated room decontamination technologies have been developed and added to room turnover procedures in some facilities. ultraviolet light irradiation and hydrogen peroxide vapor systems have been shown to reduce surface contamination with common pathogens and decrease the risk of acquiring hais caused by those pathogens when these systems are added to a terminal cleaning regimen. [ ] [ ] [ ] at specific wavelengths, ultraviolet light breaks the molecular bonds in dna, thus destroying the organisms. ultraviolet technology also has been considered as a method of disinfecting ppe, as a risk mitigation strategy for hcp caring for patients with evd. these technologies supplement, but do not replace, standard cleaning and disinfection because surfaces must be physically cleaned of particulate matter and debris. other disadvantages of these systems are that they cannot be used when people are in the rooms, room turnover is delayed, and the systems are expensive to purchase. no recommendations have been made for routine use or specific indications because research on antimicrobial effectiveness, cost effectiveness, and feasibility of these systems is ongoing. patients with the syndromes or conditions listed may have atypical signs or symptoms (e.g., neonates and adults with pertussis may not have paroxysmal or severe cough). the clinician's index of suspicion should be guided by the prevalence of specific conditions in the community, as well as clinical judgment. c the organisms listed under the column "potential pathogens" are not intended to represent the complete, or even most likely, diagnoses, but rather possible etiologic agents that require additional precautions beyond standard precautions until they can be excluded. influenza season. several children's hospitals provide influenza vaccine or tetanus, diphtheria, and acellular pertussis (tdap) vaccine, or both, to household contacts at no charge, thereby supporting the cocooning strategy endorsed by the advisory committee on immunization practices and the american academy of pediatrics. for patients requiring contact precautions, the use of ppe by visitors is determined by the nature of the interaction with the patient and the likelihood that the visitor will frequent common areas on the patient's unit or interact with other patients and their families. it is important to distinguish parents or guardians from nonhousehold visitors when determining whether the visitor should wear ppe. the risk-benefit decision should weigh not only the specific pathogen in question, but also the effect of parental or guardian ppe on breastfeeding, bonding, and family participation in the child's medical care. for family members who are rooming in with children who have prolonged hospitalizations, restriction of visitation to other patients is emphasized. a shea expert guidance document has been published to summarize the principles to follow to prevent transmission of infectious agents by visitors to patients because few data are available to inform evidence-based recommendations. although most pediatricians encourage visits by siblings in inpatient areas, the medical risk must not outweigh the psychosocial benefit. families favorably regard sibling visitation, and no evidence indicates increased bacterial colonization or subsequent bacterial infection in the neonate or older child who has been visited by siblings. strict guidelines for sibling visitation should be established and enforced in an effort to maximize visitation opportunities and minimize risks of transmission of infectious agents, most frequently viruses. the following recommendations regarding visitation can guide policy development: . sibling visitation is encouraged in the well-child nursery and nicu, as well as in areas for care of older children. . before visitation, parents should be interviewed by a trained staff nurse concerning the current health status of the sibling. siblings should not be allowed to visit if they are delinquent in recommended vaccines, have fever or symptoms of an acute illness, or are within the incubation period following exposure to a known infectious disease. after the interview, the physician or nurse should place a written consent for sibling visitation in the patient's permanent record and a name tag indicating that the sibling has been approved for visitation for that day. . asymptomatic siblings who recently were exposed to varicella but who previously were immunized can be assumed to be immune. . the visiting sibling should visit only his or her sibling and not be allowed in playrooms with groups of patients. . visitation should be limited to periods of time that ensure adequate screening, observation, and monitoring of visitors by medical and nursing staff members. . children should perform hand hygiene before and after contact with the patient or upon entry and departure from the patient's room. . during the entire visit, sibling activity should be supervised by parents or another responsible adult. animal-assisted therapy can be of substantial clinical benefit to the child hospitalized for prolonged periods; therefore it is important for healthcare facilities to provide guidance for safe visitation. many zoonoses and infections are attributable to animal exposure (see chapter ) . most infections result from inoculation of animal flora through a bite or scratch or self-inoculation after contact with the animal, the animal's secretions or excretions, or contaminated environment. although few data support a true evidence-based guideline for animal visitation (including personal pets) in healthcare facilities, updated expert guidance is provided in the shea expert guidance on animals in healthcare facilities: recommendations to minimize potential risk, which includes a review of the literature related to animal-assisted activities. prudent visitation policies should limit visitation to animals that: ( ) are domesticated; ( ) do not require a water environment; ( ) do not bite or scratch; ( ) can be brought to the hospital in a carrier or easily walked on a leash; ( ) are trained to defecate and urinate outside or in appropriate litter boxes; ( ) can be bathed before visitation; and ( ) are known to be free of respiratory, dermatologic, and gastrointestinal tract disease. despite the established risk of salmonellosis can harbor microbes in protected cracks, crevices, and hinges; and ph and temperature. sterilization is the eradication of all forms of microbial life, including fungal and bacterial spores. sterilization is achieved by physical and chemical processes such as steam under pressure, dry heat, ethylene oxide, and liquid chemicals. the spaulding classification of patient care equipment as critical, semicritical, and noncritical items with regard to sterilization and disinfection is used by the cdc. critical items require sterilization because they enter sterile body tissues and carry a high risk of causing infection if they are contaminated; semicritical items require disinfection because they may contact mucous membranes and nonintact skin; and noncritical items require routine cleaning because they come in contact only with intact skin. if noncritical items used on patients requiring transmission-based precautions, especially contact precautions, must be shared, these items should be disinfected between uses. guidelines for specific objects and specific disinfectants are published and updated by the cdc. multiple published reports and manufacturers similarly recommend the use and reuse of objects with appropriate sterilization, disinfection, or cleaning recommendations. recommendations in guidelines for reprocessing endoscopes to avoid contamination focus on training of personnel, meticulous manual cleaning, high-level disinfection followed by rinsing and air-drying, and proper storage. however, outbreaks of mdr gnb infections associated with exposure to duodenoscopes used for retrograde cholangiopancreatography that have been reprocessed according to recommendations suggest a need for new endoscope reprocessing technologies. , these endoscopes have a complex design with long, narrow channels, crevices that are difficult to access with a cleaning brush, right-angle turns, and heavy microbial contamination following procedures. until new methods are developed, meticulous adherence to recommended processes with enhancements should be followed. medical devices that are designed for single use (e.g., specialized catheters, electrodes, biopsy needles) must be reprocessed by third parties or hospitals according to the guidance issued by the food and drug administration (fda) in august, with amendments in september, ; such reprocessors are considered and regulated as "manufacturers." available data show that single-use devices reprocessed according to the fda regulatory requirements are as safe and effective as new devices. deficiencies in disinfection and sterilization leading to infection have resulted either from failure to adhere to scientifically based guidelines or failures in the disinfection or sterilization processes. when such failures are discovered, an investigation must be completed, including notification of patients and, in some cases, testing for infectious agents. a guidance document for risk assessment and communication to patients in such situations is published. healthcare facility waste is all biologic or nonbiologic waste that is discarded and not intended for further use. medical waste is material generated as a result of use with a patient, such as for diagnosis, immunization, or treatment, and it includes soiled dressings and intravenous tubing. infectious waste is that portion of medical waste that potentially could transmit an infectious disease. microbiologic waste, pathologic waste, contaminated animal carcasses, blood, and sharps are all examples of infectious waste. methods of effective disposal of infectious waste include incineration, steam sterilization, drainage to a sanitary sewer, mechanical disinfection, chemical disinfection, and microwave treatment. state regulations guide the treatment and disposal of regulated medical waste. recommendations are available for developing and maintaining a program within a facility for safe management of medical waste. special visitation policies are required in pediatric units, especially the high-risk units, because acquisition of a seemingly innocuous viral infection in neonates and in children with underlying diseases can result in unnecessary evaluations and empiric therapies for suspected septicemia as well as serious, life-threatening disease. all visitors with signs or symptoms of respiratory or gastrointestinal tract infection should be restricted from visiting patients in healthcare facilities. increased restrictions may be required during a community outbreak (e.g., sars, pandemic influenza, enterovirus d ). during respiratory virus season, the number of visitors can be limited and the age restriction increased. it is preferred for all visitors to be immunized against influenza during part i understanding, controlling, and preventing infectious diseases respiratory viruses, norovirus, and tuberculosis. important preventive procedures for hcp with infants at home or who are pregnant are as follows: ( ) consistent training and observance of standard precautions, transmission-based precautions, and especially hand hygiene according to published recommendations; ( ) annual influenza and -time tdap immunization (unless pregnant, when a tdap immunization during each pregnancy is recommended); ( ) routine tuberculosis screening; ( ) assurance of immunity or immunization against poliomyelitis, measles, mumps, hepatitis b, and rubella; ( ) early medical evaluation for acute infectious illnesses; ( ) routine, on-time immunization of infants; and ( ) prompt initiation of prescribed prophylaxis or therapy following exposure or development of certain infections. hcp who are, could be, or anticipate becoming pregnant should feel comfortable working in the healthcare workplace. in fact, with standard precautions and appropriate adherence to environmental cleaning and isolation precautions, vigilant hcp can be at less risk than a preschool teacher, childcare provider, or mother of children with many playmates in the home. pathogens of potential concern to pregnant hcp include cytomegalovirus, hepatitis b virus, influenza, measles, mumps, parvovirus b , rubella, vzv, m. tuberculosis, and, since , zika virus. the causal association between zika virus and microcephaly and other neurodevelopmental abnormalities has led to recommended precautions. although zika virus is more frequently acquired outside of healthcare, pregnant hcp are advised to follow safe injection practices for prevention of exposure to infectious blood. pregnancy is an indication for influenza vaccine to prevent the increased risk of serious disease and hospitalization that occurs in women who develop influenza in the second or third trimester of pregnancy. in , the cdc recommended universal immunization with tdap (if previously not immunized with tdap) for pregnant women after weeks of gestation, and since , the cdc recommends a dose of tdap with each pregnancy. pregnant workers should assume that all patients potentially are infected with cytomegalovirus and other "silent" pathogens and should use hand hygiene and gloves when handling body fluids, secretions, and excretions. table . summarizes information about infectious agents that are relevant to the pregnant woman working in healthcare. chapters on each agent may be consulted for more specific information. the risk of hais in pediatric ambulatory settings is substantial, and it usually is associated with lack of adherence to routine ipc practices and procedures, especially disinfection, sterilization, and hand hygiene. respiratory viral agents and m. tuberculosis are noteworthy pathogens transmitted in ambulatory settings. transmission of rsv in an hsct outpatient clinic has been demonstrated using molecular techniques. crowded waiting rooms, toys, furniture, lack of isolation of children, unwell children, contaminated hands, contaminated secretions, and susceptible hcp are only some of the factors that result in sporadic and epidemic illness in outpatient settings. the association of communityassociated mrsa in hcp working in an outpatient hiv clinic with environmental community-associated mrsa contamination of that clinic indicates the potential for transmission in this setting. patientto-patient transmission of burkholderia species and p. aeruginosa in outpatient clinics for patients with cystic fibrosis has been confirmed and prevented by implementing recommended ipc methods. ipc guidelines and policies for pediatric outpatient settings, including office practices, were published by the american academy of pediatrics in , reaffirmed in , and are updated currently. prevention strategies include definition of policies, education, and strict adherence to guidelines. in pediatrics, among the most important interventions are separation of children with respiratory tract illnesses from well children and consistent implementation of respiratory etiquette or cough hygiene. a guideline for ipc for outpatient settings with a checklist and a guideline for outpatient oncology settings can be found on the cdc website. principles and recommendations for safe living after hsct and for patients with cystic fibrosis are valuable contributions to management of infectious risks for specific populations in the ambulatory setting. a guideline based on data and expert consensus opinion for ipc in residential facilities for associated with reptiles (e.g., turtles, iguanas), many reports of outbreaks of invasive disease associated with reptiles continue to be published ; reptiles should be excluded from pet visitation programs, and families should be advised not to have pet reptiles in the home with young infants or immunocompromised persons. exotic animals that are imported should be excluded because of unpredictable behavior and the potential for transmission of unusual pathogens (e.g., monkeypox in the us in ). , visitation should be limited to short periods and confined to designated areas. visiting pets must have a certificate of immunization from a licensed veterinarian. children should observe hand hygiene after contact with animals. most pediatric facilities restrict pet interaction with severely immunosuppressed patients and patients in icus. occupational health and student health collaboration with the ipc department of a healthcare facility is required by the occupational safety and health administration. hcp are at increased risk of infection in hospitals caring for children because ( ) children have a high incidence of infectious diseases, ( ) personnel can be susceptible to many pediatric pathogens, ( ) pediatric care requires close contact, ( ) children lack good personal hygiene, ( ) infected children can be asymptomatic, and ( ) hcp are exposed to multiple family members who also may be infected. the occupational health department is an educational resource for information on infectious pathogens in the healthcare workplace. in concert with the ipc service, occupational health provides preemployment education and respirator fit testing and annual retraining for all employees regarding routine health maintenance, available recommended and required vaccines, standard and transmission-based precautions, and exposure control plans. screening for tuberculosis at regular intervals, as determined by the facility's risk assessment, can use either tuberculin skin testing or interferon-γ release assays. with new pathogens being isolated, new diseases and their transmission described, and new prophylactic regimens and treatment available, it is mandatory that personnel have an up-to-date working knowledge of ipc and know where and what services, equipment, and therapies are available for hcp. all hcp should be screened by history or serologic testing, or both, to document their immune status to specific agents, and immunization should be provided for the following for all employees who are nonimmune and who do not have contraindications to receiving the vaccine: diphtheria toxoid, hepatitis b virus, influenza (yearly), mumps, poliomyelitis, rubella, rubeola, varicella, and tdap. the advisory committee on immunization practices recommendation to administer a single dose of tdap to certain hcp was amended in to have no restriction based on age or time interval since the last td dose. providing vaccines at no cost to hcp increases acceptance. influenza vaccine coverage among hcp has increased over time to % overall for the to influenza season, with the highest coverage rate of % in hcp working in hospitals and the lowest rate of % in long-term care settings. although mandatory influenza vaccination programs for all employees in healthcare facilities are endorsed by many professional societies, , some facilities have had success using novel strategies that include incentives, without a mandate. publications from several large institutions, including children's hospitals, indicate that mandatory programs with only medical and religious exemptions are well received, and only rare employees are terminated for failure to be vaccinated. , special concerns of healthcare personnel hcp who have common underlying medical conditions should be able to obtain general information on wellness and screening when needed from the occupational health service. hcp with direct patient contact who have infants < year of age at home often are concerned about acquiring infectious agents from patients and transmitting them to their susceptible children. an immune healthcare worker who is exposed to vzv does not become a silent "carrier" of vzv. however, pathogens to which the healthcare worker is partially immune or nonimmune can cause a severe, mild, or asymptomatic infection in the employee that can be transmitted to family members. examples include influenza, pertussis, rsv and other pediatric patients and their families provides practical guidance for settings where high-risk patients live with their families for varying periods of time. ipc challenges now are being 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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 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malaria epidemiology evidence of airborne transmission of the severe acute respiratory syndrome virus key: cord- - xbu hnq authors: slingenbergh, jan title: animal virus ecology and evolution are shaped by the virus host-body infiltration and colonization pattern date: - - journal: pathogens doi: . /pathogens sha: doc_id: cord_uid: xbu hnq the current classification of animal viruses is largely based on the virus molecular world. less attention is given to why and how virus fitness results from the success of virus transmission. virus transmission reflects the infection-shedding-transmission dynamics, and with it, the organ system involvement and other, macroscopic dimensions of the host environment. this study describes the transmission ecology of the world main livestock viruses, in total, a mix of rna, dna and retroviruses. following an iterative process, the viruses are virtually ranked in an outer- to inner-body fashion, by organ system, on ecological grounds. also portrayed are the shifts in virus host tropism and virus genome. the synthesis of the findings reveals a predictive virus evolution framework, based on the outer- to inner-body changes in the interplay of host environment-transmission modes-organ system involvement-host cell infection cycle-virus genome. outer-body viruses opportunistically respond to the variation in the external environment. for example, respiratory and enteric viruses tend to be associated with poultry and pig mass rearing. ruminant and equine viruses tend to be more deep-rooted and host-specific, and also establish themselves in the vital inner-body systems. it is concluded that the framework may assist the study of new emerging viruses and pandemic risks. animal viruses may be split into transmissible and persistent viruses. it has been proposed that transmissible viruses correlate with replication and virulence and that virus persistence instead permits a lower transmission rate [ ] . this insight builds on earlier work suggesting that virus persistence may pave the way for virus-host symbiosis [ ] . viruses are considered essential agents within the roots and stems of the tree of life [ ] . for example, rna viruses in vertebrates tend to broadly follow the evolutionary history of their hosts that began in the ocean and extended for hundreds of millions of years [ ] . the symbiotic virus-host relationships can take many forms, from antagonistic to mutualistic, and viruses, like other symbionts, lie on a continuum that can shift with environmental changes [ ] . the present study seeks to take these insights to the next level. starting point in the analysis is the link between virus propagation and transmission success. virus transmission may be considered to present the backbone of virus ecology, determining the viruses selected for. unfortunately, the current classification of animal viruses emphasizes the importance of virus genomic architecture and the host cell infection cycle [ ] . less attention is given to why and how virus fitness results from the virus transmission success. for example, an animal virus may become established in the upper respiratory tract and transmit via aerosols to the next host. an enteric virus features a fecal-oral cycle. a skin virus may transmit on the basis of touch. a virus colonizing the distal urogenital tract may transmit during sexual contact. hence, an analysis of the virus transmission success requires a consideration of the overt clinical signs of infection, the gross pathology, the matching virus shedding profile, and of the ensuing modes of transmission. the current analysis explores how the virus molecular world and the macroscopic dimensions of the host environment are intertwined, integral to one and the same virus transmission ecology. in vertebrate hosts the more vital organ systems are shielded off from external aggressors, small or large. it may be assumed that also the host immune defenses are structured to ensure that harmful viral pathogens remain confined to the outer-body environment, the epithelia. epithelial viruses interface with the external environment and respond to the variation encountered here. opposingly, infiltrative viruses establish in the inner-body environment and are expected to evolve towards a more intimate virus-host relationship. given that the virus-host relationship changes with the position of the virus in the outer-to inner-body continuum the analysis focuses on the extent of virus host-body infiltration. the virus organ system tropism is assumed to evolve in harmony with the virus cell tropism. this may be inferred from the dichotomy in the release of viruses from epithelial cells. apart from direct cell-to-cell transmission [ ] , viruses may be released from the apical cell surface and so end-up in the outer-body environment. these viruses colonize mucosae and skin. in contrast, viruses released from the basolateral cell surface infiltrate underlying tissues. these viruses end-up in the lymph drainage, enter the blood circulation and so may infect any of the internal organs. infiltration of and establishment in the inner-body environment may translate in additional, non-epithelial transmission modes. for example, virus establishment in the reproductive organs may translate in intrauterine or lactogenic transmission [ ] . in birds, virus may be shed into yolk or albumen and so transmit vertically [ ] . virus circulation in the bloodstream may enable virus transmission via needles or arthropod vectors [ ] . taking an invasion ecology perspective, the host-body is viewed as a mosaic of organ systems. viruses and organ systems are virtually portrayed in an outer-to inner-body fashion, based on the outer-to inner-body shifts in the virus infection-shedding-transmission characteristics which, in turn, result from the shift in virus organ system tropism. it is assumed that the nature of the virus-host interaction changes with the position of the virus in the outer-to inner-body continuum. the study describes the transmission ecology of the world main livestock viruses. the rationale for selecting the world main livestock viruses relates to the host damaging effects of these pathogens, the overt clinical signs and gross pathology, translating in prominent virus shedding and obvious virus transmission modes. moreover, because of the major economic impact of these diseases, the causative viruses and the corresponding infection-transmission dynamics have been well studied. placed in a wider perspective the analysis builds on the growing perception that viruses deserve to be viewed as evolving living entities [ ] [ ] [ ] . as biological replicators viruses require a propagation strategy in order to become transmitted to the next host [ ] . for this, a virus may turn host damaging or instead evolve a friendly, persisting virus-host relationship [ ] . the analysis entailed an iterative process. as a first step, the one-to-three scores allocated to the livestock viruses for the four ecological variables were examined in more detail. the scores are shown in figure s b . the variables comprise the extent of virus host-body infiltration, the length of the infection period, the infection severity level, and the virus environmental survival rate. the one-to-three infiltration score reflects the organ systems involvement in infection-transmission and concerns, respectively, virus transmission based on the involvement of the epithelia, transmission involving epithelia and internal organs, and transmission involving just internal organs. the score for the length of the infection period reflects, respectively, acute, acute plus persistent, and persistent infections. likewise, the score for the infection severity level concerns a case fatality of less than one, one to ten, and above ten percent. the score for the virus environmental survival rate refers to the number of days that the virus remains infective outside the host-body, ranging from up to three, three to ten, to over ten days. with one exception, the variables did not increase or decrease in value together. just the association between the extent of virus host-body infiltration and the length of the infection period was found to be monotonic. spearman correlation yielded an r = . and p < . . it was thus found that viruses infiltrating internal organs either cause persistent infections or a combination of acute and persistent infections. conversely, persistent viruses either colonize internal organs or a combination of internal organs and epithelia. hence, the length of the infection period appears to present a measure for the extent of virus host-body infiltration. as a next step, the eleven virus families in the study were grouped and ranked a-d on the basis of the infiltration scores allocated to the individual family viruses, see figure . the transmission of the viruses belonging to the orthomyxoviridae and the paramyxoviridae was found to strictly result from the involvement of the epithelia. the transmission of the viruses belonging to the coronaviridae, the picornaviridae and the poxviridae was in part modulated also by the internal organ systems. the transmission of the viruses belonging to the arteriviridae, the flaviviridae, the herpesviridae, plus also the single infectious bursal disease virus (ibdv), resulted from epithelial modes as well as internal organ systems involvement. finally, the transmission of the single bluetongue virus (btv) plus the viruses belonging to the retroviridae family either reflected the involvement of epithelia plus internal organ systems or of just internal organ systems. a spearman correlation of the a-d virus family specific infiltration ranking and the length of the infection period scores yielded an r = . and p = . the result indicates that the interrelationships among virus families may be defined in ecological terms and that the virus families may be neatly lined up in an outer-to inner-body fashion, virtually. one to ten, and above ten percent. the score for the virus environmental survival rate refers to the number of days that the virus remains infective outside the host-body, ranging from up to three, three to ten, to over ten days. with one exception, the variables did not increase or decrease in value together. just the association between the extent of virus host-body infiltration and the length of the infection period was found to be monotonic. spearman correlation yielded an r = . and p < . . it was thus found that viruses infiltrating internal organs either cause persistent infections or a combination of acute and persistent infections. conversely, persistent viruses either colonize internal organs or a combination of internal organs and epithelia. hence, the length of the infection period appears to present a measure for the extent of virus host-body infiltration. as a next step, the eleven virus families in the study were grouped and ranked a-d on the basis of the infiltration scores allocated to the individual family viruses, see figure . the transmission of the viruses belonging to the orthomyxoviridae and the paramyxoviridae was found to strictly result from the involvement of the epithelia. the transmission of the viruses belonging to the coronaviridae, the picornaviridae and the poxviridae was in part modulated also by the internal organ systems. the transmission of the viruses belonging to the arteriviridae, the flaviviridae, the herpesviridae, plus also the single infectious bursal disease virus (ibdv), resulted from epithelial modes as well as internal organ systems involvement. finally, the transmission of the single bluetongue virus (btv) plus the viruses belonging to the retroviridae family either reflected the involvement of epithelia plus internal organ systems or of just internal organ systems. a spearman correlation of the a-d virus family specific infiltration ranking and the length of the infection period scores yielded an r = . and p = . the result indicates that the interrelationships among virus families may be defined in ecological terms and that the virus families may be neatly lined up in an outer-to inner-body fashion, virtually. next, the organ system tropisms of the viruses belonging to each family were collectively fitted and with the naked eye aligned with the figure line-up of families. for this, the within-group, alphabetical family order was adjusted to secure an optimal visual match. as indicated in figure , from outer-to inner-body the virus organ system appears to shift from the respiratory plus the alimentary tract to the skin, the distal urogenital tract or cloaca, the peripheral nerves and ganglia, the reproductive organs system, the lungs, to the immune plus the circulatory systems. hence, there are indications that both viruses and organ systems may be lined up in an outer-to inner-body fashion, virtually. next, the organ system tropisms of the viruses belonging to each family were collectively fitted and with the naked eye aligned with the figure line-up of families. for this, the within-group, alphabetical family order was adjusted to secure an optimal visual match. as indicated in figure , from outer-to inner-body the virus organ system appears to shift from the respiratory plus the alimentary tract to the skin, the distal urogenital tract or cloaca, the peripheral nerves and ganglia, the reproductive organs system, the lungs, to the immune plus the circulatory systems. hence, there are indications that both viruses and organ systems may be lined up in an outer-to inner-body fashion, virtually. next, the a-d family ranking was converted into a one-to-four virus infiltration score applicable to individual viruses. further, these scores are shown in supplementary figure s b. to make the scoring compatible with the a-d family ranking, the one-to-four scores reflects, respectively, virus transmission strictly based on epithelial modes, primarily based on epithelial modes, involving epithelia and internal organ systems, and primarily involving internal organ systems. there are several differences with the a-d family ranking shown in figure . among the viruses of family group b, tgev, aev, fmdv, and lsdv received a score of three for transmitting on the basis of the involvement of both epithelia and internal organs. pev and svdv of group b were considered primarily epithelial and so received a two score. both these viruses are persistently shed in feces, including in the absence of clinical signs, indicating a systemic infection component. the herpesviruses of group c were split into two. bhv- , dev, ehv- , and gahv were considered primarily epithelial while ehv- , gahv- , and shv- were considered to involve epithelia and internal organs. among the d group viruses alv was considered to involve epithelia and internal organs, unlike caev, jsrv, and mvv, for which the involvement of the epithelia did not appear to contribute to the overall virus transmission success. the latter viruses were allocated a score of four. when the new, one-to-four virus infiltration scores were matched to the scores for the length of the infection period spearman r became . , and p = . when the somewhat atypical, vector borne next, the a-d family ranking was converted into a one-to-four virus infiltration score applicable to individual viruses. further, these scores are shown in supplementary figure s b. to make the scoring compatible with the a-d family ranking, the one-to-four scores reflects, respectively, virus transmission strictly based on epithelial modes, primarily based on epithelial modes, involving epithelia and internal organ systems, and primarily involving internal organ systems. there are several differences with the a-d family ranking shown in figure . among the viruses of family group b, tgev, aev, fmdv, and lsdv received a score of three for transmitting on the basis of the involvement of both epithelia and internal organs. pev and svdv of group b were considered primarily epithelial and so received a two score. both these viruses are persistently shed in feces, including in the absence of clinical signs, indicating a systemic infection component. the herpesviruses of group c were split into two. bhv- , dev, ehv- , and gahv were considered primarily epithelial while ehv- , gahv- , and shv- were considered to involve epithelia and internal organs. among the d group viruses alv was considered to involve epithelia and internal organs, unlike caev, jsrv, and mvv, for which the involvement of the epithelia did not appear to contribute to the overall virus transmission success. the latter viruses were allocated a score of four. when the new, one-to-four virus infiltration scores were matched to the scores for the length of the infection period spearman r became . , and p = . when the somewhat atypical, vector borne bluetongue virus was removed from the correlation, r remained . for the one-to-four scoring, became . for the a-d virus family specific ranking, and . , with p = × − , for the one-to-three infiltration ranking. next, all of the above findings were considered in conjunction with the literature data on the transmission ecology collated for each of the viruses in figure s a . pieced together on this basis was an outer-to inner-body line-up of viruses by organ system or combination of organ systems, guided by the one-to-four virus infiltration score, the corresponding virus organ system tropism, the matching virus transmission modes, length of the infection and shedding periods, infection severity level, and virus environmental survival rate, see figure and, also, figure s d . bluetongue virus was removed from the correlation, r remained . for the one-to-four scoring, became . for the a-d virus family specific ranking, and . , with p = × − , for the one-to-three infiltration ranking. next, all of the above findings were considered in conjunction with the literature data on the transmission ecology collated for each of the viruses in figure s a . pieced together on this basis was an outer-to inner-body line-up of viruses by organ system or combination of organ systems, guided by the one-to-four virus infiltration score, the corresponding virus organ system tropism, the matching virus transmission modes, length of the infection and shedding periods, infection severity level, and virus environmental survival rate, see figure and, also, figure s d . for the epithelial, outer-body viruses it turned out that the length of the infection and shedding periods, as well as the virus environmental survival rate generally increased from respiratory tract to alimentary tract to skin. the respiratory viruses transmitted on the basis of aerosols, direct contact or fomites. alimentary tract viruses were found to transmit on the basis of a fecal-oral cycle, through direct contact, contamination of feed and water, or involving fomites, persons and vehicles. viruses infecting both respiratory and alimentary tract featured a mix of these transmission modes. mostly, these viruses caused rather severe infections. among the skin viruses, the more infiltrative viruses affecting all layers of the skin caused slowly healing lesions. the transmission of these deep-rooted skin viruses was found to rely on abrasion or biting flies rather than on direct touch or on indirect contact, more typical for superficial skin lesions. some of the epithelial viruses are shed in feces over a prolonged time period, also in the absence of clinical signs, and these infections were considered to feature a systemic component. next, the epithelial herpesviruses establishing latently in peripheral nerves and ganglia were found to cause a recurrence or persistence of the mucosal and/or skin infection, including of the distal urogenital tract and external genitalia. virus infiltration of the inner-body environment frequently implicated the genital tract or reproductive system in general. this was found to be the case for the rna, the dna and for the retroviruses in the study. virus establishment in the reproductive system translated in seminal transmission, haphazard abortion, late term abortion, stillbirth, birth of infected, yet apparently healthy offspring or, also, lactogenic transmission. the vertical transmission modes were common among the utmost deep-rooted viruses, the viruses infiltrating also the immune and circulatory systems. some of the utmost infiltrative viruses featured an absence of epithelial transmission modes and were environmentally labile. virus infiltration of the immune system associated with immune-suppression, severe infections, neoplasia, or instead with in-apparent, persistent infection. virus infiltration of immune and circulatory systems associated with iatrogenic transmission modes. virus circulation in the bloodstream facilitated arthropod borne transmission. as indicated in figure , the transmission of the bluetongue virus, the sole arbovirus in the study, was considered somewhat atypical because the virus usually causes a transient infection in the ruminant host while in midges remains infective for life. hence, the involvement of the biological vector complicates a direct comparison with the transmission ecology of the remaining viruses. the finding that virus environmental survival in the outer-body environment increased from respiratory tract to alimentary tract to skin and decreased with the shift from the outer-to the inner-body environment prompted a re-examination of the relationship between the extent of virus host-body infiltration and virus environmental survival. virus infiltration scores two-to-four, running from primarily epithelial transmission, to transmission involving also internal organ systems, to transmission primarily involving internal organ systems, were matched to the one-to-three virus environmental survival rate scores, yielding an r = − . and p = < . . the indication that at least in broad terms the extent of virus inner-body infiltration correlated with a loss of virus robustness was applied in the virus ranking, along with the other factors. furthermore, the outer-to inner-body shifts in virus host tropism and virus genome were examined. underlined in figure are ruminant and equine viruses, contrasted to the remaining, poultry and pig viruses. excluded from the host tropism correlations was the multiple-host fmdv. the remaining viruses all formed part of either of the two virus host groupings. it was found that the rna, dna and retroviruses broadly line up in an outer-to inner-body fashion. virus host tropism and the virus genome line-up were matched. additional correlations concerned the virus host tropism and the four virus ecological variable scores, as well as the virus genome type and the four virus ecological variable scores. the extent of the host-body infiltration was found to increase from rna to dna to retrovirus, with r = . and p < . . from rna to dna to retrovirus the ruminant and equine viruses gained in prominence, with r = . and p < . , and the infection severity level decreased, with r = − . and p < . . moreover, the ruminant and equine viruses were found to cause less severe infections than the poultry and pig viruses, with spearman r = − . and p < . . hence, from outerto inner-body, the virus genome type and host tropism appear to shift in concert, along with the infection-transmission dynamics. the synthesis of the findings is presented in figure . the host environment frames the virus transmission modes and, with it, explains the organ system involvement, the specifics of the host-cell infection cycle, and the virus genome. vice versa, the virus life history explains the virus genomics, the host-cell infection cycle and, with it, the macroscopic level virus-host interactions and the host population ecology. the interplay of the host environment-transmission modes-organ system involvement-host cell infection cycle-virus genome changes from outer-to inner-body, resulting in two opposite virus evolution pathways, respectively for generalist and specialist type viruses. the extent of the host-body infiltration was found to increase from rna to dna to retrovirus, with r = . and p < . . from rna to dna to retrovirus the ruminant and equine viruses gained in prominence, with r = . and p < . , and the infection severity level decreased, with r = − . and p < . . moreover, the ruminant and equine viruses were found to cause less severe infections than the poultry and pig viruses, with spearman r = − . and p < . . hence, from outer-to inner-body, the virus genome type and host tropism appear to shift in concert, along with the infection-transmission dynamics. the synthesis of the findings is presented in figure . the host environment frames the virus transmission modes and, with it, explains the organ system involvement, the specifics of the host-cell infection cycle, and the virus genome. vice versa, the virus life history explains the virus genomics, the host-cell infection cycle and, with it, the macroscopic level virus-host interactions and the host population ecology. the interplay of the host environment-transmission modes-organ system involvement-host cell infection cycle-virus genome changes from outer-to inner-body, resulting in two opposite virus evolution pathways, respectively for generalist and specialist type viruses. implied by figure is that the crowding conditions observed in poultry and in pig husbandry tend to attract horizontally transmitting respiratory and enteric viruses. the pathogenicity level of the viruses evolves to match the dynamics in host abundance and contact rate. at the molecular level, these rna viruses become released from the apical surface of epithelial cells directly into the implied by figure is that the crowding conditions observed in poultry and in pig husbandry tend to attract horizontally transmitting respiratory and enteric viruses. the pathogenicity level of the viruses evolves to match the dynamics in host abundance and contact rate. at the molecular level, these rna viruses become released from the apical surface of epithelial cells directly into the outer-body environment. thus, proliferative virus replication, generalized infection of respiratory plus enteric mucosae, profuse virus shedding, and swift onward transmission all go hand-in-hand. a diametrically opposite scenario is given by relatively stable host environments observed in ruminant and equine husbandry, with parent stock and their young grazing together in the open, not unlike wild herbivore ecologies. the viruses attracted and selected for establish in the vital inner-body systems and transmit vertically, via needles or via bloodsucking arthropods. at the molecular level, virus establishment in the vital body systems is matched by low replication rates and minor or slowly evolving host damage. the utmost infiltrative viruses in the study are the retroviruses. in addition, some of other rna viruses are deep-rooted. the dna viruses in the study take an intermediary position. it has been established that epithelial viruses are highly evolvable, more so than inner-body viruses [ ] . epithelial viruses are responsive to the dynamics in the environment external to the host-body. this may be illustrated on the basis of the genetically related virus pairs in the study. for example, the influenza virus circulating in horses (eiv) generates a transient, dry cough supporting swift virus transmission via aerosols [ ] . in pigs, the virus (siv) causes coughing and sneezing, resulting from significant mucus production [ ] . the virus transmits on the basis of close direct contact, in line with the social behavior and body size of pigs. the rinderpest virus (rpv) in cattle and buffaloes primarily colonizes the alimentary tract and transmits on the basis of direct muzzle-to-muzzle contact [ ] . in small ruminants, the identical peste des petits ruminants virus affects also the respiratory tract and transmits also via aerosols. likewise, the lumpy skin disease virus (lsdv) in cattle causes persistent, deep, necrotic skin plugs and transmits via biting insects, mechanically. in sheep and goats, the virus (sgpv) causes transient lesions [ ] . the caprine arthritis-encephalitis virus (caev) and the maedi-visna virus (mvv) present an example of closely related lentiviruses establishing in the inner-body organ systems of sheep and goats. the viruses display overlap in host tropism and both transmit mainly vertically via colostrum and milk. the difference between the two viruses mainly concerns the differential inner-body virus organ system tropism. projected on a long evolutionary timescale, inner-body viruses tend to become locked in within the host body. this internalization may turn progressive when the epithelial transmission modes are being replaced by internal organ system-based modes. virus establishment in the reproductive system translates in vertical transmission, in turn enhancing virus-host co-evolution [ ] . virus infiltration of also immune and circulatory systems may yield in-apparent, persistent infections, indicating low levels of pathogenicity and/or enhanced host tolerance. the division between virus and host may become blurred and given enough time the two may become one [ ] . the nature of species jumps differs between generalist and specialist type viruses. for example, an opportunistic, epithelial virus of wildlife origin is likely to be found circulating in livestock before becoming first detected in humans as host. this has been the case for influenza [ ] , henipah [ ] and mers corona viruses [ ] . further, the sars corona virus infected civet cats raised as food animals before appearing in humans as host [ ] . in contrast, more infiltrative viruses establish in the vital inner-body systems. specialist viruses circulating in the bloodstream of non-human primates may directly jump to humans as host, as a result of complex ecological, socio-economic, demographic and other drivers. examples comprise hiv-aids [ ] , chikungunya [ ] , and zika viruses [ ] . hence, knowing how species jumps differ for the different host ecologies may assist the study of pandemic risks. a subtotal of livestock viruses of global animal health significance was extracted from the oie-listed diseases, infections and infestations in force in [ ] . livestock infections and diseases resulting from virus spill-over from wildlife were excluded from the analysis. the common livestock hosts, described in the colloquial oie terminology, comprise horses, donkeys, cattle, buffaloes, sheep, goats, swine, chicken, turkeys, ducks, and geese. the total of livestock viruses belong to eleven different families and form a mix of rna (n = ), dna (n = ), and retroviruses (n = ). shown in figure s a for each of the viruses are the virus family, virus genomic architecture, virus name in full, abbreviated, and the common names given to the infection or disease. also presented is a brief summary on the transmission ecology for each virus, with references to the primary livestock host, the virus organ system tropism, the length of the infection and shedding period, the infection severity level, the transmission modes, and the virus environmental survival rate. presented in figure s b are one-to-three scores allocated to the viruses for four ecological variables. the variables comprise the extent of virus host-body infiltration, the length of the infection period, the infection severity level, and the virus environmental survival rate. the one-to-three infiltration score reflects the organ system involvement in infection-transmission and concerns, respectively, virus transmission based on the involvement of the epithelia, transmission involving epithelia and internal organs, and transmission involving just internal organs. also shown is a one-to-four virus infiltration score, an outcome of the iterative analysis process and reflecting, respectively, virus transmission strictly based on epithelial modes, primarily based on epithelial modes, involvement of epithelia and internal organ systems, and of primarily internal organ systems. the score for the length of the infection period reflects, respectively, acute, acute plus persistent, and persistent infections. likewise, the score for the infection severity level concerns a case fatality of less than one, one to ten, and above ten percent. the score for the virus environmental survival rate refers to the number of days that the virus remains infective outside the host body, ranging from up to three, three to ten, to over ten days. also indicated in figure s b is the virus host range as observed in both livestock and wildlife. figure s c lists the literature sources on which figure s a ,b is based. the analysis concerned an iterative process. as a first step, the one-to-three scores allocated to the viruses for the four ecological variables were examined in more detail and the monotonic associations subjected to spearman correlation. just the scores for the virus host-body infiltration and for the length of the infection period were found to increase in value together. next, given the coarse match between virus infiltration and persistence, it was examined how this relationship played out at the virus family level. for this, the eleven virus families in the study were grouped and ranked a-d on the basis of the one-to-three infiltration scores allocated to the individual family viruses. also, this a-d infiltration ranking was held against the length of the infection period scores. next, given the indication, from the above, that the virus families may be neatly lined up in an outerto inner-body fashion, it was examined how the organ system tropisms of the family viruses aligned with it. for this, the organ system tropisms of the viruses belonging to each family were collectively fitted and with naked eye aligned with the a-d family groups. for this, the alphabetical family order within the family groups was abandoned in order to obtain an optimal visual match. the result confirms that also the organ systems may be lined up in an outer-to inner-body fashion, virtually. next, the a-d family ranking was converted into a one-to-four virus infiltration score applicable to individual viruses, as described in section . , and also these scores were matched to the length of the infection period scores. next, since the infiltration-persistence match for the individual viruses was found to be about as strong as for the virus families, the viruses were individually lined up in an outer-to inner-body fashion, irrespective the family origin, strictly on ecological grounds. for this, all of the above obtained results were considered in conjunction with the literature data on the transmission ecology collated for each of the viruses in figure s a . pieced together on this basis was an outer-to inner-body line-up of viruses by organ system or combination of organ systems, guided by the one-to-four virus infiltration score, the corresponding virus organ system tropism, the matching virus transmission modes, length of the infection and shedding periods, infection severity level, and virus environmental survival rate. the finding that virus environmental survival in the outer-body environment increased from respiratory tract to alimentary tract to skin and decreased with the shift from the outer-to the inner-body environment prompted a re-examination of the relationship between the extent of virus host-body infiltration and virus environmental survival. virus infiltration scores two-to-four, running from primarily epithelial transmission, to transmission involving also internal organ systems, to transmission primarily involving internal organ systems, were found to match with the one-to-three virus environmental survival rate scores. the indication that, at least in broad terms, the extent of virus inner-body infiltration correlated with a loss of virus robustness was applied in the virus ranking, along with the other factors. next, furthermore examined were the outer-to inner-body shifts in virus host tropism and virus genome. for this, the ruminant plus equine viruses were contrasted to the poultry plus pig viruses. excluded from the host tropism correlations was the multiple host fmdv. the remaining viruses all formed part of either of the two host groupings. it was found that rna, dna and retroviruses broadly line up in an outer-to inner-body fashion. virus host tropism and the virus genome line-up were matched. additional correlations concerned virus host tropism and the four virus ecological variable scores, as well as virus genome type, and the four virus ecological variable scores. it was found that from outer-to inner-body, the virus genome type and host tropism appear to shift in concert, along with the infection-transmission dynamics. the collective results above served the compilation of the predictive framework for animal virus evolution shown in figure , discussion section. the online rho calculator https://www.socscistatistics.com/tests/spearman/default.aspx was used for the spearman correlations. this software has been audited by established statistics packages. virus ecology: a gap between detection and prediction. emerg. microbes infect. , , e virus-host symbiosis mediated by persistence viruses are essential agents within the roots and stem of the tree of life the evolutionary history of vertebrate rna viruses move over, bacteria! viruses make their mark as mutualistic microbial symbionts virus taxonomy: the database of the international committee on taxonomy of viruses (ictv) direct cell-to-cell transmission of respiratory viruses: the fast lanes preventive and therapeutic strategies for bovine leukemia virus: lessons for htlv detection of avian leukosis virus in albumen of chicken eggs using reverse transcription polymerase chain reaction nosocomial transmission of dengue fever via needlestick. an occupational risk what ecologists can tell virologists predicting virus emergence amid evolutionary noise life history determines genetic structure and evolutionary potential of host-parasite interactions are viruses alive? the replicator paradigm sheds decisive light on an old but misguided question the good viruses: viral mutualistic symbioses cell tropism predicts long-term nucleotide substitution rates of mammalian rna viruses equine influenza (infection with equine influenza virus) in world organisation for animal health (oie) manual of diagnostic tests and vaccines for terrestrial animals, oie technical disease cards, swine influenza. oie technical disease cards, rinderpest. oie technical disease cards, sheep pox and goat pox (oie, ) transmission modes and evolution of the parasitism-mutualism continuum on the concept and elucidation of endogenous retroviruses spatiotemporal distribution and evolution of the a/h n pandemic influenza virus in pigs in france from to : identification of a potential swine-specific lineage transmission of henipaviruses mers coronavirus: diagnostics, epidemiology and transmission beyond the cut hunter: a historical epidemiology of hiv beginnings in central africa a scoping review of published literature on chikungunya virus zika virus: history, emergence, biology, and prospects for control oie-listed diseases, infections and infestations in force in world health organization in animal health yearbook fao-oie-who this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license acknowledgments: i am grateful to epke le rütte, lenny hogerwerf, anneke engering, marjan leneman, jelle bruinsma, dorothea van ooyen and marleen slingenbergh for discussions. the author declares no conflict of interest. sponsors had no role in the design, execution, interpretation, or writing of the study. key: cord- -jwpb authors: kagan, lori j.; aiello, allison e.; larson, elaine title: the role of the home environment in the transmission of infectious diseases date: journal: j community health doi: . /a: sha: doc_id: cord_uid: jwpb the purpose of this paper is to examine current health care literature ( – ) regarding the microbiology of the home environment, to summarize evidence of transmission within the home, and to assess effectiveness of cleaning practices and products. the home environment, particularly the kitchen and bathroom, serves as a reservoir of large numbers of microorganisms, particularly enterobacteriacae,and infectious disease transmission has been demonstrated to occur in – % of households in which one member is ill. current food preparation and cleaning practices provide multiple opportunities for intra-household member spread. routine cleaning is often sufficient, but in cases of household infection, may not adequately reduce environmental contamination. the effectiveness of disinfectants varies considerably and depends on how they are used as well as their intrinsic efficacy. the behavioral aspects of infection prevention in the home (e.g., foodhandling and cleaning practices) warrant increased public attention and education. during the past few decades, research on the epidemiology of infections has focused on hospitals, day care facilities, and schools, but little attention has been paid to the home. recent events, including widespread media coverage of foodborne outbreaks and increased marketing of a variety of antibacterial products for personal hygiene and hard surface disinfection, have resulted in a resurgence of interest and public concern about hygiene and cleanliness in the home. hygiene refers to conditions or practices by which people maintain or promote health by keeping them and their surroundings clean. the question that persists is: how do house-hold cleanliness and personal hygiene affect the risk of infectious disease transmission? the purpose of this paper is to examine current health care literature regarding the microbiology of the home environment, to summarize evidence of transmission within the home, and to assess the effectiveness of cleaning and disinfecting practices and products in controlling transmission. it is our intention that this information will provide perspective regarding microbial risks in the home environment and a basis for developing more appropriate strategies for home hygiene based on what has been shown to effectively reduce infection risk rather than on fear or speculation. database, and columbia university's on-line catalogue were searched for research articles related to home hygiene during the years - . key words included: home hygiene, domestic hygiene, food hygiene, and crosscontamination. open searches, using the same key words, also were conducted on internet search engines, including yahoo and excite. the search was restricted to developed countries, and only to articles in english or with english abstracts. excluded were articles pertaining to assisted living facilities, nursing homes, schools, and hospitals. studies have shown that areas in the home, particularly the kitchen, bathroom and possibly the laundry, can serve as reservoirs for microbial colonization. dirty dish rags, cloths and wet sponges have been shown to spread microbial contamination throughout the kitchen. [ ] [ ] [ ] [ ] [ ] changes in laundering processes have also made transmission of disease via the washing machine a possibility. [ ] [ ] [ ] despite the fact that globalization of food distribution and international travel can transport microorganisms around the world in a matter of hours, in england, wales, and the netherlands % of salmonella and campylobacter infections are acquired in the home. [ ] [ ] further, social and demographic changes have increasingly led to the care of certain "at risk" groups within the home, not only neonates and the elderly, but other per-sons with compromised immune systems as well. in the united states, % of the population is estimated to fall into these categories. in one of the early studies of the domestic kitchen, de wit et al. used an indicator organism, escherichia coli k , to determine the extent of cross contamination from frozen chickens. cross-contamination occurred in a large proportion of those kitchens surveyed and in many cases the indicator organism persisted even after washing and rinsing of the kitchen surfaces. scott et al. measured numbers and types of bacteria at various sites in more than english homes. the highest counts were isolated from wet areas such as u-tubes, kitchen sink, draining board, cleaning cloths and mops, and dishcloths, and pseudomonads were isolated in over % of the homes. in a subsequent study enterobacteriaceae were detected in % of the homes surveyed. contaminated dishcloths and other cleaning utensils also may act both as reservoirs and disseminators of pathogenic organisms. , although drying reduces the number of organisms on clean, laminate surfaces, large numbers of bacteria have been recovered from contaminated surfaces and both clean and soiled cloths as much as to hours after drying. thus, drying alone is not sufficient to eliminate contaminating organisms. further, finger contact with contaminated surfaces and cloths resulted in the transfer of large numbers of organisms to the hands. cloths used for cleaning and/or drying kitchen utensils may transfer contamination throughout the kitchen especially when the same cloth is used for multiple purposes. in some households, the same cloth is used to wash cooking and eating cutlery and then to wipe down the drain board and counters. since plain soap does not necessarily kill microorganisms, soap and water cleaning of contaminated surfaces and hands may actually spread microbial contamination in the environment. speirs et al. sampled kitchens including the following key sites: worktop, chopping board, draining board, sinks, water tap handles, insides of rubber gloves, refrigerator shelf, and dish washing cloth. they isolated various enterobacteria including enterobacter cloacae, klebsiella pneumoniae and escherichia coli. in addition, bacillus subtilis, pseudomonas aeruginosa, staphylococcal and micrococcal species were isolated. the highest counts were found in the wet areas around the sink and the cloths used for wiping and/or drying kitchen surfaces and appliances. in another study, the sink drain was the most contaminated site, harboring . - . log (> . % reduction) of microorganisms. enriquez et al. studied cellulose sponges and cotton dishcloths from households in four u.s. cities and isolated and different bacterial species, respectively. most commonly isolated were pseudomonads, but salmonella was also isolated in . % of the sponges and . % of the cloths. other commonly isolated gram-negative bacteria included species of enterobacter, serratia, and klebsiella. salmonella can be transferred to sponges and towels and survive there, resulting in contamination of other areas of the kitchen. specific risk factors for domestic outbreaks of foodborne pathogens include improper food storage, undercooking, and cross-contamination, which may be responsible for % of salmonella outbreaks in the home. during food preparation salmonella can be spread throughout the workspace by such actions as whisking batter; bacteria have been found one meter away from each side of the site. powered cooking equipment like the electric blender can also lead to widespread distribution, up to a - meter radius around the site. in experiments with chickens contaminated with salmonella and campylobacter, a variety of sites in the kitchen, including cutting boards, sinks, handles, faucets, and work areas tested positive after the usual meal preparation procedures were used. , in a case control study of food preparation, salmonella was isolated from dishcloths not only in case homes in which salmonella infection persisted but also in control homes. salmonella from dried foods that have contact with moist foods, such as fruit or meat, can transfer within seconds to the wet foods. within a few hours potentially infective doses can be reached as the bacteria multiply under moist conditions. temperature of the water used for "washing up" can also influence microbial survival. for dishes washed by hand, the dishwashing water temperature often is below °c at the start and will continue to drop during the dishwashing process. this temperature is not high enough to destroy most organisms. a few studies have demonstrated that when sterile cookware was washed in water inoculated with salmonella or campylobacter, transfer of the pathogen to the dishes occurred. , bathroom like the kitchen, the bathroom can be a reservoir of large numbers of microorganisms, particularly in wet areas. in homes in which a family member had salmonellosis, four of six toilets tested positive for salmonella under the recess of the toilet bowl rim, an area difficult to reach with domestic toilet cleaners. in one toilet, salmonella was still present four weeks after the infection, despite the use of cleansers. after artificial contamination of the toilet, flushing led to contamination of the toilet seat and lid, and in one instance salmonella was isolated from an air sample taken after flushing. there is limited evidence of antibiotic-resistant organisms being present in the home environment. in both the bathrooms and the kitchens of randomly selected homes in north carolina, four of enterococcal isolates were vancomycin-resistant and one of escherichia coli isolates was ampicillin-resistant. klebsiella and enterobacter strains had the highest frequency of resistance to ampicillin, and pseudomonal strains were uniformly susceptible to of the tested antibiotics. rutala et al. concluded that in comparison to organisms causing clinical infections in hospitals, those isolated in homes are less likely to be antimicrobial resistant. while the kitchen and the bathroom are logical places for the introduction and transmission of pathogens, one area of the home that may seem less likely to allow the survival and dissemination of microorganisms is the washing machine. various common laundering practices allow bacteria at varying levels to remain in laundered items. standard detergent washing and rinsing practices do not always produce large reductions in microbial contamination. damp cloths that had been washed in detergent and then stored at room temperature over a -hour period showed an increase in contamination indicative of the survival and multiplication of microbes. drying was the most reliable method of decontamination when carried out at a temperature of °c for hours. in a study to evaluate the survival of bacteria and enteric viruses during washing and drying as performed in u.s. homes, sterile cotton swabs were inoculated with mycobacterium fortuitum, salmonella typhimurium, staphylococcus aureus, e. coli, rotavirus sa , hepatitis a virus, and adenovirus type . the contaminated swabs were then added to sterile cotton underwear, t-shirts, and a pillowcase that contained an organic load typical of homes. all test organisms survived the wash process; wash and rinse cycles alone reduced enteric viruses by - % and bacteria by > %. during the drying cycle, viruses were more resistant to killing than bacteria. drying was most effective, in decreasing order, for s. typhimurium, s. aureus, and m. fortuitum. detectable levels of e. coli were not found after drying. together, washing and drying reduced all bacteria by at least . %, adenovirus type by . %, hepatitis a virus by . % and rotavirus by . %. the test organisms contaminated other laundry in the machine, as well as the washing machine itself, which led to the contamination of subsequent loads of laundry. using the petrocci and clarke ( ) method, several powder and liquid laundry detergents that are now on the market were tested for activity against s. aureus and k. pneumoniae from wash water and fabric (table ; personal communication, j. kain, procter and gamble, cincinnati, oh, august ) sanitizing powder detergents reduced s. aureus and k. pneumoniae in the laundry fabric by > %. all other laundry detergents were less active. test products were all commercially available detergents with built in oxygen-based bleach systems. all products were purchased at local grocery stores in the cincinnati ohio area during . no additional laundry additives, such as chlorine bleach, were tested either alone or in conjunction with detergents. percent reduction (% reduction) refers to the calculated reduction in bacteria relative to a water + . % polysorbate baseline control. polysorbate was added to the water as a non-toxic surfactant control to improve the relevancy of organism removal characteristics of the control relative to the high surfactancy test treatments. a "sanitizing detergent with oxygen bleach" is one that meets us epa criteria for sanitization claims and a "non-sanitizing detergent with bleach" is a detergent that has a bleaching ingredient that may also have antimicrobial properties but not at the concentration and in the formulation matrix of this detergent and, therefore, does not meet us epa's criteria for sanitization claims. (unpublished data. d. j. kain, principal scientist, the procter and gamble company, cincinnati, oh, / ). although there are large numbers of microorganisms present in the home, it does not necessarily follow that this will result in infectious disease transmission. in this section, routes of transmission and evidence of actual transmission in the home are reviewed. bacteria, viruses, and fungi exist throughout our environment and can be transmitted to individuals through a variety of methods. direct contact includes person-to-person spread or contact with blood and other body fluids, such as occurs in fecal-oral spread. endogenous infection occurs when an individual contaminates one region of the body with microbial flora from another area. other modes of transmission include contact with droplets and airborne spread by droplet nuclei. indirect contact is transmission through a contaminated intermediate object. usually, the intermediary is the hands. for example, a parent who changes a diaper of a baby infected with shigella and proceeds to prepare a meal for the family without handwashing could transmit the pathogen to the entire family. another example of indirect transmission is use of a cutting board to prepare raw chicken and then to slice fresh fruits and vegetables. common source transmission is often responsible for e. coli o :h outbreaks caused by consuming undercooked, contaminated meat. although we did not find any data published between - regarding viral contamination in the home, viruses are a major cause of common illnesses and can survive in the home environment. worldwide, respiratory syncytial virus (rsv) is the primary cause of childhood viral respiratory infection. rsv is transmitted via inanimate objects and direct contact with infected persons. the virus is capable of surviving for a number of hours on inanimate objects and surfaces, providing ample opportunities to contaminate the hands of caregivers. contaminated hands can indirectly spread the virus to others in the home, including the caregivers if they touch their eyes or nose without handwashing. while barrier precautions have proven effective in lowering the rates of transmission in a hospital setting, goldmann asserts that it is entirely probable that careful handwashing after contact with infected infants would have been equally effective. perhaps more widespread than rsv among people of all ages is the common cold. children can expect to average to , and adults, three to five episodes per year. there are more than serologic types of rhi-novirus, and contracting one type provides no immunity against another. influenza is spread via airborne nuclei droplets, but the most likely route of transmission of rhinovirus is contaminated hands. in the united states, the second most common community infection is gastroenteritis. an important cause of gastroenteritis is rotavirus, which is transmitted by the fecal-oral route and possibly through respiratory spread and contaminated hands and surfaces. rotavirus has been implicated in outbreaks in hospitals, daycare centers, schools, and nursing homes. there is the potential for transmission of rotavirus within the home since it is present on hands, various surfaces and objects. other gastrointestinal pathogens, such as hepatitits a virus, parvovirus, adenovirus, and other enteroviruses follow a similar transmission pattern as rotavirus. , hepatitis a, for example, has been implicated in numerous foodborne outbreaks and in various settings such as hospitals, day-care centers, and schools. it is commonly spread via contaminated food and water. in laboratory experiments, bidawid et. al simulated cross contamination of fresh lettuce with hepatitis a from fingers of adult volunteers. the potential for cross-contamination in the kitchen has already been briefly discussed. when not properly cleaned and/or disinfected, countertops, cutting boards, and other kitchen surfaces provide an optimum milieu for survival of microbes. according to the centers for disease control and prevention, between - the primary food preparation practices contributing to foodborne disease were improper storage temperatures and poor personal hygiene of the food handler, and these faulty practices are common in the home. in a study of kitchens in australian homes, daily practices were videotaped over the course of to weeks. the most common unhygienic practices viewed included infrequent and poor handwashing technique, lack of handwashing prior to preparing meals, pets in the kitchen, hand contact with the face, mouth, nose, and hair during food preparation, and an all-purpose towel for hands and dishes. in addition to these lapses in hygiene, deli meat was left outside the refrigerator and uncovered for hours; a dish towel that had fallen to the floor and been stepped on was subsequently used to wipe off the counter; and a dishtowel was also used to cover cooked meat and thereby cross-contaminate it. practices caught on film in american homes did not differ substantially from their australian counterparts. the same towel used to wipe up raw meat juice was then used to dry washed hands. in only in homes were raw meat and seafood properly stored on the bottom shelf of the refrigerator so as to prevent dripping liquids from contaminating other foods; % of those preparing meatloaf undercooked it, % undercooked the chicken, and % did not completely cook the fish. further, the american society for microbiology conducted a telephone survey of more than , people in the united states. eighty-one percent of respondents claimed to wash their hands prior to handling or eating food. after petting an animal, % reported that they do not wash their hands, nor do % after coughing or sneezing, or % after handling money. in a telephone survey conducted in australian homes, % of respondents allowed raw meat to thaw at room temperature, % cooled cooked food to room temperature prior to refrigeration, and close to % did not know the right temperature for refrigeration of perishables. in addition, in respondents did not recognize handwashing as important in the reduction of cross-contamination and foodborne illness. based on these findings, it is likely that everyday activities in the home will result in microbial spread. a study of the transfer of serratia rubidea and the virus prd- from common household articles to the hands confirmed that infection is possible from daily contact with contaminated objects. transmission of the bacterium and the virus were demonstrated on telephone receivers, faucet handles, and sponges, and transfer to hands was highest from hard, nonporous surfaces. if a small amount of stool from a person infected with salmonella were transferred from the individual's contaminated hands to the receiver, the next user could pick up > colony-forming units (cfu) on his/her fingertips, and could transfer > . × cfu, or % of the total, to the mouth, a dose sufficient to cause disease. after wringing out a household sponge, - bacteria and viruses were found on the hands of test subjects. in another study, bacteriophage [phis] x was applied to door handles and the hands of volunteers. test persons touched the handles and shook hands with the volunteers. the hands of the test persons were then sampled for the virus. both skin surfaces and contaminated door handles were efficient sources for transfer. up to people became contaminated after touching the same door handle, and subsequent transmission was traced to six additional people from these primary contacts. each year million americans develop food poisoning, and about % of reported foodborne illnesses occur in the home. ninety percent of salmonella infections are thought to be associated with the home environment. in the uk, cross-contamination has been implicated in about % of foodborne outbreaks within the home, while poor hand hygiene is responsible for about %. in addition, it has been estimated that cross-contamination in the home contributed to % of salmonellosis outbreaks. in a household in which one person has been sick with salmonella, it has been estimated that there is a % chance that at least one other member of the household will also be infected. both hands and inanimate surfaces are responsible for the cross-contamination that leads to secondary infections in the home. other bacteria and viruses transmitted via the fecaloral route most likely spread throughout the home in the same manner. in another study, the home environment was implicated in the spread of salmonellosis among children under four years of age. isolates were obtained from children infected with salmonella and samples were taken from multiple locations in the home. pulsed-field gel electrophoresis patterns showed identical serotypes from the index case and the home environment. isolates which exhibited identical serotypes were found in locations such as vacuum cleaner, dirt surrounding front door, and refrigerator shelf as well as in household members and pet animals. children can carry the infections acquired in nursery schools or play groups into the home, where up to % of household members may become infected via cross-contamination. in a study of an outbreak of diarrhea caused by e. coli o in new jersey, % of contaminated hamburgers were consumed in the home. while the home may not have been the primary source of contamination, proper cooking may have prevented the spread of the organism. the use of communal laundry facilities also has been correlated with the transmission of microbes and higher rates of infectious disease symptoms among household members. in this study, a variety of home hygiene practices in households were examined, including personal hygiene, food handling and general cleaning and laundry practices. in a logistic regression analysis of these potential risk factors only communal laundry practices (p = . ) and lack of bleach (p = . ) were significantly associated with increased risk of infectious illnesses among household members. in households in which one member had a primary infection of campylobacter jejuni, % of household contacts were symptomatic during the same time period. while most instances were attributed to a common source, intrafamilial spread of infection was implicated in / ( . %) cases. a welsh study concluded that the secondary household transmission rate for sporadic shiga toxin-producing e. coli o (stec o ) infection was between % and %. in another study, colonization of one family member with s. aureus had no bearing on the observed carriage rate of another family member. when both child and guardian were colonized with methicillin resistant s. aureus, however, the same strain was most often seen, indicating that transmission between household members probably occurred. recently, risk models such as the hazard analysis and critical control point (haccp) and quantitative microbial risk assessment (qmra) based on early detection and prevention of future health risks within the home and community have been proposed. , , cleaning refers to the mechanical removal of dirt and soil from an object or area. disinfection, on the other hand, is the chemical destruction, inactivation, or killing of microbes. detergents and water are the preferred products for cleaning; products containing substances such as alcohol, bleach, quaternary ammonium compounds , and phenolics can be disinfectants depending on the formulation and use of the product. under normal conditions, cleaning is adequate for households, but in some circumstances such as an outbreak or the handling of potentially contaminated food, disinfection may be indicated. in a study designed to test the effectiveness of a variety of household products against several enteric bacterial pathogens, commercial products containing ammonia resulted in a - log reduction and phenolic and alcohol based products were associated with a reduction of logs. baking soda and vinegar were generally ineffective (< log reduction). the commercial disinfectants inactivated both antibiotic-susceptible and resistant bacteria. in another study, only bleach was effective against s. aureus, salmonella typhi, and e. coli. while concentrated ammonia and vinegar were effective against s. typhi and e. coli, none of the other productsborax, ammonia, baking soda, vinegar, or dishwashing detergent-demonstrated antimicrobial activity against s. aureus. four disinfecting agents were evaluated for their ability to prevent the transfer of a human rotavirus from stainless steel disks to the fingers of volunteers: disinfectant spray ( . % o-phenylphenol and % ethanol), domestic bleach ( % sodium hypochlorite diluted to ppm of free chlo-rine), quaternary ammonium-based product ( . % quaternary diluted : in tap water), and a phenol-based agent ( . % phenol diluted : in tap water). viral reductions on disks treated with the disinfectant spray were > . %, . % for bleach, % for phenolic, . % for quaternary, and . % with tap water. virus was not detected on the fingers that had contact with disks treated with disinfectant, bleach, and phenolic, but contact with tap water or quaternary-treated disks resulted in transfer of . % and . % of the residual virus, respectively. the same products were tested against rhinovirus. after to minutes of contact with the virus, the alcohol and phenolic-based disinfectant spray reduced virus infectivity by > . %. virus was not detected on the fingers of volunteers who had contact with the treated disks. bleach reduced the viral load by . % after minutes of contact, and once again no detectable virus was transferred to fingers. the quaternary-based product inactivated only . % of the virus, and the phenolic only . %. contact with the quaternary-based treated disk resulted in the transfer of . % of the residual infectious virus, while the phenolic-treated disks resulted in the transfer of . %. a particularly impressive study was one in which volunteers licked dried human rotavirus that had not been treated with anything, and all became infected. an alcohol and phenolic-based disinfectant spray applied to the virus interrupted the transfer of the virus; none of the volunteers who consumed the spray-treated virus became infected, whereas of who ingested the unsprayed virus became infected. disinfection in the home is dependent not just on the product, but also on how it is applied. during a week study in arizona, homes were supplied with a variety of disinfectant products, but no specific use instructions were given. subsequently, most of the disinfectants were removed, specific ones were introduced, and a cleaning schedule was established. while the greatest reductions in coliforms occurred after initial introduction of products, introduction of the cleaning schedule led to even greater microbial reductions in the kitchen and bathroom sites studied. these results are consistent with the findings of an earlier study demonstrating that disinfectants used in a timely manner after contamination by food or hands reduced further contamination. kitchen. studies in the uk have demonstrated that cleaning with detergent and hot water alone did not significantly reduce campylobacter and salmonella from contaminated kitchen areas. however, when cleaning was supplemented with hypochlorite there was a significant reduction in the number of bacteria from contaminated sites. in addition, detergent and water washing of dishware was only effective if followed by a rinsing process. in fact, soap and water can actually increase contamination in the home when not followed by rinsing. this suggests that when rinsing is impractical or not feasible, cleaning alone may be insufficient and disinfection may be indicated. in the uk, antibacterial dishwashing liquid has been shown to effectively reduce numbers of recoverable microorganisms on dishes, but not on used sponges. , zhao et al., inoculated raw chicken with an indicator organism, enterobacter aerogenes. the same cutting board was then used to prepare chicken and chop raw vegetables, and - cfu of bacteria was transferred to the vegetables. treating the cutting board with a kitchen disinfectant after preparing the chicken reduced the transmission of bacteria to almost undetectable levels. disinfection in conjunction with paper towel wiping are reported to be the best procedure for cleaning surfaces contaminated with raw meat. laundry. standard laundry practices have changed over the years, and may also contribute to the transmission of microbes in the home. people less frequently hang their clothing and linens outside where the sunlight can aid in denaturing many of the microbes, and ironing, which allows steam to penetrate and reduce the microbial load in the fabric, has become less common. finally, lower water temperatures with smaller volumes of water are used for washing. , jaska and fredell ( ) found no significant differences between a phosphate or a phosphate substitute detergent on s. aureus survival on laundered fabrics and reported that the most important predictor of bacterial reduction in the laundry was the water temperature. the temperature of the water used for washing does not seem to affect the bacterial counts in the fabric in the presence of sodium hypochlorite bleach; that is, both hot and cold water in combination with the bleach cycle are equally successful in reducing bacteria counts, , but in the absence of bleach, warmer washing temperatures ( °c) are more effective and colder temperatures may increase the cross-contamination rate of articles washed together. hence, attaining maximal bacterial reductions in both the machine and fabrics depends both on bleach and the water temperature. [ ] [ ] [ ] although relying on wash water temperatures to achieve meaningful bacterial reductions is impractical in north america since water heaters are typically set at &scedil;c, sodium hypochlorite bleaches for compatible fabrics and newer laundry products containing oxygenated bleach which can be used on colored fabrics will achieve such reductions. bathroom. in the bathroom, splashing and aerosol droplets are responsible for transfer of some contamination from toilets and sinks to surrounding areas in the bathroom, but a chlorine block effectively reduced the level of contamination in the toilet. surrounding areas, however, were not affected by the chlorine, suggesting that direct shedding or hand contact was responsible for contamination of the toilet seat, handle, and floor. a summary of studies of the activity of various household cleaning and disinfecting products are summarized in table . this body of research suggests that a product containing an ingredient with disinfectant properties, such as alcohol, bleach or a phenolic, may be indicated for home use if a household member is ill with an infectious disease or in other high-risk situations. reviews of studies linking hand hygiene and reduced risk of infection have been recently published. , the major benefits of hand hygiene for the general public is for prevention of infectious agents found transiently on hands and spread by the fecal-oral route and from the respiratory tract. , in general, non-antimicrobial soaps are adequate to reduce such transient flora, but in experimental studies reviewed by keswick et al., use of antimicrobial soaps was associated with significant reductions in rates of superficial cutaneous infections. another experimental studies reviewed demonstrated a reduction in bacteria on the skin with use of antimicrobial soaps, but none of these studies assessed rates of infection as an outcome. increasing public awareness stimulated by several highly publicized and serious outbreaks from commercially prepared foods has raised questions about food safety and the appropriate hygienic practices of food handlers. this concern extends to others such as child care providers, educators, sales personnel, and homemakers who have physical contact with members of the public. despite public awareness, however, hand hygiene as practiced by the general public does not meet recommended standards-members of the public wash too infrequently and for very short periods of time. a single recommendation for hand hygiene practices in the home is probably inappropriate. hand hygiene is clearly indicated before and after behaviors that are associated with microbial contamination, especially including toileting, diapering, and preparing or eating food. options for hand hygiene include plain soap and water or use of an antiseptic. generally, plain soaps do not kill microorganisms but rather wash them off with friction and rubbing, removing the majority of microorganisms. for general home use when household members are healthy, plain soaps are often considered to be sufficient. many antiseptic products are available over-the-counter, and are often labeled "antibacterial." these are detergent-based, requiring a traditional handwash with water. non detergent-based antiseptic products are waterless hand rinses, gels or wipes, which usually contain alcohol. they are also readily available to the public over the counter, can be used when no running water or towels are available, and, similar to antiseptic hand washes, have rapid and broad spectrum activity and excellent microbicidal characteristics. such products, however, are not a substitute for handwashing when the hands are physically soiled, since they are not good cleaning agents. , alcohol-based products may be most beneficial in circumstances where immediate antimicrobial activity is needed after encounters that result in a high probability of contamination and where soap, running water, and/or clean towels are not readily available. because the skin is the most important and first-line barrier to infections, it is vital that the skin of the hands be kept as intact and healthy as possible. the skin's water content, humidity, ph, intracellular lipids, and rates of shedding each play a role in retaining the protective barrier properties of the skin, and these factors are affected by hand hygiene. for example, changes in skin ph associated with handwashing may pose a concern since some of the antibacterial characteristics of the skin are associated with its normally acidic ph. some soaps can result in longstanding changes in skin ph, reduction in fatty acids, and, subsequently, changes in the microbial flora. , hence, some hand hygiene practices such as frequent washing with detergents can result in skin dryness, irritation, cracking and other problems. moisturizers prevent dehydration, damage to barrier properties, desquamation, and loss of skin lipids, restore the water-holding capacity of the keratin layer, and increase the width of corneocytes. , they may even help to prevent the transmission of microorganisms from the hands. , for those individuals with dry or damaged skin on the hands, it is important to use emollients or lotions to replace lost fatty acids and keep the hands hydrated. several recent reviews regarding hand and skin hygiene have been published. for additional information, the reader is referred to references. , since hands serve as one primary mode of fecal-oral and respiratory transmission, specific indications for use of antiseptic hand products in the general public occur when: • there is close physical contact with individuals at high risk for infection (e.g., neonates, the very old, or immunosuppressed); • an individual is infected with an organism and may potentially transmit the agent by the direct contact route (diarrhea, upper respiratory infection, skin infections) or in close physical contact (touching) with infected individuals; • an individual is working in a setting in which infectious disease transmission is likely (food preparation, crowded living quarters such as chronic care residences, prisons, child care centers, and preschools). the purpose of this paper was to examine research literature from the last twenty years to determine the potential role of the home environment in the transmission of infectious disease. kitchens, bathrooms, and washing machines harbor a wide range of potential pathogens, and routine practices within these areas of the home can either prevent or facilitate cross-contamination within the home. the potential for transmission of microbes in the home exists, and several studies have demonstrated that transmission does occur. hence, even though infectious risks in the home may be less than in healthcare settings such as the hospital or nursing home, they are certainly present. commercial disinfectants and cleaning products vary in their ability to remove microbes from 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when is clean too clean? stability and bactericidal activity of chlorine solutions compatitive testing of disinfectant and antiseptic products using proposed european suspension testing methods inactivation of particle-associated coliforms by chlorine and monochloramine laboratory studies of disinfectants against legionella pneumophila chemical disinfection of non-porous inanimate surfaces experimentally contaminated with four human pathogenic viruses mechanism of chlorine inactivation of dna-containing parvovirus h- the inactivation of foot-and mouth disease virus by chemicals and disinfectants hantavirus infection-southwestern united states: interim recommendations for risk reduction chemical disinfection of human rotavirus-contaminated inanimate surfaces uses of inorganic hypochlorite (bleach) in health-care facility the effect of blood on the antiviral activity of sodium hypochlorite, a phenolic, and a quaternary ammonium compound comparative studies on the detoxification of aflatoxins by sodium hypochlorite and commercial bleaches feasibility of a combined carrier test for disinfectants: studies with a mixture of five types of microorganisms the effect of disinfectants on a geosmin-producing strain of streptomyces griseus key: cord- -emdj vj authors: kampf, günter; brüggemann, yannick; kaba, hani e.j.; steinmann, joerg; pfaender, stephanie; scheithauer, simone; steinmann, eike title: potential sources, modes of transmission and effectiveness of prevention measures against sars-cov- date: - - journal: j hosp infect doi: . /j.jhin. . . sha: doc_id: cord_uid: emdj vj during the current sars-cov- pandemic new studies are emerging daily providing novel information about sources, transmission risks and possible prevention measures. in this review, we aimed to comprehensively summarize the current evidence on possible sources for sars-cov- , including evaluation of transmission risks and effectiveness of applied prevention measures. next to symptomatic patients, asymptomatic or pre-symptomatic carriers are a possible source with respiratory secretions as the most likely cause for viral transmission. air and inanimate surfaces may be sources; however, viral rna has been inconsistently detected. similarly, even though sars-cov- rna has been detected on or in personnel protective equipment, blood, urine, eyes, the gastrointestinal tract and pets, these sources are currently thought to play a negligible role for transmission. finally, various prevention measures such as hand washing, hand disinfection, face masks, gloves, surface disinfection or physical distancing for the healthcare setting and public are analysed for their expected protective effect. the end of the infectious period. in fact, real-time reverse transcriptase pcr results remained positive - days after the loss of transmissibility [ ] . for sars coronavirus, viral rna was detectable in the respiratory secretions and stools of some patients after onset of illness for more than month, but live virus could not be detected by culture after week [ ] . the inability to differentiate between infective and non-infective (dead or antibody-neutralised) viruses therefore remains a major limitation of nucleic acid detection methods. despite this limitation, given the difficulties in culturing infectious virus from clinical specimens during a pandemic, using viral rna load as a surrogate remains plausible for generating careful clinical hypotheses. the association between viral load and clinical outcome including severity of symptoms is still poorly characterized although the majority of studies reported an association between higher viral loads and more severe symptoms [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . transmission dynamics of sars-cov- are heterogeneously [ ] . numerous individual infection clusters in particular in asia with variable size have been reported [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . originating from a single travel-associated primary case from china, the first documented chain of multiple human-to-human transmissions of sars-cov- outside of asia allowed a detailed study of transmission events and identified several factors (e.g. cumulative face-toface contact, direct contact with secretions or body fluids of a patient, personal protective equipment) to classify contacts as low or high risk [ ] . furthermore, factors such as immune suppression, increased disease severity and viral load, asymptomatic individuals, the practice of seeking care at multiple healthcare facilities, frequent inter-hospital transfer, large numbers of contacts and prolonged duration of exposure facilitate transmission [ ] . household transmission is also common [ ] . superspreading is regarded as a normal feature of disease spread and has also been described with sars-cov- [ , ] . importantly, a recent study observed that transmission clusters occurred in many, predominantly indoor settings and most clusters involved fewer than cases, with the exceptions being in healthcare (hospitals and elderly care), large religious gatherings, food processing plants, schools, shopping, and large co-habiting settings (worker dormitories, prisons and ships) [ ] . given the predominately mild, non-specific symptoms, infectiousness before symptom onset the successful containment of covid- relies on stringent and urgent surveillance and infection-control measures. based on the definition of the who a confirmed case is a person with laboratory confirmation (detection of viral genomic material) of sars-cov- , irrespective of clinical signs and symptoms [ ] . asymptomatic coronavirus infections have been described before [ ] and might together with pre-symptomatic spread form a potential source of covid- infections acquired in a social or nosocomial context [ , [ ] [ ] [ ] [ ] [ ] [ ] . in february , a total of , confirmed cases were reported for china with a proportion of . % of asymptomatic cases [ ] . data from the first of april based on more rigorous testing of contact persons suggest in a small cohort of new cases a proportion of % as asymptomatic cases [ ] . irrespective of the frequency of asymptomatic carriers, they are considered to be important for the transmission of the disease [ ] . various studies reported sars-cov- infections, originating from asymptomatic carriers during close contacts such as household contacts or residents of a long-term care skilled nursing facility [ , [ ] [ ] [ ] [ ] [ ] . importantly, several studies have reported that viral rna loads in pre-symptomatic, asymptomatic and symptomatic patients do not differ significantly [ ] [ ] [ ] . others have reported no transmission from contacts (patients, family members, hospital staff) to asymptomatic carriers and concluded that the infectivity of some asymptomatic carriers may be weak [ ] . as summarized in table i , the proportions of asymptomatic sars-cov- cases at the time point of testing have been determined for different cohorts of patients. in hospitalized patients it was described to range be between . % and . % [ ] [ ] [ ] [ ] . in a long-term care facility, it was quite high with . % [ ] . in family clusters it was found between % and . % [ , ] . in children in china the proportion was . % [ ] . among japanese nationals evacuated from wuhan by chartered flights it was . % in contrast to german nationals with . % [ , ] . on board of a cruise ship asymptomatic carriers were detected in . % of the cases. the delay-adjusted asymptomatic proportion, however, was only . % [ ] . in iceland, a proportion of . % of the general population ( out of inhabitants) were investigated. overall, of them ( , %) were positive with a proportion of % asymptomatic carriers. among inhabitants with a high risk for infection the proportion of asymptomatic cases was only % [ ] . overall, asymptomatic sars-cov- infections seem to account for up to % of sars-cov- infections in selected cohorts, suggesting a significant factor for the rapid progression of the covid- pandemic [ , , ] . for comparison, the prevalence of asymptomatic influenza virus carriage (total absence of symptoms) ranged from . % to . % and subclinical cases (illness that did not meet the criteria for acute respiratory or influenza-like illness) between . % to . % [ ] . with mers a proportion of . % of cases was asymptomatic [ ] . follow-up examinations, however, indicate that the majority of initially tested asymptomatic cases ( . % - %) develop moderate but detectable clinical symptoms over time and therefore should be considered as pre-symptomatic. only in a small group of patients, no symptoms or radiological findings became apparent, but were described as potentially infectious for up to d (table ii) [ ] . of note, patients with negative pcr result prior to discharge may also become transient asymptomatic carriers again. one patient, for example, was retested positive for sars-cov- during the weeks quarantine after discharge [ ] . two healthcare workers (hcws) were also tested (throat swab) after discharge (covid- ) and were weakly positive in of samples and positive in of samples (case sampled over d), and weakly positive in of samples and positive in of samples (case sampled over d) [ ] . however, these results have to be interpreted with caution as currently applied pcr methods can lead to fluctuating results in weakly positive samples due to detection limits of the assays. indeed, a single case was described with low viral rna loads or negative rt-qpcr results, despite a sars-cov- infection confirmed by the presence of anti-sars-cov- specific antibodies [ ] . importantly, a systematic meta-analysis of different cohort studies observed that asymptomatic patients with covid- seems to correlate with young age and social activity [ , ] . in particular, future studies aiming to understand the contribution of young aged patients such as children to asymptomatic transmission of sars-cov- should be prioritised [ ] . in summary, the prevalence of asymptomatic sars-cov- infection and duration of pre-symptomatic infection are not well understood, as asymptomatic individuals are not routinely tested. studies on the immune response of asymptomatic carriers are lacking, which could contribute to a better characterization of the protective factors under natural conditions [ ] . several sources have been described that could possibly be involved in sars-cov- transmission based on the detection of viral rna. these include the respiratory tract, air contamination, the gastrointestinal tract, eyes, inanimate surfaces, personnel protective equipment, pets, and rather less likely blood and the urinary tract. sars-cov- has been frequently associated with droplet-based transmission [ , ] . likewise, person-to-person transmission has been assumed for sars-cov- very early [ ] . importantly, a more efficient transmission of sars-cov- compared to sars-cov- has been suggested, due to active pharyngeal viral shedding while symptoms are still mild and typical of upper respiratory tract infection [ ] . table iii summarizes the frequency and magnitude of sars-cov- viral rna loads in respiratory tract samples obtained from covid- patients. the viral rna load with sars-cov- can be as high as . log cpm (table iii) . it seems to be particularly high in the early and progressive stage of disease [ ] or two days before and one day after symptom onset [ ] . however, in some cases rna could still be found up to days after the first positive test with negative results in-between [ , ] . influenza a virus rna has even been released for up to d with negative results in-between although infectious virus was only detected for d after symptom onset [ ] . age was also associated with high viral rna load [ ] . most studies observed decreased viral rna loads over time [ , ] . one study shows that sars-cov- was detected by culture in out of clinical samples (nasopharyngeal swab) from covid- patients [ ] . the viral rna load detected in the asymptomatic patient was similar to that in the symptomatic patients, which suggests the transmission potential of asymptomatic or minimally symptomatic patients [ ] . it is important to differentiate between detection of rna and the isolation of infectious virus in cell culture. pcr for rna of sars-cov- does not distinguish between infectious virus and non-infectious nucleic acid. thus, interpretation of duration of viral shedding and infection potential should be based on viable virus from cell culture and needs to be carefully evaluated when solely based on pcr results. j o u r n a l p r e -p r o o f a strict distinction between droplet versus airborne transmission routes for infections is not possible [ ] . virus transmission via droplets and aerosols enables many viruses to spread efficiently between humans [ ] . airborne transmission is defined as the transmission of infection by expelled particles of comparatively small in size and which can remain suspended in air for long periods of time [ ] . the world health organization uses a particle diameter of ߤm to delineate between airborne (≤ ߤm) and droplet (> ߤm) transmission [ ] . transmission of infectious diseases by the airborne route is dependent on the interplay of several factors, including particle size (i.e., particle diameter) and the extent of desiccation [ ] . particle desiccation is a critical variable and depending on environmental factors as even large, moisture laden droplet particles desiccate rapidly [ ] . for example, wells showed that particles begin desiccating immediately in a rapid fashion upon air expulsion: particles up to ߤm can desiccate completely within approximately . seconds [ ] . rapid desiccation is a concern since the smaller and lighter the infectious particle, the longer it will potentially remain airborne. hence, even when infectious agents are expelled from the respiratory tract in a matrix of mucus and other secretions, causing large, heavy particles, rapid desiccation can lengthen the time they remain airborne (the dried residuals of these large aerosols, termed droplet nuclei, are typically . - ߤm in diameter) [ ] . of further concern, very large aerosol particles may initially fall out of the air only to become airborne again once they have desiccated [ ] . one of the challenges facing practitioners, particularly in an enclosed building, is that even large-sized droplets can remain suspended in air for long periods. the reason is that droplets settle out of air onto a surface at a velocity dictated by their mass [ ] . if the upward velocity of the air in which they circulate exceeds this velocity, they remain airborne. hence, droplet aerosols up to ߤm diameter have been shown to remain suspended in air for prolonged periods when the velocity of air moving throughout a room exceeds the terminal settling velocity of the particle [ ] . respiratory virus shedding can occur via sneezing, coughing or talking. sneezing distributes approximately , particles (droplets or airborne microorganisms) per sneeze, coughing approximately particles per cough, and talking approximately particles per words [ ] . using highly sensitive laser light scattering observations a recent study describes that loud speech can emit thousands of oral fluid droplets per second [ ] , indicating that normal speaking may also contribute to virus transmission in stagnant air. most of the , large droplet particles caused by a single sneeze will desiccate immediately into small, infectious droplet nuclei, with % of the particles being smaller than ߤm [ ] . the transmission of infectious diseases via airborne or droplet routes may further also depend on the frequency of the initiating activity. a single sneeze may produce more total infectious particles, while overall coughing may potentially be a more effective route of airborne transmission (e.g. during infection with coxsackievirus a) [ ] . coronavirus-infected humans coughed on average times over min during exhaled breath collection [ ] . given that dry cough is also a common symptom of covid- patients [ ] , it may therefore contribute to potential airborne transmission of this pathogen. in this context, airborne transmission has been considered to be possible in a cluster of infections in a restaurant with air conditioning [ ] . few studies are available to evaluate the role of air for transmission of sars-cov- , most of them obtained in hospitals with covid- patients. from the data shown in table iv viral copies were only detected in large air volumes of l with a larger proportion on icu ( % detection rate) compared to general wards ( . % detection rate). in smaller volumes such as l, , l or . m no virus was detected. even directly in front of a covid- patient it was not possible to detect the sars-cov- rna in the air [ ] . the viral rna loads of the first confirmed case were . × copies per ml in the pooled nasopharyngeal and throat swabs and . × copies per ml in saliva on the day of air sampling [ ] . the air samples of l were collected at a distance of cm at the level of patient's chin while the patient performed different manoeuvres (i.e., normal breathing, deep breathing, speaking " , , " continuously, and coughing continuously) while putting on and putting off the surgical mask were all undetectable for sars-cov- rna [ ] . nosocomial transmission of sars-cov- by an airborne route has been described to be very unlikely [ ] . nonetheless, sars-cov- can remain infectious in air for h measured in a goldberg drum with a decline of viral load from . log to . log per litre of air [ ] . in a subset of study participants with a symptomatic seasonal coronavirus infection but without any coughing during the min exhaled breath collection no coronavirus rna was detected in respiratory droplets or aerosols [ ] . other aspects influencing droplet or airborne transmission are temperature and humidity because they correlate with the spread of and deaths associated with covid- [ ] [ ] [ ] . in china, the number of confirmed cases increased with higher temperature and higher humidity in most of the provinces [ , ] . covid- lethality significantly worsened ( times on average) with environmental temperatures between °c and °c and relative humidity between % and % [ ] . biktasheva et al., however, described that the covid- mortality correlates with low air humidity, probably caused by a lower resistivity of dry or very dry mucous membranes [ ] . huang et al. described that % of all covid- cases are found in places with an air temperature between °c and °c [ ] . in brazil a °c increase in temperature has been associated with a decrease in confirmed cases of % [ ] . in wuhan and xiaogan temperature was the only meteorological parameter constantly but inversely correlated with covid- incidence [ ] . at low temperature and low humidity, droplets tend to remain suspended in air [ ] . high relative humidity will increase the droplet sizes due to the hygroscopic growth effect, which increases the deposition fractions on both humans and the ground [ ] . overall, a seasonal pattern of covid- is very likely. sars-cov- aerosolized from infected patients and deposited on surfaces could remain infectious outdoors for considerable time during the winter in many temperate-zone cities, with continued risk for re-aerosolization and human infection [ ] . conversely, sars-cov- should be inactivated in the environment relatively fast during summer in many populous cities of the world, indicating that sunlight should have a role in the occurrence, spread rate, and duration of coronavirus pandemics [ ] . simulated sunlight has been described to rapidly inactive sars-cov- [ , ] . indoor transmission of sars-cov- is much more likely compared to outdoor transmission [ ] . in a closed seafood market, the risk of a costumer to acquire sars-cov- infection via the aerosol route after h exposure in the market with one infected shopkeeper was about . × − . the risk rapidly decreased outside the market due to the dilution by ambient air j o u r n a l p r e -p r o o f and became below − at m away from the exit [ ] . outdoor, these virus particles are very strongly diluted by the open air [ ] . some patients displayed diarrhoea at the beginning or during the course of infection suggesting that sars-cov- may also affect the gastrointestinal tract. viral rna was detected in a proportion between . % and % in covid- patients with up to . log viral copies per g (table v) . one study including patients with of them reporting gastrointestinal manifestations ( %) reported diarrhea as the most common symptom ( %), followed by abdominal pain ( %), dyspepsia ( %), and nausea ( %) [ ] . analysing two groups of overall patients, none of the stool samples resulted in successful virus isolation in cell culture, irrespective of viral rna concentration [ , ] . in contrast, one study described the successful isolation of virus by cell culture from out of patients [ ] . of note, another study showed higher viral rna loads in fecal samples of mildly symptomatic or asymptomatic children compared to nasopharyngeal swabs [ ] . these results indicate the possibility of fecal-oral transmission or fecal-respiratory transmission through aerosolized feces. furthermore, the presence of sars-cov- rna in bile juice was reported from one patient and speculated that rna in fecal specimens may partly originate from bile juice [ ] . finally, a recent study suggested that detectable sars-cov- rna in the digestive tract could be a potential warning indicator of severe disease [ ] , however further evidence will be needed. transmission of sars-cov- through the ocular surface was considered to be possible [ ] . conjunctivitis has been reported in a patient in the middle phase of covid- , the conjunctival swab specimens remained positive for sars-cov- on and days after onset and were negative on day [ ] . another study showed among covid- patients that the virus was detected in tears and conjunctival secretions only in the one patient with conjunctivitis [ ] . furthermore, in another group of covid- patients two of them were identified with positive findings for sars-cov- in their conjunctival as well as nasopharyngeal specimens, a total of patients had ocular manifestations consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, or increased secretions [ ] . in addition, no virus was detected on the conjunctiva in other covid- patients [ ] . one patient was described with persistent conjunctivitis with viral rna detection until day after symptom onset and confirmation of infectious virus in the first rna-positive ocular sample [ ] . even though the virus can be detected rarely in the conjunctival sac at very low levels [ , ] , there is no evidence that it can replicate locally [ ] . that is why the conjunctiva were considered not to be the preferred gateway into the respiratory tract [ ] . a study analysed human post-mortem eyes for the expression of ace (the receptor for sars-cov- ) and tmprss . in all samples the expression of ace and tmprss was detected in the conjunctiva, limbus, and cornea, with especially prominent staining in the superficial conjunctival and corneal epithelial surface [ ] . in contrast, another study from germany found no relevant conjunctival expression of the ace receptor on mrna and protein levels [ ] . in summary, the detailed pathophysiology of ocular transmission of sars-cov- remains not completely understood [ ] and both the presence of viral particles in tears and conjunctiva, and the potential for conjunctival transmission remains controversial [ ] . in conclusion, spread of covid- from ocular secretions cannot be ruled out but seems to be very unlikely. indirect transmission of covid- has been assumed to be possible via fomites although direct evidence is currently not available [ ] . in hospitals some data were collected to describe the frequency of detection of sars-cov- rna on inanimate surfaces in the immediate patient surrounding. the detection rate was variable on icu surfaces ( % - %), in isolation rooms ( . - %) and on general wards ( % - %). the mean virus concentration per swab were . - . log on icus and . - . log on general wards. a positive correlation between patient viral rna load and positivity rate of surface samples was described [ ] . however, on cleaned and disinfected surfaces viral rna could mostly not be detected (table vi) . detection of viral rna on the floor is indicative for sedimentation of contaminated droplets. surfaces outside the covid- patient room were also investigated. on icu the virus was rarely detected as "weak positive" on the floor and on door knobs in buffer rooms, dressing rooms and a nurse station ( of samples; . %) [ ] . on the general ward the virus was rarely detected on the patient floor ( samples; one "weak positive" result on the computer mouse or keyboard) and never detected on doorknobs and the floor in buffer rooms and dressing rooms ( samples) [ ] . viral rna could be detected even d after discharge of covid- on surfaces of pagers and in drawers of the isolation wards. the relevance of finding, however, is not clear because it is not known if infectious virus was present at that time [ ] . in a microbiology laboratory the detection rate on surfaces was . %. in the domestic environment of sars-cov- carriers the detection rate on surfaces was overall low ( % - . %; table vi) . it has to be mentioned that in most studies only pcr was performed for rna. but detection of viral rna on surfaces does not provide any information about viral infectivity or viability [ ] . new findings from a covid- cohort in gangelt, germany, and with cases in italy provide data on the detection of infectious sars-cov- on surfaces. although viral rna was detected in . % of surface samples in households of confirmed covid- -cases and on . % of sampled surfaces around covid- -cases in italy, infectious sars-cov- was not found in any sample [ , ] . similar findings were described with sars-cov and influenza-virus. in canada, a total of samples from inanimate surfaces were taken in a sars-hospital. viral sars-cov rna was present in . % of samples, but none of the samples revealed infectious virus [ ] . in thailand and taiwan rna of sars-cov was detected on . % of surface samples in a sars-hospital or in a sars-ward; in none of the samples infectious sars-cov was found [ ] . similar data were reported from households with proven h n influenza virus infections in children. viral rna was detected on . % of inanimate surfaces but virus could never be cultured [ ] . in cell culture studies, sars-cov- has been described to remain infectious on stainless steel and plastic for - d, on glass and banknote for d, on wood for d, all with a decrease of viral infectivity with time [ , ] . in the close surrounding of covid- patients in hospitals sars-cov- rna is detected more frequently compared to surfaces outside the patient rooms but samples were so far consistently negative for infectious virus. if infectious sars-cov- may be detected in a relevant amount on various surfaces in the public when only a short exposure to potentially infected, may be even asymptomatic people exists, is currently unknown but very unlikely. surfaces in air planes or trains in coughing or sneezing distance for potentially infected long-distance travellers may theoretically have a higher risk for contamination. the rna of sars-cov- has so far mainly been found on ppe used by healthcare workers on icu ( % - %), mainly on shoes and gloves. in other settings ppe was only very rarely contaminated with sars-cov- (table vii) . all studies performed pcr assays for sars-cov- rna detection. blood sars-cov- rna has occasionally been detected in blood of covid- patients, i.e. in of patients on days , , and after onset of disease [ ] , in of covid- patients ( . %) [ ] , in of asymptomatic and symptomatic patients with sars-cov- infection [ ] , or in of samples ( . %) obtained from covid- patients [ ] . sars-cov- rna can very rarely (in of samples) be detected in plasma during routine screening of blood donors considered to be healthy population [ ] . detection of sars-cov- rna in blood is considered a strong indicator for further clinical severity [ ] . so far, no cases of transmission due to transfusion of blood products have been reported for sars-cov, mers-cov, and sars-cov- , and clinically ill patients are not considered as blood donors [ ] . therefore, no immediate risk can be derived for the transfusion system [ ] . based on the existing evidence, transmission of covid- by handling potentially contaminated blood products (laboratory technician) or by contact with blood e.g. from a wound to intact skin is very unlikely. sars-cov- rna has occasionally been detected in urine swabs from patients. in patients with confirmed sars-cov- infections one of the patients was positive for viral rna in urine [ ] . this observation is supported by observations among sars-cov- positive children with of them positive for viral rna in urine ( %) [ ] . importantly, infectious virus could be detected from urine in one covd- patient [ ] . however, other studies with a total of patients [ , , ] failed to detect sars-cov- rna in urine. these data indicate that urine might be a potential source of infection but further evidence is needed. there is evidence that the main entry receptor of sars-cov- , ace , is expressed in cells of the reproductive system [ , ] . however, one study with covid- patients in the acute ( patients) and recovery phase ( patients) failed to detect viral rna in semen [ ] , indicating a low probability of sexual transmission through semen. sars-cov- rna has temporarily been detected in breast milk samples in one study in one of two infected mothers with approximately viral copies per ml [ ] . similarly, the presence of viral rna was reported in breast milk of an actively breastfeeding mildly symptomatic covid- patient raising the possibility of a potential transmission from breast milk [ ] . so far, no evidence for transmission of the virus from pet animals to humans exists [ ] . however, shi et al. reported that ferrets and cats were highly susceptible to sars-cov- , while dogs had a low susceptibility and livestock including pigs, chickens, and ducks were not susceptible to the virus, under experimental conditions [ ] . one of cats (france) and two of cats (wuhan) of covid- patients has been described to have a sars-cov- infection with mild respiratory and digestive symptoms whereas all dogs (france) and of dogs (wuhan) were sars-cov- and serologically negative [ , ] . interestingly, viral transmission between cats has been observed [ ] . out of six naïve cats (three subadults and three juveniles), each exposed to a sars-cov- inoculated cat, transmission occurred in two cats (one cat of each age group). similar findings were reported by halfmann et al. [ ] . this indicates that cats, being common companion animals, might theoretically transmit the virus to other animals and humans. however, there is so far no clear evidence that cat-to-human transmission of sars-cov- can occur. several practices are recommended with the aim to limit further transmission of sars-cov- in clinical practice but also public settings. these include hand washing, hand disinfection, wearing of face masks and gloves, disinfection of surfaces and physical distance. based on an integrated theoretical and statistical analysis of the influence of individual variation in infectiousness on disease emergence it has been suggested that individual-specific control measures outperform population-wide measures [ ] . a hand soap solution ( : ) has been described to have some effect (≥ . log reduction of viral infectivity) against sars-cov- in min [ ] . for healthcare workers hand washing is only useful when hands are visibly soiled [ ] . although sars-cov- has never been detected on hands of the public population yet, it seems reasonable to assume that the hand contamination by droplets from others may take place in the public with an unknown viral load. apart from avoiding hand-face-contacts in general, hand washing is first choice for the decontamination of hands, especially after returning home from public places with many close contacts to potentially infected people. ethanol and iso-propanol inactivate sars-cov- at concentration between % and % (both v/v) in s [ ] . both who-recommended hand rubs based on % iso-propanol or % ethanol (both v/v) also inactivate sars-cov- in only s [ ] . similar results were obtained with a propanol-based hand rub against sars-cov [ ] . on clean hands use of an alcohol-based hand rub is first choice in healthcare for the decontamination of hands due to the better activity against nosocomial pathogens including bacteria and yeasts and a better dermal tolerance [ ] . it may also be useful for covid- patients, e.g. before leaving the patients room for examinations. in this situation it is reasonable to recommend a hand disinfection in order to reduce potential transmission by direct hand contacts. the routine use of alcohol-based hand rubs for the general population should be discouraged, since there are currently no clear indications when to use them. it may be useful if a contamination of hands with sars-cov- is likely and a hand washing facility is not available. otherwise the widespread use of alcohol-based hand rubs may even enhance the shortage of the products in patient care which should be avoided by all means [ ] . inadequate ppe including facemask at the beginning of the epidemic in china has resulted in infections and deaths among healthcare workers [ , ] . unprotected patient care with long and close contacts was also later a major risk for healthcare workers to acquire covid- [ ] . in covid- cases face masks can at least reduce the viral spread. in individuals with a symptomatic seasonal coronavirus infection a surgical face mask was able to reduce the proportion of viral rna detection in droplets from % to % and in aerosols from % to % during min exhaled breath collection suggesting a protective effect when worn by infected patients [ ] . in another study covid- patients coughed times in front of a petri dish ( cm distance) with a surgical mask, a cotton mask or without a mask. without a mask . log viral copies per ml were detected, with a surgical mask it was . , and with a cotton mask . log viral copies per ml [ ] . household transmission was more likely when the primary case and other household members did not wear a mask at home resulting in the possibility of unprotected transmission [ ] . data on a protective effect of face masks when only worn by healthy subjects in an endemic covid- setting are not available. despite these results it was shown in south korea that none of hcws with close contacts to a covid- patient developed symptoms or were pcr positive in the nasopharynx although they only wore a surgical mask for more than ten minutes during activities including aerosol-generating procedures such as intubation [ ] . in addition, one study could show that a days surgical mask partition between cages reduces the risk of noncontact transmission between artificially infected and naïve golden syrian hamsters [ ] . importantly, a used face mask worn by a sars-cov- spreader will be contaminated. after only coughs all surgical or cotton face masks worn by covid- patients were contaminated on the outer surface whereas samples from the inner surface were mostly negative [ ] . chin et al. found that the virus can remain infectious or detectable for up to days on the outer layer of a surgical mask, on the inner layer for days [ ] . although the results are only based on three independent triplicates, this finding should have implications for the re-use of face masks in a shortage situation [ ] . wearing a face mask is recommended for healthcare workers in case of suspected or confirmed covid- patients [ , ] although it was described in hong kong that of hcws had unprotected exposure to confirmed covid- cases, none of these were infected [ ] . wearing a face mask may also be useful for hcws when mild respiratory symptoms occur because in the netherlands . % of such healthcare workers were positive for sars-cov- [ ] . even universal masking in hospitals by healthcare workers has been proposed although the expected effect was described as marginal [ ] . suspected and confirmed covid- cases should wear a face mask to prevent the spread of infectious droplets [ ] . so-called mass masking has been proposed as a considerable option [ , ] . many countries have recommended or legally ordered the use of fabric masks or face coverings for the general public. the who, however, acknowledged that the widespread use of masks by healthy people in the community setting is not yet supported by high quality or direct scientific evidence and that there are potential benefits and harms to consider [ ] . but in areas of known or suspected widespread community transmission and limited or no capacity to implement other containment measures, governments should encourage the general public to wear masks in specific situations and settings [ ] . some recent studies suggest that general face mask usage by the healthy population in the community reduces the risk of transmission [ , ] . but in order to evaluate only the effect of masks worn by healthy people in the community on the prevention of transmission in a country or region, some relevant variables with a proven impact on transmission should have been considered for the study period: the seasonal effect on the incidence (similar weather conditions), the main mode of transmission during the period of observation (mainly local clusters or mainly transmission in buildings or mainly transmission in the public), the total number of new cases in the observation period (mass masking in a region with new case per day may have a different effect compared to a region with . new cases per day) and the extent of community lockdown (the less people are in the public the less likely a protective effect of general masks can be expected). in an endemic population scenario without restrictions regarding physical distance and close or long face-to-face contacts it may indeed be useful, especially for the part of the population which has a high risk for a severe covid- infection. it is, however, a controversial debate among the scientific community if any additional protective effect by mass masking is expectable if a minimum distance between people is assured (e.g. m) and contacts are only of short duration. gloves can partially prevent the contamination of the hands with specific pathogens or all types of bioburden [ ] . however, at the same time wearing gloves is associated in hospitals with a lower compliance in hand hygiene [ , ] . use of gloves is recommended for hcws in specific patient care activities, e.g. when soiling of the hands is expected and when caring for covid- patients [ , ] . if there is any protective effect by wearing gloves by the general population in the public is speculative. one aspect is that wearing gloves may result in more awareness too reduce face hand contacts. and yet it seems reasonable not be encourage the general population to routinely wear gloves in the public. even if a hand contact yields a transient contamination with sars-cov- on the hands it does not make a difference if the virus is found on the bare or gloved hand; the essential preventive measure in this case is to avoid hand-face contacts and to wash hands when returning from the public. the resident hand flora is even able to provide some colonisation resistance in contrast to the glove [ ] . if wearing gloves by the general population has a similar effect on hand hygiene compliance as it has been described for healthcare workers wearing gloves in the public may even have the unwanted effect of less hand washing potentially increasing the risk of transmission via hands. some surface disinfectant agents have been described to inactivate sars-cov- in s such as ethanol and iso-propanol ( % - %, v/v) [ ] . in min household bleach ( : and : ) and . % benzalkonium chloride were also very effective against sars-cov- [ ] . limited data from surface samples in covid- settings support their efficacy [ , ] . in healthcare settings routine cleaning and disinfection of surfaces with which the patient is in contact is recommended [ ] . so far, no studies were reported to address if sars-cov- (viral rna or infectious virus) may be found on public inanimate surfaces. disinfection of surfaces in a household with chlorine-or ethanol-based products can reduce the risk of transmission when the primary case has diarrhoea [ ] . the frequent use of household disinfectants also results in a remarkable increase of exposures reported to us poison centers, especially via ingestion in the age group between and years [ ] . general disinfection of frequently touched surfaces in the public such as shopping carts or door handles is, however, unlikely to add any protective value because even in covid- wards inanimate surfaces were mainly contaminated in the permanent and immediate surrounding of symptomatic patients (detection of viral rna, not of infectious virus) and only rarely one room away [ ] suggesting that the risk to find sars-cov- on frequently touched surfaces in the public is low. future research will hopefully clarify the role of public inanimate surfaces for the spread of sars-cov- . close and long contacts are probably the main risk for transmission of sars-cov- from asymptomatic or symptomatic patients to healthy people as shown in clusters in families, a cruise ship, hospitals and nursing homes [ ] . the mode of transmission is very likely by droplets during coughing, sneezing or talking. the risk of long and close contacts is supported with experimental data obtained with syrian hamsters which were inoculated with viral copies in µl intranasally. h later each hamster was transferred to a new cage with one naïve hamster as close contact. sars-cov- was detected in nasal secretions, trachea and lung after days in all naïve contact hamsters [ ] . physical distancing is another option to slow down the spread of sars-cov- . early data from china suggests that quarantine, physical distancing, and isolation of infected populations can flatten the epidemic [ ] . so far, there are no "real-life" data which provide conclusive evidence regarding effectiveness of physical distancing interventions. however, in a simulation model the likelihood of sars-cov- human-to-human transmission in a singaporean population was predicted [ ] . they could demonstrate that the combined intervention, in which quarantine, school closure, and workplace distancing were implemented, was the most effective compared with the baseline scenario of no interventions, which reduced the estimated median number of covid- infections by . % when r was . , by . % when r was . , and by . % when r was . [ ] . nevertheless, an evaluation of the effect of physical distancing alone is currently not possible. maintaining a physical distance of at least m from other individuals is regarded as one of the most effective preventive measures by the who [ ] . günter kampf has received personal fees from dr. schumacher gmbh, germany, for presentation and consultation. yannick brueggemann, hani e. j. kaba, joerg steinmann, stephanie pfaender, simone scheithauer and eike steinmann have no conflicts of interest. 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equipment by sars-cov- during routine care of patients with mild covid- j o u r n a l p r e -p r o o f [ ] j o u r n a l p r e -p r o o f [ ] *no absolute numbers reported; **first survey; ***second survey two weeks later.j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f samples significantly higher than for nasopharyngeal swab specimens cpm = copies per ml; cpg = copies per g; cps = copies per whole swab; pfu = plaque forming units. key: cord- - w dz authors: jaichenco, andre l.; lima, luciana cavalcanti title: infectious disease considerations for the operating room date: - - journal: a practice of anesthesia for infants and children doi: . /b - - - - . - sha: doc_id: cord_uid: w dz the risk of infection transmission by anesthesia providers in their work area environment is reviewed. the dynamics of transmission and the strategies for preventing infection transmission in health care institutions are discussed. anesthesiologists have long been patient safety advocates and have taken on increasing responsibility for preventing health care–associated infections. anesthesia providers practice in a nonsterile environment within the operating room and have an impact on bacterial transmission and infection rates. understanding the characteristics of transmission elements provides the practicing anesthesiologist with methods to protect susceptible patients and themselves to avoid spreading infection. it is vital to have in place proper systems to remove contaminated air to minimize the risk of airborne pathogens being transmitted by children. preoperative patient skin and other bacterial reservoir decontamination and hand hygiene by anesthesia providers reduces contamination of the work area and iv access ports. hand hygiene is a well-known and effective solution to the problem of bacterial transmission within and across patients and is considered the most important and cost-effective individual intervention in the prevention of health care–associated infections in children and health care providers compliance with the current “ moments” world health organization guidelines could make a major inroad into reducing provider hand and workspace contamination. surgical antimicrobial prophylaxis is an essential tool to reduce the risk of postoperative infections, and the anesthesia team plays a central role in ensuring the proper timing of drug administration. protocols, although effective, require continuous feedback and revision. the presence of a susceptible host is an important element in the chain of infection that paradoxically results from advances in current medical therapies and technology (e.g., children undergoing organ transplantation or chemotherapy, or extremely premature neonates) and the presence of children with diseases that compromise their immune systems (e.g., aids, tuberculosis, malnutrition, or burns). the organism may enter the host through the skin, mucous membranes, lungs, gastrointestinal tract, genitourinary tract, or the bloodstream via iv solutions, after laryngoscopy, or from surgical wounds. organisms may also infect the individual because of work accidents with cutting or piercing devices. the development of the rabbit hole that is the perioperative environment is not well understood by the majority of our general pediatric colleagues. similarly, the rabbit hole of the primary care clinic or the pediatric inpatient ward is not well understood by the majority of our anesthesiology colleagues. a pediatric patient may repeatedly enter the rabbit hole over the course of a hospital admission, a journey fraught with dangers of airway mishaps, respiratory and/or cardiac arrests, hemorrhage, profound anxiety and stress experienced by the young patient and his or her family, as well as infection risks. anesthesiologists have long been patient safety advocates. it is not surprising that anesthesia providers in the st century have taken on increasing responsibility for preventing health careassociated infections (hais), including surgical site infections (ssis). anesthesia providers practice in a nonsterile environment within the operating room (or) and frequently contact areas of the patient known to have a high rate of contamination such as the axilla, nares, and pharynx. there are two recognized but poorly implemented interventions: preoperative patient skin and other bacterial reservoir decontamination and hand hygiene by anesthesia providers. anesthesia providers have an impact on bacterial transmission and infection rates. specifically, anesthesiologists are known to contaminate their work environment within the or. contamination of the work environment includes contamination of intravenous (iv) access ports. without encouragement, anesthesiologists perform hand hygiene less frequently than once per hour during a case, but with reminders, the rate of hand hygiene is more frequent. improved hand hygiene reduces contamination of the work area and iv access ports from % to %, which in turn significantly reduces hais. , the transmission of infection depends on the presence of three interconnected elements: a causative agent, a source, and a mode of transmission ( fig. . ). understanding the characteristics of each element provides the practicing anesthesiologist with methods to protect susceptible patients and themselves to avoid spreading infection. there has always been concern about the transmission of infectious agents to the patient from the anesthesiologist and vice versa. in addition, there are many sites within the hospital environment where moist or desiccated organic material with the membranes. droplets remain suspended for only a short duration and distance from the source, but this may be affected by temperature, humidity, force of expulsion, and air currents. larger particle sizes contact the mucosa of the upper airway, whereas aerosols are capable of penetrating into the lower respiratory tract. infectious agents vary in their affinity for receptors in different regions of the respiratory tract. , when a person coughs, the exhaled air may reach a speed of up to km/hour ( mph). however, because the droplets are relatively large, they tend to descend quickly and remain suspended in the air for a very brief period, thus obviating the need for special handling procedures for the or air. examples of droplet-borne diseases include influenza, respiratory syncytial virus (rsv), severe acute respiratory syndrome (sars), diphtheria, haemophilus influenzae, neisseria meningitidis, mumps, pertussis, rhinovirus, rubella, and ebola. droplet precautions include communication of infectious risk infection is influenced by the host defense mechanisms that may be classified as either nonspecific or specific: ■ nonspecific defense mechanisms include the skin, mucous membranes, secretions, excretions, enzymes, inflammatory responses, genetic factors, hormonal responses, nutritional status, behavior patterns, and the presence of other diseases. ■ specific defense mechanisms or immunity may occur because of exposure to an infectious agent (antibody formation) or through placental transfer of antibodies; artificial defenses may be acquired through vaccines, toxoids, or exogenously administered immunoglobulins. microorganisms are transmitted in the hospital environment through a number of different routes; the same microorganism may also be transmitted via more than one route. in the or, the three main routes of transmission are through the air and by direct and indirect contact. airborne infections that may infect susceptible hosts are transmitted via two mechanisms: droplets and droplet nuclei. droplet contamination is considered a direct transmission of organisms because there is a direct transfer of microorganisms from the colonized or infected person to the host. this generally occurs with particles whose diameters are greater than µm that are expelled from an individual's mouth or nose, mainly during sneezing, coughing, talking, or during procedures such as suction, laryngoscopy, and bronchoscopy ( fig. . ). transmission occurs when the microorganism-containing droplets, expelled or shed by the infected person (source), are propelled a short distance (usually not exceeding cm or about feet through the air) and deposited on the host's conjunctivae or oral or nasal mucous droplet nuclei result from the evaporation of droplets while suspended in the air. unlike droplets, the nuclei have an outer layer of desiccated organic material and a very small diameter ( - µm) and remain suspended in air indefinitely. the microorganisms contained within these nuclei may be spread by air drafts over great distances, depending on the environmental conditions (dry and cold atmosphere, with limited or no exposure to sunlight favoring the spread). in contrast to droplets, which are deposited on mucous membranes, droplet nuclei may enter the susceptible host by inhalation; examples of droplet nuclei-borne diseases include tuberculosis, varicella, and measles, zoster, smallpox, sars, and middle eastern respiratory syndrome. direct and indirect contacts are the most significant and frequent methods of hospital infection transmission. this type of disease transmission involves direct physical contact between two individuals. the physical transfer of microorganisms from an infected or colonized person to a susceptible host may occur from child to health care provider or from health care provider to child during professional practice (e.g., venous cannulation, laryngoscopy, burn care, or suction of secretions). health care providers working in the or may be exposed to skin contamination by body fluids. this is an issue of grave concern because of the potential exposure of health care providers to patients with unrecognized infections, especially hepatitis b virus (hbv), hepatitis c virus (hcv), and human immunodeficiency virus (hiv). hepatitis b is a highly infectious virus that requires a small amount of blood ( − - − ml) to transmit the disease. the incidence of skin contamination of anesthesiologists and related personnel by blood and saliva is substantial. one study examined anesthetic procedures during consecutive days. the blood of patients ( %) contaminated the skin of anesthesiologists in incidents. of these contamination events, ( %) occurred during venous cannulation. of anesthesiologists who had been contaminated by blood, of ( %) had cuts in the skin of their hands. the importance of this observation is that seroconversion of health care providers has been reported after skin contamination by infected blood from hiv carriers and hbv infection after blood splashing into health care workers' (hcws') eyes. scabies, pediculosis, and herpes simplex are among the diseases most frequently transmitted by direct contact. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] meticulous hand washing before and after every patient contact and routine use of barriers such as gloves and eye protection are essential basic methods for protecting ourselves even during routine procedures such as starting an iv line or performing laryngoscopy. indirect contact involves the transmission of microorganisms from a source (animate or inanimate) to a susceptible host by means of a vehicle (e.g., an intermediary object) contaminated by body fluids. tables . and . provide examples of diseases associated with bodily fluids to which hcws may be exposed. the vehicle for transmission may be the hands of a health care provider who is not wearing gloves or a provider who fails to wash his or her hands after providing care to a child. , [ ] [ ] [ ] this type of contact can also come from health care providers who touch (with or without gloves) contaminated monitoring or other patient care devices (e.g., blood pressure cuffs, stethoscopes, electrocardiographic cables, or ventilation systems [respirators, corrugated tubes, y-pieces, valves]) that are used without proper cleaning or disinfection between each use. [ ] [ ] [ ] knowledge about the transmission of the spread of bacteria from patients to hcws' hands and to the hospital environment ( fig. . ) has driven many interventions that have reduced patient risks for developing hais. disease transmitted blood hbv, hiv, hcv, cmv, ebv, nanbh seminal fluid hiv, hbv, cmv vaginal discharge hiv, hbv, cmv saliva and sputum hsv, tb, cmv, respiratory diseases cerebrospinal fluid encephalopathic organisms (see table characterization of the transmission dynamics of frequently encountered gram-negative bacteria in the anesthesia work area environment demonstrates that the spread follows an epidemiologic pattern similar to that seen in icus and inpatient wards: from patient, to environment and hcws' hands, and to other patients ( fig. . ) . in this report, provider hands were less likely to serve as a transmitter of infection than contaminated environmental or patient skin surfaces. these findings have clinical implications for the risk of colonization and subsequent hcis-for example, ssis. this calls attention to the need to develop and enforce strict hand hygiene guidelines for personnel who are providing anesthesia care, but more importantly the need to increase compliance with environmental disinfection of the or (between cases and terminal cleaning), and to study further the directions of the spread of pathogens in the or and anesthesia work areas. this study unequivocally underscores our need to improve cleaning procedures in the or and equipment surfaces to reduce infection risk. there are also reports of equipment, fomites, and drugs (mainly propofol) that have resulted in hospital-acquired infections. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] propofol is widely used for both inpatient and outpatient anesthesia. this hypnotic agent is a nutrient-rich drug. it is hypothesized that propofol increases bacterial contamination of iv stopcocks and may compromise safety of iv tubing sets when continued to be used after propofol anesthesia. there is a covert incidence of iv stopcock bacterial contamination during anesthesia that is aggravated by the prior presence of propofol. propofol may increase the risk for postoperative infection because of bacterial growth in iv stopcock dead spaces. other facets that may also contribute to infection include the following: ■ up to % of anesthetic equipment in direct or indirect contact with a child (blood pressure cuffs, cables, oximeters, laryngoscopes, monitors, respirator settings, and horizontal and vertical surfaces) may be contaminated with blood because of inadequate cleansing procedures between uses. , , , , ■ in some institutions, up to % of the bain circuits that were reused without previous sterilization were contaminated. ■ contamination of syringe contents has occurred with glass particles during ampule opening, which in turn may compromise the sterility of the contents, presumably because of the passage of bacteria contained on glass particles into the solution. - ■ iv tubing has both blood contamination as well as contamination by blood from syringes used to inject medications. this can occur with the absence of visible blood reflux in the tubing or syringe. simply replacing the needle on a syringe that will be reused is ineffective in preventing cross-infection; it is essential to not use the same syringe in multiple patients. ■ refilling both glass and plastic syringes several times has also been shown to result in contamination of the contents; single use is therefore recommended. studies on vancomycin-resistant enterococci established the importance of a domino effect of contamination in intensive care units (icus) and inpatient wards: spread of vancomycin-resistant enterococci that colonize patients' gastrointestinal tracts ("rectal carriage"), to patients' skin, to the hospital environment, to hands of hcws, and then to other patients. the skin contamination of patients with enteric organisms inspired the rather graphic description, the patient's "fecal patina." also referred to as a "stool veneer," this coating with enteric organisms is limited not only to patients' skin but also extends to surfaces in the surrounding environment that are touched, and thereby contaminated, by patients and by hcws. the environmental contamination spreads out from the patient in a target-like concentric pattern, with the densest contamination closest to the rectum of patients who have rectal carriage of the problem bacteria. this interplay among the blood of a patient in an advanced disease stage or with a higher hiv viral load; a deep percutaneous injury; a procedure wherein the sharp was in the vein or artery of an infected source patient; an injury with a hollow-bore, blood-filled needle; and limited or delayed access to postexposure prophylaxis. after exposure, the risk of infection varies for specific bloodborne pathogens. for hbv, if the source patient has active hbv and the hcp do not already have immunity, the risk for infection after percutaneous injury is between % and %. if the source patient has active hcv, the risk of hepatitis c transmission is approximately . % (range %- %) after a percutaneous injury. if the source patient has hiv infection, the risk of hiv transmission is approximately . % after a percutaneous exposure and . % after a mucous membrane exposure. the risk of hiv transmission for an exposure with nonintact skin has not been determined and is estimated to be less than the risk after a mucous membrane exposure. anesthesia staff lacking hbv protective antibodies are at great risk for acquiring the disease. , these infection rates underscore the need for the use of "safe" needles and the need to advocate the use of "needleless" systems even though they are significantly more expensive. , this also emphasizes the need for meticulous handling and disposal of needles and other sharp instruments, as well as the use of special "sharps boxes" designed to minimize accidental needlesticks (e.g., "mailbox"-type boxes that do not allow the hand to enter the disposal area). [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the u.s. centers for disease control and prevention (cdc) has estimated that in the united states there are approximately , cutting and piercing accidents annually among hcp in hospitals; % of these occur in the or. however, the actual prevalence is thought to be much greater, because many of these events are unreported. the distribution of these accidents among anesthesiologists is shown in fig. . a; the distribution of the items most frequently associated with cutting and piercing injuries in health care providers is shown in fig. . b. should such an accident occur (e.g., needle puncture, exposure to nonintact skin, or mucous membrane ■ needles that have been used for spinal or epidural anesthesia were contaminated with coagulase-negative staphylococci ( . %), yeasts ( . %), enterococci ( . %), pneumococci ( . %), and micrococci ( . %), suggesting that there may be needle contamination despite standard skin preparation and cleansing. it is unclear whether these skin organisms can be transmitted and cause an infection during administration of a neuraxial block. ■ blood and saliva frequently contaminate the skin of anesthetic personnel during routine anesthetic practice. ■ violations of contemporary guidelines for preventing infections (e.g., hand washing, wearing gloves, surgical masks, ocular protection, scrubs, or syringe reuse) by anesthesiologists are frequent. anesthesia staff are aware that they work in a potentially infectious environment, but they commonly do not adopt appropriate protective measures to reduce infections in both themselves and their patients ( %- %). , - percutaneous contamination from a cutting or piercing accident is the most effective means to transmit bloodborne pathogens. evidence suggests that this is the main route of hiv, hbv, and hcv infection, [ ] [ ] [ ] especially if the injury is caused by hollow-bore needles that were used to draw blood or establish iv access. , over other bloodborne pathogens have been transmitted by this means, including those causing herpes, malaria, and tuberculosis. the risk of exposure to blood and bloodborne pathogens is greater for health care personnel (hcp) than for people who do not work around blood. an exposure to infected blood, tissue, or other potentially infectious body fluids can occur by percutaneous injury or contact with mucous membrane or nonintact skin. the risk of infection after an exposure depends on a number of variables and appears to be greater with exposure to a larger quantity of blood or other infectious fluid; prolonged or extensive exposure of nonintact skin or mucous membrane to blood or other infectious fluid or concentrated virus in a laboratory setting; exposure to institutional administrative measures aimed at developing, implementing, and monitoring specifically designed accident prevention policies and procedures are important for reducing and preventing transmission of infectious agents in health care centers. to this end, centers should consider the following: , , ■ include infection control as a major goal in the organizational mission statement and implement safety programs, both for patients and hcws. ■ provide sufficient administrative and financial support to carry out this mission. ■ provide sufficient administrative and financial support for the microbiology laboratory and implement an infection surveillance plan, especially for postsurgical infections. ■ establish a multidiscipline cross-functional team (e.g., a team manager, an epidemiologist, a representative from industrial health, and a person trained in quality control) to identify health and safety issues within the institution, analyze trends, assess outcomes, implement interventions, and make recommendations to other members of the organization. ■ provide sufficient administrative and financial support to develop and implement education programs for health care providers, patients, and their families. one positive example of such education is that anesthesiologists who have read the cdc's universal precaution guidelines for the prevention of occupational transmission of hiv and hbv have developed better hygienic practices. ■ provide hcws with hepatitis a and b vaccine and document that an appropriate immunologic response was achieved. provide hepatitis a and b immune globulins (haig, hbig) for those exposed who do not have established immunity. ■ provide a health care service for employees for counseling and postexposure prophylaxis should an exposure to hiv occur. , there are now specific recommendations regarding immediate assessment of risk, assessment of the exposure source (chart review, inform the patient that an accident has occurred and ask permission to determine hbv, hcv, and hiv serologic status), and rapid initiation of appropriate antiviral treatment of the hcw. it is advised to obtain as much information regarding the patient as possible-if the patient is known-to ( ) obtain a sample of blood from the patient for determination of potential carrier state (table . ) and ( ) report to the health service for immediate institution of prophylaxis and follow-up ( air is delivered to each or from the ceiling, with downward movement toward several exhaust or return ducts near the floor. this design helps provide steady movement of clean air through the breathing and working zones. the aia has specific guidelines for the location of outside fresh air inlets to minimize contamination from exhaust systems and noxious fumes. a greater air inflow rate and a larger air-inlet area are desirable for contaminant control, but these approaches are detrimental to the thermal comfort of the staff and patient. the aia recommends an air-change rate in an or of to air changes per hour (ach) for ceiling heights between feet wound contamination in the or is the result of the patient's skin flora and bacteria shed on airborne particles from the or personnel. room ventilation affects the distribution of these airborne particles in four ways: total ventilation (dilution), air distribution (directional airflow), room pressurization (filtration barrier), and filtration (contaminant removal). as the air flows of the room increase, the greater the dilutional effect on airborne particles. balancing this phenomenon is important because while increased flow increases the effectiveness of air exchange, the resultant turbulent flow increases microbial distribution throughout the room. low-velocity unidirectional flow minimizes the spread of microbes in the room. directional flow can be inward, from the outside into the or (negative pressure), or outward, from the or to the outside (positive pressure). negative-pressure ventilation is used for highly infective rooms in the hospital (e.g., isolation rooms for tuberculosis patients), and positive-pressure ventilation is used for protective environments (e.g., ors and pep step : treat exposure site • use soap and water to wash areas exposed to potentially infectious fluids as soon as possible after exposure. • flush exposed mucous membranes with water. • flush exposed eyes with water or saline solution. • do not apply caustic agents, or inject antiseptics or disinfectants into the wound. step : report and document standard precautions assume that any person or patient is potentially infected or colonized by microorganisms that could be transmitted and cause an infectious process. standard precautions must be implemented with all patients and include the following: ■ universal precautions-blood and body fluid precautions, developed to reduce bloodborne pathogen transmission ■ body substance isolation, designed to reduce the risk of pathogen transmission by moist body substances standard precautions are used to reduce the transmission of all infectious agents from one person to another, thus protecting health care providers and children against exposure to the most common microorganisms. standard precautions are implemented for any contact with blood and body fluids, secretions, and excretions (except sweat), whether or not they contain visible blood, as well as for any contact with nonintact skin, mucous membranes, and intact skin that is visibly soiled with blood and/ or body fluids. prevention is primary. all hcps should be familiar with standard precautions: wash hands frequently and thoroughly before and after patient care; use personal protective equipment: gloves, gowns, boots, shoe covers, eyewear, masks, and shields, as appropriate for the patient care situation; gloves must be worn when any kind of venous or arterial access is being performed; use sharps with caution: plan ahead (use sharps in a safe environment with a sharps container nearby), dispose of used sharps in puncture-proof receptacles immediately after use, do not recap needles, and use safety devices if available. all hcps should be vaccinated with the hepatitis b vaccine series and should undergo testing for hbsab response after completion of the series to document adequate protection. employees who have not gone through the vaccination series previously should be offered the hepatitis b series through their employer at no cost. summaries of standard precautions, droplet precautions, airborne precautions, and contact precautions are available on line. , [ ] [ ] [ ] hand washing overall hand hygiene compliance across health care providers remains less than %, with anesthesia providers identified as a particularly noncompliant group (one study found a compliance rate of only %). bacterial contamination of anesthesia providers has been directly linked to high-risk bacterial transmission events to iv stopcocks and -day postoperative infections. the vast majority of ssis are caused by staphylococcus aureus. transmission of specific staphylococcal phenotypes within and between patients is a major contributor to ssis and hais. , , the role of anesthesia-provider hand contamination in transmission of enterococcus to the workstation and patient biome is concerning, even though it was not associated with actual infection, because of rising rates of antibiotic-resistant organisms and the observation that enterococcus is becoming a more prevalent pathogen. , two approaches are indicated: improved methods of patient reservoir decontamination and more effective and frequent decontamination of provider hands. hand hygiene is a well-known and effective solution to the problem of bacterial transmission within and across patients. compliance with the current " moments" world health organization guidelines could make a major inroad into reducing provider hand and workspace contamination. one study found that only % of anesthesia providers demonstrated complete knowledge regarding who hand hygiene guidelines. failure of providers to recognize prior contact with the environment and prior contact with the patient as hand hygiene opportunities contributed to this low percentage. several cognitive factors were associated ( . meters) and feet ( . meters). some controversy exists between engineers and clinicians over the need for laminar airflow ventilation in the or to further minimize airborne infection. careful mathematical analyses of airflow suggest that laminar airflow is not necessary. clinical studies are confirmatory. similarly, the use of ultraviolet light to cleanse the room air is no longer recommended. table . shows the healthcare infection control practices advisory committee and cdc general recommendations for ventilation system specifications for the or. children with tuberculosis require special consideration because of the high risk of occupational transmission of mycobacterium tuberculosis, , especially after the emergence of multidrug-resistant strains (table . ). an easy preventive measure is to screen all children before coming to the or to determine recent exposure to infectious disease such as measles, mumps, rubella, and chickenpox because these infections can pose a significant risk to hcws and patients, especially those who are immunocompromised. , another potential source for airborne spread of pathogens is through the anesthesia circuit; this may be reduced by the use of circuit filters. however, at present there are no regulatory requirements to use such devices, and performance characteristics vary widely. • pep should be initiated within hours of the exposure. • the eficacy of pep initiation is thought to diminish after to hours following an exposure. • if the fourth-generation combination hiv ag/ab assay is used to test the source patient, hiv follow-up testing can be completed months after exposure. hand washing is considered the most important and costeffective individual intervention in the prevention of hais in children and health care providers. its importance in medical practice had not been universally accepted, despite the pioneering work by oliver wendell holmes ( ) and ignaz semmelweis with a reduced risk of incomplete knowledge, including providers responding positively to washing their hands after contact with the environment, disinfecting their environment during patient care, believing that they can influence their colleagues, and intending to adhere to guidelines. these results suggest that anesthesia providers have knowledge deficits pertaining to opportunity-based hand hygiene in the intraoperative arena hiv-positive class : asymptomatic hiv infection or known low viral load (e.g., < ribonucleic acid copies/ml). hiv-positive class : symptomatic hiv infection, acquired immunodeficiency syndrome, acute seroconversion, or known high viral load. if drug resistance is a concern, obtain expert consultation. initiation of pep should be delayed pending expert consultation, and because expert consultation alone cannot substitute for face-to-face counseling, resources should be available to provide immediate evaluation and follow-up care for all exposures. the recommendation "consider pep" indicates that pep is optional; a decision to initiate pep should be based on a discussion between the exposed person and the treating clinician regarding the risks versus benefits of pep. g if pep is offered and administered and the source is later determined to be hiv-negative, pep should be discontinued. recommendations for surgical hand preparation are as follows: remove rings, wristwatch, and bracelets before beginning surgical hand preparation (ii); artificial nails are prohibited (ib); sinks should be designed to reduce the risk of splashes (ii); if hands are visibly soiled, wash hands with plain soap before surgical hand preparation (ii); remove debris from underneath fingernails using a nail cleaner, preferably under running water (ii); brushes are not recommended for surgical hand preparation (ib); surgical hand antisepsis should be performed using either a suitable antimicrobial soap or suitable alcohol-based handrub, preferably with a product ensuring sustained activity, before donning sterile gloves (ib); if the quality of water is not assured in the operating theatre, surgical hand antisepsis using an alcohol-based handrub is recommended before donning sterile gloves when performing surgical procedures (ii); when performing surgical hand antisepsis using an antimicrobial soap, scrub hands and forearms for the length of time recommended by the manufacturer, typically - minutes. long scrub times (e.g., minutes) are not necessary (ib); when using an alcohol-based surgical handrub product with sustained activity, follow the manufacturer's instructions for application times. apply the product to dry hands only (ib); do not combine surgical hand scrub and surgical handrub with alcohol-based products sequentially (ii); when using an alcoholbased handrub, use sufficient product to keep hands and forearms wet with the handrub throughout the surgical hand preparation procedure (ib); after application of the alcohol-based handrub as recommended, allow hands and forearms to dry thoroughly before donning sterile gloves (ib). at present, alcohol-based handrubs are the only known means for rapidly and effectively inactivating a wide array of potentially harmful microorganisms on hands. the who recommends alcohol-based handrubs based on the following factors: evidencebased, intrinsic advantages of fast-acting and broad-spectrum microbicidal activity with a minimal risk of generating resistance to antimicrobial agents; suitability for use in resource-limited or remote areas with lack of accessibility to sinks or other facilities for hand hygiene (including clean water, towels, and so on); capacity to promote improved compliance with hand hygiene by making the process faster and more convenient; economic benefit by reducing annual costs for hand hygiene, representing approximately % of extra costs generated by an hci; minimization of risks from adverse events because of increased safety associated with better acceptability and tolerance than other products. after hand washing, it is very important to dry the hands properly with appropriate paper towels, hot air flow, or both, because the level of pathogen transmission from a hcw's hands to a patient is greatly increased if the hands are wet. sterile cloth towels are most frequently used in ors to dry wet hands after surgical hand antisepsis. several methods of drying have been tested without significant differences between techniques. transmission may also occur from patients' wet sites, such as groins or armpits, or when a hcw gets his or her hands wet when opening parenteral solutions. it is critical for health institutions to establish written procedures and protocols to support adherence to the recommended hand hygiene practices. wearing clean or sterile gloves while caring for children is an effective means of reducing hais. gloves remain a supplementary barrier to infection that should not replace proper hand hygiene. more frequent (on average, opportunities per patient-hour). the greatest adherence rate ( %) was observed in pediatrics, where the average intensity of patient care was smaller than elsewhere (on average, opportunities per patient-hour). the results suggest that full adherence to guidelines is unrealistic and that easy access to hand hygiene at the point of patient care, (i.e., in particular, alcohol-based handrubbing) could help improve adherence to hand hygiene. perceived barriers to adherence with hand hygiene practice recommendations include skin irritation caused by hand hygiene agents, inaccessible hand hygiene supplies, interference with hcw-patient relationships, patient needs perceived as a priority over hand hygiene, wearing of gloves, forgetfulness, lack of knowledge of guidelines, insufficient time for hand hygiene, high workload and understaffing, and the lack of scientific information showing a definitive impact of improved hand hygiene on hai rates. lack of knowledge of guidelines for hand hygiene, lack of recognition of hand hygiene opportunities during patient care, and lack of awareness of the risk of cross-transmission of pathogens are barriers to good hand hygiene practices. furthermore, some hcws believed that they washed their hands when necessary even when observations indicated that they did not. the risk of pathogen transmission via the hands is proportional to the power of the number of times a child is touched. table . presents . wash hands with soap and water when visibly dirty or visibly soiled with blood or other body fluids (ib) or after using the toilet (ii). . if exposure to potencial spore-forming pathogens is strongly suspected or proven, including outbreaks of clostridium difficile, hand washing with soap and water is the preferred means (ib). . use an alcohol-based handrub as the preferred means for routine hand antisepsis in all other clinical situations described in terms (a) to (f) listed below, if hands are not visibly soiled (ia). if alcohol-based handrub is not obtainable, wash hands with soap and water (ib). . perform hand hygiene: a. before and after touching the patient (ib); b. before handling an invasive device for patient care regardless of whether or not gloves are used (ib); c. after contact with body fluids or excretions, mucous membranes, non-intact skin, or wound dressings (ia); d. if moving from a contaminated body site to another body site during care of the same patient (ib); e. after contact with inanimate surfaces and objects (including medical equipment) in the immediate vicinity of the patient (ib); f. after removing sterile (ii) or nonsterile gloves (ib). . before handling medication or preparing food, perform hand hygiene using an alcohol-based handrub or wash hands with either plain or antimicrobial soap and water (ib). . soap and alcohol-based handrub should not be used concomitantly (ii). gloves protect patients by reducing health care provider hand contamination and the subsequent transmission of pathogens to other children, provided the gloves are changed after providing care to each child. additionally, when the use of gloves is combined with cdc standard precautions, they protect the health care provider against exposure to bloodborne infections or infections transmitted by any other body fluids, such as excretions, secretions (except sweat), mucous membranes, and nonintact skin. examination gloves are single-use and usually nonsterile. sterile surgical gloves are required for surgical interventions. some nonsurgical care procedures, such as central vascular catheter insertion, also require surgical glove use. in addition to their sterile properties, these gloves have characteristics of thickness, elasticity, and strength that differ from other medical gloves. the use of gloves in situations when their use is not indicated represents a waste of resources without necessarily reducing crosstransmission. the wide-ranging recommendations for glove use have led to very frequent and inappropriate use. indications for gloving and glove removal are shown in table . . situations that require and that do not require glove use are presented in fig. . . ranked consensus recommendations for the use of gloves, categorized according to the cdc/hicpac system, include the following , , : ■ wear gloves in case of contact with blood or any other potentially infecting body fluid, such as excretions, secretions (except sweat), mucous membranes, and nonintact skin (ic). ■ remove the gloves immediately after providing care to a child. staff should not wear the same pair of gloves to take care of more than one child, nor should they touch the surfaces of any equipment, monitoring devices, or even light switches. ■ alcohol-based handrub dispensers and clean glove boxes (at least two sizes) should be in place near every patient care site (e.g., on top of every anesthesia cart, medication cart, or in the nursing station). ■ disposable gloves should not be washed, resterilized, or disinfected (ib). if gloves are reused, appropriate reprocessing methods should be in place to ensure the physical integrity of the gloves and their full decontamination (ii). ■ sterile gloves are much more expensive than clean, disposable gloves and should be used only for certain procedures, such as when hands are in contact with normally sterile body areas or when inserting intravascular or urinary catheters. clean gloves should be used during any other procedure, including wound dressing. ■ latex-free gloves should be worn when caring for children at risk for latex allergy. surgical antimicrobial prophylaxis is an essential tool to reduce the risk of postoperative infections, and the anesthesia team plays a central role in ensuring the proper timing of drug administration. , the aim of the perioperative administration of antibiotics is to obtain plasma and tissue drug concentrations exceeding the minimal inhibitory concentration of those organisms most likely to cause an infection. this will reduce the microbial load of the intraoperative contamination; it is not the intent to cover all possible pathogens, because this can lead to the selection of drug-resistant bacteria. there have been few studies regarding the effectiveness of prophylactic guidelines for prevention of ssis in children. currently, prophylactic antibiotic guidelines exist for certain subsets of the pediatric surgical population, but there are no global recommendations, and the guidelines that exist are mostly based on studies from adults or from expert opinion. a retrospective study suggested that the appropriate use of antibiotic prophylaxis was a vital modifiable risk factor and may be the easiest factor to influence. primary failure to administer the correct dose of antibiotics at the appropriate time resulted in an almost -fold increase in the risk of developing an ssi. the importance of correct antibiotic usage and dosing plays a major role in decreasing risk of ssis in children. recommendations are provided for adult (age ≥ years) and pediatric (age - years) patients. the guidelines do not specifically address newborn (premature and full-term) infants (table . although pediatric-specific prophylaxis data are sparse, available data have been evaluated for specific procedures. selection of antimicrobial prophylactic agents mirrors that in adult guidelines, with the agents of choice being first-and second-generation cephalosporins, reserving the use of vancomycin for patients with documented β-lactam allergies. while the use of a penicillin with a β-lactamase inhibitor in combination with cefazolin or vancomycin and gentamicin has also been studied in pediatric patients, the number of patients included in these evaluations remains small. as with adults, there is little evidence supporting the use of vancomycin, alone or in combination with other antimicrobials, for routine perioperative antimicrobial prophylaxis in institutions that have a high prevalence of methicillin-resistant s. aureus (mrsa). vancomycin may be considered in children known to be colonized with mrsa and decreases mrsa infections. mupirocin is effective in children colonized with mrsa, but choice, alternative antibiotics should be administered to those children at risk of anaphylaxis to β-lactams, based on their history or diagnostic tests (e.g., skin testing). however, the incidence of severe allergic reactions to first-generation cephalosporins in children with reported allergy to penicillin is rare (but not zero) , ; furthermore, skin testing does not reliably predict the likelihood of adverse reactions to cephalosporins in those with reported allergy to penicillin. [ ] [ ] [ ] there is no evidence of any risk of cross-reactivity between penicillin and second-and thirdgeneration cephalosporins. for the most part, "allergies" to oral antibiotics that appear on children's charts (rash, vomiting, gastrointestinal disturbances) are reactions to the additives in the antibiotic formulation, including food dyes, fillers, and other compounds, or a manifestation of the underlying infection. iv administration of small test doses of the pure antibiotic in a fully monitored (and anesthetized) child will determine whether the child is at risk for an allergic reaction to the antibiotic. in the case of surgical procedures where antibiotic prophylaxis is mainly directed at gram-positive cocci, children who are truly allergic to β-lactams (cephalosporins) should receive either vancomycin or clindamycin. however, in those children where the history is consistent with either an ige-mediated penicillin allergy (urticaria, angioedema, anaphylaxis, bronchospasm) or a severe non-igemediated reaction (interstitial nephritis, toxic epidermal necrolysis, hemolytic anemia, or stevens-johnson syndrome) it is advisable to switch out the cefazolin. cross-sensitivity occurs when the r side chains of the penicillins and cephalosporins are similar, which perhaps surprisingly is not the case with cefazolin. cephalosporins with r side chains similar to penicillins include cephalexin, cefaclor, and cefadroxil. the risk associated with use of first-or second-generation cephalosporins with dissimilar side chains, or third-or fourth-generation cephalosporins, "appears to be very low in patients with mild-to-moderate reactions to penicillin g, ampicillin, or amoxicillin. dismissing cefazolin use when there is a vague history of any penicillin allergy should be reconsidered." indications for prophylactic antibiotics surgical wounds are classified into four categories (table . ). the use of antibiotic prophylaxis for postoperative infections is well established for clean-contaminated procedures. within the clean category, prophylaxis has been traditionally reserved for surgical procedures involving a foreign body implantation or for any surgical procedure where an ssi would be catastrophic (e.g., cardiac surgery or neurosurgical procedures). however, there is evidence that postoperative infections resulting from procedures not involving prosthetic elements are underreported; estimates show that more than % of all complications occur after the patient is discharged and are thus unrecognized by the surgical team. therefore antibiotic prophylaxis is also recommended for certain procedures, such as herniorrhaphy. , the direct and indirect costs of these complications may not affect the hospital budget; however, they represent a substantial cost for the community at large. in the case of contaminated or dirty procedures, bacterial contamination or infection is established before the procedure begins. accordingly, the perioperative administration of antibiotics is a therapeutic, not a prophylactic, measure. the use of antibiotics in children has implications not only for the response to the current treatment but also to future treatments. thus all medical professionals are jointly responsible for the rational use of antibiotics. protocols, although effective, require continuous feedback on their acceptance and ssi results. no surgical protocol can replace there are limited data supporting its use perioperatively. , most recommendations for adults are the same for pediatric patients. dosing recommendations in pediatric patients are limited and have been extrapolated from adult data; therefore nearly all pediatric recommendations are based on expert opinion. pediatric efficacy data are few. fluoroquinolones should not be routinely used for surgical prophylaxis in pediatric patients because of the potential for toxicity in this population. the same principle of preoperative dosing within minutes before incision has been applied to pediatric patients. additional intraoperative dosing may be needed if the duration of the procedure exceeds two half-lives of the antimicrobial agent or there is excessive blood loss during the procedure. as with adult patients, single-dose prophylaxis is usually sufficient. if antimicrobial prophylaxis is continued postoperatively, the duration should be less than hours, regardless of the presence of intravascular catheters or indwelling drains. there are sufficient pharmacokinetic studies of most agents to recommend pediatric dosages that provide adequate systemic exposure and, presumably, efficacy comparable to that demonstrated in adults. therefore the pediatric doses recommended in guidelines are based largely on pharmacokinetic data and the extrapolation of adult efficacy data to pediatric patients. because few clinical trials have been conducted in pediatric surgical patients, strength of evidence criteria have not been applied to these recommendations. with few exceptions (e.g., aminoglycoside dosages), pediatric doses should not exceed the maximum adult recommended dosages. generally, if a dose is calculated on a milligram-per-kilogram basis for children weighing more than kg, the calculated dosage will likely exceed the maximum recommended dose for adults; adult dosages should therefore be used for larger children. the timing of antibiotic prophylaxis the revised policy paper on prophylactic antibiotics developed jointly by the american society of health-system pharmacists (ashp), the infectious disease society of america, the surgical infection society, and the society for healthcare epidemiology of america states: successful prophylaxis requires the delivery of the antimicrobial to the operative site before contamination occurs. thus, the antimicrobial agent should be administered at such a time to provide serum and tissue concentrations exceeding the minimum inhibitory concentration (mic) for the probable organisms associated with the procedure, at the time of incision, and for the duration of the procedure. current evidence suggests that for most β-lactams, a bolus dose at to minutes before incision is ideal and provides maximum interstitial fluid concentrations at the time of initial bacterial seeding (see table . ). because diffusion distances from capillary to pathogen are greater in obese patients, for this patient subset initiating antibiotic infusion minutes or longer before incision is warranted on theoretical grounds. the initial β-lactam bolus dose should be followed by additional doses at every to half-lives per the ashp guidelines. the use of a ssi prevention bundle in pediatric patients improves compliance with preincision antibiotic administration and decreases the ssi infection rate. allergy to β-lactams several studies have shown that the true incidence of allergy to antibiotics is less than that reflected in medical charts. for surgical procedures where cephalosporins are the prophylaxis of the judgment of the medical professional; clinical reasoning must be tailored to the individual circumstances. finally, children with congenital heart disease and a subgroup of those with repaired congenital heart disease may require bacterial endocarditis prophylaxis (see also tables . and . ). preventing the transmission of pathogenic microbes during anesthesia infection control and anesthesia: lessons learned from the toronto sars outbreak fecal patina in the anesthesia work area intensive care unit environments and the fecal patina: a simple problem? transmission dynamics of gram-negative bacterial pathogens in the anesthesia work area serratia marcescens bacteremia traced to an infused narcotic postoperative infections traced to contamination of an intravenous anesthetic, propofol staphylococcus aureus bloodstream infections among patients undergoing electro-convulsive therapy traced to breaks in infection control and possible extrinsic contamination by propofol postsurgical candida albicans infections associated with an extrinsically contaminated intravenous anesthetic agent occupationally acquired infections in health care workers. part ii occupationally acquired infections in health care workers. part i transmission of hepatitis c virus by a cardiac surgeon transmission of infection by gastrointestinal endoscopy and bronchoscopy nosocomial transmission of multidrug-resistant mycobacterium tuberculosis. a risk to patients and health care workers disease transmission by inefficiently sanitized anesthetizing apparatus contamination, disinfection, and cross-colonization: are hospital surfaces reservoirs for nosocomial infection? pseudomonas aeruginosa respiratory tract infection acquired from a contaminated anesthesia machine pseudomonas aeruginosa cross-infection due to contaminated respiratory apparatus patient-to-patient transmission of hiv in private surgical consulting rooms hepatitis b virus transmission associated with a multiple-dose vial in a hemodialysis unit fine-particle humidifiers. source of pseudomonas aeruginosa infections in a respiratory-disease unit pseudomonas aeruginosa epidemic traced to delivery-room resuscitators an alternative strategy for infection control of anesthesia breathing circuits: a laboratory assessment of the pall hme filter nosocomial contamination of laryngoscope handles: challenging current guidelines leaving more than your fingerprint on the intravenous line: a prospective study references all boats rise with the tide bacterial reservoirs in the operating room transmission of pathogenic bacterial organisms in the anesthesia work area reduction in intraoperative bacterial contamination of peripheral intravenous tubing through the use of a novel device anaesthetics and inhalers blood contamination of anesthesia equipment and monitoring equipment the routine wearing of gloves: impact on the frequency of needlestick and percutaneous injury and on surface contamination in the operating room infection control in the outpatient setting infection prevention in anesthesia practice: a tool to assess risk and compliance safe infection control practices for protection of prevention of airborne exposure during endotracheal intubation guidelines for environmental infection control in health-care facilities. recommendations of cdc and the healthcare infection control practices advisory committee (hicpac) blood contamination of anaesthetic and related staff update: human immunodeficiency virus infections in health-care workers exposed to blood of infected patients the eyes as a portal of entry for hepatitis and other infectious diseases molluscum contagiosum the epidemiology of molluscum contagiosum in children nosocomial outbreak of scabies in a hospital in spain an outbreak of scabies in a teaching hospital: lessons learned herpes simplex cross infection in the operating room herpetic whitlow infection in a general pediatrician-an occupational hazard herpetic whitlow: an infectious occupational hazard hand contamination of anesthesia providers is an important risk factor for intraoperative bacterial transmission reducing perioperative infection is as simple as washing your hands hand hygiene in the intensive care unit hygienic practices of consultant anaesthetists: a survey in the north-west region of the uk joint working party of the hospital infection society and the surgical infection study group workbook for designing, implementing and evaluating a sharps injury prevention program pep steps: a quick guide to postexposure prophylaxis in the health care setting. mountain plains aids education and training center the risk of needlestick injuries and needlesticktransmitted diseases in the practice of anesthesiology percutaneous injuries in anesthesia personnel sharp truth: health care workers remain at risk of bloodborne infection universal treatment success among healthcare workers diagnosed with occupationally acquired acute hepatitis c prevention of needle-stick injury. efficacy of a safeguarded intravenous cannula strategies for preventing sharps injuries in the operating room preventing transmission of blood-borne pathogens: a compelling argument for effective device-selection strategies accidental needlesticks in the phlebotomy service of the department of laboratory medicine and pathology at mayo clinic rochester don't get stuck with unsafe needles. instead, get involved in needle device selection update on needlestick and sharps injuries: the needle stick safety and prevention act of multicenter study of contaminated percutaneous injuries in anesthesia personnel needle injuries among pediatric housestaff physicians in new york city device-specific sharps injury and usage rates: an analysis by hospital department needlestick injuries among health care workers. a literature review sharps injuries among hospital support personnel prevalence of safer needle devices and factors associated with their adoption: results of a national hospital survey effect of implementing safety-engineered devices on percutaneous injury epidemiology a review of sharps injuries and preventative strategies preventing needlestick injuries among healthcare workers: a who-icn collaboration sharps disposal in the ed: simple techniques and equipment monografía-manual para el desarrollo de un programa de prevención de infecciones de sitio quirúrgico, escuela de salud pública prevención de infección de sitio quirúrgico y seguridad del paciente en pre, intra y postquirúrgico, instituto nacional de epidemiología documento de consenso on propofol anesthesia and implications of stopcock contamination recombinant factor viii for the treatment of previously untreated patients with hemophilia a. safety, efficacy, and development of inhibitors kogenate previously untreated patient study group a simple, cost-effective method of preventing laryngoscope handle contamination contamination and resterilization of the bain circuit glass particle contamination: influence of aspiration methods and ampule types glass particle contamination in single-dose ampules drug contamination from opening glass ampules a microbiological study of the contamination of the syringes used in anaesthesia practice anesthesiologists should not give iv medications with common syringe bacterial growth in ropivacaine hydrochloride ropivacaine . % with sufentanil microg/ml inhibits in vitro growth of pseudomonas aeruginosa and does not promote multiplication of staphylococcus aureus growth of staphylococcus aureus in four intravenous anesthetics propofol, but not thiopental, supports the growth of candida albicans growth of microorganisms in propofol, thiopental, and a : mixture of propofol and thiopental outbreak of severe sepsis due to contaminated propofol: lessons to learn infectious disease risk associated with contaminated propofol anesthesia bacterial contamination of needles used for spinal and epidural anaesthesia preventing perioperative transmission of infection: a survey of anesthesiology practice accidental needlesticks: do anesthesiologists practice proper infection control precautions? anesthesia practice-a vector of infection? letter: hepatitis-b antigen on environmental surfaces susceptibility of healthcare workers to measles, mumps rubella and varicella lessons learned: protection of healthcare workers from infectious disease risks guidelines for prevention of transmission of human immunodeficiency virus and hepatitis b virus to health-care and public-safety workers the dynamics of enterococcus transmission from bacterial reservoirs commonly encountered by anesthesia providers hand hygiene knowledge and perceptions among anesthesia providers infection control-a problem for patient safety classic pages in obstetrics and gynecology. oliver wendell holmes. the contagiousness of puerperal fever the etiology, concept, and prophylaxis of childbed fever puerperal sepsis hand washing and hand disinfection: more than your mother taught you effectiveness of gloves in the prevention of hand carriage of vancomycin-resistant enterococcus species by health care workers after patient care quantification of hand hygiene compliance in anesthesia providers at a tertiary care center in northern india apic guideline for handwashing and hand antisepsis in health care settings compliance with handwashing in a teaching hospital improving compliance with hand hygiene in hospitals effectiveness of a hospital-wide programme to improve compliance with hand hygiene hand hygiene: improved standards and practice for hospital care improving adherence to hand hygiene practice: a multidisciplinary approach guideline for hand hygiene in health-care settings. recommendations of the healthcare infection control practices advisory committee and the hipac/shea/apic/idsa hand hygiene task force preliminary analysis of the transmission dynamics of nosocomial infections: stochastic and management effects touch contamination levels during anaesthetic procedures and their relationship to hand hygiene procedures: a clinical audit guideline for isolation precautions in hospitals. the hospital infection control practices advisory committee how-to guide: improving hand hygiene. a guide for improving practices among health care workers bacterial contamination of the hands of hospital staff during routine patient care anatomy of a defective barrier: sequential glove leak detection in a surgical and dental environment examination gloves as barriers to hand contamination in clinical practice prevention of central venous catheter-related bloodstream infections using non-technologic strategies benchmarking for prevention: the centers for disease control and prevention's national nosocomial infections surveillance (nnis) system experience public health service guidelines for the management of occupational exposures to hbv, hcv, and hiv and recommendations for postexposure prophylaxis varicella and paediatric staff: current practice and vaccine cost-effectiveness varicella serological status of healthcare workers as a guide to whom to test or immunize controlling varicella in the healthcare setting: the cost effectiveness of using varicella vaccine in healthcare workers varicella vaccination for healthcare workers at a university hospital: an analysis of costs and benefits a survey of policies at children's hospitals regarding immunity of healthcare workers: are physicians protected? prevention and control of varicella-zoster infections in healthcare facilities predicting transient particle transport in enclosed environments with the combined computational fluid dynamics and markov chain method room ventilation systems. operating room design manual occupational transmission of tuberculosis: implications for anesthesiologists occupational transmission of mycobacterium tuberculosis to health care workers in a university hospital in the bacterial and viral filtration performance of breathing system filters prevention of cross contamination, patient to anesthesia apparatus to patient, using filters heat and moisture exchangers and breathing system filters: their use in anaesthesia and intensive care. part -history, principles and efficiency heat and moisture exchangers and breathing system filters: their use in anaesthesia and intensive care. part -practical use, including problems, and their use with paediatric patients hidden hazards and dangers associated with the use of hme/filters in breathing circuits. their effect on toxic metabolite production, pulse oximetry and airway resistance who guidelines on hand hygiene in health care: first global patient safety challenge clean care is safer care water-assisted liposuction for body contouring and lipoharvesting: safety and efficacy in consecutive patients world health organization. practical guidelines for infection control in health care facilities. searo regional publication no. hand hygiene among physicians: performance, beliefs, and perceptions multiple reservoirs contribute to intraoperative bacterial transmission retrospective evaluation of antimicrobial prophylaxis in prevention of surgical site infection in the pediatric population effects of controlled perioperative antimicrobial prophylaxis on infectious outcomes in pediatric cardiac surgery role of decolonization in a comprehensive strategy to reduce methicillin-resistant staphylococcus aureus infections in the neonatal intensive care unit: an observational cohort study immediate control of a methicillinresistant staphylococcus aureus outbreak in a neonatal intensive care unit clinical practice guidelines for antimicrobial prophylaxis in surgery clinical practice guidelines for antimicrobial prophylaxis in surgery administration of parenteral prophylactic beta-lactam antibiotics in : a review reducing surgical site infections at a pediatric academic medical center drug allergies in the surgical population is there cross-reactivity between penicillins and cephalosporins? a review of evidence supporting the american academy of pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients practical aspects of choosing an antibiotic for patients with a reported allergy to an antibiotic hypersensitivity reactions to beta-lactam antibiotics anaphylactic shock due to cefuroxime in a patient taking penicillin prophylaxis antimicrobial prophylaxis for surgery: an advisory statement from the national surgical infection prevention project comprehensive surveillance of surgical wound infections in outpatient and inpatient surgery community surveillance of complications after hernia surgery quality in pediatric anesthesia prevention of bacterial endocarditis. recommendations by the american heart association key: cord- -eby gm authors: l'huillier, a.g.; tapparel, c.; turin, l.; boquete-suter, p.; thomas, y.; kaiser, l. title: survival of rhinoviruses on human fingers date: - - journal: clin microbiol infect doi: . /j.cmi. . . sha: doc_id: cord_uid: eby gm rhinovirus is the main cause of the common cold, which remains the most frequent infection worldwide among humans. knowledge and understanding of the rhinovirus transmission route is important to reduce morbidity as only preventive measures are effective. in this study, we investigated the potential of rhinovirus to survive on fingers. rhinovirus-b was deposited on fingers for , , and min. survival was defined as the ability of the virus to grow after days, confirmed by immunofluorescence. rhinovirus survival was not dependent on incubation time on fingers. droplet disruption had no influence on survival. survival was frequent with high rhinovirus concentrations, but rare with low-concentration droplets, which corresponded to the usual rhinovirus concentrations in mucus observed in children and adults, respectively. our study confirms that rhinovirus infectiousness is related to the viral concentration in droplets and suggests that children represent the main transmission source, which occurs only rarely via adults. it confirms also that rhinovirus hand-related transmission is possible and supports hand hygiene as a key prevention measure. rhinoviruses are non-enveloped, positive-stranded rna viruses belonging to the enterovirus genus within the picornaviridae family and the main causative agent of the common cold [ ] , the most frequent infection worldwide. although usually a selflimited viral disease, it remains a source of significant morbidity in the community. rhinovirus is associated also with asthma/wheezing and chronic obstructive pulmonary disease exacerbations, as well as several complications, such as acute otitis media, sinusitis, bronchitis and, in some cases, lower respiratory tract diseases. pre-school children seem to be the main reservoir [ ] , as approximately six rhinovirus infections are observed per year and per child [ ] . there are more than different rhinovirus types with almost no cross-protection, which explains the frequency of rhinovirus infections and the absence of an effective vaccine or antiviral treatment. only preventive measures are currently effective against these highly prevalent viruses and understanding their mode of transmission is important to reduce the number of infected patients. the nasal mucosa and posterior nasopharynx have been documented as the main sites of viral replication and therefore the main shedding site [ , ] . it is reported that person-to-person transmission is most likely due to the contamination of hands by the nasal secretions of the infected person passed to a susceptible individual, either directly to the fingers or via an environmental intermediary; infection then follows from self-inoculation to the upper nasal airways or eyes [ ] [ ] [ ] [ ] . the required infecting virus dose is below one median tissue culture infectious dose/ml (tcid ) [ , ] . three possible transmission routes have been described: via aerosols of respiratory droplets, direct contact by hands, or indirect contact with environmental objects (fomites). aerosols produced by coughing or sneezing originate mainly from saliva [ ] in which the viral load is approximately times lower than in nasal secretions [ , ] . as rhinovirus transmission depends on the concentration of virus in secretions [ ] , this supports expert opinion that aerosol or oral transmission is a rare event [ ] [ ] [ ] . direct contact appears to play a major role in transmission. rhinoviruses have been shown to transiently survive on human skin [ , , , ] , leading to the hypothesis that hand-related transmission is the main transmission mechanism [ , , ] . although less frequently than on skin [ , , ] , rhinovirus has been shown to survive on fomites. in an experimental study, % of volunteers who touched their nasal mucosa or conjunctiva after handling a contaminated fomite developed infection [ ] . however, many authors consider that indirect transmission is unlikely because of the important loss of infectivity during the process [ , , ] . our study was designed to test rhinovirus stability on fingers under experimental conditions, which aimed to reproduce natural conditions as far as possible. we conducted a series of experiments to assess the duration of human rhinovirus infectiousness duration on fingers, as well as the impact of viral concentration on survival rates. survival was defined as the ability of the virus to grow on helaoh cells after days, confirmed by immunofluorescence. experimental conditions aimed to reproduce natural conditions as far as possible. all experiments were performed using the rv-b strain and helaoh cells (kindly provided by f.h. hayden, university of virginia, charlottesville, va, usa) for viral culture. rv-b stock ( × e tcid /ml) was diluted with respiratory mucus to obtain three different concentrations: × e tcid /ml (high concentration (hc)); × e tcid /ml (average concentration (ac)); and × e tcid /ml (low concentration (lc)). each hc and ac droplet contained . × e and . × e viral rna copies ( . × e and . × e copies/ml), respectively. lc droplet viral copies were below the limit of detection by realtime rt-pcr assay, but they were expected to represent viral copies given their equivalence to dilutions of the ac. hc represents the average viral load of paediatric nasopharyngeal swabs in our laboratory, whereas lc corresponds to the average measured adult concentration. these values also correlate with epidemiological findings in the literature for paediatric and adult patients [ , , , ] . respiratory mucus was obtained by mixing clinical samples sent for routine testing that were rt-pcr and cell culture negative for the usual human respiratory viruses (influenza virus a/b, human metapneumovirus, coronavirus e/hku /oc /nl , respiratory syncytial virus a/b, picornavirus and parainfluenza virus / / ). a further min of ultraviolet radiation ensured inactivation of putative undetected viruses. to guarantee optimal growth, only mucus with a ph between . and was retained. participants and finger contamination procedure six specialized laboratory collaborators (technicians and md/ phd graduates) were recruited on a voluntary basis as previously described [ ] . the protocol was approved by the institutional review board of the university hospitals of geneva. determination of infectiousness a -μl drop of viral suspension of human rv-b mixed with respiratory secretions was deposited on the fingertips of each participant. this volume represents the mean size of a large respiratory droplet and can be easily reproduced [ ] . for each subject, nine drops containing rhinovirus at different concentrations (three hc, three ac, three lc) were deposited and one negative control (mucus only). each contaminated finger was kept untouched for a defined period of time at room temperature before testing for the presence of infectious rhinovirus. participants' fingers were then immersed in wells (becton dickinson and co., franklin lakes, nj, usa) containing ml of mccoy's a medium ( ×) with % serum (gibco, new york, ny, usa) for seconds. then, μl of this eluate was used to immediately inoculate helaoh cells. this represents an additional . -fold dilution of the viral load present in droplets before inoculation onto cell cultures ( . × e viral copies for hc, . × e viral copies for ac, and < copies for lc). after h of adsorption at °c, ml of mccoy's a medium ( ×) with % serum (gibco) was added and cells were incubated in % co at °c for days. for each -well plate, a negative control as well as a mock-infected control finger was included. the cytopathic effect was read daily until day . cells were collected after days and submitted to an immunofluorescence assay. a j mouse monoclonal antibody [ ] that recognizes doublestranded rna and an anti-mouse monoclonal igg fluorescein isothiocyanate-conjugated antibody were used to confirm the presence of viral infection (chemicon-millipore, zug, switzerland). based on preliminary pilot experiments, we determined that rhinovirus survival on fingertips was equivalent across different incubation times as it remained infectious on all fingers after , , and min. immediately after deposition, half of the droplets were disrupted and spread on the surface of the fingertip using a pipette tip to determine whether disrupting the integrity and environment of the droplet decreased virus survival. as all intact and disrupted droplets yielded positive culture results, we decided to continue experiments with disrupted droplets only so as to reproduce real-life conditions as much as possible. one hour after the deposit of disrupted droplets on the fingers of the six volunteers, infectious viruses could be detected by culture in all subjects contaminated with hc droplets ( / ), in four of the six volunteers with ac droplets, and none of the six volunteers with lc droplets, which confirmed the influence of concentration on survival (fig. ) . of note, when droplets were directly incubated without a passage on fingers, the virus survived in % ( / ) of tested fingers at hc compared with % ( / ) at lc, despite being below the limit of detection by pcr (data not shown). overall, the proportion of fingers with detectable viruses was / fingers at hc, compared with / and / for the ac and lc droplets, respectively (fig. ) . laboratory room (mean ± standard deviation . ± . °c) and hood ( . ± . °c ) temperature, as well as humidity ( . ± . %), were similar for all experiments with all subjects. we aimed to investigate rhinovirus transmission by person-toperson contact, the main transmission route for the most prevalent human respiratory infection worldwide. experiments were designed to reproduce, as much as possible, conditions that could lead to rhinovirus contamination of fingertips in the community. our study showed that rhinovirus can survive on hands for several hours, similar to previous reports of virus survival on human skin [ , , , , ] , emphasizing that handrelated transmission is the main transmission route. there was no influence of drying time on virus survival under h, in contrast to the study of ansari et al. where virus survival decreased during the first hour [ ] . our study showed that virus survival, and therefore infectiousness, was related to the viral concentration in droplets. this correlates well with d'alessio et al. who found that the secondary attack rate was related to the viral concentration in the nose [ ] . inoculum seems to be a restrictive factor for transmission, with infectiousness rapidly dropping below a given concentration. as infected children appear to have a higher viral load than adults, this may explain why children are considered to be the main transmission vector. the fact that the viral load in lc droplets was below the level of detection explains why the virus could not be recovered at these concentrations, except in one case without a passage on fingers. lc droplets correspond to the viral concentration recovered in rhinovirus-infected adults and this suggests that transmission via adults occurs rarely. a recent study investigating the transmission of cold-like illnesses between siblings showed that younger children tended to become infected first in most cases. however, the secondary attack rate was greater for older siblings, probably because of a higher viral load in younger siblings' secretions. as younger children tend also to touch nasal secretions directly with their fingers, it is probable that this enhances transmission. the viral load in the mucus of more than rhinovirus-infected children below year of age was . × e tcid /ml, which is to times higher than our hc of × e (regamey et al., private communication). it is very probable that the difference in virus survival between adults and children is even higher than in our results. we showed that virus survival increased at lc when there was no passage on hands. the loss of infectiousness during interhuman contact or fomite manipulation has already been described [ , ] , highlighting again the importance of viral load for transmission. similarly, rhinovirus was more frequently recovered on fingers from subjects with a high nasal viral load compared with a low nasal viral load [ ] . our study confirmed that droplet disruption had no influence on survival at a given concentration. we have previously shown that influenza virus survival on fingers was not related to virus concentration in a study using a similar methodology to the present experiments [ ] . survival of influenza virus on fingers declined rapidly, with less than % of the fingers remaining positive after min [ ] . the influenza envelope, which is known to be a determinant factor decreasing virus survival, may explain why survival was shorter and affected by droplet disruption, which was not the case for rhinovirus [ ] . in a similar study, rv- in -μl droplets at . × e to . × e tcid /ml survived for h on almost % of fingers [ ] . the fact that virus survival was lower compared with our results, despite the use of bigger droplets and higher viral concentrations, may be explained by the fact that our volunteers did not wash their hands or use an alcohol-based hand rub before experiments as hand rubbing has been shown to decrease virus survival even several hours after use [ ] . the fact that disinfecting hands or objects with an iodine or alcoholbased solution reduces the secondary illness rate of rhinovirus infections emphasizes also the importance of hand-related transmission [ , , ] . in conclusion, these laboratory results confirm that handrelated transmission of rhinovirus is possible and support hand hygiene as a key measure to prevent transmission, particularly in children who represent the main transmission source. the authors declare that they have no conflicts of interest. viruses and bacteria in the etiology of the common cold temporal relationships for cold-like illnesses and otitis media in sibling pairs picornavirus infections in children diagnosed by rt-pcr during longitudinal surveillance with weekly sampling: association with symptomatic illness and effect of season transmission of experimental rhinovirus colds in volunteer married couples sites of rhinovirus recovery after point inoculation of the upper airway hand-to-hand transmission of rhinovirus colds effect of route of inoculation on experimental respiratory viral disease in volunteers and evidence for airborne transmission mechanisms of transmission of rhinovirus infections inoculation of human volunteers with a strain of virus isolated from a common cold relation between naturally acquired immunity and infectivity of two rhinoviruses in volunteers experiments on the spread of colds. . laboratory studies on the dispersal of nasal secretion production of tracheobronchitis in volunteers with rhinovirus in a small-particle aerosol transmission of rhinovirus colds by self-inoculation rhinovirus infections in an industrial population. iv. infections within families of employees during two fall peaks of respiratory illness transmission of experimental rhinovirus infection by contaminated surfaces rhinovirus transmission: one if by air, two if by hand an investigation of the possible transmission of rhinovirus colds through indirect contact survival of human rhinovirus type dried onto nonporous inanimate surfaces: effect of relative humidity and suspending medium near disappearance of rhinovirus along a fomite transmission chain role of infectious secretions in the transmission of rhinovirus quantitative rhinovirus shedding patterns in volunteers survival of influenza virus on human fingers an rna replication-center assay for high content image-based quantifications of human rhinovirus and coxsackievirus infections potential role of hands in the spread of respiratory viral infections: studies with human parainfluenza virus and rhinovirus interruption of experimental rhinovirus transmission efficacy of organic acids in hand cleansers for prevention of rhinovirus infections we thank all volunteers who participated in the experiments as well as rosemary sudan for editorial assistance. this study was supported by grants from the swiss national science foundation (me , _ and me , b_ / ) and by the laboratory of virology of the university hospitals of geneva. key: cord- -qxya cs authors: bryant, everett title: biology and diseases of birds date: - - journal: laboratory animal medicine doi: . /b - - - - . - sha: doc_id: cord_uid: qxya cs nan the domestic fowl has been the most useful in experimental axonomy trials. the fast maturing and highly inbred chicken can be used with great statistical confidence. diseases can be prevented most avian species used for research purposes fall within ? a n d i s o l a t i o n r e a r j n g j s n e j t h e r d i f f i c u , t n q r ^, three orders: galliformes, which includes domestic fowl, quail, pheasants, turkeys, partridges, grouse, guinea fowl and brush turkeys; anseriformes, which includes ducks, geese, swans, and screamers; and the columbiformes, which includes c · availability of chickens for research pigeons, doves, and sand grouse. the bird fits into the overall taxonomic scheme as follows: specific pathogen-free (spf) fertile eggs, day-old chicks, or kingdom, animal; phylum, chordata; class, aves; order, started pullets are available for use in research. specific pathoorders with approximately species. a clear outline of the gen-free chickens or eggs come from breeding stock negative avian orders listing the common names of birds in each may be to diseases caused by mycoplasmas, newcastle disease, infecfound in steiner and davis ( ) . tious bronchitis, avian encephalomyelitis, infectious bursal disease, quail bronchitis, salmonellosis, pasteurellosis, and in fectious coryza. somes ( ) lists the sources of specialized lines, strains, mutations, breeds, and varieties of chickens, turkeys, and ja panese quail. chromosome linkage maps for the three species and modes of inheritance are also given for most genetic traits. bickford, ; woodard et al., ; schwartz, ) quality animal welfare and optimal comfort for birds is nec essary to insure reliable research data. the ability periodically to observe birds on experimental test through a glass window is ideal; however, if an observation point is not available, the animal technician should check the birds at least twice a day for paleness, dehydration, and other signs indicative of diseases. death before weeks of age may be due to chilling, over heating, crowding, and omphalitis. mortality at - weeks in research chickens may be due to coccidiosis or one of the enteritides. brooding temperature for -day-old chicks should be be tween °- °f and gradually reduced to °- °f by the third week. chicks will constantly peep if too hot or too cold. lowered humidity will cause poor feathering, and if the en vironment is too moist, disease problems will be more pro nounced. a relative humidity of - % is ideal. therefore, frequent monitoring to control temperature and humidity should be practiced. fresh air, without drafts, helps to mini mize moisture accumulation. stale air retards growth of birds and enhances respiratory diseases. the density of broilers and layer replacements may vary with the experimental procedure, but table i will serve as a guideline. there are many kinds of feeders, waterers, and brooders available. the simplest and least expensive may be the best for experimental work. while adjusting to the feeders newly hatched chicks and poults should be fed on papers from day to day . trough feeders work well for birds raised on the floor. it is important to have an adjustable feeder. the level of the feed in the trough should be equal to the level of the back of a standing chicken. this allows the bird access to the feed and prevents waste of feed. tube feeders that hang from the ceiling have the advantage of holding more feed without waste. they are adjustable, and the feed should be at the same level, as described for trough feeding. too many feeders of either type impede available floor space for the chickens. two -ft trough feeders or two tube feeders are adequate for birds at any age. waterers should provide clean, fresh water ad libidum. birds should never be without water. there are many types, but a simple gallon jug with a plastic bottom containing a groove circling the jug is ideal for birds from to days of age. an automatic trough waterer, one -ft long per hundred birds, is adequate. automatic waterers can stop working, run over, and make it difficult to measure water consumption. therefore, large can-type waterers or open pan-type waterers may be bet ter for some types of trials. they are more easily cleaned and control water intake better. incidence of candidiasis in a flock of birds is directly related to the level of water sanitation, and proper attention to water quality greatly reduces this disease in research birds. commercially available cage equipment will also have feeders and waterers and sometimes a heat source. daily clean ing of fecal material from cages enhances the level of sanita tion. external and internal parasitism is increased in birds reared in dirty cages. for heat and ventilation, brooder stoves fueled by gas, oil, coal, and electricity are available. for small groups of birds, heat lamps are adequate. supplementary room heat is neces sary for small groups in colder climates. air conditioning may be necessary during extremely hot weather. an exhaust fan is necessary to ensure removal of stale air. for young chicks, è ft /min will exchange air quite well and for older birds, ft / min is adequate. modern animal facilities meeting the criteria for the nih ' 'guide for the care and use of laboratory ani mals" will provide acceptable heat, ventilation, and air condi tioning needs (see chapter ). nests are needed for laying birds. adequate nests should be provided to ensure one nest for every four birds. nests should be constructed of metal for ease of cleaning and should be well ventilated. lack of sharp corners minimizes trauma, and dry materials, such as shavings, sawdust, or peanut hulls, make excellent nest material. a completely sanitized and disinfected room with sterilized equipment is necessary for research purposes. birds are coprophagic, and many diseases of the digestive tract are trans mitted in this manner. physical cleaning of room surfaces with high pressure of hot water will remove fecal material, mucus, and other debris from walls and floors. cages should be sani tized in appropriate cage washers. while the pen is still warm and wet, fumigation with formaldehyde gas is quite effective. the temperature should be °f and the humidity % or high er to be most efficient. formaldehyde vapors have a potential health risk to humans, and the reader should refer to the discus sion of disinfectants by hofstad et al. ( ) before using this product. once the area and equipment are cleaned, iodines, quatern ary ammonium compounds, chlorines, or other agents can be used to disinfect the premises. no one should be admitted to isolation areas without a show er, clean clothing, and clean boots. doors should be locked at all times, and animal technicians should not be assigned to care for any other birds. birds have pneumatic bones, with air spaces and channels, which add buoyancy in flight. this system of pneumatic bones provides direct channels from the air sacs through the bones so that air carrying infecting organisms may travel throughout the bird rather rapidly. certain respiratory infections and parasites use these channels for distribution of the microorganisms. small birds lack teeth; the organ of mastication is the gizzard which contains grit or gravel, thereby enabling grinding of hard grains. if the feed is an all-mash or all-pellet diet, no grit is needed in the diet. most birds possess a crop, a dilatation in the midesophageal region. pigeons and pet birds regurgitate and feed their young on crop milk. this process allows transmission of parasites to the young from healthy adult carriers. only the left ovary and oviduct are functional in the hen. frequently a cyst, the remnant of the right oviduct, is found; however, this causes no pathological disturbance. b. applied physiology (see sturkie, ) birds can stand extreme variations of environmental tem perature for short periods of time. as the relative humidity increases, the temperature tolerance of the chicken decreases. normal heart rate for the chicken is about beats/min and will increase substantially during excitement and periods of stress. the normal respiration for the chicken is approximately /min, and will also increase rapidly as the temperature goes up. artificial light is important. fourteen to hr of light per day is needed for optimum egg production. the optimum tem perature for egg production is between °- °f. any varia tion thereof may cause a decrease in egg production. growth rate has improved so rapidly that textbooks cannot keep up-to-date. feed conversions of less than . are being reported on a lb average weight broiler at days of age. these are under excellent field management with optimum nu trition, genetics, and freedom from disease. egg production flocks have also improved their efficiency. the average flock today will peak above % by the time they reach weeks of age. for a complete treatment of avian hematology, the reader is referred to sturkie ( ) . blood volume in the bird is about % of total body weight. this will vary according to age, sex, and species. an atlas on avian hematology is also available (lucas and jamroz, ) . data shown in table ii were taken from olson ( ) . chickens, turkeys, and other birds require the six major nu trients: carbohydrates for energy, fats for energy and essential fatty acids, protein for meat and egg production, minerals for bones and shells, vitamins for chemical catalysts, and water. birds should have a complete and balanced ration with very little supplementation. unnecessary supplementation may create other deficiencies. age and functional status of the flock will determine the for mula needed. table iii lists approximate types of formulas needed for various ages and classes of birds. high quality protein is necessary for growth and mainte nance of birds. all the essential amino acids must be present in the diet as the bird cannot convert them from raw protein. min erals and vitamins must be provided in balance. calcium and phosphorus should be in a ratio of : for young growing chickens. antioxidants should always be used to prevent oxidation of fats and fat-soluble vitamins. feed additives, especially arsenicals and certain drugs, should be fed according to the manufac turer's directions. consumption of eggs from these birds dur ing this time should be avoided. for a more detailed account of nutrition in birds, the reader is referred to the specific texts by scott et al. ( ) , by the national research council of the national academy of sciences ( ) , and to the chapter in hofstad ei a/. ( ) . specific nutritional deficiencies will be discussed in section viii. poultry and other birds are easily startled. flashing lights, loud noises, and shadows will cause birds to pile up on each other causing the pen mates underneath to suffocate. hysteria, caused by sudden fright, will result in birds flying against the wall for no apparent reason. many experts argue that a sudden change in air pressure will cause hysteria. when the author has encountered this disease, the birds have usually been raised in a filtered-air, positive-pressure facility. b. clinical signs and lesions. escherichia coli may be a primary infectious agent; clinical onset is rapid and daily mor tality can approach . - . %. the usual lesions noted are air sacculitis, fibrinous pericarditis, and fibrinous perihepatitis. rarely is the trachea involved. colîgranuloma (hjarre's dis ease) may be caused by a pathogenic e. coli serotype. avian tuberculosis may be confused with colibacillosis. granulomas of the intestine are differentiated from tuberculosis by the use of the acid-fast stain. escherichia coli, of course, is not acid fast. other lesions caused by e. coli include arthritis leading to lameness and death, navel infection leading to high mortality, and foot pad infections. c. epizootiology. hens with e. coli infection, especially of the oviduct, contaminate the egg shell. bacteria may then penetrate the egg shell and the chick is hatched with a yolk sac infected with e. coli. d. diagnosis. escherichia coli should always be consid ered a potential pathogen in birds. if an air sacculitis syndrome develops, with no isolation of pasteur ella sp., mycoplasma sp., or hemophilus sp., it is essential to consider e. coli as the potential pathogen. isolations of e. coli from yolk sacs, joints, or bone marrow should always be considered a primary cause of disease. e. prevention. good management of the chicks must in clude proper ventilation and the proper care of hatching eggs. this is the most important means of preventing navel ill. dirty, contaminated eggs should never be used for hatching. /. treatment. as with all bacterial infections in poultry, antimicrobial susceptibility testing should be used to determine the treatment of choice for any generalized e. coli infection. g. research implications. escherichia coli infection will damage experimental flocks, causing uneven growth. a. etiology. the cause of coryza is hemophilus paragallinarum. it is a gram-negative, bipolar staining rod and can easily be demonstrated in sinus exudate. b. clinical signs. signs include a sudden onset with high morbidity, reduction in feed intake and growth, and depressed egg production. uncomplicated coryza is a disease of the up per respiratory tract causing ocular and nasal discharge, facial edema, and swollen infraorbital sinuses. c. epizootiology and transmission. transmission is ac complished mainly by ill or recovered carrier birds. inhalation of infectious material and ingestion of contaminated feed and water provide the best means of transmission. d. necropsy findings. at necropsy, there is conjuncti vitis, cheesey exudate in the conjunctival sac, nasal discharge, and a catarrhal inflammation of the nasal passages and sinuses. the infraorbital sinuses may be filled with exudate. e. diagnosis. history, signs, and lesions will suggest coryza. a gram-stained smear of sinus exudate showing gramnegative bipolar rods warrant a strong presumptive diagnosis of coryza. incubation in a c atmosphere of a culture of the exudate on blood agar with a staphylococcus nurse colony will confirm the presence of//, paragallinarum. f. prevention. depopulation of all birds before introducing chicks is essential, and a complete sanitizing and disinfecting of the brooder facilities is also necessary. a bacterin is avail able and can be used in birds weeks of age or older with a booster every weeks. several injections are necessary to con fer protective immunity. g. treatment. continuous medication appears to suppress clinical infection, but when removed relapses occur. medica tions used with success include streptomycin, erythromycin, spectinomycin, tylosin tartrate, and sulfadimethoxine. h. research complications. a diagnosis of h. paragallinarum infection in a research unit would warrant termina tion of the experiment. salvage of an experiment with this dis ease would provide questionable research data at best. the chronicity of the disease and the recovered carrier bird would further jeopardize a research colony. a. etiology. the important etiological agents appear to be clostridium septicum and staphylococcus aureus (frazier et al., ) . the host is likely to be immunosuppressed, and probably undergoing a simultaneous outbreak of infectious bursal disease. (see section iv,b.) b. clinical signs. signs in -to -week old chickens and turkeys include a sudden increase in morbidity and mortality. wet, gangrenous areas can be seen in the skin of the wings and legs. c. epizootiology and transmission. skin wounds of chickens are a common occurrence, and secondary infections are expected. however, gangrenous dermatitis appears to be a specific disease complicated by the presence of heavily con taminated environment containing clostridium spp. and staphylococcus spp. the syndrome was rare until immunosuppression caused by bursal damage from infectious bursal disease virus, mycotoxins, and possibly other factors became more common. d. necropsy findings. usual findings include necrosis of the skin and underlying areas of the thigh, breast, wing tips, hip, and back. hemorrhagic, necrotizing myositis has also been described. e. pathogenesis. it would appear that the toxin of the staphylococcus species causes necrosis and anerobiosis; the clostridium then multiplies and contributes to the gangrene. /. differential diagnosis. signs and bacterial cultures from the lesions will give a presumptive diagnosis. selenium deficiency that causes an exudative diathesis may mimic gang renous dermatitits. eliminating all causes of skin trauma and improving the sanitation plus instituting an immunization pro-gram for infectious bursal disease will help prevent the disease. h. treatment. a susceptibility test for the staphylococcus isolated will suggest the antibiotic of choice. most broad-spec trum drugs will aid the recovery of affected birds. i. research complications. widespread gangrenous der matitis in birds may compromise the study. because this dis ease is often a complication of infectious bursal disease im mune competence may have been altered; therefore research data collected on affected bird may be unreliable. a. etiology. the cause of necrotic enteritis is thought to be clostridium perfringens. other inciting factors may be neces sary, but have eluded investigators studying this disease. the disease is seen mostly when high energy, broiler-type rations are used. b. clinical signs. necrotic enteritis is usually seen in broilers; many times only the males, at about - weeks of age, are affected. birds show profound depression, and mor tality may start at % per day and last about week (helmboldt and bryant, ). c. epizootiology and transmission. it appears that trans mission is direct and via the feces. d. necropsy findings. a fibrinonecrotic enteritis is noted, and the entire small intestine becomes dilated with fluid debris and becomes very friable. e. pathogenesis. there is evidence that a toxin damages the villus tips, and eventually the integrity of the rest of the intestinal wall is lost. /. differential diagnosis. this disease can be differenti ated from ulcerative enteritis (quail disease) by isolation and identification of the clostridium perfringens. eimeria brunetti may be present as a secondary problem. g. prevention. sanitation, disinfection, and isolation will provide the best protection against necrotic enteritis. low level feeding of antibiotics at gm per ton ( mg/lb) of feed from to weeks of age will totally prevent the disease. h. treatment. the organism is very easily treated with high levels of tetracyclines, furazolidone, streptomycin, or bacitracin. i. research complications. diagnosis of disease in a pen warrants instituting a low level antibiotic therapy for succeed ing flocks. a. etiology. clostridium colinum, a gram-positive, sporeforming bacillus, is the cause of ulcerative enteritis. this bac terium is best recovered from fresh liver cultured on tryptose agar or the yolk sac of - day embryos. b. clinical signs. affected quail exhibit high morbidity with mortality sometimes approaching %. chickens and turkey poults, on the other hand, may experience low mor talities of only - %. listlessness, drooping wings, ruffled feathers, and diarrhea are typical signs of this disease. c. epizootiology and transmission. the disease is highly contagious among quail. it spreads mainly through feces from ill or recovered carrier birds. f. differential diagnosis. coccidiosis caused by eimeria brunetti may produce a necrotizing enteritis of the large intes tine, which resembles ulcerative enteritis. scrapings of the in testinal mucosa will usually reveal oocysts of e. brunetti. nec rotic enteritis caused by clostridium perfringens can also mimic quail disease. histologically, necrotic enteritis produces no ulcers, and the intestinal lesion is villus tip loss and cystic dilatation of the deeper glands. g. prevention. birds should be reared in a clean, disin fected and isolated environment. low level of antibiotics, - gm per ton of feed, will prevent the disease. strep tomycin, bacitracin, terramycin, aureomycin, and furazoli done are therapeutically effective. h. treatment. all of the above antibiotics at gm per ton of feed ( mg/lb) will curtail and in some cases termi nate the mortality. /. research complications. substantial morbidity and mortality would terminate most experiments. preventive levels of antibiotics are indicated from to weeks in birds housed in a building where the disease was previously encountered. a. etiology. the ingestion of the toxin produced by clostridium botulinum is the cause of botulism. the lethal tox in, which must be produced under anaerobic conditions, is found in decaying feed, dead birds, and maggots. clostridium botulinum organisms per se are not considered pathogenic. b. clinical signs. drowsiness, weakness, and a progres sive paralysis of the legs, wings, and neck are all suggestive of botulism. c. epizootiology and transmission. the ingestion of pre formed toxin is necessary to produce the disease. poultry or wild birds should not be allowed to ingest wet, moldy feed. accidental water spillage in a research unit could result in con ditions necessary for the development of the toxin. d. necropsy findings. the absence of lesions may be the best indication that the birds are dying from botulism. the of fending decayed matter containing the toxin may be found in the crop, proventriculus, or intestine. e. differential diagnosis. history, signs, and the presence of decaying feed may help identify the disease. gizzard or in testinal contents may be washed and some of the fluid inocu lated into mice, half of which have been previously protected with c. botulinum antiserum, for a definitive diagnosis. tran sient paralysis, a mild form of marek's disease, can produce signs similar to botulism. in pheasants, paralysis caused by eastern encephalomyelitis virus could be confused with botulism. /. prevention. if birds are raised under clean conditions, botulism is rare. g. treatment. type a and c antitoxin may be indicated when valuable animals are affected. laxatives may also be used with some success. it is important to provide fresh, clean water in a botulism outbreak. h. research complications. it would be a rare to encoun ter this disease under research condition. a. etiology. the cause of erysipelas is erysipelothrix rhusiopathiae, a gram-positive, pleomorphic rod. it primarily affects turkeys, though chickens can be infected. b. clinical signs. usually the disease starts with sudden onset followed by depression, diarrhea, lameness, and a rapidly increasing morbidity and mortality. the snood of the male turkey often becomes swollen. c. epizootiology and transmission. fecal shedding of e. rhusiopathiae occurs in recovered turkeys and continues for about weeks. the oral-fecal route is a significant source of transmission. cutaneous injuries of the snood and head also may allow entry of the bacterium, and fighting among males is a common method of transmitting this disease. d. necropsy findings. the lesions are those of a septicemia and vasculitis. there is a degeneration and hemorrhage in pericardial fat. the heart muscle, kidney, spleen, and liver may also show hemorrhage. fibrinopurulent exudate in the joints, vegetative endocarditis, and dark, crusty skin lesions are also common. e. differential diagnosis. history, signs, lesions, and cul ture of e. rhusiopathiae will aid in a diagnosis of erysipelas. it should be differentiated from colibacillosis, fowl cholera, salmonellosis, and possibly a velogenic strain of newcastle disease. /. prevention. turkey poults should be raised away from older turkeys, sheep, and swine. poults should be vaccinated with a bacterin at - weeks of age. raw fish meal may harbor e. rhusiopathiae organisms and should be avoided. g. treatment. penicillin and erysipelas bacterin may be in jected simultaneously in an outbreak. tetracyclines in the feed or water will also help reduce losses. h. research complications. erysipelas is a septicémie dis ease; therefore, it will significantly retard growth and weight gain in animals recovering from the disease. a. etiology. predisposing causes of omphalitis may in clude excessive humidity and excessive fecal contamination of the incubator. fecal contamination of eggs used for hatching purposes will also contribute to omphalitis. as the navel fails to close at hatching, a route of entry for bacteria, such as e. coli, pseudomonas, and proteus, as well as staphylococci is available. chilling or overheating baby chicks may also pre cipitate or exacerbate this condition. b. clinical signs. depression, drooping of the head, and huddling near a heat source are usual signs. a scab over the unhealed navel is often present, and mortality usually is high-est on the third and fourth days posthatching, sometimes reach ing - % during the first week. c. epizootiology and transmission. the disease is trans mitted through infection of the yolk sac prior to hatching. it is not contagious from chick to chick. d. necropsy findings. infected navels, large unabsorbed yolks, and extensive peritonitis are the common lesions com monly noted. e. differential diagnosis. isolation and identification of the bacteria from infected yolk will pinpoint omphalitis and its cause. /. prevention. proper hatching egg management, empha sizing care and sanitation of the incubators will reduce the inci dence of omphalitis. there is no treatment for omphalitis except removing affected chicks. effective drug levels cannot eradi cate the infection in the yolk sac. h. research complications. affected chicks usually die during the outbreak. those that do survive, appear to grow well. a. etiology. fowl cholera, an acute septicémie disease of poultry, turkeys, waterfowl, and wild birds, is caused by pasteurella multocida, a gram-negative, bipolar rod (panigraphy and glass, ) . thirteen serotypes of this bacterium have been identified. b. clinical signs. fowl cholera usually affects young adults. birds affected with the acute form of fowl cholera may show no signs other than sudden deaths. hens may die while laying an egg and will be found dead on the nest. in less acute cases, birds will show depression, anorexia, and cyanosis. a white-green diarrhea is usually present. in the chronic form, localized infections of the joints, wattles, foot pads, sinuses, and middle ear is clinically manifested by lameness and torticollis. c. epizootiology and transmission. ingestion of decaying carcasses, contaminated feed and water, and feces from re covered carriers are sources off*, multocida. wild birds, and rodents are also potential transmitters. transovarian transmis sion does not play a role in transmission. d. necropsy findings. peracute deaths may preclude the presence of gross lesions. pinpoint hemorrhages are common in the coronary fat suggesting an acute septicemia. in birds that die less acutely, pericarditis and perihepatitis are usually found. cheesy exudate may also be seen around the oviduct. chronic lesions consist of inflammation of the wattles, joints, conjunctival sac, infraorbital sinus, middle ear, and sometimes the bones of the skull. fibrinous pneumonia is common in turkeys. e. pathogenesis. fowl cholera is a septicemia with the agent spreading via the bloodstream to many organs. /. differential diagnosis. isolation and identification of the organism is necessary to differentiate this disease from erysipelas in turkeys and colibacillosis in hens. birds reared in clean, isolated premises usually are free of pastuerella infections. addition of birds with unknown health status to a clean flock should be avoided. healthy-appearing birds can carry p. multocida and are a com mon source of introduction of the organism to a premise. bacterins are protective in hens. the key to successful production of immunity is to use the correct serotype for immunization. two doses, about month apart, are necessary for adequate protection. live oral cultures of the pasteurella are available for use in endemic areas; however, use of this product may cause disease in unvaccinated birds. h. treatment. drugs will arrest mortality, but will not cure the disease. sulfaquinoxaline will work well but will depress egg production. therapeutic results are obtained with tetracycline at gm per ton ( mg/lb) of feed for about weeks. however, it is important to note that not all pasteurella isolates are susceptible to the tetracyclines. improved sanita tion, immediate removal of sick and dead birds, and preven tion of cannibalism are necessary to control the disease. /. research complications. research birds affected with pasteurella sp. do not yield reliable research data; termination of the experiment, therefore, is recommended. a. etiology. the cause of fowl typhoid is salmonella gallinarum; it also cross-agglutinates with salmonella pullorum. salmonella gallinarum is a gram-negative rod with no spores or capsule. b. clinical signs. affected chickens have ruffled feathers, pale heads, and shrunken combs. in turkeys, listlessness and a greenish diarrhea are often recognized clinically. c. epizootiology and transmission. egg transmission via the yolk or shell surface often perpetuates the disease from dam to offspring. d. necropsy findings. a bile-stained liver, bronzed in ap pearance and greatly swollen, is the most distinguishing lesion of fowl typhoid. all other lesions are similar to pullorum disease. e. differential diagnosis. this disease is now rare in the united states and must be differentiated from pullorum disease and paratyphoid infections. isolation and identification of salmonella is necessary for a diagnosis. /. prevention. the purchase of pullorum-typhoid-clean chicks from the national poultry improvement program hatch eries is necessary for research. no treatment is effective. it is a reportable disease to the state veterinarian, and depopulation will be recommended. h. research complications. salmonella-infected birds should not be used for research purposes. a. etiology. the cause of pullorum disease is salmonella pullorum. it is a gram-negative bacillus and cross-reacts with s. gallinarum. b. clinical signs. infected adults may show no signs but transmit the agent through their eggs. young chicks and poults will show white pasting around the vents, and huddling near the heat source. mortality may reach - %. c. epizootiology and transmission. egg transmission through the yolk and hatchery transmission via the infected eggs and chicks in the incubators and hatchers are the usual methods of transmitting s. pullorum. d. necropsy findings. myocarditis, pericarditis, and atro phied ovaries are classical lesions of pullorum disease in adults. in young birds, gray nodules may appear on the spleen, peritoneum, lung, liver, heart, and intestine. as with any salmonella infection, cecal cores are commonly seen. an en larged spleen is present, but this is a nonspecific lesion since it is usually seen with many bacterial infections. e. differential diagnosis. a positive serum agglutination plus isolation, identification, and typing of the agent from the yolk sac, gallbladder, spleen, or cecal tonsil will confirm the diagnosis of s. pullorum. /. prevention. the purchase of pullorum-typhoid-clean chicks and poults is essential for research. no treatment is available. the disease is reportable to the state veterinarian, who when notified will prob ably insist on depopulation. h. research complications. salmonella-infected birds should not be used for research purposes. a. etiology. any species of a large group of salmonella sp. may infect birds and mammals and are not host specific. the most common one isolated from birds is salmonella typhimurium. other common serotypes include s. enteritis, s. oranienberg, s. montivideo, s. newport, s. anatum, s. derby, and s. bredeny. many others exist and may cause mortality. b. clinical signs. dehydration, pasting of the vents, and huddling near the heat source are signs of a salmonella out break. high morbidity and mortality are usually the first signs. c. epizootiology and transmission. diarrhea in the breeders will cause contamination of the qgg shells, and salmonella is often transmitted in this way. contaminated feed ingredients such as meat scraps may also transmit infection. transovarian transmission is possible, and human carriers may also be a factor in transmission (see chapter by fox et al.). d. necropsy findings. dehydration, enteritis, and focal necrosis of the intestinal mucosa are common lesions. pigeons usually have joint infections and conjunctivitis. cheesy cores in the ceca, common in all salmonella infections, will usually be found. e. differential diagnosis. the isolation and identification of the offending bacterium is essential for diagnosis. all salmonella infections may have similar signs and lesions. in addi tion, coccidiosis and blackhead will produce cheesy cores in the cecae. /. prevention. use clean birds free of salmonella. isolate the new brood and feed only pelleted feed or crumbles to pre vent introduction of salmonella via the feed. g. treatment. attempts to treat the infection usually have been discouraging. most cases do not respond to therapy and carrier birds are produced. furazolidone in pigeons is partially effective. sulfa drugs will suppress mortality but will not cure the disease. h. research complications. salmonella-infected birds should not be used for research purposes. a. etiology. avian tuberculosis is caused by mycobacterium avium, an acid-fast, very resistant bacterium. it is sepa rate and distinct from human and cattle types, but will infect swine and sensitize cattle to the bovine tuberculin test. b. clinical signs. emaciation in the presence of good feed intake may suggest tuberculosis. diarrhea and lameness is common. birds appear very pale, especially the comb and wattles. c. epizootiology and transmission. transmission is by in gestion of m. avium. association of young chicks with their dams during the growing period in backyard flocks ensures transmission of the bacteria to susceptible birds. d. necropsy findings. extreme emaciation, nodules along the intestinal tract, and discrete granulomas in liver and spleen are typical of tuberculosis. granulomas may also be found in the bone marrow and more rarely in the lung. e. differential diagnosis. coligranuloma can mimic avian tuberculosis. the presence of acid-fast bacilli in liver or spleen impression smears will confirm the presence of m. avium. f. prevention. an all-in, all-out system of poultry rearing will prevent avian tuberculosis. g. treatment. because of drug resistance and the possible public health significance of this disease, treatment is dis couraged. depopulation is recommended by the state's veteri nary authorities. no tuberculosis-affected birds should be used for research purposes. turkeys] (see jordan, ) a. etiology. the primary cause of crd is mycoplasma gallisepticum, but the following agents will enhance effects of m. gallisepticum and cause a complicated respiratory syn drome with high mortality: infectious bronchitis virus, infec tious laryngotracheitis virus, newcastle disease virus, escherichia coli, pasteur ella multocida, hemophilus gallinarum, and others. b. clinical signs. hens reaching the age of full egg pro duction ( weeks) will not reach peak egg production referred to as genetic potential for that specific strain. coughing and sneezing may be noticed, particularly at night. the disease is more pronounced in broilers. chronic respiratory disease plus secondary bacterial infection, will produce high mortality, high morbidity and high condemnations due to air sacculitis, pericarditis, and perihepatitis. turkeys may have sinusitis, with exudate in the infraorbital sinuses. c. epizootiology and transmission. transovarian trans mission is the most important method of transmitting m. gallisepticum. lateral spread through aerosols from infected off spring occurs in the hatchers or brooders. wild birds and fomites can also be a source of agent transmission. d. necropsy findings. thickened air sacs, mucus in the trachea, sinusitis, and air sacculitis are the common lesions in uncomplicated chronic respiratory disease. in chronic respira tory disease with secondary bacterial infection, the classic le sions include air sacculitis with fibrinous hepatitis and perciarditis. e. differential diagnosis. many of the respiratory dis eases of poultry appear similar and are differentiated with diffi culty. a positive m. gallisepticum agglutination test in at least ten birds from a previously known m. gallisepticum negative flock would strongly suggest a diagnosis of chronic respiratory disease. histology of the trachea, lungs, and air sacs will show hyperplastic lymphoid follicles if m. gallisepticum is present; however, this lesion is not pathognomonic. isolation of the mycoplasma is the best means of establishing a diagnosis of chronic respiratory disease. /. prevention. mycoplasma gallisepticum-ïrzt chicks are easy to obtain; therefore use of positive chicks in experimental work is not warranted. controlled exposure using the live cul ture of the "chick f " strain is not recommended except in multi-age, egg-producing flocks. it is not recommended in breeders or experimental trials. g. treatment. improved management and broad-spectrum antibiotics may help control the losses due to secondary bac teria. tylosin is the most effective drug against m. gallisepticum. h. research complications. positive mycoplasma birds should not be used in research trials. a. etiology. the cause is mycoplasma meleagridis, an egg-transmitted mycoplasmal agent of turkeys. the usual man ifestation is air sacculitis in young poults, but since organisms are shed in semen as well as yolk it can also be considered a venerai disease of this species. b. clinical signs. the signs are usually found only in young growing turkeys. mild respiratory signs, poor growth, crooked necks, and leg weaknesses are considered signs of this infection. c. epizootiology and transmission. transovarian trans mission is of primary importance. semen contains the mycoplasma organism, so toms as well as hens serve to transmit m. meleagridis. lateral spread is similar to other mycoplasmas in that stresses and/or other infections seem to enhance the severity of this disease. h. research complications. turkeys infected with m. meleagridis should not be used for research since birds free of the disease can be purchased. a. etiology. the cause of infectious synovitis is mycoplasma synoviae. it can be isolated in broth media or in -to -day-old embryonating chicken eggs. isolates of m. synoviae vary in their pathogenicity and also in their susceptibility to drugs. b. clinical signs. lameness and crouching are the most common signs. usually morbidity and mortality are low, but retarded growth is a common finding. c. epizootiology and transmission. the transovarian route is the most important means of transmitting the agent from dam to progeny. it is thought that a small number of infected eggs are laid and positive offspring spread infection to pen mates during the growing period. d. necropsy findings. lesions include yellow exudate in the leg and wing joints but may also be found in the tempormandibular joint, shoulder, and keel bursa. foot pads are usu ally swollen and hot. the liver will be greenish due to bile retention. air sacculitis may also be present. b. clinical signs. in mild cases, slight respiratory signs and diarrhea will be seen. in severe turkey cases, depression, weakness, anorexia, and reduced weight are noted. mortality may reach %. in pigeons, conjunctivitis is a feature of the disease, while in the psittacine caged birds, depression, anorexia, diarrhea, rales, and death may be seen. c. epizootiology and transmission. transmission appears to be by direct contact with infected carriers. inhalation and ingestion of feces are the two most important means of trans mission of chlamydia psittaci. d. necropsy findings. an enlarged congested spleen is al most always found in chlamydiosis in all avian species. le sions of air sacculitis, pericarditis, and perihepatitis are com monly noted. unfortunately, these are the same lesions noted in turkeys suffering from mycoplasmosis. e. differential diagnosis. history, clinical signs, and gross lesions aid in the diagnosis. the findings of intracytoplasmic inclusion (lcl bodies) in impression smears of the air sacs or cut surface of the spleen stained by the macchiavello or giemsa method will suggest a diagnosis of chlamydiosis. isolation and identification of the agent should not be attempted by an inexperienced person or without proper hoods and facilities to protect laboratory personnel. this agent, in laboratory culture, is easily transmitted to research technicians. /. prevention. avoid any cross-exposure of research birds to caged pet birds or wild birds. an all-in, all-out system will successfully prevent chlamydiosis. all new arrivals of psit tacine birds should be treated for days at gm per gallon of drinking water with tetracycline or with pellets containing an equivalent level of antibiotic. g. treatment. chlamydiosis is a reportable disease and all infected flocks and their treatments should be reported to the proper authorities. chlamydia psittaci should be used for research purposes. a. etiology. infectious bronchitis affects only chickens and is caused by a coronavirus. it does not hemagglutinate erythrocytes. many serotypes exist, but the two most common are massachusetts and connecticut. b. clinical signs. in young chicks, a sudden onset of coughing, sneezing, and rales occurs. the birds are weak and crowd toward the source of heat. feed intake may drop by % in broiler-type birds. in adults, severe respiratory signs accom panied by a severe drop in egg production are evident. egg quality, as evidenced by watery albumen and soft shells with sandpaperlike ends, renders the flock economically useless for egg production. c. epizootiology and transmission. aerosol transmission over long distances is common. recovered carriers and con taminated premises may serve as a source of the virus for days or more. d. necropsy findings. air sacculitis and excessive tra chéal mucus are the most common findings. in very young chicks, bronchi can be filled with yellow exudate (fig. ). e. differential diagnosis. isolation of the virus in -to day-old chick embryos will confirm the diagnosis. determina tion of infectious bronchitis immunity with a serum neutraliza tion test using acute and convalescent serum will also help de termine the presence of infectious bronchitis virus. /. prevention. isolation of research birds may prevent in troduction of infectious bronchitis. however, it is one of the most widespread and contagious diseases of chickens. vac cines are very effective. they are given at days to weeks of age in the drinking water. correct serotypes must be se lected for the strain of agent present in the area. g. treatment. antibiotics will usually stimulate feed con sumption. increased pen temperature and improved ventilation are helpful in aiding recovery of young birds. h. research complications. adult laying flocks should be terminated because they will not return to normal egg production. a. etiology. infectious bursal disease is caused by a virus loosely placed in the orbi virus category. it damages primarily b lymphocytes in the bursa of fabricius, thymus, spleen, and cecal tonsil. infection with this agent reduces and sometimes totally eliminates humoral immunity. b. clinical signs. the age incidence is usually - weeks, but it may occur at a later age. birds are depressed and droopy, with ruffled feathers. morbidity is high, and mortality also may be high. vent picking and a bloody diarrhea are some times noted. c. epizootiology and transmission. transmission by di rect contact is rapid. the agent is resistant and lives in the environment for long periods of time. d. necropsy findings. the bursa of fabricius will first en large and later atrophy (fig. ) . serum-colored edema may be present on the surface of the bursa. the bursa may also contain yellow exudate and hemorrhages. hemorrhages also may be present in the skeletal muscles, and the kidneys can contain urate crystals. e. differential diagnosis. signs and lesions provide a pro visional diagnosis. a serum neutralization test and histopathology will usually confirm a diagnosis of the infectious bursal disease. /. prevention. drinking water vaccines are available and give adequate protection. a program for highly susceptible, antibody-free, -day-old research chicks require vaccination or possibly none at all depending on exposure risk and degree of isolation. under field conditions, maternal antibodies interfere with vaccines administered early in life. to overcome this, some of the vaccines are quite pathogenic and should not be used in highly susceptible chicks. complications. an outbreak would dictate termination of most experiments, especially when immu nologie data is important. a. etiology. epidemic tremor is caused by a picornavirus. it will grow in the embryos from a susceptible flock, but will not cause lesions unless it becomes egg "adapted." b. clinical signs. signs of ataxia, paralysis, and fine tremors of the head and neck will usually be seen between and weeks of age. turkeys, quail, and pheasants, as well as chickens, may be affected. growing birds, past weeks of age, show no clinical signs, although recovered birds may sometimes have cataracts. c. epizootiology and transmission. the virus is usually spread through fecal shedding. adult hens may shed virus in a small percentage of their eggs during infection. chicks hatch infected with the agent or become infected by fecal contact. d. necropsy findings. there are no gross lesions, but histologically a nonpurulent encephalomyelitis is present. sec tions of the brain, proventriculus, and pancreas should be ex amined microscopically. central chromatolysis and lymphoid aggregates are seen in the cerebellum and proventriculus, re spectively (butterfield et ai, ) . e. differential diagnosis. signs, especially head tremors, will suggest avian encephalomyelitis. histopathology will usu ally confirm the diagnosis. direct fluorescent antibody tests, serum neutralization tests, and isolation of the virus are used to diagnose the disease. avian encephalomyelitis signs are simi lar to those of newcastle disease and encephalomalacia. in pheasants, avian encephalomyelitis must be differentiated from eastern equine encephalomyelitis. /. prevention. to protect baby chicks, the dams must be immunized. both live and inactivated virus vaccines are available. g. research complications. chicks from immune dams will be satisfactory research birds. however, chicks encounter ing an outbreak of avian encephalomyelitis are not reliable for research purposes. a. etiology. eastern equine encephalomyelitis is caused by a togavirus, originally classified as an arbovirus. wild birds appear to be the natural host of this agent, and serve as a reser voir of infection for man, horses, and swine, in addition to pheasants. b. clinical signs. pheasants and horses are the primary animals affected, but in epizootics, chickens, wild turkeys, sparrows, domestic turkeys, quail, and doves may be infected. incoordination, paresis, and progressive paralysis are seen in about - % of a flock. if the flock is debeaked, mortality and morbidity will be markedly reduced. if the flock is not de beaked, feather picking and cannibalism are common. c. epizootiology and transmission. clinical cases are usu ally found near swamps and lowland areas, especially during a season with a high mosquito population. birds are bitten by the mosquito culiseta melanura, whereas the disease in mammals is usually transmitted by aedes and mansonia spp. horses are a monitor of the impending danger of eastern equine encepha lomyelitis to humans, since horses have equal susceptibility but a much greater risk of exposure. d. necropsy findings. no gross lesions are seen; micro scopically, there is a nonsuppurative encephalitis characterized by perivascular infiltrates, diffuse gliosis, and vasculitis with vascular infiltrates. e. differential diagnosis. signs, histopathology, and virus isolation are required for a diagnosis as other viruses may produce encephalitis in domestic fowl. newcastle disease, avi an encephalomyelitis in poults, and marek's disease in poults and pheasants must also be considered in the differential diagnoses. /. prevention. it is important to protect against mosquitoes with screens and sprays and to discourage cannibalism with debeaking and spectacles. vaccination at - weeks may re duce mortality, but this method has not been as successful in birds as it has in horses. should be terminated if an outreak of eee develops. a. etiology. infectious laryngotracheitis (ilt) is caused by a herpesvirus producing type a intranuclear inclusion bodies in epithelium lining the trachea. similar inclusions are produced in epithelium of the chorioallantoic membrane of ex perimentally infected fertile eggs. domestic fowl, pheasants, and pea fowl may be naturally infected (crawshaw et al., ) . b. clinical signs. marked dyspnea with "pump handle" breathing followed by coughing and moist rales are the promi-nent signs. shaking of the head and expectoration of blood also are common. mortality in adults rarely exceeds %. related or identical to the virus of hemorrhagic enteritis of turkeys. c. epizootiology and transmission. recovered carriers are a common source of infection for susceptible birds. it ap pears that fomites are more important in ilt transmission than most of the other respiratory diseases. d. necropsy findings. the larynx and trachea are acutely inflamed and sometimes filled with blood clots, or later, case ous cores (fig. ) . there is usually sinusitis and conjunctivitis. histopathology of the trachea will reveal intranuclear inclusion bodies in the epithelial tags pulled from the necrotic lining. e. differential diagnosis. signs, lesions, and virus isola tion are the main methods of arriving at a diagnosis. the pres ence of inclusion bodies in trachéal epithelium are pathognomonic. /. prevention. a modified live ilt vaccine is available and is relatively safe. it will spread to susceptible birds in the same pen but usually not to other pens. all birds should be vaccinated at the same time and quarantined for - weeks (bryant, e. differential diagnosis. clinical signs and gross lesions suggest the diagnosis. intranuclear inclusions in the spleen will further support msd as a diagnosis (wyand et al., ) . agar gel precipitin tests may be used to identify antibodies as an indication of prior infection. no commercial vaccine is available, but avirulent strains of hemorrhagic enteritis virus are being uti lized in experimental vaccines. h. research complications. this disease is usually found on range flocks. infected birds would not contribute valid ex perimental data. a. etiology. the cause of marble spleen disease of pheas ants is an avian adenovirus (iltis et al., ) . it is closely '£^< ;:^^# a. etiology. the causative agent is an avian adenovirus, the type strain referred to as celo (chick embryo lethal or phan) virus. it causes very high mortality in young bobwhite quail. b. clinical signs. in quail under weeks, coughing, sneezing, rales, and huddling are common. mortality may range from to %, but usually ranges between and %. c. epizootiology and transmission. chickens, turkeys, and other birds may be inapparent carriers. airborne and me chanical transmission are thought to be important means of spread. d. necropsy findings. trachéal and bronchial mucus is present. cloudy air sacs, conjunctivitis, and infraorbital si nusitis are quite characteristic lesions of this disease. e. differential diagnosis. isolation of virus is necessary for a definitive diagnosis. pulmonary aspergillosis may present similar signs but the microscopic lesion would be a fungal granuloma and easy to differentiate from that produced by quail bronchitis virus. /. prevention. isolation, sanitation, and good husbandry should prevent quail bronchitis. g. research complications. the mortality in quail would cause termination of any research trial. a. etiology. newcastle disease is the result of a paramyxovirus infection. there are three major strains as distinguished by their pathogenicity: (a) lentogenic, mild disease, used as vaccine, an example is serotype b- ; (b) mesogenic, moderate disease, domestic newcastle disease usually seen in the united states; (c) velogenic, very pathogenic, exotic newcastle dis ease. newcastle disease virus hemagglutinates chicken erythrocytes and forms the basis for the hemagglutination inhi bition test for anti-ndv antibodies. b. clinical signs. a sudden onset of anorexia and respira tory signs will develop in adults. the eggshells of brown-egglaying hens will often turn white. egg production and egg quality will be diminished. in young chicks with no parental immunity, central nervous system signs are seen. mortality will be high. torticollis ("star-gazers") is very common. se vere dypsnea, diarrhea, paralysis, and acute death are the signs of velogenic strains. mortality may reach %. caution must be advised regarding velogenic newcastle disease since spe cies of pet birds may be inapparent carriers of velogenic strains. c. epizootiology and transmission. newcastle disease has a wide host range. many wild birds can transmit newcastle virus to domestic birds. it affects many wild birds, pet birds, and most game birds. aerosol transmission is the important means of spread. contaminated feed, water, and equipment are almost as important. egg transmission occurs but only for the first few hours during the acute onset of infection in breeders. velogenic newcastle disease may be brought into the country with pet birds and fighting cocks. the latter are often smuggled into the country. d. necropsy findings. the mesogenic strains produce le sions characteristic of a tracheitis and a "frothy type" air sacculitis. velogenic strains, on the other hand, produce massive hemorrhages in all the visceral organs especially the gi tract. e. differential diagnosis. signs, lesions, and hi tests are usually adequate for diagnosing newcastle disease. immunofluorescence tests may be done very quickly to detect the presence of the virus at the time of disease onset. all avian respiratory diseases must be differentiated from newcastle dis ease. histopathology will serve to differentiate the cns form of newcastle disease from those produced in avian encephalomyelitis and encephalomalacia. /. prevention. excellent newcastle disease vaccines are available for immunization of laying hens, breeders, and broilers. one-day-old chicks are given water vaccines and are given boosters several times before sexual maturity. g. control. eradication has been practiced by the united states department of agriculture for the velogenic viscerotropic type of newcastle disease. all newcastle disease outbreaks should be reported if high mortality is a feature. pet birds should be kept separate from poultry, turkey, or game bird flocks. h. research complications. a researcher may immunize the flock or raise birds in strict isolation. the latter is ideal but not always successful as newcastle disease can be transmitted through aerosols. if an outbreak occurs, the trial should be terminated. a. etiology. pox is caused by a large dna virus. the fol lowing commonly encounted strains infect their respective spe cies: fowl pox, turkey pox, pigeon pox, and canary pox. pox virus is very resistant in the environment and spreads slowly through a flock. b. clinical signs. two forms exist. skin pox affects the comb, head, and vent regions; wet pox affects mucous mem-branes of the larynx and can cause choking. viremia exists in both forms, and decreased ^gg production is present for ex tended periods. c. epizootiology and transmission. scabs and skin debris that contaminate the litter feed and water are the usual source of virus. mosquitoes and cannibalism are secondary means of spread. d. necropsy findings. scabs on the comb and other unfeathered areas of the body are suspect pox lesions. diphtheri tic lesions of the pharynx, larynx, and trachea are common in wet pox. the laryngeal opening is usually plugged with a tight ly adhered plaque. if cannibalism is a simultaneous problem, the vents may show severe skin necrosis. e. differential diagnosis. demonstration of intracytoplasmic inclusion ibodies in cutaneous and oral lesions are pathognomonic for pox. virus inoculation onto the chorioallantoic membrane of embryonating eggs will also produce pocks and cytoplasmic inclusions. pox must be differentiated from can nibalism, infectious laryngotracheitis and mycoplasmosis. trachéal plugs are seen in the latter if the strain is highly pathogenic. /. prevention. vaccination by the wing-web stick method is recommended for pigeons and chickens. turkeys should be vaccinated by the thigh-stick method. an experimental vaccine is available for canaries. the pigeon pox strain of vaccine is preferred in areas of low incidence, thus preventing spread of the fully virulent fowl pox vaccine to susceptible birds. g. research complications. it would be unwise to collect data from pox-infected birds. a. coccidiosis a. etiology. coccidiosis is caused by a protozoan parasite. there are nine species of coccidia affecting chickens, six affect turkeys, but only three are pathogenic. in geese, three species affect the gastrointestinal tract, and one affects the kidney. the duck and pheasant, each have at least one species that is patho genic for the gastrointestinal tract. all species in the genus rimeria appear to be host specific with no cross-transfer. each species has a characteristic size and shape and specific life cy cle. immunity is usually specific for one species only and af fords no cross-protection against other species of coccidia. b. clinical signs. signs may include pale legs and beaks, ruffled feathers, and listlessness. birds infected with certain species of coccidia may have bloody fecal droppings. poor growth and high mortality are the effects of coccidia multiply ing in intestinal epithelial cells. c. epizootiology and transmission. ingestion of the sporulated oocysts from feces and litter is necessary for transmis sion. each gram of feces may contain about , oocysts. each sporulated oocyst will produce eight sporozooites, first generation merozoites, second generation merozoites, and will damage about , , intestinal host cells. d. necropsy findings. table iv illustrates the complexity of diagnosing coccidiosis by gross lesions (see also fig. ). e. pathogenesis. disease is based on the interrelation of age of host, species of coccidia, and dose of organism (degree of exposure). an unsporulated oocyst in the presence of oxy gen, % moisture, and room temperature will become an in fective oocyst in - hr. the infective oocyst is ingested by a susceptible host, and the life cycle begins. the prepatent period varies by species from to days. /. differential diagnosis. a differential diagnosis in the chicken and turkey must include various species of coccidia in addition to salmonellosis and histomoniasis. the signs and le- from bryant and helmboldt ( ) . sions of ulcerative and necrotic enteritis are similar to coc cidiosis. direct scrapings of the gut accompanied by histopathology will aid in the diagnosis. prevention of coccidiosis must include re ducing the number of infective oocysts. dry pens and good sanitation practices and/or wire floors will prevent coccidiosis. immunity is species specific. vaccines will protect birds but require skillful maintenance of litter at % moisture postvac cination to ensure cycling of coccidia for immunization. coccidiostats are efficacious. amprolium, coban, and others are available. they are administered continuously at a dose of . % to allow low level infection but protect against severe disease. h. treatment. amprolium, sulfa drugs, and the nitrofurans have all been used with good success. /. research complications. used for research purposes coccidiostat. all birds from to weeks should be fed a low level a. etiology. the cause of histomoniasis is histomonas meleagridis, a protozoan flagellate that inhabits the cecal lumen. b. clinical signs. turkeys, chickens, and pea fowl with this disease exhibit anorexia, droopiness, listlessness, yellow diarrhea, and cyanosis of the head and face. morbidity and mortality may be high in young poults. c. epizootiology and transmission. fresh feces contain the histomonad and may be ingested. more often, the histomonad is contained within the cecal worm (heterakis gallinarum) and the worm is ingested. a third possiblity is heterakis larvae contained within earthworms which in turn may also be ingested. d. necropsy findings. the liver will show discrete, irreg ular, depressed areas of focal necrosis. the thickened walls of the cecal lumen surround laminated, yellow, caseous cores (fig. ). e. differential diagnosis. hematoxylin and eosin sections of the liver and cecal wall are best for demonstrating the histomonads. direct smears and scrapings may also reveal the organism. /. prevention. the continuous use of antihistomonal drugs is the most effective way to prevent blackhead. hepzide, histostat and emtryl will all prevent the disease. g. treatment. the above drugs serve as effective thera peutic agents at the recommended treatment level. h. research complications. poults and game birds, es pecially pea fowl, should be administered anithistomonal drug until - weeks of age. a. etiology. ascaridia species are found in most birds. the following species have been reported: ascardia galli, chicken; ascaridia numidae, guinea fowl; ascaridia columbae, pigeon; ascaridia dissimilis, domestic and wild turkeys; ascaridia compar, bob white quail. b. clinical signs. decreased egg production, poor growth and vigor, diarrhea, and visible presence of worms in the feces are often noted. c. epizootiology and transmission. the life cycle is di rect. infective eggs are swallowed and hatch in the proventriculus or anterior portion of the intestinal tract. larvae live for - days in the lumen and then enter the mucosal wall and produce damage. on the seventeenth to eighteenth day, young worms again enter the lumen and remain there until maturity, usually days postingestion. d. necropsy findings. evidence of anemia and retarded growth is seen. the presence of ascardia sp. is the most out standing feature. a complete intestinal blockage is sometimes present (fig. ). e. differential diagnosis. the presence of intestinal roundworms may not be the primary cause of clinical disease, especially when mortality is a common feature. further exam ination may reveal capillariasis, coccidiosis, or bacterial infec tions in combination with ascaridia infestation. /. prevention. a complete depopulation and disinfection will usually prevent recurrence of the disease in the next flock. dirt floors or ranges are impossible to clean and should be rotated annually. a. etiology. capillaria obsignata infests the chicken, tur key, and probably other bird hosts. capillaria columbae is as sociated with pigeons. in game birds, c. contorta is found in the crop and esophagus. b. clinical signs. a sudden drop in egg production and an unthrifty appearance of the flock may often be the result of capillaria infestation. c. epizootiology and transmission. the life cycle is di rect. eight-day embryonated capillaria eggs are ingested by the host, and larvae penetrate the duodenal mucosa. adult worms are found within - days postingestion of embryonated eggs (fig. ) . slight enteritis may be present. nematodes washed from mucosal scrapings will confirm the diagnosis. e. prevention. clean facilities will prevent capillaria infestations. e. prevention and treatment. the continuous feeding of thiabendazole has been very effective. more recently, levamizole hydrochloride in the water has been used with success as a treatment. rotating ranges for pheasants will also help mini mize infection. c. epizootiology and transmission. spores of a. fumigatus are found in great numbers in old litter. when the spores are inhaled, they produce typical respiratory signs and lesions. d. necropsy findings. yellow plaques are found in the lungs, air sacs, tracheas, and peritoneal surfaces (fig. ) . the brain also may contain foci of fungal growth. histopathology will reveal the presence of hyphae in granulomas stained with periodic acid-schiff or gridley stain. e. differential diagnosis. signs and typical histologie le sions of lung and air sacs will confirm the presence of the aspergillus spp. /. prevention. use clean, dry litter. wet sawdust may con tain numerous spores of aspergillus fumigatus, and its use is contraindicated. g. treatment. commercial poultry and turkey flocks are not usually treated. individual, valuable birds may be treated with nystatin or amphotericin b. h. research complications. flocks infected with as pergillosis should be depopulated. a. etiology. candida albicans, a yeastlike fungus, is the causative agent of crop mycosis. it grows well on sabouraud's agar at room temperature. it is cautioned, however, that c. albicans can be a normal floral inhabitant of the crop and lower digestive tract. b. clinical signs. depressed egg production and diarrhea are the two most commonly observed signs. c. epizootiology and transmission. unsanitary waterers and warm humid weather will often combine to produce the necessary environmental conditions for the development of disease. indiscriminate use of antibiotics may alter normal bac terial flora allowing the yeast to multiply and ellicit disease. d. necropsy findings. the crop and esophagus are cov ered with a diffuse, white exudate. often the pharnygeal mucosa is involved. enteritis with a white, pseudomembrane covering duodenal and jejunal mucosa may sometimes be found. e. differential diagnosis. culture of the yeast and histo pathology will confirm the diagnosis. /. prevention. optimum sanitation of waterers and feeders especially during hot, humid weather is necessary. disinfec tants such as chlorine, iodine, and quaternary ammonium com pounds are needed to keep the yeasts and fungi from multiply ing in the drinking water. depression and emaciation characterize visceral involvement. palpable muscle tumors may also be noted. c. epizootiology and transmission. the virus is released in association with dander from feather follicles, which then contaminates the environment. d. necropsy findings. tumors of various visceral organs, skin, or muscle may be seen. swollen sciatic and brachial nerves are common. microscopic lesions feature pleomorphic cellular infiltrates of plasma cells, macrophages, lymphocytes, and lymphoblastic cells. nerves may have inflammatory or proliferati ve lesions or a combination of both types. e. differential diagnosis. marek's disease must be differ entiated from lymphoid leukosis (ll). for many years, both these diseases were thought to be caused by a common agent. marek's disease occurs prior to sexual maturity, but both may occur after sexual maturity. only marek's disease affects the nerves and thus causes paralysis. both produce tumors and en larged visceral organs. gray eyes, feather follicle inflamma tion, and muscle tumors are found only in marek's disease. tumors of the bursa of fabricius are rare in md, but are an invariable finding in ll. /. prevention. depopulation and thorough disinfection be fore introducing a new flock is recommended. baby chicks should be vaccinated at day of age with the nononcogenic turkey herpesvirus if it is not possible to provide strict isola tion. genetic resistance varies among strains of chickens, and is effective in reducing losses in marek's disease virus-ex posed birds. h. research complications. herpesvirus of turkeys (hvt) marek's vaccine should be administered to all birds at day of age to prevent the disease. a. etiology. lymphoid leukosis is caused by an oncogenic retrovirus. it is a member of the leukosis-sarcoma group. sub groups a and b occur in commençai chickens. various virus strains may cause a variety of neoplasms of mesodermal tissues in addition to typical ll. b. clinical signs. sudden death of adult chickens may be the only sign. an enlarged abdomen due to a swollen liver is also a common finding. thickening of the leg bones as a result of osteopetrosis is another possible consequence of infection with some strains of leukosis virus. other lesions may include erythroid or myeloid leukemias, hemangiomas, or nephroblastomas. c. epizootiology and transmission. egg transmission is the most important means of introducing the virus into a flock. lateral spread from infected saliva and feces then ensues. ear ly infection is generally required for tumors to develop. findings. an enlarged liver, sometimes sig nificantly displacing other abdominal organs, is a common finding. tumors in the spleen and kidney are also seen. the bursa of fabricius will usually reveal a discrete, nodular tumor that constitutes the primary lesion. other sites are thought to become involved as the result of métastases from the bursa. e. differential diagnosis. lymphoid leukosis does not de velop until - months of age. in contrast, marek's disease may be seen as early as - weeks of age. both diseases can simultaneously occur in the same bird. the presence of a bursal tumor frequently indicates ll, whereas nerve, skin, or muscle involvement indicates md. /. prevention. lymphoid leukosis-free chicks are avail able. a rigid isolation rearing system should be followed. h. research complications. if birds are not kept until the age of sexual maturity, little or no ll should be encountered. a. etiology. vitamin a is necessary for growth, normal vision, and integrity of epithelium lining the respiratory, diges tive, urinary, and genital tracts. severity of deficiency signs and age of incidence will vary with the vitamin a levels in the feed and the maternal reserve of vitamin a passed onto the chick. breeders on adequate vitamin a diets store this vitamin in the egg yolk, which provides the chick with sufficient vi tamin a to last for several weeks. chicks hatched with margin al reserves of vitamin a and placed on a deficient diet will have clinical signs by - days of age. however, if chicks are hatched from hens receiving adequate vitamin a, they have no signs or lesions until about weeks. b. signs. signs of vitamin a deficiency include pale head, muscles of the thigh, and skin. weakness, lethargy sometimes associated with ataxia, and lacrimation with conjunctivitis are other signs noted. decreased sperm counts and reduced sperm motility are reported to be a common finding in vitamin adeficient roosters. cartilage and bone development may be de pressed. the incidence and severity of blood spots in eggs are increased as dietary vitamin a is reduced. recovery from in testinal diseases is improved when the level of vitamin a in the feed is increased. c. gross lesions. lesions of vitamin a deficiency consist of small white pustules in the nasal passages, mouth, esopha gus, pharynx, and crop. in addition, there may be marked ac cumulation of urates in the renal tubules. d. histopathology. histopathology reveals cytoplasmic atrophy and loss of cilia of the respiratory tract epithelium. there is marked karyorrhexis of nuclei. chronic vitamin a deficiency results in squamous metaplasia in epithelial lining of the nasal cavities, trachea, bronchi, and submucous glands (bryant and helmboldt, ) . e. prevention. the normal requirement for vitamin a in chicks from day old to weeks of age is iu/lb of feed. for growing chickens and turkeys ( - weeks of age), iu/lb of feed is recommended. for laying hens, iu/lb of feed, and for breeding hens and turkeys, iu/lb of feed is needed. five thousand iu/lb feed is also recommended for pheasants, pigeons, and quail. /. treatment. treatment levels for vitamin a deficiency is iu/lb of feed. a. etiology. vitamin d is needed for metabolism of cal cium and phosphorus in the formation of bones, egg shells, beaks, and claws. vitamin d stimulates the gastrointestinal ab sorption of calcium. serum alkaline phosphatase is elevated when vitamin d-deficient diets are fed even in the presence of sufficient calcium and phosphorus. b. signs. retarded growth, poor feathering, and soft bones (rickets) are features of vitamin d deficiency in young chicks - weeks of age. the chicks are unsteady and walk only a short distance before falling, or affected chicks may sit on their hocks and rest for several minutes (bryant, ) . adults will lay a large percentage of thin-shelled and softshelled eggs leading eventually to a decrease in total egg pro duction. signs from a deficiency of vitamin d usually occur about months after vitamin d is withheld. hatchability is also reduced. c. lesions. characteristic lesions in young birds include soft pliable bones, beaded ribs, and s-shaped keel bone. the beak and long bones can be bent without breaking. an in dented rib cage is evident and causes pressure on the lungs and the heart. in adults, the lesions seen in young birds are present but usually to a lesser degree. pathological fractures of the ribs and vertebrae may be a feature. the histological features of vitamin d deficiency include an enlarged parathyroid gland with a diffuse hyperplasia. a decrease of normal calcified bone with an excess of osteoid tissue in the long bones is also seen. poor calcification is best identified at the epiphysis of the tibia or femur. turkeys of all ages should receive vitamin d in the amount of iu/lb of feed. hens and young chicks require iu/lb, while growing chickens, - weeks of age, should have iu/lb of feed. pheasants, quail, and pigeons will grow well on iu/lb of feed. e. treatment. the feeding of a one-time, very high dose of vitamin d , approximately , iu/lb of feed, will pro vide the most effective therapy. this should be given in a sin gle dose, as hypervitaminosis d can result. dystrophie cal cification of the aorta and certain arteries, in addition to kidney tubules, is one complication of hypervitaminosis d. vitamin d (irradiated ergosterol) is a poor form of vitamin d for birds and can even be toxic at high levels. a. etiology. vitamin e is necessary for normal egg pro duction, fertility, and hatchability. multiple problems result if a deficiency of vitamin e occurs in birds. i. encephalomalacia ("crazy chick disease"). this con dition is a vitamin e deficiency characterized by ataxia, back ward retraction of the head, increased incoordination, and death. it is usually seen between and weeks of age. if the breeder flock is deficient in vitamin e, signs may be seen dur ing the first week posthatching. grossly, the cerebellum ap pears wet with petechial hemorrhages. histologically, ische mie necrosis as a result of capillary thrombosis is the main feature. this disease must be differentiated from avian encephalomyelitis (ae) in which the neurons show central chromatolysis. this condition is characterized by cells appearing pale in the center due to loss of the nissl substance (helmboldt), ). ii. exudative diathesis. this condition is characterized by subcutaneous blood-tinged edema of young birds caused by an abnormal permeability of capillary walls. it appears that tissue peroxides increase causing damage to capillary membranes. vitamin e and glutathione peroxidase, a selenium-containing enzyme, protect the capillary endothelium against damage by peroxides, thus explaining the dual role of vitamin e and se lenium in preventing exudative diathesis. hi. nutritional muscular dystrophy. dystrophie muscles in chickens, ducklings, and turkeys at approximately weeks of age is caused by vitamin e deficiency, as well as by a defi ciency of sulfur-containing amino acids. it is primarily seen in breast muscle but may be found in any of the skeletal muscles. grossly, there are separated muscle fiber bundles that appear light in color. the microscopic lesions consist of typical zenker's necrosis, which include hyaline degeneration, pro liferation of muscle nuclei and fibroblasts, disruption of mus cle fibers, and edema containing heterophiles. vitamin e defi ciency and selenium deficiency in the turkey may show heart and gizzard myopathy. iv. enlarged hocks. turkeys on a vitamin e-deficient diet have enlarged hocks and bowed legs at - weeks of age. the same condition is produced by a deficiency of phosphorus, choline, glycine, nicotinic acid, zinc, and biotin. b. prevention. the recommended level of vitamin e for chickens and laying hens is iu/lb of feed; for breeding hens . iu/lb is recommended. poults from to weeks require iu/lb, and breeder turkeys need iu/lb of feed. c. treatment. therapeutic levels of vitamin e and se lenium, iu/lb and . ppm, respectively, will prevent en cephalomalacia, exudative diathesis, and gizzard myopathy. a. etiology. vitamin k is needed to synthesize prothrombin, an important component of the blood clotting mechanism. if vitamin k is deficient, prolonged blood clotting time is noted. b. signs and lesions. diets deficient in vitamin k can cause cutaneous hemorrhage of the legs, wings, and breast in addition to hemorrhage into body cavities. anemia is often seen due to blood volume loss and a hypoplastic nonregenerative bone marrow. embryos will die during egg incubation from hemorrhages. c. prevention. vitamin k deficiency is rare and hard to reproduce. the dietary requirement for all birds at any age is mg/lb of feed. d. treatment. a normal clotting time returns within hr after treatment with menadione sodium bisulfite. cutaneous hemorrhages and anemia usually take several days to resolve once adequate vitamin k levels are fed. e. thiamin deficiency (vitamin b,) a. etiology. thiamin is important in carbohydrate metabo lism. signs of thiamin deficiency include polyneuritis, extreme anorexia, and death. b. signs and lesions. vitamin b, deficiency can be seen in chicks and adults. usual signs are weight loss, ruffled feath ers, leg weakness, and unsteady gait followed by muscle paral ysis. due to anterior neck muscle paralysis, retraction of the head results in a typical posture referred to as "star gazing." c. treatment. the requirement of thiamin is mg/lb of feed for birds of all ages. oral therapy with thiamin results in a rapid clinical recovery if the birds are eating; however if anorexia is present, force feeding or injection of thiamin may be necessary. a. etiology. riboflavin is an important component of many enzymes associated with oxidation-reduction reactions and cell respiration. b. signs and lesions. signs in chicks may include poor growth, weakness and emaciation, diarrhea, and refusal to walk. appetite is not affected. toes will curl medially (bryant, ) . in laying hens decreased egg production and hatchability occurs. increased fat content of the liver is also noted. embryos are dwarfed and edematous. in turkeys, riboflavin deficiency results in a dermatitis with defective down feathers similar to pantothenic acid deficiency in chickens. micro scopic nerve lesions in chicks show degenerative changes in the myelin nerve sheath. c. prevention. the normal requirement for riboflavin in all birds is to . mg/lb of feed. d. treatment. the administration of adequate riboflavin will usually cure the deficiency rapidly. a. etiology. pantothenic acid is part of coenzyme a, which is involved in the metabolism of carbohydrates, pro-everett bryant teins, and fats. it is required for hatchability and will prevent edema and subcutaneous hemorrhages in the embryos. b. signs and lesions. changes noted in pantothenic acid deficiency include a severe dermatitis, perosis, broken feath ers, poor growth, and death. poor hatchability with the em bryos dying during the last days of incubation is typically noted. c. prevention and treatment. six to mg/lb of feed is needed for a normal diet. for therapeutic effect, - mg/lb of feed administered for a few days either orally or by injection is needed. biotin deficiency causes a dermatitis around the beak, eye lids, and feet. biotin deficiency also can cause perosis. ap proximately . mg/lb of feed will prevent the dermatitis and perosis caused by biotin deficiency. a. etiology. vitamin b is involved in nucleic acid syn thesis, methyl synthesis, and metabolism of carbohydrates and fats. b. signs and lesions. signs include retarded growth, poor feed efficiency, mortality, small egg size, and reduced hatchability. vitamin b x -deficient embryos may have hemor rhages, edema, perosis, and fatty livers. c. prevention and treatment. the inclusion of . mg/lb of feed will prevent deficiency of vitamin b i . therapy includes the addition of mg/ton of feed into the breeding ration. a. etiology. calcium is essential for bone formation, egg shell production, normal blood clotting, normal striated mus cle, and maintenance of acid-base balance. phosphorus is required for carbohydrate and fat metabolism, calcium trans port, bone formation, and eggshell production. b. signs and lesions. calcium and/or phosphorus defi ciency will cause signs and lesions of rickets, decreased egg production, and increased numbers of soft shelled and shellless eggs (also see section vii,b on vitamin d deficiency). c. prevention and treatment. the recommended levels are as follows: for nonlaying chickens, % calcium and . % available phosphorus; for laying and breeding hens, . % cal cium and . % available phosphorus; for nonlaying turkeys, . % calcium and . % phosphorus; and for laying turkeys, . % calcium and . % phosphorus. the above levels used therapeutically will correct any deficiency. a. etiology. sodium is found in the blood and body fluids and is associated with regulation of the hydrogen ion con centration of blood. it is also necessary for normal physiologi cal activity of the heart. b. signs. poor growth, softening of the bones, corneal keratinization, gonadal inactivity, decrease in cardiac output, hypotension, hemoconcentration, and uremia are signs of so dium deficiency. in adults, a sodium deficiency results in de creased egg production and egg size in addition to loss of weight and cannibalism. c. prevention and treatment. levels of . % sodium and . % chlorine are recommended for optimum growth and egg production. salt toxicity develops at a level of gm/kg of body weight. intense thirst, weakness, convulsions, and death are the signs associated with salt toxicity. a. etiology. manganese is essential for growth, egg pro duction, and prevention of perosis. b. signs. results of a manganese-deficient diet include poor quality eggshells, thickened and shortened leg bones, lowered hatchability, and chondrodystrophy in embryos. c. prevention and treatment. the normal requirement of manganese is - ppm. this level is also used therapeu tically to treat manganese-deficient birds. a. etiology. iodine is necessary for the normal function of the thyroid gland. thyroxine is % iodine and regulates body metabolism. with iodine deficiency, the thyroid gland en larges and is referred to as "goiter." b. prevention and treatment. the recommended level of differential diagnoses in avian medicine, i. diseases of the central nervous system a program for eradication of infectious laryngótracheitis from new england poultry flocks differential diagnosis in avian medicine. ii. diseases of the digestive system differential diagnoses in avian medicine. iii. diseases of the respiratory system an epizootic of eastern equine encephalomyelitis in connecticut studies on avian encephalomyelitis. iv. early incidence and longevity of histopathologic lesions in chickens a bibliography of avian mycosis infectious laryngótracheitis in pea fowl and pheasants gangrenous dermatitis of chickens the pathology of necrotic enter itis in domestic fowl histopathologic differentiation of diseases of the nervous system of the domestic fowl (gallus gallus) isolation and identification of avian pathogens diseases of poultry demonstration of an avian adenovirus as the causative agent of marble spleen disease avian microplasmas. in "the mycoplasmas nutrient requirements of poultry variations in the cells and hemoglobin content in the blood of the normal domestic chicken outbreaks of fowl cholera in quail diseases of cage and aviary birds poultry health handbook nutrition of the chicken international registry of poultry genetic stocks caged bird medicine avian physiology avian disease manual ja panese quail husbandry in the laboratory marble spleen disease in ring-necked pheasants: histology and ultrastructure key: cord- -nr fu qb authors: wang, yu; tian, huaiyu; zhang, li; zhang, man; guo, dandan; wu, wenting; zhang, xingxing; kan, ge lin; jia, lei; huo, da; liu, baiwei; wang, xiaoli; sun, ying; wang, quanyi; yang, peng; macintyre, c. raina title: reduction of secondary transmission of sars-cov- in households by face mask use, disinfection and social distancing: a cohort study in beijing, china date: - - journal: bmj glob health doi: . /bmjgh- - sha: doc_id: cord_uid: nr fu qb introduction: transmission of covid- within families and close contacts accounts for the majority of epidemic growth. community mask wearing, hand washing and social distancing are thought to be effective but there is little evidence to inform or support community members on covid- risk reduction within families. methods: a retrospective cohort study of people in families and with at least one laboratory confirmed covid- case was conducted from february to march , in beijing, china. the outcome of interest was secondary transmission of severe acute respiratory syndrome coronavirus (sars-cov- ) within the family. characteristics and practices of primary cases, of well family contacts and household hygiene practices were analysed as predictors of secondary transmission. results: the secondary attack rate in families was . % ( / ). face mask use by the primary case and family contacts before the primary case developed symptoms was % effective in reducing transmission (or= . , % ci . to . ). daily use of chlorine or ethanol based disinfectant in households was % effective (or= . , % ci . to . ). wearing a mask after illness onset of the primary case was not significantly protective. the risk of household transmission was times higher with frequent daily close contact with the primary case (or= . , % ci . to . ), and four times higher if the primary case had diarrhoea (or= . , % ci . to . ). household crowding was not significant. conclusion: the study confirms the highest risk of transmission prior to symptom onset, and provides the first evidence of the effectiveness of mask use, disinfection and social distancing in preventing covid- . we also found evidence of faecal transmission. this can inform guidelines for community prevention in settings of intense covid- epidemics. introduction transmission of covid- within families and close contacts accounts for the majority of epidemic growth. community mask wearing, hand washing and social distancing are thought to be effective but there is little evidence to inform or support community members on covid- risk reduction within families. methods a retrospective cohort study of people in families and with at least one laboratory confirmed covid- case was conducted from february to march , in beijing, china. the outcome of interest was secondary transmission of severe acute respiratory syndrome coronavirus (sars-cov- ) within the family. characteristics and practices of primary cases, of well family contacts and household hygiene practices were analysed as predictors of secondary transmission. results the secondary attack rate in families was . % ( / ). face mask use by the primary case and family contacts before the primary case developed symptoms was % effective in reducing transmission (or= . , % ci . to . ). daily use of chlorine or ethanol based disinfectant in households was % effective (or= . , % ci . to . ). wearing a mask after illness onset of the primary case was not significantly protective. the risk of household transmission was times higher with frequent daily close contact with the primary case (or= . , % ci . to . ), and four times higher if the primary case had diarrhoea (or= . , % ci . to . ). household crowding was not significant. conclusion the study confirms the highest risk of transmission prior to symptom onset, and provides the first evidence of the effectiveness of mask use, disinfection and social distancing in preventing covid- . we also found evidence of faecal transmission. this can inform guidelines for community prevention in settings of intense covid- epidemics. in the absence of a vaccine for covid- , non-pharmaceutical interventions (npis) are the only available disease control measures. we have shown that population level npis, including travel bans and the national emergency response, were effective in flattening summary box what is already known? ► mitigation of the covid- pandemic depends solely on non-pharmaceutical interventions until drugs or vaccines are available. transmission of covid- within families and close contacts accounts for the majority of epidemic growth. community mask wearing, hand washing and social distancing are thought to be effective but the evidence is not clear. what are the new findings? ► the overall secondary attack rate in households was . %. face masks were % effective and disinfection was % effective in preventing transmission, while close frequent contact in the household increased the risk of transmission times, and diarrhoea in the index patient increased the risk by four times. the results demonstrate the importance of the pre-symptomatic infectiousness of covid- patients and shows that wearing masks after illness onset does not protect. what do the new findings imply? ► the findings inform universal face mask use and social distancing, not just in public spaces, but inside the household with members at risk of getting infected. this further supports universal face mask use, and also provides guidance on risk reduction for families living with someone in quarantine or isolation, and families of health workers, who may face ongoing risk. the covid- epidemic curve in china. however, the effect of other npis, such as mask use and hygiene practices, have not been well studied in the covid- pandemic. in the usa, the use of face masks in the community has been recommended. it is thought that universal face mask use (ufmu) may reduce outward transmission from asymptomatically infected people and protect well people from becoming infected. however, the world health organization and public health england recommend against ufmu on the grounds that there is little evidence from randomised controlled trials to support this. some experts suggest that in a pandemic, the precautionary principle should be used and ufmu encouraged as it is unlikely to cause harm and may result in public health gain. in countries where personal protective equipment is scarce, people are making their own masks. in china, over % of human-to-human transmission of severe acute respiratory syndrome coronavirus (sars-cov- ) occurred in families. however, data to inform covid- risk reduction in households are unavailable. given epidemic growth is dominated by household transmission, studying the use of npis, such as face masks, social distancing and disinfection in the household setting, may inform community epidemic control and prevent transmission of covid- in households. we conducted a retrospective cohort study involving families of laboratory confirmed covid- cases in beijing, china. we defined family members as those who had lived with primary cases in a house for days before and for more than hours after the primary cases developed illness related to covid- . as of february , all laboratory confirmed covid- cases reported in beijing were enrolled in our study and followed-up. the outcome of interest was secondary transmission in the household. families with secondary transmission were defined as those where some or all of the family members become infected within one incubation period ( weeks) of symptom onset of the primary case. to analyse the predictors of household transmission, we compared families with and without secondary transmission for various measured risk factors, preventive interventions and exposures. definition of confirmed case according to national prevention and control guideline (fifth edition), confirmed cases were those who met the clinical, epidemiological and laboratory testing criteria for covid- simultaneously. . clinical criteria included: (a) fever and/or one or more respiratory symptoms; (b) radiological evidence of pneumonia; (c) white blood cell count normal or decreased, and lymphocyte count decreased at the early stage of illness. . epidemiological criteria included: (a) visits to/living in wuhan or cities around wuhan or other communities which had already reported covid- cases in the days prior to the onset of symptoms; (b) having contact with a person known to have infection with sars-cov- in the days prior to onset of symptoms; (c) having contact with a person who had fever or respiratory symptoms and came from wuhan or adjacent cities or other communities which had already reported covid- cases in the days prior to onset of symptoms; (d) being one of the cluster cases. suspected cases met one of the epidemiological criteria and any two of the clinical criteria, or met all of the clinical criteria. confirmed cases were those suspected cases who met one of the following criteria: (a) respiratory or blood specimen tested positive for sars-cov- by real time reverse transcriptase-polymerase chain reaction; (b) virus in respiratory or blood specimen was highly homologous with known sars-cov- through gene sequencing. data collection a three part structured questionnaire was developed. the first part included demographic and clinical information of the primary case. the second part was mainly focused on the primary case's knowledge about and attitudes toward covid- , and their self-reported practices (mask wearing, social distancing, living arrangements) and activities in the home. the third part was about self-reported behaviours of all family members, as well as the family's accommodation and household hygiene practices from days before the illness onset to the day the primary case was isolated, including room ventilation, room cleaning and disinfection. close contact was defined as being within m or feet of the primary case, such as eating around a table or sitting together watching tv. the frequency of contact, disinfection and ventilation was measured. after diagnosis, the primary case was hospitalised as per standard practice in beijing. eligible primary cases and their family members were interviewed between february and march. data on the primary case were extracted from epidemiological investigating reports from beijing centre for disease prevention and control and supplemented by interview. the clinical severity of the covid- case was categorised as mild, severe or critical. mild disease included nonpneumonia and mild pneumonia cases. severe disease was characterised by dyspnoea, respiratory frequency ≥ /min, blood oxygen saturation ≤ %, pao /fio ratio < and/or lung infiltrates > % within - hours. critical cases were those who exhibited respiratory failure, septic shock and/or multiple organ dysfunction/ failure. statistical analysis risk factors for secondary transmission were analysed by characteristics of the primary case, characteristics of well family members and household hygiene practices. categorical variables are presented as counts and percentages, and continuous variables as medians (iqr). the χ test and fisher exact test were applied to compare difference between groups when necessary. a composite covid- knowledge score and hand hygiene score were created with multiple sub-questions. a multivariable logistic regression model was used to identify risk factors associated with sars-cov- household transmission. univariable analysis was first performed with all measures and only those variables significant at p< . could be selected in the following multivariable logistic regression analysis. backward elimination was performed to establish a final model retaining those with p< . in the model. statistical analyses were performed using sas software (v. . ). as our study was embedded within the covid- prevention and control practice within public health units, and the telephone interview was a supplementary survey of the epidemiological field investigation, ethics approval was not required. we obtained subjects' verbal informed consent before the start of the interviews. no patients or the public were involved in the study design, setting the research questions, interpretation or writing up of results, or reporting of the research. as of february , confirmed covid- cases in families were reported in beijing. four family clusters were excluded because we were unable to determine whether there was secondary transmission or co-exposure, leaving families. after reviewing information in the epidemiological investigation reports and survey calls, families were excluded as they did not meet the study inclusion criteria. a further families declined to be interviewed and were also excluded, leaving families for study (figure ). over the weeks of follow-up from onset of the primary case, secondary transmission occurred in / families ( secondary cases), and / families had no secondary transmission. the overall secondary attack rate in families was . % ( / ). in the secondary transmission group, primary cases caused secondary cases, with a median secondary case number in families of (iqr - ). in the secondary transmission group, the secondary attack rate in children < years of age was . % ( / ), compared with . % ( / ) in adults, and the difference between these two age groups was significant (χ²= . , p< . ). the median age of the secondary child cases was years (iqr - ), / were bmj global health in multivariable logistic regression model, four factors remained significantly associated with secondary transmission. the primary case having diarrhoea in the home and daily close contact with the primary case in the home increased the risk. transmission was significantly reduced bmj global health by frequent use of chlorine or ethanol based disinfectant in households and family members (including the primary case) wearing a mask at home before the primary case developed the illness (table ) . this study confirms that the highest risk of household transmission is prior to symptom onset, but that precautionary npis, such as mask use, disinfection and social distancing in households can prevent covid- transmission during the pandemic. this study is the first to confirm the effectiveness of mask use prior to symptom onset by family members, daily household disinfection and social distancing in the home. this could inform precautionary guidelines for families to reduce intrafamilial transmission in areas where there is high community transmission or other risk factors for covid- . household transmission is a major driver of epidemic growth. further, in countries where health system capacity is exhausted, many people with infection are required to self-isolate at home, where their household contacts will be at risk of infection. in our study, the median family size of the families was (range - ), usually with children, parents and grandparents, which is similar to the social structure of most chinese families. therefore, the risk of sars-cov- household transmission is high if a primary case was introduced and no measure was adopted. we showed that npis are effective at preventing transmission, even in homes that are crowded and small. ufmu is a low risk intervention with potential public health benefits. the results suggest that community face mask use is likely to be the most effective inside the household during severe epidemics. almost a quarter of family members became infected, and the findings suggest that the risk was highest either before symptom onset or early in the clinical illness, as most primary cases were hospitalised after diagnosis, and interventions were not effective if applied after symptom onset. in the univariate analysis, wearing a mask after illness onset was significant, but in multivariate analysis, only wearing it before symptom onset was effective. viral load is highest in the days before symptom onset and on the first day of symptoms, and up to % of transmission is during the pre-symptomatic period in settings with substantial household clustering. this supports ufmu, probably by reducing onward transmission from people in the pre-symptomatic phase of the illness as well as protecting well mask users. randomised clinical trials of face masks in the household have confirmed protection against other respiratory viruses if compliant, if used within hours of the primary case symptom onset, and alone or in combination with hand hygiene. this study now provides specific evidence for ufmu in settings of high epidemic growth to protect against covid- . in our study, . % ( / ) of primary cases had a high score on hand hygiene, but it was not effective, confirming the results of previous randomised clinical trials which showed hand bmj global health hygiene alone did not protect against respiratory transmissible viruses, but masks combined with hand hygiene did have effect. as the compliance of ufmu would be poor in the home, there was difficulty and also no necessity for everyone to wear masks at home. we recommended that those families with members who were at risk of getting infected with sars-cov- (such as ever having contact with a covid- patient, medical workers caring for a covid- patient or having a history of travelling to high risk areas) should apply ufmu to reduce the risk of household transmission. this study showed that social distancing within the home is effective and having close contact (within m or feet, such as eating around a table or sitting together watching tv) is a risk factor for transmission. the study also provides evidence of effectiveness of chlorine or ethanol based household disinfection in areas with high community transmission, or where one family member is a health worker, or where there is a risk of covid- , such as during home quarantine, consistent with advice provided by local health authorities or organisations. diarrhoea as a symptom in the primary case is also a risk factor for sars-cov- transmission within families, which highlights the importance of disinfection of the bathroom and toilet, as well as closing the toilet lid when flushing to prevent aerosolisation of the virus. our study has limitations. telephone interview has inherent limitations, including recall bias. it would take about min to complete an interview, and % ( / ) of interviews were rated as informative by the interviewers. the evaluation results of mask wearing were reliable, but we did not collect data on the concentration of disinfectant used by families. the strengths of the study were that we had complete follow-up data and were able to accurately ascertain the incidence of secondary transmission in the cohort. household transmission in the pre-symptomatic or early symptomatic period of covid- is a driver of epidemic growth and any measure aimed at reducing this can flatten the curve. this study reinforces the high risk of transmission in households but importantly shows that ufmu and hygiene measures can significantly reduce the risk of household transmission of covid- , independent of household size or crowding. this is the first study to show the effectiveness of precautionary mask use, social distancing and regular disinfection in the household, and can inform guidelines for prevention of household transmission. the results may also be informative for families of high risk groups, such as health workers, quarantined individuals or situations where cases of covid- have to be managed at home. an investigation of transmission control measures during the first days of the covid- epidemic in china recommendation regarding the use of cloth face coverings, especially in areas of significant community-based transmission face masks for the public during the covid- crisis covid- : should the public wear face masks? yes-population benefits are plausible and harms unlikely report of the who-china joint mission on coronavirus disease (covid- ) new coronavirus pneumonia prevention and control program the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- ) -china china statistical yearbook- virological assessment of hospitalized patients with covid- temporal dynamics in viral shedding and transmissibility of covid- potential presymptomatic transmission of sars-cov- presumed asymptomatic carrier transmission of covid- face mask use and control of respiratory virus transmission in households facemasks and hand hygiene to prevent influenza transmission in households: a cluster randomized trial hand hygiene and risk of influenza virus infections in the community: a systematic review and meta-analysis centers for disease control and prevention. cleaning and disinfection for households: interim recommendations for u.s. households with suspected or confirmed coronavirus disease (covid- acknowledgements we thank the staff members in the district and municipal centres for disease prevention and control, and medical settings in beijing for conducting field investigation, specimen collection, laboratory detection and case reporting. we also thank all patients and families involved in the study.contributors all authors approved the final draft of the manuscript. the corresponding authors attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.funding this work was supported by beijing science and technology planning project (z ). competing interests none declared.patient and public involvement patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. provenance and peer review not commissioned; externally peer reviewed. open access this is an open access article distributed in accordance with the creative commons attribution non commercial (cc by-nc . ) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. see: http:// creativecommons. org/ licenses/ by-nc/ . /. key: cord- -klpmipaj authors: zachreson, cameron; mitchell, lewis; lydeamore, michael; rebuli, nicolas; tomko, martin; geard, nicholas title: risk mapping for covid- outbreaks using mobility data date: - - journal: nan doi: nan sha: doc_id: cord_uid: klpmipaj covid- is highly transmissible and containing outbreaks requires a rapid and effective response. because infection may be spread by people who are pre-symptomatic or asymptomatic, substantial undetected transmission is likely to occur before clinical cases are diagnosed. thus, when outbreaks occur there is a need to anticipate which populations and locations are at heightened risk of exposure. in this work, we evaluate the utility of aggregate human mobility data for estimating the geographic distribution of transmission risk. we present a simple procedure for producing spatial transmission risk assessments from near-real-time population mobility data. we validate our estimates against three well-documented covid- outbreak scenarios in australia. two of these were well-defined transmission clusters and one was a community transmission scenario. our results indicate that mobility data can be a good predictor of geographic patterns of exposure risk from transmission centres, particularly in scenarios involving workplaces or other environments associated with habitual travel patterns. for community transmission scenarios, our results demonstrate that mobility data adds the most value to risk predictions when case counts are low and spatially clustered. our method could assist health systems in the allocation of testing resources, and potentially guide the implementation of geographically-targeted restrictions on movement and social interaction. similar to other respiratory pathogens such as influenza, the transmission of sars-cov- occurs when infected and susceptible individuals are co-located and have physical contact, or exchange bioaerosols or droplets [ , ] . behavioural modification in response to symptom onset (i.e., self-isolation) can act as a spontaneous negative feedback on transmission potential by reducing the rate of such contacts, making epidemics much easier to control and monitor. however, covid- (the disease caused by sars-cov- virus) has been associated with relatively long periods of pre-symptomatic viral shedding (approximately - days), during which time case ascertainment and behavioural modification are unlikely [ , ] . in addition, many cases are characterised by mild symptoms, despite long periods of viral shedding [ ] . transmission studies have demonstrated that asymptomatic and pre-symptomatic transmission hamper control of sars-cov- [ ] [ ] [ ] . pre-symptomatic and asymptomatic transmission has also been documented systematically in several residential care facilities in which surveillance was essentially complete [ , ] . currently, there are no prophylactic pharmaceutical interventions that are effective against sars-cov- transmission. therefore, interventions based on social distancing and infection control practices have constituted the operative framework, applied in innumerable variations around the world, to combat the covid- pandemic. social distancing policies directly target human mobility. therefore, it is logical to suggest that data describing aggregate travel patterns would be useful in quantifying the complex effects of policy announcements and decisions [ ] . the ubiquity of mobile phones and public availability of aggregated near-real-time movement patterns has led to several such studies in the context of the ongoing covid- pandemic [ ] [ ] [ ] . one source of mobility data is the social media platform facebook, which offers users a mobile app that includes location services at the user's discretion. these services document the gps locations of users, which are aggregated as origindestination matrices and released for research purposes through the facebook data for good program. the raw data is stored on a temporary basis and aggregated in such a way as to protect the privacy of individual users [ ] . several studies have utilised subsets of this data for analysis of the effects of covid- social distancing restrictions [ ] [ ] [ ] [ ] in this work, we complement these studies by addressing the question: to what degree can realtime mobility patterns estimated from aggregate mobile phone data inform short-term predictions of covid- transmission risk? to do so, we develop a straight-forward procedure to generate a relative estimate of the spatial distribution of future transmission risk based on current case data or locations of known transmission centres. to critically evaluate the performance of our procedure, we retrospectively generate risk estimates based on data from three outbreaks that occurred in australia when there was little background transmission. the initial wave of infections in australia began in early march, , and peaked on march th with new cases. the epidemic was suppressed through widespread social distancing measures which escalated from bans on gatherings of more than people (imposed on march th) to a nation-wide "lockdown" which began on march th and imposed a ban on gatherings of more than people. by late april, daily incidence numbers had dropped to fewer than per day [ ] . the outbreaks we examine occurred during the subsequent period over which these general suppression measures were progressively relaxed. one of these occurred in a workplace over several weeks, one began during a gathering at a social venue, and one was a community transmission scenario with no single identified outbreak center, which marked the beginning of australia's "second wave" (which is ongoing as of august, ). the term "community transmission" refers to situations in which multiple transmission chains have been detected with no known links identified from contact tracing and no specific transmission centres are clearly identifiable. in each case, we use the facebook mobility data that was available during the early stages of the outbreak to estimate future spatial patterns of relative transmission risk. we then examine the degree to which these estimates correlate with the subsequently observed case data in those regions. our results indicate that the accuracy of our estimates varies with outbreak context, with higher correlation for the outbreak centred on a workplace, and lower correlation for the outbreak centred on a social gathering. in the community transmission scenario without a well-defined transmission locus, we compare the risk prediction based on mobility data to a null prediction based only on active case numbers. our results indicate that mobility is more informative during the initial phases of the outbreak, when detected cases are spatially localised and many areas have no available case data. our general method is to use an origin-destination (od) matrix based on facebook mobility data to estimate the diffusion of transmission risk based on one or more identified outbreak sources. the data provided by facebook comprises the number of individuals moving between locations occupied in subsequent -hr intervals. for an individual user, the location occupied is defined as the most frequently-visited location during the -hr interval. more details on the raw data, the aggregation and pre-processing performed by facebook before release, and our pre-processing steps can be found in the supplemental information. covid- case data is made publicly available by most australian state health authorities on the scale of local government areas (lgas). in these urban and suburban regions, lga population densities typically vary from approximately . × to × residents per km , but can be low as residents per km in the suburban fringe where lgas contain substantial parkland and agricultural zones. the output of our method is a relative risk estimate for each lga based on their potential for local transmission. the general method is as follows: . construct the prevalence vector p, a column vector with one element for each location with a value corresponding to the transmission centre status of that location. for pointoutbreaks in areas with no background transmission, we use a vector with a value of for the location containing the transmission centre and for all other locations. for outbreaks with transmission in multiple locations, we construct p using the number of active cases as reported by the relevant public health agency. . construct an od matrix m, where the value of a component m ij gives the number of travellers starting their journey at location i (row index) and ending their journey at location j (column index). to approximately match the pre-symptomatic period of covid- , we average the od matrix over the mobility data provided by facebook during the week preceding the identification of the targeted transmission centre. by averaging over an appropriate time interval, the od matrix is built to represent mobility during the initial stages of the outbreak, when undocumented transmission may have been occurring. the choice of appropriate time interval varied by scenario, as described below. . multiply the od matrix by the prevalence vector to produce an unscaled risk vector r with a value for each location corresponding to the aggregate strength of its outgoing connections to transmission centres, weighted by the prevalence in each transmission centre. this is re-scaled to give the relative transmission risk for each region r i . in other words, we treat the od matrix as analogous to the stochastic transition matrix in a discrete-time markov chain, and compute the unscaled vector of risk values r as: so that r is approximately proportional to the average interaction rate between susceptible individuals from location i and infected individuals located in the outbreak centres. these approximate interaction rates are then re-scaled to give relative risk values r i between and : for point-outbreaks, this is simply: where k is the column index of the single outbreak location. the numerator is the number of individuals travelling from region i to the outbreak centre, and the denominator is the total number of travellers into the outbreak centre over all origin locations j. in addition to the typical assumptions about equilibrium mixing (in the absence of more detailed interaction data), this interpretation is subject to the assumption that the strength of transmission in each centre is proportional to the number of active cases in that location. this assumption is consistent with the observation that the majority of individuals start and end their journeys in the same locations, but there is not sufficient data to unequivocally determine the relationship between transmission risk within an area and active case numbers in the resident population of that area. therefore, it is appropriate to think of our method as a heuristic approach to estimating transmission risk based only on qualitative information about epidemiological factors and informed by near-real-time estimates of mobility patterns. these are derived from a biased sample of the population (a subset of facebook users), and aggregated to represent movement between regions containing on the order of to outbreaks occur in different contexts, some of which may suggest use of external data sources to infer at-risk sub-populations. such inference can be used to refine spatial risk prediction. for example, the workplace outbreak we investigated occurred in a meat processing facility, where the virus spread among workers at the plant and their contacts. to adapt the general method to this context, we averaged od matrices over the subset of our data capturing the transition between nighttime and daytime locations, as an estimate of work-related travel. in addition, we examined the effect of including industry of employment statistics as an additional risk factor. in this case, we used data collected by the australian bureau of statistics (abs) to estimate the proportion of meat workers by residence in each lga, and weighted the outgoing traveller numbers by the proportion associated with the place of origin. the resulting relative risk value r i is a crude estimate of the probability that an individual: • travelled from origin location i into the region containing the outbreak centre; • travelled during the period when many cases were pre-symptomatic and no targeted intervention measures had been applied; • made their trip(s) during the time of day associated with travel to work and; • were part of the specific subgroup associated with the outbreak centre (in this case, those employed in meat-processing occupations). the variation described above is specific for workplace outbreaks in which employees are infected, but could be generally applied to any context where a defined subgroup of the population is more likely to be associated (e.g., school children, aged-care workers, etc.), or in which habitual travel patterns associated with particular times of day are applicable. for each of the three outbreak scenarios, we present the mobility-based estimates of the relative transmission risk distribution, and a time-varying correlation between our estimate and the case numbers ascertained through contact tracing and testing programs. for details of these correlation computations, see the supplementary information. cedar meats is an abattoir (slaughterhouse and meat packing facility) in brimbank, victoria. it is located in the western area of melbourne. it was the locus of one of the first sizeable outbreaks in australia after the initial wave of infections had been suppressed through widespread physical distancing interventions. meat processing facilities are particularly high-risk work environments for transmission of sars-cov- , so it is perhaps unsurprising that the first large outbreak occurred in this environment [ , ] . it began at a time when community transmission in the region was otherwise undetected. as the transmission cluster grew, it was thoroughly traced and subsequently controlled. the contact-tracing effort included (but was not limited to) intensive testing of staff, each of which required a negative test before returning to work, -day isolation periods for all exposed individuals, and daily follow-up calls with every close contact. the outbreak was officially recognised on april th, when four cases were confirmed in workers at the site and, according to media reports, victoria dhhs informed the meatworks of these findings [ ] . we also explored the effect of weighting mobility by a context-specific factor: the proportion of employed persons with occupations in meat processing ( figure b ). the geographic distribution of relative transmission risk due to mobility into brimbank during the nighttime → daytime transition is presented in figure (a), while the distribution generated by including both mobility and the proportion of meat workers in each lga is shown in figure (b). to validate our estimate, we computed spearman's correlation between this risk estimate for each region to the time-dependent case count for each region documented over the course of the outbreak (supplied by the victorian department of health and human services). we use spearman's rather than pearson's correlation because while we expect monotonic dependence between estimated relative risk and case counts, we have no reason to expect linear dependence or normally-distributed errors. the outbreak case data was supplied as a time series of cumulative detected cases in each lga for each day of the outbreak. therefore, we present our correlation as a function of time from april th, when recorded case numbers began to increase dramatically (before may st, the number of affected lgas was too small compute a confidence interval (n ≤ )). as case numbers increase, correlation between our risk estimates and case numbers hume ( ) melton ( ) wyndham ( ) whittlesea ( ) moorabool ( ) brimbank ( ) greater geelong ( ) banyule ( ) darebin ( ) moreland ( ) hobsons bay ( ) melbourne ( ) moonee valley ( ) maribyrnong ( ) yarra ( ) stonnington ( ) port phillip ( ) b) whittlesea ( ) moorabool ( ) brimbank ( ) greater geelong ( ) banyule ( ) darebin ( ) moreland ( ) hobsons bay ( ) melbourne ( ) moonee valley ( ) maribyrnong ( ) yarra ( ) stonnington ( ) port phillip the next scenario we examine began with a single spreading event that occurred during a large gathering at a social venue in western sydney. while workplaces have frequently been the locus of covid- clusters, many outbreaks have also been sparked by social gatherings [ , ] . in urban environments, such outbreaks can prove more challenging to trace, as the exposed individuals may be only transiently associated with the outbreak location. the crossroads hotel was the site of the first covid- outbreak to occur in new south wales after the initial wave of infections was suppressed. the cluster was identified on july th, , during a period when new cases numbered fewer than notifications per day. however, the second wave of community transmission in victoria produced sporadic introductions in nsw, one of which led to a spreading event at the crossroads hotel [ ] . based on media reports, state contact-tracing data indicated that the cluster began on the evening of july rd, during a large gathering [ ] . unlike the cedar meats cluster, the crossroads hotel scenario was not a workplace outbreak with transmission occurring in the same context for a sustained time period, but a single spreading event in a large social centre. for this reason, to estimate relevant mobility patterns we averaged trip numbers over all time-windows in our data (daytime → evening → nighttime → daytime) for the period of june th -july th. it was also necessary to perform some pre-processing of the mobility data provided by facebook in order to correlate case data provided by new south wales health to our mobility-based risk estimates due to substantial differences in the geographic boundaries used in the respective data sets (see supplemental information and technical note). aside from these minor differences, the method applied in this scenario is essentially the same as the one described above for the cedar meats outbreak. risk of transmission in an area is assessed as the proportion of travellers who entered the outbreak location from that area (see equation ). correlation of our risk estimate to the number of cases in each lga as a function of time is shown in figure (a) . heat maps of estimated risk and case numbers are shown in figures (b) and (c), respectively. in this analysis, the available data did not explicitly identify the outbreak to which each case was associated, however, it did distinguish between cases associated with local transmission clusters and those associated with international importation. because the crossroads hotel cluster was the only documented outbreak during this time, we attribute to it all cluster-associated cases during the period investigated. this assumption is anecdotally consistent with media reports that specify more detailed information about the residential location of individuals associated with the outbreaks. the covid- case data for new south wales is publicly available [ ] . could have been predicted based on case numbers and mobility data that were available in early june. our goal is to examine whether the effectiveness of mobility patterns in predicting relative transmission risk from point outbreaks can extend to community transmission scenarios in which outbreak sources are unknown. in the community transmission scenario, as with the crossroads hotel outbreak, there were no clear context-dependent factors that suggested the use of other population data. in contrast to the first two scenarios, community transmission was occurring in multiple locations at the beginning of our investigation period. for each day, the unscaled risk estimate r i is the product of the od matrix (averaged over the preceding week) and the vector of active case numbers in each location (see equation ). therefore, in this case the relative risk value r i represents the proportion of travellers into all areas containing active cases, with the contribution of each infected region weighted by the number of active cases (see equation ). for this scenario, we investigate the correlation between relative risk estimates at time t, and incident case numbers (notifications) at time t , for all dates between june st and july st. we the results of our correlation analysis for the victoria community transmission scenario are shown in figure the goal of this study was to develop and critically analyse a simple procedure for translating aggregate mobility data into estimates of the spatial distribution of relative transmission risk from covid- outbreaks. our results indicate that aggregate mobility data can be a useful tool in estimation of covid- transmission risk diffusion from locations where active cases have been identified. the utility of mobility data depends on the context of the outbreak and appears to be more helpful in scenarios involving environments where context indicates specific risk factors. the procedure we presented may also be useful during the early stages of community transmission and could help determine the extent of selective intervention measures. in community transmission scenarios, mobility will already have played a role in determining the distribution of case counts when community transmission is detected. our results indicate that the insight added by the incorporation of mobility data diminishes as case counts grow. however, we also observed low correlations due to stochastic effects in the crossroads hotel scenario. taken together, these results indicate that there is an optimal usage window that opens when case counts are high enough for aggregate mobility patterns to shed light on transmission patterns, and closes when these transmission patterns begin to determine the distribution of active cases which then predict their own future distribution with only limited information added by considering mobility. our examination of the second wave of community transmission in victoria showed that several weeks before it was recognised, the spatial distribution of a small number of active cases it is essential that the use of mobility data for disease surveillance comply with privacy and ethical considerations [ ] . due to this requirement, there will always be trade-offs between the spatiotemporal resolution of aggregated mobility data and the completeness of the data set after curation, which typically involves the addition of noise and the removal of small numbers based on a specified threshold. to help ensure users cannot be identified, facebook removes od pairs with fewer than unique users over the -hr aggregation period. the combination of this aggregation period with the -user threshold affects regional representation in the data set, particularly in more sparsely populated areas. the final product resulting from these choices contains frequently-updated and temporally-specific mobility patterns for densely populated urban areas, at the cost of incomplete data in sparsely populated regions. in general, increased temporal or spatial resolution will reduce trip numbers in any given set of raw data, which can have a dramatic impact on the amount of information missing from the curated numbers [ ] . the comparison of our results from the cedar meats outbreak and those from the crossroads hotel cluster demonstrate that the utility of aggregated mobility patterns in estimation of the spatial distribution of relative risk depends on the context of the outbreak, with more value in situations involving habitual mobility such as commuting to and from work. detailed examination of the inconsistencies between risk estimates and case data from the crossroads hotel outbreak indicate that small numbers of people travelling longer distances were responsible for the relative lack of correspondence in that scenario. in particular, news reports discussed instances of single individuals who had travelled from the rural suburbs to visit the crossroads hotel for the july rd gathering who then infected their family members. these scenarios were not consistent with the risk predictions produced by the mobility patterns into and out of the region and exemplify the limitations of risk assessment based on aggregate behavioural data. the mobility data provided by the facebook data for good program represents a non-uniform and essentially uncharacterised sample of the population. while it is a large sample, with aggregate counts on the order of % of abs population figures, the spatial bias introduced by the condition of mobile app usage cannot be determined due to data aggregation and anonymisation. while it is possible to count the number of facebook users present in any location during the specified time-intervals, it is not possible to distinguish which of those are located in their places of residence. in order to account for the (possibly many) biases affecting the sample, a detailed demographic study would be necessary that is beyond the scope of the present work. a heat map (supplemental figure s ) of the average number of facebook users present during the nighttime period ( am to am) as a proportion of the estimated resident population reported by the abs ( [ ] ) shows qualitative similarity to the spatial distributions of active cases and relative risk shown in figure on a fundamental level, mobility patterns are responsible for observed departures from continuum mechanics observed in real epidemics [ ] . over the past two decades, due to public health concern over the pandemic potential of sars, mers, and novel influenza, spatially explicit models of disease transmission have become commonplace in simulations of realistic pandemic intervention policies [ , ] . such models rely on descriptions of mobility patterns which are usually derived from static snapshots of mobility obtained from census data [ , , ] . while this approach is justifiable given the known importance of mobility in disease transmission, it is also clear that the shocks to normal mobility behaviour induced by the intervention policies of the covid- pandemic will not be captured by static treatments of mobility patterns. to account for the dynamic effects of intervention, several models have been developed to simulate the imposition of social distancing measures through adjustments to the strength of contextspecific transmission factors [ , ] . this type of treatment implicitly affects the degree of mixing between regions without explicitly altering the topology of the mobility network on which the model is based and it is unclear whether such a treatment is adequate to capture the complex response of human population behaviour. given the results of our analysis, the incorporation of real-time changes in mobility patterns could add policy-relevant layers of realism to such models that currently rely on static, sometimes dated, depictions of human movement. example scripts and data used for computing risk estimates and correlations can be found in the associated github repository: https://github.com/cjzachreson/covid- -mobility-risk-mapping however, due to release restrictions on the mobility data provided by facebook, the od matrices are not included as these were derived from the data provided by the facebook data for good program (random matrices are included as placeholders). the processed mobility data used in this work may be made available upon request to the authors, subject to conditions of release consistent with the facebook data for good program access agreement. a generic implementation of the code used to re-partition od matrices between different geospatial boundary definitions is enclosed in the supplementary technical note. the data used in our study was provided by the facebook data for good program. the data set (in the disease prevention maps subset) is aggregated from individual-level gps coordinates collected from the use of facebook's mobile app. therefore, the raw data is biased to over- (national-scale) and smaller (city-scale) regions of interest, we determined that the state-level data provided the best balance, with trip numbers large enough to produce a sufficiently dense network of connections while still providing a subregion size that is usually smaller than the local government areas for which case data is reported. because the raw mobility data is provided as movements between tiles, while case data is provided based on the boundaries of local government areas. we note that while facebook releases data aggregated to administrative regions, these regions were not geographically consistent with the current lga boundaries for australia. in order to ensure consistency of our method across datasets and jurisdictions, we produced our own correspondence system. we did this by performing two spatial join operations. these associate either tiles or lgas with meshblocks (the smallest geographic partition on which the australian bureau of statistics releases population data). meshblocks were associated based on their centroid locations. each meshblock centroid s was associated to the tile with the nearest centroid and to the lga containing it. we did not split meshblocks whose boundaries lay on either side of an lga or tile boundary, as their sizes are sufficiently small that edge effects are negligible (in addition, the set of lgas forms a complete partition of meshblocks, so edge effects were only observed for tile associations). we then associated tiles to lgas proportionately based on the fraction of the total meshblock population within that tile that was associated with each overlapping lga. once a correspondence is established between the tile partitions on which mobility data is released and the lga partitions on which case data is released, the matrix of connections between tiles must be converted into a matrix of connections between lgas. the supplementary technical note explains how we performed this step, and gives a general method for converting matrices between partition schemes. briefly, the number of trips between two locations in the initial data is split between the overlapping set of partitions in the new set of boundaries (in this case, local government areas), based on the correspondence between partition schemes determined as explained in the previous subsection. to investigate the spatial sample biases present in the mobility data provided by facebook, we examined the ratio of facebook users to abs population for each suburb in victoria. while the true number varies from day to day, an example of this distribution is shown as a heat map in supplemental figure s , which displays the average number of facebook mobile app users indexed to each lga between the hours of am and am from may th to june th, divided by the estimated resident population reported by the abs in . the distribution is narrow, with most urban areas falling in the range of % to % facebook users. however, this is not an exact representation of residential population proportions, as many mobile users work during the nighttime and will not be located at their residence during the selected period. unfortunately, it is not possible to precisely quantify the bias introduced by facebook's sampling scheme. despite these limitations, it may still be informative to examine whether accounting for the bias for the cedar meats outbreak scenario, accounting for the facebook sample bias in this way improves the correlation between our mobility-based relative risk estimate and the recorded case counts ( figure s a ). for the community transmission scenario, performing this extra step does not appear to substantially change the result shown in figure (compare figure s b and figure c ). we used spearman's rank correlation to investigate the correspondence between our relative risk estimates and documented case data. this measure of correlation is typically used when comparing ordinal data, or, more generally, when monotonic relationships are expected, but errors are not normally-distributed. in order to investigate the monotonicity between relative risk estimates and reported case numbers, we aligned the documented case data for all regions in which infections had been tabulated against the corresponding relative risk estimates for those regions. note that our correlations did not include regions for which no case data was available. therefore, our correlation results illustrate the degree to which risk estimates are monotonic with case numbers, but do not account for any risk estimates made in areas with no cases to compare to. this results in a high degree of uncertainty when the number of affected areas is small, reflected by the wide confidence intervals observed in the early stages of the cedar meats and crossroads hotel outbreaks (figures , and a , respectively). the % confidence intervals were computed using fisher's z transformation with quantile parameter α = . . two data sets from the australian bureau of statistics were used in this study: ) number of residents by industry of occupation ( ), and ) resident population ( ). the distributions shown in figure s were computed by dividing the number of facebook users indexed to each lga during the nighttime period by the resident population in each lga. we obtained the population data from the abs population dataset which is publicly available [ ] . the facebook user populations are provided by the data for good program in addition to the mobility data discussed above. as a context-specific risk factor for the cedar meats outbreak we obtained the number of to compute the factors used to weight the mobility-based relative risk predictions, we divided the total number of workers in both of the above categories by the number of employed persons (those employed full time or part-time) in each lga, which we also drew from the australian census via census tablebuilder. covid- case data by local government area is available from australian jurisdictional health authorities. for this work, we used data provided by nsw health [ ] (all data is publicly s available) and from victoria dhhs. the data used for the cedar meats outbreak scenario was obtained from dhhs through a formal request to the victorian agency for health information (vahi) and cannot be made public in this work. the case data by lga used to evaluate the victoria community transmission scenario was taken directly from the covid- daily update archives available on the dhhs public website [ ] . transmission routes of respiratory viruses among humans. current opinion in virology guideline for isolation precautions: preventing transmission of infectious agents in health care settings the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application temporal dynamics in viral shedding and transmissibility of covid- epidemiologic features and clinical course of patients infected with sars-cov- in singapore quantifying sars-cov- transmission suggests epidemic control with digital contact tracing substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov- ) presymptomatic transmission of sars-cov- -singapore presymptomatic 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response to covid- in france covid- ) at a glance - covid- among workers in meat and poultry processing facilities- states interregional sars-cov- spread from a single introduction outbreak in a meat-packing plant in northeast first cedar meats covid- case confirmed on infection fatality rate of sars-cov- infection in a german community with a super-spreading event. medrxiv high sars-cov- attack rate following exposure at a choir practice covid- weekly surveillance in nsw, epidemiological week , ending fears of further spread as crossroads hotel virus cases become infectious within a day nsw covid- cases by location and likely source of infection updates about the outbreak of the coronavirus disease (covid- ) creating a surrogate commuter network from australian bureau of statistics census data. scientific data by region synchrony, waves, and spatial hierarchies in the spread of influenza mitigation strategies for pandemic influenza in the united states interfering with influenza: nonlinear coupling of reactive and static mitigation strategies what can urban mobility data reveal about the spatial distribution of infection in a single city investigating spatiotemporal dynamics and synchrony of influenza epidemics in australia: an agent-based modelling approach impact of non-pharmaceutical interventions (npis) to reduce covid mortality and healthcare demand modelling transmission and control of the covid- pandemic in australia bing maps tile system about tablebuilder; key: cord- -q w fb i authors: ewald, paul w. title: evolution of virulence date: - - journal: infect dis clin north am doi: . /s - ( ) - sha: doc_id: cord_uid: q w fb i at the close of the th century, the germ theory had generated a new understanding of the causes of acute infectious diseases and revealed new directions for study. this understanding contributed to the greatest improvements in health in the history of medicine. at the end of the th century, the second stage of this disciplinary development is occurring. the old germ theory is being expanded into a new germ theory, which, by integrated the full spectrum of biologic disciplines. this new germ theory is emphasizing how environments and human activities influence the characteristics of infectious agents and the broader role of infection as a cause of chronic diseases. human history cannot be understood well without understanding the causes and consequences of human disease. this fact has become amply apparent over the past few decades as the impacts of infectious diseases have been studied in the context of war, colonization, and competition [ ] [ ] [ ] [ ] [ ] . it is much less widely appreciated that the reverse is also true. historical studies of infectious diseases may help guide modern health sciences to recognize options for controlling diseases of the present and future. ecologic and evolutionary perspectives are enmeshed with the historical perspective of infectious diseases, because infectious agents spread and evolve over times scales that accord with historical events. they may influence historical events and may be influenced by such events. the influence of historical events on the evolution of pathogens largely has been neglected until the past quarter century. it has become clear that activities that were undertaken for one purpose can have unforeseen effects on the evolution of important characteristics of pathogens, such as virulence (which is defined broadly here to mean the degree of harm imposed on the host). an understanding of these evolutionary effects helps in understanding why some pathogens cause more harm than others, the environmental circumstances that permit this harm, and, most importantly for the future, the human activities that can ameliorate or prevent this harm. for most of the th century, the prevailing dogma was that disease organisms eventually should evolve toward benign coexistence with their hosts; harmful diseases were interpreted as a transitory state of maladaptation [ ] [ ] . this belief has not been useful for ameliorating the suffering caused by infectious diseases, because it suggests that the occurrence of severe disease is bad luck and that not much can be done to control this evolutionary process. this view arose more from assumptions about the harmony of nature than from rigorous application of evolutionary principles. specifically, it failed to cast the problem in the context of natural selection. rather than asking whether harmful or mild variants would win out in competition with each other over the short run, the focus was on what was stable over the long run. natural selection is powerless to favor long-term stability if the variants that win in the short term destabilize the system. natural selection may favor the evolution of extreme harmfulness if the host exploitation that causes this harm enhances the competitive success of the harmful variants over benign variants in the short run. if predator-like variants of a pathogen population out-produce and out-transmit benign variants, benign coexistence may be precluded. instead of generating longterm stability, the evolutionary conflict of interest between a predator-like pathogen and its host generates an evolutionary arms race in which pathogen and host each evolve characteristics that give them a leg up on the other, shifting the level of host exploitation closer to the optimum for the pathogen or that of the host. before the last decades of the th century, a few authors expressed reservations about the traditional dogma [ ] [ ] [ ] , but they largely were ignored. over the past quarter century, however, the evolution of virulence has been broadly investigated by a theoretical framework that is based on the principles of natural selection [ ] [ ] [ ] [ ] [ ] . this framework offers explanations for the broad range of virulence found among host parasite relationships and offers possibilities for virulence management (ie, the control of diseases by controlling the evolution of virulence) [ ] . the evolutionary framework also provides insight into the true scope of infectious causation of chronic disease and a sense of which diseases can be prevented or cured by developing disease-control strategies, such as vaccines and antibiotics. for acute infectious diseases, theory about the evolution of virulence focuses on the negative effects of virulence on transmission of pathogens between hosts. much of the variation in these negative effects of virulence depends on whether pathogens can be transmitted from hosts that have become immobilized by the infections. pathogens that can be transmitted readily from immobile hosts should be molded by natural selection to exploit hosts severely and to be highly virulent [ ] . the reason is simple. variants that exploit severely gain the competitive advantages of this exploitation while incurring little, if any, competitive cost from the illness that their exploitation generates, because they still can be transmitted from hosts that have the severe, immobilizing illness. specific applications of this idea are presented. parasites transmitted by biting arthropods can be transmitted effectively from immobilized hosts and therefore should evolve to a higher level of virulence than directly transmitted parasites. a comparison of viral, bacterial, and protozoal agents of human diseases showed that vector-borne pathogens are more lethal on a per-infection basis than are directly transmitted pathogens [ ] . the association between vector-borne transmission and virulence explains why diseases such as malaria, yellow fever, dengue, sleeping sickness, and visceral leishmaniasis are so severe, whereas most of the respiratory-tract pathogens of humans are relatively benign. a follow-up comparison of vector-borne pathogens indicates that this greater virulence of vector-borne pathogens is related to adaptation to the conditions of vector-borne transmission rather than to some spurious correlate of vector-borne transmission, such as injection of a pathogen below the surface of the skin. this follow-up comparison used historical data to assess the virulence of particular vector-borne pathogens in humans in relation to the degree to which the pathogen had evolved in response to vector-borne transmission between humans. specifically, it compared the virulence of vector-borne pathogens that had just been transmitted to humans with the virulence of the same kind of vector-borne pathogen that had been cycling extensively in humans and should be better adapted to vector-borne transmission between humans. as expected from evolutionary theory, the pathogens that had been cycling in humans were more severe in humans than those that recently had been introduced to humans from some other vertebrate host [ ] . the yellow fever virus, for example, was less deadly in humans just after it entered the human population than it was in outbreaks that involved extensive cycling of transmission between mosquitoes and humans. evolutionary management of the virulence of vector-borne diseases requires interventions that elevate the immobilization of hosts more costly to the infecting pathogens. logic dictates that this goal can be accomplished by mosquito proofing of dwellings. people who are immobilized by illness are more likely to be at home or in a hospital than people who do not feel ill; transmission from homes and hospitals therefore should tend to involve relatively virulent variants. when such dewllings are mosquito-proof, however, vectors cannot gain access to the severely ill people who are incapacitated inside these dewllings. the vectors will instead transmit pathogens from those infected people who feel healthy enough to get up out of bed and walk outdoors. these pathogens should tend to be relatively benign. the vector proofing of dwellings therefore should favor transmission of the benign strains from people in the outside environment instead of transmission of the more virulent strains that infect the bed-ridden. this favoring of benign strains through the mosquito proofing of dewllings would be manifested as an evolutionary decline in virulence. though this idea has not been tested directly, geographic variations in virulence and the demonstrated effect of vector proofing of houses on disease transmission suggests that it will work [ ] . strains of malaria are mild where the potential for vector-borne transmission is low and sporadic [ ] [ ] , and mosquito proofing of houses has had a strong inhibitory effect on transmission of plasmodia [ ] . as with vector-borne pathogens, evolutionary theory predicts that waterborne pathogens should evolve to relatively high levels of virulence, because they can be transmitted from immobilized people. reliance on the mobility of infected hosts is low for water-borne pathogens, because the wastedisposal activities of attendants and the movement of water can contaminate sources of drinking water. the lethality of diarrheal bacteria is correlated positively with the extent to which they are water borne [ ] . geographic comparisons also support the idea that the virulence of diarrheal diseases is linked to water-borne transmission; among shigella, for example, severe strains have been disproportionately common where the potential for waterborne transmission is high [ ] . changes in such ratios over time support the idea that the virulence of diarrheal pathogens couuld be managed evolutionary by blocking waterborne transmission. diarrheal pathogens, such as shigella and vibrio cholerae, evolved toward lower virulence as the water supplies were cleaned up in north america, south america, europe, and asia. [ , ] . like vector-borne and water-borne pathogens, pathogens acquired while in the hospital can be transmitted from immobile hosts. in this case, the transporting is done on the hands of doctors, nurses, and other attendants and the objects they touch. such attendant-borne transmission is the major route for most serious hospital-acquired pathogens, such as the staphylococci, streptococci, enterococci, pseudomonas, and clostridium difficile [ ] . attendants usually do not get infected, partly because they are less vulnerable than their patients, they wash their hands before leaving the environment, and they may have generated some immunity to the hospital organisms. although the evolution of virulence in hospitals has been studied only superficially, the available information supports the idea that cycling in hospitals makes pathogens more harmful. a review of all hospital outbreaks of escherichia coli-related infection that occurred in the united states and united kingdom before the effective use of antibiotics assessed whether increased attendant-borne transmission was associated with increased lethality [ ] . a statistically significant association was found; strains that had been circulating for a week rarely caused death, but strains that had circulated for many months killed about in infants [ ] . the implications for virulence management of attendant-borne transmission in hospitals mirror the implications for vector-borne and waterborne pathogens. if the attendant-borne transmission is blocked through proper hand washing and glove use, strains circulating in hospitals increasingly are represented by strains that are brought from the outside community; such community strains depend on host mobility for transmission and tend to be less virulent than strains that have been cycling in hospital environments. pathogens that are durable in the external environment also can be transmitted from very ill people, because such pathogens can reach susceptible individuals by relying on the mobility of susceptible, rather than infected, people. the high durability of smallpox, mycobacterium tuberculosis, and corynebacterium diphtheriae in the external environment helps explain why these pathogens have been scourges throughout history. the agent of plague, yersinia pestis, can be transmitted as a durable pathogen by the respiratory route and as a vector-borne pathogen. a re-analysis of plague from evolutionary and historical perspectives suggests that both routes were important in the black death of the th century [ ] . perhaps it was this combination that led this outbreak of y pestis to be so unusually destructive. as is the case with the preceding categories, virulence management of sitand-wait pathogens requires selective blocking of transmission from immobile individuals. in this case, however, the intervention requires selective inhibition of durable pathogens from the chain of transmission; this goal could be accomplished by requiring frequent air exchanges and decontamination of surfaces. vaccination programs generally do not eradicate target pathogens; at the global level, only the smallpox vaccine has eradicated its target from the human population. when eradication does not occur, policymakers must consider effects of vaccination not only on the frequency of infection but also on the virulence of the pathogens that are left in the wake of the vaccination program. vaccination programs that cause evolutionary reductions in the virulence tend to be successful because they leave behind mild variants that may circulate and protect unvaccinated individuals against virulent variants that might remain in the population, arise by mutation, or enter from other areas. the circulating, benign strains may protect unvaccinated individuals and the population as a whole against the spread of harmful strains. this process of virulence management can be accomplished by a virulence antigen strategy. this strategy dictates that vaccines should be based on virulence antigens (ie, antigens that make mild but transmissible organisms harmful) [ , ] . the virulence antigen strategy differs from the traditional approach to vaccine development, which selects antigens on the basis of the protection conferred to study subjects regardless of whether the antigens are virulence antigens. by selectively suppressing the virulent variants, virulence antigen vaccines force the target pathogens to evolve toward benignity. the virulence-antigen strategy is well illustrated by the diphtheria toxoid vaccine, which is based on a modified diphtheria toxin. the intact toxin liberates nutrients to the bacterium by killing nearby human cells. the immunologic response to the toxoid vaccine neutralizes the toxin and causes the toxin to be a net drain on the bacterium's nutrient budget. toxinless c diphtheriae still can infect and be transmitted from people [ ] ; the toxin therefore qualifies as a virulence antigen, because it makes viable benign pathogens harmful. when vaccination prevents the negative effects of the toxin, the toxinless strains should have a competitive advantage over the toxigenic strains, because the toxinless strains do not waste valuable resources by producing an ineffective toxin. toxinless strains therefore should increase in frequency relative to toxigenic-strains wherever toxoid vaccines have been administered extensively. this transition is confirmed by the historical data [ ] [ ] [ ] [ ] . the most detailed data set came from the vaccination program administered in romania from through . as the acquired immunity rose to %, the percentage of isolates that produced toxin dropped from % to %, and diphtheria vanished [ ] . if all of the costs of vaccine development and administration could be tallied and health benefits per dollar spent calculated, the control of diphtheria by the toxoid vaccine surely would be one of the most costeffective vaccine programs in history. only the smallpox vaccination program would rank higher, because it eradicated smallpox, which allowed for the abandonment of continuous vaccination. theory about the evolution of virulence is fundamentally different for chronic infectious diseases than for acute infectious diseases. this difference is well illustrated by the virulence of sexually transmitted diseases, which are intermediate between acute and chronic infectious diseases. syphilis has an acute phase that is characterized by a primary chancre, an early chronic phase that is characterized by a pervasive rash, and a late chronic phase (tertiary syphilis), which may involve mental illness, tumors, paralysis, meningitis, tremors, and cardiovascular disease. in other sexually transmitted diseases, the acute phase is inconspicuous or entirely lacking. hiv type (hiv- ) causes a mild flu-like illness within about a month of the onset of infection but is generally lethal in its chronic phase. the human tlymphotropic virus type causes asymptomatic acute infection soon after the onset of infection but causes paralysis, leukemia, or lymphoma decades later in a minority of infected people. because infected hosts generally must be mobile to engage in sexual activity, natural selection favors benignity of sexually transmitted pathogens over the short run. to be successful in the context of natural selection, however, sexually transmitted parasites must be infectious over relatively long periods of time, because options for sexual transmission of a given infection are generally less frequent than opportunities for transmission of typical agents of acute infectious diseases-a person generally has sex with many fewer people per week than he can sneeze on. natural selection therefore favors long-term persistence and contagiousness of sexually transmitted pathogens within each host. accordingly, most sexually transmitted pathogens are characterized by adaptations that allow the pathogen to evade the immune system to persist in and be transmitted from the body. although sexually transmitted pathogens are molded by natural selection to be benign over the short run, this long-term persistence within hosts raises the possibility of long-term damage, even though there is low probability of severe damage during any small period of time during the first years of infection. according to this framework, the evolution of virulence depends on the potential for sexual transmission in the host population. if the population is characterized by a high potential for sexual transmission (high rates of partner changes and unprotected intercourse), pathogen variants that replicate to relatively high levels soon after infection tend to have a greater chance of being transmitted to new partners. if the host population is characterized by a low potential for sexual transmission, the chance of a partner change occurring soon after infection is low, and the advantages of a high shedding of pathogens soon after infection is also low. if sexual partners remain together for a long period of time, a low probability of infecting the partner per act of sexual intercourse is of little consequence to the probability of pathogen transmission between the partners, because a large number of sexual contacts will occur during the long-term relationship. the low potential for sexual transmission thus favors low levels of exploitation and low virulence. a high potential for sexual transmission should favor elevated exploitation, which should increase the chances that negative side effects eventually will occur in the long run. this theoretical framework leads to two central predictions: the virulence of sexually transmitted pathogens ( ) should be greater in populations in which the potential for sexual transmission is greater and ( ) should increase within a population in response to an increase in the potential for sexual transmission. tests of these predictions uniformly have confirmed them whenever comparisons provide clear differences in the potential for sexual transmission and the virulence of infections. these comparisons involve hiv, human papillomavirus, human herpesvirus , and human t-lymphotropic viruses [ ] . the confirmations suggest that the virulence of sexually transmitted pathogens could be reduced by reducing the potential for sexual transmission through interventions designed to reduce partner changes and increase the use of barrier-type contraception. information on the virulence of sexually transmitted pathogens from restricted regions provides a sense of the potential effect of such interventions. the evidence from senegal is perhaps the most informative in this regard. the population in senegal has a low potential for sexual transmission relative to populations of other countries in sub-saharan africa. the relatively benign hiv type has not been replaced by the more virulent hiv- in senegal, as it has in other areas of west africa [ ] . the hiv- subtype that predominates in senegal is more benign than the hiv- subtypes that predominate in sub-saharan countries with a higher potential for sexual transmission [ ] . a similar difference occurs among the strains of the sexually transmitted bacterium chlamydia trachomatis. the strains of c trachomatis that predominate in senegal are more mild than the strains that predominate in sub-saharan countries with a higher potential for sexual transmission [ ] . these comparisons illustrate how a low potential for sexual transmission can favor benign sexually transmitted pathogens even in relatively small populations that are not isolated from surrounding populations. chronic infectious diseases may seem passe´relative to the acute emerging diseases that have monopolized the headlines, such as ebola virus and severe acute respiratory syndrome. chronic diseases, however, pose a much greater threat over the near term, and something important probably can be done to control them if their causes are examined. these two claims may seem presumptuous at first. the worst plagues of history have been acute infectious diseases that spread swiftly and lethally through human populations. the most damaging examples generally have been well adapted to transmission through human populations, either directly from person to person or indirectly through a biologic vector, such as a mosquito, or a nonbiologic vehicle, such as water. these diseases as a rule were longadapted to humans and caused their harm when they spread through previously unexposed human populations. measles and smallpox decimated native populations in the americas when they were introduced during the early colonial period [ ] [ ] [ ] [ ] . syphilis probably caused large amounts of death in previously unexposed populations in europe as a result of a reciprocal introduction into europe from the new world [ ] [ ] . these outbreaks were devastating largely because they were introduced from human populations with which they had been in evolutionary arms races into populations that had no acquired immunity and little if any evolved resistance. terrible new outbreaks of long-standing human diseases are unlikely to be a great threat in the future because the current high level of worldwide transportation is far greater than the level needed for global transport of well-adapted human pathogens. so far as is known, the only pathogens of humans that have not already been mixed globally by human travel are zoonotic (ie, newly introduced into humans from other species). zoonotic diseases generally have limited potential for spread in human populations and therefore have little potential for causing devastating epidemics. aids is the only exception; however, even aids causes minor damage compared with the decimation that was caused in new world populations on contact with old world pathogens. the diseases that are known to be a threat in the near future are those that currently are killing massive numbers of humans. in rich countries, these diseases are chronic diseases that have been and still widely are presumed to be caused by bad genes and harmful environments rather than by infectious agents. for most of the th century, the accepted wisdom has been that the scope of infectious chronic diseases is narrow, largely limited to the chronic phases of sexually transmitted diseases and a handful of other diseases, such as tuberculosis and shingles, diseases that were thought of as chronic sequelae to acute infectious diseases. evolutionary theory, however, suggests that many if not most of the major chronic diseases of humans are caused by infection [ ] . the logic leading to this conclusion involves a simple application of natural selection. there are three general categories of disease causation: genetic, parasitic, and nonparasitic environmental. (''parasitic'' is broadly defined to include infectious causes.) evolutionary considerations severely limit the feasibility of genetic causation for the most common severe chronic diseases, because such diseases tend to reduce any causal alleles down to a frequency that can be maintained by mutation [ ] . if an allele provides some compensating benefit (as is the case with the allele for sickle cell anemia), it can be maintained, but few of the common and harmful diseases with unknown causes have characteristics that are consistent with such a scenario. although a great amount of research effort has been spent on attempts to discover genetic causes of chronic diseases, this research generally has identified only genetic predispositions to common damaging diseases rather than direct causes. even in the case of cancer, where mutational causes have been identified, these causes are insufficient to explain any more than a minuscule portion of human cancer without invoking other categories of causation. in no case has the research on genetic causation of chronic disease led to a practical breakthrough that decisively controls or cures any common and damaging chronic disease. in contrast to this lack of success, infectious causes of chronic diseases have been documented (table ) , and preventive or curative interventions have been enacted (with vastly less funding). peptic ulcers, stomach cancer, and liver cancer are recognized as being caused by infection. peptic ulcers and some stomach cancer can be cured and prevented by antibiotic treatment [ ] , and many cases of liver cancer have been prevented by screening the blood supply for hepatitis b and c viruses. infectious agents have been associated with a large proportion of the most common severe chronic diseases of unknown cause, such as diabetes, alzheimer's disease, atherosclerosis, and schizophrenia ( table ) . because infectious causation of chronic diseases generally cannot be demonstrated with the same level of certainty as infectious causation of acute diseases (eg, koch's postulates generally cannot be satisfied), acceptance of infectious causation is more protracted for chronic diseases [ ] . the evidence for infectious causation of these diseases is steadily mounting and often is making sense of the evidence for genetic and noninfectious environmental causation. this coalescence of perspectives is well illustrated by the e alleleassociated diseases: atherosclerosis, stroke, alzheimer's disease, rheumatoid arthritis, and multiple sclerosis. the e allele is maintained at frequencies that range from about % to % in different human populations. its frequency is lowest in populations that have been living in high densities for the past few thousand years. the frequency is higher in populations that have been relatively small and isolated during this time, and it is highest in people who have been hunter-gatherers into the th century. even the lowest frequency of the e allele is too great to be maintained simply by mutation. the e allele is the primary allelic form of the apolipoprotein e gene in other primates and cannot be considered a defective allele. one possible explanation is that the e allele increases vulnerability to at least one infectious cause of the e allele-associated diseases. although many pathogens have been associated with these diseases (table ) , one pathogen, chlamydia pneumoniae, has been associated with all of them. this finding raises the possibility that the e allele increases vulnerability to c pneumoniae infection. as a respiratory-tract pathogen, c pneumoniae undoubtedly inflicts a heavier cost on dense human populations than on sparse populations. if so, the longer that a particular ethnic group has lived in high-density populations, the greater the cumulative selective pressure against the e allele. in accordance with this scenario, individuals who are infected with c pneumoniae are about four times as likely to have the e allele as are individuals from the general population [ ] . c pneumoniae apparently has evolved to take advantage of people who have the e allele and has driven down the frequency of e allele over time. the theoretical framework for understanding the evolution of virulence of sexually transmitted pathogens provides clues about which infectious agents are the most likely causes of these illnesses. the primary requirement for infectious causation of chronic disease is persistent infection, and this a question mark indicates transmission route is uncertain. abbreviations: ebv, epstein-barr virus; n, nonsexually transmitted; s-o, sexually transmitted by oral contact; s-g, sexually transmitted by genital contact. theoretical framework proposes that sexual transmission favors persistent infections more than any other mode of transmission. one caveat applies. pathogens transmitted by sexual oral contact should be selected to be persistent for the same reason that pathogens transmitted by sexual genital contact are selected to be persistent (ie, because sexual oral contact occurs rarely relative to contact through coughing or sneezing). if sexual transmission is defined broadly to include transmission through sexual oral and genital contact, sexually transmitted pathogens over the past quarter century have been responsible for a disproportionately large fraction of the chronic diseases that have been accepted as being caused by infection; about % of all human pathogens are sexually transmitted by this definition, but about half of the pathogens that cause these chronic diseases are sexually transmitted (see table ). they are also candidate causes of the chronic diseases for which infectious causation strongly is implicated but not yet accepted (see table ). to identify infectious causes of chronic diseases, one should look closely at the sexually transmitted pathogens. ecological imperialism. the biological expansion of europe plagues and peoples guns, germs and steel epidemics and 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atherosclerosis in non-obese japanese type diabetic patients periodontal disease and cardiovascular disease: epidemiology and possible mechanisms maternal herpesvirus infections and risk of acute lymphoblastic leukemia in the offspring human papillomavirus type infection and squamous cell carcinoma of the head and neck in never-smokers: a matched pair analysis identification of a proviral structure in human breast cancer mouse mammary tumor virus-like gene sequences in breast tumors of australian and vietnamese women jc virus dna is present in the mucosa of the human colon and in colorectal cancers association of human polyomavirus jcv with colon cancer: evidence for interaction of viral t-antigen and beta-catenin hepatitis c virus infection and incident type diabetes is crohn's disease caused by a mycobacterium? comparisons with leprosy, tuberculosis, and johne's disease i thank gregory m. cochran and levi g. ledgerwood for contributing to the development of the ideas presented in this article. key: cord- -xbw k m authors: castano, nicolas; cordts, seth; jalil, myra kurosu; zhang, kevin; koppaka, saisneha; bick, alison; paul, rajorshi; tang, sindy ky title: fomite transmission and disinfection strategies for sars-cov- and related viruses date: - - journal: nan doi: nan sha: doc_id: cord_uid: xbw k m contaminated objects or surfaces, referred to as fomites, play a critical role in the spread of viruses, including sars-cov- , the virus responsible for the covid- pandemic. the long persistence of viruses (hours to days) on surfaces calls for an urgent need for surface disinfection strategies to intercept virus transmission and the spread of the disease. elucidating the physicochemical processes and surface science underlying the adsorption and transfer of virus between surfaces, as well as their inactivation, are important in understanding how the disease is transmitted, and in developing effective interception strategies. this review aims to summarize the current knowledge and underlying physicochemical processes of virus transmission, in particular via fomites, and common disinfection approaches. gaps in knowledge and needs for further research are also identified. the review focuses on sars-cov- , but will supplement the discussions with related viruses. membrane. the lipid bilayer is susceptible to chemical disruption, for example, by surfactants. disruption of the lipid envelope could render the virus inactive. in addition to the lipid layer, the m and e proteins could be targets for the inactivation or weakening of sars-cov- due to their critical roles in viral envelope assembly and replication. while enveloped viruses are more susceptible to inactivation than non-enveloped viruses, they possess the ability to adapt the envelope molecular profile to evade immune systems. , while the exact size of sars-cov- has not been reported, the approximate diameter of the closely related sars-cov- is - nm, with spikes that extend ~ nm out (total diameter of ~ - nm). the isoelectric point (pi) of viruses is important in determining their adsorption characteristics. based on the protein composition, the pi of the m and n proteins of other coronaviruses have been computed theoretically to be ~ . - . . [ ] [ ] [ ] the pi of the m and n proteins on sars-cov- are likely to be within the same range. although the overall isoelectric points of coronaviruses have not been reported, they are expected to be largely influenced by the isoelectric properties of m and n proteins, , and can be further approximated by accounting for the dissociation constants of all amino acids of the virus. sars-cov- requires biosafety level (bsl) facilities to handle. to facilitate the investigation of its infectivity, transmission, and disinfection, it is useful to identify surrogates with similar structures to sars-cov- but with reduced risk of human infection. the first class of surrogates involves the use of natural viruses with low infectivity in humans. table shows these surrogate viruses, host cells, and bsl levels reported thus far. , a second class of surrogates is pseudotyped viruses. they are derived from parent viruses such as the murine leukemia virus (mlv), human immunodeficiency virus (hiv), and herpes simplex virus (hsv). the genome of the parents are modified for safer use in bsl labs. the synthesis of pseudotyped viruses is highly adaptable and allows for the incorporation of various kinds of envelope glycoproteins. , for example, sars-cov- s glycoprotein has been incorporated into a lentiviral pseudotyped virion system to determine the potential drug targets for the virus. a third class of surrogates involves artificial capsids that emulate the viral architecture. for example, peptide capsids have been constructed using capsid proteins to serve as nonpathogenic viral surrogates. they have been used to study aspects of viral infectivity, applied as antimicrobial agents to disrupt bacterial lipid bilayer membranes, and programmed to carry specific genetic cargo and deliver into the cytoplasm of human cells. understanding the transmission routes of viruses is crucial to the development of effective control measures. three primary transmission routes have been found to contribute to the spread of respiratory viruses (e.g., sars-cov- and - , measles, hcov, rhinovirus, and influenza virus) ( figure a ): ) direct contact between individuals, ) indirect contact via contaminated objects (fomites), ) airborne transmission via droplets and aerosols. direct contact involves the transmission of the virus through physical contact between an infected host and a susceptible individual. direct contact is a potent transmission route since the viral load can be large, and the virus spends a shorter amount of time outside of a host compared with other routes of transmission. for mers, sars-cov- , and sars-cov- , direct contact is considered a major transmission route. , indirect contact involves the transmission of the virus through a contaminated intermediate object called a fomite. fomites are inanimate objects or surfaces that can become contaminated by the physical contact with either another infected fomite or skin, or by settling airborne particles. fomite transmission can occur when an individual touches a contaminated fomite, and then touches their facial membranes ( figure b ). numerous studies have implicated fomites as a significant virus transmission route in a range of environments. , although the transfer efficiency of sars-cov- from fomites to other fomites or skin is not well characterized, the transfer efficiency of a number of viruses has been investigated, and will be detailed in section . respiratory viruses can also become airborne and spread via particles generated by sneezing, coughing, talking, or exhaling. the particles generated can be classified into droplets or aerosols based on a cut-off diameter of μm. these airborne droplets and aerosols can cause infection through inhalation into the respiratory tract, or by settling onto fomites. due to their large size, droplets typically fall within - m of the source within seconds (figure ). , [ ] [ ] [ ] aerosols are smaller and can remain suspended in the air for minutes to hours (figure ) , depending on the environmental conditions. , such prolonged suspension could increase the distance the virus travels from the source, and the number of individuals and fomites exposed to the virus. detailed experimental and theoretical approaches have estimated that more violent events such as sneezing can deposit droplets and aerosols up to - m away from the source. , following the initial respiratory event, nearby air currents (e.g., from ventilation or wind) can re-suspend aerosols and extend the range over which aerosols can travel. although the degree to which sars-cov- can be transmitted by aerosol remains unclear, early evidence from a study in wuhan hospitals reported that the virus was detected in aerosol samples from areas open to the general public, ~ - meters from the source. airborne droplets and aerosols can also deposit onto and contaminate fomites. a study on sars-cov- infected patients in isolation rooms showed contamination of high-contact surfaces such as doorknobs and bedrails, as well as air outlet fans which indicated virus transfer from aerosols to a surface. while the transmission routes discussed above are generally accepted as the main transmission routes of respiratory viruses, sewage and dust-borne transmission have also been implicated as possible routes. sars-cov- and sars-cov- have both been detected in sewage, suggesting the possibility of transmission via the fecal-oral route, or via aerosolization of sewage caused by flushing. , furthermore, dust-borne transmission has been proposed as a possible mechanism in the spread of avian influenza in chickens. the relative importance of each transmission route in the spread of sars-cov- and most respiratory viruses remains an open question. a trend that is generally accepted, though, is that the risk of infection increases for persons who are in close proximity to an infected individual for extended periods of time. for example, the probability of transmission of sars-cov- between family members and close contacts and among passengers and workers on cruise ships were much higher than that among the general population. additionally, a ferret model showed high transmission efficiencies of sars-cov- among ferrets living in close quarters, while ferrets separated by a permeable partition were infected less efficiently. because of the uncertainty or unavailability of quantitative data, it is difficult to draw conclusions about how each transmission route contributes to the increased risk of infection in close proximity. furthermore, there is often a confounding effect between transmission routes. for example, persons in sufficiently close proximity for droplet-based transmission are likely exposed to a great intensity of virus-laden aerosols simultaneously. in a model of influenza infection assessing the relative contributions of each transmission route to infection risk within a household, fomite transmission was estimated as a major, if not the dominant, transmission route. although the relative importance of each transmission route remains poorly understood, there has been a growing consensus that contaminated fomites play a critical role in the spread of viruses. in order to determine the viability of a virus on surfaces and in aerosols, it is crucial that the methods of collecting virus particles are effective in representing the virus titer from the environmental sample accurately. additionally, the methods used to analyze the collected samples must have high specificity and sensitivity. in this section, we summarize the current collection and analysis methods, as well as opportunities for improvement. the most common methods of collecting aerosolized virus particles use a gelatin filter because it is highly efficient in collecting virus particles without affecting viral infectivity. gelatin filters can also be dissolved easily for harvesting, culturing, and quantifying live virus particles. in a recent study, the stability of sars-cov- and sars-cov- in aerosols was measured by generating an aerosol and feeding the aerosol into a goldberg drum containing a gelatin filter. alternative methods for collecting aerosolized viruses have been covered in a previous review. briefly, these methods use solid impactors (e.g., andersen sampler, slit sampler, and cyclone sampler), liquid impactors (e.g., all-glass impingers, swirling aerosol collector), filters (e.g., gelatin, cellulose, polycarbonate, ptfe, or cotton), or electrostatic precipitators. the downside of these approaches is the significant time delay (minutes to hours) between particle collection and virus quantification. in an effort to develop real-time methods for virus aerosol collection and detection, microfluidicsbased assays have been developed. briefly, these methods include microfluidic optical immunosensing of latex agglutination, , aerosol detection by impingement onto a microfluidic droplet detector, and label-free virus capture using carbon nanotubes and detection by raman spectroscopy. however, these approaches are still in development and are not yet validated for wide-spread use. no study has evaluated the efficiency of virus collection from an exhaustive list of surfaces. in a recent study examining commonly used collection methods, the most effective method for recovering ms bacteriophages from nonporous fomites used polyester-tipped swabs pre-wetted in either one-quarter-strength ringer's solution or saline solution. this method recovered a median fraction of . for infective ms , and . for ms rna from stainless steel and pvc surfaces. the two prevailing methods for detecting viral rna and viable virus particles are reverse transcriptase polymer chain reactions (rt-pcr) and plaque assays, respectively. rt-pcr assays are used to determine both the presence of viral rna and the number of copies of viral rna. while various forms of rt-pcr exist (e.g. rrt-pcr, qrt-pcr, and lamp-pcr), they all follow a general principle of amplifying specific viral rna for detection and quantification. rt-pcr assays are well characterized, straight-forward to perform, and do not require cell culture. their limitation is the inability to determine virus infectivity. plaque assays involve culturing cells that are susceptible to virus infection in a titration of the collected virus samples, monitoring the cytopathic effects, and counting plaque forming units (pfu). several recent preprint publications have used vero e cells to quantify the presence of infective sars-cov- and sars-cov- . , - while plaque assays are the most popular method for determining infectivity, they have several limitations, including: ) the propensity to human error, ) the long duration of the assay (possibly exceeding a week) due to the time required for observable cytopathic effects and/or pfus, ) the lack of a reliable host cell model for some viruses, and ) the absence of plaque formation in some viruses. to address some of these limitations, alternative approaches have been developed. one alternative is the % tissue culture infectious dose (tcid ), an endpoint dilution assay that quantifies the infectious titer required to produce cytopathic effects in % of a tissue culture. however, the tcid assay is also susceptible to some of the limitations of the plaque assay (e.g., long durations before cytopathic effects are detectable). to improve the detection limit of plaque assays, integrated cell culture followed by quantitative pcr (icc-qpcr) has been used. the number of infective virus particles is enhanced for detection by first culturing the virus particles with host cells. the virus is then extracted for rt-pcr to quantify the amount of viral rna. samples that had infective virus particles produced a larger end-point value during rt-pcr than samples that did not have viable virus. icc-qpcr has been used for many virus strains. , [ ] [ ] [ ] [ ] an alternative method to detect viable viruses without cell culture is to pretreat the collected samples with proteinase k and rnase before performing rt-pcr. if the virus envelope is damaged (i.e., the virus is non-infective), proteinase k and rnase will break down the capsid and any rna that is not in a stable viral envelope. however, this method still requires optimization and broader validation. , other detection methods exist but have not been fully developed or validated for coronavirus. for example, elisa and immunofluorescence assays that take - minutes have been developed for influenza virus detection. while these tests have high specificity ( . % from bivariate random-effects regression), they have modest sensitivity ( . %) only. as can be seen, most current methods take a few hours to measure virus rna concentration and days to measure virus infectivity. additionally, most methods require instrumentation and/or cell culture that may be inaccessible. there is a critical need for the rapid detection (< hours) of viable infective virus not only from patient samples, but also from aerosols, droplets, and fomites to better understand the infection risk via these transmission routes. mathematical models of infection risk can be useful to estimate the relative importance of transmission routes and to evaluate the effectiveness of preventative measures. here we discuss several existing models of an individual's risk of infection from their immediate environment. a more detailed review can be found elsewhere. large-scale models at the community level are beyond the scope of this review, but can be found in prior work. , models of infection risk often consist of two tasks: estimating the viral load, or dose, received, and estimating the infection risk based on the dose received. infection risk models can be classified as deterministic, where an individual is infected if the dose exceeds a critical value, or stochastic, where an individual's probability of infection is a function of the dose received. typically, stochastic models are more biologically relevant. to estimate the dose received, various strategies exist to model the transmission routes of the virus from the surroundings to the individual. in the case of aerosol transmission, a poisson distribution is often used to describe the distribution of virus particles in the air. this distribution can be used to estimate the dose an individual receives through aerosol inhalation. for the wells-riley model (discussed later), the airborne "dose" is formulated in terms of a hypothetical unit called a quantum of infection. , the wells-riley "dose" includes parameters such as the quanta generation rate, room ventilation rate, and exposure time to describe aerosol transmission and can be further modified to account for complexities such as uneven mixing. in the case of fomite transmission, some models estimate the surface concentration through deposition from an airborne source, while others directly prescribe a distribution on a surface based on experimental measurements. the rate of virus transferred between two surfaces is often formulated as the product of contact frequency, transfer efficiency, surface concentration, and contact area in eq. , where Ṅ is the rate of virus transferred to surface , , is the frequency of contact between surfaces and , , is the transfer efficiency from surface to , is the virus concentration on surface , and , is the contact area between surface and . the virus can be transferred serially between surfaces before finally transferring to an individual's facial membranes, giving the final dose received through fomite transmission. more complex models integrate multiple transmission routes and phenomena together, such as a markov chain model of fomite and aerosol transmission that include a gradual loss of virus viability. to estimate the infection risk based on the dose received, two popular models have emerged: the wells-riley model and the dose-response model. the wells-riley curve is an exponential curve and is based on a hypothetical "dose" unit called a quantum of infection as described above. , a basic form of the wells-riley curve is shown in eq. , where is the probability of infection, is the number of infectors, is the quanta generation rate, is the pulmonary ventilation rate of the susceptible individual, is the exposure time interval, and is the room ventilation rate with clean air. while the wells-riley model is convenient to use, its formulation based on the quantum of infection limits its application to aerosol transmission only. still, it remains a useful model and has been applied to various cases including sars-cov- . the dose-response model was adapted for respiratory viruses from models of toxicity. the dose input is a physical quantity of the virus, and can be extended to multiple situations including aerosol transmission, fomite transmission, and the efficacy of surface disinfection strategies. a basic form of an exponential dose-response curve is shown in eq. , where is the probability of infection, is the number of infectors, is the number of airborne pathogens released per infector per unit time, is the pulmonary ventilation rate of the susceptible individual, is the deposition fraction of pathogens in the alveolar region, is the exposure time interval, and is the room ventilation rate with clean air. extensions and alternative forms of the dose-response curve can be found elsewhere. , some studies have begun to apply these models of individual infection risk to a larger system such as a household. for example, interactions between multiple healthy individuals, infected individuals, and objects in a household can be modelled and the dose-response model is then applied to each individual. , ultimately, the choice of the model depends on the application, and models of infection risks have emphasized the effectiveness of promising interventions including fomite disinfection. , the ability of a virus to transfer between and persist on different surfaces, including skin, plays a crucial role in the overall infectivity of a virus by means of fomite transmission. understanding the adsorption and transfer rates between skin and fomites is critical for modeling the spread of viruses. , furthermore, understanding virus persistence on different surfaces under different environmental factors can inform decision making for disinfection protocols. in this section, we will review the factors affecting virus adsorption, transfer, and persistence on different surfaces, and then discuss surfaces that are at high risk of contamination. the adsorption of virus on fomites and their subsequent transfer to other surfaces is a multi-factor problem that depends on the properties of the virus, the fomite, and the environment. the physical description of virus adsorption borrows from formulations of colloid adsorption, treating virus particles as soft colloidal spheres and using gibbs free energy to model the interactions between virus particles and the adsorbing surface. like colloid adsorption onto surfaces, virus adsorption onto fomites is primarily driven by electrostatic, hydrophobic, and van der waals interactions ( figure ). the relative contribution of these interactions is modulated by environment ph and ionic strength. , , classical models of virus adsorption adopt the derjaguin-landau-verwey-overbeek (dlvo) theory for colloid adsorption onto surfaces. it accounts for electrostatic and van der waals interactions between viruses and surfaces. [ ] [ ] [ ] however, the extended-dlvo (xdlvo) model, which considers hydrophobic interactions, was found to agree more with experimental observations of virus adsorption. [ ] [ ] [ ] xdlvo is expressed in terms of gibbs free energy of interaction, shown in eq. , where electrostatic or double-layer (dl), hydrophobic (hyd), and van der waals (vdw) contributions are summed. entropy changes ( ) are usually ignored. a negative favors adsorption. , detailed formulations for each component of the total free energy for a spherical virus particle adsorbing onto a flat plate can be found in prior work. electrostatic forces drive long-range adsorption dynamics dictated by the radius of the virus's electrical double-layer (debye length) and the charge of the absorbing surface. , all viruses, including sars-cov- , express unique protein markers on their surfaces. these markers consist of weakly acidic or basic polypeptides and amino acids ionizing residues that give viruses characteristic isoelectric points (pi) (also see section . ). , the net charge of a virus is thus determined by the ph of its environment. the net charge on a virus causes the formation of an electrical double-layer that extends from the stern layer, the first layer of immobile charges attached to the surface of the virus particles, and across the gouy diffuse layer, the region of charge imbalance that results in an electrical potential. [ ] [ ] [ ] in addition to ph, the ionic strength of the surrounding medium is another important parameter affecting electrostatic interaction. at high ionic concentrations (> mm nano ) , electrostatic screening stunts the zeta potential at the charge slipping plane and weakens the effects of surface charge for both attractive and repulsive interactions. in the absence of electrostatic interaction, if adsorption occurs, it is typically attributed to hydrophobic interactions. , the hydrophobic effect causes an attractive force between a virus and adsorbing surface. the effect is due to electron-donor and -acceptor, i.e., lewis acid-base, interfacial interactions. under hydrophobic interactions, there is a tendency of apolar species such as molecular chains or particles to aggregate, providing an energetically favorable mechanism of adsorption due to the minimization of interfacial area between the virus and the adsorbing material. in the absence of electrostatic interactions, hydrophobic effects dominate because they are apolar by nature. the energy of hydrophobic interactions largely depends on the prevalence of hydrophobic groups on a virus particle's surface. greater virus hydrophobicity has been shown to correlate with higher rates of adsorption regardless of ionic strength. , , the presence of chaotropic (i.e., scn -, ci ccoo -) or anti-chaotropic (i.e., no -, so -, f -) agents can promote or hinder, respectively, hydrophobic adsorption. hydrophobic interactions are considered to have a short-range effect compared with electrostatics. van der waals forces are considered to be of secondary importance. their relative contribution, as with electrostatic and hydrophobic interaction, is a function of virus and environmental properties. for example, van der waals forces may play a significant role in the adsorption of viruses that carry a neutral charge in their environment. furthermore, materials known to generate large van der waals potentials are also more likely to adsorb viruses. the contribution of van der waals forces to adsorption can be quantified by lifshitz theory, which predicts that materials with higher dielectric susceptibility produce higher van der waals potentials. by this reasoning, metals have better adsorbing effectiveness than most organic substances. in general, the effectiveness of materials to absorb viruses follows: metals > sulfides > transition metal oxides > sio > organics. this theory suggests that high ionic strength or a fluid ph equal to virus pi is necessary for adsorption to most organics. under these conditions, the debye length is shortened and viruses are able to get sufficiently near to organic surfaces to absorb by van der waals interactions. , , there exist some gaps in the comprehensive understanding of the physicochemical mechanisms in virus adsorption onto fomites. while xdlvo theory on virus adsorption can begin to explain the observations of many virus strains, including sars-cov- , readily adsorbing to a variety of non-porous surfaces (e.g., steel, glass, plastic), , , , , the observed virus adsorption onto porous fomite surfaces (e.g., cardboard, cloth) is not well described by xdlvo. some studies have indicated the need to account for steric effects and surface roughness. , other studies emphasized the pitfalls of modeling viruses as soft colloids with homogeneous charge distributions. unlike a soft colloid or even a virus-like particle (vlp) engineered with viral structural proteins, the pi of true viruses depends on the complex physicochemical structure of the outer surface and the genetic material packed within the capsid. , , , the state of understanding in physicochemical mechanisms of virus adsorption in aqueous environments is fairly advanced, but there is still significant room for research in elucidating the mechanisms of dry contact transfer. although a number of studies have quantified the rates of transfer between dry surfaces, including skin (also see section . ), the precise physicochemical basis for virus transfer in dry conditions has been unaddressed. the tendency of a virus to transfer between fomites is likely determined by differences in adsorption energies between the two surfaces. in the case of porous materials, lower rates of transfer are likely due to viruses entrapped in their matrix due to increased surface area for attachment. , to our knowledge, no work has examined the physicochemical interactions, adsorption, and transfer kinetics of sars-cov- on different surfaces especially in dry conditions. despite a lack of data on the transfer efficiency of coronaviruses, numerous studies have examined the transfer efficiency for other viruses. an overall mean transfer efficiency of % ± % was found between fingerpads (either washed or unwashed prior to inoculation with a virus) and glass for three types of non-enveloped bacteriophages (ms , φx , and fr). the efficiency was calculated by measuring the viral pfu of the surface before and after contact. in this study, prior handwashing was found to reduce the transfer efficiencies only slightly. the reduction due to washing was greater in fingerpad-to-glass transmission than glass-to-fingerpad. this result is likely because of changes in the skin moisture or ph due to handwashing before inoculation with a virus. a similar transfer efficiency was found for ms from fingertips to glass and to acrylic (~ %), but this value increased to . % in humid conditions. transfer efficiency of psd- phage from hand to mouth was found to be . %, representing a skin to skin pathway. studies have shown that viruses adsorbed on surfaces can maintain high rates of survival and infection potential. exactly how long viruses retain their viability on a surface is highly variable and dependent on: ) surface porosity, ) environmental factors, and ) virus envelope characteristics. , first, nonporous surfaces, compared with porous surfaces, are more effective in receiving and transferring viruses, and are typically better at preserving virus viability because they do not draw moisture away from adsorbed viruses. however, if a porous material is inoculated, it is capable of harboring most strains of viruses (especially at low temperatures e.g., ℃), and can remain contagious despite the lower rates of transfer to skin. sars-cov- has demonstrated an ability to contaminate a wide range of porous and nonporous fomites. table shows the persistence of sars-cov- and other coronaviruses on various surfaces. to our knowledge, no studies have evaluated the persistence of sars-cov- or sars-cov- on skin. however, parainfluenza was shown to be % viable within minutes, while rhinovirus was shown to be . % and % viable on skin after and hours, respectively. the percent of viability was determined by comparing pfu before inoculation and at various times points. we note that no work has explicitly investigated the physicochemical reasons why some surfaces support longer virus persistence. as viruses can be inactivated by desiccation, improved persistence is likely due to the ability of a surface to maintain a moist microenvironment. second, environmental variables such as temperature, humidity, and resident microfauna can influence virus adsorption and viability. in general, increased temperature and moderate humidity levels have adverse effects on the persistence and viability of coronaviruses and other viruses. in a study on the viability of dried sars-cov- on smooth plastic surfaces, the virus was found to be viable for over days at - °c with - % relative humidity (rh). however, virus viability decreased significantly (> log reduction) at °c with > % rh. in another study using phi as a surrogate, the virus survived best at high (> %) and low (< %) rhs. they also found that rh is a more significant factor in virus survivability than absolute humidity (ah). in addition to temperature and humidity, the presence of other microbes can also influence the survival of viruses. though the presence of microbes can reduce the rate of desiccation of the viral particles enhancing their persistence and viability, microbial proteases and fungal enzymes can be harmful to their existence. , third, viral persistence on fomites also depends on the type and the strain of the virus. in general, non-enveloped enteric viruses (e.g., adenovirus, rotavirus) can persist on fomites longer than enveloped viruses (e.g., coronaviruses). the lack of a lipid membrane in non-enveloped viruses make them less susceptible to inactivation than enveloped viruses, where the disintegration of the lipid envelope (e.g., by common disinfectants; see details in section ) causes the loss of the viral envelope proteins involved in virus adsorption and cell penetration thereby rendering them inactive. additionally, non-enveloped viruses are less susceptible to desiccation than their enveloped counterparts because of their lack of lipid membrane envelopes. these characteristics make them easier to spread and persist on surfaces over long periods of time compared with enveloped viruses. in principle, all surfaces or objects can be considered potential fomites and are at risk of contamination. , in practice, knowledge of which objects are at high-risk of contamination could guide the design of optimal disinfection strategies. for a given object, the risk of contamination can depend on the interaction between the virus and the material, the frequency at which the object is contacted, the object's distance from an infected individual, and the environmental conditions. first, the combination of virus composition and surface properties can influence the likelihood of contamination (see details in section . ). second, objects that are frequently handled or are in high contact with individuals are at higher risk of contamination. in a hospital setting, contamination has been detected on numerous high-contact surfaces, including door handles, bed rails, tables, call/control panels, other near-patient surfaces, office equipment, and even sterile packaging. , a study of the isolation rooms of sars-cov- infected patients in singapore showed contamination of a similar list of high-contact surfaces. while the floor of the isolation room and the shoes worn by individuals entering and exiting the room tested positive for sars-cov- , the floor immediately outside tested negative, suggesting contamination by footwear is low. third, an object's proximity to an infected individual affects its risk of contamination. an object can be contaminated from a distance due to deposition of droplets or aerosols onto its surface. the risk of contamination by droplets or aerosols decreases when the object is further away from infected individuals, as viral shedding by coughing, sneezing, or exhaling can potentially deposit droplets and aerosols onto fomites as far as - m away. , in the aforementioned singapore study, all air samples taken from the isolation room tested negative while the air outlet fans tested positive, suggesting that sars-cov- is not detectably aerosolized in these conditions but is still able to transfer from air to a potential fomite. a study in wuhan hospitals found that the highest concentrations of sars-cov- in the air were, surprisingly, not in patient rooms but in toilet facilities. . even aerosol generation from personal protective equipment (ppe) removal can create fomites. doffing ppe has the potential to aerosolize the virus and transfer it to other ppe in changing rooms. fourth, the environmental conditions can affect an object's risk of contamination. air currents could potentially determine the flight path of droplets and aerosols, as proposed in a case study of a guangzhou restaurant where the sars-cov- infection pattern aligned with the air conditioning currents. the amount of foot traffic and the degree of connectivity between rooms could also affect where high sars-cov concentrations may be found. we note a limitation to many of these studies is the use of rt-pcr to identify viral rna. the presence of viral rna is not indicative of viability, and viral culture is needed to determine infective virus . the above factors can be used to help identify and predict surfaces at high-risk of contamination. to further quantify the role of these surfaces as fomites, surface viral concentrations need to be measured, and contact frequencies can be derived from observational studies. such quantifications can be used as input parameters in modeling infection risk and designing optimal disinfection strategies. for example, a model of disinfecting strategies for methicillin-resistant staphylococcus aureus (mrsa) predicted once-daily whole room cleaning to be less efficient than frequent targeting of high contact surfaces in preventing indirect contact transmission. strategies to intercept fomite transmission revolve around inactivating the virus, improving personal hygiene, or using ppe. here, we discuss different mechanisms of virus inactivation on surfaces and hands, focusing on strategies that have been shown to inactivate sars-cov- and other enveloped viruses. we will not discuss ppe as it has been discussed elsewhere. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in order for a virus to be infective, it must fuse with a host cell, insert its genome into the cell, and replicate. these processes require an enveloped virus to have an intact envelope and nucleocapsid. to inactivate a virus, at least one of these components needs to be disrupted. it is important to understand the mechanisms of virus inactivation based on virus composition, structure and function in order to: ) understand the efficacy of disinfectants on viruses, ) predict the response of a new strain of virus to a disinfectant, ) identify common sites on proteins, envelopes or genomes that are vulnerable to disinfectant treatment that are shared by many viruses, and ) enhance the design of antiviral agents and therapies that target specific viral components. one method of predicting virus inactivation mechanisms is a composition-based method. it takes into account the reaction rate constants between disinfectants and specific nucleotides and amino acids found in viral structures (e.g., proteins, nucleic acids, and envelope lipids) ( table ). the relative contribution of a viral structure to inactivation can be predicted by summing the relative abundance of each nucleotide or amino acid multiplied by the respective rate constants for a given disinfectant. , a limitation of the composition-based method is that it does not account for the complex interactions between adjacent monomers. to our knowledge, no model exists that accounts for viral structure as well as composition. this section summarizes current disinfection strategies and their effectiveness for sars-cov- and related viruses (figure ) . uv irradiation is a widely-used method of surface disinfection. here, we discuss the inactivation of sars-cov- by uvc and solar irradiation. uvc irradiation ( - nm, typically nm is used) damages nucleic acid bases in genetic material, and to a lesser extent, proteins in virus capsids. , uvc irradiation induces dimerization of adjacent uracil bases in rna, forming pyrimidine dimers that disrupt the rna structure, which inhibits the viral replication process and inactivates the virus. , exposure of sars-cov- to a uvc light source ( nm, µw/cm ) held cm above the virus resulted in a ~ . log tcid /ml reduction in virus titer within minutes. after this point, virus inactivation plateaued, until viral activity became undetectable at minutes. exposure to other uv wavelengths (e.g., uva) was found to be insufficient to inactivate the virus. uvc irradiation as a disinfection strategy poses a few challenges. the time required to inactivate sars-cov- using uvc ( nm, µw/cm ), ~ minutes, is significantly longer than the time required using chemical disinfectants ( s to min). , this time to inactivate only applies to regions of an object directly exposed to uvc irradiation. disinfectant effectiveness reduces significantly in shadowed regions. additionally, uvc radiation may pose health risks, including skin cancer and ocular damage to exposed individuals. nonetheless, uvc-based disinfection can be valuable for use in applications where the irradiation can be shielded from humans, and have been used in, for example, empty buses and other vehicles. the inactivation of viruses by solar irradiation has also been studied, especially in the context of the disinfection of water. the range of uv wavelengths in sunlight that reach the surface of the earth is between and nm, as uvc is typically completely blocked by the atmosphere. , the antiviral properties of sunlight primarily come from uvb light, which can also form pyrimidine dimers, but these mechanisms are not as well studied as the mechanisms of uvc-based disinfection. additionally, the solar spectrum, especially in the uv wavelengths, can vary significantly depending on environmental factors, the time of day, and the season. such factors can lead to large variations in the efficiency of virus inactivation by sunlight. a wide variety of chemical disinfectants are currently available to combat the spread of sars-cov- (table ). the effectiveness varies depending on the virus inactivation mechanism. in general, there are modes of inactivation by disinfectants: ) disruption of the lipid layer of the envelope (e.g., ethanol and detergents), , ) modification of important protein sites on the envelope or capsid (e.g., chlorine and glutaraldehyde), , , , , and ) reaction with the nucleotides and amino acids in the genetic material, leading to the degradation of the nucleic acids (e.g., chlorine). , chemical disinfectants are typically evaluated with suspension and carrier tests. suspension tests combine a known titer of a virus in solution with a disinfectant and evaluate virus titer after a period of time that depends on the disinfectant manufacturer's directions of use. however, suspension tests are considered less challenging for the disinfectant under scrutiny, and may not reflect the practical usage of disinfectants to clean contaminated surfaces. quantitative carrier tests are performed by allowing an aliquot of virus solution to dry on a surface before applying the disinfectant. this test is conducted under conditions that are more relevant to practical use of disinfectants, and is, therefore, a more appropriate measure of disinfectant effectiveness. chemical disinfectants have been evaluated for their ability to inactivate various types of coronavirus. , for sars-cov- , % and % household bleach, % ethanol, . % povidoneiodine, . % chloroxylenol, . % chlorhexidine, and . % benzalkonium chloride have been found to reduce an initial viral load of ~ . log tcid /ml to undetectable levels at room temperature within minutes in suspension tests. for other coronaviruses (e.g., sars-cov- , mers-cov, and mhv), %, %, % and % ethanol; - % -propanol; a mixture of % -propanol and % -propanol; . % sodium hypochlorite; and %, % and . % povidone iodine were found to reduce viral activity by at least log within seconds in suspension tests. carrier tests performed on stainless steel disks showed > log reduction within minute for hcov- e, mhv, and tgev exposed to % ethanol and for hcov- e exposed to . - . % sodium hypochlorite and % glutaraldehyde. in another study, hydrogen peroxide vapor inactivated tgev in a carrier test by a reduction of . - . log , but it took - hours to do so. prior carrier tests have been performed primarily on stainless steel, and to our knowledge, no carrier tests have been conducted for sars-cov- on any material. results using stainless steel carriers may not reflect disinfectant effectiveness on other fomites with different surface properties (e.g., surface chemistry, wettability, porosity, roughness). the dependence of disinfectant effectiveness on surface properties remains an open question. plasma is an ionized gas made up of charged and uncharged particles (i.e., ions and electrons, and molecules and atoms, respectively), reactive species, and uv photons. inactivates sars-cov- . uv light may be applicable to surfaces sensitive to heat or chemicals. uv irradiation is less efficient at low temperatures (e.g., < °c ) and is not suitable for all environments. incompatible with photosensitive materials. as heavy particles. cold atmospheric plasma (cap) is a low-temperature, non-thermal plasma that is produced by a variety of methods using gases such as helium, argon, nitrogen, heliox and/or air. two common methods for producing cap are dielectric barrier discharge and atmospheric pressure plasma jet. cap has been considered for disinfection applications in dentistry and oncology and in food processing. , the antimicrobial properties of cap are attributed to reactive oxygen and nitrogen species generated in the non-thermal plasma. [ ] [ ] [ ] the detailed inactivation mechanisms are still under investigation. however, it is believed that the reactive species damage genetic material and proteins. in one study, singlet oxygen in plasma was implicated in the inactivation of bacteriophages through multiple mechanisms involving reactions with amino acids and dna nucleotide oxidation and crosslinking, but the primary mechanism was thought to be singlet oxygen-induced crosslinking of capsid proteins. cap has been shown to inactivate potato virus y in water, in a study aimed to decontaminate water supply systems. cap was found to inactivate potato virus y in minute, compared with minutes using mg/l of hydrogen peroxide. plasma-activated water (paw) is another form of plasma-based disinfection. water is treated with non-thermal plasma to produce paw, which is more acidic and contains more reactive oxygen and nitrogen species than regular water rendering it antimicrobial. paw has been proposed as an antiviral agent. for example, in a study testing paw for its potential application in producing an inactivated vaccine for newcastle disease (nd), the enveloped virus responsible for avian nd was found to be fully inactivated in paw. paw has also been proposed for its potential application in the disinfection of fresh produce. while promising in these studies, the effectiveness of cap or paw on inactivating coronaviruses remains to be demonstrated. heat treatment is a well-known method for disinfecting surfaces. at temperatures exceeding ~ °c, viral capsid proteins are denatured and rna is damaged. sars-cov- has been shown to become inactivated within minutes at °c, with a reduction from an initial concentration of ~ . log tcid /ml to undetectable levels. sufficiently high temperatures should be used. moderately high temperatures ( - °c) only cause minor damage to the protein capsid, and fail to inactivate some viruses. autoclave is a common method of sterilizing equipment using heat treatment in a laboratory or clinical environment. autoclaves produce steam at high temperatures (~ °c) in a pressurized chamber. at this temperature, most microbes, including viruses, are inactivated. the surface being sterilized is exposed to the high temperature and pressure environment for a varying amount of time, depending on the material and size of the object. liquids are usually sterilized for - minutes, while objects made of glass and plastics require ~ minutes of sterilization. in one experiment, avian coronavirus and avian pneumovirus carried by cotton swabs were inactivated after heat treatment using an autoclave for minutes. in the same study, heating the same viruses in a microwave oven for seconds was also found to be sufficient for inactivation. engineering self-disinfecting surfaces is an emerging avenue of research for preventing infection transmission by fomites. while certain materials like copper and silver have long been known to possess intrinsic antimicrobial properties, various types of surface modification and functionalization can also give rise to antimicrobial properties against bacteria and viruses. , only a limited number of works have focused on virus-specific self-disinfection. this section highlights some of these studies. readers are referred to a recent review for details. copper and silver alloys are known viricidal agents that inactivate viruses through multiple modes of action. the primary mechanism involves direct interaction between metal ions and microbial proteins, or indirect interaction through the formation of radicals that are damaging to dna and lipid membranes. , copper has been shown to retain its effectiveness across a range of humidities and temperatures, while silver had drastically reduced antimicrobial effectiveness at low humidities (~ % rh). pure copper and alloys with - % copper were found to be most effective in inactivating viruses. abrasion and removal of the outer oxide layer caused a slight decrease in effectiveness. in one study, x pfu/cm of non-enveloped murine norovirus was inactivated in under hours at room temperature. inactivation of norovirus by copper was found to be up to x faster in dry conditions compared to wet, but the mechanisms underlying such differences were unclear. in another study, copper yielded a near -log reduction in enveloped influenza a virus particle count after hours. table includes the effectiveness of copper on some coronaviruses in lowering viability periods. some studies examining the clinical effectiveness of copper surfaces have shown notable improvement towards infection control benchmarks with % less bacteria when compared with control plastic surfaces on icu beds. photocatalytic action has been shown to be highly effective in inactivating microbes by damaging dna and lipid membranes via the photocatalyzed formation of hydroxyl radicals in the presence of photoactive oxides. , numerous enveloped and non-enveloped viruses have been shown to become inactivated by photocatalytic disinfection. titanium dioxide (tio ) is a popular photocatalytic material due to its long lifetime, effectiveness over a wide range of microbes, and environmental friendliness. tio has the potential to provide antiviral protection to a range of materials. for example, cotton fabrics have been impregnated with tio via magnesium nanoparticle carriers. tio impregnated into resin, fiberglass, and pvc have also been used to coat various surfaces in hospitals, schools, and other public places. despite the potentials that self-disinfecting surfaces present, widespread adoption of selfdisinfecting surfaces, especially in hospitals, has been limited by three main obstacles. the first is a lack of clinical trials showing their efficacy in practice. second, the costs associated with upgrading or retrofitting equipment discourages hospitals from taking initiatives to introduce selfdisinfecting surfaces, though the savings from decreasing nosocomial infections could offset this cost. third, characterization of effectiveness over repeated cycles has not yet been quantified. frequent handwashing can lower the incidence of transfer from fomites to facial membranes via contact. considering the frequency that adults touch their faces ( times per hour) and the risk of infection that is associated with face touching, handwashing is a critically important personal hygiene habit. in a hospital setting, the who recommends critical moments for healthcare workers to wash hands: ) before contact with a patient, ) before a cleaning procedure, ) after exposure to bodily fluids, ) after contact with a patient, and ) after contact with fomites surrounding patients. although virus transfer to hands is only mildly reduced after recent handwashing, , handwashing is effective in reducing the spread of a virus from hands. , however, handwashing is only as effective as the frequency, the effectiveness of the antiseptic, and thoroughness. the cdc recommends washing for a minimum of seconds. this recommendation was based on a few empirical studies, [ ] [ ] [ ] including one that investigated handwashing practices such as wash time ( s vs. s) and effect of soiled hands on infectivity reduction. to evaluate the effectiveness of a handwashing, a fingerpad method is typically used. , here a virus is inoculated on pre-cleaned fingerpads, allowed to dry, then subjected to exposure to an antiseptic by static contact with the fingerpad. , the astm specifies that an effective handwashing antiseptic must yield a minimum reduction of log ( . %) in virus titer from the initial inoculation titer. however, this standard does not specify a minimum contact time between the fingerpad and the antiseptic. another potential drawback of these standard tests is that they may not be representative of in vivo handwashing behavior of healthcare workers or the general public. viruses present a unique challenge for handwashing in that their structure and ability to survive on skin may evade inactivation by handwashing methods customized for bacterial disinfection. alcohol and isopropanol-based antiseptics ( - % ethanol) are the most effective non-hazardous antiseptic, especially against enveloped viruses. other who-recommended antiviral antiseptics (from the most to the least effective) are iodophors ( . - %), chlorhexidine ( . - %), and chloroxylenol ( . - %), all of which are less effective than alcohol. in regard to hand sanitizers, sars-cov- has been confirmed to be the most susceptible to ethanol and isopropanol using suspension tests with part virus at tcid /ml, part media, and parts by volume of an ethanol-or isopropanol-based who-recommended antiseptic formulation. a > log sars-cov- reduction was achieved in seconds using ethanol and isopropanol formulations at % and % concentrations, respectively, and using dilutions as low as %. , . methods of applying chemical disinfectants chemical disinfection remains one of the most commonly used methods for virus disinfection. the effectiveness of chemical disinfection depends on the disinfectant contact time, the surface properties of the fomite, and other environmental factors. as such, how the chemical disinfectant is applied has a significant impact on the disinfection effectiveness. this section discusses two common methods of disinfectant application: wiping, and spraying. for chemical disinfectants to work properly, they must be directly applied to the target surface. the most straightforward and conventional method of applying a chemical disinfectant to a surface is to use a manual wipe. manual wiping utilizes both physical removal of viruses (which may not kill the viruses), and chemical activity of the disinfectant. the chemical disinfectant can be applied immediately before wiping, or the wipe can be packaged and pre-wetted with the disinfectant. the wipe process typically takes seconds to complete. despite its convenience, manual wiping is limited by human error and cross-contamination between surfaces. , if the proper protocols are followed, manual wiping can effectively disinfect surfaces contaminated with norovirus, , adenovirus polyomavirus, and numerous bacteria including staphylococcus aureus and clostridium difficile. however, the effectiveness of manual wiping depends on multiple factors including the type of wipe, the type of disinfectant, the target pathogen, the wiping technique (e.g., area covered, pressure applied), and the ratio of disinfectant volume to target surface area. insight into these factors, such as the effectiveness of microfiber wipes, the number of wipe passes over a surface, and adsorption of disinfectants to wipe material, could serve to optimize wipe protocols. the key limitations of manual wiping arise from human error in the wiping process, and cross-contamination of pathogens. multiple studies reported that only ~ % of near-patient surfaces in hospitals were cleaned according to policy. if wipes are re-used between surfaces, there is a risk of transferring pathogens between surfaces. these limitations could potentially have serious consequences especially in a hospital setting, and highlight the need for an automated and effective disinfection strategy. while spray disinfectants are commonly used to disinfect surfaces, their effectiveness has not been well characterized. to our knowledge, no comprehensive model has characterized spray disinfection efficiency taking into account aerosol physics, virus heterogeneity, and surface characteristics. nevertheless, given that disinfection effectiveness depends on disinfectant contact time (and thus disinfectant volume, if the evaporation of disinfectant is fast), the spray characteristics (e.g., spray droplet size and density) and disinfectant droplet deposition on surfaces are critical factors that must be considered in any attempt to evaluate the effectiveness of spray disinfection ( figure ). atomization is a general term referring to the disintegration of a liquid stream into droplets. table summarizes a few common commercial atomizers. atomizers that have been used for applying surface disinfectants (and pesticides) include electrostatic atomizers, hydraulic atomizers, pressure atomizers, spill return atomizers, and ultrasonic atomizers. in particular, spill return atomizers, being able to produce fine sprays, have been shown to be applicable for disinfecting healthcare surfaces. for classroom, healthcare, and general disinfection purposes, handheld electrostatic sprayers also exist with adjustable spray parameters. , in the agriculture industry, electrostatic spray systems have been mounted on unmanned aerial vehicles for spraying pesticides on crops. , drop size and drop-size distribution are critical parameters determining spray disinfection efficiency. table summarizes several considerations in the choice of droplet size for spray disinfection. the covid- pandemic has revealed major gaps in our scientific knowledge, not only in the biology of how the virus infects humans, but also the role of physicochemical processes and surface science in the transmission and inactivation of the virus. box lists some of the open questions we have identified. addressing these questions will allow us to devise more effective strategies to combat the spread of the disease. for example, quantitative models predicting the locations of high-risk areas within a building and high-risk objects within those areas can inform the prioritization for disinfection. the identification of surfaces with high contamination risk also presents an opportunity for self-cleaning communal surfaces such as water faucets or door handles. a better understanding of disinfectant effectiveness on different surfaces and their potential side effects allows one to choose the optimal disinfection strategy for specific applications. while our review is by no means exhaustive, we hope that it can provide the basis for researchers in the 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the drop size in sprays? rotary atomizers for spray dryers twin-fluid atomization of viscous liquids: the effect of atomizer construction on breakup process, spray stability and droplet size ultrasonic atomization sonics & materials, inc. vibra-cell ultrasonic liquid processors ultrasonic atomization: effect of liquid phase properties we acknowledge support from the national science foundation (award # ). key: cord- -zdft q authors: cauchemez, simon; ferguson, neil m. title: methods to infer transmission risk factors in complex outbreak data date: - - journal: j r soc interface doi: . /rsif. . sha: doc_id: cord_uid: zdft q data collected during outbreaks are essential to better understand infectious disease transmission and design effective control strategies. but analysis of such data is challenging owing to the dependency between observations that is typically observed in an outbreak and to missing data. in this paper, we discuss strategies to tackle some of the ongoing challenges in the analysis of outbreak data. we present a relatively generic statistical model for the estimation of transmission risk factors, and discuss algorithms to estimate its parameters for different levels of missing data. we look at the problem of computational times for relatively large datasets and show how they can be reduced by appropriate use of discretization, sufficient statistics and some simple assumptions on the natural history of the disease. we also discuss approaches to integrate parametric model fitting and tree reconstruction methods in coherent statistical analyses. the methods are tested on both real and simulated datasets of large outbreaks in structured populations. data collected during field outbreak investigations are essential to better understand the clinical and epidemiological features of an infectious disease. they can also provide useful insights for outbreak management and control. for example, evaluating the risk factors governing transmission is important to design efficient control measures, and identify those individuals that are most at risk of infection or are the main contributors of infection and should therefore be targeted first. however, characterizing transmission from outbreak data can be challenging. first, the transmission process is usually imperfectly observed. for example, we may observe the date of symptoms onset of a case, but we rarely know where, when and by whom a case was infected. inference, therefore, requires integrating over 'missing data', which may quickly become cumbersome. over the last years, data augmentation methods have been used to tackle this problem: data are augmented with missing data (e.g. dates of infection) that are needed to write down the likelihood; in a bayesian setting, the joint posterior distribution of parameters and augmented data is explored usually via markov chain monte carlo (mcmc) sampling [ ] . this methodology is now well established in the field and has been successfully applied to analyse a range of complex datasets. however, for relatively large outbreaks with detailed data, this approach may require very long computational times. interested readers can, for example, read references [ - ] . the second challenge is that the type of dependency between observations that is typically observed in an outbreak (i.e. the risk of infection of an individual depends on the infection status of other individuals) is specific to communicable diseases and needs to be accounted for with dedicated methods. this usually requires that the statistical model used to analyse the data is explicitly based on a mechanistic model of disease spread [ ] . transmission parameters of interest, for example, the reproduction number (the number of individuals infected by a case), are usually mathematically defined in those models. fitting such parametric mechanistic models to outbreak data can give useful insights on transmission [ , [ ] [ ] [ ] , but is subject to the same limitations as parametric fitting in other fields. for example, although there are some exceptions [ ] , the approach usually requires to predefine time intervals on which transmission rates are constant. this can sometimes be difficult to achieve in a non-ad hoc way. an alternative approach that has become increasingly popular is to reconstruct the transmission tree and derive important summary statistics from it, for example, the temporal trends in the reproduction number [ - ] . this may give greater flexibility (for example, there is no need to specify time intervals with constant transmission rates), potentially at the cost of larger variance of the estimates [ , ] . however, since these methods generally only consider disease *author for correspondence (s.cauchemez@imperial.ac.uk). cases rather than the uninfected, but potentially susceptible bulk of the population, they can say little about the risk factors for infection or provide estimates of transmissibility in different contexts (e.g. households, schools or as a function of distance between a susceptible and an infected individual). overall, the two methodologies (fitting of a parametric mechanistic model and tree-reconstruction methods) are largely complementary. fitting a mechanistic model seems to be the only way to account for the depletion of susceptibles, the information on uninfected individuals leading to a quantification of relative risks; and it may ensure a better control of the variance of the estimates. tree-reconstruction methods can provide further insights on what effectively happened during the outbreak with summary statistics on who was infected by whom, when and where and temporal change in the reproduction number. they can also provide a framework to detect abnormal features in the data that are not initially accounted for in a mechanistic model. it is therefore important that the two approaches can be integrated in a coherent way. in this paper, we discuss strategies to tackle some of the ongoing challenges in the analysis of outbreak data. we present a relatively generic statistical model for the estimation of transmission risk factors, and discuss algorithms to estimate its parameters for different levels of missing data. we look at the problem of computational times for relatively large datasets and show how they can be reduced by appropriate use of discretization, sufficient statistics and some simple assumptions on the natural history of the disease. we also discuss approaches to integrate parametric model fitting and tree reconstruction methods in coherent statistical analyses. the methods are tested on both real and simulated datasets of large outbreaks in structured populations. assume that we observe the spread of a disease in a population of size n from day to day t. for each individual i ¼ , . . . , n, let y t i ¼ ; if individual i is infected between and t; otherwise. each individual i is characterized by a vector of q covariates z i (t) ¼ fz i (t), . . . , z i q (t)g such as age, gender, location, household id, etc . . . that may vary with day t. we want to quantify the transmission risk factors. we first consider the situation where day t i of infection of each case i is observed (by convention, . this assumption is relaxed in § . for a directly transmitted disease, the first step to estimate transmission risk factors is usually to propose a model for transmission hazard l i!j ðtjqÞ from case i to subject j on day t, i.e. define l i!j ðtjqÞ as a function of the individual covariates z i (t) and z j (t) and a set of parameters q. for example, the transmission hazard l i!j ðtjqÞ may depend on: -the time lag t-t i between day t and the day of infection t i of case i since infectiousness of a case may vary during the course of infection. the functional form between l i!j ðtjqÞ and t-t i will depend on the assumed natural history of the disease; -the individual characteristics of subjects i and j. for example, some subjects may be more infectious while others are more susceptible; and -the type of interactions that exist between subjects i and j. the contact rate might, for example, depend on whether the subjects live in the same household or go to the same school, etc. it could also depend on the spatial distance between them. examples of specifications for the transmission hazard l i!j ðtjqÞ are given in § § and . the force of infection exerted on individual j on day t is then the sum: l i!j ðtjqÞ: the contribution to the likelihood of case j is: where the first term is the probability of infection on day t, and the second term is the probability to escape infection up to day t (the link between the continuous time and discrete time transmission model is discussed in appendix a). the contribution of non-case j is: the log-likelihood is therefore: the number of pairs of farms to be considered per calculation of the likelihood is over [ ] . even with the recent increase in computational power, brute force exploration of the system, though feasible, is very time consuming. fast and efficient algorithms are necessary to provide real-time support to decision making. here, we explore the extent to which the discretization of the transmission risk factors can reduce the computational burden associated with the evaluation of equation ( . ). therefore, we now restrict our analysis to the situation where each transmission risk factor takes a finite set of values. we will then explore how the approach can be used to investigate continuous risk factors. assume that the transmission hazard between two individuals depends on k risk factors x ¼ fx , . . . ,x k g and that the k-th risk factor x k (k ¼ , . . . , k ) takes a finite number (¼c k ) of values fv k ; . . . ; v k c k g. the set c of possible values for risk factor vector x ¼ fx , . . . , x k g has size q k k¼ c k . for example, the list of risk factors might include the (discretized) distance between the individuals (either spatial or social, e.g. members of the same household), the time lag since infection or individual characteristics, such as age. we model the transmission hazard between a case and a susceptible individual in the population by: where the specific effect of x k on the transmission hazard is measured by function b k ðx k ; u k Þ ! , and u k ¼ fu k ; . . . ; u k l k g is a parameter vector of size l k . this expression makes the simplifying assumption that the effect of all risk factors on the hazard can be expressed as the product of the impacts of each factor. parameters of the model are remembering that z i denotes data available for individual i, we assume here that risk factors for transmission from case i to individual j on day t are a function of triplet fz i , z j , tg: x ði;j;tÞ ¼ fx ði;j;tÞ ; . . . ; x k ði;j;tÞ g, where for k ¼ , . . . , k, x k ði;j;tÞ ¼ g k ðfz i ; z j ; tgÞ. the transmission hazard l i!j ðt j jqÞ from case i to individual j on day t is therefore: l i! j ðtjqÞ ¼ bðx ði;j;tÞ ; qÞ: the total hazard of infection for individual j on day t is then: where here d a,b is the kronecker delta or identity function (¼ if a ¼ b and otherwise). m x counts the number of day-transmission events of type x, which might have occurred before time t but did not. equation ( . ) has important implications in terms of computational speed since it shows that the computational burden can be substantially reduced without loss of information. the first term of equation ( . ) only involves disease cases; the second term characterizes the probability of escaping infection up to time t. so, data needs for inference reduce to: -'case data'; -table fm x g x[c of sufficient statistics that characterize the interaction of cases with any individual of the population. it can be pre-computed and stored once, given they do not functionally depend on the parameters. tree reconstruction [ , [ ] [ ] [ ] is a useful complement to the likelihood-based estimates of the parameters derived from equation ( . ) . here, we present and discuss different strategies to perform tree reconstruction and parameter estimation in a coherent statistical framework. given parameter q and given that case j was infected on day t j , the probability that case j was infected by case i (t i , t j ) is simply (see appendix a): a natural way to integrate tree reconstruction and parameter estimation in a coherent setting is to proceed sequentially. for example, in a bayesian setting, a sample fq m g m¼ ;...;m can be drawn from the posterior distribution of q via mcmc sampling relying on equation ( . ) . then, for each parameter value in the sample m ¼ , . . . ,m, a source of infection r j can be drawn from its distribution f p i!j ðt j jq m Þg i for each case j. this gives a sample of m transmission trees drawn from their predictive distribution. for example, we used this strategy when analysing detailed data from an influenza outbreak in a school [ ] . here, we explore an alternative strategy where the two tasks are performed simultaneously. the method formalizes those introduced in work undertaken in on the uk fmd epidemic of that year [ ] . the idea is that the source of infection r j for each case j is considered as 'augmented' data. the augmented loglikelihood is: in many situations, where the force of infection exerted on individuals is relatively small, the likelihood simplifies to: the analysis of the augmented likelihood can be performed in a frequentist or in a bayesian setting. in the frequentist setting, it is straightforward to implement an expectation conditional maximization (ecm) algorithm [ , ] to both derive maximum-likelihood estimates of the parameters of the model and reconstruct the transmission tree. the pseudo-code for this algorithm is given in box . in the common situation, where one is interested in relative risks (i.e. comparison with a reference group) and where the force of infection exerted on individuals is relatively small, no maximization routine is needed since the maximum value is simply a ratio of two sums (appendix a) [ ] . confidence intervals can be obtained from the fisher information matrix derived at the maximum value for the incomplete log-likelihood (equation . ). the approach, therefore, requires that the second derivative of the log-likelihood with respect to q exists. alternatively, inference can be performed in a bayesian setting via mcmc [ ] , with a pseudo-code presented in box . the key difference is in the way missing data are handled: in the bayesian approach, one realization of the missing data is drawn from its expected distribution; by contrast in the em algorithm, the whole expected distribution of the missing data is used in the expression of the augmented likelihood. often, the day of symptom onset s j of case j is observed but not the day of infection t j . as a consequence, box . the em algorithm when the days of infection are observed. assume that at the beginning of iteration n, parameter vector is q n : -expectation step: (i) for each case j, compute probabilities f p i!j ðt j Þg i given q n (equation . ; see appendix a), and (ii) for x in c, compute the expected number of transmission events of type x : other parameters being fixed (see appendix a): bayesian algorithm when the days of infection are observed. at iteration n: -update missing data: (i) for each case j, compute probabilities f p i!j ðt j Þg i given q n (equation . ; see appendix a), (ii) for each case j, draw the source r j of case j from distribution f p i!j ðt j Þg i , and (iii) for x in c, compute the number of transmission events of type x: -update parameters: (i) for k ¼ , . . . , k, and (ii) for j ¼ , . . . , l k : mcmc update u k j relying on the augmented likelihood l c (see appendix a): methods to infer transmission risk factors s. cauchemez and n. m. ferguson likelihood as shown in equation ( . ) is no longer available. if the incubation period (time lag between the day of infection and the day of symptoms onset) has a known density f (s j jt j ), a common strategy to tackle the problem is to augment the data with the day of infection of each case. a particular computational burden is then that updating the day of infection of a single case may require re-calculation of the whole likelihood as the update may affect the risk of infection of all other individuals. in order to avoid this computational cost, we introduce the additional assumption: (h ) given the day of symptoms onset s j , infectiousness over time is independent of the day of infection t j . this is, for example, the case if infectiousness starts with symptom onset. this assumption seems acceptable for a relatively wide range of diseases since infectivity is often triggered or influenced by symptoms. under h , there is no need to re-compute the whole likelihood each time a day of infection is updated. it would be possible to extend the em approach to the situation when the days of infection are unobserved. inference would work as in the previous section except that one would have to take the expectation on both the contact tracing information and the day of infection. however, for this second application, it is no longer possible to easily derive the variance of the estimates. this is because, although maximum-likelihood point estimates could be derived from the likelihood for the 'complete' dataset, estimation of the variance of the estimates has to rely on the likelihood of the observed dataset (equation . ). this expression cannot be computed here since days of infection are not observed. the bayesian approach does not suffer from this limitation and makes it possible to easily obtain bayesian credible intervals (box ). we explore how the discretization of risk factors and the algorithms introduced in § can reduce the computational burden of inference. for simplicity, farms are partitioned into three groups on the basis of the number of cattle n c and the number of sheep n s : cattle (cattle farm: n c ! n s ), sheep (sheep farm: n s . n c ) and small (small farm: n c þ n s , ) [ ] . we assume that the latent period of fmd is days and that infectious farms remain so until the time of slaughter. the transmission hazard b between case farm i and susceptible farm j that is introduced in equation ( . ) is modelled as a function of the following characteristics: -the type (cattle, sheep or small) of case farm i. we estimate the relative infectivity of sheep farms ðg sh i Þ and small farms ðg sm i Þ relative to cattle box . bayesian algorithm when only days of symptom onset are observed. at iteration n: -gibbs sampling for missing data: (i) for each case j, compute probabilities f p j ðtÞg t for the day of infection of the case given q n (see appendix a), (ii) for each case j, draw the day t j of infection of the case from distribution f p j ðtÞg t , (iii) for each case j, compute probabilities f p i!j ðt j Þg i given q n (equation . ; see appendix a), (iv) for each case j, draw the source r j of case j from distribution f p i!j ðt j Þg i , and (v) for x in c, compute the number of transmission events of type x: -update parameters: (i) for k ¼ , . . . , k, and (ii) for j ¼ , . . . , l k : mcmc update u k j relying on the augmented likelihood. the augmented likelihood is slightly different from the case when days of infection are known (equation . ). in particular, since days of infection of cases change during the inference procedure, it is no longer possible to pre-compile and store the contribution of cases to matrix fm x g (i.e. number of day-transmission events of type x that could have occurred but did not); but one can still pre-compile and store the contribution fmm x g of non-cases, which is usually the key computational burden. the augmented likelihood is: farms. so the multiplicative term on the transmission hazard is g sh i ; if case farm is a sheep farm, g sm i if it is a small farm and if it is a cattle farm; -the type (cattle, sheep or small) of susceptible farm j. we estimate the relative susceptibility of sheep farms ðg sh s Þ and small farms ðg sm s Þ relative to cattle farms; and -the distance d ij between farm i and farm j. two models are considered: m : discrete model. we assume that the transmission kernel is a step function with k þ change points fd k g k¼ , . . . ,k and where the multiplicative term on the transmission hazard is g k d if d k , d ij d k . in practice, we take change points f , . , , . ð : Þ where qða; bÞ ¼ = Ð d¼ ð þ u=aÞ Àb du is a normalizing constant. here, we introduce a discretized version of this kernel. consider k þ change points fd k g k¼ , . . . ,k . we define d k ; the mean distance between farms i and j satisfying d k , d ij d k : the transmission kernel is the step function: in for the ecm algorithm, we consider that convergence is achieved at iteration n if the relative change in parameter values between iteration n and iteration n þ is smaller than for all parameters. in the bayesian implementation of the model, we specify the following priors for our parameters. parameters g sh i ; g sm i ; g sh s ; g sm s ; g d ; . . . ; g k d all have a gamma prior g(a, a) with a ¼ . we also do a sensitivity analysis for a ¼ , . for model m , we specify a uniform prior u [ , ] for kernel parameters a and b and a gamma prior g(a, a) for parameter c. the mcmc is run for iterations with a burn in of iterations. transmission parameters are estimated for time interval rd february (when the national ban on animal movements was introduced) to th october , conditional on the state of the epidemic on rd february. computation times are given for single threaded code running on an intel xeon x system. we first use the ecm algorithm (box ) to estimate model m (table ) . convergence is achieved in only iterations (figure ). total computational time is min s with most of the time ( s) spent reading the data and computing the table fm x g x[c of sufficient statistics (equation . ). in particular, there is no need to use maximization routines since there is an analytical solution to the conditional maximization step (see appendix a). computational times are also very short ( min s) for the bayesian algorithm (box ). estimates of transmission kernel m are obtained in min s (table ) . those computational times contrast with those needed through brute calculation of the likelihood (equation . ). replacing model m by the exact continuous parametric kernel (equation . ) and using equation ( . ) does not affect estimates (table ); but computational times move to a month for the same number of iterations of the mcmc, on the same machine and with no serious attempt to optimize the code. while algorithmic optimization and parallel programming allows this to be reduced to a few days [ ] , the algorithms presented here still give comparable estimates two orders of magnitude more rapidly than brute force approaches. we simulate an epidemic in a city that is structured in households and hospitals and where community transmission can happen. table summarizes the structure of the city. we consider a city of size with an average household size of . persons and with household demographics consistent with the french census [ ] . the city has three hospitals with staff members and beds each, a bed occupancy of per cent outside the epidemic period for a duration of hospitalization of days. we simulate the spread of a disease in this population and would like to assess how the techniques described above can be used to evaluate and monitor transmission in the different settings (community, hospital and household), infectivity and susceptibility of different types of individuals (here: children versus adults) along with the efficacy of the interventions that are put in place in the different settings. we are interested in a scenario like the severe acute respiratory syndrome (sars) rather than, for example, an influenza scenario; that is a disease for which it is possible to detect and identify a substantial proportion of cases. we assume that the incubation period of the disease has a geometric distribution (with probability . , truncated after days); that individuals start to be infectious on the day of symptoms onset with an infectivity profile following that time which has an exponential shape with mean days (truncated after days). we assume that per cent of cases are hospitalized with equal probability of hospitalization occurring or days after symptoms onset. we assume that children are . -fold more susceptible and more infectious than adults. following cauchemez et al. [ ] , we assume that the person-to-person household transmission rate is inversely proportional to the size of the household. the epidemic starts with five cases infected on day . control measures targeting community, household and hospital transmission each with an efficacy of reducing transmission of per cent are implemented on day of the outbreak. we consider different scenarios for the proportion of cases that are detected in the population. initially, we assume that all cases are detected. in alternative scenarios, we investigate the situations where or per cent of cases are randomly detected in the community/hospital, but where follow-up of households with detected cases is good ( %) and, last, the situation where detection of cases among household members is of the same quality as detection of cases in the community and in hospitals. the transmission hazard b between case i and individual j that is introduced in equation ( . ) depends on the following characteristics: -setting, i.e. whether individuals i and j are (i) members of the same household, (ii) have visited the same hospital or (iii) other (i.e. community transmission)-the multiplicative term on the transmission hazard is b hous /n (n: size of the household), b hosp /n hosp (n hosp : number of staff members plus average hospital occupancy outside an epidemic) and b com /n com (n com : size of the city). we specify a gamma prior g( , ) for b hous , b hosp and b com ; -infectivity profile from symptom onset of case imodelled with a normalized discretized exponential distribution with a mean to be estimated. we specify a uniform prior u [ , ] for the mean value; -whether or not case i is a child-we estimate the infectivity of children relative to adults. we specify a lognormal prior distribution with log-mean and log-variance for the relative infectivity of children g i . this ensures that g i has the same prior as /g i ; -whether or not individual j is a child-we estimate the susceptibility of children relative to adults, g s , assuming a lognormal prior distribution with log-mean and log-variance ; and -efficacy of interventions implemented in the different settings (i.e. household, hospital and community). after implementation of the intervention (day ), the transmission rate in the household, hospital and community is multiplied by parameter g hous , g hosp and g com , respectively; where g hous , g hosp and g com have the same prior as the relative infectivity and susceptibility of children. figure summarizes the data that would need to be collected during the outbreak with the age and dates of symptom onset of cases (figure a), a follow-up of households with cases and tracking of hospitalizations and more generally of hospital occupancy (figure b) and a follow-up of epidemics in hospitals (figure c). inference also requires having information on the age distribution of the population. in the simulated outbreak, there were a total of cases with ( %) child cases. in the scenario, where all cases are identified, figure shows how estimates change in real-time. on day , only cases have been detected and credible intervals of parameters are therefore wide. the credible interval includes the true value for all parameters except the relative infectivity of children. on day , with cases detected, posterior means are always relatively close to the true simulation value although credible intervals remain wide for some parameters like the relative infectivity and susceptibility of children and the mean generation time. on day ( cases detected), we would rightly conclude that children are more infectious and susceptible than adults although here again the credible intervals remain relatively wide. properly characterizing the infectivity profile requires substantially more data ( cases detected by day ). only days after control measures are implemented, fairly accurate estimation of the efficacy of interventions in different settings becomes possible. when only per cent of cases in the community and in hospitals are detected, performance of the approach remains satisfying although as expected credible intervals are wider and it takes longer for accuracy to be acceptable (figure ). when per cent of cases in the community and in hospitals are detected, precision of estimates starts to break down (electronic supplementary material, figure s ). although estimates of transmission rates in the community and the hospital are not strongly affected by under-reporting in those settings, this is not true of estimates of transmission rates in small closed settings such as households (electronic supplementary material, figure s ). the method also allows disaggregated monitoring of the reproduction number and the number of cases infected in different settings (figure ). in this paper, we have presented strategies to tackle some of the challenges associated with the estimation of transmission characteristics of infectious diseases and the risk factors affecting transmission patterns. the dependency that is typically observed in outbreak data (i.e. the risk of infection for an individual depends on the infection status of other individuals) can potentially lead to long computational times. we showed that if risk factors are discretized, the inferential problem can be simplified to the analysis of (i) a dataset on cases only and (ii) a pre-compiled summary table on interactions between individuals of the population and cases. in the fmd application, discretization reduced the computational time from few weeks to few minutes with no change in the estimates of the transmission kernel. it is likely that with substantial effort and parallel programming, we could have reduced the computation time of brute force approach by one or two orders of magnitude. even so, it seems unlikely that computational times could have gone much below few days. this has to be compared with the few minutes needed to run our algorithms on the fmd dataset. for small datasets, discretization may provide no computational gain if it takes longer to explore the set c of transmission risk factors than to sum over the pairs fcase i, individual jg. discretization may be difficult to implement on particularly complex transmission models [ , ] in which case brute force calculation of the likelihood may be needed. we presented two strategies to perform parameter estimation and tree reconstruction in a coherent way. the first one is a sequential approach that we used to analyse data from an influenza school outbreak [ ] . here, we implemented an alternative strategy where transmission parameters and the transmission tree are estimated simultaneously. there are pros and cons for each of those strategies. a nice feature of simultaneous inference is that the information on the transmission for situations when the dates of infection are unknown, we presented models which assumed that infectivity depends on the time elapsed since symptom onset, and is independent of the time of infection. this assumption reduces the computational burden since it implies that the infection hazard an individual is exposed to solely depends on measured quantities plus the parameters of the model, rather than on the unobserved days of infection of other cases. in practice, assumption h seems acceptable for a relatively wide range of diseases since infectivity is often triggered or influenced by symptoms. however, where the assumption is invalid, more computationally intensive methods accounting for the unobserved times of infection become necessary [ ] . in the simulation study, we considered an epidemic for which it would be possible to detect and identify a substantial proportion of cases; this would therefore be more applicable to a sars-like scenario rather than pandemic influenza. the simulation study showed that even in situations where under-reporting is substantial (e.g. %), it would still be possible to obtain informative estimates of key characteristics. we found that estimates of the transmission rate in the community and in the hospital were relatively robust to under-reporting in those settings. this can be explained by the fact that in a large population, the exponential growth rate of the epidemic is not affected by under-reporting. but estimates of transmission rates in small social units such as households were-as might be expected-strongly affected by under-ascertainment of cases. estimates of relative infectivity were particularly sensitive to underreporting, with large variance and sometimes important bias. estimating relative infectivity is in general quite challenging because it requires that one can compare the offspring of one group of individuals (e.g. adults) with that of another group (e.g. children) and this becomes very difficult as under-reporting increases. it is likely that estimates would be less robust to underreporting, if reporting rates changed over time, as probably happens in real epidemics. here, we have presented relatively simple approaches to reduce computational burden in the estimation of transmission parameters and to integrate parameter estimation and tree reconstruction in a coherent way. however, the analysis of outbreak data is subject to many other challenges. for example, it may be difficult to infer which parametric distribution should be used for the infectivity profile and the incubation period; data augmentation strategies may fail in a context when data are not missing at random or when there are false-positives or false-negatives [ ] . a particular challenge in outbreak data is that they are rarely informative about the incubation period of the disease. in the simulations study, for example, we made the assumption that the distribution of the incubation period of the disease was known. if it was not the case, one would require extra data to estimate it. for example, in the past, data from outbreaks in an aeroplane [ ] or in a bus [ ] were used to estimate the incubation period of influenza. a key practical challenge to implement the methods presented here in real time is the rapid collection and digitization of sufficiently detailed epidemiological data. however, recent experience demonstrates that it is possible to collect very detailed epidemiological data even during large outbreaks [ , [ ] [ ] [ ] , ] . cleaning and processing those data so that they are ready for analysis close to real-time remain a huge challenge, but the recent examples of the fmd outbreak in the uk [ , ] , the sars epidemic [ , ] and the h n pandemic [ ] show that this is increasingly feasible. however, reporting delays should always be expected and it will be important to account for those delays in future developments of the statistical method presented here. last, a key limit on the more widespread use of the type of methods presented in this paper is the relatively high technical hurdle to implement them, given there is currently no user-friendly statistical software package that allows easy implementation of this type of analysis. developing such tools is therefore a priority. we thank the mrc methodology programme, the nigms midas initiative, the eu fp emperie consortium and research council uk for research funding. we explain here the link between the continuous time and discrete time transmission models. at any (continuous) time point u during day t (i.e. u [ [t;t þ )), the instantaneous hazard of infection exerted on individual j is l à j ðuÞ ¼ l j ðtÞ for t u , t þ ; where l j (t) is defined in the main text. so, we make the assumption that the instantaneous hazard of infection is a step function with daily steps. conditional on the fact that individual j has not been infected up to day t, the probability that individual j is infected on day t is equal to in the continuous time model, conditional on the (continuous) time of infection u j of case j with u j [ [t j ; t j þ ), the probability that case i is the case source is: p à i!j ðu j jqÞ ¼ l i!j ðu j jqÞ p k:t k ,t j l k!j ðu j jqÞ ¼ l i!j ðt j jqÞ p k:t k ,t j l k!j ðt j jqÞ : and we note that this probability is constant for u j [ [t j ; t j þ ). conditional on the day t j of infection, the probability that case i is the case source given in equation ( . ) is: u j ¼t j p à i!j ðu j jqÞpðu j jt j Þdu j and p i!j ðt j jqÞ ¼ l i!j ðt j jqÞ p k:t k ,t j l k!j ðt j jqÞ ð t j þ u j ¼t j pðu j jt j Þdu j ¼ l i!j ðt j jqÞ p k:t k ,t j l k!j ðt j jqÞ : let consider the common situation where -we are interested in relative risks (i.e. comparison with a reference group). for example, the population is partitioned in c k groups fn k ; . . . ; n k c k g on the basis of risk factor k so that the multiplicative term associated with risk factor k in equation ( for the conditional maximization of the likelihood with respect to u k m in the ecm algorithm (box ), the log-likelihood can be re-written: markov chain monte carlo in practice stochastic epidemic models and their 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and control of severe acute respiratory syndrome key: cord- -f ny ur authors: kim, seung woo; park, jung wan; jung, hee-dong; yang, jeong-sun; park, yong-shik; lee, changhwan; kim, kyung min; lee, keon-joo; kwon, donghyok; hur, young joo; choi, boyoul; ki, moran title: risk factors for transmission of middle east respiratory syndrome coronavirus infection during the outbreak in south korea date: - - journal: clin infect dis doi: . /cid/ciw sha: doc_id: cord_uid: f ny ur background. transmission heterogeneity was observed during the korean outbreak of middle east respiratory syndrome coronavirus (mers-cov) infection. only of cases transmitted the infection, and super-spreading events caused transmissions. we investigated the risk factors for mers-cov transmission. methods. epidemiological reports were used to classify patients as nonspreaders, spreaders, or those associated with a super-spreading event ( or more transmissions). logistic regression analyses were used to evaluate the factors for mers-cov transmission. results. compared to nonspreaders, spreaders exhibited a longer interval from symptom onset to isolation ( days vs days) and more frequent pre-isolation pneumonia diagnoses ( . % vs . %). spreaders also exhibited higher values for pre-isolation contacts ( vs . ), pre-isolation hospitalization ( . % vs . %), and emergency room (er) visits ( % vs . %). spreaders exhibited lower cycle thresholds for the upe and orf a genes ( . vs . and . vs . , respectively). in multivariate analysis, transmission was independently associated with the cycle threshold (odds ratio [or], . ; % confidence interval [ci], . – . ) and pre-isolation hospitalization or er visits (or, . ; % ci, . – . ). the super-spreading events exhibited higher values for pre-isolation contacts ( vs ), pre-isolation er visits ( % vs . %), and doctor shopping ( % vs . %) compared to non-super-spreading events. conclusions. these findings indicate that transmission is determined by host infectivity and the number of contacts, whereas super-spreading events were determined by the number of contacts and hospital visits. these relationships highlight the importance of rapidly enforcing infection control measures to prevent outbreaks. transmission heterogeneity was a significant characteristic of the south korean outbreak of middle east respiratory syndrome coronavirus (mers-cov) infection [ ] . transmission heterogeneity describes a state in which most transmissions are related to a few patients and most patients do not transmit the disease. numerous other infectious diseases exhibit transmission heterogeneity [ ] , and this concept is important for understanding epidemics. the course of an epidemic is influenced by the basic reproduction number (r = the average number of cases that case produces in a susceptible population) and transmission heterogeneity [ ] . as r represents an average quantity, it is often insufficient to explain individual variation, and as transmission heterogeneity reflects individual variation, it can help predict the likelihood of super-spreading events. even in instances with a low r , a disease with high transmission heterogeneity (eg, severe acute respiratory syndrome [sars]) can cause super-spreading events [ ] , such as the super-spreading that occurred during the sars outbreak [ , ] . transmission heterogeneity was observed during early mers-cov outbreaks [ ] and became prominent during the south korean outbreak. among the confirmed korean cases of mers-cov infection, > % of the transmissions were epidemiologically associated with patients [ ] , and almost % of the cases caused no transmission. furthermore, a recent study revealed that mers has greater transmission heterogeneity compared to sars [ ] . therefore, to successfully control mers-cov infection, it is essential to identify high-risk patients and perform targeted infection control [ ] . however, these patients are difficult to identify, as an individual's infectiousness is affected by complex interactions between the pathogen, host, and environment. several researchers have attempted to identify risk factors for super-spreading events during the sars outbreak [ , , ] , although there is little information regarding the high-risk group(s) from the mers-cov outbreak. the recent south korean mers-cov outbreak was triggered by a single imported case, and epidemiological tracing was performed for all laboratory-confirmed cases and their close contacts [ , [ ] [ ] [ ] [ ] [ ] [ ] . thus, it is possible to precisely reconstruct the transmission chain and identify patients who transmitted mers-cov infection. therefore, we analyzed the epidemiological characteristics that were associated with mers-cov transmission and super-spreading events. cases of mers-cov infection were confirmed using real-time reverse-transcription polymerase chain reaction (rt-pcr) assays, regardless of their clinical manifestations. the epidemiological reports were analyzed by epidemic intelligence service officers who participated in the mers-cov outbreak investigation. when a case was exposed to multiple confirmed cases, the transmission was attributed to the case with the highest likelihood of transmission, and any conflicts were resolved through the consensus of the epidemic intelligence service officers. spreaders were defined as confirmed cases of mers-cov infection that were epidemiologically suspected of transmitting mers-cov to or more persons. super-spreading events were arbitrarily defined as transmission of mers-cov infection to or more cases. the patient who triggered the outbreak was defined as patient zero. cases that were infected by patient zero were defined as first-generation cases; cases that were infected by first-generation cases were defined as second-generation cases; and cases that were infected by second-generation cases were defined as third-generation cases [ ] . isolation was defined as separating symptomatic patients from others to prevent spreading, and quarantine was defined as separating or restricting the movement of healthy individuals who may have been exposed to the infection within the maximum incubation period. the transmission date was defined as the date of contact between the spreader and suspected secondary case during the spreader's infectious period. in cases with an exposure duration of longer than day, the transmission date was defined as the day with the highest likelihood of transmission or as the median day during the exposure period in cases with consistent contact throughout the exposure. the date of sampling was the day on which the first positive respiratory specimen was collected. close contacts were defined using the guidelines on middle east respiratory syndrome [ ] , which include persons who stayed in a room or ward with a confirmed case, who directly contacted respiratory secretions from confirmed cases, or who stayed within m from the confirmed cases without wearing appropriate personal protective equipment. pre-isolation pneumonia diagnoses were based on radiographic evidence. doctor shopping was defined as visiting multiple healthcare facilities without an official interhospital transfer after developing mers-cov symptoms [ ] . epidemiological reports from the outbreak were evaluated to collect data regarding basic demographic characteristics, medical history, mers-cov exposure, symptoms and their onset date(s), sampling date(s), contact history, and post-exposure infection control. the reports were drafted during the outbreak based on direct interviews with the confirmed cases and follow-up epidemiological investigations that were performed to identify the exposure route and close contacts. hospital information systems were reviewed to identify patients who stayed in the hospital during the exposure period and healthcare providers who contacted the patient(s). persons who contacted confirmed cases outside healthcare facilities were also traced. data from closed circuit television, credit card transactions, and health insurance services were also reviewed [ ] . the numbers of close contacts were calculated based on the number of quarantines during the outbreak. all data were collected as part of the public health response and in accordance with the infectious disease control and prevention act [ ] . clinical specimens were collected in sterile containers and immediately transferred to qualified facilities. sputum samples were mixed with - × phosphate-buffered saline and vortexed vigorously to reduce their viscosity. viral rna was extracted from the clinical specimens using a qiagen viral rna mini kit (qiagen, hilden, germany). all laboratory diagnoses of mers-cov were confirmed using the world health organization guidelines [ ] and results from real-time rt-pcr assays that target upstream of the mers-cov envelope protein gene (upe) and the open reading frame a gene (orf a) [ ] . cycle threshold (ct) values for the upe and orf a genes were obtained during testing. we analyzed the ct value from the first positive mers-cov specimen (or the specimen obtained immediately after a positive screening test). categorical variables were compared using the χ test and fisher exact test, and the mann-whitney test was used for continuous variables. the variables' associations with mers-cov transmission were evaluated using multiple logistic regression analyses, and covariates were selected based on a p value of < . in the univariate analyses. a p value of < . was considered statistically significant. all analyses were performed using r software (version . . ; r foundation, vienna, austria). we identified cases of confirmed mers-cov infection. patient zero infected first-generation cases. among the cases, were responsible for transmission to second-generation cases. among the cases, infected third-generation cases. one patient with an unclear source of infection (case ) transmitted the infection to another patient. four patients exhibited unclear sources of transmission (cases , , , and ). each confirmed case transmitted the infection to - secondary cases ( figure ). there were nonspreaders and spreaders ( or more transmission). of the spreaders, cases transmitted the infection to or more cases (super-spreading event). after excluding the cases with unclear infection sources, we identified transmissions generated by spreaders. a total of transmission events ( . %) were epidemiologically linked to the super-spreading events. twenty-five transmission events ( . %) occurred within days after symptom onset, transmissions ( . %) occurred - days after symptom onset, and transmissions ( . %) occurred > days after symptom onset. a total of transmission events ( . %) occurred on the day of or after a radiographically confirmed diagnosis of pneumonia. a total of transmissions ( . %) occurred before appropriate in-hospital isolation. seven transmissions ( . %) occurred between confirmed cases and healthcare personnel after in-hospital isolation: (cases , , , and ) were doctors or nurses who managed confirmed cases, (case ) participated in cardiopulmonary resuscitation of a confirmed case, (case ) involved portable radiography for a confirmed case, and (case ) rode in an ambulance with a confirmed case during a hospital transfer. ; p = . ). the intervals from symptom onset to diagnosis or obtaining a respiratory specimen were also significantly longer among spreaders (to diagnosis: [ . - ] days vs [ ] [ ] [ ] [ ] [ ] [ ] days; p = . and to sampling: [ - . ] days vs [ ] [ ] [ ] [ ] [ ] days; p < . ). furthermore, the interval from symptom onset to isolation was longer among spreaders ( [ . - ] days vs [ ] [ ] [ ] [ ] [ ] [ ] days; p = . ). spreaders exhibited a significantly higher proportion of pre-isolation pneumonia diagnoses ( . % vs . %; p < . ) and a longer interval from the pneumonia diagnosis to isolation ( [ ] [ ] [ ] [ ] [ ] days vs [ - ] days; p = . ). the overall number of contacts was significantly larger among spreaders compared to nonspreaders ( [ . - . ] vs . [ - . ]; p = . ). compared to nonspreaders, spreaders exhibited a significantly higher proportion for pre-isolation hospitalization ( . % vs . %; p < . ), visiting outpatient clinics ( . % vs . %; p = . ), and visiting emergency rooms (ers; % vs . %; p < . ). we used logistic regression analyses to evaluate the risk factors for transmission (table ). in the univariate analyses, transmission was associated with underlying respiratory disease, ct value, interval from symptom onset to diagnosis, number of contacts, and pre-isolation hospitalization or er visits. in the multivariate analyses, transmission was independently associated with a low ct value for upe (odds ratio [or], . ; % confidence interval [ci], . - . ) and pre-isolation hospitalization or er visits (or, . ; % ci, . - . ). we compared the epidemiological characteristics of the spreaders with or more transmissions and the spreaders with or fewer transmissions (table ) . both groups exhibited similar host factors and contact durations. however, spreaders with or more transmissions exhibited higher values for we evaluated the epidemiological characteristics of patients who transmitted mers-cov during the recent south korean outbreak. among the confirmed mers-cov cases, only cases transmitted the infection to other individuals. these spreaders had higher host infectivity and wider and prolonged contacts compared to nonspreaders. the risk factors for super-spreading events included a larger number of contacts and a pre-isolation er visit. doctor shopping was marginally associated with a super-spreading event. however, both spreaders with or more transmissions and spreaders with or fewer transmissions exhibited similar levels of host infectivity. it appears that both host infectivity and the number of contacts influenced mers-cov transmission, whereas super-spreading events were mostly associated with a greater likelihood of encountering other people under diverse environmental conditions. during the outbreak, approximately % of the transmissions occurred during days - after symptom onset, and this may be a period when the risk of transmission is particularly high. furthermore, this high-risk period was temporally associated with other epidemiological factors. first, the period overlapped with the confirmed cases' visits to healthcare facilities, as hospitalization and er visits peaked during days - after symptom onset. it is well known that mers-cov outbreaks generally occur in the healthcare setting [ , , , ] , and the high-risk period may be associated with healthcare-seeking behaviors. second, the high-risk period was several days ( - days) after the radiographic diagnoses of pneumonia, which generally occurred on days - after symptom onset. although the significance of pre-isolation pneumonia has not been discussed previously, a radiographic diagnosis of pneumonia may influence transmission in ways. first, it may directly increase the chance of transmission by actively generating lower respiratory tract secretions and a productive cough. second, it may be an indirect index of disease severity and hospital visiting status. in our study, cases with pre-isolation pneumonia had lower ct values and more frequent pre-isolation hospital visits. the epidemiological significance of the high-risk period could also be observed when we compared the spreaders and nonspreaders. the spreaders were typically isolated after the high-risk period (median, days after symptom onset and days after a diagnosis of pneumonia), whereas nonspreaders were typically isolated before this period (median, days after symptom onset and day after a diagnosis of pneumonia). similar results were observed in a study of the sars outbreak, which revealed that late admission to healthcare facilities (especially > days after symptom onset) was associated with super-spreading events [ ] . thus, infection prevention measures should target isolation before this critical period (ie, within - days after symptom onset and within day after the detection of pneumonia). interestingly, the average duration from symptom onset to isolation dropped to < days during the first week of june , and reports of new cases have rapidly decreased since that time. among the host factors that were associated with transmission, only the ct value was statistically significant in the multivariate analyses. the ct value is a semiquantitative continuous variable that is inversely proportional to the viral load. ct values are associated with the severity of mers-cov infection [ ] , although its relationship with transmission has rarely been studied. in the present study, spreaders had significantly lower ct values compared to nonspreaders, which suggests that ct values might reliably predict transmission. moreover, the cases with very low ct values (ct < ) tended to transmit the infection in uncommon circumstances. in both the present study and previous studies, mers-cov transmission usually occurred in the hospital setting [ , , , ] . in contrast, cases with very low ct values transmitted the infection in more diverse settings in the present outbreak (eg, their household, in an ambulance, in an outpatient clinic, or to healthcare personnel after in-hospital isolation). these findings suggest that cases with very low ct values can potentially transmit the infection in unexpected conditions. however, our data regarding the ct values have several limitations. first, various amounts of phosphate-buffered saline were added to dilute the respiratory specimens, and this there was no multicollinearity between the independent variables (all variables: r score of < . ). abbreviations: ci, confidence interval; or, odds ratio. may have affected the ct values. second, the ct value is influenced by the specimen type and the interval between symptom onset and sample collection [ , ] , but various different types of specimens were collected at different time points in the present study. however, we only evaluated nonsputum specimens, and there was no linear correlation between the ct values and the interval from onset to sampling. our comparison of the spreaders with or more transmissions and spreaders with or fewer transmissions revealed that the spreaders with or more transmissions had an approximately -fold higher number of contacts. furthermore, there were no significant differences in host infectivity. these findings may suggest that the underlying likelihood of transmission has the greatest influence on super-spreading events rather than an intrinsic difference in host infectivity. a similar finding was observed in a previous study of the sars super-spreading event [ ] , with those super-spreaders having - contacts compared to - contacts for the spreaders with - transmissions. our study also revealed that a pre-isolation er visit and doctor shopping were associated with super-spreading events. in addition, super-spreading events were associated with the number of healthcare facilities that each patient visited for hospitalization or er treatment but not with the number of hospitals visited for outpatient treatment. in south korea, patients who seek hospitalization without prior arrangements tend to visit the er, and a history of or more er visits strongly suggests that the patient had been doctor shopping during hospitalization. specific environmental conditions have been suggested to increase the likelihood of a super-spreading event [ ] , and doctor shopping may increase the likelihood of encountering these conditions. for example, when a confirmed case changes hospital during hospitalization without an official interhospital transfer, multiple environments are exposed to the infected case (an ambulance, an er, and a ward). thus, doctor shopping can greatly increase the likelihood of encountering conditions that are suitable for a super-spreading event. in the present outbreak, of the super spreaders (cases , , , and ) transmitted the infection at or more hospitals, as they had visited multiple healthcare facilities. therefore, it is very important to have an early suspicion of mers-cov infection and minimize doctor shopping during the early stage of an outbreak. our study has several limitations. first, some of the confirmed cases had multiple potential sources of infection, and we attributed the transmission to the case with the highest epidemiological probability. the source of infection was clear in > % of the transmissions, and we excluded cases that had contact with multiple cases and an unclear source of transmission. however, as the analyses of the epidemiological data are ongoing, the list of spreaders may change if new epidemiological evidence is uncovered. second, we did not have access to genomic sequencing data, which might have provided information regarding the relatedness of transmitted strains. third, transmission may be affected by other epidemiological factors, including aerosol-generating procedures, differences in environmental conditions, and variations in crowdedness [ , , ] . however, these factors were not included in the present analysis. fourth, serological testing was not performed for every close contact, and additional asymptomatic cases may have been present. however, the seropositive rate was . % in a recent serological study of close contacts [ ] . thus, the absence of serological testing likely did not significantly influence our results. we evaluated the epidemiological risk factors for mers-cov transmission during the recent south korean outbreak. superspreading events were not related to intrinsic host characteristics and were attributable to the likelihood of transmission. therefore, strict er triage and minimizing doctor shopping during an outbreak's early stage may help prevent super-spreading events. hospital outbreak of middle east respiratory syndrome coronavirus superspreading and the effect of individual variation on disease emergence why did outbreaks of severe acute respiratory syndrome occur in some hospital wards but not in others? superspreading sars events middle east respiratory syndrome coronavirus outbreak in the republic of korea transmission characteristics of mers and sars in the healthcare setting: a comparative study super-spreaders in infectious diseases mers outbreak in korea: hospital-to-hospital transmission epidemiologic features of the first mers outbreak in korea: focus on pyeongtaek st. mary's hospital epidemiological investigation on the th confirmed mers-cov case with the indefinite mode of transmission in pyeongtaek outbreak the first case of the korean middle east respiratory syndrome outbreak mers epidemiological investigation to detect potential mode of transmission in the th mers confirmed case in pyeongtaek mers-cov outbreak following a single patient exposure in an emergency room in south korea: an epidemiological outbreak study ministry of health and welfare. guidelines on middle east respiratory syndrome doctor shopping: a phenomenon of many themes korea ministry of government legislation infectious disease control and prevention act world health organization. laboratory testing for middle east respiratory syndrome coronavirus. interim recommendations complete genome sequence of middle east respiratory syndrome coronavirus kor/knih/ _ _ , isolated in south korea mers-cov outbreak in jeddah-a link to health care facilities predicting super spreading events during the severe acute respiratory syndrome epidemics in hong kong and singapore association of higher mers-cov virus load with severe disease and death, saudi arabia an observational, laboratory-based study of outbreaks of middle east respiratory syndrome coronavirus in jeddah and riyadh, kingdom of saudi arabia respiratory tract samples, viral load, and genome fraction yield in patients with middle east respiratory syndrome aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review surveillance of the middle east respiratory syndrome (mers) coronavirus (cov) infection in healthcare workers after contact with confirmed mers patients: incidence and risk factors of mers-cov seropositivity acknowledgements. the authors thank sung soon kim and jeong-gu nam (division of respiratory viruses, center of infectious disease, korea centers for disease control and prevention) for laboratory assistance and technical support in the production of the manuscript. in addition, we thank all administrative and laboratory staff of the korea centers for disease control and prevention who participated in the mers-cov outbreak control effort.author contributions. s. w. k. performed the literature search, study design, data collection, analysis, interpretation, and writing. m. k. contributed to the study design, data interpretation, and writing. j. w. p., y. s. p., c. l., k. m. k., k. j. l., and d. k. contributed to the data collection and interpretation. h. d. j. and j. s. y. contributed to the data collection, mers pcr testing, data interpretation, and analysis. y. j. h. and b. y. c. contributed to the study design, data interpretation, and revising the manuscript. s. w. k. and m. k. revised the manuscript. all authors contributed to writing and approved the final manuscript.potential conflicts of interest. authors certify no potential conflicts of interest. the authors have 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. key: cord- - c qsek authors: paul, s. k.; jana, s.; bhaumik, p. title: on nonlinear incidence rate of covid- date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: c qsek classical susceptible-infected-removed model with constant transmission rate and removal rate may not capture real world dynamics of epidemic due to complex influence of multiple external factors on the spread. on top of that transmission rate may vary widely in a large region due to non-stationarity of spatial features which poses difficulty in creating a global model. we modified discrete global susceptible-infected-removed model by using time varying transmission rate, recovery rate and multiple spatially local models. no specific functional form of transmission rate has been assumed. we have derived the criteria for disease-free equilibrium within a specific time period. a single convolutional lstm model is created and trained to map multiple spatiotemporal features to transmission rate. the model achieved . % mean absolute percent error in terms of cumulative infection cases in each locality in a -day prediction period. local interpretations of the model using perturbation method reveals local influence of different features on transmission rate which in turn is used to generate a set of generalized global interpretations. a what-if scenario with modified recovery rate illustrates rapid dampening of the spread when forecasted with the trained model. a comparative study with current normal scenario reveals key necessary steps to reach baseline. ynamical systems equations based on compartmental modelling of epidemiology have been widely used to predict the spread of an epidemic. susceptible-infected-removed or sir model is one such simplified set of differential equations to model the spread. however, accurately determining parameter values like the transmission rate for a specific disease is a challenge. the dynamics of a disease may vary across space and time. many external factors may influence the transmission rate. considering the transmission rate constant for a disease, grossly oversimplifies the model, thus compromising accuracy. secondly, knowing the factors influencing the transmission rate and the dynamics of the influence can provide a vivid understanding of the disease progression. there are several different types of nonlinear incidence rate suggested in the literature [ , , , , , , ] . however, most of them adopt some type of simple predefined function with few parameters to model the incidence rate. simple functions have low representational capability. thus, they may not capture the detail dynamical variations of the incidence rate caused by multiple factors. we propose a convolutional lstm based spatiotemporal model to map the transmission rate of covid- with respect to multiple input features and thereby map the derived incidence rate from transmission rate. the model can forecast incidence rate with high spatiotemporal resolution provided availability of clean historical data in that resolution. exploratory analysis reveals probable influence of external features on transmission rate and eventually helped in feature selection. a spatiotemporal local interpretation method of a black box model is proposed which in turn is used to explain the trained model. the explanations reveal local influence of different external features on the transmission rate. a generalized global explanation is also generated to find common influence of factors across multiple locations and over a period. we experimented with available data of covid- across multiple regions of usa and the model achieved . % and . % mean absolute percent error in terms of new infection cases in each locality and cumulative total infection cases across the country in a -day prediction period respectively. the generated explanations revealed high influence of population density, somewhat medium influence of gender ratio and median population age on the transmission rate, globally. there are minor influences of temperature and temperature deviation but barely any observable influence of humidity. however, local influences of features vary widely across multiple small regions. a criterion for disease-free equilibrium within a specific time period has been derived for discrete sir model with variable transmission and recovery rate. a long-term forecast using the trained model and modified recovery rate to satisfy disease-free equilibrium criteria reveals rapid damping of active infection cases to reach the baseline. however frequent spikes due to resurgence are seen in this scenario. a comparative study is made with forecasted dynamics using current normal recovery rate to reveal necessary actions for rapid containment of the disease. the paper is organized as following. we conducted a brief literature survey in section . section briefly explains the discrete sir model with variable transmission rate. section discusses about spatiotemporal modelling of transmission rate. section discusses on spatiotemporal influence ----------------of external features on transmission rate. we conduct long term forecasting of disease progression with a current normal scenario and a "what-if" scenario in section . section concludes the paper. kermack and mckendrick [ ] modelled communicable diseases using differential equations. hethcote introduced the sir model [ ] where population is compartmentalized into susceptible, infected and removed groups. a set of differential equations modeled the dynamics of population in different compartments. in traditional sir model incidence rate or the number of new infections per unit time varies bilinearly with the number of infections and number of susceptible in a population considering the transmission rate as constant. however, assumptions like homogenous mixing, non-dependence on external factors, no psychological effects on population etc. may not be realistic in many cases. thus, several authors [ , , , , , , ] introduced different types of non-linear incidence rates mostly addressing the saturation and psychological effect. saturation effect states that the incidence rate might slow down and saturate as number of infected individuals increases due to low availability of susceptible individuals. psychological effect on the population results in increased cautiousness among susceptible individuals as the epidemic spreads thus, slowing down the transmission rate. most of the incidence rates stated above satisfy weakly non-linear property and are too simple to capture any arbitrary effects of the environment. sir model with time varying transmission recovery rate have been studied in [ ] and thresholds theorems are derived. liu et. al. [ ] introduced a time varying switched transmission rate to model nonlinear incidence. hu et. al. developed a modified stacked autoencoder model of the epidemic spread in china and they claimed to achieve high level of forecasting accuracy [ ] . on observing a universality in the epidemic spread in each country, fanelli and piazza [ ] applied mean-field kinetics of susceptible-infected-recovered/dead epidemic model to forecast the spread and provided an estimation of peak infections in italy. zhan et. al. [ ] integrated the intercity migration data in china with susceptible-exposed-infected-removed model to forecast an estimation of epidemic spread in china. hong et. al. [ ] considered variable transmission rate of covid and came up with variable rnaught factor of covid- . xi et. al. [ ] used deep residual networks to model spatiotemporal characteristics of the spread of influenza and experimented with real dataset of shenzhen city in china. paul et. al. [ ] used ensemble of convlstm networks to forecast covid- total infection cases. in sir model the total population in a region is compartmentalized into classes, namely susceptible (s), infected (i) and removed (r). initially the whole population is in susceptible class. an individual can move from susceptible to infected class on contracting the disease. an infected individual can move to removed class by either getting recovered and immune to the disease or deceased. the dynamics of the disease spread can be modelled by the following set of differential equations. where ( ) is disease transmission rate or contact rate and ( ) is removal rate which is sum of recovery rate and mortality rate. it is assumed the population size ( ) remains constant during the course of epidemic. ( ), ( ) and ( ) are scaled as fraction of total population. thus, the following equation holds true. from [ ] we get the following ∀ > , where = ( ), ( ) ≥ ∀ > and ( ) ≥ we consider discrete time steps in our modelling and measurements are taken on daily basis. thus, replacing differential with difference equation. solving for ( ) expanding log as taylor series and taking only the first term, considering a constant average difference between transmission rate and removal rate = − within the period considering ( ) < as disease free equilibrium state, the upper bound of can be derived as following such that the epidemic reaches baseline in time t. maintaining > asymptotically converges the total infection count to at exponential rate thus makes the disease-free equilibrium stable. assuming a constant mortality rate, from ( ) it can be deduced that increasing the recovery rate will directly reduce the time span of the disease outbreak. however, there is a hard limit for the removal rate, ( ) ≤ . but ( ) can be greater than , specially during initial outbreak when total infection count is low. in such situation dampening the . cc-by . international license it is made available under a preprint in perpetuity. is the author/funder, who has granted medrxiv a license to display the (which was not certified by peer review) this preprint the copyright holder for this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint spread of infection will not be possible only with treatment facilities. immediate restriction of mobility in area of outbreak and rapid isolation of infected individuals can reduce the transmission rate. once it comes down below , enhanced treatment facilities can increase the recovery rate, thus reducing the span of the disease outbreak. the transmission rate can vary spatially as well as temporally based on multiple variables. geographical location, weather conditions [ ] , human mobility [ ] , population statistics might be some of the impacting factors changing the dynamics of the spread. an exploratory analysis reveals probable dependency of multiple spatial and temporal features on the transmission rate. spatially co-located regions might have similar dynamics of the spread with high autocorrelation of transmission rate in a localized region. however distant regions may have dissimilar transmission dynamics with low correlation. thus, a large geographic area has been divided into small regions called as grids. each grid has been divided even further into smaller regions called pixels. a population within a pixel is assumed to be constant and transmission dynamics is modeled by separate sir models for each pixel. each grid consists of co-located regions which might be impacting each other's transmission rate. feature is constructed for each grid as multichannel temporal sequence of matrices which in turn used for training a convlstm [ ] network to model the transmission rate. data has been obtained for a region in united states from multiple sources [ , , , , , , ] . the time span of the data is from - - to - - . covid daily data at usa county level are filtered by a spatial region of usa as shown in fig. . the region is geospatially divided in m x n grids of equal sizes bounded by calculated latitudes and longitudes. fig. a illustrates a grid bounded by latitudes and longitudes. the dotted line box is called as frame. the overlapping areas in all directions in a frame allows flow of spatial influence from neighboring grids. a frame is in turn divided into l x l pixel. each pixel represents a bounded area in geospatial region. each pixel contains a value mapped to certain feature in the bounded geospatial region. frame matrices are constructed for each feature and concatenated through a third axis called channels. for example, transmission rate and population density are two features and they represent two separate l x l matrices in a frame concatenated across a third axis. some features like transmission rate, active infection fraction, weather etc. are distributed spatio temporally. whereas other features like population density, female fraction, median age are assumed time invariant and have no temporal component. thus, they are only distributed spatially and copied along temporal axis. population density has been log transformed to reduce skewness and normalized. other features are only normalized in - scale. daily transmission rate and removal rates at pixel level have been calculated as following, where ∈ { . . } denotes each pixel, ∆ + ( ) and ∆ ( ) are fraction of new cases in infected class and new individuals in removed class respectively at time in pixel . each training sample of a frame is represented by a tensor of dimension t x l x l x c, where t is the total time span and c is number of channels or features. as shown in fig the forecasting problem is framed as supervised learning problem. given a sequence of observed multichannel frames of spatial data as matrices , … the objective of the model is to predict the next single channel frame + . the training samples are divided into input sequences of length w and output frames. the model forecasts the transmission rate in each pixel in a frame for each timestep. thus, the output frame consists of only channel. the input training dataset (x train ) can be represented as a tensor of size s train x w x l x l x c and the output dataset (y train ) as is the author/funder, who has granted medrxiv a license to display the (which was not certified by peer review) this preprint the copyright holder for this version posted october , . . s train x w x l x l x . for training, the input sequences are selected from all frames having non-zero total infection count. fig. b illustrates the sequence of a frame. the frames t- to t- represents an input training sequence (x train ) of length w. the output frame (y train ) for this training sample is t- . other training samples are generated by sliding the window w+ backwards in time by . the most recent images t- and t- represents the test output images (y test ) and immediate sequence of images t- to t- is the test input sample (x test ). the test set x test is represented by a tensor of size (m * n) x w x l x l x c and y test by (m * n) x w′ x l x l x . the primary purpose of the exploratory analysis is to understand the distribution of transmission rate and identify probable influence of different features on the transmission rate. eight external features are analyzed against transmission rate to find probable influence. among eight features, four are spatial features having no temporal component, namely population density, housing density, female fraction, median age. fig. illustrates scatter charts between average transmission rate and four spatial features for multiple pixels. the color gradient represents log transformed cumulative number of infection cases in each pixel. only those pixels are filtered which experienced at least days of running infection cases and having at least cumulative infection cases at the beginning of the observation period. fig a and b displays scatter charts and regression lines of average transmission rate with respect to population density and housing density in each pixel respectively. the two external features are log transformed and scaled to get upper bounded by . log transformation reduces skewness and influence of outliers in data. as observed in the charts the transmission rate is positively correlated with both the features which is quite intuitive. places with high population density is expected to experience rapid spread of the disease. locations with high population density also experienced highest number of cumulative cases. fig. c and b displays scatter charts and regression lines of transmission rate with respect to female fraction and median age of the population respectively. in fig c, pixels have been filtered out having female fraction less than . to remove the skewness in the data. there is a slight positive correlation between female fraction and transmission rate. however, this might not invoke a suggestive idea about the dependency of this external feature on transmission rate as majority of the pixels resides in the range of . - . female fraction with barely any trend in that range. also, there is an indirect correlation as in general pixels with high female fraction has high population density. median age has negative correlation with transmission rate. there is an indirect correlation in this case also as in general pixels with high median age has low population density. another intuitive assumption can be, population with high median age are less mobile thus is the author/funder, who has granted medrxiv a license to display the (which was not certified by peer review) this preprint the copyright holder for this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint restricting the spread of the disease. apart from four spatial features four other external spatiotemporal features are analyzed to observe any influence on transmission rate. fig. illustrates time lagged cross correlation between transmission rate and other spatio-temporal features at pixel level. the external features are time lagged from to time steps and cross correlated with transmission rate for each lag. in the plot, pixels are arranged in increasing order of total infection cases. fig. a and b shows the plot of cross correlation of transmission rate with respect to average daily temperature and -day running window temperature standard deviation respectively. average temperature is slightly positively correlated in time lag range of - . in the plot, offset denotes time lag and offset as time lag . the correlation with temperature variation varies widely across pixels. however, on average there is a minor positive correlation in time lag range of - . for both the features pixels having high total infections have negative correlation with transmission rate in the time lag range of - . fig. c and d shows the plot of cross correlation of transmission rate with respect to average daily relative humidity and daily removal rate respectively. there is an overall positive correlation with respect of relative humidity specially in pixels with highest infection cases. removal rate is mostly negatively correlated with transmission rate except in few pixels having highest infection cases. correlation might not represent causality. thus, we performed granger causality test [ ] of transmission rate with respect to different features. granger causality is a statistical hypothesis test for finding if one time series can help improving the forecasting accuracy of another time series. it might not measure true causality rather it measures predictive causality. chi square test is chosen as the hypothesis testing method and minimum pvalues for each pixel are calculated. augmented dickey-fuller test [ ] is performed to test stationarity of all the timeseries. table displays the result of granger causality and dickey-fuller tests. the column '% of pvalue < . ' represents percentage of pixels for which the granger causality test gave pvalue less than . for each feature. the column '% of adf< %' represents percentage of pixels for which the dickey-fuller test gave test statistic less than % critical value and having pvalue less than . for each feature. from the observed results it seems for majority of the pixels the weather features and removal rate have predictive causal relation with transmission rate. also, for majority of the pixels the feature timeseries are stationary or weakly stationary. recurrent neural networks (rnn) are a class of artificial neural networks with nodes having feedback connections thereby allowing it to learn patterns in variable length temporal sequences. however, it becomes difficult to learn long term dependencies for traditional rnn due to vanishing gradient problem [ ] . lstms [ ] solve the problem of learning long term dependencies by introducing a specialized memory cell as recurrent unit. the cells can selectively remember and forget long term information in its cell state through some control gates. in convolutional lstm [ ] a convolution operator is added in state to state transition and input to state transition. all inputs, outputs and hidden states are represented by d tensors having spatial dimensions and temporal dimension. this allows the model to capture spatial correlation along with the temporal one. in our model we configured multichannel input such that distinct features can be passed through different channels. multiple convolutional lstm layers are stacked sequentially to form a network with high nonlinear representation. the final layer is a d convolutional layer having one filter which constructs a single channel output image as the next frame prediction. we assume the transmission rate saturates as number of infection cases increases. thus, the modified transmission rate is calculated as ′ ( ) = ( ) * (τ + ( )) which serves as the response variable for the model and τ = / and is total population in pixel . the model is tested by feeding in input sequence of frames and next output frame is predicted which in turn is combined with other features along channel and appended with the input sequence. the new input sequence is fed to the model again to get the next predicted frame. this continues until forecasting completes for a desired time period. "mean absolute percent error" (mape) and kullback-liebler (kl) divergence [ ] are used to measure the accuracy of the model. the model predicts the transmission rate for a future time period for each pixel which in turn is used to calculate daily new infection cases ∆ + ( ) using equation . the removal rate is estimated as running average of previous -days and daily removed cases are calculated using equation . the active infection cases ( ( )) and susceptibles ( ( )) are calculated using equation and . cumulative infection cases (∑ ∆ + ( )) are calculated by summing up all new infection cases upto a certain day. mape of modified transmission rate is calculated at pixel level for the prediction period and averaged. the pixels with susceptible population count are filtered out while calculating mape and kl divergence. pixel mape is calculated as per equation , where g is set of all grids and g′ set of all pixels such that the frame for each corresponding grid have non zero cumulative infection count, ′ is prediction time period, ′′ = − ′ is total time period in training set, ̂′ ( ) and ′ ( ) are predicted and actual modified transmission rate for ℎ pixel at time respectively. kl divergence at pixel level is calculated for modified transmission rate in the prediction period to measure the dissimilarity of distribution of predicted transmission rate with respect to actual. is softmax function applied after . cc-by . international license it is made available under a preprint in perpetuity. is the author/funder, who has granted medrxiv a license to display the (which was not certified by peer review) this preprint the copyright holder for this version posted october , . . scaling a series in to scale and ( ) is probability distribution of . softmax is applied to convert total infection cases as probability distribution across pixels. since kl divergence measures the dissimilarity between two distribution thus a lower value of it indicates better performance of the model. mape is also calculated at grid and country level with respect to cumulative predicted infection cases across the region during the prediction period. the model is constructed by stacking convolutional lstm layer sequentially and terminating the network with a convolutional d layer. the final layer is followed by exponential linear unit as activation. the input and other hidden convolutional lstm layers are followed by sigmoid activation. each convolutional lstm layer has filters and kernel size x . the input layer is configured to take tensors of size x x . eight input features are constructed and fed into the model as separate channels. namely transmission rate, population density, female fraction, median age, active infection fraction, average temperature, temperature standard deviation and average relative humidity. the model is trained for epochs with batch size of and mean squared error as loss function. out of samples are used for training the model and are for validation. the model is trained and tested twice. once with all the eight features another with only five leaving out the weather features. the dataset has a time span of days out of which data from nd to st day is used for testing the model and rest for training and validation. table displays the training, validation and test results of the model. statistics suggests there is a slight improvement of overall accuracy when weather features are included while training the model. pixel mape and grid mape are below % in both the cases and country mape is below %. predicted total infection cases at the end of prediction period is little overestimated than actual ( ) when weather features are included in modelling and overestimated when weather features are not included. all future reference of trained model suggests the model has been trained with all eight features unless otherwise mentioned. fig. illustrates different plots of predicted vs actual infection cases in -day prediction period. fig. a and b shows the plot of predicted vs actual new infection cases and cumulative infection cases per day in -day period. fig. c and d shows the plot of predicted vs actual log transformed total new infection cases and cumulative infection cases per grid in -day prediction period. all the predicted curves closely approximate the actual values. one of our goal of this study is to understand how different external features are influencing the transmission rate. we expect to find simple interpretable predictive causal relations between transmission rate and different features. one of the ways to find such relations is building an accurate predictive model followed by explaining the predictions in terms of input features. as described in previous sections deep neural networks can model the dynamics of epidemic quite accurately due to its high nonlinear representation. however high accuracy is tradeoff against model interpretability. given the complexity of the convolutional lstm network used to model the transmission rate it is nearly impossible to find how each feature is influencing the transmission rate just by studying the weight matrices. using a high bias predictive model like linear regression or shallow decision tree not only is the author/funder, who has granted medrxiv a license to display the (which was not certified by peer review) this preprint the copyright holder for this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint reduces the accuracy but also drops interpretability [ ] . simple models can serve as interpretable models but may fail to capture true relations among features globally. this problem can be solved by building simple local models and drawing local explanations of feature relations. however, there may not be enough data points available or data distribution may be highly skewed in a local region to confidently build a predictive model and draw interpretations on it. thus, we use the trained convolutional lstm model as the global model and draw spatio-temporal local interpretations of it using locally perturbated synthetic data by satisfying a criterion called local fidelity [ ] . local fidelity suggests the explanations should be locally faithful with the model behavior. local fidelity does not imply global fidelity however global fidelity implies local. to increase interpretability simple surrogate models can be trained with local data as it is expected that the response variable varies with the features almost linearly in a local region. in fact, there is a tradeoff between local fidelity and interpretability that needs to be made. model agnostic methods perturbs the input features in a local region around a single or a group of datapoints and feeds the model to obtain predicted response variable. this synthetic data is in turn used to train simple surrogate models to obtain local interpretations of global model. there are several existing methods available in the literature to derive local interpretations of a model [ , , ] . few works also proposed methods to derive global explanations from local interpretations of any black box models [ , ] . similar to as stated in [ ] deriving explanations requires optimization of the following function, where g is set of interpretable surrogate models in a locality, is the global model to be explained, is the distribution function defining the locality of , ℒ is the loss function and is the complexity of the model . it is desirable to minimize both Ω and ℒ. however, in general they are inversely proportional when the spread of is large. a very small spread of is also not desirable as it will oversimplify g to draw any meaningful explanations in the locality. thus, a choice of is important to derive meaningful interpretations. the locality of is defined by a threshold distance in all directions from both spatially and temporally and it is defined by the following tuple, where and are spatial and temporal components of observation . and are spatial and temporal threshold distances from to the boundary of locality. fig. illustrates spatiotemporal locality of observation . spatial locality is bounded by pixels up to in all direction from such that locality of is bounded by a square box of pixels of size ( + ) x ( + ). no paddings are applied at the edges. thus, perimeter defining locality of pixels at the edges of a frame are trimmed. as illustrated in fig. temporal locality is also defined similarly. combining spatial and temporal locality the local region of observation is defined by a sequence of group of pixels with equal time lead and lag from unless resides on temporal edge of an input tensor in which case temporal locality is trimmed on the direction of the edge. perturbated data points are generated by randomly perturbing the pixel values of following a uniform distribution. perturbated distribution is calculated separately for each feature. the perturbated sample distribution is calculated as following, where ( , ′) is uniform distribution with upper and lower bound as , ′, ( ( )) is standard deviation of all observations in the locality of and randomly selects one sample from two. the spatial features are only perturbated spatially and same values are copied temporally along the corresponding channel. the channels having temporal component are perturbated for different time slice within an input tensor. each perturbated pixel in a time slice represents a separate feature. input tensors are constructed using the perturbated values and passed through the blackbox model to generate a predicted output value. the set of all input perturbated data points of and the corresponding predicted output values serves as the training dataset for the surrogate model . each input channels and the predicted values are normalized to mean and standard deviation prior to training the surrogate model. normalization is done to convert the features into same scale so that coefficients of a linear regression surrogate model gives the relative influence of the features on the response variable. thus, the loss function is defined as following, where the function constructs the input tensor in the original representation from perturbated samples. though can be created by perturbing all features of a pixel in each channel within an input tensor, however in our analysis only a subset of all features is perturbated to produce to find effect of those features on transmission rate. other features are kept constant as per the original observation. is the author/funder, who has granted medrxiv a license to display the (which was not certified by peer review) this preprint the copyright holder for this version posted october , . . intuitively this will explain the effect of the chosen features on the transmission rate in a single pixel area given all other parameters remain constant including feature values of spatio temporal neighboring pixels. in our analysis is created by perturbing the following features only. population density, female fraction, median age, weather at th , th and th time lag. weather includes average daily temperature, -day temperature standard deviation and average daily relative humidity. apart from the weather features the other three features have no temporal component. so, for them the perturbated values are copied temporally in the input tensor during reconstruction. the weather features from th to th time lag is chosen by assuming the average incubation period of sars-cov- between to days. the spatial ( ) and temporal ( ) distance for defining locality is taken as . the perturbated samples for each feature are generated by equation . local interpretations are carried out for each pixel which experienced at least cumulative infection cases on st march . the objective is to deduce the influence of aforementioned features on the transmission rate in each pixel given all other parameters remains constant. perturbated input samples are generated for each pixel. the samples are reconstructed in tensor format and fed to the model to obtain the predicted transmission rate and together they form the input output samples. for each pixel a linear regression surrogate model is trained with the training samples. the coefficients of each feature denote the influence on the transmission rate. fig. illustrated the feature influence chart for different pixels in grid . we choose grid as it experienced highest number of cumulative infection cases with nearly % of total infection cases in usa as of st may . only those coefficients are plotted which have pvalue < . . the features whose absolute value of median and standard deviation across all days are less than . , are considered unimportant and filtered out from the plot. the counties covered by each pixel in grid which have nonzero population is stated in table . the influence values are smoothed using rd degree polynomial. new york & bronx have somewhat positive influence of population density (pop den) and female fraction (f perc) on transmission rate. median age (med age) has positive effect in the mid period and negative on early and later days. th day time lag temperature (t temp) have slight negative effect on later days. on average putnam also have positive influence of population density, median age and female fraction. however, population density and female fraction shows negative influence on later days. th time lag and th time lag relative humidity (t rh & t rh) have slight negative impact on average. at grid level population density and female fraction positively impacts transmission rate on daily basis. median age has minor positive impact on earlier days and negative impact on later days . fig d. shows median of influence across all days for different pixels in grid . population density and female fraction have positive impact across all pixels. median age closely resembles a sinusoidal curve which implies that its influence varies widely across pixels. fig. illustrates the global effects of the features on transmission rate. to generate global interpretations local surrogate models are built for each pixel with perturbated samples. for each feature the distribution of influence values for all pixels with nonzero population is plotted against time. considering the median of the distribution, population density, female fraction has positive impact across all days whereas median age has negative impact. temperature has minor positive impact, temperature standard deviation has minor negative impact and relative humidity barely have any noticeable impact on transmission rate. from this study it is clear local influence of features at pixel and grid level may widely deviate from global average. this is important as spread of infection is highly skewed regionally such that few hotspots contribute majority of the infection cases. thus, studying the local influence of features can shed light on the local dynamics of spread and at the same time global influence charts provides a general idea of the influence on spread. classical sir model assumes a constant transmission rate and it typically predicts a smooth bell curve of active is the author/funder, who has granted medrxiv a license to display the (which was not certified by peer review) this preprint the copyright holder for this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint infection cases with respect to time with a single peak. however, transmission rate may vary with respect to multiple external factors including intervention methods like lockdown. a variable transmission rate may result in periodic subsidence and resurgence of the spread of infection and in turn producing multiple peaks of active infection cases along time. along with this the recovery rate may also change due to multiple intervention methods like enhancing hospital facilities, improving treatment procedure etc. as shown in equation , recovery rate is very important in achieving disease free stable equilibrium state. in general, the average removal rate (recovery rate + death rate) over a period should exceed average transmission rate in order to reach the disease-free equilibrium. considering the death rate to be constant and quite small compared to recovery rate of covid- , the time required to reach the equilibrium state is inversely proportional to the difference between recovery rate and transmission rate. in our experiments we used the trained model to do long term forecasting of the epidemic with current normal parameters and compared with an "what if" analysis by modifying the removal rate. a days forecasting is carried out for the grid . since weather features barely impacts transmission rate in grid thus the model trained without weather features is used for forecasting. "what if" analysis is done by setting high removal rate to expedite disease-free equilibrium and compared with current normal forecasting by setting removal rate as running average of past days. in "what if" analysis removal rate is set as per equation by setting t = with upper hard limit . . as removal rate changes daily active infection cases which in turn impacts future transmission rate and due to upper hard limit of removal rate the value of in some pixels is less than upper bound calculated by equation . from fig. a and b it is evident that number of active infection cases reduced much faster in the "what if" analysis and most of the pixels hit near baseline state at least once within -day period. however rapid periodic resurgence of the disease is seen in this case. as recovery rate has upper hard limit thus in some cases resurgence with high transmission rate resulted in destabilizing disease-free equilibrium. the growth is again quickly dampened due to high recovery is the author/funder, who has granted medrxiv a license to display the (which was not certified by peer review) this preprint the copyright holder for this version posted october , . . rate in future periodic resurgences. this can be empirically explained by the fact that population gets cautious and maintains social distancing with low intermixing when infection cases are high and vice versa. fig. c and d suggests there is rapid periodic resurgence of new infection cases in "what if" analysis compared to current normal and multiple short low new infection periods are seen. the resurgences in some cases (pixel , ) are stronger compared to current normal. thus, it is evident, by only increasing recovery rate abruptly, infection spread may not be controlled fully unless other intervention methods are adopted to prevent spike of transmission rate during resurgence periods. fig. a and b shows the plot of daily active infections when only pixel and are subjected to modified recovery rate respectively and other pixels are set with current normal recovery rate. in both the cases there is a quick dampening of active cases in and pixels and resurgence spike is shorter and weaker compared to fig. b . it is evident there is spatial influence of neighboring active cases and transmission rate. one explanation can be, isolated intervention measures to dampen the spread does not breaks the cautiousness and preventive measures among the population. this makes determining an ideal recovery rate for a region a complex optimization problem. fig. shows active infection cases at grid level quickly reaches baseline in "what if" scenario compared to current normal, but it is not eradicated fully. there are also small periodic spikes in future. the current normal scenario suggests unless strict intervention actions are not taken to reduce transmission rate or recovery rate it is going to take long time to reach the baseline. the trace of new infection cases suggests the trend is quite similar in both the scenarios with more frequent and stronger spikes in "what if" scenario. in current normal scenario the model estimates new infection cases and removed cases in -day period. in "what if" scenario it estimates new infection cases and removed cases. however, fig. c suggests most of the removal happens in initial days of forecast period due to abrupt increase of removal rate in forecast period. in real world such abrupt increase of removal rate may not be possible. however, on an average if the difference between removal rate and transmission rate can be maintained as per equation it is possible to dampen the spread of infection within desired time period. though in our analysis we took removal in strict sense however it may not refer to complete recovery. identification and complete isolation of a patient such that there is negligible chance of further spread of the infection from the patient may also be referred to removal. thus, maintaining high recovery rate, rapid and strict isolation of infected patient and intervention methods to reduce transmission rate are the keys to rapid convergence to diseasefree equilibrium. a thorough study on the transmission rate of covid in usa revealed several insights. key influencers are identified. however, there might be other influencers like human mobility, demographics, government interventions etc. on availability of those feature data, proposed methods may be applied to find influences. these methods can also be applied to other countries. though a threshold condition is derived for disease free equilibrium, yet it is not straightforward to determine ideal recovery rate to rapidly dampen the infection spread due to complex dependency of transmission rate. a general solution method may be investigated to solve this optimization problem and come up with ideal regional recovery rate. is the author/funder, who has granted medrxiv a license to display the (which was not certified by peer review) this preprint the copyright holder for this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint containing papers of a mathematical and physical character qualitative analyses of communicable disease models influence of nonlinear incidence rates upon the behavior of sirs epidemiological models nonlinear biological dynamics system a delayed epidemic model with pulse vaccination. discrete dynamics in nature and society regulation and stability of hostparasite population interactions: i. regulatory processes analysis of a delayed sir model with nonlinear incidence rate. discrete dynamics in nature and society dynamic analysis of an sir epidemic model with nonlinear incidence rate and double delays a simple sis epidemic model with a backward bifurcation infectious disease models with time-varying parameters and general nonlinear incidence rate on the final size of epidemics with seasonality estimation of time-varying transmission and removal rates underlying epidemiological processes: a new statistical tool for the covid- pandemic temperature and latitude analysis to predict potential spread and seasonality for covid- modelling and prediction of the coronavirus disease spreading in china incorporating human migration data convolutional lstm network: a machine learning approach for precipitation nowcasting us covid- daily cases with basemap investigating causal relations by econometric models and cross-spectral methods. econometrica: journal of the distribution of the estimators for autoregressive time series with a unit root the vanishing gradient problem during learning recurrent neural nets and problem solutions lstm can solve hard long time lag problems from local explanations to global understanding with explainable ai for trees. nature machine intelligence explaining the predictions of any classifier how to explain individual classification decisions anchors: highprecision model-agnostic explanations model agnostic supervised local explanations artificial intelligence forecasting of covid- in china analysis and forecast of covid- spreading in china, italy and france a deep residual network integrating spatial-temporal properties to predict influenza trends at an intra-urban scale us covid- daily cases with basemap : an overview of the global historical climatology network-daily database climate reference network after one decade of operations: status and assessment a multivariate spatiotemporal spread model of covid- using ensemble of con-vlstm networks key: cord- - rrhiw m authors: hertzberg, vicki stover; weiss, howard title: on the -row rule for infectious disease transmission on aircraft date: - - journal: ann glob health doi: . /j.aogh. . . sha: doc_id: cord_uid: rrhiw m background: with over two billion airline passengers annually, in-flight transmission of infectious diseases is an important global health concern. many instances of in-flight transmission have been documented, but the relative influence of the many factors (see below) affecting in-flight transmission has not been quantified. long-standing guidance by public health agencies is that the primary transmission risk associated with air travel for most respiratory infectious diseases is associated with sitting within two rows of an infectious passenger. the effect of proximity may be one of these factors. objective: the aim of this study was to determine the risk of infection within and beyond the -row rule given by public health guidance. methods: we searched the literature for reports of in-flight transmission of infection which included seat maps indicating where the infectious and infected passengers were seated. findings: there is a ∼ % risk to passengers seated within the -rows of infected individual(s) and there is ∼ % risk to passengers seated beyond -rows from the infectious individual. discussion: contact tracing limited to passengers within -rows of the infectious individual(s) could fail to detect other cases of infections. this has important consequences for assessing the spread of infectious diseases. conclusions: infection at a distance from the index case indicates other factors, such as airflow, movement of passenger/crew members, fomites and contacts between passengers in the departure gate before boarding, or after deplaning, are involved. with more than billion airline passengers annually, in-flight transmission of infectious diseases is an important global health concern. , many instances of in-flight transmission have been documented, including cases of cholera, influenza, - measles, , meningococcal infections, norovirus, severe acute respiratory syndrome (sars), , shigellosis, and tuberculosis. [ ] [ ] [ ] however, the risks of in-flight transmission are largely unknown. cabin transmission of infectious diseases can occur through several routes. in this paper we concentrate on droplet transmission, which occurs via respiratory droplets (! microns) propelled short distances (mostly meter) when an infectious traveler sneezes, coughs, talks, or breathes. [ ] [ ] [ ] droplets are sufficiently large to be largely impervious to cabin airflow. direct transmission occurs when pathogencontaining droplets fall onto a susceptible traveler's conjunctiva or mucosa or are inhaled. indirect transmission occurs when droplets are deposited onto fomites (surfaces such as tray tables, seat belts, or lavatory door handles) or an infected traveler's hand. a susceptible traveler who touches these surfaces and then touches her or his conjunctiva or mucosa allows the pathogen to enter the body. the -row transmission zone guideline. longstanding guidance by public health agencies is that the primary transmission risk associated with air travel for most respiratory infectious diseases is associated with sitting within rows of an infectious passenger. this transmission zone, which actually comprises rowsd in front of the index case, behind the index case, and the row in which the index case is seateddhas been based on investigations of in-flight transmission of tuberculosis but is believed to have wide applicability. this rule is empirical and does not directly take into account the physical and biological bases for droplet transmissiondthat is, meter of contact. figure appears in centers for disease control and prevention (cdc) guidelines to public health officers needing to find and alert travelers who may have been exposed to an ill passenger during flight. implicit in this guideline is that cabin airflow and passenger and crew movements play negligible roles in disease transmission. thus there are serious questions about this guideline. case study: sars. sars is a viral respiratory illness likely transmitted through both droplets and aerosols. sars was first reported in the guangdong province of southern china in november . the illness quickly spread by air travel to countries, infecting more than people, with a case fatality rate of nearly %. in march , a -year-old passenger with sars infected passengers and flight attendants on a -hour flight from hong kong to beijing. the infectious passenger died days later. only ( %) of the infected passengers were seated within rows of the index case two-row rule for infectious disease transmission (fig. ) . indeed, more transmissions occurred to passengers sitting across the center aisle than on the infectious passenger's side of the plane. case study: novel h n influenza. the outbreak of novel swine-origin influenza a (h n ) pdm virus began in veracruz, mexico. several months later, mexican health officials acknowledged the severity of the epidemic after the first cases began to appear in mexico city in mid-march. this was about the same time as the first cases appeared in the united states. within days mexico city was effectively shut down in an attempt to contain the spread of the epidemic. however, it continued to spread within mexico and globally. in june, the world health organization and cdc declared the outbreak a pandemic. individuals in countries were infected, with , confirmed deaths worldwide. the disease was particularly severe in individuals younger than years of age. in april , on a . -hour flight from mexico to birmingham, uk, a passenger contagious with novel h n virus infected passengers. only of the infected passengers were seated within rows of the infectious passenger. in this paper we document reports of in-flight transmission of respiratory infectious diseases by large droplets for which seat plans are given. we summarize these reports and estimate the risks for passengers seated within and outside the -row risk zone. in addition to those described earlier, we identified reports of respiratory infectious disease transmission on airplanes for which enough information was available to calculate post-flight attack rates inside and outside the -row transmission zone. five reports concerned diseases transmitted by droplets, specifically sars, influenza, and measles. table summarizes the reported literature. there are cases of infection transmission within rows of an index case. there were cases of infection transmission to passengers seated outside of this risk zone on these same flights. thus, although there is an elevated relative risk for passengers inside the ae row zone (mantel-haenszel relative risk estimate [ % confidence interval ¼ . ( . , . )]), there is still a non-negligible chance of cross infection beyond this zone. these inflight transmissions highlight ( ) how air travel serves as a conduit for rapid spread of newly emerging infections with potential to start pandemics, and ( ) how there must be or more other factors affecting transmission other than seating. contact tracing limited to passengers within rows of the infectious individual may lead to failure to determine other cases, which may have important, potentially dire consequences for spread of infectious diseases. we speculate that infection at a distance from the index case is due to factors such as cabin airflow and movements of passengers and flight attendants. public health officers § reported in a letter to the editor. origin and destination airports were not given. the flight was to a remote mining community in northwestern australia. k authors reported data on flights on which passengers who were seated within ae rows of an infectious passenger became infected. aircraft types were not given. the average flight time was hours, minutes. { conservatively assumed that all flights were on large long-haul carriers with -passenger capacity and estimated seats per row. investigating suspected disease transmission on an airplane should prioritize passengers seated within rows of the index case for surveillance but should not neglect other passengers for follow-up. transmission of infectious diseases during commercial air travel travel and the emergence of infectious diseases an outbreak of cholera from food served on an international aircraft transmission of pandemic a/h n influenza on passenger aircraft: retrospective cohort study transmission of influenza on international flights in-flight transmission of novel influenza a (h n ) clinical and molecular evidence for transmission of novel influenza a(h n / ) on a commercial airplane international flight-related transmission of pandemic influenza a(h n ) pdm : an historical cohort study of the first identified cases in the united kingdom risk of measles transmission on aeroplanes: australian experience - an outbreak of measles associated with a new york / tel aviv flight meningococcal diseasedprobable transmission during an international flight likely transmission of norovirus on an airplane introduction of sars in france transmission of the severe acute respiratory syndrome on aircraft an international foodborne outbreak of shigellosis associated with a commercial airline transmission of multidrug-resistant mycobacterium tuberculosis during a long airplane flight tuberculosis risk after exposure on airplanes two-step tuberculin testing of passengers and crew on a commercial airplane prevention and control of influenza: recommendations of the advisory committee on immunization practices cdc guideline for isolation precautions in hospitals diseases of air travel contact tracing for influenza a(h n ) pdm viruseinfected passenger on international flight influenza outbreak related to air travel the authors received support from the boeing company (hnw) by way of a subcontract to the georgia institute of technology (vsh). both authors had access to the sources used to develop the manuscript. key: cord- - e gz bo authors: khan, suliman; liu, jianbo; xue, mengzhou title: transmission of sars-cov- , required developments in research and associated public health concerns date: - - journal: front med (lausanne) doi: . /fmed. . sha: doc_id: cord_uid: e gz bo severe acute respiratory syndrome coronavirus (sars-cov- ) is rapidly spreading across the world to cause thousands of mortalities each day. poor responses from the authorities to the spread of infection, lack of effective measures for prevention, unavailability of promising treatment options, and sufficient diagnostic options have created an alarming for the world. the transmission routes from human to human of sars-cov- can be the direct transmission, droplet inhalation transmission, contact transmission, transmission through saliva, and transmission via fecal–oral routes. due to the asymptomatic spread of sars-cov- 's, developing control and prevention measures is challenging. implementing proper strategies addressing the infection control and clinical supplies, understanding the mechanism associated with pathogenesis, advancing in preventive measures and effective treatment and diagnostic options are necessary to control the ongoing pandemic. in this article, we briefly discuss the features, entry mechanism, infectiousness, and health consequences related to the covid- outbreak. introduction sars-cov- has infected over five million people worldwide after its emergence in wuhan, china ( ) . the world has witnessed that this virus can spread rapidly to cause the death-causing covid- disease. although the rate of recovery is higher in people with strong immune responses, however, the immune-compromised individuals are at higher risks to be readily killed by the infection ( ) . the major reasons for higher morbidity and mortality rates are rapid human-human transmission, unavailability of promising diagnostic and therapeutic options, scarcity of clinical supplies, shortage of medical and clinical staff, and lack of effective preventive measures ( ) . besides the physical illness, the covid- epidemic has also increased the risk of psychological problems among healthcare workers, infected individuals, and the general public ( , ) , due to the fear of treatment failure, higher morbidity and mortality, lack of psychological interventions, and infodemia ( , , ) . during the early days of the epidemic in china, a number of countries suspended travel to and from china, evacuated their nationals from the epicenter, and placed them in quarantine to curb the risks of pandemic ( ) . these responses were not sufficient to prevent the spread of covid- , therefore, it became a global pandemic ( ) . considering the seriousness of this situation scientists and medical researchers came forward and extended their services to the development of therapeutic strategies, preventive measures, and strategies to control the unfolding pandemic. until now, researchers have unveiled some of the important biological and clinical features for covid- infection, including the characterization of the whole genome ( ) and spike glycoproteins ( ) , investigation of clinical features and evaluation of different broad-spectrum antiviral drugs in combination with either antibacterial, antimalarial and/or traditional chinese medicines ( ) . nevertheless, more research work is required to further investigate the sources of transmission, the biology of viral incubation and reemergence, and the potential of vertical transmission from mothers to neonates. in this article, we discuss the features of coronaviruses, the mechanism of infectiousness of sars-cov- , and its medical consequences. we also describe the populations at higher risk and challenges in research progress. this narrative review article will benefit the public and scientific community regarding the current progress and the need for further work. to identify and select the papers in this review we searched the published research and review articles relevant to origin and outbreaks of three human coronaviruses, and features, transmission, spread, entry mechanisms, infectiousness, control strategies, and animals hosts for sars-cov- . we also search the papers published on sars and mers coronaviruses in the aspects of animal models and sources of transmission. we reviewed the world health organization, u.s. centers for disease control and prevention, nature reports, medline, pubmed central, embase, google scholar, and sciencedirect, according to the relevancy as explained earlier, until april , . the search terms "novel coronavirus, sars-cov- and covid- , sars and mers" were broadly used. studies conducted in laboratory and clinical based observations, and/or conducted through bioinformatics techniques were included. pneumonia is one of the most frequent manifestations of covid- infection, which is characterized by fever, bilateral infiltrates on chest imaging, cough, and dyspnea ( ) . the period from infection to symptoms appearance ranges from to days, while the average period reported so far is ∼ days ( ) . one of the previous studies reported the onset of fever and respiratory symptoms ∼ - days in a family cluster of infections ( ) . similarly, in an analysis of patients with confirmed covid- pneumonia, the estimated mean incubation period was days ( ) . furthermore, the majority of the individuals showed moderate symptoms whereas % of the infected patients showed severe illness of respiratory failure and septic shock and gastrointestinal complications ( , ) . common laboratory abnormalities associated with covid- are lymphopenia and elevated aminotransferase levels ( ) . creactive protein (crp) levels have been reported to alter with the development of symptoms, such that patients with severe pneumonia present high crp levels ( , ) . in a recent study, wang ( ) reported that crp levels at the early stage of covid- are positively correlated with lung lesions and symptoms development, which can be used as one of the key indicators for disease development and severity. wang et al. ( ) investigated patients [median age; years, interquartile range; - years] with covid- pneumonia in wuhan and reported that patients developed fever, patients had a dry cough and patients had fatigue. besides lymphopenia, parenchymal lung abnormalities were also common among all patients as depicted from computed tomography of the chest, including bilateral patchy shadows or ground-glass opacities. nonetheless, some people have been reported to be initially asymptomatic and may remain asymptomatic or go on to develop disease on later stages (who; march , ). although it is important to know about the symptoms' appearance and severity, however, understanding the transmission of the infection to healthy individuals from covid- patients and zoonotic sources can be of great importance in the aspects of developing strategies to prevent and control the spread of covid- . during november , a novel coronavirus caused sars epidemic in guangdong, china ( ), followed by subsequent outbreaks in hong kong ( , ) . this outbreak was reported to be caused by sars-cov, originated from market civets before its transmission and infection in humans ( ) . by the end of the epidemic, sars-cov infected , people and caused fatalities in different countries ( ) . later on, during june a patient infected with mers-cov developed severe pneumonia and died in jeddah, saudi arabia ( , ) , following by series of clustered outbreak in the middle east and several other countries ( , ) . before transmitting into humans, mers-cov originated and replicated in dromedary camels ( ) . until , mers-cov infected , individuals and caused fatalities worldwide ( , ) . in december , clusters of patients reported with covid- caused by sars-cov- were epidemiologically found linked to animals and the seafood selling market in wuhan, china ( ) . the zoonotic source of its origin and transmission is still debatable, however, some reports suggested bats ( ) as the possible sources of transmission ( ) . the human-to-human transmission of sars-cov- is thought to occur mainly via respiratory droplets produced by coughing or sneezing from an infected individual ( ) . the rapid increase in suspected as wellconfirmed cases has also been inferred with viral transmission through the fecal-oral route and aerosol formation. the halflife on the surfaces of stainless steel, copper, and cardboard is ∼ . h, while that on the plastic surface is . h ( ) . moreover, several reports have confirmed the asymptomatic transmission while there is a chance for the animal to humans transmission ( ) . overall, these observations indicate that appropriate care is necessary while handling both confirmed and suspected individuals. moreover, the surfaces of potentially viruscontaminated places, objects, and containers should be cleaned with effective disinfectants. the sars-cov- contains a single-stranded rna with , nucleotides, encoding for , amino acids ( ) . the spike glycoproteins of sars-cov- contain two subunits (s and s ) ( ) . the s subunit contains transmembrane and cytoplasmic domains along with fusion peptide. novel coronavirus has over % identity with sars-cov. however, spike receptor-binding domains (rbd) are only % identical ( ) , while structural elements open reading frame (orf) b and orf were found with no homology ( ) . coronaviruses contain six orfs regions which serve as templates for the production of sub-genomic mrnas and encode protein, spike, nucleocapsid, and membrane proteins. orfs are responsible for the production of pp a and pp ab polypeptides ( ) . both sars-cov and mers-cov infect bronchial epithelial cells and type ii pneumocytes through ace and cd receptors, respectively ( , , ) . the mechanism associated with the infectiousness of sars-cov- is yet to investigate, however, it likely infects the bronchial cells through ace . in general, a virus entry to the host cell comprises a series of fundamental interactions; (i) binding to a target host cell via cellular receptors; (ii) fusing the envelope with a cellular membrane; and (iii) forking over its genetic material inside the cell (figure ). the process of viral genomic delivery of nucleic acids into the host cell is highly dependent upon binding specificity to receptors, proteolytic activation, and endocytosis efficiency ( , ) . coronaviruses demonstrate a great degree of plasticity regarding the entry pathways, which can occur at the plasma membrane or through the endocytic pathway ( ) (figure ) . the entry to the host cell process of sars-cov- is regulated by glycosylated spike (s) fusion protein and host receptor known as ace . the s proteins is capable of significant structural rearrangement thus, play a crucial role in fusing the viral membrane with the host cell membrane ( ) . this fusion process sparks off with binding of the s subunit to ace and is linked with the accessibility of receptor determined by hingelike conformational movements of the receptor-binding domain (rbd) of s . thus, rbd can transiently hide or expose the determinants of receptor binding through receptor-inaccessible state or receptor-accessible state, respectively ( ) . once the virus has entered to the host cell, the replication-transcription complex (rtc) is organized in double-membrane vesicles to initiate transcription of polyprotein a/ ab (pp a/pp ab). these pp a/pp ab proteins encode chymotrypsin-like protease ( clpro), main protease (mpro), and papain-like proteases for the production of non-structural proteins (nsps) ( ) . transmembrane helical segments in the orf ab region encodes for nsp and nsp ( ) . the structural proteins and nsps play a role in the pathogenicity of sars-cov- by blocking the innate immune response and assembly and release of newly synthesized virions ( ) . during the first days of the wuhan epidemic, two strains of novel coronavirus were reported namely s strain and l strain. observations suggested that l strain was more aggressive and more fatal as compared to s strain. a group of researchers from pasteur institute shanghai and peking university reported that the rate of infection for l strain was as high as %, while that of s was ∼ % as indicated by the analyzed samples. on the other hand, s type strain was found to be the ancestral version and was closely related to viruses like tg . further analysis based on population genetics indicated that these strains mainly differed at orf ab and orf regions. interestingly, the development of new variations of the spike protein in sars-cov- variants is linked to mutations, and natural selection ( ) . therefore, further studies should evaluate the combinational impacts of genomic data, epidemiological data, and chart records of the clinical symptoms of patients with covid- . after the identification of sars-cov- , debates started among scientists on its sources of origination and zoonotic source of transmission to humans ( ) . the identity of the animal source of sars-cov- , is still one of the key missing gaps that scientists are being racing to investigate. it is a known fact that coronaviruses circulate in mammals and birds ( ) , and researchers have already suggested bats to be the source of origination for sars-cov- ( ). however, an intermediate animal was probably the source of transmission of the virus to humans. early claims came figure | the sars-cov- transmission from bats via unknown intermediate to humans causes infectiousness known as covid- disease. the binding of s protein to ace receptor initiates the life cycle which is then followed by conformational changes in the s protein, which further facilitates the fusion of viral envelope and host cell membrane. following the fusion through endosomal pathway, sars-cov- then releases rna into the host cell, which is translated into pp a and pp ab. next, viral proteinases cleave the translated proteins into small products, meanwhile a series of sub-genomic mrnas are produced by polymerase enzyme through discontinuous transcription, which are then translated into specific viral proteins. these viral proteins and genome rna are assembled to form virions in golgi and endoplasmic reticulum, which are later transported out of the cell via vesicles. this figure was designed by updating and modifying the information from our previously published paper ( ) . frontiers in medicine | www.frontiersin.org from researchers related to intermediate sources of transmission faced controversies ( ) . a recent report discredited an earlier statement that pangolin could be the possible intermediate source that might have received the virus from the bat and transferred it to humans ( ) . according to more recent study on molecular and phylogenetic analyses, it is unlikely that sars-cov- emerged directly from the pangolin coronaviruses ( ) , suggesting that pangolins may not be responsible for the transmission of sars-cov- to humans. with further spread of the virus after its outbreak in wuhan, more people became infected, thus, human to human transmission became more evident. one of the reasons for the high rate of infectiousness in humans is thought to be the higher affinity of rbd for binding to ace receptors ( , ) . in addition, the determination of host range and binding to the ace are highly dependent on six rbd amino acids "l , f , q , s , n , and y in sars-cov- " in sars-cov- , thus, rbd can also bind to ace from ferrets and cats ( ) . on the other hand, the highaffinity of rbd to human ace is thought to be linked with natural selection on a human ace , indicating that sars-cov- was not produced with purposeful manipulation ( ) . these observations support the hypothesis that sars-cov- was transmitted from a yet unknown intermediate zoonotic source to humans. spike glycoproteins have been well-documented in the aspects of transmission and entry of sars-cov- into host cells ( , ) . it is notable that the polybasic cleavage site of sars-cov- at the junction of s and s allows cleavage by proteases such as furin, which plays a crucial role in infectiousness and determining host range. despite the unknown functional consequence, the higher genetic variation in spike indicates that sars-cov- with polybasic cleavage sites may be discovered in several other species ( , ) , which can be the possible source of transmission for sars-cov- to humans. interestingly, the mutation found in the polybasic cleavage site was not related to that of the bat and pangolin viruses ( ) , therefore, it may be linked with the virus's ability for transmission and infection in humans. the determination of polybasic cleavage and predicted o-linked glycans further suggest that the virus was most likely transferred from an animal with ace to humans, as these are not possible in cell cultures ( ) . further research to determine the impact of polybasic cleavage and predicted o-linked glycans on transmissibility and pathogenesis is necessary. although investigating the mechanisms underlying entry to host cell, transmission, polybasic cleavage, and predicted olinked glycans are required to determine the research gaps associated with transmission and origination, however, this work requires suitable animal models. unfortunately, there is no promising model while the non-human primates tested for sars and mers were unable to develop severe diseases in response to the infectiousness ( ) . nevertheless, the models developed for the expression of human ace and dpp ( ) can be further modified and used to study the transmission and infectiousness of sars-cov . moreover, crispr-interceded genetically modified small animals can be also utilized for the study of the pathogenicity of sars-cov- . nevertheless, it is important to investigate the ultimate source of viral transfer to humans, as even if the virus is eradicated with social distancing, other sources including zoonotic and environmental sources can again cause the transfer into humans, and thus another outbreak will be the result. the ability of rapid human to human transmission of covid- infection especially through asymptomatic infected individuals and aerosol, has paralyzed life across the globe ( , ) . although the covid- infection primarily affects physical health, however, it can also affect mental health through the fear of transmission from unknown sources and high mortality rate that can further paralyze life ( ) . it is deemed necessary that timely effective services should be provided to the vulnerable populations as reported by khan et al. ( ) . the adverse impacts of covid- are specific to the populations, therefore, we discuss the most vulnerable populations, the current evidence on known vulnerable groups and the associated health risks in response to the covid- infection. rapidly increasing mortalities and morbidities in healthcare workers are causing serious medical concerns and adversely affecting healthcare services worldwide ( ) . the fear of being infected due to close contacts with infected symptomatic and asymptomatic patients, and prolonged working schedules may decrease the working efficiency in current doctors and nurses ( , ) . a large number of medical and clinical staff are likely to be infected with covid- infection. only in wuhan, more than hundred persons from healthcare settings were reported infected ( ) . in addition to the high risk of contracting infection due to direct interaction with infected and suspected individuals ( ), healthcare workers have also been reported to develop severe mental conditions including stress, anxiety, and related mental illnesses ( , ) . to mitigate the risk of contracting infection the medical staff should adhere to standard precautions while providing patient care ( , ) . according to the cdc report on coronavirus disease, individuals with underlying chronic medical conditions are at higher risk for contracting covid- infection. huang et al. reported that % of sars-cov- infected individuals had diabetes, hypertension, and cardiovascular disease ( ) . the fatality rate was also high in individuals who had diabetes mellitus, chronic lung disease ( ), cerebrovascular diseases ( ) , and hypertension ( ) . furthermore, covid- infection in patients with lung cancer can develop severe covid- disease that can lead to death ( ) . luo et al. ( ) reported that more than half of the covid- infected individuals who had lung cancer, needed hospitalization, whereas nearly a quarter of them died. however, people living with human immunodeficiency virus do not present excess morbidity and mortality among symptomatic covid- patients ( ) . the higher risk of disease and death in individuals with underlying diseases might be linked with weaker or comprised immune responses. the elder individuals are comparatively more affected by covid- infection; however, individuals of any age can acquire the infection ( ) . according to the previous reports, % of infected individuals were between and years old. moreover, the mortality rate was higher in older people. the case fatality rate of % was observed among individuals having age between and years, while % fatality rate was reported in people with years or older ( ) . covid- infection in pregnant women is of serious concern, as it might have detrimental effects not only on mother's health but also on neonatal health can be at risk ( ) . in a recent study, covid- infection was found to cause adverse neonatal outcomes. two of the neonates were tested positive, and for covid- while, five were found with neonatal pneumonia, suggesting the possibility of a link between adverse pregnancy outcomes and covid- infection ( ). dong et al. ( ) reported a newborn with elevated igm antibodies to sars-cov- , who was born to a mother with covid- , suggesting the possibility of vertical transmission. therefore, further investigations should focus on adverse pregnancy outcomes and the possibility of vertical transmission. the approach to prevention, evaluation, diagnosis, and treatment of pregnant women with suspected covid- should be similar to that in non-pregnant individuals, with the consideration that pregnant women with other potentially severe respiratory infections, such as influenzaappear to be more vulnerable to developing severe sequelae. moreover, pregnant women should be given attention and provided with the utmost facilities in terms of treatment and diagnosis. controlling the spread and transmission of infection is one of the major issues that authorities are currently considering with serious attention. world health organization (who) and u.s. centers for disease control and prevention (cdc) recommend face and eye protection for droplet and contact precautions. during aerosol-generating procedures, such as non-invasive ventilation, tracheotomy, cardiopulmonary resuscitation, tracheal intubation, bronchoscopy, and manual ventilation before intubation, additional precautions are warranted such as airborne infection isolation room and wearing the appropriate personal protective equipment (ref and ref ) . to control the transmission requires the identification and isolation of the infected individuals. samples from the nasopharyngeal swab, oropharyngeal swab, sputum, tracheal aspirate, or bronchoalveolar lavage should be tested for the detection of the virus ( ) . the symptoms of covid- pneumonia are primarily similar to influenza and seasonal allergies ( , , ) , therefore using thermo-scanners and physical observations are not are not able to adequately differentiate between those conditions. although quantitative real time polymerase chain reaction (qrt-pcr) is the major confirmatory test however, to provide further testing support developing additional testing kits that could rapidly detect sars-cov- with maximum accuracy in suspected, confirmed, and asymptomatic patients may be useful. to control the ongoing pandemic and risk of future epidemics, the development of safe and effective vaccines is necessary, that should be available for individuals at high risk of contracting covid- infection. until now, effective vaccine against covid- is not available, however, some vaccines with preventive potential against covid- infection are in pipeline. such as the mrna-based vaccine developed by national institute of allergy and infectious diseases in usa, is being trialed ( ) . while the ino- -dna based vaccine is currently being developed ( ) . moreover, center for disease control and prevention (ccdc) in china has started working on inactivated virus vaccine that may be used widely if found promising ( , ) . stermirna therapeutics has reported the development of mrna-based vaccines that can soon be available for trials ( , ) . nevertheless, more work is required; sars-cov specific live-attenuated ( ) and rhesus θ-defensin and protein cage nanoparticles based vaccines can be evaluated for covid- infection ( , ) . moreover, monoclonal antibodies should be considered that are effective in inhibiting virus-cell receptor binding and virus-cell fusion ( ) . sars-cov- is likely originated in bats and introduced to the world through a yet unknown intermediate. without finding the missing intermediate, sars-cov- may reemerge even if the current spread is controlled completely through social distancing and isolation. an earlier report that indicated pangolins as the possible source of transmission of sars-cov- has been discredited, therefore, further work is required to identify the unknown intermediate animal source that caused the transmission of the virus to humans. based on their role in transmission and infectiousness, spike glycoproteins, rbd binding to ace and mutations in polybasic cleavage sites related to different animals should be studied further. given the importance of the current outbreak in wuhan, further studies are necessary to provide deep understating of replication, pathogenesis, and biological properties using the relevant biological techniques such as reverse genetics and molecular techniques. to unveil pathogenesis and entry mechanisms further investigations should focus on structural elements orf b and orf in novel coronavirus. these regions may play an important role in high human to human spread and may be linked to the severity of the disease. these investigations will help the control and prevention of covid- mediated pneumonia and novel emerging diseases in the future. the covid- outbreak has affected millions of people around the globe by causing mortalities and morbidities. thus, curbing covid- and preventing it from spreading further requires the development of effective strategies t related to detection of the virus, curing the disease, vaccination and prevention, and identification of the transmission sources. the research work should focus on preventing the spread and transmission of the virus, however, without taking effective measures the virus will come back again. sk is the leading author while jl and mx contributed to revisions. all authors contributed to the article and approved the submitted version. world health organization ( ) why tocilizumab could be an effective treatment for severe covid- ? novel coronavirus: how the things are in wuhan timely mental health care for the novel coronavirus outbreak is urgently needed impact of coronavirus outbreak on psychological health novel coronavirus is putting the whole world on alert novel coronavirus, poor quarantine, and the risk of pandemic genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding cross-species transmission of the newly identified coronavirus -ncov clinical 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retrospective review of medical records first case of novel coronavirus in the united states covid- : learning from lessons to guide treatment and prevention interventions. msphere rhesus theta-defensin prevents death in a mouse model of severe acute respiratory syndrome coronavirus pulmonary disease inducible bronchus-associated lymphoid tissue elicited by a protein cage nanoparticle enhances protection in mice against diverse respiratory viruses the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © khan, liu and xue. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -j iawzp authors: fitzpatrick, meagan c.; bauch, chris t.; townsend, jeffrey p.; galvani, alison p. title: modelling microbial infection to address global health challenges date: - - journal: nat microbiol doi: . /s - - - sha: doc_id: cord_uid: j iawzp the continued growth of the world’s population and increased interconnectivity heighten the risk that infectious diseases pose for human health worldwide. epidemiological modelling is a tool that can be used to mitigate this risk by predicting disease spread or quantifying the impact of different intervention strategies on disease transmission dynamics. we illustrate how four decades of methodological advances and improved data quality have facilitated the contribution of modelling to address global health challenges, exemplified by models for the hiv crisis, emerging pathogens and pandemic preparedness. throughout, we discuss the importance of designing a model that is appropriate to the research question and the available data. we highlight pitfalls that can arise in model development, validation and interpretation. close collaboration between empiricists and modellers continues to improve the accuracy of predictions and the optimization of models for public health decision-making. m icrobial pathogens are responsible for more than million years of life lost annually across the globe, a higher burden than either cancer or cardiovascular disease . diseases that have long plagued humanity, such as malaria and tuberculosis, continue to impose a staggering toll. recent decades have also witnessed the emergence of new virulent pathogens, including human immunodeficiency virus (hiv), ebola virus, severe acute respiratory syndrome (sars) coronavirus, west nile virus and zika virus. the persistent global threat posed by microbial pathogens arises from the nonlinear mechanisms of disease transmission. that is, as the prevalence of a disease is reduced, the density of immune individuals drops, the density of susceptible individuals rises and disease is more likely to rebound. the resultant temporal trajectories are difficult to predict without considering this nonlinear interplay. for instance, many microbial diseases exhibit periodic spikes in the number of cases that are unexplainable by pathogen natural history or environmental phenomena. by explicitly defining the nonlinear processes underlying infectious disease spread, transmission models illuminate these otherwise opaque systems. forty years ago, nature published a series of papers that launched the modern era of infectious disease modelling , . since that time, these methodologies have multiplied . transmission models now employ a variety of approaches, ranging from agent-based simulations that represent each individual to compartmental frameworks that group individuals by epidemiological status, such as infectiousness and immunity , . accompanying the methodological innovations, however, are challenges regarding selection of appropriate model structures from among the wealth of possibilities . at this anniversary of the publication of these landmark papers , , we reflect on contributions that transmission modelling has made to infectious disease science and control. through a series of case studies, we illustrate the overarching principles and challenges related to model design. with expanding computational capacity and new types of data, myriad opportunities have opened for transmission modelling to bolster evidence-based policy (box ) , . in all pursuits, modelling is most informative when conducted collaboratively with microbiologists, immunologists and epidemiologists. we offer this perspective as an entry point for non-modelling scientists to understand the power and flexibility of modelling, and as a foundation for the transdisciplinary conversations that bolster the field. even within the same disease system, the ideal model design depends on the specifics of the questions asked. here, we highlight a series of models focused on one of the defining infectious agents of our era: hiv. the virus has challenged science, medicine and public health at every scale, from its deft immune evasion to its death toll of more than million over the last four decades . we describe how clinical needs, research questions and data availability have shaped the design of hiv models across these scales. unless otherwise indicated, the term 'hiv' is inclusive of both hiv- and hiv- . within-host models. at a within-host scale (table ) , models can be used to simulate cellular interactions, immunological responses and treatment pharmacokinetics . in such simulations, viral dynamics are often modelled using a compartmental structure, with the growth of one population, such as circulating virions, dependent on the size of another population, such as infected cells. for example, a seminal within-host model fit to viral load data by perelson et al. revealed high turnover rates of hiv- , counter to what was then the prevailing assumption that hiv- remained dormant during the asymptomatic 'latency' phase. the corollary to these high rates of viral turnover was that drug resistance would likely evolve rapidly under monotherapy. further analyses of this model indicated that a combination of at least three drugs was necessary to maintain drug sensitivity . once combination therapy did become available, extension of the perelson et al. model demonstrated that the two-phase decline in viral load observed following treatment initiation was attributable to a reservoir of long-lived infected cells . with this insight also came the realization that prolonged treatment would be necessary to suppress viral load. the incorporation of meagan c. fitzpatrick , , chris t. bauch , jeffrey p. townsend , , and alison p. galvani , , * the continued growth of the world's population and increased interconnectivity heighten the risk that infectious diseases pose for human health worldwide. epidemiological modelling is a tool that can be used to mitigate this risk by predicting disease spread or quantifying the impact of different intervention strategies on disease transmission dynamics. we illustrate how four decades of methodological advances and improved data quality have facilitated the contribution of modelling to address global health challenges, exemplified by models for the hiv crisis, emerging pathogens and pandemic preparedness. throughout, we discuss the importance of designing a model that is appropriate to the research question and the available data. we highlight pitfalls that can arise in model development, validation and interpretation. close collaboration between empiricists and modellers continues to improve the accuracy of predictions and the optimization of models for public health decision-making. stochasticity into this within-host framework allowed model fitting to 'viral blips'-transient peaks in viral load, even under antiretroviral treatment . analysis of this data-driven stochastic model demonstrated that homeostatic proliferation maintained the infected cell reservoir and produced these viral blips, a finding that was later confirmed experimentally , . the implication for clinical care was that intensified antiretroviral treatment would be unable to eliminate the latent reservoir of infected cells as had been hypothesized, sparing patients from potentially fruitless trials with such regimens. individual-based models. whereas the unit of interest for withinhost modelling is an infected cell, the analogous unit for individualbased models is an infected person (table ) , , . individual-based models are often used to explore the interplay between disease transmission and individual-level risk factors, such as comorbidities, sexual behaviours and age. such models are capable of incorporating data with individual-level granularity, including those regarding contact patterns, patient treatment cascades and clinical outcomes. individual-based models are uniquely suited for representing overlap in individual-level risk factors and translating the implications of this overlap for public health policy. for example, an individual-based model was recently used to demonstrate that the majority of hiv transmission among people who inject drugs in new york city is attributable to undiagnosed infections . these modelling results underscore the urgency for the city to invest in more comprehensive screening and improved diagnostic practices. population models. most commonly, models are created at the population scale, capturing the spread of a pathogen through a large group (table ) . at this scale, compartmental models shift in focus from the pathogen to the host. unlike individual-based models, compartmental models will aggregate individuals with a similar epidemiological status. for instance, the archetypical 's-i-r' model separates the entire population of interest into one of three categories: s, susceptible to infection; i, infected and infectious; or r, recovered and protected . in practice, most models will have additional compartments or stratification beyond this simple structure. age stratification is essential when either the disease risk or the intervention is age-specific. as an example, an age-stratified multipathogen model demonstrated that schistosomiasis prevention targeted to zimbabwean schoolchildren could cost-effectively reduce hiv acquisition later in life . this framework was extended to additional countries with a range of age-specific disease prevalence and co-infection rates to assess the potential value of treating schistosomiasis in adults. although adult treatment is not usually considered efficient, the model showed that it could be cost-effective in settings with high hiv prevalence . these models strengthened the investment case for treatment of schistosomiasis, an otherwise neglected tropical disease. network models are also deployed to represent dynamics on the population scale (table ) . these models impose a structure on contacts between hosts, unlike compartmental models which assume that contacts are random among hosts within a compartment. in a network model, nodes represent individuals and the connections between nodes represent contacts through which infection may spread . sources for network parameterization may include surveys, partner notification services or phylogenetic tracing , . as with individual-based models, network models tend to require significant amounts of data to fully parameterize, but various computational and statistical methods have been developed to analyse the impact of uncertain parameter values on model predictions . network models are applied to discern the influence of contact structure on disease transmission and on the effectiveness of targeted intervention strategies. for instance, network models predicted that hiv would spread more quickly through sexual partnerships that are concurrent versus serially monogamous, even if the total numbers of sexual acts and partners remain constant . the study prompted a more rigorous engagement of epidemiologists with sociological data to tailor interventions for specific settings . other network models have focused on the more rapid transmission within clusters of high-risk individuals and slower transmission to lower-risk clusters, a dynamic which explains discrepancies between observed incidence patterns and the expected pattern based on an assumption of homogeneous risks . these studies both illustrate the importance of accounting for network-driven dynamics when individuals are highly aggregated with regards to their risk factors, and when appropriate data for parameterization are available. metapopulation models. metapopulation models represent disease transmission at dual scales, considering not just the interactions of individuals, but also the relationships between groups of individuals, which are typically defined geographically (table ) . transmission intensity is often higher within groups than across groups, especially when the groups are spatially segregated . one metapopulation model of hiv in mainland china considered there are the three principal objectives of modelling, all of which can inform public health policy. predicting disease spread. models can be used to estimate the infectiousness of a pathogen within a given population. a fundamental concept is that of r , the basic reproduction number, which quantifies the number of infections that would result from a single index case in a susceptible population. r governs the temporal trajectory of an outbreak and the scale of interventions required for its containment. models may be used to infer r as well as forecast changes in r that could drive transitions in epidemic dynamics, such as the shift from sporadic outbreaks to sustained chains of transmission. example: assessing real-time zika risk in texas . selecting among alternative control strategies. simultaneous field trials of multiple infectious disease control options are often infeasible. models can simulate a wide range of control strategies and thus optimize public health policies according to translational objectives and real-world constraints. modelling can also extrapolate from the individual clinical outcomes of interventions or novel therapeutics to the population-level impacts. extrapolating to the population level is essential to evaluate the indirect benefits of interventions, including a reduction in transmission, or unanticipated repercussions, such as evolution of resistance. example: comparing antibiotic 'cycling' versus 'mixing' to minimize the evolution of antimicrobial resistance . hypothesis testing. it is often logistically or ethically infeasible to empirically test scientific hypotheses in the field or experimentally. modelling can identify parsimonious explanations of observed phenomena, including complex outcomes that can arise from the nonlinear processes common in microbiological systems. even simple models can be useful to help us understand dynamics that are common to many microbiological systems through identification of basic mechanisms that apply across a range of infections. by examining a new infectious agent through the lens of previously characterized systems, models provide insight into the ways that a particular microbial infection might follow or break from typical patterns. example: investigating whether individual heterogeneity within social networks significantly impacts disease spread . transmission within and between provinces, driven by the mobility of migrant labourers . the study suggested that hiv prevention resources could be most effectively targeted to provinces with the greatest initial incidence, as rising incidence in other provinces is driven more by migration from the high-burden provinces than by local transmission. given that the chinese provinces with employment opportunities for migrants are also those with the heaviest burden of hiv, migrant workers who acquire hiv often do so in the province where they work. however, government policy requires migrants to return to their home province for treatment. the movement of these workers perpetuates the disease cycle, as new migrants move to fill the vacated jobs and themselves become exposed to elevated hiv risk. these results therefore call for reconsideration of provincial treatment restrictions. multinational models. global policies, such as the treatment goals set by the joint united nations programme on hiv/aids (unaids), have been modelled on a global scale (table ) by considering the effectiveness of the policies for each nation. for example, a compartmental model was used to evaluate the potential impact of a partially efficacious hiv vaccine on the epidemiological trajectories in countries that together constitute over % of the global burden . the model was tailored to each country by fitting to country-specific incidence trends as well as diagnosis, treatment and viral suppression data. this model revealed that, even with efficacy as low as %, a hiv vaccine would avert millions of new infections worldwide, irrespective of whether ambitious treatment goals are met. these results identify the synergies between vaccination and treatment-as-prevention, and provide evidence to support continued investment in vaccine development , . from the cellular level to the population level, hiv modelling has led to improvements in drug formulations, clinical care and resource allocation. as scientific advances continue to bring pharmaceutical innovations, modelling will remain a useful tool for illuminating transmission dynamics and optimizing public health policy. hiv was not controlled before it became a pandemic, but our response to future outbreaks has the potential to be more timely . when diseases emerge in new settings, such as ebola in west africa and sars in china, modelling can be rapidly deployed to inform and support response efforts (fig. ) . unfortunately, the urgency of public health decisions during such outbreaks tends to be accompanied by a sparsity of data with which to parameterize, calibrate and validate models. as detailed below, uncertainty analysis-a method of analysing how uncertainty in input parameters translates to uncertainty in model outcome variables-becomes all the more vital in these situations. media attention regarding model predictions is often heightened during outbreaks, ironically at a time when modelling results are apt to be less robust than for well-characterized endemic diseases. we discuss the importance of careful communication regarding model recommendations and associated uncertainty to inform the public without fuelling excessive alarm. despite these challenges, and especially if these challenges can be navigated, the timely assessment of a wide range of intervention scenarios made possible by modelling would be particularly valuable during infectious disease emergencies. ebola virus outbreaks. the ebola virus outbreak struck a populous region near the border of guinea and sierra leone, sparking a crisis in a resource-constrained area that had no prior experience with the virus. as the caseload mounted and disseminated geographically, it became apparent that the west african outbreak would be unprecedented in its devastation. models were developed to estimate the potential size of the epidemic in the absence of intervention, demonstrating the urgent need for expanded action by the international community [ ] [ ] [ ] , and to calculate the scale of the required investment . initial control efforts included a militarily enforced quarantine of a liberian neighbourhood in which ebola was spreading. modelling analysis in collaboration with the liberian ministry of health demonstrated that the quarantine was ineffective and possibly even counterproductive . connecting the microbiological and population scales, another modelling study integrated within-host viral load data over the course of ebola infection and between-host transmission parameterized by contact-tracing data. the resulting dynamics highlighted the imperative to hospitalize most cases in isolation facilities within four days of symptom onset . these modelling predictions were borne out of empirical observations. early in the outbreak, when the incidence was precipitously growing, the average time to hospitalization in liberia was above six days . as contact tracing improved, the concomitant acceleration in hospitalization was found to be instrumental in turning the tide on the outbreak . in another approach, phylogenetic analysis and transmission modelling were combined to estimate underreporting rates and social clustering of transmission . this study informed public health authorities regarding the optimal scope and targeting of their efforts, which were central to stemming the epidemic. although data can be scarce for emerging pathogens, modellers can exploit similarities with better-characterized disease systems to investigate the potential efficiency of different interventions (box ). as vaccine candidates became available against ebola, ring vaccination was proposed based on the success of the strategy in eliminating smallpox , another microorganism whose transmission required close contact between individuals and for which peak infectiousness occurs after the appearance of symptoms. compartmental models had suggested parameter combinations for which ring vaccination would be superior to mass vaccination , and methodological advances subsequently allowed for explicit incorporation of contact network data . modelling based on social and healthcare contact networks specific to west africa supported implementation of ring vaccination , and the approach was adopted for the clinical trial of the vaccine . in , two independent outbreaks of ebola erupted in the democratic republic of the congo. during the initial outbreak in Équateur province, modellers combined case reports with time series from previous outbreaks to generate projections of final epidemic size that could inform preparedness planning and allocation of resources . ring vaccination was again deployed, this time within two weeks of detecting the outbreak. a spatial model quantified the impact of vaccine on both the ultimate burden and geographic spread of ebola, highlighting how even one week of additional delay would have substantially reduced the ability of vaccination to contain this outbreak . the second outbreak was reported in august in the north kivu province. armed conflict in this region has interfered with the ability of healthcare workers to conduct the necessary contact tracing, vaccination and treatment. as conditions make routine data collection difficult and even dangerous, modelling has the potential to provide crucial insights into the otherwise unobservable characteristics of this outbreak. in contrast to the unexpected emergence of ebola in a new setting, the influenza virus has repeatedly demonstrated its ability to cause pandemics. a pandemic is an event in which a pathogen creates epidemics across the entire globe. the pandemic killed an estimated million people worldwide , exceeding the combined military and civilian casualties of world war . while the % case-fatality rate of the strain was approximately times higher than is typical for influenza , pathogenic strains with case-fatality rates exceeding % periodically emerge . modelling has illustrated how repeated zoonotic introductions impose selection for elevated human-to-human transmissibility, which thereby exacerbates the threat of a devastating influenza pandemic . such threats underscore the importance of surveillance systems and preparedness plans, which can be informed by modelling (box ). transmission models are able to optimize surveillance systems, accelerate outbreak detection and improve forecasting [ ] [ ] [ ] [ ] . for example, a spatial model integrating a variety of surveillance data streams and embedded in a user-friendly platform is currently implemented by the texas department of state health services to generate real-time influenza forecasts (http://flu.tacc.utexas.edu/). modelling has also motivated the development of dynamic preparedness plans, which adapt in response to the unfolding events of a pandemic, as models identified that adaptive efforts would be more likely to contain an influenza pandemic than static policies chosen a priori . other pandemic influenza analyses used agestructured compartmental models to study the trade-off between targeting influenza vaccination to groups that transmit many infections but experience relatively low health burdens (for example, schoolchildren) versus groups that transmit fewer infections but experience greater health burdens (for example, the elderly) . such examples illustrate the insights that modelling has provided to the decision makers charged with maintaining readiness against simultaneously rare but catastrophic situations. modelling has also examined the impact of human behaviour, including vaccination decisions and social interactions, on the course of an epidemic. public health interventions are not always sufficient to ensure disease control, as behavioural factors can thwart progress [ ] [ ] [ ] [ ] . for example, reports in of potential neurological side effects from the whole-cell pertussis vaccine led to a steep decline in vaccine uptake throughout the uk, followed by a slow recovery (fig. a) . vaccine uptake ebbed and flowed over the next two decades, with higher rates of vaccination in the wake of large pertussis outbreaks (fig. b) , . compartmental models analysing the interplay between vaccine uptake and disease dynamics confirmed the hypothesis that increases in vaccination were a response to the pertussis infection risk , and showed that incorporating this interplay can improve epidemiological forecasts. network models extending these coupled disease-behaviour analyses types of projection that can be generated include outbreak trajectories, disease burdens and economic impact. d, probabilistic uncertainty analyses convey not only model projections of policy outcomes, but also quantification of confidence in the projections. e, as policies are adopted and the microbiological system is influenced accordingly, the model can be iteratively updated to reflect the shifting status quo, thereby progressively optimizing policies within an evolving system. have illustrated how the perceived risk of vaccination can have greater influence on vaccine uptake than disease incidence . more recently, vaccine refusal has led to the resurgence of measles in the usa , . researchers are turning to social media to gather information about attitudes toward vaccines and infectious diseases, and to glean clues about vaccinating behaviour , , . for instance, signals that vaccine refusal is compromising elimination can be detected months or years in advance of disease resurgence by applying mathematical analysis of tipping points to social media data that have been classified on the basis of sentiment using machine learning algorithms . these and other data science techniques might help public health authorities identify the specific communities that are at increased risk of future outbreaks. on shorter timescales, the near-instantaneous availability of social media data facilitates its integration into models developed for outbreak response , . other behavioural factors that have been incorporated into transmission models include attendance at social gatherings, sexual behaviour and commuting patterns-elements which are also often affected by perceived infection risk , , . antimicrobial resistance. a substantial portion of the increase in human lifespan over the last century is attributable to antibiotics , but the emergence of pathogen strains that are resistant to antimicrobials threatens to reverse these gains. the extensive use and misuse of antibiotics has led to the evolution of multidrug-resistant, extensively drug-resistant and even pan-drug-resistant pathogens across the globe. precariously, this evolution outpaces the development of new antibiotics. mathematical modelling is being used to identify strategies to forestall the emergence and re-emergence of antimicrobial resistance , . models are particularly valuable for comparing alternative strategies, such as administration of different antibiotics within the same hospital ward, temporal cycling of antibiotics and combination therapy [ ] [ ] [ ] [ ] . high-performance computing now permits the rapid exploration of multidimensional parameter space. models can thereby narrow an array of possible interventions down to a subset likely to have the highest impact or optimize between trade-offs, such as effectiveness and cost (box ). by contrast, expense, feasibility and ethical considerations may impose more limitations on in vivo investigations (box ). not only can models identify the optimal strategy for a given parameter set, but they can generate the probability that this intervention remains optimal across variation in the parameters. for example, an optimization routine combined with simulation of hospital-based interventions identified combination therapy as most likely to reduce antibiotic resistance . as a complementary approach, modelling can incorporate economic considerations into these evaluations. a stochastic compartmental model showed that infection control specialists dedicated to promoting hand hygiene in hospitals are cost-effective for limiting the spread of antibiotic resistance . although most models of antibiotic resistance have focused on transmission in healthcare settings, the importance of antibiotic resistance in natural, agricultural and urban settings has been increasingly recognized [ ] [ ] [ ] [ ] [ ] [ ] [ ] . for example, a metapopulation model of antimicrobial-resistant clostridium difficile simulated its transmission within and between hospitals, long-term care facilities and the community. this model demonstrated that mitigating risk in the community has the potential to substantially avert hospital-onset cases by decreasing the number of patients with colonization at admission and thereby the transmission within hospitals . this study illustrates how models can consider the entire ecosystem of infection to elucidate dynamics that might not be captured through focus on a single setting. during the initial phase of an outbreak, the predictive power of models is often constrained by data scarcity. this challenge is exacerbated for outbreaks of novel emerging diseases given that our understanding of the disease will rely on the unfolding epidemic (fig. ) . not only can the absence of data constrain model design, but sparse data requires extensive sensitivity analyses to evaluate the robustness of conclusions. univariate sensitivity analyses, in which individual parameters are varied incrementally above and below a point estimate, can identify which parameters most influence model output (box ). such comparisons reveal both salient gaps in knowledge and targets for preventing and mitigating the outbreak (box ) . as an outbreak progresses, each day has the potential to provide more information about the new disease, including its duration of latency, the symptomatic period, infectiousness, transmission modalities, underreporting and the case-fatality rate. however, collecting detailed data to inform each of these parameters can strain resources when they are thinly spread during an emergency response. sensitivity analysis can support clinicians and epidemiologists in prioritizing data collection efforts . parameterization challenges are compounded for complicated disease systems, such as vector-borne diseases. for example, models of zika virus infection span both species and scales, as the disease trajectory is influenced by factors ranging from mosquito seasonality and mosquito abundance down to viral and immunological dynamics within human and mosquito hosts , . adding to this complexity, the ecological parameters vary seasonally and geographically-heterogeneities that may be amplified by socioeconomic factors modulating human exposure to infected mosquitoes . in the absence of the high-resolution data that would be ideal to tailor a mosquitodriven disease system to a given setting, uncertainty analysis can unify parameterization from disparate data sources. in contrast to univariate sensitivity analyses, uncertainty analysis simultaneously samples from empirical-or expert-informed distributions for many or all input parameters. collaboration between modellers and disease experts is thus instrumental to ensuring the biological plausibility of these parameter distributions , . the uncertainty analysis produces both a central point estimate and a range for each outcome, a combination which can inform stakeholders about the best-case and worst-case scenarios as well as the likelihood that an intervention will be successful [ ] [ ] [ ] . in constructing models and communicating results, there are common pitfalls which can compromise the rigor and impact of the research. a pervasive pitfall is the incorporation of excessive model complexity, particularly through inclusion of more parameters than can be reliably parameterized from data. intuition might suggest that a complex representation of a microbiological system would more closely represent reality. however, the predictive power of a model can be degraded if incorporating additional parameters only marginally improves the fit to data. this tendency results in complicated transmission models that overfit data in much the same way that complicated statistical regressions can overfit data, replicating not only the relevant trends but also the noise in a particular data set. these overfit models thus become less useful for prediction and generalization , . to guide appropriate model complexity and parameterization, modellers have used the mathematical theory of information to develop criteria which quantify the balance between realism and simplicity. such criteria penalize additional parameters but reward substantial improvements in fit, thereby identifying the simplest model that can adequately fit the data , , . these methods can be applied to select among models or alternatively to calculate weighted average predictions across models. in a similar vein, modelling consortiums serve to address uncertainty surrounding model design [ ] [ ] [ ] . in a consortium, several modelling groups develop their models independently, each applying their particular expertise and perspective. for example, consortia of malaria modellers were convened to predict the effectiveness of interventions, including a vaccine candidate and mass drug administration . congruence of output among models engenders confidence that model results are robust. another pitfall concerns the quality of data used to inform the model. incompleteness of data has been an issue since , when daniel bernoulli published a compartmental model of smallpox and acknowledged that more extended analyses would have been possible if the data had been age-stratified . even today, using data to develop models without knowledge of how the data were collected or the limitations of the data can be risky. data collected for an alternative purpose can contain gaps or biases that are acceptable for the original research question, yet lead to incorrect conclusions when incorporated for another purpose in a specific model. in ideal circumstances, modellers would be involved in the design of the original study, ensuring both seamless integration of the results into the model and awareness on the part of the modeller with regard to data limitations. failing that, it is very helpful for modellers to collaborate with scientists familiar with the details of empirical studies on which their results might depend. this lack of familiarity with the biases or incompleteness of data sources may be particularly dangerous in the era of digital data. 'big data hubris' can blind researchers to the limitations of the dataset, such as being a large but unrepresentative sample of the general population, or the alteration of search engine algorithms partway through the data collection process . some of these limitations can be addressed by using digital data as a complement to traditional data sources. in this way, the weakness of one data source (for example, low sample size of traditional surveys or bias in large digital data) can be compensated by the strengths of another data source (for example, balanced representation in small survey versus large scale of digital data). a final pitfall that often arises in the midst of an ongoing outbreak concerns the interpretation of epidemic projections. initial models may assume an absence of intervention as a way to assess the potential consequences of inaction. such projections may contribute to the mobilization of government resources towards control, as was the case during the west african ebola outbreak , , . in this respect, the projections are intended to make themselves obsolete . in retrospect and without knowledge of the initial purpose of the model, it may appear that the initial predictions were excessively pessimistic . additionally, people living in outbreak zones often change their behaviour to reduce infection risks, thereby mitigating disease spread through, for example, reducing social interactions or increasing vaccine uptake (fig. ) , , . thus, risk assessment constitutes a 'moving target' . for example, input parameters estimated from contact tracing early in an outbreak could require adjustments to reflect these behaviour changes and accurately predict subsequent dynamics . the need for proficient communication skills is heightened during an outbreak. this concern is particularly relevant when presenting sensitivity and uncertainty analyses. although predictions at the extreme of sensitivity analyses also tend to be less probable than mid-range projections, there can be a temptation to focus on the most sensational model scenarios. ensuing public pressure on the basis of misunderstood findings can cause unwarranted alarm and trigger counterproductive political decisions. in both publications and media interactions, underscoring the improbability of extreme scenarios explored during sensitivity analysis, as well as how improved interventions turn a predictive model into a counterfactual one, may pre-empt this pitfall . the role for modelling in supporting epidemiologists, public health officials and microbiologists has progressively expanded since the foundational publications forty years ago, in concert with the growing abundance and granularity of data as well as the refinement of quantitative approaches. models have now been developed for virtually every human infectious disease, as well as in many that affect animals and plants, and have been applied across the globe. interdisciplinary collaboration among empiricists, policymakers and modellers facilitates the development of scientifically grounded models for specific settings and generates results that will be actionable in the real world. reciprocally, modelling results may guide the design of experiments and field studies by revealing key gaps in our understanding of microbiological systems. furthermore, modelling is a feasible and cost-effective approach for identifying impactful policies prior to implementation decisions. through all these avenues, epidemiological modelling galvanizes evidence-based action to alleviate disease burden and improve global health. vaccine uptake appears to be entrained by surges in infection incidence. mathematical models can capture the interplay between natural and human dynamics exemplified in this dataset and a wide variety of other study systems. global, regional, and national age-sex specific mortality for causes of death, - : a systematic analysis for the global burden of disease study population biology of 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reduce antimicrobial resistance in hospitals the authors gratefully acknowledge funding from the notsew orm sands foundation (grants to m.c.f., j.p.t. and a.p.g.), the national institutes of health (grant nos. k ai and u gm to m.c.f. and a.p.g., respectively) and the natural sciences and engineering research council of canada (grant no. rgpin- - to c.t.b.). the authors also thank c. wells and a. pandey, both members of the yale center for infectious disease modeling and analysis, for their helpful discussions regarding the hiv and ebola modelling literature. m.c.f. and a.p.g. drafted the initial manuscript. m.c.f., c.t.b., j.p.t. and a.p.g. all critically revised the content. the authors declare no competing interests. correspondence should be addressed to a.p.g.reprints and permissions information is available at www.nature.com/reprints.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- - zuhilmu authors: conly, john; seto, w. h.; pittet, didier; holmes, alison; chu, may; hunter, paul r. title: use of medical face masks versus particulate respirators as a component of personal protective equipment for health care workers in the context of the covid- pandemic date: - - journal: antimicrob resist infect control doi: . /s - - - sha: doc_id: cord_uid: zuhilmu currently available evidence supports that the predominant route of human-to-human transmission of the sars-cov- is through respiratory droplets and/or contact routes. the report by the world health organization (who) joint mission on coronavirus disease (covid- ) in china supports person-to-person droplet and fomite transmission during close unprotected contact with the vast majority of the investigated infection clusters occurring within families, with a household secondary attack rate varying between and %, a finding that is not consistent with airborne transmission. the reproduction number (r( )) for the sars-cov- is estimated to be between . – . , compatible with other respiratory viruses associated with a droplet/contact mode of transmission and very different than an airborne virus like measles with a r( ) widely cited to be between and . based on the scientific evidence accumulated to date, our view is that sars-cov- is not spread by the airborne route to any significant extent and the use of particulate respirators offers no advantage over medical masks as a component of personal protective equipment for the routine care of patients with covid- in the health care setting. moreover, prolonged use of particulate respirators may result in unintended harms. in conjunction with appropriate hand hygiene, personal protective equipment (ppe) used by health care workers caring for patients with covid- must be used with attention to detail and precision of execution to prevent lapses in adherence and active failures in the donning and doffing of the ppe. the mechanisms of transmission (airborne, droplet, contact, vector or common vehicle) for microorganisms supports a specific combination of barrier precautions chosen on the basis of a point-of-care risk assessment by the health care worker (hcw) [ , ] . any person who is in close contact (generally considered to be within m) with someone who has respiratory symptoms (e.g., sneezing or coughing) is at risk of being exposed to potentially infective respiratory droplets. moreover, droplet transmission may also produce fomites on any surface in the immediate environment around the infected person. airborne transmission refers to the presence of microbes within droplet nuclei (generally considered to be particles < - μm in diameter), which result from the evaporation of larger droplets and/or exist within dust particles and may remain in the air for long periods of time and may be transmitted to others over longer distances such as the measles virus [ ] [ ] [ ] . however, it is important to recognize that in the course of medical care, aerosols of particles generally considered to be < - μm may be generated in certain procedures considered to be "aerosol-generating medical procedures" (agmp) and transmitted at limited distances beyond m, which has been referred to as "opportunistic" airborne transmission and airborne precautions are appropriate for these settings [ ] . within the context of the general understanding of the routes of droplet and opportunistic airborne transmission, controversy exists about the relative contribution and importance of the routes of each of them related to specific viruses. for example a systematic review of the literature concluded that influenza virus transmission in humans occurs only over short distances consistent with predominantly the droplet route [ ] , but tellier suggested that limited aerosol transmission over longer distances can occur in addition to droplet transmission [ , ] . it is recognized that there is a continuum of transmission routes between large droplet and aerosol and it is an important concept. particles of a variety of sizes are expelled from the human airway during coughing, sneezing, talking and medical procedures. the aerobiology of expired large droplets and smaller particles and the transmission dynamics to allow for a replication competen and tinfection competent virus to establish an invasive infection in humans is complex. the size of the particles and the distance the particles may be expelled is variable and depends on many factors, including the size distribution of the particles, the propulsive force generated by the individual or the procedure, the relative humidity, evaporation level, settling velocity, direction and velocity of air flow, the number of air changes per hour, temperature, crowding and other environmental factors. in addition there is variability in the type of the respiratory virus in question, the dispersion, quantity, and distribution of the virus within the droplets and smaller particles, the stability of the virus, its replication and infection competence, ability to enter the respiratory tract, ability to bind to specific host cell receptors and to establish invasive infection in a susceptible host. the process is further complicated by debate regarding how well the use of quantitative polymerase chain reaction (pcr) techniques performed on respiratory specimens can be interpreted with respect to recovery of viable virus and its titer, depending on the timing of presentation and stage of illness [ ] [ ] [ ] [ ] [ ] . regardless of the uncertainties, one certainty is that the use of personal protective equipment (ppe) including gloves, gowns, medical masks and eye protection in combination with patient placement in adequately ventilated single rooms represents one component of the infection prevention and control (ipc) response to prevent transmission of pathogenic microorganisms to hcws [ , ] . however the effectiveness of ppe depends on its availability, the proper physical environmental controls, adequate staff training, strict adherence to hand hygiene and appropriate human behaviour [ , ] . currently available evidence supports that the predominant route of human-to-human transmission of the sars-cov- is through respiratory droplets and/or contact routes [ , [ ] [ ] [ ] [ ] [ ] . the report by the world health organization (who) joint mission on coronavirus disease (covid- ) in china which analyzed the experience with , cases supports person-to-person droplet and fomite transmission during close unprotected contact, with the majority of sars-cov- transmission occurring within families in close contact with each other [ ] . the vast majority ( - %) of the investigated infection clusters occurred within families, with a household secondary attack rate varying between and %, a finding that is not consistent with airborne transmission [ ] . the reproduction number (r ) for the sars-cov- was estimated to be between . - . , compatible with influenza and other respiratory viruses typical for a droplet/contact mode of transmission and very different than a classical airborne virus such as measles which is estimated to have a r of greater than and widely cited to be between and [ , ] . other detailed reports have also been consistent, finding a r of . - . for sars-cov- [ , ] . multiple clinical and epidemiologic reports have now lent considerable support that the predominant route of human-to-human transmission of the sars-cov- is through respiratory droplets and/or contact routes and do not support significant airborne transmission. an investigation of close contacts sitting within m of a symptomatic index case with cough and a presymptomatic case, both confirmed to have covid- , multiple exposed flight crew members and potentially all passengers on board an airplane during a -h flight revealed no evidence of transmission of sars-cov- [ ] supporting a droplet as opposed to airborne transmission route. although the cases were reported to be wearing masks on the flight, it is not possible to wear masks during eating and drinking and the filtration capacity of the mask would not likely have been adequate for the entire hour flight. another report in a clinical setting in which health care workers (hcws) were exposed for over min and within m of a patient with confirmed covid- during an intense and difficult intubation and non-invasive ventilation scenario, involving multiple agmps, revealed no transmission events of sars-cov- with repetitive testing of all the hcws [ ] . the majority ( %) of the hcws were wearing a medical mask and other appropriate ppe while the remainder wore an n respirator. another recent investigation of an initially undiagnosed covid- patient with severe pneumonia with a confirmed high frequency of coughing and receiving oxygen therapy at l/min who was nursed in an open bed cubicle of a general ward for h, with minimal spacing between patients, led to an exposure of staff and patients, including staff and patients who fulfilled the criteria of 'close contact' (within two metres of the index case for a > min or had performed agmps without a n respirator), identified no sars-cov- nosocomial transmission events [ ] . all patients and / staff with close contact tested negative for covid- despite inconsistent use of medical masks by the patients and either use of medical masks or n respirators by the hcws. in total tests were performed on contacts of which all were negative, and all other identified contacts remained asymptomatic during the day post-contact surveillance period [ ] . the authors concluded that sars-cov- is not spread by the airborne route and that basic infection control measures, including the use of medical masks, hand and environmental hygiene are adequate to prevent nosocomial transmission of sars-cov- . another recent study of persons involved in a nosocomial outbreak of sars-cov- infections in the pediatric dialysis unit of the university hospital of münster found that after contact with the index case, hcws, patients and one accompanying person became infected. all had either cumulative min of faceto-face contact or were hcws with exposure within a distance of ≤ m, which occurred without use of any ppe. of the remaining contacts who had shared the same indoor environment without face-to-face contact or who had contact but at a distance of > m but without any use of ppe, none were found to be positive for covid- on testing [ ] . additional data supporting that airborne transmission is not a predominant mode of transmission and therefore that n respirators or their equivalent are not required for routine use is accruing from sites which use only medical masks as the component of ppe in the care of covid- patients but have a well-trained and prepared staff complement. there have been an estimated person hours of continuous hcw exposure to covid- inpatients, using ppe consisting of gowns, gloves, medical masks, and face shields or goggles for routine care and the addition of a n respirator for any agmps within "designated" covid- medical wards at acute care hospitals in calgary, canada over the first months of care delivery with no nosocomial sars-cov- transmission events documented in any hcws to date [ ] . data from studies that sampled surfaces in the environment for the presence of sars-cov- rna in the immediate airspace surrounding infected patients who had known significant viral loads in their respiratory secretions have provided both negative and positive results [ , , [ ] [ ] [ ] [ ] . several studies have now reported positive results for the presence of sars-cov- rna in air samples but in extremely low copy numbers/m or per liter of air sampled and would be highly unlikely to represent viable virus [ ] [ ] [ ] . no studies to date have been able to find viable sars-cov- within air samples [ ] . even if viable virus were to be found in air samples, it would need to be demonstrated that sars-cov- in the samples was both replication and infection competent in the context of health care settings where ppe is being used appropriately in conjunction with diligent hand hygiene to consider that airborne transmission represents a significant mode of transmission. a recent experimental laboratory study suggested that aerosol transmission of sars-cov- is plausible, because they demonstrated that the virus can remain viable in aerosols for h based on their experimental design. however, they used a collison -jet nebulizer to shear a large volume liquid suspension of a high viral inoculum to generate aerosolized viral particles which were then impacted against a hard surface inside a drum [ ] . this mode of artificial mechanical aerosol production has been used for testing bioterrorism agents [ , ] and has little relevance to a coughing patient with covid- in the clinical setting and does not offer evidence that the virus is routinely present in aerosols at the bedside. another report suggested that based on laser light scattering observations, loud speech could emit oral droplet nuclei of about um in size that persist as a slowly descending cloud which remain airborne for more than min and theoretically could contain viable virus capable of being inhaled into the lungs [ ] . however this conjecture is dependent on the independent action hypothesis (iah) and the authors readily admit that there is no evidence the iah is valid for humans and sars-cov- .other reports have suggested that airborne transmission is a significant route of transmission for the sars-cov- ; the title of one report suggests that the world should face the reality that the virus is airborne [ ] [ ] [ ] . these studies represent opinion pieces, one systematic review of mainly modelling plus some experimental studies, and brief case reports which do not utilize robust methods to rule out contact or fomite transmission or opportunistic airborne transmission. a recent who report indicated that sars-cov- rna has been detected in in feces in % of cases within a few days of symptom onset and live virus was cultivated from stools in some cases [ ] . this latter observation and our knowledge of the extensive transmission that has emerged in hundreds of outbreaks of norovirus on cruise ships raises the possibility of the fecal-oral route as an additional means of transmission for sars-cov- which deserves attention and further study [ ] [ ] [ ] . a recent report from the diamond princess cruise ship reported that before disinfection, sars-cov- rna was identified on multiple surfaces up to days after cabins were vacated from both symptomatic and asymptomatic infected passengers suggesting widespread contamination but likely no viable virus was present [ ] . similar extensive environmental contamination of surfaces by sars-cov- from infected patients has been reported [ ] . additional evidence is emerging about the recognition of contact as a major route of transmission with a recent report from china finding poor hand hygiene before and after contact with patients and improper ppe as significantly associated with hcw with poor hand hygiene being retained in the logistic regression with the highest relative risk [ ] . guidance from the who states that "health care workers should wear a medical face mask (herein after termed medical mask) when entering a room where patients suspected or confirmed of being infected with sars-cov- are admitted and in any situation of care provided to a suspected or confirmed case". the use of a particulate respirator at least as protective as a us national institute for occupational safety and health (niosh)-certified n , european union (eu) standard ffp , or equivalent, is recommended when performing aerosol-generating medical procedures [ , ] . some jurisdictions and professional societies have suggested that the precautionary principle [ ] should be applied in the event of an outbreak of any new respiratory virus. in the context of the current covid- outbreak, several institutions initially issued guidance indicating that particulate respirators (designed to protect against % of airborne particulates when tested against a . -μm particles) should be used as a component of the ppe for the hcws, rather than medical masks. persisting with this approach and the subsequent differences in recommendations for the type of masks creates risk perception disparities for hcws, which may be increased in jurisdictions in the world with limited or no access to particulate respirators, and in the event of domestic or global supply disruptions. strict adherence to the use of administrative controls and using medical masks as a component of ppe were shown to be effective with no reported transmission events to hcws during the sars outbreak in [ , ] and in one setting without the use of airborne isolation rooms [ ] . although the appropriate use of fit tested particulate respirators as a component of ppe may be equally effective compared the use of medical masks for hcws in the management of patients infected with coronavirus strains including sars-cov- , it is important to note that there were multiple reports documenting sars coronavirus transmission to hcws despite the use of particulate respirators in conjunction with other ppe in accordance with guidelines which reflect failures to prevent transmission to hcws using them [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the mechanisms of transmission in these latter settings are not well understood but draw attention to the points that the use of particulate respirators as a component of ppe do not provide infallible levels of protection to hcws. it is likely that these failures relate to inappropriate use or self contamination events. multiple studies using systems-based human factors analysis have demonstrated that lapses in adherence and active failures in the donning and doffing of ppe resulting in self-contamination, which may be the genesis of inoculation events leading to transmission of pathogens to hcws [ , ] . a review of the literature following the sars outbreak in suggested that for ppe to be effective, its use should be as uncomplicated as possible and focus on key principles, strict adherence to protocols including those related to appropriate use of ppe, high compliance, and lend itself to achieve the highest level of effectiveness in preventing hcw transmission events [ , ] . these studies suggest there is a need to simplify the ppe processes to ensure that compliance may be achieved. there were multiple reports of sars among hcws in hospital outbreaks reported from canada, china, hong kong, taiwan and vietnam followed by mers outbreaks with hcw transmission events in the middle east and south korea which were caused by a very similar coronavirus to the sars-cov- . these hospital outbreaks serve to focus attention on the critical importance of ipc practices, including appropriate ppe use, and having adequate training and knowledge among hcws to ensure that ppe, barrier precautions and hand hygiene practices are used appropriately [ , , ] . the single most important concept identified in the management of patients affected by viruses transmitted by the droplet/contact route is the precision of execution in the use of ppe, and which should be the primary focus rather than on the type of mask used by hcws as a component of ppe. the findings from multiple systematic reviews and meta analyses over the last decade have not demonstrated any significant difference in the clinical effectiveness of particulate respirators compared to the use of medical masks when used by hcws in multiple health care settings for the prevention of respiratory virus infections, including influenza [ ] [ ] [ ] . a recent large well conducted cluster randomized multi-center, multi-year pragmatic effectiveness study study no evidence of greater clinical effectiveness of particulate respirators compared to medical masks in the prevention of acquisition of laboratory confirmed influenza in hcws [ ] . one of the systematic reviews commented about the harms of particulate respirators, especially when worn for prolonged periods [ ] . other studies have demonstrated side effects associated with the use of particulate respirators including facial dermatitis from the respirator components, increased work of breathing, respiratory fatigue, impaired work capacity, increased oxygen debt, early exhaustion at lighter workloads, elevated levels of co , increased nasal resistance, and increased noncompliance events leading to self-contamination (adjustments, respirator or face touches, under-the-respirator touches, and eye touches) [ ] [ ] [ ] [ ] [ ] [ ] [ ] . these side effects are not encountered with the same frequency with the appropriate use of medical masks. an additional study has suggested pregnant women were not able to maintain their minute ventilation and had decreased oxygen uptake and increased carbon dioxide production even at rest [ ] . the effects on the developing fetus are unknown. studies of the use of particulate respirators in clinical settings have demonstrated anywhere between and % of hcws do not use the respirators properly [ ] . our view is that the weight of the scientific evidence to date indicates that particulate respirators offer no advantage over medical masks as a component of ppe for the prevention of respiratory viral infections transmitted by the droplet/contact route, when used for routine care in clinical settings. to date, the available evidence supports that the predominant route of transmission of sars-cov- is consistent with the droplet/contact route. there are potential unintended consequences of the use of particulate respirators that put hcws at risk particularly with prolonged use, which have not been associated with the use of medical masks. hcws should be apprised accordingly in an open and transparent manner regarding potential harms of particulate respirators in jurisdictions where particulate respirators are chosen for routine use as a component of ppe. in addition, particulate respirators are more costly, require fit testing, necessitate additional time and resources, do not provide an adequate fit in individuals with beards, and may provide a false sense of security. moreover, in the current covid- pandemic, shortages have been documented from overuse such that respirators were not available in settings where agmps are performed and where is evidence for their need. regardless of whether jurisdictions choose the precautionary principle with consequent use of particulate respirators instead of medical masks as a component of ppe for routine care of covid- patients, this choice must not detract from the critical importance of emphasizing that ppe is only one measure within a bundle that comprises administrative, environmental and engineering controls, as described in who's infection prevention and control of epidemic-and pandemic-prone acute respiratory infections in health care [ ] . ppe used by hcws caring for patients with covid- must be used with attention to detail and precision of execution which involves selecting the proper ppe and being trained in how to correctly don, doff and dispose of itwithout self-contaminating oneself in the process, the latter underscoring the importance and attention required for hand hygiene. additional evidence on the use of medical masks and respirators needs to be generated to help define and inform knowledge gaps as we learn more about the covid- epidemic and hcw practices. coronavirus disease (covid- ) technical guidance: infection prevention and control. geneva: world health organization infection prevention and control of epidemicand pandemic-prone acute respiratory infections in health care. geneva: world health organization the spread of influenza and other respiratory viruses: complexities and conjectures airborne transmission of communicable infection--the elusive pathway transmission of 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epidemiology to control cluster of severe acute respiratory syndrome cases among protected health-care workers -toronto, canada control measures for severe acute respiratory syndrome (sars) in taiwan cluster of cases of severe acute respiratory syndrome among toronto healthcare workers after implementation of infection control precautions: a case series infection control and sars transmission among healthcare workers world health organization. sars outbreak in the philippines identification and characterization of failures in infectious agent transmission precaution practices in hospitals: a qualitative study human factors risk analyses of a doffing protocol for ebola-level personal protective equipment: mapping errors to contamination protecting health care workers from sars and other respiratory pathogens: organizational and individual factors that affect adherence to infection control guidelines research gaps in protecting healthcare workers from sars and other respiratory pathogens: an interdisciplinary, multi-stakeholder, evidence-based approach physical interventions to interrupt or reduce the spread of respiratory viruses effectiveness of n respirators versus surgical masks in protecting health care workers from acute respiratory infection: a systematic review and meta-analysis effectiveness of masks and respirators against respiratory infections in healthcare workers: a systematic review and meta-analysis n respirators vs medical masks for preventing influenza among health care personnel: a randomized clinical trial adverse skin reactions to personal protective equipment against severe acute respiratory syndrome--a descriptive study in singapore skin reactions following use of n facial masks allergic contact dermatitis from formaldehyde textile resins in surgical uniforms and nonwoven textile masks effects of long-duration wearing of n respirator and surgical facemask: a pilot study physiologic and other effects and compliance with long-term respirator use among medical intensive care unit nurses respiratory consequences of n -type mask usage in pregnant healthcare workers-a controlled clinical study use and efficacy of tuberculosis infection control practices at hospitals with previous outbreaks of multidrug-resistant tuberculosis publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we are thankful to nicole lamont and jenine leal for reference checks and editing assistance. authors' contributions jc, whs, dp, ah, mc, prh contributed to the conception of this work. all authors were provided a draft of the manuscript for comments and were provided with an opportunity to present revisions. jc wrote the initial drafts of the manuscript and collated comments from the principal authors engaged in the conception of the work and later comments from all authors. all authors were provided a final version of the manuscript for approval. this commentary was unfunded.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests. the members of the world health organization (who) covid- infection prevention and control research and innovation advisory group who participated in the development of this manuscript, provide independent advice to who in their capacity as individuals with expertise in infection prevention and control.author details university of calgary and alberta health services, calgary, alberta, canada. university of hong kong , hong kong, china. university of east anglia, norwich, uk. hopitaux universitaires de genève, geneva, switzerland. imperial college, london, united kingdom. colorado school of public health, aurora, colorado, usa.received: june accepted: july key: cord- -k imddzr authors: siegel, jane d.; rhinehart, emily; jackson, marguerite; chiarello, linda title: guideline for isolation precautions: preventing transmission of infectious agents in health care settings date: - - journal: am j infect control doi: . /j.ajic. . . sha: doc_id: cord_uid: k imddzr nan . clinical syndromes or conditions warranting additional empiric transmission-based precautions pending confirmation of diagnosis table . infection control considerations for highpriority (cdc category a) diseases that may result from bioterrorist attacks or are considered bioterrorist threats table . recommendations for application of standard precautions for the care of all patients in all health care settings table . components of a protective environment . the transition of health care delivery from primarily acute care hospitals to other health care settings (eg, home care, ambulatory care, freestanding specialty care sites, long-term care) created a need for recommendations that can be applied in all health care settings using common principles of infection control practice, yet can be modified to reflect setting-specific needs. accordingly, the revised guideline addresses the spectrum of health care delivery settings. furthermore, the term ''nosocomial infections'' is replaced by ''health care-associated infections'' (hais), to reflect the changing patterns in health care delivery and difficulty in determining the geographic site of exposure to an infectious agent and/ or acquisition of infection. . the emergence of new pathogens (eg, severe acute respiratory syndrome coronavirus [sars-cov] associated with sars avian influenza in humans), renewed concern for evolving known pathogens (eg, clostridium difficile, noroviruses, communityassociated methicillin-resistant staphylococcus aureus [ca-mrsa]), development of new therapies (eg, gene therapy), and increasing concern for the threat of bioweapons attacks, necessitates addressing a broader scope of issues than in previous isolation guidelines. . the successful experience with standard precautions, first recommended in the guideline, has led to a reaffirmation of this approach as the foundation for preventing transmission of infectious agents in all health care settings. new additions to the recommendations for standard precautions are respiratory hygiene/cough etiquette and safe injection practices, including the use of a mask when performing certain highrisk, prolonged procedures involving spinal canal punctures (eg, myelography, epidural anesthesia). the need for a recommendation for respiratory hygiene/cough etiquette grew out of observations during the sars outbreaks, when failure to implement simple source control measures with patients, visitors, and health care workers (hcws) with respiratory symptoms may have contributed to sars-cov transmission. the recommended practices have a strong evidence base. the continued occurrence of outbreaks of hepatitis b and hepatitis c viruses in ambulatory settings indicated a need to reiterate safe injection practice recommendations as part of standard precautions. the addition of a mask for certain spinal injections grew from recent evidence of an associated risk for developing meningitis caused by respiratory flora. . the accumulated evidence that environmental controls decrease the risk of life-threatening fungal infections in the most severely immunocompromised patients (ie, those undergoing allogeneic hematopoietic stem cell transplantation [hsct] ) led to the update on the components of the protective environment (pe). . evidence that organizational characteristics (eg, nurse staffing levels and composition, establishment of a safety culture) influence hcws' adherence to recommended infection control practices, and thus are important factors in preventing transmission of infectious agents, led to a new emphasis and recommendations for administrative involvement in the development and support of infection control programs. . continued increase in the incidence of hais caused by multidrug-resistant organisms (mdros) in all health care settings and the expanded body of knowledge concerning prevention of transmission of mdros created a need for more specific recommendations for surveillance and control of these pathogens that would be practical and effective in various types of health care settings. this document is intended for use by infection control staff, health care epidemiologists, health care administrators, nurses, other health care providers, and persons responsible for developing, implementing, and evaluating infection control programs for health care settings across the continuum of care. the reader is referred to other guidelines and websites for more detailed information and for recommendations concerning specialized infection control problems. part i reviews the relevant scientific literature that supports the recommended prevention and control practices. as in the guideline, the modes and factors that influence transmission risks are described in detail. new to the section on transmission are discussions of bioaerosols and of how droplet and airborne transmission may contribute to infection transmission. this became a concern during the sars outbreaks of , when transmission associated with aerosol-generating procedures was observed. also new is a definition of ''epidemiologically important organisms'' that was developed to assist in the identification of clusters of infections that require investigation (ie multidrug-resistant organisms, c difficile). several other pathogens of special infection control interest (ie, norovirus, sars, centers for disease control and prevention [cdc] category a bioterrorist agents, prions, monkeypox, and the hemorrhagic fever viruses) also are discussed, to present new information and infection control lessons learned from experience with these agents. this section of the guideline also presents information on infection risks associated with specific health care settings and patient populations. part ii updates information on the basic principles of hand hygiene, barrier precautions, safe work practices, and isolation practices that were included in previous guidelines. however, new to this guideline is important information on health care system components that influence transmission risks, including those components under the influence of health care administrators. an important administrative priority that is described is the need for appropriate infection control staffing to meet the ever-expanding role of infection control professionals in the complex modern health care system. evidence presented also demonstrates another administrative concern: the importance of nurse staffing levels, including ensuring numbers of appropriately trained nurses in intensive care units (icus) for preventing hais. the role of the clinical microbiology laboratory in supporting infection control is described, to emphasize the need for this service in health care facilities. other factors that influence transmission risks are discussed, including the adherence of hcws to recommended infection control practices, organizational safety culture or climate, and education and training. discussed for the first time in an isolation guideline is surveillance of health care-associated infections. the information presented will be useful to new infection control professionals as well as persons involved in designing or responding to state programs for public reporting of hai rates. part iii describes each of the categories of precautions developed by the health care infection control practices advisory committee (hicpac) and the cdc and provides guidance for their application in various health care settings. the categories of transmission-based precautions are unchanged from those in the guideline: contact, droplet, and airborne. one important change is the recommendation to don the indicated personal protective equipment (ppe-gowns, gloves, mask) on entry into the patient's room for patients who are on contact and/or droplet precautions, because the nature of the interaction with the patient cannot be predicted with certainty, and contaminated environmental surfaces are important sources for transmission of pathogens. in addition, the pe for patients undergoing allogeneic hsct, described in previous guidelines, has been updated. five tables summarize important information. table provides a summary of the evolution of this document. table gives guidance on using empiric isolation precautions according to a clinical syndrome. table summarizes infection control recommendations for cdc category a agents of bioterrorism. table lists the components of standard precautions and recommendations for their application, and table lists components of the pe. a glossary of definitions used in this guideline also is provided. new to this edition of the guideline is a figure showing the recommended sequence for donning and removing ppe used for isolation precautions to optimize safety and prevent self-contamination during removal. appendix a provides an updated alphabetical list of most infectious agents and clinical conditions for which isolation precautions are recommended. a preamble to the appendix provides a rationale for recommending the use of or more transmission-based precautions in addition to standard precautions, based on a review of the literature and evidence demonstrating a real or potential risk for person-to-person transmission in health care settings. the type and duration of recommended precautions are presented, with additional comments concerning the use of adjunctive measures or other relevant considerations to prevent transmission of the specific agent. relevant citations are included. new to this guideline is a comprehensive review and detailed recommendations for prevention of transmission of mdros. this portion of the guideline was published electronically in october and updated in november (siegel jd, rhinehart e, jackson m, chiarello l and hicpac. management of multidrug-resistant organisms in health care settings, ; available from http://www.cdc.gov/ ncidod/dhqp/pdf/ar/mdroguideline .pdf), and is considered a part of the guideline for isolation precautions. this section provides a detailed review of the complex topic of mdro control in health care settings and is intended to provide a context for evaluation of mdro at individual health care settings. a rationale and institutional requirements for developing an effective mdro control program are summarized. although the focus of this guideline is on measures to prevent transmission of mdros in health care settings, information concerning the judicious use of antimicrobial agents also is presented, because such practices are intricately related to the size of the reservoir of mdros, which in turn influences transmission (eg, colonization pressure). two tables summarize recommended prevention and control practices using categories of interventions to control mdros: administrative measures, education of hcws, judicious antimicrobial use, surveillance, infection control precautions, environmental measures, and decolonization. recommendations for each category apply to and are adapted for the various health care settings. with the increasing incidence and prevalence of mdros, all health care facilities must prioritize effective control of mdro transmission. facilities should identify prevalent mdros at the facility, implement control measures, assess the effectiveness of control programs, and demonstrate decreasing mdro rates. a set of intensified mdro prevention interventions is to be added if the incidence of transmission of a target mdro is not decreasing despite implementation of basic mdro infection control measures, and when the first case of an epidemiologically important mdro is identified within a health care facility. this updated guideline responds to changes in health care delivery and addresses new concerns about transmission of infectious agents to patients and hcws in the united states and infection control. the primary objective of the guideline is to improve the safety of the nation's health care delivery system by reducing the rates of hais. instruct symptomatic persons to cover mouth/nose when sneezing/ coughing; use tissues and dispose in no-touch receptacle; observe hand hygiene after soiling of hands with respiratory secretions; wear surgical mask if tolerated or maintain spatial separation, . feet if possible. *during aerosol-generating procedures on patients with suspected or proven infections transmitted by respiratory aerosols (eg, severe acute respiratory syndrome), wear a fittested n or higher respirator in addition to gloves, gown, and face/eye protection. -proper construction of windows, doors, and intake and exhaust ports -ceilings: smooth, free of fissures, open joints, crevices -walls sealed above and below the ceiling -if leakage detected, locate source and make necessary repairs d ventilation to maintain $ air changes/hour d directed air flow; air supply and exhaust grills located so that clean, filtered air enters from one side of the room, flows across the patient's bed, and exits on opposite side of the room d positive room air pressure in relation to the corridor; pressure differential of . . pa ( . -inch water gauge) d air flow patterns monitored and recorded daily using visual methods (eg, flutter strips, smoke tubes) or a hand-held pressure gauge d self-closing door on all room exits d back-up ventilation equipment (eg, portable units for fans or filters) maintained for emergency provision of ventilation requirements for pe areas, with immediate steps taken to restore the fixed ventilation system d for patients who require both a pe and an airborne infection isolation room (aiir), use an anteroom to ensure proper air balance relationships and provide independent exhaust of contaminated air to the outside, or place a hepa filter in the exhaust duct. ( ) reaffirm standard precautions as the foundation for preventing transmission during patient care in all health care settings; ( ) reaffirm the importance of implementing transmission-based precautions based on the clinical presentation or syndrome and likely pathogens until the infectious etiology has been determined ( table ) ; and ( ) provide epidemiologically sound and, whenever possible, evidence-based recommendations. this guideline is designed for use by individuals who are charged with administering infection control programs in hospitals and other health care settings. the information also will be useful for other hcws, health care administrators, and anyone needing information about infection control measures to prevent transmission of infectious agents. commonly used abbreviations are provided, and terms used in the guideline are defined in the glossary. medline and pubmed were used to search for relevant studies published in english, focusing on those published since . much of the evidence cited for preventing transmission of infectious agents in health care settings is derived from studies that used ''quasiexperimental designs,'' also referred to as nonrandomized preintervention and postintervention study designs. although these types of studies can provide valuable information regarding the effectiveness of various interventions, several factors decrease the certainty of attributing improved outcome to a specific intervention. these include: difficulties in controlling for important confounding variables, the use of multiple interventions during an outbreak, and results that are explained by the statistical principle of regression to the mean (eg, improvement over time without any intervention). observational studies remain relevant and have been used to evaluate infection control interventions. , the quality of studies, consistency of results, and correlation with results from randomized controlled trials, when available, were considered during the literature review and assignment of evidencebased categories (see part iv: recommendations) to the recommendations in this guideline. several authors have summarized properties to consider when evaluating studies for the purpose of determining whether the results should change practice or in designing new studies. , , this guideline contains changes in terminology from the guideline: . the term ''nosocomial infection'' is retained to refer only to infections acquired in hospitals. the term ''health care-associated infection'' (hai) is used to refer to infections associated with health care delivery in any setting (eg, hospitals, long-term care facilities, ambulatory settings, home care). this term reflects the inability to determine with certainty where the pathogen was acquired, because patients may be colonized with or exposed to potential pathogens outside of the health care setting before receiving health care, or may develop infections caused by those pathogens when exposed to the conditions associated with delivery of health care. in addition, patients frequently move among the various settings within the health care system. of infectious agents, a susceptible host with a portal of entry receptive to the agent, and a mode of transmission for the agent. this section describes the interrelationship of these elements in the epidemiology of hais. i.b. . sources of infectious agents. infectious agents transmitted during health care derive primarily from human sources but inanimate environmental sources also are implicated in transmission. human reservoirs include patients, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] hcws, , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and household members and other visitors. [ ] [ ] [ ] [ ] [ ] [ ] such source individuals may have active infections, may be in the asymptomatic and/or incubation period of an infectious disease, or may be transiently or chronically colonized with pathogenic microorganisms, particularly in the respiratory and gastrointestinal tracts. other sources of hais are the endogenous flora of patients (eg, bacteria residing in the respiratory or gastrointestinal tract). [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] i.b. . susceptible hosts. infection is the result of a complex interrelationship between a potential host and an infectious agent. most of the factors that influence infection and the occurrence and severity of disease are related to the host. however, characteristics of the host-agent interaction as it relates to pathogenicity, virulence, and antigenicity also are important, as are the infectious dose, mechanisms of disease production, and route of exposure. there is a spectrum of possible outcomes after exposure to an infectious agent. some persons exposed to pathogenic microorganisms never develop symptomatic disease, whereas others become severely ill and even die. some individuals are prone to becoming transiently or permanently colonized but remain asymptomatic. still others progress from colonization to symptomatic disease either immediately after exposure or after a period of asymptomatic colonization. the immune state at the time of exposure to an infectious agent, interaction between pathogens, and virulence factors intrinsic to the agent are important predictors of an individual's outcome. host factors such as extremes of age and underlying disease (eg, diabetes , , human immunodeficiency virus/acquired immune deficiency syndrome [hiv/ aids], , malignancy, and transplantation , , ) can increase susceptibility to infection, as can various medications that alter the normal flora (eg, antimicrobial agents, gastric acid suppressors, corticosteroids, antirejection drugs, antineoplastic agents, immunosuppressive drugs). surgical procedures and radiation therapy impair defenses of the skin and other involved organ systems. indwelling devices, such as urinary catheters, endotracheal tubes, central venous and arterial catheters, [ ] [ ] [ ] and synthetic implants, facilitate development of hais by allowing potential pathogens to bypass local defenses that ordinarily would impede their invasion and by providing surfaces for development of biofilms that may facilitate adherence of microorganisms and protect from antimicrobial activity. some infections associated with invasive procedures result from transmission within the health care facility; others arise from the patient's endogenous flora. clothing, uniforms, laboratory coats, or isolation gowns used as ppe may become contaminated with potential pathogens after care of a patient colonized or infected with an infectious agent, (eg, mrsa, vancomycin-resistant enterococci [vre], and c difficile ). although contaminated clothing has not been implicated directly in transmission, the potential exists for soiled garments to transfer infectious agents to successive patients. i.b. .b. droplet transmission. droplet transmission is technically a form of contact transmission; some infectious agents transmitted by the droplet route also may be transmitted by direct and indirect contact routes. however, in contrast to contact transmission, respiratory droplets carrying infectious pathogens transmit infection when they travel directly from the respiratory tract of the infectious individual to susceptible mucosal surfaces of the recipient, generally over short distances, necessitating facial protection. respiratory droplets are generated when an infected person coughs, sneezes, or talks , or during such procedures as suctioning, endotracheal intubation, [ ] [ ] [ ] [ ] cough induction by chest physiotherapy, and cardiopulmonary resuscitation. , evidence for droplet transmission comes from epidemiologic studies of disease outbreaks, [ ] [ ] [ ] [ ] from experimental studies, and from information on aerosol dynamics. , studies have shown that the nasal mucosa, conjunctivae, and, less frequently, the mouth are susceptible portals of entry for respiratory viruses. the maximum distance for droplet transmission is currently unresolved; pathogens transmitted by the droplet route have not been transmitted through the air over long distances, in contrast to the airborne pathogens discussed below. historically, the area of defined risk has been a distance of , feet around the patient, based on epidemiologic and simulated studies of selected infections. , using this distance for donning masks has been effective in preventing transmission of infectious agents through the droplet route. however, experimental studies with smallpox , and investigations during the global sars outbreaks of suggest that droplets from patients with these infections could reach persons located feet or more from their source. it is likely that the distance that droplets travel depends on the velocity and mechanism by which respiratory droplets are propelled from the source, the density of respiratory secretions, environmental factors (eg, temperature, humidity), and the pathogen's ability to maintain infectivity over that distance. thus, a distance of , feet around the patient is best considered an example of what is meant by ''a short distance from a patient'' and should not be used as the sole criterion for determining when a mask should be donned to protect from droplet exposure. based on these considerations, it may be prudent to don a mask when within to feet of the patient or on entry into the patient's room, especially when exposure to emerging or highly virulent pathogens is likely. more studies are needed to gain more insight into droplet transmission under various circumstances. droplet size is another variable under investigation. droplets traditionally have been defined as being . mm in size. droplet nuclei (ie, particles arising from desiccation of suspended droplets) have been associated with airborne transmission and defined as , mm in size, a reflection of the pathogenesis of pulmonary tuberculosis that is not generalizeable to other organisms. observations of particle dynamics have demonstrated that a range of droplet sizes, including those of diameter $ mm, can remain suspended in the air. the behavior of droplets and droplet nuclei affect recommendations for preventing transmission. whereas fine airborne particles containing pathogens that are able to remain infective may transmit infections over long distances, requiring aiir to prevent its dissemination within a facility; organisms transmitted by the droplet route do not remain infective over long distances and thus do not require special air handling and ventilation. examples of infectious agents transmitted through the droplet route include b pertussis, influenza virus, adenovirus, rhinovirus, mycoplasma pneumoniae, sars-cov, , , group a streptococcus, and neisseria meningitides. , , although rsv may be transmitted by the droplet route, direct contact with infected respiratory secretions is the most important determinant of transmission and consistent adherence to standard precautions plus contact precautions prevents transmission in health care settings. , , rarely, pathogens that are not transmitted routinely by the droplet route are dispersed into the air over short distances. for example, although s aureus is transmitted most frequently by the contact route, viral upper respiratory tract infection has been associated with increased dispersal of s aureus from the nose into the air for a distance of feet under both outbreak and experimental conditions; this is known as the ''cloud baby'' and ''cloud adult'' phenomenon. [ ] [ ] [ ] i.b. .c. airborne transmission. airborne transmission occurs by dissemination of either airborne droplet nuclei or small particles in the respirable size range containing infectious agents that remain infective over time and distance (eg, spores of aspergillus spp and m tuberculosis). microorganisms carried in this manner may be dispersed over long distances by air currents and may be inhaled by susceptible individuals who have not had face-to-face contact with (or even been in the same room with) the infectious individual. [ ] [ ] [ ] [ ] preventing the spread of pathogens that are transmitted by the airborne route requires the use of special air handling and ventilation systems (eg, aiirs) to contain and then safely remove the infectious agent. , infectious agents to which this applies include m tuberculosis, - rubeola virus (measles), and varicella-zoster virus (chickenpox). in addition, published data suggest the possibility that variola virus (smallpox) may be transmitted over long distances through the air under unusual circumstances, and aiirs are recommended for this agent as well; however, droplet and contact routes are the more frequent routes of transmission for smallpox. , , in addition to aiirs, respiratory protection with a national institute for occupational safety and health (niosh)-certified n or higher-level respirator is recommended for hcws entering the aiir, to prevent acquisition of airborne infectious agents such as m tuberculosis. for certain other respiratory infectious agents, such as influenza , and rhinovirus, and even some gastrointestinal viruses (eg, norovirus and rotavirus ) , there is some evidence that the pathogen may be transmitted through small-particle aerosols under natural and experimental conditions. such transmission has occurred over distances . feet but within a defined air space (eg, patient room), suggesting that it is unlikely that these agents remain viable on air currents that travel long distances. aiirs are not routinely required to prevent transmission of these agents. additional issues concerning small-particle aerosol transmission of agents that are most frequently transmitted by the droplet route are discussed below. although sars-cov is transmitted primarily by contact and/or droplet routes, airborne transmission over a limited distance (eg, within a room) has been suggested, although not proven. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] this is true of other infectious agents as well, such as influenza virus and noroviruses. , , influenza viruses are transmitted primarily by close contact with respiratory droplets, , and acquisition by hcws has been prevented by droplet precautions, even when positive-pressure rooms were used in one center. however, inhalational transmission could not be excluded in an outbreak of influenza in the passengers and crew of an aircraft. observations of a protective effect of ultraviolet light in preventing influenza among patients with tuberculosis during the influenza pandemic of - have been used to suggest airborne transmission. , in contrast to the strict interpretation of an airborne route for transmission (ie, long distances beyond the patient room environment), short-distance transmission by small-particle aerosols generated under specific circumstances (eg, during endotracheal intubation) to persons in the immediate area near the patient also has been demonstrated. aerosolized particles , mm in diameter can remain suspended in air when room air current velocities exceed the terminal settling velocities of the particles. sars-cov transmission has been associated with endotracheal intubation, noninvasive positive pressure ventilation, and cardiopulmonary resuscitation. , , , , although the most frequent routes of transmission of noroviruses are contact and foodborne and waterborne routes, several reports suggest that noroviruses also may be transmitted through aerosolization of infectious particles from vomitus or fecal material. , , , it is hypothesized that the aerosolized particles are inhaled and subsequently swallowed. roy this conceptual framework can explain rare occurrences of airborne transmission of agents that are transmitted most frequently by other routes (eg, smallpox, sars, influenza, noroviruses). concerns about unknown or possible routes of transmission of agents associated with severe disease and no known treatment often result in the adoption of overextreme prevention strategies, and recommended precautions may change as the epidemiology of an emerging infection becomes more well defined and controversial issues are resolved. i.b. .d.ii. transmission from the environment. some airborne infectious agents are derived from the environment and do not usually involve person-to-person transmission; for example, anthrax spores present in a finely milled powdered preparation can be aerosolized from contaminated environmental surfaces and inhaled into the respiratory tract. , spores of environmental fungi (eg, aspergillus spp) are ubiquitous in the environment and may cause disease in immunocompromised patients who inhale aerosolized spores (through, eg, construction dust). , as a rule, neither of these organisms is subsequently transmitted from infected patients; however, there is well-documented report of person-to-person transmission of aspergillus sp in the icu setting that was most likely due to the aerosolization of spores during wound debridement. the pe involves isolation practices designed to decrease the risk of exposure to environmental fungal agents in allogeneic hsct patients. , , , [ ] [ ] [ ] [ ] environmental sources of respiratory pathogens (eg, legionella) transmitted to humans through a common aerosol source is distinct from direct patient-to-patient transmission. i.b. .e. other sources of infection. sources of infection transmission other than infectious individuals include those associated with common environmental sources or vehicles (eg, contaminated food, water, or medications, such as intravenous fluids). although aspergillus spp have been recovered from hospital water systems, the role of water as a reservoir for immunosuppressed patients remains unclear. vectorborne transmission of infectious agents from mosquitoes, flies, rats, and other vermin also can occur in health care settings. prevention of vectorborne transmission is not addressed in this document. this section discusses several infectious agents with important infection control implications that either were not discussed extensively in previous isolation s vol. no. supplement guidelines or have emerged only recently. included are epidemiologically important organisms (eg, c difficile), agents of bioterrorism, prions, sars-cov, monkeypox, noroviruses, and the hemorrhagic fever viruses (hfvs). experience with these agents has broadened the understanding of modes of transmission and effective preventive measures. these agents are included for information purposes and, for some (ie, sars-cov, monkeypox), to highlight the lessons that have been learned about preparedness planning and responding effectively to new infectious agents. i.c. . epidemiologically important organisms. under defined conditions, any infectious agent transmitted in a health care setting may become targeted for control because it is epidemiologically important. c difficile is specifically discussed below because of its current prevalence and seriousness in us health care facilities. in determining what constitutes an ''epidemiologically important organism,'' the following criteria apply: d a propensity for transmission within health care facilities based on published reports and the occurrence of temporal or geographic clusters of more than patients, (eg, c difficile, norovirus, rsv, influenza, rotavirus, enterobacter spp, serratia spp, group a streptococcus). a single case of health care-associated invasive disease caused by certain pathogens (eg, group a streptococcus postoperatively, in a burn unit, or in a ltcf; legionella spp, , aspergillus spp ) is generally considered a trigger for investigation and enhanced control measures because of the risk of additional cases and the severity of illness associated with these infections. i.c. .a. clostridium difficile. c difficile is a sporeforming gram-positive anaerobic bacillus that was first isolated from stools of neonates in and identified as the most frequent causative agent of antibioticassociated diarrhea and pseudomembranous colitis in . this pathogen is a major cause of health care-associated diarrhea and has been responsible for many large outbreaks in health care settings that have proven extremely difficult to control. important factors contributing to health care-associated outbreaks include environmental contamination, persistence of spores for prolonged periods, resistance of spores to routinely used disinfectants and antiseptics, hand carriage by hcws to other patients, and exposure of patients to frequent courses of antimicrobial agents. antimicrobials most frequently associated with increased risk of c difficile include third-generation cephalosporins, clindamycin, vancomycin, and fluoroquinolones. since , outbreaks and sporadic cases of c difficile with increased morbidity and mortality have occurred in several us states, canada, england, and the netherlands. [ ] [ ] [ ] [ ] [ ] the same strain of c difficile has been implicated in all of these outbreaks; this strain, toxinotype iii, north american pulsedfield gel electrophoresis (pfge) type , and polymerase chain reaction (pcr)-ribotype (nap / ), has been found to hyperproduce toxin a (a -fold increase) and toxin b (a -fold increase) compared with isolates from other pfge types. a recent survey of us infectious disease physicians found that % of the respondents perceived recent increases in the incidence and severity of c difficile disease. standardization of testing methodology and surveillance definitions is needed for accurate comparisons of trends in rates among hospitals. it is hypothesized that the incidence of disease and apparent heightened transmissibility of this new strain may be due, at least in part, to the greater production of toxins a and b, increasing the severity of diarrhea and producing more environmental contamination. considering the greater morbidity, mortality, length of stay, and costs associated with c difficile disease in both acute care and long-term care facilities, control of this pathogen is becoming increasingly important. prevention of transmission focuses on syndromic application of contact precautions for patients with diarrhea, accurate identification of affected patients, environmental measures (eg, rigorous cleaning of patient rooms), and consistent hand hygiene. using soap and water rather than alcohol-based handrubs for mechanical removal of spores from hands and using a bleachcontaining disinfectant ( ppm) for environmental disinfection may be valuable in cases of transmission in health care facilities. appendix a provides for recommendations. i.c. .b. multidrug-resistant organisms. in general, mdros are defined as microorganisms-predominantly bacteria-that are resistant to or more classes of antimicrobial agents. although the names of certain mdros suggest resistance to only a single agent (eg, mrsa, vre), these pathogens are usually resistant to all but a few commercially available antimicrobial agents. this latter feature defines mdros that are considered to be epidemiologically important and deserve special attention in health care facilities. other mdros of current concern include multidrug-resistant streptococcus pneumoniae, which is resistant to penicillin and other broad-spectrum agents such as macrolides and fluroquinolones, multidrug-resistant gram-negative bacilli (mdr-gnb), especially those producing esbls; and strains of s aureus that are intermediate or resistant to vancomycin (ie, visa and vrsa). mdros are transmitted by the same routes as antimicrobial susceptible infectious agents. patient-to-patient transmission in health care settings, usually via hands of hcws, has been a major factor accounting for the increase in mdro incidence and prevalence, especially for mrsa and vre in acute care facilities. [ ] [ ] [ ] preventing the emergence and transmission of these pathogens requires a comprehensive approach that includes administrative involvement and measures (eg, nurse staffing, communication systems, performance improvement processes to ensure adherence to recommended infection control measures), education and training of medical and other hcws, judicious antibiotic use, comprehensive surveillance for targeted mdros, application of infection control precautions during patient care, environmental measures (eg, cleaning and disinfection of the patient care environment and equipment, dedicated single-patient use of noncritical equipment), and decolonization therapy when appropriate. the prevention and control of mdros is a national priority, one that requires that all health care facilities and agencies assume responsibility and participate in community-wide control programs. , a detailed discussion of this topic and recommendations for prevention published in is available at http:// www.cdc.gov/ncidod/dhqp/pdf/ar/mdroguideline . pdf. i.c. . agents of bioterrorism. the cdc has designated the agents that cause anthrax, smallpox, plague, tularemia, viral hemorrhagic fevers, and botulism as category a (high priority), because these agents can be easily disseminated environmentally and/or transmitted from person to person, can cause high mortality and have the potential for major public health impact, might cause public panic and social disruption, and necessitate special action for public health preparedness. general information relevant to infection control in health care settings for category a agents of bioterrorism is summarized in table . (see http:// www.bt.cdc.gov for additional, updated category a agent information as well as information concerning category b and c agents of bioterrorism and updates.) category b and c agents are important but are not as readily disseminated and cause less morbidity and mortality than category a agents. health care facilities confront a different set of issues when dealing with a suspected bioterrorism event compared with other communicable diseases. an understanding of the epidemiology, modes of transmission, and clinical course of each disease, as well as carefully drafted plans that specify an approach and relevant websites and other resources for disease-specific guidance to health care, administrative, and support personnel, are essential for responding to and managing a bioterrorism event. infection control issues to be addressed include ( ) identifying persons who may be exposed or infected; ( ) preventing transmission among patients, hcws, and visitors; ( ) providing treatment, chemoprophylaxis, or vaccine to potentially large numbers of people; ( ) protecting the environment, including the logistical aspects of securing sufficient numbers of aiirs or designating areas for patient cohorts when an insufficient number of aiirs is available; ( ) providing adequate quantities of appropriate ppe; and ( ) identifying appropriate staff to care for potentially infectious patients (eg, vaccinated hcws for care of patients with smallpox). the response is likely to differ for exposures resulting from an intentional release compared with a naturally occurring disease because of the large number of persons that can be exposed at the same time and possible differences in pathogenicity. various sources offer guidance for the management of persons exposed to the most likely agents of bioterrorism. federal agency websites (eg, http://www. usamriid.army.mil/publications/index.html and http:// www.bt.cdc.gov) and state and county health department websites should be consulted for the most upto-date information. sources of information on specific agents include anthrax, smallpox, [ ] [ ] [ ] plague, , botulinum toxin, tularemia, and hemorrhagic fever viruses. , i.c. .a. pre-event administration of smallpox (vaccinia) vaccine to health care workers. vaccination of hcwsl in preparation for a possible smallpox exposure has important infection control implications. [ ] [ ] [ ] these include the need for meticulous screening for vaccine contraindications in persons at increased risk for adverse vaccinia events; containment and monitoring of the vaccination site to prevent transmission in the health care setting and at home; and management of patients with vaccinia-related adverse events. , the pre-event us smallpox vaccination program of is an example of the effectiveness of carefully developed recommendations for both screening potential vaccinees for contraindications and vaccination site care and monitoring. between december and february , approximately , individuals were vaccinated in the department of defense and , in the civilian or public health populations, including approximately , who worked in health care settings. no cases of eczema vaccinatum, progressive vaccinia, fetal vaccinia, or contact transfer of vaccinia were reported in health care settings or in military workplaces. , outside the health care setting, there were cases of contact transfer from military vaccinees to close personal contacts (eg, bed partners or contacts during participation in sports such as wrestling ). all contact transfers were from individuals who were not following recommendations to cover their vaccination sites. vaccinia virus was confirmed by culture or pcr in cases, of which resulted from tertiary transfer. all recipients, including breast-fed infant, recovered without complications. subsequent studies using viral culture and pcr techniques have confirmed the effectiveness of semipermeable dressings to contain vaccinia. [ ] [ ] [ ] [ ] this experience emphasizes the importance of ensuring that newly vaccinated hcws adhere to recommended vaccination site care, especially those caring for high-risk patients. recommendations for pre-event smallpox vaccination of hcws and vacciniarelated infection control recommendations are published in the morbidity and mortality weekly report, , with updates posted on the cdc's bioterrorism website. i.c. . prions. creutzfeldt-jakob disease (cjd) is a rapidly progressive, degenerative neurologic disorder of humans, with an incidence in the united states of approximately person/million population/year. , cjd is believed to be caused by a transmissible proteinaceous infectious agent known as a prion. infectious prions are isoforms of a host-encoded glycoprotein known as the prion protein. the incubation period (ie, time between exposure and and onset of symptoms) varies from years to many decades. however, death typically occurs within year of the onset of symptoms. approximately % of cjd cases occur sporadically with no known environmental source of infection, and % of cases are familial. iatrogenic transmission has occurred, with most cases resulting from treatment with human cadaver pituitary-derived growth hormone or gonadotropin, , from implantation of contaminated human dura mater grafts, or from corneal transplants. transmission has been linked to the use of contaminated neurosurgical instruments or stereotactic electroencephalogram electrodes. [ ] [ ] [ ] [ ] prion diseases in animals include scrapie in sheep and goats, bovine spongiform encephalopathy (bse, or ''mad cow disease'') in cattle, and chronic wasting disease in deer and elk. bse, first recognized in the united kingdom in , was associated with a major epidemic among cattle that had consumed contaminated meat and bone meal. the possible transmission of bse to humans causing variant cjd (vcjd) was first described in and was subsequently found to be associated with consumption of bse-contaminated cattle products primarily in the united kingdom. there is strong epidemiologic and laboratory evidence for a causal association between the causative agent of bse and vcjd. although most cases of vcjd have been reported from the united kingdom, a few cases also have been reported from europe, japan, canada, and the united states. most persons affected with vcjd worldwide lived in or visited the united kingdom during the years of a large outbreak of bse ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) and may have consumed contaminated cattle products during that time (see http://www.cdc.gov/ncidod/ diseases/cjd/cjd.htm). although there has been no indigenously acquired vcjd in the united states, the sporadic occurrence of bse in cattle in north america has heightened awareness of the possibility that such infections could occur and have led to increased surveillance activities. updated information may be found at http://www.cdc.gov/ncidod/diseases/cjd/cjd.htm. the public health impact of prion diseases has been reviewed previously. vcjd in humans has different clinical and pathologic characteristics than sporadic or classic cjd, including ( ) younger median age at death ( [range, to ] vs years), ( ) longer median duration of illness ( months vs to months), ( ) increased frequency of sensory symptoms and early psychiatric symptoms with delayed onset of frank neurologic signs; and ( ) detection of prions in tonsillar and other lymphoid tissues, not present in sporadic cjd. similar to sporadic cjd, there have been no reported cases of direct human-tohuman transmission of vcjd by casual or environmental contact, droplet, or airborne routes. ongoing blood safety surveillance in the united states has not detected sporadic cjd transmission through blood transfusion; - however, bloodborne transmission of vcjd is believed to have occurred in patients in the uited kingdom. , the following fda websites provide information on steps currently being taken in the united states to protect the blood supply from cjd and vcjd: http://www.fda.gov/cber/gdlns/cjdvcjd.htm and http:// www.fda.gov/cber/gdlns/cjdvcjdq&a.htm. standard precautions are used when caring for patients with suspected or confirmed cjd or vcjd. however, special precautions are recommended for tissue handling in the histology laboratory and for conducting an autopsy, embalming, and coming into contact with a body that has undergone autopsy. recommendations for reprocessing surgical instruments to prevent transmission of cjd in health care settings have been published by the world health organization (who) and are currently under review at the cdc. questions may arise concerning notification of patients potentially exposed to cjd or vcjd through contaminated instruments and blood products from patients with cjd or vcjd or at risk of having vcjd. the risk of transmission associated with such exposures is believed to be extremely low but may vary based on the specific circumstance. therefore, consultation on appropriate options is advised. the united kingdom has developed several documents that clinicians and patients in the united states may find useful (see http://www.hpa.org.uk/infections/topics_az/cjd/ information_documents.htm). i.c. . severe acute respiratory syndrome. sars is a newly discovered respiratory disease that emerged in china late in and spread to several countries. , in particular, mainland china, hong kong, hanoi, singapore, and toronto have been significantly affected. sars is caused by sars-cov, a previously unrecognized member of the coronavirus family. , the incubation period from exposure to the onset of symptoms is typically to days, but can be as long as days and in rare cases even longer. the illness is initially difficult to distinguish from other common respiratory infections. signs and symptoms usually include fever above . c and chills and rigors, sometimes accompanied by headache, myalgia, and mild to severe respiratory symptoms. a radiographic profile of atypical pneumonia is an important clinical indicator of possible sars. compared with adults, children are affected less frequently, have milder disease, and are less likely to transmit sars-cov. , [ ] [ ] [ ] the overall case fatality rate is approximately %; underlying disease and advanced age increase the risk of mortality (see http://www.who.int/csr/sarsarchive/ _ _ a/en/). outbreaks in health care settings, with transmission to large numbers of hcws and patients, haa been a striking feature of sars; undiagnosed infectious patients and visitors have been important initiators of these outbreaks. , [ ] [ ] [ ] the relative contribution of potential modes of transmission is not known precisely. there is ample evidence for droplet and contact transmission; , , however, opportunistic airborne transmission cannot be excluded. , [ ] [ ] [ ] [ ] [ ] , for example, exposure to aerosol-generating procedures (eg, endotracheal intubation, suctioning) has been associated with transmission of infection to large numbers of hcws outside of the united states. , , , , therefore, aerosolization of small infectious particles generated during these and other similar procedures could be a risk factor for transmission to others within a multibed room or shared airspace. a review of the infection control literature generated from the sars outbreaks of concluded that the greatest risk of transmission is to those who have close contact, are not properly trained in use of protective infection control procedures, and do not consistently use ppe, and that n or higher-level respirators may offer additional protection to those exposed to aerosol-generating procedures and high-risk activities. , organizational and individual factors that affect adherence to infection control practices for sars also were identified. control of sars requires a coordinated, dynamic response by multiple disciplines in a health care setting. early detection of cases is accomplished by screening persons with symptoms of a respiratory infection for history of travel to areas experiencing community transmission or contact with sars patients, followed by implementation of respiratory hygiene/cough etiquette (ie, placing a mask over the patient's nose and mouth) and physical separation from other patients in common waiting areas. the precise combination of precautions to protect hcws has not yet been determined. at the time of this publication, the cdc recommends standard precautions, with emphasis on the use of hand hygiene; contact precautions, with emphasis on environmental cleaning due to the detection of sars-cov rna by pcr on surfaces in rooms occupied by sars patients; , , and airborne precautions, including use of fit-tested niosh-approved n or higher-level respirators and eye protection. in hong kong, the use of droplet and contact precautions, including the use of a mask but not a respirator, was effective in protecting hcws. however, in toronto, consistent use of an n respirator was found to be slightly more protective than a mask. it is noteworthy that no transmission of sars-cov to public hospital workers occurred in vietnam despite inconsistent use of infection control measures, including use of ppe, which suggests other factors (eg, severity of disease, frequency of high-risk procedures or events, environmental features) may influence opportunities for transmission. sars-cov also has been transmitted in the laboratory setting through breaches in recommended laboratory practices. research laboratories in which sars-cov was under investigation were the source of most cases reported after the first series of outbreaks in the winter and spring of . lessons learned from the sars outbreaks are useful in devising plans to respond to future public health crises, such as pandemic influenza and bioterrorism events. surveillance for cases among patients and hcws, ensuring availability of adequate supplies and staffing, and limiting access to health care facilities were important factors in the response to sars. guidance for infection control precautions in various settings is available at http://www.cdc.gov/ncidod/sars. i.c. . monkeypox. monkeypox is a rare viral disease found mostly in the rain forest countries of central and west africa. the disease is caused by an orthopoxvirus that is similar in appearance to smallpox but causes a milder disease. the only recognized outbreak of human monkeypox in the united states was detected in june , after several people became ill after contact with sick pet prairie dogs. infection in the prairie dogs was subsequently traced to their contact with a shipment of animals from africa, including giant gambian rats. this outbreak demonstrates the importance of recognition and prompt reporting of unusual disease presentations by clinicians to enable prompt identification of the etiology, as well as the potential of epizootic diseases to spread from animal reservoirs to humans through personal and occupational exposure. only limited data on transmission of monkeypox are available. transmission from infected animals and humans is believed to occur primarily through direct contact with lesions and respiratory secretions; airborne transmission from animals to humans is unlikely but cannot be excluded, and may have occurred in veterinary practices (eg, during administration of nebulized medications to ill prairie dogs ). in humans, instances of monkeypox transmission in hospitals have been reported in africa among children, usually related to sharing the same ward or bed. , additional recent literature documents transmission of congo basin monkeypox in a hospital compound for an extended number of generations. there has been no evidence of airborne or any other person-to-person transmission of monkeypox in the united states, and no new cases of monkeypox have been identified since the outbreak in june . the outbreak strain is a clade of monkeypox distinct from the congo basin clade and may have different epidemiologic properties (including human-to-human transmission potential) from monkeypox strains of the congo basin; this awaits further study. smallpox vaccine is % protective against congo basin monkeypox. because there is an associated case fatality rate of , %, administration of smallpox vaccine within days to individuals who have had direct exposure to patients or animals with monkeypox is a reasonable policy. for the most current information on monkeypox, see http://www.cdc.gov/ncidod/mon keypox/clinicians.htm. i.c. . noroviruses. noroviruses, formerly referred to as norwalk-like viruses, are members of the caliciviridae family. these agents are transmitted via contaminated food or water and from person to person, causing explosive outbreaks of gastrointestinal disease. environmental contamination also has been documented as a contributing factor in ongoing transmission during outbreaks. , although noroviruses cannot be propagated in cell culture, dna detection by molecular diagnostic techniques has brought a greater appreciation of their role in outbreaks of gastrointestinal disease. reported outbreaks in hospitals, and large crowded shelters established for hurricane evacuees has demonstrated their highly contagious nature, their potentially disruptive impact in health care facilities and the community, and the difficulty of controlling outbreaks in settings in which people share common facilites and space. of note, there is nearly a -fold increase in the risk to patients in outbreaks when a patient is the index case compared with exposure of patients during outbreaks when a staff member is the index case. the average incubation period for gastroenteritis caused by noroviruses is to hours, and the clinical course lasts to hours. illness is characterized by acute onset of nausea, vomiting, abdominal cramps, and/or diarrhea. the disease is largely self-limited; rarely, death due to severe dehydration can occur, particularly in elderly persons with debilitating health conditions. the epidemiology of norovirus outbreaks shows that even though primary cases may result from exposure to a fecally contaminated food or water, secondary and tertiary cases often result from person-to-person transmission facilitated by contamination of fomites , and dissemination of infectious particles, especially during the process of vomiting. , , , , , , , widespread, persistent, and inapparent contamination of the environment and fomites can make outbreaks extremely difficult to control. , , these clinical observations and the detection of norovirus dna on horizontal surfaces feet above the level that might be touched normally suggest that under certain circumstances, aerosolized particles may travel distances beyond feet. it is hypothesized that infectious particles may be aerosolized from vomitus, inhaled, and swallowed. in addition, individuals who are responsible for cleaning the environment may be at increased risk of infection. development of disease and transmission may be facilitated by the low infectious dose (ie, , viral particles) and the resistance of these viruses to the usual cleaning and disinfection agents (ie, they may survive , ppm chlorine). [ ] [ ] [ ] an alternate phenolic agent that was shown to be effective against feline calicivirus was used for environmental cleaning in one outbreak. , there are insufficient data to determine the efficacy of alcohol-based hand rubs against noroviruses when the hands are not visibly soiled. absence of disease in certain individuals during an outbreak may be explained by protection from infection conferred by the b histo-blood group antigen. consultation on outbreaks of gastroenteritis is available through the cdc's division of viral and rickettsial diseases. i.c. . hemorrhagic fever viruses. hfv is a mixed group of viruses that cause serious disease with high fever, skin rash, bleeding diathesis, and, in some cases, high mortality; the resulting disease is referred to as viral hemorrhagic fever (vhf). among the more commonly known hfvs are ebola and marburg viruses (filoviridae), lassa virus (arenaviridae), crimean-congo hemorrhagic fever and rift valley fever virus (bunyaviridae), and dengue and yellow fever viruses (flaviviridae). , these viruses are transmitted to humans through contact with infected animals or via arthropod vectors. although none of these viruses is endemic in the united states, outbreaks in affected countries provide potential opportunities for importation by infected humans and animals. furthermore, there is a concern that some of these agents could be used as bioweapons. person-to-person transmission has been documented for ebola, marburg, lassa, and crimean-congo hfvs. in resource-limited health care settings, transmission of these agents to hcws, patients, and visitors has been described and in some outbreaks has accounted for a large proportion of cases. [ ] [ ] [ ] transmission within households also has been documented in individuals who had direct contact with ill persons or their body fluids, but not in those who did not have such contact. evidence concerning the transmission of hfvs has been summarized previously. , person-to-person transmission is associated primarily with direct blood and body fluid contact. percutaneous exposure to contaminated blood carries a particularly high risk for transmission and increased mortality. , the finding of large numbers of ebola viral particles in the skin and the lumina of sweat glands has raised concerns that transmission could occur from direct contact with intact skin, although epidemiologic evidence to support this is lacking. postmortem handling of infected bodies is an important risk for transmission. , , in rare situations, cases in which the mode of transmission was unexplained among individuals with no known direct contact have led to speculation that airborne transmission could have occurred. however, airborne transmission of naturally occurring hfvs in humans has not been documented. a study of airplane passengers exposed to an in-flight index case of lassa fever found no transmission to any passengers. in the laboratory setting, animals have been infected experimentally with marburg or ebola virus through direct inoculation of the nose, mouth, and/or conjunctiva , and by using mechanically generated viruscontaining aerosols. , transmission of ebola virus among laboratory primates in an animal facility has been described. the secondarily infected animals were in individual cages separated by approximately meters. although the possibility of airborne transmission was suggested, the investigators were not able to exclude droplet or indirect contact transmission in this incidental observation. guidance on infection control precautions for hvfs transmitted person-to-person have been published by the cdc , and by the johns hopkins center for civilian biodefense strategies. the most recent recommendations at the time of publication of this document were posted on the cdc website on may , . inconsistencies among the various recommendations have raised questions about the appropriate precautions to use in us hospitals. in less developed countries, outbreaks of hfvs have been controlled with basic hygiene, barrier precautions, safe injection practices, and safe burial practices. , the preponderance of evidence on hfv transmission indicates that standard, contact, and droplet precautions with eye protection are effective in protecting hcws and visitors coming in contact with an infected patient. single gloves are adequate for routine patient care; doublegloving is advised during invasive procedures (eg, surgery) that pose an increased risk of blood exposure. routine eye protection (ie goggles or face shield) is particularly important. fluid-resistant gowns should be worn for all patient contact. airborne precautions are not required for routine patient care; however, use of aiirs is prudent when procedures that could generate infectious aerosols are performed (eg, endotracheal intubation, bronchoscopy, suctioning, autopsy procedures involving oscillating saws). n or higher-level respirators may provide added protection for individuals in a room during aerosol-generating procedures ( table , appendix a). when a patient with a syndrome consistent with hemorrhagic fever also has a history of travel to an endemic area, precautions are initiated on presentation and then modified as more information is obtained ( table ) . patients with hemorrhagic fever syndrome in the setting of a suspected bioweapons attack should be managed using airborne precautions, including aiirs, because the epidemiology of a potentially weaponized hemorrhagic fever virus is unpredictable. numerous factors influence differences in transmission risks among the various health care settings. these factors include the population characteristics (eg, increased susceptibility to infections, type and prevalence of indwelling devices), intensity of care, exposure to environmental sources, length of stay, and frequency of interaction between patients/residents with each other and with hcws. these factors, as well as organizational priorities, goals, and resources, influence how different health care settings adapt transmission prevention guidelines to meet their specific needs. , infection control management decisions are informed by data regarding institutional experience/epidemiology; trends in community and institutional hais; local, regional, and national epidemiology; and emerging infectious disease threats. i.d. . hospitals. infection transmission risks are present in all hospital settings. however, certain hospital settings and patient populations have unique conditions that predispose patients to infection and merit special mention. these are often sentinel sites for the emergence of new transmission risks that may be unique to that setting or present opportunities for transmission to other settings in the hospital. i.d. .a. intensive care units. intensive care units (icus) serve patients who are immunocompromised by disease state and/or by treatment modalities, as well as patients with major trauma, respiratory failure, and other life-threatening conditions (eg, myocardial infarction, congestive heart failure, overdose, stroke, gastrointestinal bleeding, renal failure, hepatic failure, multiorgan system failure, and extremes of age). although icus account for a relatively small proportion of hospitalized patients, infections acquired in these units account for . % of all hais. in the national nosocomial infection surveillance (nnis) system, . % of hais were reported from icu and high-risk nursery (neonatal icu [nicu]) patients in (nnis, unpublished data). this patient population has increased susceptibility to colonization and infection, especially with mdros and candida spp, , because of underlying diseases and conditions, the invasive medical devices and technology used in their care (eg central venous catheters and other intravascular devices, mechanical ventilators, extracorporeal membrane oxygenation, hemodialysis/filtration, pacemakers, implantable left-ventricular assist devices), the frequency of contact with hcws, prolonged lengths of stay, and prolonged exposure to antimicrobial agents. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] furthermore, adverse patient outcomes in this setting are more severe and are associated with a higher mortality. outbreaks associated with various bacterial, fungal, and viral pathogens due to common-source and person-to-person transmissions are frequent in adult icus and pediatric icus (picus). , [ ] [ ] [ ] [ ] [ ] [ ] i.d. .b. burn units. burn wounds can provide optimal conditions for colonization, infection, and transmission of pathogens; infection acquired by burn patients is a frequent cause of morbidity and mortality. , , the risk of invasive burn wound infection is particularly high in patients with a burn injury involving . % of the total body surface area (tbsa). , infections occurring in patients with burn injuries involving , % of the tbsa are usually associated with the use of invasive devices. mssa, mrsa, enterococci (including vre), gram-negative bacteria, and candida spp are prevalent pathogens in burn infections, , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and outbreaks of these organisms have been reported. [ ] [ ] [ ] [ ] shifts over time in the predominance of pathogens causing infections in burn patients often lead to changes in burn care practices. , [ ] [ ] [ ] [ ] burn wound infections caused by aspergillus spp or other environmental molds may result from exposure to supplies contaminated during construction or to dust generated during construction or other environmental disruption. hydrotherapy equipment is an important environmental reservoir of gram-negative organisms. its use in burn care is discouraged based on demonstrated associations between the use of contaminated hydrotherapy equipment and infections. burn wound infections and colonization, as well as bloodstream infections, caused by multidrug-resistant p aeruginosa, acinetobacter baumannii, and mrsa have been associated with hydrotherapy; thus, excision of burn wounds in operating rooms is the preferred approach. advances in burn care (specifically, early excision and grafting of the burn wound, use of topical antimicrobial agents, and institution of early enteral feeding) have led to decreased infectious complications. other advances have included prophylactic antimicrobial use, selective digestive decontamination, and use of antimicrobial-coated catheters; however, few epidemiologic studies and no efficacy studies have been performed to investigate the relative benefit of these measures. there is no consensus on the most effective infection control practices to prevent transmission of infections to and from patients with serious burns (eg, single-bed rooms, laminar flow, and high-efficiency particulate air [hepa] filtration, or maintaining burn patients in a separate unit with no exposure to patients or equipment from other units ). there also is controversy regarding the need for and type of barrier precautions in the routine care of burn patients. one retrospective study demonstrated the efficacy and cost-effectiveness of a simplified barrier isolation protocol for wound colonization, emphasizing handwashing and use of gloves, caps, masks, and impermeable plastic aprons (rather than isolation gowns) for direct patient contact. however, to date no studies have determined the most effective combination of infection control precautions for use in burn settings. prospective studies in this area are needed. i.d. .c. pediatrics. studies of the epidemiology of hais in children have identified unique infection control issues in this population. , , [ ] [ ] [ ] [ ] [ ] pediatric icu patients and the lowest birth weight babies in the nicu monitored in the nnis system have had high rates of central venous catheter-associated bloodstream infections. , ) . close physical contact between hcws and infants and young children (eg. cuddling, feeding, playing, changing soiled diapers, and cleaning copious uncontrolled respiratory secretions) provides abundant opportunities for transmission of infectious material. such practices and behaviors as congregation of children in play areas where toys and bodily secretions are easily shared and rooming-in of family members with pediatric patients can further increase the risk of transmission. pathogenic bacteria have been recovered from toys used by hospitalized patients; contaminated bath toys were implicated in an outbreak of multidrug-resistant p. aeruginosa on a pediatric oncology unit. in addition, several patient factors increase the likelihood that infection will result from exposure to pathogens in health care settings (eg, immaturity of the neonatal immune system, lack of previous natural infection and resulting immunity, prevalence of patients with congenital or acquired immune deficiencies, congenital anatomic anomalies, and use of life-saving invasive devices in nicus and picus). there are theoretical concerns that infection risk will increase in association with innovative practices used in the nicu for the purpose of improving developmental outcomes, such factors include cobedding and kangaroo care, which may increase opportunity for skin-to-skin exposure of multiple gestation infants to each other and to their mothers, respectively; although the risk of infection actually may be reduced among infants receiving kangaroo care. children who attend child care centers , and pediatric rehabilitation units may increase the overall burden of antimicrobial resistance by contributing to the reservoir of ca-mrsa. [ ] [ ] [ ] [ ] [ ] [ ] patients in chronic care facilities may have increased rates of colonization with resistant garm-negative bacilli and may be sources of introduction of resistant organisms to acute care settings. i.d. . nonacute health care settings. health care is provided in various settings outside of hospitals, including long-term care facilities (ltcfs) (eg nursing homes), homes for the developmentally disabled, behavioral health service settings, rehabilitation centers, and hospices. in addition, health care may be provided in non-health care settings, such as workplaces with occupational health clinics, adult day care centers, assisted-living facilities, homeless shelters, jails and prisons, school clinics, and infirmaries. each of these settings has unique circumstances and population risks that must be considered when designing and implementing an infection control program. several of the most common settings and their particular challenges are discussed below. although this guideline does not address each setting, the principles and strategies provided herein may be adapted and applied as appropriate. i.d. .a. long-term care. the designation ltcf applies to a diverse group of residential settings, ranging from institutions for the developmentally disabled to nursing homes for the elderly and pediatric chronic care facilities. [ ] [ ] [ ] nursing homes for the elderly predominate numerically and frequently represent longterm care as a group of facilities. approximately . million americans reside in the nation's , nursing homes. estimates of hai rates of . to . per resident-care days have been reported, with a range of to per resident-care days in the more rigorous studies. [ ] [ ] [ ] [ ] [ ] the infrastructure described in the department of veterans affairs' nursing home care units is a promising example for the development of a nationwide hai surveillance system for ltcfs. lctfs are different from other health care settings in that elderly patients at increased risk for infection are brought together in one setting and remain in the facility for extended periods; for most residents, it is their home. an atmosphere of community is fostered, and residents share common eating and living areas and participate in various facility-sponsored activities. , because able residents interact freely with each other, controlling infection transmission in this setting can be challenging. a residents who is colonized or infected with certain microorganisms are in some cases restricted to his or her room. however, because of the psychosocial risks associated with such restriction, balancing psychosocial needs with infection control needs is important in the ltcf setting. , , , ) and bacteria, including group a streptococcus, , b pertussis, nonsusceptible s pneumoniae, , other mdros, and c difficile ). these pathogens can lead to substantial morbidity and mortality, as well as increased medical costs; prompt detection and implementation of effective control measures are needed. risk factors for infection are prevalent among ltcf residents. , , age-related declines in immunity may affect the response to immunizations for influenza and other infectious agents and increase the susceptibility to tuberculosis. immobility, incontinence, dysphagia, underlying chronic diseases, poor functional status, and age-related skin changes increase susceptibility to urinary, respiratory, and cutaneous and soft tissue infections, whereas malnutrition can impair wound healing. [ ] [ ] [ ] [ ] [ ] medications (eg, drugs that affect level of consciousness, immune function, gastric acid secretions, and normal flora, including antimicrobial therapy) and invasive devices (eg, urinary catheters and feeding tubes) heighten the susceptibility to infection and colonization in ltcf residents. [ ] [ ] [ ] finally, limited functional status and total dependence on hcws for activities of daily living have been identified as independent risk factors for infection , , and for colonization with mrsa , and esbl-producing klebsiella pneumoniae. several position papers and review articles provide guidance on various aspects of infection control and antimicrobial resistance in ltcfs. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the centers for medicare and medicaid services has established regulations for the prevention of infection in ltcfs. because residents of ltcfs are hospitalized frequently, they can transfer pathogens between ltcfs and health care facilities in which they receive care. , [ ] [ ] [ ] [ ] this also is true for pediatric long-term care populations. pediatric chronic care facilities have been associated with the importation of extendedspectrum cephalosporin-resistant, gram-negative bacilli into a picu. children from pediatric rehabilitation units may contribute to the reservoir of community-associated mrsa. , [ ] [ ] [ ] i.d. .b. ambulatory care. over the past decade, health care delivery in the united states has shifted from the acute, inpatient hospital to various ambulatory and community-based settings, including the home. ambulatory care is provided in hospital-based outpatient clinics, nonhospital-based clinics and physicians' offices, public health clinics, free-standing dialysis centers, ambulatory surgical centers, urgent care centers, and other setting. in , there were million visits to hospital outpatient clinics and more than million visits to physicians' offices; ambulatory care now accounts for most patient encounters with the health care system. adapting transmission prevention guidelines to these settings is challenging, because patients remain in common areas for prolonged periods waiting to be seen by a health care provider or awaiting admission to the hospital, examination or treatment rooms are turned around quickly with limited cleaning, and infectious patients may not be recognized immediately. furthermore, immunocompromised patients often receive chemotherapy in infusion rooms, where they stay for extended periods along with other types of patients. little data exist on the risk of hais in ambulatory care settings, with the exception of hemodialysis centers. , , transmission of infections in outpatient settings has been reviewed in studies. [ ] [ ] [ ] goodman and solomon summarized clusters of infections associated with the outpatient setting between and . overall, clusters were associated with common source transmission from contaminated solutions or equipment, were associated with person-to-person transmission from or involving hcws, and were associated with airborne or droplet transmission among patients and health care workers. transmission of bloodborne pathogens (ie, hbv, hcv, and, rarely, hiv) in outbreaks, sometimes involving hundreds of patients, continues to occur in ambulatory settings. these outbreaks often are related to common source exposures, usually a contaminated medical device, multidose vial, or intravenous solution. , [ ] [ ] [ ] [ ] [ ] in all cases, transmission has been attributed to failure to adhere to fundamental infection control principles, including safe injection practices and aseptic technique. this subject has been reviewed, and recommended infection control and safe injection practices have been summarized. airborne transmission of m tuberculosis and measles in ambulatory settings, most often emergency departments, has been reported. , , , , [ ] [ ] [ ] measles virus was transmitted in physicians' offices and other outpatient settings during an era when immunization rates were low and measles outbreaks in the community were occurring regularly. , , rubella has been transmitted in the outpatient obstetric setting; there are no published reports of varicella transmission in the outpatient setting. in the ophthalmology setting, adenovirus type epidemic keratoconjunctivitis has been transmitted through incompletely disinfected ophthalmology equipment and/or from hcws to patients, presumably by contaminated hands. , , , [ ] [ ] [ ] [ ] preventing transmission in outpatient settings necessitates screening for potentially infectious symptomatic and asymptomatic individuals, especially those at possible risk for transmitting airborne infectious agents (eg, m tuberculosis, varicella-zoster virus, rubeola [measles]), at the start of the initial patient encounter. on identification of a potentially infectious patient, implementation of prevention measures, including prompt separation of potentially infectious patients and implementation of appropriate control measures (eg, respiratory hygiene/cough etiquette and transmission-based precautions) can decrease transmission risks. , transmission of mrsa and vre in outpatient settings has not been reported, but the association of ca-mrsa in hcws working in an outpatient hiv clinic with environmental ca-mrsa contamination in that clinic suggests the possibility of transmission in that setting. patient-to-patient transmission of burkholderia spp and p aeruginosa in outpatient clinics for adults and children with cystic fibrosis has been confirmed. , i.d. .c. home care. home care in the united states is delivered by more than , provider agencies, including home health agencies, hospices, durable medical equipment providers, home infusion therapy services, and personal care and support services providers. home care is provided to patients of all ages with both acute and chronic conditions. the scope of services ranges from assistance with activities of daily living and physical and occupational therapy to the care of wounds, infusion therapy, and chronic ambulatory peritoneal dialysis. the incidence of infection in home care patients, other than that associated with infusion therapy, has not been well studied. [ ] [ ] [ ] [ ] [ ] [ ] however, data collection and calculation of infection rates have been done for central venous catheter-associated bloodstream infections in patients receiving home infusion therapy [ ] [ ] [ ] [ ] [ ] and for the risk of blood contact through percutaneous or mucosal exposures, demonstrating that surveillance can be performed in this setting. draft definitions for home care-associated infections have been developed. transmission risks during home care are presumed to be minimal. the main transmission risks to home care patients are from an infectious home care provider or contaminated equipment; a provider also can be exposed to an infectious patient during home visits. because home care involves patient care by a limited number of personnel in settings without multiple patients or shared equipment, the potential reservoir of pathogens is reduced. infections of home care providers that could pose a risk to home care patients include infections transmitted by the airborne or droplet routes (eg, chickenpox, tuberculosis, influenza), skin infestations (eg, scabies and lice), and infections transmitted by direct or indirect contact (eg, impetigo). there are no published data on indirect transmission of mdros from one home care patient to another, although this is theoretically possible if contaminated equipment is transported from an infected or colonized patient and used on another patient. of note, investigations of the first case of visa in home care and the first reported cases of vrsa , , , found no evidence of transmission of visa or vrsa to other home care recipients. home health care also may contribute to antimicrobial resistance; a review of outpatient vancomycin use found that % of recipients did not receive prescribed antibiotics according to recommended guidelines. although most home care agencies implement policies and procedures aimed at preventing transmission of organisms, the current approach is based on the adaptation of the guideline for isolation precautions in hospitals, as well as other professional guidance. , this issue has proven very challenging to the home care industry, and practice has been inconsistent and frequently not evidence-based. for example, many home health agencies continue to observe ''nursing bag technique,'' a practice that prescribes the use of barriers between the nursing bag and environmental surfaces in the home. although the home environment may not always appear clean, the use of barriers between noncritical surfaces has been questioned. , opportunites exist to conduct research in home care related to infection transmission risks. i.d. .d. other sites of health care delivery. facilities that are not primarily health care settings but in which health care is delivered include clinics in correctional facilities and shelters. both of these settings can have suboptimal features, such as crowded conditions and poor ventilation. economically disadvantaged individuals who may have chronic illnesses and health care problems related to alcoholism, injected drug use, poor nutrition, and/or inadequate shelter often receive their primary health care at such sites. infectious diseases of special concern for transmission include tuberculosis, scabies, respiratory infections (eg, n meningitides, s pneumoniae), sexually transmitted and bloodborne diseases (eg, hiv, hbv, hcv, syphilis, gonorrhea), hepatitis a virus, diarrheal agents such as norovirus, and foodborne diseases. , [ ] [ ] [ ] [ ] a high index of suspicion for tuberculosis and ca-mrsa in these populations is needed; outbreaks in these settings or among the populations they serve have been reported. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] patient encounters in these types of facilities provide an opportunity to deliver recommended immunizations and screen for m tuberculosis infection, along with diagnosing and treating acute illnesses. recommended infection control measures in these nontraditional areas designated for health care delivery are the same as for other ambulatory care settings. therefore, these settings must be equipped to observe standard precautions and, when indicated, transmission-based precautions. as new treatments emerge for complex diseases, unique infection control challenges associated with special patient populations must be addressed. i.e. . immunocompromised patients. patients who have congenital primary immune deficiencies or acquired disease (eg. treatment-induced immune deficiencies) are at increased risk for numerous types of infections while receiving health care; these patients may be located throughout the health care facility. the specific immune system defects determine the types of infections most likely to be acquired (eg, viral infections are associated with t cell defects, and fungal and bacterial infections occur in patients who are neutropenic). as a general group, immunocompromised patients can be cared for in the same environment as other patients; however, it is always advisable to minimize exposure to other patients with transmissible infections, such as influenza and other respiratory viruses. , the use of more intense chemotherapy regimens for treatment of childhood leukemia may be associated with prolonged periods of neutropenia and suppression of other components of the immune system, extending the period of infection risk and raising the concern that additional precautions may be indicated for select groups. , with the application of newer and more intense immunosuppressive therapies for various medical conditions (eg, rheumatologic disease, , inflammatory bowel disease ), immunosuppressed patients are likely to be more widely distributed throughout a health care facility rather than localized to single patient units (eg, hematologyoncology). guidelines for preventing infections in certain groups of immunocompromised patients have been published previously. , , published data provide evidence to support placing patients undergoing allogeneic hsct in a pe. , , in addition, guidelines have been developed that address the special requirements of these immunocompromised patients, including use of antimicrobial prophylaxis and engineering controls to create a pe for the prevention of infections caused by aspergillus spp and other environmental fungi. , , as more intense chemotherapy regimens associated with prolonged periods of neutropenia or graft-versus-host disease are implemented, the period of risk and duration of environmental protection may need to be prolonged beyond the traditional days. i.e. . cystic fibrosis patients. patients with cystic fibrosis (cf) require special consideration when developing infection control guidelines. compared with other patients, cf patients require additional protection to prevent transmission from contaminated respiratory therapy equipment. [ ] [ ] [ ] [ ] [ ] such infectious agents as b cepacia complex and p aeruginosa. , , , have unique clinical and prognostic significance. in cf patients, b cepacia infection has been associated with increased morbidity and mortality, [ ] [ ] [ ] whereas delayed acquisition of chronic p aeruginosa infection may be associated with an improved long-term clinical outcome. , person-to-person transmission of b cepacia complex has been demonstrated among children and adults with cf in health care settings , and from various social contacts, most notably attendance at camps for patients with cf and among siblings with cf. successful infection control measures used to prevent transmission of respiratory secretions include segregation of cf patients from each other in ambulatory and hospital settings (including use of private rooms with separate showers), environmental decontamination of surfaces and equipment contaminated with respiratory secretions, elimination of group chest physiotherapy sessions, and disbanding of cf camps. , the cystic fibrosis foundation has published a consensus document with evidence-based recommendations for infection control practices in cf patients. i.f. new therapies associated with potentially transmissible infectious agents i.f. . gene therapy. gene therapy has has been attempted using various viral vectors, including nonreplicating retroviruses, adenoviruses, adeno-associated viruses, and replication-competent strains of poxviruses. unexpected adverse events have restricted the prevalence of gene therapy protocols. the infectious hazards of gene therapy are theoretical at this time but require meticulous surveillance due to the possible occurrence of in vivo recombination and the subsequent emergence of a transmissible genetically altered pathogen. the greatest concern attends the use of replication-competent viruses, especially vaccinia. to date, no reports have described transmission of a vector virus from a gene therapy recipient to another individual, but surveillance is ongoing. recommendations for monitoring infection control issues throughout the course of gene therapy trials have been published. [ ] [ ] [ ] i.f. . infections transmitted through blood, organs, and other tissues. the potential hazard of transmitting infectious pathogens through biologic products is a small but ever-present risk, despite donor screening. reported infections transmitted by transfusion or transplantation include west nile virus infection, cytomegalovirus infection, cjd, hepatitis c, infections with clostridium spp and group a streptococcus, malaria, babesiosis, chagas disease, lymphocytic choriomeningitis, and rabies. , therefore, it is important to consider receipt of biologic products when evaluating patients for potential sources of infection. i.f. . xenotransplantation. transplantation of nonhuman cells, tissues, and organs into humans potentially exposes patients to zoonotic pathogens. transmission of known zoonotic infections (eg, trichinosis from porcine tissue) is of concern. also of concern is the possibility that transplantation of nonhuman cells, tissues, or organs may transmit previously unknown zoonotic infections (xenozoonoses) to immunosuppressed human recipients. potential infections that potentially could accompany transplantation of porcine organs have been described previously. guidelines from the us public health service address many infectious diseases and infection control issues that surround the developing field of xenotransplantation; policies and procedures that explain how standard precautions and transmission-based precautions are applied, including systems used to identify and communicate information on patients with potentially transmissible infectious agents, are essential to ensure the success of these measures. these policies and procedures may vary according to the characteristics of the organization. a key administrative measure is the provision of fiscal and human resources for maintaining infection control and occupational health programs that are responsive to emerging needs. specific components include bedside nurse and infection prevention and control professional (icp) staffing levels, inclusion of icps in facility construction and design decisions, clinical microbiology laboratory support, , adequate supplies and equipment including facility ventilation systems, adherence monitoring, assessment and correction of system failures that contribute to transmission, , and provision of feedback to hcws and senior administrators. , , , the positive influence of institutional leadership has been demonstrated repeatedly in studies of hcws' adherence to recommended hand hygiene practices. , , , , , [ ] [ ] [ ] [ ] [ ] [ ] health care administrators' involvement in the infection control processes can improve their awareness of the rationale and resource requirements for following recommended infection control practices. several administrative factors may affect the transmission of infectious agents in health care settings, including the institutional culture, individual hcw behavior, and the work environment. each of these areas is suitable for performance improvement monitoring and incorporation into the organization's patient safety goals. , , , ii.a. .a. scope of work and staffing needs for infection control professionals. the effectiveness of infection surveillance and control programs in preventing nosocomial infections in ust hospitals was assessed by the cdc through the study on the efficacy of nosocomial infection control (senic project) conducted between and . in a representative sample of us general hospitals, those with a trained infection control physician or microbiologist involved in an infection control program and at least infection control nurse per beds were associated with a % lower rate of the infections studied (cvc-associated bloodstream infections, ventilator-associated pneumonias, catheter-related urinary tract infections, and surgical site infections). since the publication of that landmark study, responsibilities of icps have expanded commensurate with the growing complexity of the health care system, the patient populations served, and the increasing numbers of medical procedures and devices used in all types of health care settings. the scope of work of icps was first assessed in - by the certification board of infection control, and has been reassessed every years since that time. , [ ] [ ] [ ] the findings of these analyses have been used to develop and update the infection control certification examination, which was first offered in . with each new survey, it becomes increasingly apparent that the role of the icp is growing in complexity and scope beyond traditional infection control activities in acute care hospitals. activities currently assigned to icps in response to emerging challenges include ( ) surveillance and infection prevention at facilities other than acute care hospitals (eg, ambulatory clinics, day surgery centers, ltcfs, rehabilitation centers, home care); ( ) oversight of employee health services related to infection prevention (eg, assessment of risk and administration of recommended treatment after exposure to infectious agents, tuberculosis screening, influenza vaccination, respiratory protection fit testing, and administration of other vaccines as indicated, such as smallpox vaccine in ); ( ) preparedness planning for annual influenza outbreaks, pandemic influenza, sars, and bioweapons attacks; ( ) adherence monitoring for selected infection control practices; ( ) oversight of risk assessment and implementation of prevention measures associated with construction and renovation; ( ) prevention of transmission of mdros; ( ) evaluation of new medical products that could be associated with increased infection risk (eg, intravenous infusion materials); ( ) communication with the public, facility staff, and state and local health departments concerning infection control-related issues; and ( ) participation in local and multicenter research projects. , , , , , none of the certification board of infection control job analyses addressed specific staffing requirements for the identified tasks, although the surveys did include information about hours worked; the survey included the number of icps assigned to the responding facilities. there is agreement in the literature that a ratio of icp per acute care beds is no longer adequate to meet current infection control needs; a delphi project that assessed staffing needs of infection control programs in the st century concluded that a ratio of . to . icp per occupied acute care beds is an appropriate staffing level. a survey of participants in the nnis system found an average daily patient census of per icp. results of other studies have been similar: per beds for large acute care hospitals, per to beds in ltcfs, and . per in small rural hospitals. , the foregoing demonstrates that infection control staffing no longer can be based on patient census alone, but rather must be determined by the scope of the program, characteristics of the patient population, complexity of the health care system, tools available to assist personnel to perform essential tasks (eg, electronic tracking and laboratory support for surveillance), and unique or urgent needs of the institution and community. furthermore, appropriate training is required to optimize the quality of work performed. , , ii.a. .a.i. infection control nurse liaison. designating a bedside nurse on a patient care unit as an infection control liaison or ''link nurse'' is reported to be an effective adjunct to enhance infection control at the unit level. [ ] [ ] [ ] [ ] [ ] [ ] such individuals receive training in basic infection control and have frequent communication with icps, but maintain their primary role as bedside caregiver on their units. the infection control nurse liaison increases the awareness of infection control at the unit level. he or she is especially effective in implementating new policies or control interventions because of the rapport with individuals on the unit, an understanding of unit-specific challenges, and ability to promote strategies that are most likely to be successful in that unit. this position is an adjunct to, not a replacement for, fully trained icps. furthermore, the infection control liaison nurses should not be counted when considering icp staffing. there is increasing evidence that the level of bedside nurse staffing influences the quality of patient care. , adequate nursing staff makes it more likely that infection control practices, including hand hygiene, standard precautions, and transmission-based precautions, will be given appropriate attention and applied correctly and consistently. a national multicenter study reported strong and consistent inverse relationships between nurse staffing and adverse outcomes in medical patients, of which were hais (urinary tract infections and pneumonia). the association of nursing staff shortages with increased rates of hai has been demonstrated in several outbreaks in hospitals and ltcfs, and with increased transmission of hepatitis c virus in dialysis units. , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in most cases, when staffing was improved as part of a comprehensive control intervention, the outbreak ended or the hai rate declined. in studies, , the composition of the nursing staff (''pool'' or ''float'' vs regular staff nurses) influenced the rate of primary bloodstream infections, with an increased infection rate occurring when the proportion of regular nurses decreased and that of pool nurses increased. ii.a. .c. clinical microbiology laboratory support. the critical role of the clinical microbiology laboratory in infection control and health care epidemiology has been well described , , [ ] [ ] [ ] and is supported by the infectious disease society of america's policy statement on the consolidation of clinical microbiology laboratories published in . the clinical microbiology laboratory contributes to preventing transmission of infectious diseases in health care settings by promptly detecting and reporting epidemiologically important organisms, identifying emerging patterns of antimicrobial resistance, and assessing the effectiveness of recommended precautions to limit transmission during outbreaks. outbreaks of infections may be recognized first by laboratorians. health care organizations need to ensure the availability of the recommended scope and quality of laboratory services, a sufficient number of appropriately trained laboratory staff members, and systems to promptly communicate epidemiologically important results to those who will take action (eg, providers of clinical care, infection control staff, health care epidemiologists, and infectious disease consultants). as concerns about emerging pathogens and bioterrorism grow, the role of the clinical microbiology laboratory assumes ever-greater importance. for health care organizations that outsource microbiology laboratory services (eg, ambulatory care, home care, ltcfs, smaller acute care hospitals), it is important to specify by contract the types of services (eg, periodic institution-specific aggregate susceptibility reports) required to support infection control. several key functions of the clinical microbiology laboratory are relevant to this guideline: ii.a. . institutional safety culture and organizational characteristics. safety culture (or safety climate) refers to a work environment in which a shared commitment to safety on the part of management and the workforce is understood and maintained. , , the authors of the institute of medicine's report titled to err is human acknowledged that causes of medical error are multifaceted but emphasized the pivotal role of system failures and the benefits of a safety culture. a safety culture is created through ( ) the actions that management takes to improve patient and worker safety, ( ) worker participation in safety planning, ( ) the availability of appropriate ppe, ( ) the influence of group norms regarding acceptable safety practices, and ( ) the organization's socialization process for new personnel. safety and patient outcomes can be enhanced by improving or creating organizational characteristics within patient care units, as demonstrated by studies of surgical icus. , each of these factors has a direct bearing on adherence to transmission prevention recommendations. measurement of an institution's culture of safety is useful in designing improvements in health care. , several hospitalbased studies have linked measures of safety culture with both employee adherence to safe practices and reduced exposures to blood and body fluids. [ ] [ ] [ ] [ ] [ ] [ ] [ ] one study of hand hygiene practices concluded that improved adherence requires integration of infection control into the organization's safety culture. several hospitals that are part of the veterans administration health care system have taken specific steps toward improving the safety culture, including error-reporting mechanisms, root cause analyses of identified problems, safety incentives, and employee education. [ ] [ ] [ ] ii.a. . adherence of health care workers to recommended guidelines. hcws' adherence to recommended infection control practices decreases the transmission of infectious agents in health care settings. , , [ ] [ ] [ ] [ ] [ ] several observational studies have shown limited adherence to recommended practices by hcws. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] observed adherence to universal precautions ranged from % to %. , , , , the degree of adherence often depended on the specific practice that was assessed and, for glove use, the circumstance in which the practice was applied. observed rates of appropriate glove use has ranged from a low of % to a high of %. however, % and % adherence with glove use have been reported during arterial blood gas collection and resuscitation, respectively, procedures in which considerable blood contact may occur. , differences in observed adherence have been reported among occupational groups in the same health care facility and between experienced and nonexperienced professionals. in surveys of hcws, self-reported adherence was generally higher than actual adherence found in observational studies. furthermore, where an observational component was included with a self-reported survey, self-perceived adherence was often greater than observed adherence. among nurses and physicians, increasing years of experience is a negative predictor of adherence. , education to improve adherence is the primary intervention that has been studied. whereas positive changes in knowledge and attitude have been demonstrated, , no or only limited accompanying changes in behavior often have been found. , self-reported adherence is higher in groups that received an educational intervention. , in one study, educational interventions that incorporated videotaping and performance feedback were successful in improving adherence during the study period, but the long-term effect of such interventions is not known. the use of videotaping also served to identify system problems (eg, communication and access to ppe) that otherwise may not have been recognized. interest is growing in the use of engineering controls and facility design concepts for improving adherence. whereas the introduction of automated sinks was found to have a negative impact on consistent adherence to handwashing in one study, the use of electronic monitoring and voice prompts to remind hcws to perform hand hygiene and improving accessibility to hand hygiene products increased adherence and contributed to a decrease in hais in another study. more information is needed regarding ways in which technology might improve adherence. improving adherence to infection control practices requires a multifaceted approach that incorporates continuous assessment of both the individual and the work environment. , using several behavioral theories, kretzer and larson concluded that a single intervention (eg, a handwashing campaign or putting up new posters about transmission precautions) likely would be ineffective in improving hcws adherence. improvement requires the organizational leadership to make prevention an institutional priority and integrate infection control practices into the organization's safety culture. a recent review of the literature concluded that variations in organizational factors (eg, safety climate, policies and procedures, education and training) and individual factors (eg, knowledge, perceptions of risk, past experience) were determinants of adherence to infection control guidelines for protection against sars and other respiratory pathogens. surveillance is an essential tool for case finding of single patients or clusters of patients who are infected or colonized with epidemiologically important organisms (eg, susceptible bacteria such as s aureus, s pyogenes [group a streptococcus] or enterobacter-klebsiella spp; mrsa, vre, and other mdros; c difficile; rsv; influenza virus) for which transmission-based precautions may be required. surveillance is defined as the ongoing systematic collection, analysis, interpretation, and dissemination of data regarding a health-related event for use in public health action to reduce morbidity and mortality and to improve health. the work of ignaz semmelweis delineating the role of person-toperson transmission in puerperal sepsis is the earliest example of the use of surveillance data to reduce transmission of infectious agents. surveillance of both process measures and the infection rates to which they are linked is important in evaluating the effectiveness of infection prevention efforts and identifying indications for change. , [ ] [ ] [ ] [ ] the study on the efficacy of nosocomial infection control (senic) found that different combinations of infection control practices resulted in reduced rates of nosocomial surgical site infections, pneumonia, urinary tract infections, and bacteremia in acute care hospitals; however, surveillance was the only component essential for reducing all types of hais. although a similar study has not been conducted in other health care settings, a role for surveillance and the need for novel strategies in ltcfs , , , and in home care [ ] [ ] [ ] [ ] have been described. the essential elements of a surveillance system are ( ) standardized definitions, ( ) identification of patient populations at risk for infection, ( ) statistical analysis (eg, risk adjustment, calculation of rates using appropriate denominators, trend analysis using such methods as statistical process control charts), and ( ) feedback of results to the primary caregivers. [ ] [ ] [ ] [ ] [ ] [ ] data gathered through surveillance of high-risk populations, device use, procedures, and facility locations (eg, icus) are useful in detecting transmission trends. [ ] [ ] [ ] identification of clusters of infections should be followed by a systematic epidemiologic investigation to determine commonalities in persons, places, and time and to guide implementation of interventions and evaluation of the effectiveness of those interventions. targeted surveillance based on the highest-risk areas or patients has been preferred over facility-wide surveillance for the most effective use of resources. , however, for certain epidemiologically important organisms, surveillance may need to be facility-wide. surveillance methods will continue to evolve as health care delivery systems change , and user-friendly electronic tools for electronic tracking and trend analysis become more widely available. , , individuals with experience in health care epidemiology and infection control should be involved in selecting software packages for data aggregation and analysis, to ensure that the need for efficient and accurate hai surveillance will be met. effective surveillance is increasingly important as legislation requiring public reporting of hai rates is passed and states work to develop effective systems to support such legislation. the education and training of hcws is a prerequisite for ensuring that policies and procedures for standard and transmission-based precautions are understood and practiced. understanding the scientific rationale for the precautions will allow hcws to apply procedures correctly, as well as to safely modify precautions based on changing requirements, resources, or health care settings. , , - one study found that the likelihood of hcws developing sars was strongly associated with less than hours of infection control training and poor understanding of infection control procedures. education regarding the important role of vaccines (eg, influenza, measles, varicella, pertussis, pneumococcal) in protecting hcws, their patients, and family members can help improve vaccination rates. [ ] [ ] [ ] [ ] education on the principles and practices for preventing transmission of infectious agents should begin during training in the health professions and be provided to anyone who has an opportunity for contact with patients or medical equipment (eg, nursing and medical staff; therapists and technicians, including respiratory, physical, occupational, radiology, and cardiology personnel; phlebotomists; housekeeping and maintenance staff; and students). in health care facilities, education and training on standard and transmission-based precautions are typically provided at the time of orientation and should be repeated as necessary to maintain competency; updated education and training are necessary when policies and procedures are revised or when a special circumstance occurs, such as an outbreak that requires modification of current practice or adoption of new recommendations. education and training materials and methods appropriate to the hcw's level of responsibility, individual learning habits, and language needs can improve the learning experience. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] education programs for hcws have been associated with sustained improvement in adherence to best practices and a related decrease in device-associated hais in teaching and nonteaching settings , and in medical and surgical icus (coopersmith, # ) . several studies have shown that in addition to targeted education to improve specific practices, periodic assessment and feedback of the hcw's knowledge and adherence to recommended practices are necessary to achieve the desired changes and identify continuing education needs. , [ ] [ ] [ ] [ ] [ ] the effectiveness of this approach for isolation practices has been demonstrated in the control of rsv. , patients, family members, and visitors can be partners in preventing transmission of infections in health care settings. , , - information on standard precautions, especially hand hygiene, respiratory hygiene/cough etiquette, vaccination (especially against influenza), and other routine infection prevention strategies, may be incorporated into patient information materials provided on admission to the health care facility. additional information on transmission-based precautions is best provided when these precautions are initiated. fact sheets, pamphlets, and other printed material may include information on the rationale for the additional precautions, risks to household members, room assignment for transmission-based precautions purposes, explanation of the use of ppe by hcws, and directions for use of such equipment by family members and visitors. such information may be particularly helpful in the home environment, where household members often have the primary responsibility for adherence to recommended infection control practices. hcws must be available and prepared to explain this material and answer questions as needed. hand hygiene has been frequently cited as the single most important practice to reduce the transmission of infectious agents in health care settings , , and is an essential element of standard precautions. the term ''hand hygiene'' includes both handwashing with either plain or antiseptic-containing soap and water and the use of alcohol-based products (gels, rinses, foams) that do not require water. in the absence of visible soiling of hands, approved alcohol-based products for hand disinfection are preferred over antimicrobial or plain soap and water because of their superior microbiocidal activity, reduced drying of the skin, and convenience. have been associated with a sustained decrease in the incidence of mrsa and vre infections primarily in icus. , , [ ] [ ] [ ] [ ] the scientific rationale, indications, methods, and products for hand hygiene have been summarized in previous publications. , the effectiveness of hand hygiene can be reduced by the type and length of fingernails. , , individuals wearing artificial nails have been shown to harbor more pathogenic organisms, especially gram-negative bacilli and yeasts, on the nails and in the subungual area compared with individuals with native nails. , in , the cdc/hicpac recommended (category ia) that artificial fingernails and extenders not be worn by hcws who have contact with high-risk patients (eg, those in icus and operating rooms), due to the association with outbreaks of gram-negative bacillus and candidal infections as confirmed by molecular typing of isolates. , , , [ ] [ ] [ ] [ ] the need to restrict the wearing of artificial fingernails by all hcws who provide direct patient care and those who have contact with other high-risk groups (eg, oncology and cystic fibrosis patients) has not been studied but has been recommended by some experts. currently, such decisions are at the discretion of an individual facility's infection control program. there is less evidence indicating that jewelry affects the quality of hand hygiene. although hand contamination with potential pathogens is increased with ring-wearing, , no studies have related this practice to hcw-to-patient transmission of pathogens. ppe refers to various barriers and respirators used alone or in combination to protect mucous membranes, airways, skin, and clothing from contact with infectious agents. the choice of ppe is based on the nature of the patient interaction and/or the likely mode(s) of transmission. specific guidance on the use of ppe is provided in part iii of this guideline. a suggested procedure for donning and removing ppe aimed at preventing skin or clothing contamination is presented in figure . designated containers for used disposable or reusable ppe should be placed in a location convenient to the site of removal, to facilitate disposal and containment of contaminated materials. hand hygiene is always the final step after removing and disposing of ppe. the following sections highlight the primary uses of and criteria for selecting this equipment. ii.e. . gloves. gloves are used to prevent contamination of hcw hands when ( ) anticipating direct contact with blood or body fluids, mucous membranes, nonintact skin and other potentially infectious material; ( ) having direct contact with patients who are colonized or infected with pathogens transmitted by the contact route (eg, vre, mrsa, rsv , , ); or ( ) handling or touching visibly or potentially contaminated patient care equipment and environmental surfaces. , , gloves can protect both patients and hcws from exposure to infectious material that may be carried on hands. the extent to which gloves will protect hcws from transmission of bloodborne pathogens (eg, hiv, hbv, hcv) after a needlestick or other puncture that penetrates the glove barrier has not yet been determined. although gloves may reduce the volume of blood on the external surface of a sharp by % to %, the residual blood in the lumen of a hollow-bore needle would not be affected; therefore, the effect on transmission risk is unknown. gloves manufactured for health care purposes are subject to fda evaluation and clearance. nonsterile disposable medical gloves made of various materials (eg, latex, vinyl, nitrile) are available for routine patient care. the selection of glove type for nonsurgical use is based on various factors, including the task to be performed, anticipated contact with chemicals and chemotherapeutic agents, latex sensitivity, sizing, and facility policies for creating a latex-free environment. , [ ] [ ] [ ] for contact with blood and body fluids during nonsurgical patient care, a single pair of gloves generally provides adequate barrier protection. however, there is considerable variability among gloves; both the quality of the manufacturing process and type of material influence their barrier effectiveness. whereas there is little difference in the barrier properties of unused intact gloves, studies have shown repeatedly that vinyl gloves have higher failure rates than latex or nitrile gloves when tested under simulated and actual clinical conditions. , [ ] [ ] [ ] [ ] for this reason, either latex or nitrile gloves are preferable for clinical procedures that require manual dexterity or will involve more than brief patient contact. a facility may need to stock gloves in several sizes. heavier, reusable utility gloves are indicated for non-patient care activities, such as handling or cleaning contaminated equipment or surfaces. , , during patient care, transmission of infectious organisms can be reduced by adhering to the principles of working from ''clean'' to ''dirty'' and confining or limiting contamination to those surfaces directly needed for patient care. it may be necessary to change gloves during the care of a single patient to prevent cross-contamination of body sites. , it also may be necessary to change gloves if the patient interaction also involves touching portable computer keyboards or other mobile equipment transported from room to room. discarding gloves between patients is necessary to prevent transmission of infectious material. gloves must not be washed for subsequent reuse, because microorganisms cannot be removed reliably from glove surfaces, and continued glove integrity cannot be ensured. furthermore, glove reuse has been associated with transmission of mrsa and gram-negative bacilli. [ ] [ ] [ ] when gloves are worn in combination with other ppe, they are put on last. gloves that fit snugly around the wrist are preferred for use with an isolation gown, because they will cover the gown cuff and provide a more reliable continuous barrier for the arms, wrists, and hands. proper glove removal will prevent hand contamination (fig ) . hand hygiene after glove removal further ensures that the hands will not carry potentially infectious material that might have penetrated through unrecognized tears or that could have contaminated the hands during glove removal. , , ii.e. . isolation gowns. isolation gowns are used as specified by standard and transmission-based precautions to protect the hcw's arms and exposed body areas and prevent contamination of clothing with blood, body fluids, and other potentially infectious material. , , , [ ] [ ] [ ] the need for and the type of isolation gown selected is based on the nature of the patient interaction, including the anticipated degree of contact with infectious material and potential for blood and body fluid penetration of the barrier. the wearing of isolation gowns and other protective apparel is mandated by the occupational safety and health administration's (osha) bloodborne pathogens standard. clinical and laboratory coats or jackets worn over personal clothing for comfort and/or purposes of identity are not considered ppe. when applying standard precautions, an isolation gown is worn only if contact with blood or body fluid is anticipated. however, when contact precautions are used (ie, to prevent transmission of an infectious agent that is not interrupted by standard precautions alone and is associated with environmental contamination), donning of both gown and gloves on room entry is indicated, to prevent unintentional contact with contaminated environmental surfaces. , , , the routine donning of isolation gowns on entry into an icu or other high-risk area does not prevent or influence potential colonization or infection of patients in those areas, however. , [ ] [ ] [ ] [ ] isolation gowns are always worn in combination with gloves, and with other ppe when indicated. gowns are usually the first piece of ppe to be donned. full coverage of the arms and body front, from neck to the mid-thigh or below, will ensure protection of clothing and exposed upper body areas. several gown sizes should be available in a health care facility to ensure appropriate coverage for staff members. isolation gowns should be removed before leaving the patient care area to prevent possible contamination of the environment outside the patient's room. isolation gowns should be removed in a manner that prevents contamination of clothing or skin (fig ) ; the outer, ''contaminated'' side of the gown is turned inward and rolled into a bundle, and then discarded into a designated container for waste or linen to contain contamination. ii.e. . face protection: masks, goggles, and face shields. ii.e. .a. masks. masks are used for primary purposes in health care settings: ( ) placed on hcws to protect them from contact with infectious material from patients (eg, respiratory secretions and sprays of blood or body fluids), consistent with standard precautions and droplet precautions; ( ) placed on hcws engaged in procedures requiring sterile technique, to protect patients from exposure to infectious agents carried in the hcw's mouth or nose; and ( ) placed on coughing patients to limit potential dissemination of infectious respiratory secretions from the patient to others (ie, respiratory hygiene/cough etiquette). masks may be used in combination with goggles to protect the mouth, nose, and eyes, or, alternatively, a face shield may be used instead of a mask and goggles to provide more complete protection for the face, as discussed below. masks should not be confused with particulate respirators used to prevent inhalation of small particles that may contain infectious agents transmitted through the airborne route, as described below. the mucous membranes of the mouth, nose, and eyes are susceptible portals of entry for infectious agents; other skin surfaces also may be portals if skin integrity is compromised (by, eg, acne, dermatitis). , [ ] [ ] [ ] [ ] therefore, use of ppe to protect these body sites is an important component of standard precautions. the protective effect of masks for exposed hcws has been demonstrated previously. , , , procedures that generate splashes or sprays of blood, body fluids, secretions, or excretions (eg, endotracheal suctioning, bronchoscopy, invasive vascular procedures) require either a face shield (disposable or reusable) or a mask and goggles. [ ] [ ] [ ] [ ] , , , , the wearing of masks, eye protection, and face shields in specified circumstances when blood or body fluid exposure is likely is mandated by osha's bloodborne pathogens standard. appropriate ppe should be selected based on the anticipated level of exposure. two mask types are available for use in health care settings: surgical masks that are cleared by the fda and required to have fluid-resistant properties, and procedure or isolation masks. ,# to date, no studies comparing mask types to determine whether one mask type provides better protection than another have been published. because procedure/isolation masks are not regulated by the fda, they may be more variable in terms of quality and performance than surgical masks. masks come in various shapes (eg, molded and nonmolded), sizes, filtration efficiency, and method of attachment (eg, ties, elastic, ear loops). health care facilities may find that different types of masks are needed to meet individual hcw needs. ii.e. .b. goggles and face shields. guidance on eye protection for infection control has been published. the eye protection chosen for specific work situations (eg, goggles or face shield) depends on the circumstances of exposure, other ppe used, and personal vision needs. personal eyeglasses and contact lenses are not considered adequate eye protection (see http://www.cdc.gov/ niosh/topics/eye/eye-infectious.html). niosh guidelines specify that eye protection must be comfortable, allow for sufficient peripheral vision, and adjustable to ensure a secure fit. a health care facility may need to provide several different types, styles, and sizes of eye protection equipment. indirectly vented goggles with a manufacturer's antifog coating may provide the most reliable practical eye protection from splashes, sprays, and respiratory droplets from multiple angles. newer styles of goggles may provide better indirect airflow properties to reduce fogging, as well as better peripheral vision and more size options for fitting goggles to different workers. many styles of goggles fit adequately over prescription glasses with minimal gaps. although effective as eye protection, goggles do not provide splash or spray protection to other parts of the face. the role of goggles in addition to a mask in preventing exposure to infectious agents transmitted through respiratory droplets has been studied only for rsv. reports published in the mid- s demonstrated that eye protection reduced occupational transmission of rsv. , whether this was due to the prevention hand-eye contact or the prevention of respiratory droplet-eye contact has not been determined. however, subsequent studies demonstrated that rsv transmission is effectively prevented by adherence to standard precautions plus contact precautions and that routine use of goggles is not necessary for this virus. , , , , it is important to remind hcws that even if droplet precautions are not recommended for a specific respiratory tract pathogen, protection for the eyes, nose, and mouth using a mask and goggles or a face shield alone is necessary when a splash or spray of any respiratory secretions or other body fluids is likely to occur, as defined in standard precautions. disposable or nondisposable face shields may be used as an alternative to goggles. compared with goggles, a face shield can provide protection to other facial areas besides the eyes. face shields extending from the chin to crown provide better face and eye protection from splashes and sprays; face shields that wrap around the sides may reduce splashes around the edge of the shield. removal of a face shield, goggles, and mask can be performed safely after gloves have been removed and hand hygiene performed. the ties, earpieces, and/or headband used to secure the equipment to the head are considered ''clean'' and thus safe to touch with bare hands. the front of a mask, goggles, and face shield are considered contaminated (fig ) . ii.e. . respiratory protection. the subject of respiratory protection as it applies to preventing transmission of airborne infectious agents, including the need for and frequency of fit testing is under scientific review and was the subject of a cdc workshop. respiratory protection currently requires the use of a respirator with n or higher-level filtration to prevent inhalation of infectious particles. information about respirators and respiratory protection programs is summarized in the guideline for preventing transmission of mycobacterium tuberculosis in health care settings. respiratory protection is broadly regulated by osha under the general industry standard for respiratory protection ( cfr . ), which requires that us employers in all employment settings implement a program to protect employees from inhalation of toxic materials. osha program components include medical clearance to wear a respirator; provision and use of appropriate respirators, including fit-tested niosh-certified n and higher-level particulate filtering respirators; education on respirator use, and periodic reevaluation of the respiratory protection program. when selecting particulate respirators, models with inherently good fit characteristics (ie, those expected to provide protection factors of $ % to % of wearers) are preferred and theoretically could preclude the need for fit testing. , issues pertaining to respiratory protection remain the subject of ongoing debate. information on various types of respirators is available at http://www.cdc.gov/niosh/ npptl/respirators/respsars.html and in several previously published studies. , , a user-seal check (formerly called a ''fit check'') should be performed by the wearer of a respirator each time that the respirator is donned, to minimize air leakage around the face piece. the optimal frequency of fit testing has not been determined; retesting may be indicated if there is a change in wearer's facial features, onset of a medical condition that would affect respiratory function in the wearer, or a change in the model or size of the respirator that was initially assigned. respiratory protection was first recommended for protection of us hcws from exposure to m tuberculosis in . that recommendation has been maintained in successive revisions of the guidelines for prevention of transmission of tuberculosis in hospitals and other health care settings. , the incremental benefit from respirator use, in addition to administrative and engineering controls (ie, aiirs, early recognition of patients likely to have tuberculosis and prompt placement in an aiir, and maintenance of a patient with suspected tuberculosis in an aiir until no longer infectious), for preventing transmission of airborne infectious agents (eg, m tuberculosis) remains undetermined. although some studies have demonstrated effective prevention of m tuberculosis transmission in hospitals in which surgical masks instead of respirators were used in conjunction with other administrative and engineering controls. , , the cdc currently recommends n or higher-level respirators for personnel exposed to patients with suspected or confirmed tuberculosis. currently, this recommendation also holds for other diseases that could be transmitted through the airborne route, including sars and smallpox, , , until inhalational transmission is better defined or health care-specific ppe more suitable for preventing infection is developed. wearing of respirators is also currently recommended during the performance of aerosol-generating procedures (eg, intubation, bronchoscopy, suctioning) in patients with sars-cov infection, avian influenza, and pandemic influenza (see appendix a). although airborne precautions are recommended for preventing airborne transmission of measles and varicella-zoster viruses, no data are available on which to base a recommendation for respiratory protection to protect susceptible personnel against these infections. transmission of varicella-zoster virus has been prevented among pediatric patients using negativepressure isolation alone. whether respiratory protection (ie, wearing a particulate respirator) will enhance protection from these viruses has not yet been studied. because most hcws have natural or acquired immunity to these viruses, only immune personnel generally care for patients with these infections. [ ] [ ] [ ] [ ] although there is no evidence suggesting that masks are not adequate to protect hcws in these settings, for purposes of consistency and simplicity, or because of difficulties in ascertaining immunity, some facilities may require the use of respirators for entry into all aiirs, regardless of the specific infectious agent present. procedures for safe removal of respirators are provided in figure . in some health care settings, particulate respirators used to provide care for patients with m tuberculosis are reused by the same hcw. this is an acceptable practice providing that the respirator is not damaged or soiled, the fit is not compromised by a change in shape, and the respirator has not been contaminated with blood or body fluids. no data are available on which to base a recommendation regarding the length of time that a respirator may be safely reused. sharps-related injuries. injuries due to needles and other sharps have been associated with transmission of hbv, hcv, and hiv to hcws. , the prevention of sharps injuries has always been an essential element of universal precautions and is now an aspect of standard precautions. , these include measures to handle needles and other sharp devices in a manner that will prevent injury to the user and to others who may encounter the device during or after a procedure. these measures apply to routine patient care and do not address the prevention of sharps injuries and other blood exposures during surgical and other invasive procedures addressed elsewhere. [ ] [ ] [ ] [ ] [ ] since , when osha first issued its bloodborne pathogens standard to protect hcws from blood exposure, the focus of regulatory and legislative activity has been on implementing a hierarchy of control measures. this has included focusing attention on removing sharps hazards through the development and use of engineering controls. the federal needlestick safety and prevention act, signed into law in november , authorized osha's revision of its bloodborne pathogens standard to more explicitly require the use of safety-engineered sharps devices. the cdc has provided guidance on sharps injury prevention, , including guidelines for the design, implementation and evaluation of a comprehensive sharps injury prevention program. ii.f. . prevention of mucous membrane contact. exposure of mucous membranes of the eyes, nose, and mouth to blood and body fluids has been associated with the transmission of bloodborne viruses and other infectious agents to hcws. , , , the prevention of mucous membrane exposures has always been an element of universal precautions and is now an element of standard precautions for routine patient care , and is subject to osha bloodborne pathogen regulations. safe work practices, in addition to wearing ppe, are designed to protect mucous membranes and nonintact skin from contact with potentially infectious material. these include keeping contaminated gloved and ungloved hands from touching the mouth, nose, eyes, or face and positioning patients to direct sprays and splatter away from the caregiver's face. careful placement of ppe before patient contact will help avoid the need to make adjustments to ppe and prevent possible face or mucous membrane contamination during use. in areas where the need for resuscitation is unpredictable, mouthpieces, pocket resuscitation masks with -way valves, and other ventilation devices provide an alternative to mouth-to-mouth resuscitation, preventing exposure of the caregiver's nose and mouth to oral and respiratory fluids during the procedure. ii.f. .a. precautions during aerosol-generating procedures. the performance of procedures that can generate small-particle aerosols (aerosol-generating procedures), such as bronchoscopy, endotracheal intubation, and open suctioning of the respiratory tract, have been associated with transmission of infectious agents to hcws, including m tuberculosis, sars-cov, , , and n meningitidis. protection of the eyes, nose, and mouth, in addition to gown and gloves, is recommended during performance of these procedures in accordance with standard precautions. the use of a particulate respirator is recommended during aerosol-generating procedures when the aerosol is likely to contain m tuberculosis, sars-cov, or avian or pandemic influenza viruses. ii.g. . hospitals and long-term care facilities. options for patient placement include single-patient rooms, -patient rooms, and multibed wards. of these, single-patient rooms are preferred when transmission of an infectious agent is of concern. although some studies have failed to demonstrate the efficacy of single-patient rooms in preventing hais, other published studies, including one commissioned by the aia and the facility guidelines institute, have documented a beneficial relationship between private rooms and reduced infectious and noninfectious adverse patient outcomes. , the aia notes that private rooms are the trend in hospital planning and design. however, most hospitals and ltcfs have multibed rooms and must consider many competing priorities when determining the appropriate room placement for patients (eg, reason for admission; patient characteristics, such as age, gender, and mental status; staffing needs; family requests; psychosocial factors; reimbursement concerns). in the absence of obvious infectious diseases that require specified airborne infection isolation rooms (eg, tuberculosis, sars, chickenpox), the risk of transmission of infectious agents is not always considered when making placement decisions. when only a limited number of single-patient rooms is available, it is prudent to prioritize room assignments for those patients with conditions that facilitate transmission of infectious material to other patients (eg, draining wounds, stool incontinence, uncontained secretions) and those at increased risk of acquisition and adverse outcomes resulting from hais (due to, eg, immunosuppression, open wounds, indwelling catheters, anticipated prolonged length of stay, total dependence on hcws for activities of daily living). , , , , , single-patient rooms are always indicated for patients placed on airborne precautions in a pe and are preferred for patients requiring contact or droplet precautions. , , , , , during a suspected or proven outbreak caused by a pathogen whose reservoir is the gastrointestinal tract, the use of single-patient rooms with private bathrooms limits opportunities for transmission, especially when the colonized or infected patient has poor personal hygiene habits or fecal incontinence, or cannot be expected to assist in maintaining procedures that prevent transmission of microorganisms (eg, infants, children, and patients with altered mental status or developmental delay). in the absence of continued transmission, it is not necessary to provide a private bathroom for patients colonized or infected with enteric pathogens as long as personal hygiene practices and standard precautions (especially hand hygiene and appropriate environmental cleaning) are maintained. assignment of a dedicated commode to a patient, and cleaning and disinfecting fixtures and equipment that may have fecal contamination (eg, bathrooms, commodes, scales used for weighing diapers) and the adjacent surfaces with appropriate agents may be especially important when a single-patient room cannot be assigned, because environmental contamination with intestinal tract pathogens is likely from both continent and incontinent patients. , the results of several studies that investigated the benefit of a single-patient room in preventing transmission of c difficile were inconclusive. , [ ] [ ] [ ] some studies have shown that being in the same room with a colonized or infected patient is not necessarily a risk factor for transmission; , - however, for children, the risk of health care-associated diarrhea is increased with the increased number of patients per room. these findings demonstrate that patient factors are important determinants of infection transmission risks. the need for a single-patient room and/or private bathroom for any patient is best determined on a case-by-case basis. cohorting is the practice of grouping together patients who are colonized or infected with the same organism to confine their care to a single area and prevent contact with other patients. cohorts are created based on clinical diagnosis, microbiologic confirmation (when available), epidemiology, and mode of transmission of the infectious agent. avoiding placing severely immunosuppressed patients in rooms with other patients is generally preferred. cohorting has been extensively used for managing outbreaks of mdros, including mrsa, rotavirus, and sars. modeling studies provide additional support for cohorting patients to control outbreaks; - however, cohorting often is implemented only after routine infection control measures have failed to control an outbreak. assigning or cohorting hcws to care only for patients infected or colonized with a single target pathogen limits further transmission of the target pathogen to uninfected patients, , but is difficult to achieve in the face of current staffing shortages in hospitals and residential health care sites. [ ] [ ] [ ] however, cohorting of hcws may be beneficial when transmission continues after implementing routine infection control measures and creating patient cohorts. during periods when rsv, human metapneumovirus, parainfluenza, influenza, other respiratory viruses, and rotavirus are circulating in the community, cohorting based on the presenting clinical syndrome is often a priority in facilities that care for infants and young children. for example, during the respiratory virus season, infants may be cohorted based solely on the clinical diagnosis of bronchiolitis, due to the logistical difficulties and costs associated with requiring microbiologic confirmation before room placement and the predominance of rsv during most of the season. however, when available, single-patient rooms are always preferred, because a common clinical presentation (eg, bronchiolitis), can be caused by more than infectious agent. , , furthermore, the inability of infants and children to contain body fluids, and the close physical contact associated with their care, increases the risk of infection transmission for patients and personnel in this setting. , ii.g. . ambulatory care settings. patients actively infected with or incubating transmissible infectious diseases are frequently seen in ambulatory settings (eg, outpatient clinics, physicians' offices, emergency departments) and potentially expose hcws and other patients, family members, and visitors. , , , , , in response to the global outbreak of sars in and in preparation for pandemic influenza, hcws working in outpatient settings are urged to implement source containment measures (eg, asking coughing patients to wear a surgical mask or cover coughing with tissues) to prevent transmission of respiratory infections, beginning at the initial patient encounter, , , as described in section iii.a. .a. signs can be posted at the facility's entrance or at the reception or registration desk requesting that the patient or individuals accompanying the patient promptly inform the receptionist of any symptoms of respiratory infection (eg, cough, flulike illness, increased production of respiratory secretions). the presence of diarrhea, skin rash, or known or suspected exposure to a transmissible disease (eg, measles, pertussis, chickenpox, tuberculosis) also could be added. prompt placement of a potentially infectious patient in an examination room limits the number of exposed individuals in the common waiting area. in waiting areas, maintaining a distance between symptomatic and nonsymptomatic patients (eg, . feet), in addition to source control measures, may limit exposures. however, infections transmitted through the airborne route (eg, m tuberculosis, measles, chickenpox) require additional precautions. , , patients suspected of having such an infection can wear a surgical mask for source containment, if tolerated, and should be placed in an examination room (preferably an aiir) as soon as possible. if this is not possible, then having the patient wear a mask and segregating the patient from other patients in the waiting area will reduce the risk of exposing others. because the person(s) accompanying the patient also may be infectious, application of the same infection control precautions may be extended to these persons if they are symptomatic. , , family members accompanying children admitted with suspected m tuberculosis have been found to have unsuspected pulmonary tuberculosis with cavitary lesions, even when asymptomatic. , patients with underlying conditions that increase their susceptibility to infection (eg, immunocompromised status , or cystic fibrosis ) require special efforts to protect them from exposure to infected patients in common waiting areas. informing the receptionist of their infection risk on arrival allows appropriate steps to further protect these patients from infection. in some cystic fibrosis clinics, to avoid exposure to other patients who could be colonized with b cepacia, patients have been given beepers on registration so that they may leave the area and receive notification to return when an examination room becomes available. ii.g. . home care. in home care, patient placement concerns focus on protecting others in the home from exposure to an infectious household member. for individuals who are especially vulnerable to adverse outcomes associated with certain infections, it may be beneficial to either remove them from the home or segregate them within the home. persons who are not part of the household may need to be prohibited from visiting during the period of infectivity. for example, in a situation where a patient with pulmonary tuberculosis is contagious and being cared for at home, very young children (age under years) and immunocompromised persons who have not yet been infected should be removed or excluded from the household. during the sars outbreak of , segregation of infected persons during the communicable phase of the illness was found to be beneficial in preventing household transmission. , several principles guide the transport of patients requiring transmission-based precautions. in the inpatient and residential settings, these include the following: . limiting transport of such patients to essential purposes, such as diagnostic and therapeutic procedures that cannot be performed in the patient's room. . when transport is necessary, applying appropriate barriers on the patient (eg, mask, gown, wrapping in sheets or use of impervious dressings to cover the affected areas) when infectious skin lesions or drainage are present, consistent with the route and risk of transmission. . notifying hcws in the receiving area of the patient's impending arrival and of the necessary precautions to prevent transmission. . for patients being transported outside the facility, informing the receiving facility and the medi-van or emergency vehicle personnel in advance about the type of transmission-based precautions being used. for tuberculosis, additional precautions may be needed in a small shared air space, such as in an ambulance. cleaning and disinfecting noncritical surfaces in patient care areas is an aspect of standard precautions. in general, these procedures do not need to be changed for patients on transmission-based precautions. the cleaning and disinfection of all patient care areas is important for frequently touched surfaces, especially those closest to the patient, which are most likely to be contaminated (eg, bedrails, bedside tables, commodes, doorknobs, sinks, surfaces and equipment in close proximity to the patient). , , , the frequency or intensity of cleaning may need to be changed, based on the patient's level of hygiene and the degree of environmental contamination and for certain infectious agents with reservoirs in the intestinal tract. this may be particularly important in ltcfs and pediatric facilities, where patients with stool and urine incontinence are encountered more frequently. in addition, increased frequency of cleaning may be needed in a pe to minimize dust accumulation. special recommendations for cleaning and disinfecting environmental surfaces in dialysis centers have been published previously. in all health care settings, administrative, staffing, and scheduling activities should prioritize the proper cleaning and disinfection of surfaces that could be implicated in transmission. during a suspected or proven outbreak in which an environmental reservoir is suspected, routine cleaning procedures should be reviewed, and the need for additional trained cleaning staff should be assessed. adherence should be monitored and reinforced to promote consistent and correct cleaning. us environmental protection agency-registered disinfectants or detergents/disinfectants that best meet the overall needs of the health care facility for routine cleaning and disinfection should be selected. , in general, use of the existing facility detergent/disinfectant according to the manufacturer's recommendations for amount, dilution, and contact time is sufficient to remove pathogens from surfaces of rooms where colonized or infected individuals were housed. this includes those pathogens that are resistant to multiple classes of antimicrobial agents (eg, c difficile, vre, mrsa, mdr-gnb , , , , , , ). most often, environmental reservoirs of pathogens during outbreaks are related to a failure to follow recommended procedures for cleaning and disinfection, rather than to the specific cleaning and disinfectant agents used. [ ] [ ] [ ] [ ] certain pathogens (eg, rotavirus, noroviruses, c difficile) may be resistant to some routinely used hospital disinfectants. , , [ ] [ ] [ ] [ ] [ ] [ ] the role of specific disinfectants in limiting transmission of rotavirus has been demonstrated experimentally. also, because c difficile may display increased levels of spore production when exposed to non-chlorine-based cleaning agents, and because these spores are more resistant than vegetative cells to commonly used surface disinfectants, some investigators have recommended the use of a : dilution of . % sodium hypochlorite (household bleach) and water for routine environmental disinfection of rooms of patients with c difficile when there is continued transmission. , one study found an association between the use of a hypochlorite solution and decreased rates of c difficile infections. the need to change disinfectants based on the presence of these organisms can be determined in consultation with the infection control committee. , , detailed recommendations for disinfection and sterilization of surfaces and medical equipment that have been in contact with prion-containing tissue or high risk body fluids, and for cleaning of blood and body substance spills, are available in the guidelines for environmental infection control in health care facilities and in the guideline for disinfection and sterilization. medical equipment and instruments/devices must be cleaned and maintained according to the manufacturers' instructions to prevent patient-to-patient transmission of infectious agents. , , , cleaning to remove organic material always must precede highlevel disinfection and sterilization of critical and semicritical instruments and devices, because residual proteinacous material reduces the effectiveness of the disinfection and sterilization processes. , noncritical equipment, such as commodes, intravenous pumps, and ventilators, must be thoroughly cleaned and disinfected before being used on another patient. all such equipment and devices should be handled in a manner that will prevent hcw and environmental contact with potentially infectious material. it is important to include computers and personal digital assistants used in patient care in policies for cleaning and disinfection of noncritical items. the literature on contamination of computers with pathogens has been summarized, and reports have linked computer contamination to colonization and infections in patients. , although keyboard covers and washable keyboards that can be easily disinfected are available, the infection control benefit of these items and their optimal management have not yet been determined. in all health care settings, providing patients who are on transmission-based precautions with dedicated noncritical medical equipment (eg, stethoscope, blood pressure cuff, electronic thermometer) has proven beneficial for preventing transmission. , , , , when this is not possible, disinfection of this equipment after each use is recommended. other previously published guidelines should be consulted for detailed guidance in developing specific protocols for cleaning and reprocessing medical equipment and patient care items in both routine and special circumstances. , , , , , , in home care, it is preferable to remove visible blood or body fluids from durable medical equipment before it leaves the home. equipment can be cleaned onsite using a detergent/disinfectant and, when possible, should be placed in a plastic bag for transport to the reprocessing location. , although soiled textiles, including bedding, towels, and patient or resident clothing, may be contaminated with pathogenic microorganisms, the risk of disease transmission is negligible if these textiles are handled, transported, and laundered in a safe manner. , , key principles for handling soiled laundry are ( ) avoiding shaking the items or handling them in any way that may aerosolize infectious agents, ( ) avoiding contact of one's body and personal clothing with the soiled items being handled, and ( ) containing soiled items in a laundry bag or designated bin. if a laundry chute is used, it must be maintained to minimize dispersion of aerosols from contaminated items. methods of handling, transporting, and laundering soiled textiles are determined by organizational policy and any applicable regulations; guidance is provided in the guidelines for environmental infection control in health care facilities. rather than rigid rules and regulations, hygienic and common sense storage and processing of clean textiles is recommended. , when laundering is done outside of a health care facility, the clean items must be packaged or completely covered and placed in an enclosed space during transport to prevent contamination with outside air or construction dust that could contain infectious fungal spores that pose a risk for immunocompromised patients. institutions are required to launder garments used as ppe and uniforms visibly soiled with blood or infective material. little data exist on the safety of home laundering of hcw uniforms, but no increase in infection rates was observed in the one published study, and no pathogens were recovered from home-or hospital-laundered scrubs in another study. in the home, textiles and laundry from patients with potentially transmissible infectious pathogens do not require special handling or separate laundering and may be washed with warm water and detergent. , , the management of solid waste emanating from the health care environment is subject to federal and state regulations for medical and nonmedical waste. , no additional precautions are needed for nonmedical solid waste removed from rooms of patients on transmission-based precautions. solid waste may be contained in a single bag of sufficient strength. the combination of hot water and detergents used in dishwashers is sufficient to decontaminate dishware and eating utensils. therefore, no special precautions are needed for dishware (eg, dishes, glasses, cups) or eating utensils. reusable dishware and utensils may be used for patients requiring transmission-based precautions. in the home and other communal settings, eating utensils and drinking vessels should not be shared, consistent with principles of good personal hygiene and to help prevent transmission of respiratory viruses, herpes simplex virus, and infectious agents that infect the gastrointestinal tract and are transmitted by the fecal/oral route (eg, hepatitis a virus, noroviruses). if adequate resources for cleaning utensils and dishes are not available, then disposable products may be used. important adjunctive measures that are not considered primary components of programs to prevent transmission of infectious agents but nonetheless improve the effectiveness of such programs include ( ) antimicrobial management programs, ( ) postexposure chemoprophylaxis with antiviral or antibacterial agents, ( ) vaccines used both for pre-exposure and postexposure prevention, and ( ) screening and restricting visitors with signs of transmissible infections. detailed discussion of judicious use of antimicrobial agents is beyond the scope of this document; however, this topic has been addressed in a previous cdc guideline (http://www.cdc.gov/ncidod/dhqp/pdf/ar/ mdroguideline .pdf). ii.n. . chemoprophylaxis. antimicrobial agents and topical antiseptics may be used to prevent infection and potential outbreaks of selected agents. infections for which postexposure chemoprophylaxis is recommended under defined conditions include b pertussis, , n meningitides, b anthracis after environmental exposure to aeosolizable material, influenza virus, hiv, and group a streptococcus. orally administered antimicrobials also may be used under defined circumstances for mrsa decolonization of patients or hcws. another form of chemoprophylaxis involves the use of topical antiseptic agents. for example, triple dye is routinely used on the umbilical cords of term newborns to reduce the risk of colonization, skin infections, and omphalitis caused by s aureus, including mrsa, and group a streptococcus. , extension of the use of triple dye to low birth weight infants in a nicu was one component of a program that controlled a long-standing mrsa outbreak. topical antiseptics (eg, mupirocin) also are used for decolonization of hcws or selected patients colonized with mrsa, as discussed in the mdro guideline , [ ] [ ] [ ] [ ] ii.n. . immunoprophylaxis. certain immunizations recommended for susceptible hcws have decreased the risk of infection and the potential for transmission in health care facilities. , the osha mandate requiring employers to offer hbv vaccination to hcws has played a substantial role in the sharp decline in incidence of occupational hbv infection. , the routine administration of varicella vaccine to hcws has decreased the need to place susceptible hcws on administrative leave after exposure to patients with varicella. in addition, reports of health care-associated transmission of rubella in obstetric clinics , and measles in acute care settings demonstrate the importance of immunization of susceptible hcws against childhood diseases. many states have requirements for vaccination of hcws for measles and rubella in the absence of evidence of immunity. annual influenza vaccine campaigns targeted at patients and hcws in ltcfs and acute care settings have been instrumental in preventing or limiting institutional outbreaks; consequently, increasing attention is being directed toward improving influenza vaccination rates in hcws. , , , [ ] [ ] [ ] transmission of b pertussis in health care facilities has been associated with large and costly outbreaks that include both hcws and patients. , , , , , , , hcws in close contact with infants with pertussis are at particularly high risk because of waning immunity and, until , the absence of a vaccine appropriate for adults. but acellular pertussis vaccines were licensed in the united states in , for use in individuals age to years and the other for use in those age to years. current advisory committee on immunization practices provisional recommendations include immunization of adolescents and adults, especially those in contact with infants under age months and hcws with direct patient contact. , immunization of children and adults will help prevent the introduction of vaccine-preventable diseases into health care settings. the recommended immunization schedule for children is published annually in the january issues of the morbidity and mortality weekly report, with interim updates as needed. , an adult immunization schedule also is available for healthy adults and those with special immunization needs due to high-risk medical conditions. some vaccines are also used for postexposure prophylaxis of susceptible individuals, including varicella, influenza, hepatitis b, and smallpox vaccines. , in the future, administration of a newly developed s aureus conjugate vaccine (still under investigation) to selected patients may provide a novel method of preventing health care-associated s aureus (including mrsa) infections in high-risk groups (eg, hemodialysis patients and candidates for selected surgical procedures). , immune globulin preparations also are used for postexposure prophylaxis of certain infectious agents under specified circumstances (eg, varicella-zoster virus, hbv, rabies, measles and hepatitis a virus , , ). the rsv monoclonal antibody preparation palivizumab may have contributed to controlling a nosocomial outbreak of rsv in one nicu, but there is insufficient evidence to support a routine recommendation for its use in this setting. ii.n. , , , and sars , [ ] [ ] [ ] . effective methods for visitor screening in health care settings have not yet been studied, however. visitor screening is especially important during community outbreaks of infectious diseases and for high-risk patient units. sibling visits are often encouraged in birthing centers, postpartum rooms, pediatric inpatient units, picus, and residential settings for children; in hospital settings, a child visitor should visit only his or her own sibling. screening of visiting siblings and other children before they are allowed into clinical areas is necessary to prevent the introduction of childhood illnesses and common respiratory infections. screening may be passive, through the use of signs to alert family members and visitors with signs and symptoms of communicable diseases not to enter clinical areas. more active screening may include the completion of a screening tool or questionnaire to elicit information related to recent exposures or current symptoms. this information is reviewed by the facility staff, after which the visitor is either permitted to visit or is excluded. family and household members visiting pediatric patients with pertussis and tuberculosis may need to be screened for a history of exposure, as well as signs and symptoms of current infection. potentially infectious visitors are excluded until they receive appropriate medical screening, diagnosis, or treatment. if exclusion is not considered to be in the best interest of the patient or family (ie, primary family members of critically or terminally ill patients), then the symptomatic visitor must wear a mask while in the health care facility and remain in the patient's room, avoiding exposure to others, especially in public waiting areas and the cafeteria. visitor screening is used consistently on hsct units. , however, considering the experience during the sars outbreaks and the potential for pandemic influenza, developing effective visitor screening systems will be beneficial. education concerning respiratory hygiene/cough etiquette is a useful adjunct to visitor screening. ii.n. .b. use of barrier precautions by visitors. the use of gowns, gloves, and masks by visitors in health care settings has not been addressed specifically in the scientific literature. some studies included the use of gowns and gloves by visitors in the control of mdros but did not perform a separate analysis to determine whether their use by visitors had a measurable impact. [ ] [ ] [ ] family members or visitors who are providing care to or otherwise are in very close contact with the patient (eg, feeding, holding) may also have contact with other patients and could contribute to transmission in the absence of effective barrier precautions. specific recommendations may vary by facility or by unit and should be determined by the specific level of interaction. there are tiers of hicpac/cdc precautions to prevent transmission of infectious agents, standard precautions and transmission-based precautions. standard precautions are intended to be applied to the care of all patients in all health care settings, regardless of the suspected or confirmed presence of an infectious agent. implementation of standard precautions constitutes the primary strategy for the prevention of health care-associated transmission of infectious agents among patients and hcws. transmission-based precautions are for patients who are known or suspected to be infected or colonized with infectious agents, including certain epidemiologically important pathogens, which require additional control measures to effectively prevent transmission. because the infecting agent often is not known at the time of admission to a health care facility, transmission-based precautions are used empirically, according to the clinical syndrome and the likely etiologic agents at the time, and then modified when the pathogen is identified or a transmissible infectious etiology is ruled out. examples of this syndromic approach are presented in table . the hicpac/cdc guidelines also include recommendations for creating a protective environment for allogeneic hsct patients. the specific elements of standard and transmission-based precautions are discussed in part ii of this guideline. in part iii, the circumstances in which standard precautions, transmission-based precautions, and a protective environment are applied are discussed. tables and summarize the key elements of these sets of precautions standard precautions combine the major features of universal precautions , and body substance isolation and are based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents. standard precautions include a group of infection prevention practices that apply to all patients, regardless of suspected or confirmed infection status, in any setting in which health care is delivered (table ). these include hand hygiene; use of gloves, gown, mask, eye protection, or face shield, depending on the anticipated exposure; and safe injection practices. also, equipment or items in the patient environment likely to have been contaminated with infectious body fluids must be handled in a manner to prevent transmission of infectious agents (eg, wear gloves for direct contact, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient). the application of standard precautions during patient care is determined by the nature of the hcw-patient interaction and the extent of anticipated blood, body fluid, or pathogen exposure. for some interactions (eg, performing venipuncture), only gloves may be needed; during other interactions (eg, intubation), use of gloves, gown, and face shield or mask and goggles is necessary. education and training on the principles and rationale for recommended practices are critical elements of standard precautions because they facilitate appropriate decision-making and promote adherence when hcws are faced with new circumstances. , [ ] [ ] [ ] [ ] [ ] [ ] an example of the importance of the use of standard precautions is intubation, especially under emergency circumstances when infectious agents may not be suspected, but later are identified (eg, sars-cov, n meningitides). the application of standard precautions is described below and summarized in table . guidance on donning and removing gloves, gowns and other ppe is presented in figure . standard precautions are also intended to protect patients by ensuring that hcws do not carry infectious agents to patients on their hands or via equipment used during patient care. , , the strategy proposed has been termed respiratory hygiene/cough etiquette , and is intended to be incorporated into infection control practices as a new component of standard precautions. the strategy is targeted at patients and accompanying family members and friends with undiagnosed transmissible respiratory infections, and applies to any person with signs of illness including cough, congestion, rhinorrhea, or increased production of respiratory secretions when entering a health care facility. , , the term cough etiquette is derived from recommended source control measures for m tuberculosis. , the elements of respiratory hygiene/cough etiquette include ( ) education of health care facility staff, patients, and visitors; ( ) posted signs, in language(s) appropriate to the population served, with instructions to patients and accompanying family members or friends; ( ) source control measures (eg, covering the mouth/nose with a tissue when coughing and prompt disposal of used tissues, using surgical masks on the coughing person when tolerated and appropriate); ( ) hand hygiene after contact with respiratory secretions; and ( ) spatial separation, ideally . feet, of persons with respiratory infections in common waiting areas when possible. covering sneezes and coughs and placing masks on coughing patients are proven means of source containment that prevent infected persons from dispersing respiratory secretions into the air. , , , masking may be difficult in some settings, (eg, pediatrics), in which case the emphasis by necessity may be on cough etiquette. physical proximity of , feet has been associated with an increased risk for transmission of infections through the droplet route (eg, n meningitidis and group a streptococcus ) and thus supports the practice of distancing infected persons from others who are not infected. the effectiveness of good hygiene practices, especially hand hygiene, in preventing transmission of viruses and reducing the incidence of respiratory infections both within and outside [ ] [ ] [ ] health care settings is summarized in several reviews. , , these measures should be effective in decreasing the risk of transmission of pathogens contained in large respiratory droplets (eg, influenza virus, adenovirus, b pertussis, and m pneumoniae ). although fever will be present in many respiratory infections, patients with pertussis and mild upper respiratory tract infections are often afebrile. therefore, the absence of fever does not always exclude a respiratory infection. patients who have asthma, allergic rhinitis, or chronic obstructive lung disease also may be coughing and sneezing. although these patients often are not infectious, cough etiquette measures are prudent. hcws are advised to observe droplet precautions (ie, wear a mask) and hand hygiene when examining and caring for patients with signs and symptoms of a respiratory infection. hcws who have a respiratory infection are advised to avoid direct patient contact, especially with high-risk patients. if this is not possible, then a mask should be worn while providing patient care. iii.a. .b. safe injection practices. the investigation of large outbreaks of hbv and hcv among patients in ambulatory care facilities in the united states identified a need to define and reinforce safe injection practices. the outbreaks occurred in a private medical practice, a pain clinic, an endoscopy clinic, and a hematology/oncology clinic. the primary breaches in infection control practice that contributed to these outbreaks were reinsertion of used needles into a multiple-dose vial or solution container (eg, saline bag) and use of a single needle/syringe to administer intravenous medication to multiple patients. in of these outbreaks, preparation of medications in the same workspace where used needle/syringes were dismantled also may have been a contributing factor. these and other outbreaks of viral hepatitis could have been prevented by adherence to basic principles of aseptic technique for the preparation and administration of parenteral medications. , these include the use of a sterile, single-use, disposable needle and syringe for each injection given and prevention of contamination of injection equipment and medication. whenever possible, use of single-dose vials is preferred over multiple-dose vials, especially when medications will be administered to multiple patients. outbreaks related to unsafe injection practices indicate that some hcws are unaware of, do not understand, or do not adhere to basic principles of infection control and aseptic technique. a survey of us health care workers who provide medication through injection found that % to % reused the same needle and/or syringe on multiple patients. among the deficiencies identified in recent outbreaks were a lack of oversight of personnel and failure to follow up on reported breaches in infection control practices in ambulatory settings. therefore, to ensure that all hcws understand and adhere to recommended practices, principles of infection control and aseptic technique need to be reinforced in training programs and incorporated into institutional polices that are monitored for adherence. iii.a. .c. infection control practices for special lumbar puncture procedures. in , the cdc investigated cases of postmyelography meningitis that either were reported to the cdc or identified through a survey of the emerging infections network of the infectious disease society of america. blood and/or cerebrospinal fluid of all cases yielded streptococcal species consistent with oropharyngeal flora and there were changes in the csf indices and clinical status indicative of bacterial meningitis. equipment and products used during these procedures (eg, contrast media) were excluded as probable sources of contamination. procedural details available for cases determined that antiseptic skin preparations and sterile gloves had been used. however, none of the clinicians wore a face mask, giving rise to the speculation that droplet transmission of oralpharyngeal flora was the most likely explanation for these infections. bacterial meningitis after myelography and other spinal procedures (eg, lumbar puncture, spinal and epidural anesthesia, intrathecal chemotherapy) has been reported previously. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] as a result, the question of whether face masks should be worn to prevent droplet spread of oral flora during spinal procedures (eg, myelography, lumbar puncture, spinal anesthesia) has been debated. , face masks are effective in limiting the dispersal of oropharyngeal droplets and are recommended for the placement of central venous catheters. in october , hicpac reviewed the evidence and concluded that there is sufficient experience to warrant the additional protection of a face mask for the individual placing a catheter or injecting material into the spinal or epidural space. there are categories of transmission-based precautions: contact precautions, droplet precautions, and airborne precautions. transmission-based precautions are used when the route(s) of transmission is (are) not completely interrupted using standard precautions alone. for some diseases that have multiple routes of transmission (eg, sars), more than transmission-based precautions category may be used. when used either singly or in combination, they are always used in addition to standard precautions. see appendix a for recommended precautions for specific infections. when transmission-based precautions are indicated, efforts must be made to counteract possible adverse effects on patients (ie, anxiety, depression and other mood disturbances, - perceptions of stigma, reduced contact with clinical staff, [ ] [ ] [ ] and increases in preventable adverse events ) to improve acceptance by the patients and adherence by hcws. iii.b. . contact precautions. contact precautions are intended to prevent transmission of infectious agents, including epidemiologically important microorganisms, which are spread by direct or indirect contact with the patient or the patient's environment as described in section i.b. .a. the specific agents and circumstance for which contact precautions are indicated are found in appendix a. the application of contact precautions for patients infected or colonized with mdros is described in the hicpac/cdc mdro guideline. contact precautions also apply where the presence of excessive wound drainage, fecal incontinence, or other discharges from the body suggest an increased potential for extensive environmental contamination and risk of transmission. a single-patient room is preferred for patients who require contact precautions. when a single-patient room is not available, consultation with infection control personnel is recommended to assess the various risks associated with other patient placement options (eg, cohorting, keeping the patient with an existing roommate). in multipatient rooms, $ feet spatial separation between beds is advised to reduce the opportunities for inadvertent sharing of items between the infected/colonized patient and other patients. hcws caring for patients on contact precautions wear a gown and gloves for all interactions that may involve contact with the patient or potentially contaminated areas in the patient's environment. donning ppe on room entry and discarding before exiting the patient room is done to contain pathogens, especially those that have been implicated in transmission through environmental contamination (eg, vre, c difficile, noroviruses and other intestinal tract pathogens, rsv). , , , , , , iii.b. . droplet precautions. droplet precautions are intended to prevent transmission of pathogens spread through close respiratory or mucous membrane contact with respiratory secretions as described in section i.b. .b. because these pathogens do not remain infectious over long distances in a health care facility, special air handling and ventilation are not required to prevent droplet transmission. infectious agents for which droplet precautions are indicated are listed in appendix a and include b pertussis, influenza virus, adenovirus, rhinovirus, n meningitides, and group a streptococcus (for the first hours of antimicrobial therapy). a single-patient room is preferred for patients who require droplet precautions. when a single-patient room is not available, consultation with infection control personnel is recommended to assess the various risks associated with other patient placement options (eg, cohorting, keeping the patient with an existing roommate). spatial separation of $ feet and drawing the curtain between patient beds is especially important for patients in multibed rooms with infections transmitted by the droplet route. hcws wear a mask (a respirator is not necessary) for close contact with infectious patient; the mask is generally donned on room entry. patients on droplet precautions who must be transported outside of the room should wear a mask if tolerated and follow respiratory hygiene/cough etiquette. iii.b. . airborne precautions. airborne precautions prevent transmission of infectious agents that remain infectious over long distances when suspended in the air (eg, rubeola virus [measles], varicella virus [chickenpox], m tuberculosis, and possibly sars-cov), as described in section i.b. .c and appendix a. the preferred placement for patients who require airborne precautions is in an aiir, a single-patient room equipped with special air handling and ventilation capacity that meet the aia/facility guidelines institute standards for aiirs (ie, monitored negative pressure relative to the surrounding area; air exchanges per hour for new construction and renovation and air exchanges per hour for existing facilities; air exhausted directly to the outside or recirculated through hepa filtration before return). , some states require the availability of such rooms in hospitals, emergency departments, and nursing homes that care for patients with m tuberculosis. a respiratory protection program that includes education about use of respirators, fit testing, and user seal checks is required in any facility with aiirs. in settings where airborne precautions cannot be implemented due to limited engineering resources (eg, physician offices), masking the patient, placing the patient in a private room (eg, office examination room) with the door closed, and providing n or higher-level respirators or masks if respirators are not available for hcws will reduce the likelihood of airborne transmission until the patient is either transferred to a facility with an aiir or returned to the home environment, as deemed medically appropriate. hcws caring for patients on airborne precautions wear a mask or respirator, depending on the disease-specific recommendations (see section ii.e. , table , and appendix a), that is donned before room entry. whenever possible, nonimmune hcws should not care for patients with vaccine-preventable airborne diseases (eg, measles, chickenpox, smallpox). diagnosis of many infections requires laboratory confirmation. because laboratory tests, especially those that depend on culture techniques, often require or more days for completion, transmission-based precautions must be implemented while test results are pending, based on the clinical presentation and likely pathogens. use of appropriate transmission-based precautions at the time a patient develops symptoms or signs of transmissible infection, or arrives at a health care facility for care, reduces transmission opportunities. although it is not possible to identify prospectively all patients needing transmission-based precautions, certain clinical syndromes and conditions carry a sufficiently high risk to warrant their use empirically while confirmatory tests are pending (see table ). icps are encouraged to modify or adapt this table according to local conditions. transmission-based precautions remain in effect for limited periods (ie, while the risk for transmission of the infectious agent persists or for the duration of the illness (see appendix a). for most infectious diseases, this duration reflects known patterns of persistence and shedding of infectious agents associated with the natural history of the infectious process and its treatment. for some diseases (eg, pharyngeal or cutaneous diphtheria, rsv), transmission-based precautions remain in effect until culture or antigen-detection test results document eradication of the pathogen and, for rsv, symptomatic disease is resolved. for other diseases (eg, m tuberculosis), state laws and regulations and health care facility policies may dictate the duration of precautions. in immunocompromised patients, viral shedding can persist for prolonged periods of time (many weeks to months) and transmission to others may occur during that time; therefore, the duration of contact and/or droplet precautions may be prolonged for many weeks. , [ ] [ ] [ ] [ ] [ ] [ ] the duration of contact precautions for patients who are colonized or infected with mdros remains undefined. mrsa is the only mdro for which effective decolonization regimens are available. however, carriers of mrsa who have negative nasal cultures after a course of systemic or topical therapy may resume shedding mrsa in the weeks after therapy. , although early guidelines for vre suggested discontinuation of contact precautions after stool cultures obtained at weekly intervals proved negative, subsequent experiences have indicated that such screening may fail to detect colonization that can persist for . year. , [ ] [ ] [ ] likewise, available data indicate that colonization with vre, mrsa, and possibly mdr-gnb can persist for many months, especially in the presence of severe underlying disease, invasive devices, and recurrent courses of antimicrobial agents. it may be prudent to assume that mdro carriers are colonized permanently and manage them accordingly. alternatively, an interval free of hospitalizations, antimicrobial therapy, and invasive devices (eg, or months) before reculturing patients to document clearance of carriage may be used. determination of the best strategy awaits the results of additional studies. see the hicpac/cdc mdro guideline for a discussion of possible criteria to discontinue contact precautions for patients colonized or infected with mdros. although transmission-based precautions generally apply in all health care settings, exceptions exist. for example, in home care, aiirs are not available. furthermore, family members already exposed to diseases such as varicella and tuberculosis would not use masks or respiratory protection, but visiting hcws would need to use such protection. similarly, management of patients colonized or infected with mdros may necessitate contact precautions in acute care hospitals and in some ltcfs when there is continued transmission, but the risk of transmission in ambulatory care and home care has not been defined. consistent use of standard precautions may suffice in these settings, but more information is needed. a pe is designed for allogeneic hsct patients to minimize fungal spore counts in the air and reduce the risk of invasive environmental fungal infections (see table for specifications). , [ ] [ ] [ ] the need for such controls has been demonstrated in studies of aspergillosis outbreaks associated with construction. , , , , as defined by the aia and presented in detail in the cdc's guideline for environmental infection control in health care facilities, , air quality for hsct patients is improved through a combination of environmental controls that include ( ) hepa filtration of incoming air, ( ) directed room air flow, ( ) positive room air pressure relative to the corridor, ( ) well-sealed rooms (including sealed walls, floors, ceilings, windows, electrical outlets) to prevent flow of air from the outside, ( ) ventilation to provide $ air changes per hour, ( ) strategies to minimize dust (eg, scrubbable surfaces rather than upholstery and carpet, and routinely cleaning crevices and sprinkler heads), and ( ) prohibiting dried and fresh flowers and potted plants in the rooms of hsct patients. the latter is based on molecular typing studies that have found indistinguishable strains of aspergillus terreus in patients with hematologic malignancies and in potted plants in the vicinity of the patients. [ ] [ ] [ ] the desired quality of air may be achieved without incurring the inconvenience or expense of laminar airflow. , to prevent inhalation of fungal spores during periods when construction, renovation, or other dust-generating activities that may be ongoing in and around the health care facility, it has been recommended that severely immunocompromised patients wear a high-efficiency respiratory protection device (eg, an n respirator) when they leave the pe. , , the use of masks or respirators by hsct patients when they are outside of the pe for prevention of environmental fungal infections in the absence of construction has not been evaluated. a pe does not include the use of barrier precautions beyond those indicated for standard precuations and transmission-based precautions. no published reports support the benefit of placing patients undergoing solid organ transplantation or other immunocompromised patients in a pe. these recommendations are designed to prevent transmission of infectious agents among patients and hcws in all settings where health care is delivered. as in other cdc/hicpac guidelines, each recommendation is categorized on the basis of existing scientific data, theoretical rationale, applicability, and, when possible, economic impact. the cdc/hicpac system for categorizing recommendations is as follows: category ia. strongly recommended for implementation and strongly supported by well-designed experimental, clinical, or epidemiologic studies. category ib. strongly recommended for implementation and supported by some experimental, clinical, or epidemiologic studies and a strong theoretical rationale. category ic. required for implementation, as mandated by federal and/or state regulation or standard. category ii. suggested for implementation and supported by suggestive clinical or epidemiologic studies or a theoretical rationale. no recommendation; unresolved issue. practices for which insufficient evidence or no consensus regarding efficacy exists. health care organization administrators should ensure the implementation of recommendations specified in this section. agents into the objectives of the organization's patient and occupational safety programs. assume that every person is potentially infected or colonized with an organism that could be transmitted in the health care setting and apply the following infection control practices during the delivery of health care. iv.a. . during the delivery of health care, avoid unnecessary touching of surfaces in close proximity to the patient to prevent both contamination of clean hands from environmental surfaces and transmission of pathogens from contaminated hands to surfaces. airborne precautions does not need to wear a mask or respirator during transport if the patient is wearing a mask and infectious skin lesions are covered. category ii v.d. . exposure management immunize or provide the appropriate immune globulin to susceptible persons as soon as possible after unprotected contact (ie, exposure) to a patient with measles, varicella, or smallpox: category ia d administer measles vaccine to exposed susceptible persons within hours after the exposure or administer immune globulin within days of the exposure event for high-risk persons in whom vaccine is contraindicated. , - d administer varicella vaccine to exposed susceptible persons within hours after the exposure or administer varicella immune globulin (vzig or an alternative product), when available, within hours for high-risk persons in whom vaccine is contraindicated (eg, immunocompromised patients, pregnant women, newborns whose mother's varicella onset was , days before or within hours after delivery). , - d administer smallpox vaccine to exposed susceptible persons within days after exposure. vi. protective environment (see table airborne infection isolation room (aiir). formerly known as a negative-pressure isolation room, an aiir is a single-occupancy patient care room used to isolate persons with a suspected or confirmed airborne infectious disease. environmental factors are controlled in aiirs to minimize the transmission of infectious agents that are usually transmitted from person to person by droplet nuclei associated with coughing or aerosolization of contaminated fluids. aiirs should provide negative pressure in the room (so that air flows under the door gap into the room), an air flow rate of to air changes per hour (ach) ( ach for existing structures, ach for new construction or renovation), and direct exhaust of air from the room to the outside of the building or recirculation of air through a highefficiency particulate air filter before returning to circulation. ( ambulatory care setting. a facility that provides health care to patients who do not remain overnight; examples include hospital-based outpatient clinics, non-hospital-based clinics and physician offices, urgent care centers, surgicenters, free-standing dialysis centers, public health clinics, imaging centers, ambulatory behavioral health and substance abuse clinics, physical therapy and rehabilitation centers, and dental practices. bioaerosol. an airborne dispersion of particles containing whole or parts of biological entities, including bacteria, viruses, dust mites, fungal hyphae, and fungal spores. such aerosols usually consist of a mixture of monodispersed and aggregate cells, spores, or viruses carried by other materials, such as respiratory secretions and/or inert particles. infectious bioaerosols (ie, those containing biological agents capable of causing an infectious disease) can be generated from human sources (eg, expulsion from the respiratory tract during coughing, sneezing, talking, singing, suctioning, or wound irrigation), wet environmental sources (eg, high-volume air consitioning and cooling tower water with legionella) or dry sources (eg, construction dust with spores produced by aspergillus spp). bioaerosols include large respiratory droplets and small droplet nuclei (cole ec. ajic ; : - ) . caregiver.. any person who is not an employee of an organization, is not paid, and provides or assists in providing health care to a patient (eg, family member, friend) and acquire technical training as needed based on the tasks that must be performed. cohorting. in the context of this guideline, this term applies to the practice of grouping patients infected or colonized with the same infectious agent together to confine their care to one area and prevent contact with susceptible patients (cohorting patients). during outbreaks, health care personnel may be assigned to a cohort of patients to further limit opportunities for transmission (cohorting staff). colonization. proliferation of microorganisms on or within body sites without detectable host immune response, cellular damage, or clinical expression. the presence of a microorganism within a host may occur with varying durations but may become a source of potential transmission. in many instances, colonization and carriage are synonymous. droplet nuclei. microscopic particles , mm in size that are the residue of evaporated droplets and are produced when a person coughs, sneezes, shouts, or sings. these particles can remain suspended in the air for prolonged periods and can be carried on normal air currents in a room or beyond, to adjacent spaces or areas receiving exhaust air. engineering controls. removal or isolation of a workplace hazard through technology. an airborne infection isolation room, a protective environment, engineered sharps injury prevention device, and a sharps container are examples of engineering controls. epidemiologically important pathogen. an infectious agent that has one or more of the following characteristics: ( ) readily transmissible, ( ) a proclivity toward causing outbreaks, ( ) possible association with a severe outcome, and ( ) difficult to treat. examples include acinetobacter spp, aspergillus spp, burkholderia cepacia, clostridium difficile, klebsiella or enterobacter spp, extended-spectrum beta-lactamaseproducing gram-negative bacilli, methicillin-resistant staphylococcus aureus, pseudomonas aeruginosa, vancomycin-resistant enterococci, vancomycin-resistant staphylococcus aureus, influenza virus, respiratory syncytial virus, rotavirus, severe acute respiratory syndrome coronavirus, noroviruses, and the hemorrhagic fever viruses. hand hygiene. a general term that applies to any one of the following: ( ) handwashing with plain (nonantimicrobial) soap and water, ( ) antiseptic handwashing (soap containing antiseptic agents and water), ( ) antiseptic handrub (waterless antiseptic product, most often alcohol-based, rubbed on all surfaces of hands), or ( ) surgical hand antisepsis (antiseptic handwash or antiseptic handrub performed preoperatively by surgical personnel to eliminate transient hand flora and reduce resident hand flora). health care-associated infection (hai). an infection that develops in a patient who is cared for in any setting where health care is delivered (eg, acute care hospital, chronic care facility, ambulatory clinic, dialysis center, surgicenter, home) and is related to receiving health care (ie, was not incubating or present at the time health care was provided). in ambulatory and home settings, hai refers to any infection that is associated with a medical or surgical intervention. because the geographic location of infection acquisition is often uncertain, the preferred term is considered to be health care-associated rather than health care-acquired. healthcare epidemiologist. a person whose primary training is medical (md, do) and/or masters-or doctorate-level epidemiology who has received advanced training in health care epidemiology. typically these professionals direct or provide consultation to an infection control program in a hospital, long-term care facility, or health care delivery system (also see infection control professional). health care personnel, health care worker (hcw). any paid or unpaid person who works in a health care setting (eg, any person who has professional or technical training in a health care-related field and provides patient care in a health care setting or any person who provides services that support the delivery of health care such as dietary, housekeeping, engineering, maintenance personnel). hematopoietic stem cell transplantation (hsct). any transplantation of blood-or bone marrow-derived hematopoietic stem cells, regardless of donor type (eg, allogeneic or autologous) or cell source (eg, bone marrow, peripheral blood, or placental/umbilical cord blood), associated with periods of severe immunosuppression that vary with the source of the cells, the intensity of chemotherapy required, and the presence of graft versus host disease (mmwr ; : rr- ). high-efficiency particulate air (hepa) filter. an air filter that removes . . % of particles . . mm (the most penetrating particle size) at a specified flow rate of air. hepa filters may be integrated into the central air handling systems, installed at the point of use above the ceiling of a room, or used as portable units (mmwr ; : rr- ). home care. a wide range of medical, nursing, rehabilitation, hospice, and social services delivered to patients in their place of residence (eg, private residence, senior living center, assisted living facility). home health care services include care provided by home health aides and skilled nurses, respiratory therapists, dieticians, physicians, chaplains, and volunteers; provision of durable medical equipment; home infusion therapy; and physical, speech, and occupational therapy. immunocompromised patient. a patient whose immune mechanisms are deficient because of a congenital or acquired immunologic disorder (eg, human immunodeficiency virus infection, congenital immune deficiency syndromes), chronic diseases such as diabetes mellitus, cancer, emphysema, or cardiac failure, intensive care unit care, malnutrition, and immunosuppressive therapy of another disease process [eg, radiation, cytotoxic chemotherapy, anti-graft rejection medication, corticosteroids, monoclonal antibodies directed against a specific component of the immune system]). the type of infections for which an immunocompromised patient has increased susceptibility is determined by the severity of immunosuppression and the specific component(s) of the immune system that is affected. patients undergoing allogeneic hematopoietic stem cell transplantation and those with chronic graft versus host disease are considered the most vulnerable to health care-associated infections. immunocompromised states also make it more difficult to diagnose certain infections (eg, tuberculosis) and are associated with more severe clinical disease states than persons with the same infection and a normal immune system. infection. the transmission of microorganisms into a host after evading or overcoming defense mechanisms, resulting in the organism's proliferation and invasion within host tissue(s). host responses to infection may include clinical symptoms or may be subclinical, with manifestations of disease mediated by direct organisms pathogenesis and/or a function of cell-mediated or antibody responses that result in the destruction of host tissues. infection control and prevention professional (icp). a person whose primary training is in either nursing, medical technology, microbiology, or epidemiology and who has acquired specialized training in infection control. responsibilities may include collection, analysis, and feedback of infection data and trends to health care providers; consultation on infection risk assessment, prevention, and control strategies; performance of education and training activities; implementation of evidence-based infection control practices or those mandated by regulatory and licensing agencies; application of epidemiologic principles to improve patient outcomes; participation in planning renovation and construction projects (eg, to ensure appropriate containment of construction dust); evaluation of new products or procedures on patient outcomes; oversight of employee health services related to infection prevention; implementation of preparedness plans; communication within the health care setting, with local and state health departments, and with the community at large concerning infection control issues; and participation in research. certification in infection control is available through the certification board of infection control and epidemiology. infection control and prevention program. a multidisciplinary program that includes a group of activities to ensure that recommended practices for the prevention of health care-associated infections are implemented and followed by health care workers, making the health care setting safe from infection for patients and health care personnel. the joint commission on accreditation of healthcare organizations requires the following components of an infection control program for accreditation: ( ) surveillance: monitoring patients and health care personnel for acquisition of infection and/or colonization; ( ) investigation: identification and analysis of infection problems or undesirable trends; ( ) prevention: implementation of measures to prevent transmission of infectious agents and to reduce risks for device-and procedure-related infections; ( ) control: evaluation and management of outbreaks; and ( ) reporting: provision of information to external agencies as required by state and federal laws and regulations (see http://www.jcaho.org). the infection control program staff has the ultimate authority to determine infection control policies for a health care organization with the approval of the organization's governing body. long-term care facility (ltcf). a residential or outpatient facility designed to meet the biopsychosocial needs of persons with sustained self-care deficits. these include skilled nursing facilities, chronic disease hospitals, nursing homes, foster and group homes, institutions for the developmentally disabled, residential care facilities, assisted living facilities, retirement homes, adult day health care facilities, rehabilitation centers, and long-term psychiatric hospitals. mask. a term that applies collectively to items used to cover the nose and mouth and includes both procedure masks and surgical masks (see http://www.fda. gov/cdrh/ode/guidance/ .html# ). multidrug-resistant organism (mdro). in general, a bacterium (excluding mycobacterium tuberculosis) that is resistant to or more classes of antimicrobial agents and usually is resistant to all but or commercially available antimicrobial agents (eg, methicillin-resistant staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing or intrinsically resistant gram-negative bacilli). nosocomial infection. derived from greek words, ''nosos'' (disease) and ''komeion'' (to take care of), refers to any infection that develops during or as a result of an admission to an acute care facility (hospital) and was not incubating at the time of admission. personal protective equipment (ppe). a variety of barriers used alone or in combination to protect mucous membranes, skin, and clothing from contact with infectious agents. ppe includes gloves, masks, respirators, goggles, face shields, and gowns. procedure mask. a covering for the nose and mouth that is intended for use in general patient care situations. these masks generally attach to the face with ear loops rather than ties or elastic. unlike surgical masks, procedure masks are not regulated by the food and drug administration. protective environment. a specialized patient care area, usually in a hospital, with a positive air flow relative to the corridor (ie, air flows from the room to the outside adjacent space). the combination of high-efficiency particulate air filtration, high numbers (. ) of air changes per hour, and minimal leakage of air into the room creates an environment that can safely accommodate patients with a severely compromised immune system (eg, those who have received allogeneic hemopoietic stem cell transplantation) and decrease the risk of exposure to spores produced by environmental fungi. other components include use of scrubbable surfaces instead of materials such as upholstery or carpeting, cleaning to prevent dust accumulation, and prohibition of fresh flowers or potted plants. quasi-experimental study. a study undertaken to evaluate interventions but do not use randomization as part of the study design. these studies are also referred to as nonrandomized, pre-/postintervention study designs. these studies aim to demonstrate causality between an intervention and an outcome but cannot achieve the level of confidence concerning an attributable benefit obtained through a randomized controlled trial. in hospitals and public health settings, randomized control trials often cannot be implemented due to ethical, practical, and urgency reasons; therefore, quasi-experimental design studies are commonly used. however, even if an intervention appears to be effective statistically, the question can be raised as to the possibility of alternative explanations for the result. such a study design is used when it is not logistically feasible or ethically possible to conduct a randomized controlled trial, (eg, during outbreaks). within the classification of quasi-experimental study designs, there is a hierarchy of design features that may contribute to validity of results (harris et al. cid : : . residential care setting. a facility in which people live, minimal medical care is delivered, and the psychosocial needs of the residents are provided for. respirator. a personal protective device worn by health care personnel over the nose and mouth to protect them from acquiring airborne infectious diseases due to inhalation of infectious airborne particles , mm in size. these include infectious droplet nuclei from patients with mycobacterium tuberculosis, variola virus [smallpox], or severe acute respiratory syndrome and dust particles that contain infectious particles, such as spores of environmental fungi (eg, aspergillus spp). the centers for disease control and prevention's national institute for occupational safety and health (niosh) certifies respirators used in health care settings (see http://www.cdc.gov/niosh/topics/respirators/). the n disposable particulate, air-purifying respirator is the type used most commonly by health care personnel. other respirators used include n- and n- particulate respirators, powered air-purifying respirators with high-efficiency filters, and nonpowered fullfacepiece elastomeric negative pressure respirators. a listing of niosh-approved respirators can be found at http://www.cdc.gov/niosh/npptl/respirators/disp_part/ particlist.html. respirators must be used in conjunction with a complete respiratory protection program, as required by the occupational safety and health administration, which includes fit testing, training, proper selection of respirators, medical clearance, and respirator maintenance. respiratory hygiene/cough etiquette. a combination of measures designed to minimize the transmission of respiratory pathogens through droplet or airborne routes in health care settings. the components of respiratory hygiene/cough etiquette are ( ) covering the mouth and nose during coughing and sneezing, ( ) using tissues to contain respiratory secretions with prompt disposal into a no-touch receptacle, ( ) offering a surgical mask to persons who are coughing to decrease contamination of the surrounding environment, and ( ) turning the head away from others and maintaining spatial separation (ideally . feet) when coughing. these measures are targeted to all patients with symptoms of respiratory infection and their accompanying family members or friends beginning at the point of initial encounter with a health care setting (eg, reception/triage in emergency departments, ambulatory clinics, health care provider offices). (srinivasin a iche ; : ; http://www.cdc.gov/flu/ professionals/infectioncontrol/resphygiene.htm). safety culture. shared perceptions of workers and management regarding the level of safety in the work environment. a hospital safety climate includes the following organizational components: ( ) senior management support for safety programs, ( ) absence of workplace barriers to safe work practices, ( ) cleanliness and orderliness of the worksite, ( ) minimal conflict and good communication among staff members, ( ) frequent safety-related feedback/training by supervisors, and ( ) availability of ppe and engineering controls. source control. the process of containing an infectious agent either at the portal of exit from the body or within a confined space. the term is applied most frequently to containment of infectious agents transmitted by the respiratory route but could apply to other routes of transmission, (eg, a draining wound, vesicular or bullous skin lesions). respiratory hygiene/cough etiquette that encourages individuals to ''cover your cough'' and/or wear a mask is a source control measure. the use of enclosing devices for local exhaust ventilation (eg, booths for sputum induction or administration of aerosolized medication) is another example of source control. standard precautions. a group of infection prevention practices that apply to all patients, regardless of suspected or confirmed diagnosis or presumed infection status. standard precautions represents a combination and expansion of universal precautions and body substance isolation. standard precautions are based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents. standard precautions include hand hygiene and, depending on the anticipated exposure, use of gloves, gown, mask, eye protection, or face shield. in addition, equipment or items in the patient environment likely to have been contaminated with infectious fluids must be handled in a manner to prevent transmission of infectious agents (eg, wear gloves for handling, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient). surgical mask. a device worn over the mouth and nose by operating room personnel during surgical procedures to protect both surgical patients and operating room personnel from transfer of microorganisms and body fluids. surgical masks also are used to protect health care personnel from contact with large infectious droplets (. mm in size). according to draft guidance issued by the food and drug administration on may , , surgical masks are evaluated using standardized testing procedures for fluid resistance, bacterial filtration efficiency, differential pressure (air exchange), and flammability to mitigate the risks to health associated with the use of surgical masks. these specifications apply to any masks that are labeled surgical, laser, isolation, or dental or medical procedure (http://www.fda.gov/cdrh/ode/guidance/ .html# ). surgical masks do not protect against inhalation of small particles or droplet nuclei and should not be confused with particulate respirators that are recommended for protection against selected airborne infectious agents (eg, mycobacterium tuberculosis). other species s use contact precautions for diapered or incontinent persons for the duration of illness or to control institutional outbreaks. giardia lamblia s use contact precautions for diapered or incontinent persons for the duration of illness or to control institutional outbreaks. noroviruses s use contact precautions for diapered or incontinent persons for the duration of illness or to control institutional outbreaks. persons who clean areas heavily contaminated with feces or vomitus may benefit from wearing masks, because virus can be aerosolized from these body substances; , , ensure consistent environmental cleaning and disinfection with focus on restrooms even when apparently unsoiled. , hypochlorite solutions may be required when there is continued transmission. [ ] [ ] [ ] alcohol is less active, but there is no evidence that alcohol antiseptic handrubs are not effective for hand decontamination. cohorting of affected patients to separate airs paces and toilet facilities may help interrupt transmission during outbreaks. rotavirus c di ensure consistent environmental cleaning and disinfection and frequent removal of soiled diapers. prolonged shedding may occur in both immunocompetent and immunocompromised children and the elderly. also for asymptomatic, exposed infants delivered vaginally or by c-section and if mother has active infection and membranes have been ruptured for more than to hours until infant surface cultures obtained at to hours of age negative after hours of incubation. susceptible hcws should not enter room if immune caregivers are available; no recommendation for face protection of immune hcws; no recommendation for type of protection (ie, surgical mask or respirator) for susceptible hcws. in an immunocompromised host with varicella pneumonia, prolong the duration of precautions for duration of illness. postexposure prophylaxis: provide postexposure vaccine as soon as possible but within hours; for susceptible exposed persons for whom vaccine is contraindicated (immunocompromised persons, pregnant women, newborns whose mother's varicella onset is # days before delivery or within hours after delivery) provide vzig, when available, within hours; if unavailable, use ivig. provide airborne precautions for exposed susceptible persons and exclude exposed susceptible health care workers beginning days after first exposure until days after last exposure or if received vzig, regardless of postexposure vaccination. variola (see smallpox) vibrio parahaemolyticus (see gastroenteritis) vincent's angina (trench mouth) s viral hemorrhagic fevers due to lassa, ebola, marburg, crimean-congo fever viruses s, d, c di single-patient room preferred. emphasize: use of sharps safety devices and safe work practices, hand hygiene; barrier protection against blood and body fluids on entry into room (single gloves and fluid-resistant or impermeable gown, face/eye protection with masks, goggles or face shields), and appropriate waste handling. use n or higher-level respirator when performing aerosol-generating procedures. largest viral load in final stages of illness when hemorrhage may occur; additional ppe, including double gloves, leg and shoe coverings may be used, especially in resource-limited settings where options for cleaning and laundry are limited. notify public health officials immediately if ebola is suspected. , , , also see table *type of precautions: a, airborne precautions; c, contact; d, droplet; s, standard; when a, c, and d are specified, also use s. y duration of precautions: cn, until off antimicrobial treatment and culture-negative; di, duration of illness (with wound lesions, di means until wounds stop draining); de, until environment completely decontaminated; u, until time specified in hours (hrs) after initiation of effective therapy; unknown: criteria for establishing eradication of pathogen has not been determined guideline for isolation precautions in hospitals. the hospital infection control practices advisory committee. infect control the use and interpretation of quasi-experimental studies in infectious diseases effect of regression to the mean on decision making in health care randomized trials or observational tribulations? comparison of evidence of treatment effects in randomized and nonrandomized studies the use of systematic reviews and meta-analyses in infection control and hospital epidemiology a systematic review of quasi-experimental study designs in the fields of infection control and antibiotic resistance system-wide surveillance for clinical encounters by patients previously identified with mrsa and vre foundations of the severe acute respiratory syndrome preparedness and response plan for healthcare facilities guidelines for environmental infection control in health-care facilities. recommendations of cdc and the healthcare infection control practices advisory committee (hicpac) guidelines for preventing the transmission of mycobacterium tuberculosis in healthcare settings guidelines for design and construction of hospital and health care facilities recommendations of cdc and the healthcare infection control practices advisory committee guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. recommendations of cdc, the infectious disease society of america, and the american society of blood and marrow transplantation guideline for hand hygiene in health-care settings. recommendations of the healthcare infection control practices advisory committee and the hicpac/shea/apic/idsa hand hygiene task force, society for healthcare epidemiology of america/association for professionals in infection control/infectious diseases society of america guideline for infection 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efficacy of selected hand hygiene agents used to remove bacillus atrophaeus (a surrogate of bacillus anthracis) from contaminated hands banning artificial nails from health care settings prospective, controlled study of vinyl glove use to interrupt clostridium difficile nosocomial transmission latex glove penetration by pathogens: a review of the literature pcr-based method for detecting viral penetration of medical exam gloves association of contaminated gloves with transmission of acinetobacter calcoaceticus var. anitratus in an intensive care unit epidemiology and prevention of pediatric viral respiratory infections in health-care institutions nosocomial transmission of rotavirus from patients admitted with diarrhea safety and cleaning of medical materials and devices surface fixation of dried blood by glutaraldehyde and peracetic acid role of environmental contamination in the transmission of vancomycin-resistant enterococci disinfection of hospital rooms contaminated with 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rooms an evaluation of hospital special ventilation room pressures nosocomial transmission of tuberculosis associated with a draining abscess an outbreak of tuberculosis among hospital personnel caring for a patient with a skin ulcer secondary measles vaccine failure in healthcare workers exposed to infected patients a cluster of primary varicella cases among healthcare workers with false-positive varicella zoster virus titers airborne transmission of nosocomial varicella from localized zoster zoster-causing varicella: current dangers of contagion without isolation detection of aerosolized varicella-zoster virus dna in patients with localized herpes zoster measles vaccination after exposure to natural measles use of live measles virus vaccine to abort an expected outbreak of measles within a closed population measles, mumps, and rubella vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the advisory 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diseases manual outbreak of amebiasis in a family in the netherlands parasitic disease control in a residential facility for the mentally retarded: failure of selected isolation procedures west nile virus: epidemiology, clinical presentation, diagnosis, and prevention person-to-person transmission of brucella melitensis isolation of brucella melitensis from human sperm prevention of laboratoryacquired brucellosis chlamydia pneumoniae as a new source of infectious outbreaks in nursing homes an epidemic of infections due to chlamydia pneumoniae in military conscripts an outbreak of surgical wound infections due to clostridium perfringens acquisition of coccidioidomycosis at necropsy by inhalation of coccidioidal endospores donor-related coccidioidomycosis in organ transplant recipients centers for disease control and prevention. acute hemorrhagic conjunctivitis outbreak caused by coxsackievirus a outbreak of adenovirus type in a neonatal intensive care unit an outbreak of epidemic keratoconjunctivtis in a pediatric unit due to adenovirus type a large outbreak of epidemic keratoconjunctivitis: problems in controlling nosocomial spread nosocomial transmission of cryptococcosis cryptococcal endophthalmitis after corneal transplantation probable transmission of norovirus on an airplane centers for disease control and prevention. prevention of hepatitis a through active or passive immunization: recommendations of the advisory committee on immunization practices (acip) hepatitis a outbreak in a neonatal intensive care unit: risk factors for transmission and evidence of prolonged viral excretion among preterm infants excretion of hepatitis a virus in the stools of hospitalized hepatitis patients hospital outbreak of hepatitis e herpes simplex virus infections neonatal herpes infection: diagnosis, treatment and prevention human metapneumovirus infection in the united states: clinical manifestations associated with a newly emerging respiratory infection in children listeria moncytogenes cross-contamination in a nursery neonatal listeriosis due to cross-infection confirmed by isoenzyme typing and dna fingerprinting outbreak of neonatal listeriosis associated with mineral oil neonatal cross-infection with listeria monocytogenes nosocomial malaria and saline flush plasmodium falciparum malaria transmitted in hospital through heparin locks nosocomial malaria from contamination of a multidose heparin container with blood hospital-acquired malaria transmitted by contaminated gloves clustering of necrotizing enterocolitis: interruption by infection-control measures how contagious is necrotizing enterocolitis? an outbreak of rotavirus-associated neonatal necrotizing enterocolitis increased risk of illness among nursery staff caring for neonates with necrotizing enterocolitis outbreak of adenovirus pneumonia among adult residents and staff of a chronic care psychiatric facility nosocomial adenovirus infection: molecular epidemiology of an outbreak a recent outbreak of adenovirus type infection in a chronic inpatient facility for the severely handicapped an outbreak of multidrugresistant pneumococcal pneumonia and bacteremia among unvaccinated nursing home residents human-to-human transmission of rabies virus by corneal transplant human rabies prevention, united states, : recommendations of the advisory committee on immunization practices (acip) rhinovirus and the lower respiratory tract concurrent outbreaks of rhinovirus and respiratory syncytial virus in an intensive care nursery: epidemiology and associated risk factors rhinovirus infection associated with serious lower respiratory illness in patients with bronchopulmonary dysplasia nosocomial ringworm in a neonatal intensive care unit: a nurse and her cat nosocomial transmission of trichophyton tonsurans tinea corporis in a rehabilitation hospital molecular epidemiology of staphylococcal scalded skin syndrome in premature infants an outbreak of fatal nosocomial infections due to group a streptococcus on a medical ward an outbreak of group a streptococcal infection among health care workers clusters of invasive group a streptococcal infections in family, hospital, and nursing home settings isolation techniques for use in hospitals us government printing office rethinking the role of isolation practices in the prevention of nosocomial infections the authors and hicpac gratefully acknowledge dr larry strausbaugh for his many contributions and valued guidance in the preparation of this guideline. the mode(s) and risk of transmission for each specific disease agent listed in this appendix were reviewed. principle sources consulted for the development of disease-specific recommendations for the appendix included infectious disease manuals and textbooks. , , the published literature was searched for evidence of person-to-person transmission in health care and non-health care settings with a focus on reported outbreaks that would assist in developing recommendations for all settings where health care is delivered. the following criteria were used to assign transmission-based precautions categories: d a transmission-based precautions category was assigned if there was strong evidence for person-to-person transmission via droplet, contact, or airborne routes in health care or non-health care settings and/or if patient factors (eg, diapered infants, diarrhea, draining wounds) increased the risk of transmission. d transmission-based precautions category assignments reflect the predominant mode(s) of transmission. d if there was no evidence for person-to-person transmission by droplet, contact or airborne routes, then standard precautions were assigned. d if there was a low risk for person-to-person transmission and no evidence of health care-associated transmission, then standard precautions were assigned. d standard precautions were assigned for bloodborne pathogens (eg, hbv, hcv, hiv) in accordance with cdc recommendations for universal precautions issued in . subsequent experience has confirmed the efficacy of standard precautions to prevent exposure to infected blood and body fluid. , , additional information relevant to use of precautions was added in the comments column to assist the caregiver in decision-making. citations were added as needed to support a change in or provide additional evidence for recommendations for a specific disease and for new infectious agents (eg, sars-cov, avian influenza) that have been added to appendix a. the reader may refer to more detailed discussion concerning modes of transmission and emerging pathogens in the background text and for mdro control in the mdro guideline. key: cord- - kfi yvu authors: de graaf, miranda; beck, relja; caccio, simone m; duim, birgitta; fraaij, pieter la; le guyader, françoise s; lecuit, marc; le pendu, jacques; de wit, emmie; schultsz, constance title: sustained fecal-oral human-to-human transmission following a zoonotic event date: - - journal: curr opin virol doi: . /j.coviro. . . sha: doc_id: cord_uid: kfi yvu bacterial, viral and parasitic zoonotic pathogens that transmit via the fecal-oral route have a major impact on global health. however, the mechanisms underlying the emergence of such pathogens from the animal reservoir and their persistence in the human population are poorly understood. here, we present a framework of human-to-human transmission of zoonotic pathogens that considers the factors relevant for fecal-oral human-to-human transmission route at the levels of host, pathogen, and environment. we discuss current data gaps and propose future research directions. in recent years there have been many examples of pathogens crossing the species barrier and infecting humans, although the vast majority of these zoonotic events did not result in sustained human-to-human transmission [ ] [ ] [ ] . nevertheless, the continuing emergence of zoonotic pathogens is a cause of concern globally, especially due to the high morbidity and mortality of pathogens like mers-cov and a/h n influenza virus [ , ] . humanto-human transmission of microorganisms generally occurs via one or multiple transmission routes, including the fecal-oral, airborne, direct contact, or vector-borne route. whilst pathogens including bacteria, parasites and viruses have very different biological properties, they can employ similar routes of transmission and emergence. identification of the mechanisms underlying the effective human-to-human transmission of emerging zoonotic pathogens and their commonalities across different pathogens, may help design of interventions aimed at reducing the risk of sustained human-to-human transmission after a zoonotic event. as part of the activities of the antigone consortium on the emergence of zoonotic pathogens, an expert opinion meeting was organized. using a comparative approach including parasites, bacteria and viruses that transmit via the fecal-oral route, the meeting aimed at identifying the key drivers of sustained human-to-human transmission after a zoonotic event, taking into account the host, the pathogen and the interface (transmission amplifiers). in addition, major knowledge gaps were identified that require future research in order to better control emerging zoonotic pathogens that potentially are transmitted through a fecal-oral route. the main conclusions of this meeting are presented in this perspective. enteric pathogens can be transmitted between humans by the fecal-oral route via direct contact or indirect contact via contaminated fluids, including surface water, food, and carriers such as fomites ( figure ). the risk of a zoonotic pathogen becoming human-to-human transmissible depends on its adaptation to the human host and the environment. to analyze this process, we considered fecal-oral transmission of a zoonotic pathogen between two human hosts as follows; the human host that is infected with a zoonotic pathogen after a zoonotic event is defined as the donor while the susceptible human host that is subsequently infected by the first human host is considered the recipient. the transmission interface is the environment that the pathogen encounters after release from the donor and before infecting the recipient. for sustained fecal-oral human-to-human transmission certain elements in this transmission cycle, which we will refer to as transmission amplifiers, appear essential whereas other elements are not an absolute requirement, but increase the likelihood of transmission. transmission amplifiers may interact and their presence may or may not depend on conditions under which transmission occurs, including for example socio-economic conditions and cultural and behavioral variation. we designed a framework of human-to-human transmission that includes the transmission amplifiers relevant for the fecal-oral transmission route at the levels of host, pathogen, and environment ( figure ). several key transmission amplifiers are specific for fecaloral transmission (figure ), such as the intestinal microbiomes of the donor and recipient hosts. individuals with a healthy intestine are less likely to become infected or colonized by opportunistic pathogens, although the resistance provided by a healthy colonization (microbiome) can, in principle, be disrupted by a pathogenic species depending on its pathogenic potential (virulence) [ , ] . the composition of the human intestinal microbiome is, amongst others dependent on the presence of a functional immune system [ ] [ ] [ ] . changes in microbiome composition, in addition to the impaired immunity itself, may impact the outcome of infection and subsequent transmission. clinical symptoms such as diarrhea and vomiting can increase the likelihood of fecal-oral transmission as they can facilitate the spread of a pathogen into the fecal-oral transmission between humans. after shedding from the host enteric pathogens can be transmitted between humans by the fecal-oral route via direct contact between humans, or via indirect contact via contaminated fluids, including surface water, food, and carriers such as fomites. environment and onto fomites [ ] . remarkably, most pathogens that transmit via the fecal-oral route are very stable and can survive under various conditions, which may be related to the fact that these pathogens have to pass the hostile conditions of the gastrointestinal tract. zoonotic pathogens need to adapt to factors specific to this niche, such as the acidic conditions in the stomach and low oxygen in the large intestine, the temperature and the availability of specific sugars and nutrients. for example, comparative genomics of cryptosporidium parvum genotype iic suggests that the ability to establish an infection in a particular host species may depend in part on the presence of transporters controlling the exchange of metabolites between the host cell and the pathogen [ ] . fecal shedding of a pathogen does not necessarily require replication in the intestine. for example, the hepatitis e virus (hev) is shed via the feces despite its liver tropism [ ] . however, the presence of receptors and the tissue distribution of these receptors is a crucial element for tropism of infection, the shedding of microorganisms in stool and subsequent human-to-human transmission. in addition, it should be noted that not all pathogens that are shed via the feces transmit via the fecal-oral route. several respiratory viruses of zoonotic origin, that are capable of human-to-human transmission, are shed in feces. during sars-cov, mers-cov and influenza a infection, viral rna can be detected in stool. however, for these pathogens there is currently no evidence of fecal-oral transmission resulting in disease [ ] [ ] [ ] [ ] [ ] [ ] . similarly, the enteric pathogen campylobacter subspecies jejuni was transmitted from human-to-human via sexual contact following a zoonotic event [ ] . once a donor is shedding the pathogen, environmental factors at the transmission interface can have a large impact on transmission efficiency. contamination of the surface water after flooding can magnify the size of an outbreak via waterborne and foodborne routes [ ] . food sources can be contaminated by irrigation with sewage-contaminated water or the use of manure that contains traces of human feces, or on site by food-handlers. anecdotally, even food preservation measures can impact transmission as some additives to preserve lettuce were shown to also increase the stability of hepatitis a virus [ ] . transmission via food can have a major impact on the global spread of pathogens. in nearly human-to-human transmission following a zoonotic event de graaf et al. framework for human-to-human transmission after a zoonotic event showing the key transmission amplifiers from the host (triangle), pathogen (blue) and environmental transmission amplifiers (green), respectively. the transmission amplifiers that are specific to the fecal-oral route are indicated with a red star. people were infected during an escherichia coli o :h outbreak in europe, resulting in deaths. epidemiological and trace-back investigations pointed to salad sprouts as the possible contaminated food source [ ] . transmission amplifiers not specific for fecaloral transmission route several factors that are important transmission amplifiers of the likelihood of fecal-oral transmission are generic to most human-to-human transmission routes. the immune system of the human host is an important factor that has to be confronted for sustained human-tohuman transmission. most pathogens that successfully transmit, have acquired genes that can counteract or evade the adaptive and or innate immune responses. pathogens may have adapted through altered domains that are recognized by the cellular or humoral immune system, to evade pre-existing immunity based on previously infecting pathogens. loss of genes or gene function may also be associated with adaptation to the human host. a salmonella enterica serotype typhimurium clone which causes bloodstream infection amongst children and hiv-infected adults in sub-saharan africa, has adapted to these immuno-compromised hosts through loss of gene functions enabling bacterial survival outside the host, whilst retaining the ability to cause enteritis in multiple host species [ ] . with the general population aging and technologies becoming more invasive, medical interventions can become an amplifier of human-to-human transmission. although medical interventions do not necessarily select for human-to-human transmissible pathogens, they can increase the duration of infection, and thereby the likelihood of evolution and adaptation [ ] . for instance, the application of extracorporeal membrane oxygenation prolongs and increases survival in patients with otherwise acute fatal infectious disease [ ] . the use of immune modulatory and suppressive drugs has created a human population that is more susceptible to prolonged pathogen proliferation and shedding [ ] [ ] [ ] [ ] [ ] . an immunodeficient individual was found to excrete a vaccine-derived poliovirus for twenty years. during this time the virus became virulent and changed antigenically [ ] . the unrestrained use of antimicrobial drugs in medical and veterinary care and in agriculture in low-income, middleincome, and high-income countries creates an unprecedented selective pressure that may select for pathogens that are more transmissible. salmonella enterica serotype typhimurium has the ability to develop a super shedder phenotype, that can be induced by antibiotic treatment in mice [ ] . a human reservoir for non-typhoid salmonella (nts) transmission of multiple serotypes was demonstrated in a study of nts-infected patients who continued to shed nts for months up to years, and strains of these patients acquired antimicrobial resistance genes and virulence genes that possibly affected host-pathogen interactions [ ] . the infectious dose, replication kinetics and the number of pathogens being shed can have a major impact on the efficiency of fecal-oral transmission. for example, norovirus and shigella spp. require a low infectious dose and can be transmitted via hands and fomites [ , ] , whereas listeria monocytogenes infections require a high infectious dose [ ] , making these transmission routes less likely. however, surprisingly little is known about the infectious dose for many fecal-orally transmitted human pathogens. as for shedding in the environment, several strategies can be successful, such as shedding of lower amounts of microorganisms over a long period (chronic/persistent infection) and thus a long period of transmission associated with mild clinical symptoms , or shedding of high loads of microorganisms for a relatively short period with significant clinical symptoms [ ] . receptor usage is a key element for successful human-tohuman transmission. not only are the site of the expression of these receptors in the host and the receptor specificity of the pathogen of importance, but also the prevalence of these receptors in the human population can potentially contribute to the likelihood of efficient transmission. for group a rotaviruses attachment to histobloodgroup antigens is an essential step for infection. interestingly, strains of the p [ ] , p[ ] and p [ ] subtypes that are generally found in cattle but can also infect humans, attach to the blood group a epitope [ ] . however, since the frequency of blood group a in human populations ranges from % to %, the majority of individuals is expected to be resistant to infection by these strains, which would constitute a barrier to transmission. sustained human-to-human transmission for a virus with a relatively low r would thus require an adaptation of the glycan binding capacity to the human hbga genetic polymorphism [ ] . hev genotype and exclusively infect humans while genotypes and infect pigs but occasionally infect and transmit between humans [ ] . the high conservation of hev attachment and entry factors may explain the observed cross-species transmission while factors limiting efficient human-to-human transmission are thought to include regulation of subgenomic translation and specific virus-host receptor interactions [ , ] . surprisingly few differences exist between the basic requirements of the different types of pathogens to become human-to-human transmissible. however, bacteria can replicate in the environment whereas viruses and parasites cannot. as the transmittable stages of parasites are environmentally very resistant, and can withstand water treatment processes, parasites are probably more likely to be transmitted via food and water compared to direct fecal-oral-transmission [ , [ _ t d $ d i f f ] ]. genome plasticity is an important factor for all pathogens but while parasites, viruses and bacteria can all adapt by mutations, recombination and lateral gene transfer, viruses can also acquire genes by genome rearrangements and bacteria can acquire mobile genetic elements that carry genes that may encode determinants that facilitate increased fitness in certain conditions. 'for a zoonotic pathogen the risk of becoming human-tohuman transmissible depends on further adaptation to the human host. for efficient fecal-oral transmission amplifiers in the transmission interface appear crucial.' the focus of the public health and emerging infectious disease communities on emerging viruses causing severe infections, has resulted in the discovery of several possible determinants of sustained human-to-human transmission of zoonotic viruses. however, the likelihood of sustained human-to-human fecal-oral transmission after a zoonotic event of any pathogen type is difficult to assess as these events are hardly described in current literature. one could conclude that zoonotic pathogens rarely become human-to-human transmissible through the fecal-oral route because there may be need for dual adaptation, i.e. to the harsh conditions in the environment in addition to the human host, and therefore these events are rare. however, we cannot exclude that we may be missing some of these events, because it can be difficult to distinguish between strictly human and zoonotic pathogens once the latter have established themselves in the human population or because they remain undistinguished with the use of current clinical microbiology tools. for example, recent results strongly suggest that a pig roundworm can act as an important source of human ascariasis [ ] [ ] [ ] but this can go unnoticed as the human and pig parasite population show minor phenotypic and genotypic differences. zoonotic pathogens that transmit via the fecal-oral route appear to cause similar clinical symptoms compared to other (related) enteric pathogens and further research is not pushed due the relative lack of (more) serious disease. we thus may neglect relevant pathogens and even if we do study these pathogens, the results may have undesired economic consequences for agriculture and food sectors. in addition, until recently we lacked tools for studying important zoonotic events; whilst the small genomes and rapid evolution of viruses allow identification of novel causative agents with limited sequencing effort, such analysis is much more complicated for bacterial and parasitic enteric pathogens which have relatively large genomes. some experimental models for fecal-oral transmission between hosts have been described, such as for norovirus [ ] , but there is a general lack of suitable animal models to study fecal-oral transmission. in fact, most research on host-pathogen interactions is focused on mechanisms of pathogenicity rather than on mechanisms of transmission, whilst the latter is crucial for the development of intervention strategies to prevent further spread and to prevent sustained human-to-human transmission of zoonotic pathogens. papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest one health, multiple challenges: the inter-species transmission of influenza a virus zoonotic aspects of rotaviruses shiga toxin-producing escherichia coli o , england and wales sars and mers: recent insights into emerging coronaviruses intestinal microbial communities associated with acute enteric infections and disease recovery salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota the intestinal microbiota and susceptibility to infection in immunocompromised patients the intestinal microbiome in early life: health and disease gut microbiota composition correlates with diet and health in the elderly makison booth c: vomiting larry: a simulated vomiting system for assessing environmental contamination from projectile vomiting related to norovirus infection comparative genome analysis of two cryptosporidium parvum isolates with different host range hepatitis a: old and new viral shedding and antibody response in patients with middle east respiratory syndrome coronavirus infection influenza virus infection among pediatric patients reporting diarrhea and influenza-like illness enteric involvement of severe acute respiratory syndrome-associated coronavirus infection long-term sars coronavirus excretion from patient cohort extra-pulmonary viral shedding in h n avian influenza patients long-lasting outbreak of erythromycin-and ciprofloxacinresistant campylobacter jejuni subspecies jejuni from to in men who have sex with men quantitative assessment of infection risk from exposure to waterborne pathogens in urban floodwater survival of hepatitis a virus on modified atmosphere-packaged (map) lettuce the enemy within us: lessons from the european escherichia coli o :h outbreak loss of multicellular behavior in epidemic african nontyphoidal salmonella enterica serovar typhimurium st strain d the potential for respiratory droplet-transmissible a/ h n influenza virus to evolve in a mammalian host year in review : extracorporeal membrane oxygenation noroviruses as a cause of diarrhea in immunocompromised pediatric hematopoietic stem cell and solid organ transplant recipients high prevalence of prolonged norovirus shedding and illness among hospitalized patients: a model for in vivo molecular evolution persistent spiking fever in a child with acute myeloid leukemia and disseminated infection with enterovirus infectious complications and vaccinations in the posttransplant population prolonged influenza virus shedding and emergence of antiviral resistance in immunocompromised patients and ferrets twentyeight years of poliovirus replication in an immunodeficient individual: impact on the global polio eradication initiative host transmission of salmonella enterica serovar typhimurium is controlled by virulence factors and indigenous intestinal microbiota this study showed that nts strains of persistently infected humans acquired antimicrobial resistance and virulence genes inoculum size in shigellosis and implications for expected mode of transmission norwalk virus shedding after experimental human infection an outbreak of gastroenteritis and fever due to listeria monocytogenes in milk cell attachment protein vp * of a human rotavirus specifically interacts with a-type histoblood group antigen noroviruses and histoblood groups: the impact of common host genetic polymorphisms on virus transmission and evolution hepatitis e: an emerging awareness of an old disease molecular biology and replication of hepatitis e virus hepatitis e virus genotype infection of swine kidney cells in vitro is inhibited at multiple levels human cryptosporidiosis in europe effect of sanitation and water treatment on intestinal protozoa infection: a systematic review and meta-analysis this systemic review and meta-analysis shows how lack of clean water is associated with increased risk of intestinal protozoa infection pig ascaris: an important source of human ascariasis in china assessing the zoonotic potential of ascaris suum and trichuris suis: looking to the future from an analysis of the past from the twig tips to the deeper branches: new insights into evolutionary history and phylogeography of ascaris prophylactic treatment with the nucleoside analogue -c-methylcytidine completely prevents transmission of norovirus the authors developed a murine fecal-oral transmission model the authors would like to thank all participants of the dahlem 'inter human barriers' workshop for their contributions and ryan kissinger (niaid, nih) for designing the figures. this work was supported by antigone (grant numbers ); edw is supported by the intramural research program of the national institute of allergy and infectious diseases, us national institutes of health; pf receives funding from the eu fp project prepare (grant number ); mdg is supported by the eu grant compare (grant number ) and the virgo consortium, funded by the dutch government (project number fes ). key: cord- -s fm rfa authors: jayaweera, mahesh; perera, hasini; gunawardana, buddhika; manatunge, jagath title: transmission of covid- virus by droplets and aerosols: a critical review on the unresolved dichotomy date: - - journal: environ res doi: . /j.envres. . sha: doc_id: cord_uid: s fm rfa the practice of social distancing and wearing masks has been popular worldwide in combating the contraction of covid- . undeniably, although such practices help control the covid- pandemic to a greater extent, the complete control of viral-laden droplet and aerosol transmission by such practices is poorly understood. this review paper intends to outline the literature concerning the transmission of viral-laden droplets and aerosols in different environmental settings and demonstrates the behavior of droplets and aerosols resulted from a cough-jet of an infected person in various confined spaces. the case studies that have come out in different countries have, with prima facie evidence, manifested that the airborne transmission plays a profound role in contracting susceptible hosts. interestingly, the nosocomial transmission by airborne sars-cov- viral-laden aerosols in healthcare facilities may be plausible. hence, clearly defined, science-based administrative, clinical, and physical measures are of paramount importance to eradicate the covid- pandemic from the world. coronavirus disease was first reported in wuhan, china, in december . the disease is caused by severe acute respiratory syndrome coronavirus (sars-cov- ) and asseverated to be transmitted from human-to-human by multiple means, namely, by droplets, aerosols, and fomites . it has been more than days that covid- , later declared as a pandemic and highly contagious, was first reported. as of may , , there have been more than . million confirmed cases and , deaths by the covid- disease worldwide (who, a) . covid- infection triggers severe acute respiratory illness, with fever, cough, myalgia, and fatigue as common symptoms at the onset of illness judson and munster, ; . infectious agents may spread from their natural reservoir to a susceptible host in different pathways. there are various classifications reported in the literature for modes of transmission of different infectious agents. morawska ( ) has presented a classification for virus transmission, including human-human transmission, airborne transmission, and other means of transmission such as endogenous infection, common vehicle, and vector spread. however, many respiratory viruses are believed to transmit over multiple routes, of which droplet and aerosol transmission paths become paramount, but their significance in transmitting the disease remains unclear (morawska and cao, ; . in general, infected people spread viral particles whenever they talk, breathe, cough, or sneeze. such viral particles are known to be encapsulated in globs of mucus, saliva, and water, and the fate/behavior of globs in the environment depends on the size of the globs. bigger globs fall faster than they evaporate so that they splash down nearby in the form of droplets liu et al., ) . smaller globs evaporate faster in the form of aerosols, and linger in the air, and drift farther away than the droplets do. respiratory particles may often be distinguished to be droplets or aerosols based on the particle size and specifically in terms of the aerodynamic diameter . one could dispute that, unlike larger droplets, aerosols may pose a greater risk of the spread of the covid- disease among many susceptible hosts positioned far from the point of origin. nevertheless, it has been proven that viral disease outbreaks via aerosol transmission are not as severe as one would think, because of dilution and inactivation of viruses that linger for extended periods in the air . there has been no discernable evidence on the minimum infectious viral load for covid- pandemic, but many researchers speculate that a few hundreds of sars-cov- virus would be enough to cause the disease among susceptible hosts. there have been numerous disagreements on the average particle size of droplets and aerosols . the world health organization (who) and centers for disease control and prevention (cdc) postulate that the particles of more than μm as droplets, and those less than μm as aerosols or droplet nuclei who, ) . conversely, there have been some other postulations, indicating that aerodynamic diameter of μm or μm or less should be reckoned to be aerosols, based on their ability to linger in the air for a prolonged period, and the reachability to the respirable fraction of the lung (alveolar region) tellier, ) . small aerosols are more susceptible to be inhaled deep into the lung, which causes infection in the alveolar tissues of the lower respiratory tract, while large droplets are trapped in the upper airways (thomas, ) . for easy apprehension, aerosols can be defined as suspensions of solid or liquid particles in the air, which can be generated by either natural or anthropogenic phenomena (judson and munster, ; tellier, ) . though social distancing would be promising in combatting the covid- , the minimum distances that have been maintained between an infected person and a host are disputable and far from being established based on any scientific evidence. nevertheless, many have believed that droplets predominate over aerosols in terms of contracting the disease; thus, over time, research work has been focused on acquiring better knowledge on the science of droplet transmission (morawska and cao, ; . however, since the recent past, evidence has been provided to refute the former hypothesis and speculated that aerosols also play a major role in transmitting the disease (morawska and cao, ; . as such, the controversy on the modes of transmission of the sars-cov- virus seems to be speculating and puzzled among many researchers, including the who (morawska and cao, ) . no conclusive studies have been conducted on differentiating between the modes of transmission of viruses via droplets and aerosols; hence, unresolved dichotomy. thus, this paper outlines the possible key deliberations cast by many researchers on the possible modes of transmission of previously identified viruses with similar characteristics of sars-cov- . it has also been argued that environmental settings, in which the sars-cov- virus transmits, trigger the disease adversely or beneficially with a susceptible host exposed to more or lesser payloads, respectively (morawska, ; tellier et al., ) . such adverse or beneficial scenarios are based on plausible changes in the fate of the virus in the environment caused by altered transport phenomena. there have been myriads of hypotheses corroborating that certain threshold levels of humidity, temperature, sunlight, and ventilation will speed up the virus-laden droplet and aerosol transmission, aggravating the spread of the sars-cov disease (morawska, ) . thus, this review paper also attempts to hypothesize how the general environmental and geographical settings in sars-cov- -affected countries impacted the susceptible hosts differently. as scientists underpin more conclusive evidence on the modes of transmission via droplets and aerosols, facemasks and respirators worn by billions of people around the globe (both infected persons and susceptible hosts) has become a common sight in day-to-day activities. in the events of the droplet and aerosol transmission, the efficacy of such personal protective equipment in combating the transmission of the sars-cov- has been poorly understood. this review paper attempts to delineate as to how such facemasks and respirators help combat transmission of virus-laden droplets and aerosols to a level less than the so-called minimum infectious dose. ever since the covid- has been declared to be a pandemic with incredibly high morbidities and mortalities worldwide, the database of research on controlling the covid- , especially in the indoor environment, has been updated with several evidence-based studies. however, less attention has been focused on the whole in controlling virus-laden droplet and aerosol shedding, their transport phenomena, and plausible methods of their dilution and destruction in different indoor settings. this review paper, therefore, outlines the best practices that could be adopted to lessen the covid- casualties in different diverse environmental settings. with more covid- cases reported worldwide, evidence-based decisions need to be adhered to in combating the disease, especially for situations in confined environments. the transmission of droplets and aerosols within confined spaces becomes profoundly complex phenomena, and the real trajectories under different micro-climatic conditions are poorly understood. the aggressive nature of the disease is directly connected with the transport phenomena of both droplets and aerosols, and the comprehension of such phenomena is vital in controlling the spread of the disease within such confined spaces. aerodynamic engineers, therefore, need to network with virologists to fully understand the possible trajectories of the viral spread within such confined spaces. in this context, computational fluid dynamics could be made use of, to simulate the trajectories resulting from coughs and sneezes of an infected person within a given space. thus, this paper attempts to illustrate how such transport phenomena of droplets and aerosols of an infected person affect other susceptible hosts. although the direct transmission from infected person/s is the primary source of aerosols and droplets, other scenarios such as medical procedures, surgeries (judson and munster, ) , fast-running tap water and toilet flushes (morawska, ) also generate aerosols contaminated with infectious pathogens. the most common types of viruses causing infections in the respiratory tract through aerosol transmission are influenza viruses, rhinoviruses, coronaviruses, respiratory syncytial viruses (rsvs), and parainfluenza viruses (morawska, ) . tellier ( ) has postulated three modes in which the influenza virus can be transmitted: aerosol transmission, droplet transmission, and self-inoculation of the nasal mucosa by contaminated hands. another classification is presented by judson and munster ( ) , which is often referred to as the term of 'airborne transmission' to describe the disease spread by small droplet aerosols and droplet nuclei, while the term 'droplet transmission' to describe infection by large droplet aerosols. the term 'airborne transmission' defined by morawska ( ) is quite similar to the same apprehended by judson and munster ( ) . besides, the direct contact and fomite transmission produced by aerosol-generating medical procedures (agmps) can also be considered as potential transmission pathways (judson and munster, ) . droplet transmission occurs by the direct spray of large droplets onto conjunctiva or mucous membranes of a susceptible host when an infected patient sneezes, talks, or coughs. in the meantime, direct physical touch between an infected individual and susceptible host and indirect contact with infectious secretions on fomites can cause the contact transmission (boone and gerba, ; brankston et al., ; tellier, ) . it is a well-known fact that covid- is transmitted by human-to-human contact; hence, contagious. one of the predominant mechanisms for covid- to be contagious is selfinoculation from contaminated fomites. self-inoculation could occur by poor hand hygiene (kwok et al., ) or by not following the common disease-controlling etiquettes. the viral transmission because of the frequent touches of contaminated fomites was found to be a source of the disease. consequently, many researchers have paid attention to the airborne transmission directly by virus-laden droplets and aerosols. however, the novelty of this viral outbreak limits the prima facie evidence to determine the potential transmission routes, and thus, it is assumed that sars-cov- also spreads as the other human coronaviruses (cdc, a) . recent studies corroborated that covid- is transmitted primarily between people through respiratory droplets and contact routes cdc, a; chan et al., ; huang et al., ; who, b) . besides, evidence has been found that fecal contamination caused by an infected person is discernible to spread the sars-cov- virus . a recent study in china has investigated , specimens collected from infected patients at three hospitals in the hubei and shandong provinces, and about % of positive cases for covid- have been observed with the transmission through feces . further, they also highlighted the fact that covid- could be transmitted via fecal routes after they detected the live infectious agents of covid- in patients' stools . contrary to what has been stated above, the who, at early hours of manifestation of covid- , has denounced that there was no supporting evidence on the fecal-oral transmission of the sars-cov- virus (who, b) . the same report also highlighted the fact that airborne transmission has not played a significant role in disease transmission from , confirmed covid- cases in china as of (who, c . in contrast to the who study, another study has reported that sars-cov- can survive in the air for many hours, causing potential aerosolized transmission (van doremalen et al., ) . with more infected persons being recorded in many countries, the who has intimated that certain hospital procedures would also generate aerosols under specific circumstances: endotracheal intubation, bronchoscopy, open suctioning, administration of nebulized treatment, manual ventilation before intubation, turning the patient to the prone position, disconnecting the patient from the ventilator, non-invasive positive-pressure ventilation, tracheostomy, and cardiopulmonary resuscitation (who, b) . as precautions to prevent such plausible airborne transmission of viruses, the who has recommended a myriad of management protocols (who, d). besides, healthcare workers are unwittingly exposed to infectious agents through person-toperson contact via respiratory droplets or aerosols and direct handling of contagious secretions (e.g., sputum, serum, blood, feces, etc.) of covid- patients. ong and his coworkers ( ) have studied the sources of covid- that could transmit the infection during the involvement in healthcare services. the results obtained from their study indicate that the samples collected from the personal protective equipment (ppe) worn by the hospital staff (physicians exiting the patient rooms) were negative for covid- . however, the samples from the air outlet exhaust fans in patient-rooms except corridors and anterooms have been reported as positive for covid- , indicating that the airborne transmission is plausible. sean and his co-workers ( ) corroborated that swabs taken from air exhaust outlets in a hospital room of a symptomatic patient of covid- in singapore tested positive, suggesting that small virus-laden aerosols have been displaced by airflows and deposited on equipment such as vents. however, there is no conclusive evidence as to how it is contaminated, and it is presumed that the aerosol particles may have got deposited in the vent. on february , , in inner mongolia of china, there has been a case of covid- reported positive when a person has passed the door of a symptomatic patient several times, giving evidence of the airborne transmission . the sars-cov- is often said to be transmitted through droplets generated when a symptomatic person coughs, sneezes, talks, or exhales (morawska and cao, ) . some of these droplets are too heavy to remain in the air, and rather fall on nearby floors or surfaces. fomites collect droplets contaminated with sars-cov- , and touching of such surfaces by a susceptible host would get infected. however, some droplets, when ejected from an infected person, convert to aerosol particles (also known as bioaerosols) with relatively smaller aerodynamic diameters and, consequently, become airborne (morawska, ) . such virusladen aerosol particles are capable of infecting people who inhale such particles, thereby spreading the disease. further, there have been several transport phenomena where larger droplets become smaller through evaporation so that such smaller particles are called droplet nuclei. such aerosol particles with the encapsulation of viruses could be termed as bioaerosols or droplet nuclei; hence, the term 'aerosol', 'bioaerosol', and 'droplet nuclei' is used in this paper interchangeably. the scenarios in respect of the generation of droplets and aerosol, particularly in the indoor environment, have not been adequately understood, and thus, insights into the plausible mechanisms are worthy of being explored. duguid ( ) , for the first time, has explored the characteristics of droplets and aerosol from human expiratory activities with chest infections, and such information is presented in table . duguid ( ) has observed that % of particles were often smaller than μm, and the majority were between - μm. the findings corroborated that breathing and exhalation originated from the nose have shed up to a few hundreds of droplets of which some were aerosols. in contrast, talking, coughing, and sneezing have produced more aerosols than droplets (table ) . on the contrary to what duguid ( ) has presented, a study conducted by with five healthy individuals has manifested that - % of particles from human expiratory activities were aerosols with the diameter being smaller than μm. the study also corroborated that the highest aerosol densities were generated during coughing and the lowest from nasal breathing, of which exhaled breath would be more responsible in transmitting the viruses (size of the order of . μm) when compared with transmitting the bacteria (> μm). it has been found that vomiting by a sars-cov infected person in the corridor of a hotel in hong kong in has contracted the disease on several people nearby by aerosol transmission (morawska, ) . the physicochemical processes affecting the fate of airborne aerosols constitute evaporation, interaction with other types of particles, transport, and removal from the air by deposition on solid surfaces (morawska, ) . particles in the air are often subjected to brownian motion, gravity, electrostatic forces, thermal gradients, electromagnetic radiation, turbulent diffusion, and inertial forces (baron and willeke, ) . of these mechanisms, the diffusion is a key mechanism of transmitting viruses with particles in the lower sub-micrometer range, together with other aerosol particles (baron and willeke, ) . for droplets larger than μm, gravity becomes significant than brownian motion in deciding the fate of such particles (cox, ) . under the standard atmospheric conditions, droplets smaller than μm often evaporate before reaching the ground, and the evaporated droplet residues linger in the air for prolonged periods (morawska, ) . when the droplets contain infectious bioaerosols, such as viruses, bioaerosols will remain in the air, even after the liquid content evaporates (morawska, ) . however, the time interval that a virus survives in the air varies from one type of bioaerosol to another type. droplets in the range of . - . μm lingering in the air are more likely to be retained in the respiratory tract and produce the infection (mccluskey et al., ) . however, droplets seem to be not present in the air for longer periods; instead, evaporation takes place, transforming droplets to bioaerosol residues, which could linger in the air for extended periods. hui and his co-workers ( ) have investigated that in different indoor environments, sars-cov could be transmitted through the airborne route. another retrospective study has found that the airborne transmission in an aircraft from an infected person to passengers located seven rows of seats ahead, indicating that the sars-cov virus could travel for a distance more than m of horizontally (olsen et al., ) . another case has been reported on infecting more than , persons in an apartment complex in hong kong because of aerosols generated by the building's sewage system (mckinney et al., ) . these observations manifest that the aerosol-laden sars-cov virus transmission is a phenomenon, which would impart greater havoc than one thinks, and precautionary measures are, therefore, of paramount importance. the sars-cov- virus has been found to remain viable in aerosols for three hours, while it, in the form of droplets, was more stable on plastic and stainless steel, copper, cardboard, and glass with durations detected up to , four, , and hours, respectively (van doremalen et al., ) . in comparison, the sars-cov virus was also found to be airborne in the form of aerosols for three hours, indicating that both sars viruses behave more or less in the same manner in the air. nevertheless, the sars-cov virus remains stable and viable in the form of droplets on plastic and stainless steel, copper, cardboard, and glass with durations (half-lives) lasting to , eight, eight, and hours, respectively (van doremalen et al., ) . the halflives of the sars-cov- and sars-cov were almost the same in aerosols, with median estimates of approximately . to . hours, indicating that both viruses have similar stability characteristics in transmitting through the air (van doremalen et al., ) . however, more profound epidemiological sustenance of sars-cov- virus may, therefore, be because of some other factors, including high viral loads in the upper respiratory tract and the capability of persons infected with covid- to shed and transmit the virus while remaining asymptomatic (bai et al., ; zou et al., ) . based on a study carried out by nicas and his co-workers in , it has been estimated that particles emitted from a cough of an infected person of a respiratory illness quickly decrease in diameter (with initial diameters of less than μm) mainly because of the water loss by approximately half of the initial volume, amounting to × − ml. exhaust ventilation, particle settling, die-off, and air disinfection methods are some prominent mechanisms by which the removal of viable airborne pathogens often takes place; each removal mechanism follows a first-order reduction rate . based on -hour viability of sars-cov- in the air (van doremalen et al., ; van doremalen et al., ) , prerequisites for the disease such as exposure, inhalation, and infection could occur minutes or a few hours later near and far from an aerosol source even in a stagnant environment (bourouiba, ) . the actual airborne times for droplets may be greater in an environment where there are significant cross-flows (who, ) . such scenarios could be expected in quarantine and healthcare centers (e.g., with doors opening, bed and equipment movement, and people walking back and forth, constantly). conversely, airborne durations for smaller droplet nuclei or aerosols may be profoundly shorter when they are subject to a significant downdraft (e.g., if they pass under a ceiling supply vent) (who, ) . when the flow of mucus or saliva ejects from an infected person, its trajectory is determined primarily by the size of droplets and airflow patterns that govern the paths of movement (tang et al., ) . the stokes' law describes the resultant trajectory of the droplets subjected to the forces of gravity downwards and air friction upwards, which governs the droplet movement in the air . coughs and sneezes usually constitute a turbulent cloud of buoyant gas with suspended droplets of various sizes. the larger droplets follow a ballistic trajectory irrespective of flow in the gas phase, whereas the aerosols are buoyant to a varying degree within the turbulent gas cloud (bourouiba et al., ) . in general, there exists an accepted notion of a -m safe exclusion zone to prevent possible droplet transmission from an infected person to a susceptible host; however, there are no comprehensive studies to support such a phenomenon. has supported the -m exclusion zone concept taking into account the evaporation-falling curve. has postulated that large droplets (> μm) will fall to the floor within a horizontal distance of m from the source. simple calculations, assumptions, and inadequate empirical data of wells's study have been later speculated by xie and his co-workers ( ) . xie and his coworkers ( ) have corroborated that for respiratory exhalation flows, the larger droplets (diameter between μm and μm) were, depending on the exhalation air velocity and relative humidity of the air, carried away for more than m of horizontal distance with the exhaled air having a velocity of m/s at the point of expiration (figure a ). such scenarios simulate sneezing events. conversely, larger droplets were found to carry for more than m afar at a velocity of m/s reordered at the point of exit, simulating coughing bouts ( figure b ). the same for exhaling events for which the velocity is at m/s was found to carry large droplets only up to about m of horizontally ( figure c ). other studies also have proven that when an infected person of a respiratory illness coughs or sneezes, a cloud of pathogenbearing droplets of different sizes appears to come out and travel even up to - m from the point of source (bourouiba et al., ; bourouiba et al., ) . moreover, recent experiments conducted after covid- contagion by bourouiba ( ) and loh and his co-workers ( ) have been in agreement with the findings of . xie and his co-workers ( ) have reported that pathogens bearing droplets of all sizes can travel for almost - m during sneezes and for more than m (maximum of . m) during coughs. incredibly, there have been contradicting insights on the distance to be maintained between healthcare workers and covid- infected patients [e.g., m (who, e) and m (cdc, b)]. however, most of the studies on the covid- virus mentioned above have been carried out in laboratories with expiration devices set on manikins; hence, no convincing information can be deduced. the most important environmental factors that could impact on the viability of airborne microorganisms are temperature, humidity, radiation (sunlight), and open-air (ventilation) (marthi, ) . the airborne microorganisms vary from large size fungal ( . - μm) and bacterial ( . - μm) aerosols to small size viral ( . - . μm) aerosols (morawska, ) . viruses in aerosols lose or gain the viability and infectivity because of environmental stresses caused by temperature, relative humidity, and sunlight before they reach a susceptible host. environmental tolerance of the viral-laden aerosols depends on the specific phenotype available, the composition of the bioaerosols containing virus and their payload, and physical characteristics in the surrounding environment . as the environmental factors play a major role in transmitting payloads of sars-cov- virus in different geographical locations of outdoor and indoor environments, it is worthy of exploring the effects of environmental factors on the transmission of sars-cov- virus. a retrospective study carried out in beijing and hong kong reports an inverse relationship between the numbers of daily sars-cov cases and daily minimum temperatures with a lagged effect of - days, while air pressure was found to be positively associated with transmission through the air for the data collected from april to may (bi et al., . another study underpins that when high payloads of transmissible gastroenteritis and mouse hepatitis viruses were emitted and deposited, they may have survived for days on surfaces at air temperatures ( °c) and relative humidity (< % or > %) typical of indoor environments . the sars-cov virus on smooth surfaces was found to retain its viability for over five days at temperatures of - °c and relative humidity of - %, which is typical of air-conditioned environments . however, virus viability has rapidly lost (> log ) at higher temperatures and higher relative humidity (e.g., °c, and relative humidity > %) . the higher stability of sars-cov coronavirus at low temperatures and low humidity environment may, therefore, facilitate its transmission faster in a community in the subtropical areas (such as hong kong) during the spring, and in air-conditioned environments . this study suggests evidence why some asian tropical countries (malaysia, indonesia, sri lanka, india, or thailand) with high temperature-and high relative humidity-environments did not have significant episodes of community outbreaks of sars-cov. a similar study has corroborated that there has been a significant negative correlation between the sars-cov cases and the environmental temperature seven days before the onset, and the seven-day time lag has corresponded well with the known incubation period for sars-cov (tan et al., ) . the optimum environmental temperature associated with the sars-cov cases has been in the range of - °c, which may have stimulated the virus growth (tan et al., ) . they have further reiterated that a sharp decrease or increase in the environmental temperature related to unexpected rapid spells of cold and warm days may have led to a rise in the sars-cov cases. such scenarios were because of the possible influence of the weather on the human immune system, indicating that there has been a higher possibility for sars-cov to reoccur in spring than that in autumn and winter. van doremalen and his co-workers ( ) have experimented the stability of mers-cov under different conditions ( °c and % relative humidity; °c and % relative humidity, and °c and % relative humidity) and found out that payloads of mers-cov were more stable and viable at low temperature/low humidity conditions even after hours. casanova and her co-workers in have investigated the effect of air temperature and relative humidity on the survival of coronaviruses in different solid surfaces. the findings of the study were analogous to the previous studies of coronaviruses in aerosols, which clearly stated that there was greater survival of virus at a low relative humidity ( %) than at high relative humidity ( %, % & %) (ijaz et al., ; kim et al., ) , and the viral survival was enhanced by lower air temperatures ( o c) ijaz et al., ) . further, the results of casanova and co-workers ( ) suggest that the relative humidity affects the inactivation of coronavirus than that by the air temperature that could prevail for any given season of the year. however, the interaction between the two factors (relative humidity and air temperature) on virus inactivation seems to be still questionable. in an indonesian study, the average daily ambient temperature prevailing in the period of january to march was significantly negatively correlated with covid- cases, while other components of weather such as minimum temperature, maximum temperature, relative humidity, and amount of rainfall had no significant correlations (tosepu et al., ) . another study on sars-cov has manifested that there was a synergistic effect of high temperature and high relative humidity on inactivation of the virus, whereas lower temperatures and low humidity enhance the survival of the virus and thus, induce the transmission . further, the same study has clearly stated that the showing that the slowest inactivation when exposed to low temperatures in the absence of ultraviolet light and different relative humidity (kormuth et al., ; lowen et al., ; mcdevitt et al., ; . similarly, the strong association of transmission rate of the influenza virus with environmental factors was observed during the winter season in temperate countries, in the rainy season, or where there were sudden seasonal changes in tropical countries (biswas et al., ; chowell et al., ; hemmes et al., ; . have investigated the effect of ambient temperature on covid- infection in cities, including wuhan, china, where the novel coronavirus was first discovered. the findings of their study have manifested that there was a positive association between ambient temperature (< o c) and the daily number of confirmed cases; hence, the temperature could be an essential factor in spreading the infection caused by sars-cov- virus. moreover, they have highlighted the fact that the sars-cov- virus may not perish itself without any public health interventions when the weather becomes warmer, and thus, there was no adequate evidence to confirm that the covid- cases could decline when the temperature increases. conversely, several studies carried out after covid- outbreak have clearly stated that there was a positive association between ambient daily average temperature and the number of covid- cases, where the number of covid- cases significantly decreased with increasing the temperature up to a comparatively lower value (around o c) wang m. et al., ) . however, they also lacked evidence to support the fact that the temperature affects the mortality of this virus. another investigation by ma and his co-workers ( ) manifests a positive relationship between diurnal temperature range and daily death counts of covid- in wuhan, china. a similar argument proposed by ma and his co-workers ( ) has been postulated by the studies of tan ( ) and park and co-workers ( ) for sars-cov and influenza viruses, respectively. a recent study has underpinned that absolute humidity was negatively associated with the daily death counts of covid- (ma et al., ) , which is similar to the study carried out by metz and finn ( ) for the influenza virus. metz and finn ( ) have reported that the absolute humidity significantly negatively correlated with the survival and transmission rate of the virus. lowen and his co-workers in have performed twenty experiments at relative humidity from % to %, and temperature from o c, o c, or o c, and the results indicated that both cold and dry conditions stimulate the transmission, which is, however, rare in tropics. lowen and his co-workers in have reported the lack of aerosol transmission at °c and at all humidity tested, indicating that there is no well-defined, recurrent influenza season affecting tropical and subtropical regions of the world. conversely, the transmission via the contact route was equally efficient at °c and °c. later, , using clausius-clapeyron relation converting relative humidity values into absolute humidity, have manifested that the seasonal cycle is consistent with a wintertime increase in influenza virus transmission and influenza virus survival, and supported the seasonality of influenza. conversely, a similar experiment conducted in the subtropical region has reported that there was no strong correlation between absolute humidity and airborne transmission of the virus, but other environmental factors such as temperature and relative humidity (tang et al., ) . the sunlight significantly negatively affects the survival and infectivity of various microorganisms, including viruses (nelson et al., ; rzeżutka and cook, ; tang, ; qiao et al., ) . the studies of and schuit and his coworkers ( ) have investigated the impact of natural and simulated sunlight on inactivation of influenza virus in liquid suspensions and aerosols, respectively. a significant loss of infectivity was observed under simulated sunlight at a range of relative humidity levels ( %, %); hence, aerosols containing the virus are more likely to transmit at night, indoor or reduced sunlight conditions than they do under direct sunlight . coronaviruses have high sensitivity to natural or simulated sunlight since they possess singlestranded nucleic acids, and are unable to repair the damage in the absence of complementary strand (tseng and li, ; who, ) . by considering this intrinsic characteristic of coronaviruses, several studies have been successfully conducted to decay the viability of the virus using natural sunlight and uv radiation (karapiperis et al., ) . duan and his colleagues ( ) have observed that the sars-cov virus lost its viability after minutes of exposure to > w/cm of uv-c light at a distance of cm. however, in a similar study of darnell and his colleagues ( ) found that the efficiency of inactivation was quite high, with the inactivation time being minutes under high intensity of uv-c light (> w/cm ) at a closer distance (< cm), while there was no effect of uv-a light on the inactivation. for natural ventilation, minimum hourly averaged ventilation rates of l/s/patient for airborne precaution rooms, l/s/patient for general wards and outpatient departments, and . l/s/m for corridors and other transient spaces without a fixed number of patients need to be provided (who, ). an airborne precaution room is defined to be a room with > air changes per hour (ach) (e.g., equivalent to > l/s for a m -room) and must have controlled direction of airflow (aia, ; mayhall, ; who, ) . a mechanically ventilated room is often provided to an airborne infection isolation room and should have a negative pressure of > . pa, an airflow having a difference between the exhaust to supply > cfm ( l/s), clean-to-dirty airflow, > ach for a new building, and > ach in existing buildings for an old building, and exhaust to the outside, or a hepa-filter if room air is recirculated (cdc, ) . the transmission of droplets and aerosols has significant implications on healthcare workers and caretakers managing patients infected with covid- , and providing appropriate personal protective equipment (ppe) is, therefore, of utmost importance. the facemasks play a major role in preventing both droplets and aerosols from transmitting the disease from an infected person to a host. facemasks are popular in controlling and preventing virus transmission, especially in connection with severe respiratory syndromes such as sars-cov, mers-cov, and covid- , since the absence of any vaccination or specific anti-infective treatments (long et al., ) . the surgical mask, n respirator, and elastomeric respirator have been popular among many countries with a different degree of success against the covid- virus. besides, with greater demand for masks in many countries, more sophisticated masks have been experimented by various researchers (balachandar et al., ; leung and sun, ) . surgical masks and n respirators are very popular and ubiquitous among millions of people worldwide as the ppe for covid- , but surgical masks are believed to be not preventing aerosol transmission, and n respirators are recognized to be preventing aerosol and droplet transmission (derrick and gomersall, ; leung et al., ; sandaradura et al., ) . the live influenza virus in the air from, in front, and behind all surgical masks have been tested, and the results indicate that a surgical mask will reduce the exposure to aerosolized infectious influenza virus (average -fold), depending on the design of the mask (booth et al., ) . another study on masks has manifested that when applied to outpatient healthcare personnel, there was no significant difference in the performances between n respirators and medical masks for the incidence of laboratory-confirmed influenza (radonovich et al., ) . long and his co-workers ( ) have corroborated that the use of n respirators compared with surgical masks was not associated with a lower risk of laboratory-confirmed influenza. this study pronounced that n respirators were not necessary for the general public and non-high risk medical staff those who were not in close contact with influenza patients or suspected patients (long et al., ) . unresolved dichotomy on the route of transmission by virus-laden droplets and aerosols suggested that the use of respirators for healthcare workers against sars was much advisable than conventional surgical masks that were ineffective against aerosols . with the unexpected escalation of the covid- cases worldwide, there has been a dearth in supply of masks, and consequently, the center for disease control and prevention, usa, has modified its guidelines on masks with the inclusion of homemade cloth or fabric masks to be worn in public areas. use of masks can be -fold: control the penetration of droplets from an infectious person into the respiratory tract of a susceptible host, and control the droplets going out from an infected patient. nevertheless, the effectiveness of the use of masks for the control of sars-cov- -laden aerosol transmission from an infected person to a susceptible host is uncertain and not fully conceivable. it has been a known fact that different commercial masks have different efficiencies in controlling the transmission of infectious agents. in general, n respirators are provided to prevent users from inhaling small airborne particles (aerosols) and need to fit tightly to the user's face. surgical masks are often used to protect people from larger droplets transmission and fit loosely to the user's face (lawrence et al., ; zhiqing et al., ) . complying with european standard en : , three different types of disposable particulate respirators known as filtering facepiece (ffp ), ffp , and ffp have been in use for controlling sars-cov- . the ffp refers to the least filtering of the three masks with an aerosol filtration of at least % and leakage to the inside of a maximum of %. this mask is mainly used as a dust mask. the ffp masks have a minimum of % filtration and a maximum of % leakage to the inside. healthcare professionals often wear them against influenza viruses, believing that they guard against aerosol transmission. the ffp masks are also used for protection against the sars-cov- . the ffp masks are the best in filtering particles and are recommended against the contraction of sars-cov- . with a minimum filtration of % and a maximum % leakage to the inside, the ffp masks protect the susceptible host against the contraction of the disease caused by very fine particles such as viral-laden aerosols from an infected person. another study comparing the efficiency of homemade masks, surgical masks, and standard ffp masks has corroborated that surgical masks provided about twice as much protection as homemade masks (van der sande et al., ) . the ffp masks were observed to provide adults with about times as much protection as homemade masks, and times compared to surgical masks (van der sande et al., ) . similarly, another study has elaborated that a surgical mask (that filtered % of viral particles) was about three times better in controlling the viral transmission than that of a homemade mask made of a tee-shirt and cotton towel (davies et al., ) . davies and his co-workers ( ) have further iterated that a homemade mask should only be considered as a last resort to prevent droplet transmission from infected individuals, but with limited success. elastomeric respirators serve as an alternative to disposable n respirator use in healthcare, as both have similar efficiencies in filtering sars-cov- . the primary advantage of elastomeric respirators is the reuse potential with proper cleaning. leung and his co-workers ( ) have carried out experiments in developing a novel charged pvdf nanofiber filter to capture aerosol particles effectively. leakage of droplets and a cloud of aerosols could be expected (figure c and d). none of these masks is guaranteed to cut off sars-cov- ; hence, social distancing is vital to be adopted, especially in the indoor environment. with the onset of the covid- pandemic, many researchers have been in the development of effective filtering mechanisms to combat sars-cov- -laden aerosol transmission; however, until early may , there have been no promising ppe developed to curtail such transmission. in the meantime, it is imperative to explore situations where an infected patient coughs without any mask worn, and a susceptible host inhales the resultant plume of droplets and aerosols with different masks worn at a distance of m ( figure ). as shown in figure a , the host without a mask worn receives a considerable payload of viruses so that it is very likely that he gets infected. however, with a surgical mask worn, he may, during inhalation, filter in - % of the payload of viruses with a lower propensity of getting infected ( figure b ). such a payload may have more than a couple of hundreds of sars-cov- , which is believed to be adequate to instill the covid- among exposed people. the host wearing n or reusable elastomeric respirator may not receive in more than %, which may, however, constitute more than a few hundreds of payloads of the virus (figure c and d). the probability of getting infected under such a scenario is still positive, although it is very minute. none of these masks is, however, guaranteed against sars-cov- . many people are reported to contract the covid- in confined spaces. thus, it is worthwhile to describe how such phenomena help intensify the mass occurrence of the covid- in different confined spaces under varying microclimatic conditions. in this respect, three confined spaces such as inside the cabin of an airplane, interior space of a car, and common dormitory-type space of a healthcare or isolation center were selected. since over two billion people travel on commercial flights each year (silverman and gendreau, ) , the behavior of sars-cov- in the cabin is paramount to be understood. air travelers spend extended periods in enclosed spaces, even for more than hours, which usually facilitates a conducive environment for the spread of infectious diseases. extensive aerodynamic modeling has been performed to get an insight into how the buoyant jet of coughing by an infected person of a respiratory illness spreads in the cabin of a flight (redrow et al., ; yang et al., ) . the hypothesis on the most affected zones within the cabin is, therefore, highlighted below. the cabin of a flight is usually provided with airflow from cabin air outlets and individual outlets located in the overhead compartment that runs the length of the cabin (figure ) . a sheet of airflow typically in the form of a jet with lower temperatures (< °c) is projected down, and finds its way towards the bottom of the cabin (return air grills located on the sidewalls) from which it goes to the underfloor area ( figure ). however, looking at a more detailed picture, there are two typical airflow fields developed ( figure a ). the first zone called the jet zone, established in the upper deck areas of the cabin, is characterized in terms of large-scale circulations, while the collision zone found in the middle and lower floor area is characterized by interactions of two lateral jets (li et al., ) ( figure a ). in general, about . - . l/s of air per passenger is provided, of which half of the volume is the filtered and recirculated air, and the other half is outside air (bagshaw and lllig, ). such an arrangement brings in a complete cabin air exchange every two to three minutes ( to air changes per hour (ach)) (bagshaw and lllig, ). the high air exchange rate controls the temperature gradients, prevents stagnant cold areas, maintains air quality, and dissipates payloads of viral-laden droplets and aerosols. in a typical aircraft, the recirculated air is passed through high-efficiency particulate air (hepa) filters, with which in excess of . % of particles characterized by aero-diameter of . μm could be removed from the ingress of cabin air. exhaled droplets and aerosols from passengers and crew often increase the humidity to an average of - %, which is below the % normally accepted as comfort level (de ree et al., ) . in the flight cabins, because of the densely packed environment, the cough-jet released by a sars-cov- infected person is expected to break the local airflow, particularly the jet zone, and travels both forward and backward directions in the proximity of the point of exit ( figure b ). since the velocity of exiting the violent expiration (coughs) is around m/s, the droplets may travel four to five seats ahead, and the aerosol-cloud could go even further away ( figure b ). however, there is no lateral movement expected except the immediate passenger on either side. in contrast to the forward movement, there is a backward movement of droplets typically by one seat, but the aerosol movement may be more. this phenomenon illustrates that about five to ten people could get infected with the disease with an infected person onboard. nevertheless, the propensity of getting sick by exposure to a plume of aerosols produced by cough-jet is poorly understood, and the actual number of contracted cases may be far from recorded. the brownian motion followed by airflow jet movement governs the aerosol plume, after the dissipation of advective transport. such movement supports an agglomeration of viral-laden aerosols in fomites at passenger levels. it is, therefore, crucial to decide by all airlines that such suspicious fomites such as papers, magazines, pillows, and blankets be disposed of perhaps subjected to thermal destruction until the covid- pandemic recedes. figure c illustrates how the cough-jet trajectory travels with the patient equipped with a surgical mask. with the surgical mask worn, the droplets are meant to travel up to one-two seats forward, and one seat backward. such phenomena maybe because of the jet coming out from either side of the mask, as the mask is not tight enough on both sides. nevertheless, the aerosol cloud will travel far from two seats front and one seat behind by the brownian motion coupled with the airflow trajectories of the cabin. the streamlines of airflow are usually directed downward so that there will be a contribution of viral-laden aerosols back to the people on board. the illustration in figure d is more or less the same as that of c, with the exception that both droplets and aerosols do not travel far. with the n mask worn, an infected patient sheds droplets forward and backward by one seat and more than one seat for aerosols. the behavior of viral-laden aerosols resulted from a cough-jet has not yet been aerodynamically modeled with reasonable accuracy; hence, the actual level of impact that a single cough-jet envisages could not be simulated well. however, there exists evidence to showcase a profound risk of covid- being spread in an aircraft when a symptomatic or even asymptomatic patient is on board. further, the environmental factors such as moderately low relative humidity ( %), low temperature (< °c), and moderate ach (< per hour) would set the platform for the sars-cov- to sustain for extended periods within the cabin. strict guidelines for the minimization of such pandemic events are, therefore, paramount. international organization of motor vehicle manufacturers (oica) has estimated that over billion passenger cars travel on roads by worldwide, indicating that one out of seven people of the world has a passenger car. when the world is open back to normalcy by lifting the present state of lockdown, people will resort to traveling by passenger cars, and consequently, there will be a propensity of spreading the covid- unless precautions are taken. we, therefore, bring in a hypothesis to illustrate the best possible ways of preventing the covid- from spreading while traveling in a passenger car. a crucial attribute that supports the spread of covid- is the interior ventilation rate in the passenger vehicle, usually expressed in ach, which depends on the vehicular speed, ventilation setting and window positions (ott et al., ) . engelmann and his co-workers ( ) have estimated that with the air-conditioning (ac) system off, the ach for a stationary vehicle was in the range of . - . per hour. with the ac on, ach was between . - . per hour, and with the ac off and the fans on, it varied in the range of . - . per hour. park and others ( ) , with the windows closed and no mechanical ventilation, have reported the ach between . and . per hour, and with the ventilation set on recirculation, between . and . per hour. with the windows closed and the fan set on fresh air, the ach was between . and . per hour, and with windows open, but no mechanical ventilation, the ach ranged from . to . per hour (park et al., ) . offermann and others ( ) have measured the ach by letting the vehicle move with an average speed of km/hour and have found that with the window open and the ventilation system off, an ach of per hour, with the ventilation system on and the windows closed, per hour, and when the ventilation system was turned off, . per hour. following the study done by khatoon and kim ( ) , a typical pattern of velocity streamlines inside the vehicular cabin with a moderate level of ach assigned to a vehicle moving at a moderate speed under conditions of "ac on and windows closed" is shown in figure a . figure a illustrates that cooled air travels to the back seats and returns towards the front on either side at a lower level. under such circumstances, an infected person sitting in the back seat may cough and the resultant cough-jet in the form of droplets and a plume of aerosols (with an average speed of m/s; relative humidity < %; temperature < °c; ach < per hour) spreads towards the front seat, and the plume of aerosols may drop the advective transport phenomena with lower velocities and get carried away with existing velocity streamlines once again towards the back seats ( figure b ). such phenomena may expose all passengers in the vehicle, and the risk of contracting the disease seems to be high. two such cases have been reported in sri lanka, where an infected passenger had traveled sitting at the back seat in a rented car for a period not greater than one hour with ac on and windows closed, and the driver was subsequently reported to have got infected of the covid- . the other case was reported that a person had accompanied one of his siblings (an asymptomatic person) in his car with ac on and windows closed for more than minutes. such situations seem to be somewhat controlled when the infected person wears a surgical mask. however, the risk factor remains the same, as loose ends of the mask shed both droplets and aerosols, although the expiration from the front of the mask is substantially reduced (figure c ). conversely, when the infected passenger is equipped with an n respirator, under the same conditions, a minute payload of droplets and a faint cloud of aerosols may come out (figure d ). however, because of the circulation within the cabin, one cannot rule out that there is no element of risk. thus, a hypothesis could be built speculating that traveling in a passenger vehicle with people aboard under conditions of ac on and window closed, has a discernible risk factor of getting susceptible hosts infected, though masks are worn. when a passenger car moves at a certain speed with windows open, the velocity streamlines are generated from front and rear windows, and finally, sweeping the passengers aboard, they exit the cabin from the rear windows (figure a ). such transport-phenomena are simulated using computational fluid dynamics, but detailed information on the behavior of streamlines under different environmental settings is poorly investigated. in the case of passenger cars with windows open, different behaviors could be expected depending on the environmental settings prevailing in different geographical regions. in other words, the environmental settings for temperate climates such as east asia, europe, and north america (relative humidity < %; temperature < °c; ach > per hour) and tropical climates, including south east asia, africa, and south america (relative humidity > %; temperature > °c; ach > per hour) could be expected. the studies done on the sustenance of sars-cov- have manifested that there may be a better chance for the viral-laden cough-jets to sustain in temperate climates than tropical climates, as the daily mortality of covid- has been positively associated with diurnal temperature range, but negatively with the absolute humidity (ma et al., ). when the car moves at higher speeds (> km/h) with the same environmental settings, the droplets do not travel far and confined to a limited space (even not beyond the driver's seat), but the cloud of aerosol will drift far and finally exits from the rear windows. the explanations given in this paper restrict the analysis only for the case where the speed is less than km/h, as such speeds become the worse scenario for the sustenance of the sars-cov- virus. the cabin environment becomes much improved when the infected person wears a surgical mask while traveling (figure c ). there seems that only a minimal payload of droplets being shed from the front, but considerable load may come from either side of the mask, as the surgical mask is usually loosely fitted to the face. conversely, the aerosol cloud may still travel to the front area of the cabin and returns with the airflow stream coming from outside the vehicle. nevertheless, the cabin airflow streamlines drive such viral-laden plume out of the cabin in seconds. the cabin environment is further improved when the infected person wears an n respirator ( figure d ). still, one has to admit the fact that there is an element of risk for susceptible hosts to get infected. when two scenarios (scenario : ac on and windows closed; scenario : ac off and windows opened) are critically reviewed, one can speculate that the scenario will be better in controlling the sars-cov- virus; hence strongly recommended at least until the covid- pandemic ceases. for example, the index patient of covid- in sri lanka was a tour guide, and when he became symptomatic, he traveled to the hospital by his car driven by his son, with his wife sitting in the front seat. he made it a point to open all windows and sat behind until they reached the hospital. the traveling time was more than minutes, and no person in the car was infected with the covid- . this story epitomizes the rationale postulated above, and the relevant authorities of affected countries should come out with strict guidelines to get such best practices implemented for reduced morbidities and mortalities. conversely, two cases were reported in sri lanka, where drivers of rental cars got infected with scenario . besides, letting the car park under direct sunlight with windows open for at least minutes would be a better option to eradicate the potential payloads of the sars-cov- virus from the cabins of passenger cars. it would be imperative to explore the plausible factors of transmitting sars-cov- virus within indoor spaces, preferably makeshift hospitals, and healthcare, quarantine and isolation centers where accommodation facilities have large open spaces with many beds laid in a sequence. such a facility is, in this paper, described in respect of a healthcare center, but could be applicable for other indoor spaces mentioned above. it is a known fact that the sars diseases became epidemic and sometimes pandemic, forcing the authorities seek isolation facilities beyond their usual capacities available. such gestures invariably drive the authorities to build appropriate healthcare centers or convert other existing facilities in a short period. such spaces often become large floor areas whose ventilation facilities maybe poor in cleaning the viral-laden airborne plumes. the transmission of sars diseases in an epidemic or pandemic situation is usually -fold. the first being the non-nosocomial transmission by which suspected patients from outside will be brought into the healthcare center. in addition, with time, susceptible hosts residing at healthcare centers will contract the disease through nosocomial transmission unless the ventilation facilities (> ach or . l/s/ m , negative pressure difference > . pa, and the airflow difference > l/s) are adequate (who, ). the differentiation of both these transmission modes for a given situation is, however, a daunting task and extremely difficult (bi et al., ) . in a confined space of a healthcare center, appropriate management of non-nosocomial transmission should be implemented to control the onset of nosocomial transmission, where ventilation methods play a vital role. given the fact that inadequate ventilation prevails in a confined space, another classification indicates that -fold transmission types are distinguished; short-range (between individuals, generally less than -m apart) and longrange (within a room, between rooms or between distant locations, generally greater than -m distances) (tang et al., ) . expiration of cough-jets of an infected person composed of droplets and aerosols enters and mixes with air in the breathing zone of a susceptible host standing nearby (e.g., medical staff), which is capable of contracting the disease (short-range transmission) between individuals may interact to infect one another. in the meantime, cough-jet travels long distances depending on the airflow pattern of the space through the aerosol plume (long-range transmission) contracting people a couple of meters away from the infected person. the airflow in the confined space is often governed by a combination of differences in temperatures and humidity. figure (figure b ). such aerosol plume developed could follow the airflow trajectories, which are often altered by moving objects, opening and closing of doors and windows, and temperature and humidity variations. besides, a certain fraction of the viral-laden aerosols will diffuse towards lateral directions by brownian motion resulting in nosocomial transmission to many susceptible hosts in the same confined room (not shown in figure b ). these aerosol-generating plumes cause long-range transmission within the confined space, contracting many susceptible hosts far more than one could imagine. figure c shows the cough-jet trajectory with the infected patient wearing a surgical mask. with the surgical mask worn, the payload of droplets from the infected patient reduces drastically and restricted to a small distance. the neighboring people on either side may not be exposed to direct contamination, but they could contract the disease by touching fomitesladen viruses. however, viral-laden aerosols will travel forward and disappear via convective and diffusion processes. such transport phenomena may carry the disease-causing viral loads, promoting nosocomial infection. a similar scenario is observed with a patient wearing an n respirator, but to a lesser extent compared to that of a surgical mask (figure d reports that as of april , , in a naval complex in colombo, there have been more than sailors contracted with the covid- . the sailors have been on duty in cordoning off of potential areas of covid- pandemic. however, it has been brought to the notice that when they returned to the base, many of them have stayed in confined areas whose ventilation potential driven by mechanical fans was rather poor. this scenario has been a classic example of the nosocomial infection caused by poor ventilation that has promoted the viral-laden aerosol plume to linger for many hours inside the building. taking all case studies mentioned above into consideration, one cannot simply ignore that both droplet and aerosol laden transmissions of covid- are uncertain; hence administrative, clinical, and physical best management practices are paramount in implementing, especially in confined spaces. researchers have speculated that both droplets and aerosols generated from non-violent and violent expirations of sars-cov- -infected people may be responsible for the nonnosocomial and nosocomial transmission of covid- disease. however, more research work should be conducted to understand the behavior of viral-laden droplets and aerosols in different environmental settings, especially confined spaces so that the transmission of covid- pandemic in the built environment could be fully ascertained. the case studies found worldwide indicate that the behavior of the sars-cov- virus has been unprecedentedly unique with more survival and viable rates in the air and believed to linger in the air for an extended period. the challenge before many healthcare workers in combatting the disease would be a daunting task unless proper administrative, clinical, and physical measures are taken within the healthcare settings. inter-disciplinary research on the behavior of the sars-cov- virus needs to be conducted to prevent covid- disease from spreading worldwide. mahesh jayaweera: conceptualization, methodology, investigation, writing -original draft, visualization, supervision, project administration. hasini perera: conceptualization, methodology, resources, validation, formal analysis, investigation, data curation, writingoriginal draft. buddhika gunawardana: validation, resources, writing -review and editing. jagath manatunge: validation, resources, writing -review and editing. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. authors wish to acknowledge the assistance rendered by many in collating information on covid- case studies. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. bagshaw negative pressure of > . pa, an airflow having a difference between the exhaust to supply > cfm ( l/s), clean-to-dirty airflow, > ach for a new building, and > ach in existing buildings for an old building, and exhaust to the outside, or a hepa-filter if room air is recirculated the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. coronavirus (sars-cov- ) and asseverated to be transmitted from human-to-human by multiple means, namely, by droplets, aerosols, and fomites (wang and du, ). it has been more than days that covid- , later declared as a pandemic and highly contagious, was first reported. as of may , , there have been more than . million confirmed cases and , deaths by the covid- disease worldwide (who, a). covid- infection triggers severe acute respiratory illness, with fever, cough, myalgia, and fatigue as common symptoms at the onset of illness judson and munster, ; . respiratory particles may often be distinguished to be droplets or aerosols based on the particle size and specifically in terms of the aerodynamic diameter . one could dispute that, unlike larger droplets, aerosols may pose a greater risk of the spread of the covid- disease among many susceptible hosts positioned far from the point of origin. nevertheless, it has been proven that viral disease outbreaks via aerosol transmission are not as severe as one would think, because of dilution and inactivation of viruses that linger for extended periods in the air . there has been no discernable evidence on the minimum infectious viral load for covid- pandemic, but many researchers speculate that a few hundreds of sars-cov- virus would be enough to cause the disease among susceptible hosts (beggs, ; smc, ). there have been numerous disagreements on the average particle size of droplets and aerosols . the world health organization (who) and centers for disease control and prevention (cdc) postulate that the particles of more than μm as droplets, and those less than μm as aerosols or droplet nuclei who, ) . brankston et al., ; tellier, ) . it is a well-known fact that covid- is transmitted by human-to-human contact; hence, contagious. one of the predominant mechanisms for covid- to be contagious is self- provinces, and about % of positive cases for covid- have been observed with the transmission through feces . further, they also highlighted the fact that covid- could be transmitted via fecal routes after they detected the live infectious agents of covid- in patients' stools . contrary to what has been stated above, the who, at early hours of manifestation of covid- , has denounced that there was besides, healthcare workers are unwittingly exposed to infectious agents through person-to- giving evidence of the airborne transmission . the sars-cov- is often said to be transmitted through droplets generated when a symptomatic person coughs, sneezes, talks, or exhales (morawska and cao, ) . some of these droplets are too heavy to remain in the air, and rather fall on nearby floors or surfaces. fomites collect droplets contaminated with sars-cov- , and touching of such surfaces by a susceptible host would get infected. however, some droplets, when ejected from an infected person, convert to aerosol particles (also known as bioaerosols) with relatively smaller aerodynamic diameters and, consequently, become airborne (morawska, ) . such virus- table . duguid ( ) has observed that % of particles were often smaller than μm, and the majority were between - μm. the findings corroborated that breathing and exhalation originated from the nose have shed up to a few hundreds of droplets of which some were aerosols. in contrast, talking, coughing, and sneezing have produced more aerosols than droplets (table ) . on the contrary to what duguid ( ) has presented, a study conducted by papineni and rosenthal ( ) with five healthy individuals has manifested that - % of particles from human expiratory activities were aerosols with the diameter being smaller than μm. the study also corroborated that the highest aerosol densities were generated during coughing and the lowest from nasal breathing, of which exhaled breath would be more responsible in by aerosol transmission (morawska, ) . the physicochemical processes affecting the fate of airborne aerosols constitute evaporation, interaction with other types of particles, transport, and removal from the air by deposition on solid surfaces (morawska, ) . particles in the air are often subjected to brownian motion, gravity, electrostatic forces, thermal gradients, electromagnetic radiation, turbulent diffusion, , ) . for droplets larger than μm, gravity becomes significant than brownian motion in deciding the fate of such particles (cox, ) . under the standard atmospheric conditions, droplets smaller than μm often evaporate before reaching the ground, and the evaporated droplet residues linger in the air for prolonged periods (morawska, ) . when the droplets contain infectious bioaerosols, such as viruses, bioaerosols will remain in the air, even after the liquid content evaporates (morawska, ) . approximately half of the initial volume, amounting to × − ml. exhaust ventilation, particle settling, die-off, and air disinfection methods are some prominent mechanisms by which the removal of viable airborne pathogens often takes place; each removal mechanism follows a first-order reduction rate . based on -hour viability of sars- cov- in the air (van doremalen et al., ) , prerequisites for the disease such as exposure, inhalation, and infection could occur minutes or a few hours later near and far from an aerosol source even in a stagnant environment (bourouiba, ) . and airflow patterns that govern the paths of movement (tang et al., ) . the stokes' law describes the resultant trajectory of the droplets subjected to the forces of gravity downwards and air friction upwards, which governs the droplet movement in the air . coughs and sneezes usually constitute a turbulent cloud of buoyant gas with suspended droplets of various sizes. the larger droplets follow a ballistic trajectory irrespective of flow in the gas phase, whereas the aerosols are buoyant to a varying degree within the turbulent gas cloud (bourouiba et al., ) . masks are believed to be not preventing aerosol transmission, and n respirators are recognized to be preventing aerosol and droplet transmission (derrick and gomersall, ; surgical mask (that filtered % of viral particles) was about three times better in controlling the viral transmission than that of a homemade mask made of a tee-shirt and cotton towel (davies et al., ) . davies and his co-workers ( ) in the meantime, it is imperative to explore situations where an infected patient coughs without any mask worn, and a susceptible host inhales the resultant plume of droplets and aerosols with different masks worn at a distance of m ( figure ). as shown in figure a , the host without a mask worn receives a considerable payload of viruses so that it is very aerodynamic modeling has been performed to get an insight into how the buoyant jet of coughing by an infected person of a respiratory illness spreads in the cabin of a flight (redrow et al., ; . the hypothesis on the most affected zones within the cabin is, therefore, highlighted below. would set the platform for the sars-cov- to sustain for extended periods within the cabin. strict guidelines for the minimization of such pandemic events are, therefore, paramount. (park et al., ) . offermann and others ( ) distinguished; short-range (between individuals, generally less than -m apart) and long- range (within a room, between rooms or between distant locations, generally greater than -m distances) (tang et al., ) . expiration of cough-jets of an infected person composed of droplets and aerosols enters and mixes with air in the breathing zone of a susceptible host standing nearby (e.g., medical staff), which is capable of contracting the disease (short-range transmission) between individuals may interact to infect one another. in the meantime, transmission to many susceptible hosts in the same confined room (not shown in figure b ). these aerosol-generating plumes cause long-range transmission within the confined space, contracting many susceptible hosts far more than one could imagine. figure c shows the cough-jet trajectory with the infected patient wearing a surgical mask. with the surgical mask worn, the payload of droplets from the infected 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crossings-in the context of covid- outbreak temperature and humidity on the daily new cases and new deaths of covid- in countries. sci. total environ how far droplets can move in indoor environments--revisiting the wells evaporation-falling curve effects of cough-jet on airflow and contaminant transport in an airliner cabin section relationship between humidity and influenza a viability in droplets and implications for influenza's seasonality fecal specimen diagnosis novel coronavirus- infected pneumonia surgical masks as source of bacterial contamination during operative procedures association between ambient temperature and covid- infection in cities from china association between short-term exposure to air pollution and covid- infection: evidence from china sars-cov- viral load in upper respiratory specimens of infected patients key: cord- -zccd mq authors: christian, michael d.; loutfy, mona; mcdonald, l. clifford; martinez, kenneth f.; ofner, mariana; wong, tom; wallington, tamara; gold, wayne l.; mederski, barbara; green, karen; low, donald e. title: possible sars coronavirus transmission during cardiopulmonary resuscitation date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: zccd mq infection of healthcare workers with the severe acute respiratory syndrome–associated coronavirus (sars-cov) is thought to occur primarily by either contact or large respiratory droplet transmission. however, infrequent healthcare worker infections occurred despite the use of contact and droplet precautions, particularly during certain aerosol-generating medical procedures. we investigated a possible cluster of sars-cov infections in healthcare workers who used contact and droplet precautions during attempted cardiopulmonary resuscitation of a sars patient. unlike previously reported instances of transmission during aerosol-generating procedures, the index case-patient was unresponsive, and the intubation procedure was performed quickly and without difficulty. however, before intubation, the patient was ventilated with a bag-valve-mask that may have contributed to aerosolization of sars-cov. on the basis of the results of this investigation and previous reports of sars transmission during aerosol-generating procedures, a systematic approach to the problem is outlined, including the use of the following: ) administrative controls, ) environmental engineering controls, ) personal protective equipment, and ) quality control. d uring the global spread of severe acute respiratory syndrome (sars) ( - ), a great deal was discovered about the illness and the sars-associated coronavirus (sars-cov) ( , ) . sars-cov infection is thought to occur primarily by either contact or large respiratory droplet transmission ( , ) . however, despite the use of infection control precautions and personal protective equipment designed to prevent contact and droplet transmission, episodes of sars-cov transmission to health-care workers have continued to occur under certain circumstances. of particular concern are procedures performed on sars patients that may aerosolize sars-cov and lead to limited airborne transmission or enhanced contact and droplet transmission ( ) . such procedures include noninvasive positive pressure ventilation (bipap), intubation, and high-frequency oscillatory ventilation. as a result, special infection control procedures have been recommended for aerosol-generating procedures ( , ) . we present the results of an investigation of the first reported transmission of sars-cov to healthcare workers that occurred during attempted cardiopulmonary resuscitation of a completely unresponsive sars patient. on the basis of the results of this investigation, as well as previous reports of sars transmission during aerosol-generating procedures, we used the continuous quality improvement framework ( ) to suggest interventions for preventing future episodes of transmission. data were collected through interviews of healthcare workers present during the attempted cardiopulmonary resuscitation where transmission of sars-cov was thought to have occurred. interviews included a structured questionnaire component. hospital and provincial policies in place at the time of the resuscitation were reviewed. the hospital patient-care environment was inspected by a team of environmental engineers and industrial hygienists. laboratory specimens, collected with nasopharyngeal swabs, were obtained from healthcare workers with symptoms that fulfilled the sars clinical case definition after exposure during the attempted cardiopulmonary resuscitation. these were tested by reverse transcriptase-polymerase chain reaction (rt-pcr) with primers specific for sars-cov ( ) . after participants gave informed consent, convalescent-phase serum was collected from all consenting healthcare workers exposed to the attempted resuscitation event as part of a larger seroprevalence study of hospital staff. for this, samples were analyzed with a commercially available indirect immunofluorescent assay (euroimmune, lübeck, germany) according to the directions of the manufacturer. in addition, a limited evaluation of the stryker t personal protection system (stryker instruments, kalamazoo, mi), worn by some of the healthcare workers involved in the resuscitation attempt, was conducted to estimate the operating parameters, including particle removal efficiency and air-flow rate. a met one model b hand-held particle counter (met one, inc., grants pass, or) was used to count ambient particles outside and inside the hood; five replicates were collected for each condition over a -minute sampling period. all information was obtained as part of an ongoing joint investigation into the cause of the second phase of the toronto sars outbreak conducted by toronto public health, health canada, and the centers for disease control and prevention ( ) . a -year-old woman with a history of asthma was admitted to hospital a on may , , with a day history of fever, cough, malaise, headache, and myalgias. the patient's mother had recently been admitted to the same hospital and died of a nosocomial pneumonia after orthopedic surgery for a fractured hip. on the basis of clinical findings and the identification of secondary infections in exposed persons, the mother's death was retrospectively determined to be due to sars. on admission, the patient was febrile and her chest radiograph showed left lower lobe and lingular infiltrates. both acute-phase serologic tests and serum rt-pcr were positive for sars-cov (national microbiology laboratory, health canada, toronto). she was admitted to the hospital and placed in respiratory isolation on the sars unit. progressive respiratory failure later developed in the patient, and within hours of admission, she required % supplemental oxygen. on may , , she was found to have no vital signs and cardiopulmonary resuscitation was attempted. nine healthcare workers participated in the resuscitation attempt. three ward nurses (rn - ) were the initial responders (table) . rn performed chest compressions while rn and rn prepared suction, oxygen, and intubation equipment. three intensive care unit nurses (icu-rn - ), two respiratory therapists (rt and ), and a physician (md) also participated in the resuscitation. icu-rn took over chest compressions from ward-rn . icu-rn inserted a peripheral intravenous catheter (iv) in the left foot of the patient and administered medications via the iv during the resuscitation attempt. icu-rn ventilated the patient with a bag-valve-mask, without a bacterial/viral filter. rt performed the endotracheal intubation, which was completed in < seconds. no suctioning was required during or after the intubation and no respiratory secretions or other bodily substances were observed in the environment. a bacterial/viral filter was placed on the bag-valve-mask after the intubation. all nurses in the room during the resuscitation were wearing protection equipment that was considered standard for routine sars patient care at this hospital. this equipment consisted of two gowns, two sets of gloves, goggles, a full-face shield (with the exception of rn and rn ), shoe covers, hair cover, and niosh-approved n disposable respirators that were not fit-tested. in addition, all nurses involved in the resuscitation were experienced in working on sars units and thus familiar with the recommended infection control policies and procedures. in contrast to the nurses, both rts and the md were wearing t personal protection systems during the resuscitation. all nurses left the room immediately after the intubation and removed their protection equipment following the standard hospital protocol. approximate exposure times are outlined in the table. on the may , , both icu-rn and icu-rn had a temperature > . °c, myalgia, and malaise. in addition, icu-rn complained of headache and nausea, and icu-rn reported dyspnea. icu-rn had a normal chest radiograph results, but the radiograph of icu-rn showed a left lower lobe infiltrate that persisted for several days. both rns were admitted to the hospital for observation; their condition remained stable. rn reported a headache and myalgia on june , , but her maximum temperature reached only . °c. she remained in home quarantine, and her symptoms resolved without further progression. results of rt-pcr performed on nasopharyngeal swabs from icu-rn and icu-rn were negative ( ) . at present, only one case (icu-rn ) meets the world health organization criteria for probable sars, one case (icu-rn ) is under investigation, and the third (rn ) does not meet the case definition as her temperature remained < . °c ( ) . a review of the -hour period before the resuscitation did not show any other likely transmission episodes. in particular, icu-rn was the charge nurse in the icu and had little or no direct patient contact in the hours before the resuscitation. five of the nine healthcare workers involved in the resuscitation agreed to participate in serologic testing. all convalescent-phase samples were collected > days after the event (table) . evaluation of the stryker t personal protection system indicated an average removal efficiency of % for particles > . µm in diameter and % for particles > µm. this equates to a reduction factor (i.e., particles outside of the hood would be reduced in number by this factor) of . and . , respectively. this report describes the apparent transmission of sars-cov from a patient to healthcare workers during an attempted resuscitation. the similar symptom onset dates suggest a point source of exposure. in this case, sars-cov was transmitted despite healthcare workers' wearing protection equipment designed to protect against contact and droplet transmission; no breaches in droplet protection equipment were identified, and exposure times were fairly brief. although sars transmission that involved intubation and bipap ( ) have been reported, this episode is unique in that the patient was neither conscious nor breathing at the time of the intubation, and the intubation procedure was performed quickly and without difficulty. these factors make it less likely that transmission occurred as a direct result of the intubation procedure. instead, it is more likely that transmission was related to events leading up to the intubation. in this case, just as in previous cases, either contact, droplet, or airborne transmission might have occurred. direct and indirect contact are the most common forms of transmission for most nosocomial pathogens; transmission between patients or from patient to healthcare worker usually follows contamination of the healthcare workers' hands after touching either the patient or a fomite that came into direct contact with the patient. large aerosol droplets (i.e., > µm) can, in addition to contaminating both animate and inanimate surfaces in close range of the patient, travel short distances through the air and make direct contact with the exposed mucous membranes of healthcare workers or other patients. in contrast, airborne transmission is mediated by respiratory aerosols. these aerosols of infectious organisms contain droplet nuclei < µm in size and, depending upon their size within this range as well as ambient environmental conditions, can float on air currents and remain airborne for many hours ( ) ( ) ( ) ( ) . a large variety of viruses ( , ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) are transmissible through both contact and airborne modes. often, investigation of the epidemiology of nosocomial viral infections, establishes the occurrence of airborne transmission ( ) . two explanations may account for the transmission observed in this case: ) an unrecognized breach in contact and droplet precautions occurred, or ) an airborne viral load was great enough to overwhelm the protection offered by droplet precautions, including non-fit-tested n disposable respirators. if the last form of transmission was responsible, airborne virus may have been generated by the coughing patient ( ) before her cardiopulmonary arrest or due to a "cough-like" force produced by the airway pressures created during asynchronous chest compressions and ventilations using the bag-valve-mask ( ) . regardless of the exact mode of transmission in this case, several lessons were learned through our investigation that may help reduce the risk of transmission to healthcare workers. a systematic approach to this problem is outlined considering the following framework: ) administrative controls, ) environmental engineering, ) protection equipment, and ) quality control. policies and protocols for emergency resuscitation involving patients known to have or suspected of having sars should include ) description of the roles and responsibilities of healthcare workers responding to the emergency, ) mechanisms to alert responders that the emergency involves a potentially contagious patient (e.g., announcing the code as an "isolation code blue"), ) steps to limit the number of healthcare workers involved to minimize potential exposures, ) plans for having auxiliary staff staged in a safe area where they can be easily called on if needed but otherwise preventing unnecessary exposure, ) plans for safe disposal and cleaning of equipment used during the emergency response, and ) procedures for disposition of the patient after the emergency, either to the icu if resuscitation is successful or the morgue if unsuccessful. policies must be developed that consider all high-risk exposures or emergency situations and not just individual procedures. policies that are too focused are of little value in dealing with the hundreds of unforeseeable possible situations that may arise. conversely, policies that educate healthcare workers to assess the risks of a task and empower them to take appropriate protective action will be more effective. these policies should be crafted at each healthcare facility by a team that involves key stakeholders, including persons involved in the clinical response along with infection control practitioners and infectious disease experts. it is also important to minimize the chance that a patient will suffer unwitnessed cardiopulmonary arrest or require emergency intubation on a sars unit. prevention of these events will involve two changes in policy. the first is to recognize that isolation wards cannot be staffed with the same nurse-to-patient ratio as a regular ward. care of patients in isolation is more time intensive due to both the physical barriers (e.g., anterooms, doors kept closed at all times) and the required use of protection equipment. the nurse-to-patient ratio on the sars ward at the time of the arrest was between : and : ; a more ideal ratio might be : or : . it is also necessary to have a lower threshold for transferring patients to a higher acuity setting (i.e., icu or stepdown unit) when they first begin to show signs of a clinical deterioration. to enable this, all patients on a sars unit should have measurement of vital signs along with pulse oximetry at a minimum of every hours. should their oxygen saturation drop below % on room air one should administer oxygen through nasal prongs - l per minute to maintain saturation > %, and increase vital signs/pulse oximetry to every hours. if the patient subsequently requires oxygen through nasal prongs at > l per minute the responsible physician should be notified and increase vital signs or pulse oximetry to every hour. finally, if the patient requires supplemental oxygen of > % to maintain saturation > %, the patient should be transferred to the intensive care unit and undergo elective intubation in a controlled manner. this later policy has worked well in other sars units, as well as in hospital a after it was implemented by one of the authors (m.l.) after this cluster. finally, policies should be developed to address the appropriateness and application of advanced cardiac life support for patients suffering cardiopulmonary arrest on a sars ward. many considerations must enter into any such discussion, including the usefulness and outcome of resuscitation efforts, particularly in unwitnessed arrests ( ) ( ) ( ) . despite even the most well-planned and wellwritten policies, if healthcare workers are not trained in proper infection control practices, sars will continue to be transmitted. staff must be trained in both the application of policies as well as the use of protection equipment. in addition to education, practice is also important; for example, consideration should be given to staging one or more "mock sars code blue" events. the second line of defense against the transmission of sars is environmental engineering controls. these consist of physical engineering elements such as negative pressure rooms, dilution ventilation, high-efficiency particulate air filtration, ultraviolet lights, and scavenging devices. the primary goal of environmental engineering processes is to contain the infectious agent in a limited area and to minimize or rapidly decrease the viral load in the environment so that in the event of a breach in infection control process or protection equipment, the chance of healthcare workers or other patients becoming infected is minimized. in this case, a breach occurred in source control; the initial bag-valve-mask used in the resuscitation did not have a viral/bacterial filter on the exhaust. this breach may have resulted in "uncontrolled" release of aerosolized virus into the environment. however, previous studies with coxsackie virus showed that little or no virus is detectable in expired air, only in respiratory aerosols and droplets from coughing or sneezing ( , ) . the final line of protection against occupational exposure is protection equipment. the use of n respirators offers a level of protection against airborne transmission of sars. however, for any form of respiratory protection to perform at the level of its full potential, it must be properly fitted to provide an adequate seal. the n disposable respirators used by healthcare workers in this instance were not fit-tested to ensure an adequate seal. thus the exact level of protection afforded by the n respirators for each person in this case is unknown. nonetheless, a higher level of respiratory protection should be considered in environments with a potentially very high sars-cov load, such as that associated with aerosol-generating procedures as a result of the transmission of sars co-v during aerosol-generating procedures, some hospitals in ontario, canada, have adopted use of the t personal protective system (stryker instruments) ( figure ). this system was originally designed to maintain a highly sterile field during surgery to prevent operative site infections. as a form of protection equipment, this system has both advantages and disadvantages. the primary advantage is that the entire body of the healthcare worker is covered, providing a high level of droplet protection. the primary disadvantage of the t is the length of time required to put one on during an emergency. in the emergency resuscitation described in this report, the delay in certain rescuers responding was due to the time required to put on the t . this resulted in the need for a second code blue to be announced for the same patient, which drew additional personnel to the code and thus increased the number of healthcare workers exposed to sars. the healthcare worker must also be attentive to avoid contamination when removing the t . moreover, the airborne reduction factors of . , for particles > . µm in diameter, and . for particles > µm were less than the protection factor of that is assigned (i.e., minimum expected in practice) for a fit-tested, disposable n respirator. however, a disposable n is commonly worn under the t used in ontario hospitals, suggesting the respiratory protection afforded healthcare workers using the t would be greater. the powered air-purifying respirators (paprs) most commonly used in healthcare settings have a disposable full hood with face shield covering the healthcare worker's upper body (figure ) . this device provides a higher level of protection against airborne infectious agents (any papr equipped with a hood or helmet with any type of particulate air filter has an assigned protection factor of [ ] ), and it may be faster and easier to apply in an emergency situation. finally, ensuring that a hospital has adequate protection against airborne diseases, even if not absolutely required for sars, will ensure that staff are prepared to deal with future emerging infectious diseases or bioterrorism events that could involve airborne agents. regardless of what device (t versus papr) is used in an institution for potentially aerosol generating procedures, it is essential that they are distributed throughout the hospital in areas where they are most likely to be required by primary responders in an emergency situation as opposed to a central area where teams must wait for them to be brought to the emergency. in addition, extra protection equipment should be included as part of any "crash cart" used by the responding code team. although there is a tendency to focus only on hightech forms of protection equipment, it is important not to forget the basics of infection control procedures such as glove changing and hand hygiene. healthcare workers must remain vigilant about not only protecting themselves from sars transmission but also protecting against patient-to-patient transmission. as was found in the second phase of the sars outbreak in toronto ( ), one of the best ways to prevent healthcare worker infections is to ensure that no sustained transmission of sars occurs within the patient population, which may act as a reservoir of infection. after developing good policies and training staff who are rehearsed for emergencies and provided with appropriate protection equipment, the last step is to ensure ongoing adherence to the standards set. this adherence is achieved through quality control. without an effective quality control program in place, lapses in infection control procedures will occur, particularly as healthcare workers become fatigued during a prolonged outbreak. a variety of quality control methods can be implemented, including administrative checks to ensure equipment is in good repair, policies are current, and training materials are up to date. another quality control practice often used by emergency services personnel dealing with hazardous situations is the "buddy system." in this system, healthcare workers always work in teams on sars units with each person being responsible for double checking to make sure that their partner is wearing appropriate equipment and following correct infection control practices before entering a patient's room. finally, a process should be in place to review responses to emergencies after they have occurred to learn from the experience and facilitate continuous quality improvement. sars has increased the medical community's awareness of issues related to occupational health and safety. it has also highlighted the importance of infection control programs and practices. a systematic approach, including administrative controls, environmental engineering, protection equipment, and quality control, is advocated to prevent future sars-cov transmission to healthcare workers. emerging infectious diseases • www.cdc.gov/eid • vol. a cluster of cases of severe acute respiratory syndrome in hong kong a major outbreak of severe acute respiratory syndrome in hong kong identification of severe acute respiratory syndrome in canada clinical features and short-term outcomes of patients with sars in the greater toronto area cumulative number of reported cases of severe acute respiratory syndrome (sars) identification of a novel coronavirus in patients with severe acute 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national institute for occupational safety and health. niosh guide to industrial respiratory protection. dhhs (niosh) publication no. - we thank randy wax and laurie mazurik for taking the figure photos.dr. christian is a consultant practicing general internal medicine, including critical care, in both academic and community hospitals. he will soon begin a combined fellowship in infectious diseases and critical care. key: cord- -sfa d ux authors: lei, h.; li, y.; xiao, s.; lin, c.‐h.; norris, s. l.; wei, d.; hu, z.; ji, s. title: routes of transmission of influenza a h n , sars cov, and norovirus in air cabin: comparative analyses date: - - journal: indoor air doi: . /ina. sha: doc_id: cord_uid: sfa d ux identifying the exact transmission route(s) of infectious diseases in indoor environments is a crucial step in developing effective intervention strategies. in this study, we proposed a comparative analysis approach and built a model to simulate outbreaks of different in‐flight infections in a similar cabin environment, that is, influenza a h n , severe acute respiratory syndrome (sars) coronavirus (cov), and norovirus. the simulation results seemed to suggest that the close contact route was probably the most significant route (contributes %, % confidence interval [ci]: %‐ %) in the in‐flight transmission of influenza a h n transmission; as a result, passengers within rows of the index case had a significantly higher infection risk than others in the outbreak (relative risk [rr]: . , % ci: . ‐ . , p = . ). for sars cov, the airborne, close contact, and fomite routes contributed % ( % ci: %‐ %), % ( % ci: %‐ %), and % ( % ci: %‐ %), respectively. for norovirus, the simulation results suggested that the fomite route played the dominant role (contributes %, % ci: %‐ %) in most cases; as a result, passengers in aisle seats had a significantly higher infection risk than others (rr: . , % ci: . ‐ . , p = . ). this work highlighted a method for using observed outbreak data to analyze the roles of different infection transmission routes. knowledge about the relative importance of different transmission route(s) is fundamental to developing effective intervention strategies for infectious respiratory and enteric diseases in indoor environments. epidemiological analysis together with in-depth environmental investigations often provides useful insights, and meta-analysis may also be carried out for a particular disease. in this study, we proposed an alternative comparative analysis approach in which we studied outbreaks of different diseases in the same environment using the same approach, by examining differences in the spatial infection patterns. this approach could partly overcome the limitation of traditional individual outbreak analysis that outbreak cannot be repeatedly observed, because the comparative analysis of different diseases in the same environment is like that one disease happened several times. our hypothesis is that the different transmission routes of infection lead to different spatial patterns of secondary cases. for example, close contact transmission always happens with - m of the source, which means that secondary cases infected via close contact route would be close to the index case(s). the airborne transmission may occur over long distance, and the secondary cases infected via airborne route would distribute uniformly in a space when the air is fully mixed. aircraft cabins were selected as the context for our study. the more or less fixed seating arrangement in aircraft cabins permits a spatial pattern of the secondary cases to be identified in some outbreaks. the norovirus is the leading cause of nonbacterial gastroenteritis in humans. , the major possible routes in aircraft cabins are close contact, airborne, and fomite. in this study, a mathematical model was built to study the in-flight infection transmission process, based on the studies by atkinson and wein and nicas and jones. this technique enables detailed physical and biological processes to be modeled and the impact of environmental parameters to be easily integrated. we compared the simulated relative importance of different transmission routes in in-flight outbreaks with the reported spatial distribution of the secondary cases. we performed a literature search for in-flight outbreaks of influenza a h n , sars cov, and norovirus in appendix s . all chosen outbreaks occurred in boeing aircraft cabins with flight duration . or hours. the main criteria for identifying suitable outbreaks include the availability of detailed seating information for both the infected and noninfected, airplane type and flight duration. figure illustrates the detailed spatial distribution of the secondary cases in the chosen outbreaks. the definitions for the relevant transmission routes ( figure ) in our multiroute model are as follows. the airborne route refers to direct inhalation of an infectious agent through small droplet nuclei, that is, the residue of large droplets containing microorganisms that have evaporated to an aerodynamic diameter of less than microns (termed respirable). these respirable droplets can deposit in the respiratory tract. close contact route includes direct contact and large droplet transmission. direct contact refers to infection through person-to-person contact with the index source passenger, such as handshaking. we assume there is no body-to-body contact between index source passenger(s) and other passengers during the flight. we only consider large droplet transmission in the model, which refers to the inhalation of the virus carried in respirable airborne particles with a diameter between and microns (termed inspirable), and the droplet spray of large droplets (> microns in diameter) onto facial target membranes. the fomite route refers to infection by touching objects or surfaces that have earlier been contaminated by hands or by direct deposition • our identification of the dominated routes, that is the close contact route (large droplet) for influenza, the fomite route for norovirus, and all routes for sars cov, suggested the relative importance of different environment intervention for different infectious diseases in air cabins and probably also in other indoor environments. for minimizing in-flight fomite transmission, the aisle seatbacks and toilets should be cleaned and disinfected effectively. f i g u r e spatial distribution for in-flight infection outbreaks, (a) norovirus, (b) sars cov, and (c) influenza a h n of infectious pathogens from the index source passenger, which is also sometimes termed indirect contact route. for respiratory disease, coughing is used as surrogate to model the virus-containing droplets from all respiratory activities such as breathing, talking, and sneezing, as the size distribution of the droplets from coughing, talking, and sneezing is similar, and the amount of droplets generated due to breathing is negligible. assume that cough frequency for infector is f c per hour and that one cough can produce n c droplets with the size distribution f c r . then, the generation rate (number/h) of droplets with radius r (μm) from individual i is given by: for enteric disease, such as norovirus, virus-containing droplets are emitted from the infector in vomit and/or diarrhea. a study by simulated vomiting device showed that the volume of the aerosolized droplets ranged from . to ml, with a mean value of . ml. to the best of our knowledge, there is no study on the size distribution of the droplets from vomit, and we assume that these droplets have same size distribution as those from coughing. for respirable droplets with aerodynamic diameter of less than microns, they could move a long distance with the airflow and dis- for inspirable droplets with a diameter between and microns, we assumed that the maximum horizontal distance they could move was m because of gravity and the relatively high deposition rate on environmental surfaces. they distributed within m of the source, and the volume of this space was denoted to be a rapid death rate of pathogens atomized into air had been observed, , and evaporation of droplets was believed to play an important role. xie et al found that there was a fast viability decline stage when the droplets completely evaporated, when viability decreased to about % and then slowly declined. here, the survival ratio due to evaporation was defined as e r ,s = l r ,t ∕l r , where l r ,t is the concentration of viable viruses (tcid /ml or genome copies/ml) in droplets with initial radius r (μm) at the time t (s) after being exhaled; t e r is the evaporation time (s) for the drop- illustration of different transmission routes considered in this study. note that all sizes of droplets are involved in the fomite route assume there is no resuspension of droplets from environmental surfaces into the air. in the air cabin, on the one hand, viable virus is generated from index case(s) at rate ( ) was the exposure through each route was modeled separately, and then the dose-response model was used to assess an integrated risk. the dose to individual i via the airborne route in the lower and upper respiratory tracts is denoted as d i al and d i au (tcid or genome copies), and for a flight duration t, they can estimated as follows: where r a is the largest radius for airborne droplets and r a = μm ; p is the pulmonary ventilation rate and p = . m /h ; r is the droplets' initial radius; and r is the final radius after complete evaporation. here, we assume that r = r / ; l (r) and u (r) are the deposition fraction of droplets with radius r in the lower and upper respiratory tracts, respectively. the model from icrp was used in this study. transmission by close contact refers to either inhalation of the virus carried in airborne particles with a diameter between and microns, or the spray of large droplets on the susceptible individuals' mucous membranes. for norovirus transmission, it is difficult for the "large" droplets generated from vomiting to move to the inhale air of the seated susceptible passengers, which is always more than one meter above the ground, because of the high downward velocity, gravity, and the relatively high deposition rate. therefore, the close contact route was not considered in the norovirus transmission. then the dose via inhalation of inspirable droplets in upper respiratory tract (d i cr (tcid or genome copies)) was where r b was radius of the maximum inspirable droplets and for the spray of large droplets on mucous membranes, because of the seating arrangement we assumed that there was no face-to- the negative exponential dose-response model was used to estimate the infection risk, which implies that a single particle can start an infection, all single particles are independent of each other. the infection risk of individual i during the flight can be calculated according to the following equation where η l η l , η u , and η m are the dose-response rates (/tcid or/genome copy) in lower/upper respiratory tracts and on mucous membranes, respectively. here it is also assumed that η u = η m . table ( ) d i cm = t ∫ o ∞ ∫ r a a m a v c i c (r) kr v t πr l r ,t drdt ( ) c j s � k + � = � c j s (k) + ∑n p i= (c i h (k)a hs τ hs −c j s (k)a hs τ sh )ps i,j (k) a s � e −b s ×Δt ( ) c i h � k + � = � c i h (k) − ∑n p i= (c i h (k)a hs τ hs −c j s (k)a hs τ sh )ps i,j (k) a h − pm i (k)a m h τ hm c i h (k) a h � e −b h ×Δt ( ) d i fm = n t ∑ k= pm i (k) a m h τ hm c i h (k) ( ) p i = − e −(η l d i al +η u d i au )−(ηud i cr +η m d i cm )−ηmd i fm in this study, we built a mathematical model to study the inflight transmission of different viruses, using a novel comparative analysis approach. the results suggested that the dominant transmission routes in air cabins are probably the close contact route for influenza, the fomite route for norovirus, and all routes (airborne, close contact, and fomite routes) for sars cov. the dominant transmission routes vary for the viruses, mainly depending on the pathogen-specific t a b l e infection risks of passengers within rows of the index case(s) and others from the simulation results and reported outbreak data, respectively (with the tuned range of the virus shedding magnitudes) outbreak data within rows (others) as far as we are aware there are no data on the dose-response rate of sars cov either on mucous membranes or in the respiratory tracts of humans. we assume that the dose-response rate on human mucous membranes is the same as that on mice mucous membranes, and the dose-response rate in the human respiratory tract is times that of mucous membranes (similar to the influenza a h n data). we also performed the sensitivity analysis of the dose-response rates, with different ratios of median dose-response rate, that is (in lower respiratory tract)/(on mucous membranes) (see detail in appendix s ), and we found that all routes were important in in-flight sars cov transmission for different ratios of median dose-response rate. the fecal-oral spread is known to be the primary mode of transmission of norovirus. the fomite route transmission of norovirus is well supported by the reported widespread environmental contamination with norovirus. , our simulation of a norovirus outbreak confirms that the fomite route is dominant in transmission. it is also suggested that vomiting can produce aerosol droplets containing norovirus particles, and inhaled by exposed susceptible individuals, depositing in the upper respiratory tract and subsequently swallowed along with the respiratory mucus. airborne norovirus was detected from an air sample in one outbreak. a study of a norovirus outbreak in a hotel found an inverse relationship between the infection risk and the distance from the person who vomited when a food source was not implicated. this study simulated both the airborne and fomite route transmission of norovirus. and the results showed that in most cases, the fomite route plays the dominant role. the predicted infection risk from the fomite route for aisle seat passengers is . times higher than that for nonaisle seat passengers. the aisle passenger-tonon-aisle passenger relative risk in the outbreak ( . ) is much higher than . , and may be attributable to a small sample size of secondary cases ( ). in conclusion, a mathematical model was built to simulate the physi- additionally, this study highlights a way to use observation outbreak data to analyze the relative importance of different routes in infection transmission. evidence of airborne transmission of the severe acute respiratory syndrome virus spread of a novel influenza a(h n ) virus via global airline transportation respiratory infections during air travel transmissibility of pandemic influenza norovirus gastroenteritis human susceptibility and resistance to norwalk virus infection transmission of infectious diseases during commercial air 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a. t.; funk, s.; reiner, r. c.; faria, n. r.; pybus, o. g.; cauchemez, s. title: reconstruction and prediction of viral disease epidemics date: - - journal: epidemiol infect doi: . /s sha: doc_id: cord_uid: j i xfs a growing number of infectious pathogens are spreading among geographic regions. some pathogens that were previously not considered to pose a general threat to human health have emerged at regional and global scales, such as zika and ebola virus disease. other pathogens, such as yellow fever virus, were previously thought to be under control but have recently re-emerged, causing new challenges to public health organisations. a wide array of new modelling techniques, aided by increased computing capabilities, novel diagnostic tools, and the increased speed and availability of genomic sequencing allow researchers to identify new pathogens more rapidly, assess the likelihood of geographic spread, and quantify the speed of human-to-human transmission. despite some initial successes in predicting the spread of acute viral infections, the practicalities and sustainability of such approaches will need to be evaluated in the context of public health responses. infectious disease outbreaks pose a significant threat to human health. the frequency of such outbreaks is thought to have increased over the past decade. for example, quickly after an epidemic of ebola virus affected guinea, sierra leone, and liberia in - [ ] , chikungunya virus (chikv) caused an extensive international epidemic in the americas and beyond, and was quickly followed by zika virus (zikv) emergence. to date, there have been more than confirmed or probable cases of zikv but the true number of cases remains unknown [ ] . yellow fever (yf), a vaccine-preventable disease, recently posed major public health problems. in - , the largest yf outbreak since the s was observed in angola and the democratic republic of the congo, causing confirmed cases and deaths [ ] . yf also poses an ongoing public health risk to large, urban and under-vaccinated populations in the coastal areas of southern brazil, a country that successfully eradicated yf in the s and s [ ] [ ] [ ] . examples of other emerging pathogens that have caused international health security concerns include the severe acute respiratory syndrome (sars) virus and the middle east respiratory syndrome coronavirus (mers-cov) [ ] [ ] [ ] [ ] . this list extends to other pathogens such as influenza, nipah and henipaviral diseases, and lassa fever [ ] . these examples show the continued risks that infectious diseases pose and highlight the challenges of large international outbreaks to epidemic planning and response. during emerging infectious disease outbreaks, empirical information and mathematical modelling techniques are now commonly used to characterise and predict the spatio-temporal dynamics of the spread of pathogens. such analyses may help policymakers to evaluate the threat to public health, determine the resources required to reduce disease burden, and guide disease surveillance efforts and the deployment of interventions. in the last decade, our ability to perform such assessments has been improved by advances in a number of disciplines, including digital disease surveillance [ ] , environmental modelling [ , ] , genomics [ ] and mathematical modelling [ ] . for example, environmental variables such as rainfall and precipitation [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] can be used to better understand the landscape within which the disease may be transmitted, and detailed transmission data from a small sampled population can be extrapolated to larger, un-surveyed areas [ ] . attempts have been made to illustrate the spatial structure of epidemics mainly using human movement data [ ] [ ] [ ] [ ] , to provide mechanistic insights in how the disease may disperse locally [ , , ] or how effective reactive vaccination campaigns may be [ ] [ ] [ ] . there are continued efforts to reconstruct epidemic dynamics using information derived from pathogen genomic data, which contain unique information about the history of transmission [ , [ ] [ ] [ ] . although each of these disciplines has an established relationship to disease prevention and control, the benefits of integrating them into a unified framework have yet to be fully achieved. here we describe the common applications and models used to predict acute viral diseases and discuss the current challenges and limitations. we then outline the advantages of integrating disparate data sources to advance our understanding of epidemic spread. we discuss how such research has been used in recent outbreaks and outline shortcomings that may be addressed in the future. phylogenetic and phylodynamic tools are increasingly being used to infer a range of outbreak properties [ ] . common spatiotemporal analyses of pathogen genomes focus on mapping and predicting virus lineage exchange among locations, with the underlying aim of reconstructing the pathways of disease introduction and spread, albeit at a coarse spatial resolution, and often retrospectively [ , , , , , ] . an additional feature that can be inferred from genomic data is the timing of individual founder introductions [ ] . blue arrows in fig. indicate the time when the first report was published inferring the likely geographic origin of four major international infectious disease outbreaks. phylogenetic tools can help to characterise the number of introductions that lead to disease transmission in a new location [ ] , quantify the risk of cross-species transmission [ ] , and infer ecological drivers of transmission [ , ] . genome-derived estimates have been compared qualitatively to those from epidemiological data, but formal model-based integration of both data sources are rare [ , ] . in principle, pairing genomic information with epidemiological inference should enable us to quantify the number of cases missed in each location and help to estimate parameters such as the basic reproductive number and doubling time of the epidemic, as done for zikv at the tail end of the epidemic (fig. a ) [ ] [ ] [ ] . a common limitation when genetic data are used is the absence of a rigorous and formal sampling scheme. in many instances, genomic sampling is affected by convenience and expedience and may not reflect underlying incidence, although this can be improved post-hoc in large data sets via sub-sampling using, for example continuous phylogenetic inference [ ] [ ] [ ] . strong sampling biases may affect estimates of the arrival time of a pathogen and its pathways of dissemination among locations [ ] . static disease mapping is a powerful tool to visualise and defines the landscape within which transmission occurs, based on ecological drivers of transmission [ , , ] . when combined with global data on human travel and mobility, it can be used to understand the global dynamic risk surface of infectious disease, especially when there are strong ecological determinants of transmission, as there are for the vector-borne diseases zika, dengue, chikungunya and yf [ , ] . publication of reports that estimate geographic spread for the diseases in fig. are indicated by green arrows. the global epidemic history of zika, for example, remains poorly understood. the challenge to accurately reconstruct the epidemic pathway of the virus is further complicated by its relatively unspecific clinical presentation. this may explain why the initial studies that aimed to understand the geographic origin of the zika epidemic in the americas were published relatively late into the epidemic (> year, fig. a ). for the other major outbreaks highlighted in fig. , estimates of the geographic origin were documented between and months after the first reports of human cases ( fig. b-d ; table ). however, given the underlying ecological determinants of transmission that restrict the reproduction of the virus in the mosquito vector species, large areas can be excluded from the risk of local virus transmission. when overlaying information on the reported presence of zika cases vs. the underlying ecological risk map, surveillance gaps may be identified [ , ] . areas where there is a mismatch in the predicted presence and reported presence (i.e. cases detected) should be targeted for active surveillance. the spatial spread process of new pathogens, however, is not only determined by the underlying ecological determinants in each location but also by the dynamic nature of importation, often driven by human movements [ ] . spatial models that take into account the patterns of human spread and mobility may, therefore, improve our ability to characterise and anticipate spatial expansion. different models have been proposed to predict the geographic spread of epidemics but rarely have they been used in real time during the course of an epidemic [ , ] (fig. ) . for example, during the yf outbreak in angola and the democratic republic of the congo, estimates of geographic spread to provinces outside luanda, the capital of angola, were published > months after the last cases were reported (fig. c) . such information could guide public health institutions to decide where and when to implement surveillance and control programs [ ] . more work, however, is needed to dynamically map the spread of infectious diseases and to extract meaningful and interpretable quantities for public health practitioners. in parallel to these efforts to model the spread of pathogens at a meta-population level (e.g. between cities, regions, countries or continents), we also need to better understand transmission dynamics at a much more granular level and assess the characteristics of the inter-human transmission. while historically, the potential for inter-human transmission has often been summarised with a single statistic; the reproduction number r (i.e. the average number of secondary infections generated by a case). however, it has long been recognised that it is also essential to assess heterogeneities in individual r values, since the presence of super-spreading events may have a major impact on the risk of emergence and our ability to control outbreaks [ ] . this was exemplified in a large mers-cov outbreak in south korea in in which only a small number of cases were responsible for the majority of infections [ , ] . other factors that may drive the spatial differences in the reproductive number are ecological (population density, climatic factors, or others) and can now be readily incorporated in transmission models [ ] . ideally, these assessments should be performed on detailed data documenting chains of transmission, as such data can provide precise quantification of the transmission potential and the impact of targeted interventions in different settings and over time, and allow testing specific hypotheses about the transmission process (e.g. what is the contribution of re-introductions to the overall dynamic?) [ ] . however, such data are rarely available as it is difficult to identify the source of infection for most pathogens. as a result, sophisticated statistical techniques are often required to reconstruct chains of transmission and estimate transmission parameters from more limited data that may include: (i) in the context of zoonoses, the size of human clusters [ ] [ ] [ ] or the proportion of surveillance cases that reported a contact with the natural reservoir [ ] , (ii) the growth rate in the case count [ ] [ ] [ ] [ ] , (iii) partial data on chains of transmission [ ] , or (iv) outbreak data where the timing of symptom onsets and location of cases are recorded in small communities such as households [ ] [ ] [ ] [ ] , schools [ ] or villages [ ] . in cases of high-density sampling, genomic data can help to reconstruct transmission chains [ ] . mechanistic models of infectious disease dynamics can be used to make predictions about the future course of an outbreak within a given location [ ] . increasingly, such models are being used in real time, such that predictions are updated every time a new data point becomes available [ , ] . some other applications track pathogen evolution over time as data become available [ ] . however, the perceived ability of such models to successfully or unsuccessfully make 'correct' predictions can generate considerable controversy [ , ] . there are few studies that systematically investigate forecasting accuracy and its relationship to the length of time that is being predicted and to the quantity and quality of data available [ , ] . other examples are forecasting challenges for ongoing epidemics such as chikv in the americas (https://www.darpa.mil/news-events/ - - ), evd in west africa [ ] and seasonal influenza [ , ] , designed and initiated by funding agencies and public health governments. this is an important area for future research. there are clear benefits to combining information from different data sources in order to better predict viral epidemic spread. previous work most commonly presents estimates from different sources side-by-side, for example, estimates of the epidemic reproductive number derived from genomic vs. epidemiological data [ ] . such comparisons are important to assess the consistency of data sources and may help to derive new hypotheses. spurred by technological innovation such as portable sequencing using the minion device (oxford nanopore technologies, oxford, uk) [ ] and by interdisciplinary collaborations during disease outbreaks, researchers have started to work to combine three types of transmission data: spatial, genomic and epidemiological which have now been published for three of the four major outbreaks we considered here (fig. , red arrows) [ , , ] . for example, such interdisciplinary work helped to identify the introduction of zika into the americas [ ] , investigated the main drivers of transmission of zikv through climatic suitability of its mosquito vectors [ ] and tried to extrapolate how many people had been infected with the virus [ , , ] . in the context of phylogenetic analyses, environmental and other spatial data may be helpful in reconstructing the drivers of transmission and spread using, for example, information on the reservoir or host movements [ , ] . in turn, phylogenetic information may complement epidemiological analysis by providing more evidence on the transmission routes that are common in an outbreak [ ] . this may be particularly useful for diseases that have a highly structured transmission dynamic, such as mers or sars, where a small number of people are responsible for the majority of secondary cases [ , ] , transmission from the animal reservoir is frequent, or importation drives locally observed epidemics [ ] . one common assumption in many epidemiological models is that it is equally likely for people to meet and infect others living in the same location and that population immunity is proportional to the demographic structure [ ] . hence, observed cases are often assumed to arise from other cases that are reported locally as long as they are consistent with the generation time of the disease. however, a wellconnected location can, in principle, accrue a large number of incident cases through recurring introductions from elsewhere, rather than via local transmission [ ] . these results can have large implications for surveillance and control, as different competing strategies (e.g. limiting importations or eradicating the disease locally) may be considered. while analytical approaches of various degrees of complexity have been proposed to probabilistically reconstruct transmission trees from incomplete outbreak data [ , , ] , contact tracing, which can be very labour intensive [ ] , remains a gold standard information source. this may allow us to is to determine the true distribution of cluster sizes (i.e. the number of subsequent cases resulting from each introduction) but is often only available for a small number of locations. however, using genomic data can help refine the understanding of heterogeneity in transmission but such framework does not yet allow to exactly quantify the fraction of observed cases that are attributable to local transmission versus introduction from elsewhere, or to determine how many importations are responsible for the local incidence, despite its crucial importance for eradication campaigns [ , , ] . in the context of the zika outbreak in florida, combining genomic data from the outbreak with epidemiological analysis revealed that the outbreak was driven by a large number of introductions rather than by persistent local transmission. in the recent yellow fever outbreak in southern brazil, linking epidemiological, spatial and genomic data and techniques could provide insights into the transmission potential and risk of urban transmission [ ] . one dataset and analysis alone would have not been strong enough to make such conclusions [ ] . inferences about epidemic processes made using mathematical models rely on a number of assumptions. geographic modelling approaches, mostly informed by spatial ecology, attempt to fill gaps where no data has been observed, hence inferences may be uncertain, as the underlying ecological process may be poorly understood and dynamical aspects of the invasion process are ignored. these deficiencies can be ameliorated, in part, by adding virus genome data that contain information about past transmission and invasion patterns [ ] . however, due to incomplete and poor sampling (as discussed above), genomic data alone may provide an incomplete picture of the timing of viral introduction and spread among locations. this, in turn, can be supported by the addition of epidemiological time series of reported cases and serological information about population immunity [ , ] . despite this, building a joint inference framework that combines all available data sources and which characterises 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types: mapping the year history understanding herd immunity use of serological surveys to generate key insights into the changing global landscape of infectious disease key: cord- - h ipcwn authors: paul, l. a.; daneman, n.; brown, k. a.; johnson, j.; van ingen, t.; joh, e.; wilson, s. e.; buchan, s. a. title: characteristics associated with household transmission of sars-cov- in ontario, canada date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: h ipcwn background: within-household transmission of sars-cov- infection has been identified as one of the main sources of spread of covid- after lockdown restrictions and self-isolation guidelines are implemented. secondary attack rates among household contacts are estimated to be five to ten times higher than among non-household contacts, but it is unclear which individuals are more prone to transmit infection within their households. methods: using address matching, a cohort was assembled of all laboratory-confirmed cases of covid- residing in private households in ontario, canada. descriptive analyses were performed to compare characteristics of cases in households that experienced secondary transmission versus those that did not. logistic regression models were fit to determine index case characteristics and neighbourhood characteristics associated with transmission. findings: between january and july, , there were , cases of covid- residing in , households. longer testing delays ([≥] days versus days or= . , % ci: . - . ) and male sex (or= . , % ci: . - . ) were associated with greater odds of household secondary transmission, while being a healthcare worker (or= . , % ci: . - . ) was associated with lower odds of transmission. neighbourhoods with larger average economic family size and a higher proportion of households with multiple persons per room were also associated with greater odds of transmission. interpretation: it is important for individuals to get tested for sars-cov- infection as soon as symptoms appear, and to isolate away from household contacts; this is particularly important in neighbourhoods with large family sizes and/or crowded households. evidence before this study: we searched pubmed and google scholar up to september , to identify individual-level cohort studies or meta-analyses on household transmission of covid- . we used the search terms ("covid" or "sars-cov- ") and ("household" [title]), and also reviewed the reference lists of any studies found during the search to identify additional studies. we considered studies that reported secondary attack rates and/or other measures of association (i.e., relative risk, odds ratio, or hazard ratio) for household transmission. we did not consider any modelling studies, studies that focused specifically on children, or small case studies that included less than three households. the search returned studies, of which were included in three meta-analyses. pooled household secondary attack rates from the three meta-analyses were %, %, and %; secondary attack rates in households were estimated to be five to ten times as high as in non-household settings. most studies were conducted in asia and identified households from contact tracing, with individual studies reporting on fewer than households. most studies did not consider households with no secondary transmission, and focused on a limited set of secondary case characteristics. added value of this study: we applied an address matching algorithm, which identified , private households of laboratory-confirmed cases of covid- in ontario, canada. ontario has the advantage of a universal healthcare system and population-wide data for the entire province. to our knowledge, this study contains the largest number of private households with at least one confirmed case of covid- . we compared a variety of individual-and neighbourhood-level characteristics of households with and without secondary transmission. we also applied logistic regression models to determine index case characteristics associated with transmission, which gave important insights into factors that may help reduce secondary transmission in households. implications of all the available evidence: findings from this study and existing evidence suggest that testing delays and household crowding play important roles in whether household secondary transmission occurs. odds of household transmission may be reduced by cases seeking testing as soon as symptoms appear, and self-isolating outside the home or in a room alone if possible. these strategies may be considered by public health officials to reduce household transmission and mitigate local spread of covid- . future research should further investigate the role of children and youth in household transmission. transmission and acquisition of sars-cov- infection has become an active area of covid- research since person-to-person transmission was confirmed at the beginning of . , in many countries, the primary source of acquisition of sars-cov- infection has transitioned from travel-related transmission early in the pandemic, to local transmission as countries implemented travel restrictions to reduce imported infections. within-household transmission in particular has been highlighted as an important source of covid- transmission for communities. [ ] [ ] [ ] [ ] [ ] the shift to household transmission has arisen due to the fact that many public health measures, ranging from teleworking to full lockdowns, encourage individuals to spend more time at home where there is increased duration and intensity of contact among household members. , however, it is unclear which individuals are more likely to transmit infection within their households. existing individual-level observational studies of household transmission typically included household contacts identified through contact tracing. [ ] [ ] [ ] [ ] [ ] [ ] these studies have estimated secondary attack rates among household contacts to be five to ten times as high as in non-household settings. , most of these studies were conducted in asia, included smaller numbers of households, and/or did not compare to households where no secondary transmission occurred. many also focused on the characteristics of the acquirers of infection (secondary cases) rather than the characteristics of the transmitters of infection (index cases) in the household. using address matching, we sought to identify all households with confirmed sars-cov- infections from ontario, canada between january and july, . we were interested in comparing characteristics of cases in households that experienced secondary transmission (i.e., additional laboratory-confirmed cases following the index case) versus those that did not, and also sought to determine individual-and neighbourhood-level characteristics of index cases associated with transmission. this work may help inform future public health strategies to reduce within-household transmission during the ongoing pandemic. we assembled a cohort of all confirmed cases of covid- reported in ontario, canada's most populous province ( million residents), among residents of private households from january , to july , . we identified confirmed cases of covid- using data from provincial reportable disease systems entered by local public health units. we obtained ethics approval from public health ontario's research ethics board. private households were defined as any residences not identified as congregate in nature, such as homeless shelters or long-term care homes. individual houses and apartments/suites within multi-unit dwellings (e.g., apartment buildings) were considered private households. for address matching, we applied a natural language processing algorithm using python's sklearn library to identify unique households that contained at least one covid- case. briefly, we broke down cases' whole address fields (including street address, city, and postal code) and found a closest match in a master list of addresses, containing congregate facilities and previously identified households. this match was then validated by checking for exact matches in the numerical portion of the address field. for unmatched addresses, we again used a natural language processing algorithm to identify duplicates, and added unique addresses to the master list for future comparisons. we excluded any cases whose address matched a known congregate facility or who had a risk factor flag for residing in a congregate setting in provincial reportable disease systems. we also examined addresses that were matched with apartment buildings in the master list for suite information, and excluded cases missing suite information as we were unable to determine conclusively whether these individuals resided in the same suite as others in the building. we excluded any cases with missing or incomplete address information. the primary outcome of interest was any secondary transmission within a household, defined as cases that occurred - days after the index case of the household. , , we used each case's symptom onset date as the date of comparison, or their specimen collection date if symptom onset date was unavailable, and excluded the rare cases . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint ( · %) that lacked information on both dates. we excluded households with multiple cases on the index date ("index clusters") from the cohort as they would present challenges for estimating the predictive value of individuallevel characteristics. we also considered two secondary outcomes of interest: household transmission to older adults (≥ years), and household transmission to severe cases (icu admission or death). we considered a variety of individual-level and neighbourhood-level covariates in our analyses that were hypothesized to influence household transmission. at the individual level, we obtained information on each case's age, sex, and health region of residence (supplementary table s ). furthermore, we included covariates for case month (january-july), employment as a healthcare worker, high risk status (≥ years of age, immunocompromised, had cardiovascular-related health issues, or had chronic obstructive pulmonary disease (copd)), and association with a known covid- outbreak outside the home (e.g., association with a workplace outbreak or long-term care home outbreak). we also considered three delay metrics for each case: ( ) the delay between the case's symptom onset and when their specimen was collected by a healthcare provider (testing delay); ( ) the delay between specimen collection and report of a positive test result to the local health unit (reporting delay); and ( ) the delay between test report and when the health unit begins entering the case into a reportable disease system for provincial notification (data entry delay). for the testing delay metric, we additionally separated out cases who were missing symptom onset date (thus specimen collection date was used) and did not have any covid- symptoms flagged in provincial disease reporting systems. we excluded cases that were missing symptom onset date but had covid- symptoms flagged from all analyses. we did not have any information on the total number of residents of each household. however, we were able to adjust for several characteristics related to the average size and composition of households at the neighbourhood level. at the neighbourhood level, we had information available from canadian census records ( · % response rate ). the canadian census is a mandatory questionnaire that collects extensive information from each of the · million dwellings across canada, with all dwellings reporting household composition, and a % sample completing a more detailed long-form questionnaire. we linked neighbourhood characteristics at the aggregate dissemination area level, which divides the country into areas with populations between , and , persons, on average. these included characteristics such as the average economic family size, proportion of households with multiple persons per room, proportion of multi-family households, and urban/rural status (see supplementary definitions). a full list of the neighbourhood characteristics is found in table . we applied logistic regression models to obtain both unadjusted and adjusted odds ratios (or) and % confidence intervals (ci) for the associations between covariates and the odds of secondary transmission within a household. we also carried out several descriptive analyses to compare the characteristics of index cases, secondary cases, and cases that were not involved in any household transmission. we explored the breakdown of these groups by outcome severity (i.e., hospital admission, icu admission, death, or no serious or severe outcome) and examined the direction of transmission by age group and high risk status. we assessed the distribution of the number of days between symptom onset dates for index cases and secondary cases (serial interval). in sensitivity analyses we adjusted the definition of household transmission to be ( ) cases that occurred - days after the index case (more specific) or ( ) cases that occurred - days after the index case (more sensitive). we also restricted the analysis to households with an index case date on or after may ; testing approaches expanded as of may , which may have improved the ability to identify secondary transmission in households. role of the funding source this study was supported by public health ontario. the authors had full access to all data in the study and accept responsibility for the decision to submit for publication. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint as of july , , there were , confirmed cases of covid- reported in ontario. after removing cases based on our inclusion criteria, we were left with , cases residing in private households, of which , cases were from households with no secondary transmission and , cases were from households with secondary transmission (figure ). of the , index cases from households with secondary transmission, the median number of secondary cases in the same household was one ( th percentile=one case, th =two cases, th =three cases). the average age of the cohort was approximately years and % were female. the median serial interval from index case to secondary case was four days ( th percentile=two days, th =seven days, th =ten days) (supplementary figure s ) . for the direction of transmission from index cases to secondary cases, individuals in the - year age group and low risk individuals were both the most frequent transmitters and most frequent acquirers of sars-cov- infections within households (figure ). transmissions to secondary cases in different age or risk groups than the index case were less frequent. compared to index cases with no household transmission, index cases with household transmission were less likely to be healthcare workers or associated with a known covid- outbreak (table ) . however, they were more likely to be male and had median testing delays that were twice as long as index cases without household transmission (four days versus two days). there was no difference in median reporting delay or data entry delay for the two groups. we also compared the characteristics of index cases and secondary cases, and found that secondary cases had shorter median testing delays than index cases (supplementary table s ). they were also less likely to have serious or severe outcomes (supplementary table s ). from adjusted logistic models, we observed increased odds of any household transmission with longer testing delays for the index case compared to -day (i.e., the individual was tested on the same day as their symptom onset) testing delays (ors: -day delay= · , -day delay= · , -day delay= · , -day delay= · , ≥ -day delay= · ) (figure , supplementary table s ). individuals with no symptoms flagged in provincial reportable diseases systems had lower odds of any household transmission ( · , % ci: · - · ). this trend was similar in our models for household transmission to older adults and to cases with severe outcomes. conversely, there were no notable trends for increased odds of household transmission with reporting delays or data entry delays. male index cases had higher odds of any household transmission ( · , % ci: · - · ) or transmission to older adults ( · , % ci: · - · ) compared to female index cases, and older (≥ years) and younger ( - years) index cases had lower odds of any household transmission compared to the - year reference group ( table ) . we observed increased odds of household transmission if the index case was high risk ( · , % ci: · - · ), and decreased odds if the index case was a healthcare worker ( · , % ci: · - · ) or was associated with a known outbreak ( · , % ci: · - · ). there were also some trends for decreased odds of transmission from may to july. the strongest associations observed for household transmission were in neighbourhoods with larger average economic family size ( · per person increase, % ci: · - · per person increase) or neighbourhoods with a higher proportion of households with multiple persons per room ( · per % increase, % ci: · - · ). we also observed increased odds for neighbourhoods with a higher proportion of multi-family households; this was a particularly strong predictor of transmission to older adults ( · per % increase, % ci: · - · ). additionally, odds of transmission were higher for neighbourhoods with a higher proportion of individuals in the ≥ year age group; individuals below the low income cut off; individuals with less than high school education; unsuitable housing; recent immigrants; non-white, non-indigenous groups; and apartments with five or more floors . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint (table ) . odds were lower for neighbourhoods with a higher proportion of individuals participating in the labour force, as well as more remote areas compared to large urban areas. we compared the estimates from our primary outcome model with those produced in our three sensitivity analyses (i.e., household transmission - days after index cases and - days after index cases, and index case dates on or after may ), and found that our associations were robust (supplementary table s ). notably, longer testing delays continued to display strong trends towards increased odds of household transmission. larger average economic family size and a higher proportion of households with multiple persons per room also continued to exhibit the strongest associations at the neighbourhood level. results from unadjusted models are not presented, but overall displayed similar associations to the adjusted models. in this retrospective study of , confirmed cases of covid- residing in , private households, we found that longer testing delays and male sex were associated with greater odds of household secondary transmission, while being a healthcare worker or linked to a known outbreak was associated with lower odds of household transmission. additionally, neighbourhoods with larger average economic family size and a higher proportion of households with multiple persons per room were associated with greater odds of household transmission. previous studies of household transmission have considered secondary attack rates (sars), defined as the proportion of household members of confirmed cases that acquire infection. the majority of these studies were conducted in asia, and some in europe and the united states. [ ] [ ] [ ] [ ] [ ] [ ] madewell et al. , lei et al. , and curmei et al. conducted meta-analyses of previous studies and found pooled household sars of % ( % ci: % - %), % ( % - %), and % ( % - %), respectively. some of the included studies compared sars in household settings verses non-household settings, and pooled estimates found that household sars were five to ten times as high as non-household sars, which highlights the role of household transmission in the spread of covid- . we identified only two other studies that considered the impact of testing delays on household transmission; xin et al. and wang et al. examined the time from illness onset to laboratory confirmation. they reported hazard ratios for household transmission of · ( % ci · - · ) (< -day delays versus ≥ -day delays) calculated from households, and · ( % ci · - · ) (< -day delays versus ≥ -day delays) calculated from households, respectively. it has been estimated that infectivity peaks - days after symptom onset , , which underlines the importance of rapid testing and self-isolation as soon as symptoms appear. our other finding of lower odds of household transmission among individuals with no symptoms is in line with estimates of lower sars among asymptomatic or mildly symptomatic individuals , , although it may be that sars are underestimated in these groups due to lower testing rates. our "no symptom" classification may have included some individuals who missed having their symptoms reported in provincial disease systems, however we would expect these individuals to bias our estimate towards the null. considering other individual-level characteristics, two studies found similar positive associations with male sex and immunodeficiency , and an inverse association with healthcare employment. in addition to healthcare employment, we also found lower odds of household transmission among individuals linked to a known outbreak. this may reflect testing practices, where outbreak-linked cases are identified and isolated faster than non-outbreaklinked cases. healthcare workers may also be part of these outbreaks, leading to more rapid identification; additionally, they may have different practices within the household given their heightened awareness of risk of exposure, and may have increased access to or use of personal protective equipment as compared to non-healthcare workers. madewell et al. and lopez bernal et al. further reported inverse relationships between household size and sar. these findings are contrasted to our result of higher odds of household transmission among neighbourhoods with larger average economic family size. madewell et al. acknowledged that household crowding may play a more important role in transmission risk than household size; lewis et al. found a relative risk of · ( % ci: · - · ) for transmission in households with > persons per bedroom compared to - persons per bedroom. our findings of . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint higher odds of household transmission among neighbourhoods with a higher proportion of multiple persons per room and multi-family households may support this hypothesis, and our association with economic family size may be capturing aspects of household crowding at the neighbourhood-level (e.g., neighbourhoods with larger average economic family size tended to be neighbourhoods with a higher proportion of multiple persons per room). one approach that has been implemented in some jurisdictions to mitigate this issue is voluntary self-isolation facilities for those who are unable to self-isolate in their home. madewell et al. also reported a pooled proportion of households with any secondary transmission of % ( % ci % - %), while we found only % of our included households experienced secondary transmission. as we did not have information on total household size, it may be that we included some single-resident households that had zero probability of household transmission. this would decrease the number of cases associated with household transmission in comparison to studies that excluded singleresident households, and may have also diluted our model estimates. our study has some limitations that merit discussion. first, we did not have information on the total number of individuals residing in each household or the characteristics of uninfected household members, thus we were unable to calculate the proportion of household contacts infected to generate sars. however, we were able to control for some neighbourhood-level characteristics of household composition including economic family size and proportion of households with multiple persons per room or multi-family households. our finding of high transmission and acquisition of sars-cov- infection between individuals in the same age group therefore likely reflects the inherent age structures of households in ontario. second, we may have misclassified some index cases if a previously infected individual within the household was untested (e.g., asymptomatic or symptomatic but did not seek testing), and we may have misclassified some secondary cases if their infection was acquired outside the household. we may also have missed secondary cases within a household that were untested. third, we only considered one index case per household, and considered all subsequent cases within a -day period to be secondary cases (i.e., did not account for tertiary transmission). fourth, as this study encompasses a period before schools were re-opened in the fall, there were few index cases among children (n= ) and as such, we were not able to determine the extent to which children played a role in household transmission. finally, because addresses in this dataset are entered manually as a free-text field, some algorithm misclassification is expected due to incorrectly entered addresses or different street and city naming conventions. this type of misclassification would be expected to decrease our pool of multiple-case households. our study also has several strengths. to our knowledge, this study contains the largest number of private households with at least one confirmed case of covid- . most previous studies included a subset of confirmed covid- cases, and used contact tracing to monitor household members for infection and/or symptoms. thus, these studies were only able to include a smaller number of households (individual studies reporting on fewer than households) compared to the , households we were able to identify through address matching of all confirmed cases of covid- in ontario. we did not find any other studies that used address matching to comprehensively identify all households with sars-cov- infections in a region, with the exception of one study from israel that used a municipal database of residents to identify household members of cases. additionally, we considered a large set of individual-and neighbourhood-level characteristics of index cases. we were able to compare these characteristics between households where secondary transmission did and did not occur, which yielded important insights into factors that may help reduce secondary transmission in households. household transmission plays a key role in local spread of sars-cov- infection. our work suggests that it is important for individuals to get tested for covid- as soon as symptoms appear. ideally, individuals should be tested on the day of symptom onset, as even a -day delay was associated with increased odds of secondary transmission. additionally, if cases are living with other individuals, it may also be important to try to isolate in a room alone or outside the home, if possible. these strategies may be considered by public health officials to reduce household transmission and help mitigate the ongoing spread of covid- . future research should focus on the role of children and youth in household transmission, particularly as lockdown restrictions are lifted and individuals return to regular activities such as work, school, and daycare. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted october , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint figure . direction of transmission from index case to secondary case by (a) age group and (b) high risk status figure . adjusted odds ratios and % confidence intervals for the associations between index case delay metrics and odds of household transmission cases were excluded from the testing delay models that had covid- symptoms flagged in provincial reportable disease systems but were missing symptom onset date. cases with no symptoms were defined as cases that were missing symptom onset date (thus specimen collection date was used) and did not have any covid- symptoms flagged in provincial reportable disease systems. cases with a testing delay of < days were those who were tested prior to the onset of their symptoms. horizontal line at or= indicating no association. no symp=no symptoms. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint table . adjusted odds ratios and % confidence intervals for the associations between index case characteristics and odds of household transmission or ( % ci)* a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster outbreak of covid- in a family epidemiological analysis on cases of covid- in epidemic clusters household transmission of sars-cov- : a systematic review and meta-analysis of secondary attack rate estimating household transmission of sars-cov- . medrxiv household transmission of covid- -a systematic review and metaanalysis changes in contact patterns shape the dynamics of the covid- outbreak in china household transmission of sars-cov- in the united states household transmission of covid- transmission dynamics of covid- in household and community settings in the united kingdom ontario ministry of health and long-term care. covid- -guidance for the health sector covid- infections among healthcare workers and transmission within households. medrxiv scikit-learn: machine learning in python reduction of secondary transmission of sars-cov- in households by face mask use, disinfection and social distancing: a cohort study in beijing, china census data collection -sampling and weighting technical report, census of population ontario opens up covid- testing across the province risk factors associated with occurrence of covid- among household persons exposed to patients with confirmed covid- in qingdao municipal risk factors associated with covid- infection: a retrospective cohort study based on contacts tracing contact tracing assessment of covid- transmission dynamics in taiwan and risk at different exposure periods before and after symptom onset secondary attack rate of covid- in household contacts: a systematic review covid- secondary attack rate and risk factors in household contacts in castellon (spain): preliminary report the role of children in the spread of covid- : using household data from bnei brak, israel, to estimate the relative susceptibility and infectivity of children the authors would like to thank garima aryal for her contributions to the address matching work. lp performed the analysis and drafted the manuscript. sb, nd, and kb conceptualized the study. sb, nd, kb, and lp developed the methodology. sb, kb, and lp verified the underlying data. jj and tvi contributed to the analysis. sb, nd, kb, jj, tvi, ej, and sw reviewed the manuscript. the line represents the direction of transmission from index case to secondary case. the shade of the line represents the age group or risk group of the index case. the width of the line is proportional to the frequency of transmission between index and secondary cases in their respective age or risk groups. yrs=years. · ( · - · ) · ( · - · ) · ( · - · ) *estimates were adjusted for age group, sex, month reported, health region, and economic family size. †cases associated with a public health declared outbreak outside the home. ‡odds ratios for neighbourhood-level characteristics are reported per % increase, except for economic family size and community type. §defined in supplementary definitions. key: cord- -y yg p authors: nofal, ahmed maged; cacciotti, gabriella; lee, nick title: who complies with covid- transmission mitigation behavioral guidelines? date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: y yg p during the past months, the world has lost almost , lives because of the outbreak of covid- , with more than million individuals diagnosed with covid- worldwide. in response, lockdowns, and various other policies have been implemented. unfortunately, many individuals are violating those policies and governments have been urging people to comply with the behavioral guidelines. in this paper, we argue that personality traits need to be considered to understand and encourage more effective public compliance with covid transmission mitigation behavioral guidelines. using a sample of , individuals from japan, we show that certain personality traits are related to the tendency to comply with covid- transmission mitigation behavioral guidelines. we emphasize the importance of understanding why people respond differently to the same authority’s messages and provide actionable insights for government policy makers and those who implement policies. since the outbreak of covid- , a number of initiatives have been put in place with the objective of mitigating transmission of the virus, such as imposing lockdowns, closing schools, and encouraging social distancing. medical scientists are racing to find a vaccine. geographers and software developers are developing applications to track people's movements in an attempt to identify and contain the virus in specific regions. health and media officials are promoting social distancing and persuading the population to follow health behavioral guidelines, often involving significant behavioral changes. despite these initiatives, as of mid- the world is still losing thousands of lives every day. in a recent statement, tedros adhanom ghebreyesus, director-general of the world health organization, stated that "although many countries have made some progress, globally, the pandemic is actually speeding up" [ ] . therefore, there is a clear need to explore further ways to help mitigate the spread of covid- . in this regard, "social and behavioral science can provide valuable insights for managing the pandemic and its impact" [ , p. ] , by enhancing our understanding of the role of human behavior in the spread of the virus, and thus contribute to the public good. while the covid- pandemic has resulted in the development and implementation of numerous behavioral guidelines intended to mitigate transmission, evidence suggests that many of these guidelines are not being followed by enough people to make them optimally effective [ ] . governments and health authorities are still pleading for individuals to behave responsibly, by complying with these imposed behavioral guidelines and rules [ , ] . however, laboratory studies show that "persuasive appeals are more effective in influencing behavior when they are tailored to individuals' unique psychological characteristics" [ , p. ]. in simple terms, what convinces one person to behave in a particular way, might not do so for another. moreover, some people are by nature more likely than others to be rule-breakers [ ] . for instance, evidence shows that emotionally unstable [ ] , and disagreeable people [ , ] are more likely to break rules in general. accordingly, while it is important to understand which behaviors influence the speed of spread of covid- [ ] , it is also important to understand the specific personality characteristics that could plausibly be related to the propensity of the population to comply with covid- transmission mitigation behavioral guidelines. to examine this, we investigate whether certain personality traits are related to compliance with transmission mitigation behavioral guidelines. particularly, we examine if major personality traits (i.e. conscientiousness, agreeableness, openness to experience, extraversion, and emotional stability) [ ] , yield differences in the tendency of people to comply with implemented covid- transmission mitigation behavioral guidelines (see s appendix). this paper makes a number of contributions. first, it draws attention to the importance of individuals' personalities when assessing the likelihood that an outbreak of the virus will occur among some people but not others. in this regard, we respond to research questions raised by davidai, day [ ] regarding who complies with covid- transmission mititgation behavioral guidelines. second, this is not the first crisis the world has faced and will, unfortunately, not be the last. thus, our work provides evidence of how different personality traits can help people face the outbreak of crises such as global pandemics, and emphasizes the importance of implementation measures which take account of individuals' personality traits. in fact, this should help to ensure that we learn important lessons from the crisis, so that the responses of governments and organizations will be more effective when future crises occur [ ] . third and most importantly, to our knowledge, the paper provides the first empirical evidence using an exogenous shock (i.e. the covid- outbreak) of the importance of personality traits and motivational propensities when monitoring people's tendency to comply with covid- transmission mitigation behavioral guidelines. in fact, there has been work exploring the effect of covid- -related messages on people's actual compliance with covid- transmission mitigation behavioral guidelines [ ] [ ] [ ] , research showing gender differences with regards to the compliance of transmission mitigation behavioral guidelines [ ] , and studies examining the effect of emotional responses to pro-social messages on the tendency of people to comply with self-isolation restrictions [ ] . however, there has been no work examining the influence of personality traits, such as the big five (i.e. conscientiousness, agreeableness, openness to experience, extraversion, and emotional stability) on the tendency of people to comply with covid- transmission mitigation behavioral guidelines. connecting literatures of emotional responses to covid- messages, and personalized/tailored communication, we believe that this research not only supports prior work in highlighting the importance of pro-social messages, but also the importance of knowing the specific personality traits that may make individuals less likely to comply with covid- transmission mitigation behavioral guidelines. hence, the aim of this paper is threefold. first, drawing from research on persuasive mass communication [e.g., ] , we aim to demonstrate if personality traits, specifically, conscientiousness, agreeableness, openness to experience, extraversion, and emotional stability, relate to the tendency of people to comply with covid- transmission mitigation behavioral guidelines. second, we highlight the importance of incorporating behavioral science into governments, and organizations' responses to crises, such as covid- . third and most importantly, we aim to provide some practical insights, such as occupational targeting and the use of social network platforms, such as facebook, twitter, and linkedin, to minimize the risk of not complying with covid- transmission mititgation behavioral guidelines. in psychology, persuasive mass communication refers to the process by which large groups of individuals are encouraged to adopt beliefs, attitudes and behaviors that are consistent with the communicator's viewpoint [ ] . persuasive mass communication theories aim, thus, to identify strategies to improve the effectiveness of persuasive mass communication messages [e.g. , ] . one such theory, psychological persuasion, assumes that persuasive communication is most effective "when tailored to people's unique psychological characteristics and motivations" [ , p. ]. this means that messages that are more congruent with an individual's motivational tendencies are processed more smoothly and assessed more positively than incongruent messages [ ] [ ] [ ] . unfortunately, in some situations where mass communication messages are needed, such as covid- transmission mitigation behavioral guidelines, it is often impractical to make the messages either personalized or individually-targeted. in these situations, it becomes even more important to understand how individual differences in motivational tendencies result in differences in the attitudes and behaviors that individuals may adopt in response to the same message [ , ] . because motivational tendencies are strongly influenced by personality traits [ ] , the latter can yield differences in beliefs, attitudes and/or behaviors even when individuals are exposed to the same mass communication message. in this respect, the behavior or the attitude towards the same authority's messages (as in the case of covid- ) can be more/less pronounced among people who possess certain personality traits. therefore, building on this literature, we consider how different personalities respond differently to the same message from authorities, and hence comply with behavioral guidelines contained in those messages. to do so, we use the big five model of personality which relies on the assumption that individual differences are best captured by five global traits [ , ] : extraversion, emotional stability, openness to experience, agreeableness, and conscientiousness. each personality trait reflects a different motivational system that influences how individuals perceive the context around them, process authority's messages, and in turn decide to adopt (or not) compliance behavior. we explore these differences and build our hypotheses next. extraversion refers to the extent to which individuals are assertive, dominant, energetic, active, talkative, impulsive, and enthusiastic [ ] . individuals who score high on extraversion tend to be cheerful, are positively disposed towards other people and large groups, and seek excitement and external stimulation. meanwhile, individuals who score low on extraversion prefer to spend more time alone and can be described as reserved, quiet, and independent [ ] . in this sense, messages containing requests to respect self-isolation and social distancing are incongruent with a motivational system that gains rewards and satisfaction from active engagement with the world, social interaction and social recognition [ ] . accordingly, such messages are not processed smoothly and effectively which results in a tendency to violate such policy measures. there is a negative association between extraversion and the tendency of people to comply with covid- transmission mitigation behavioral guidelines. emotionally unstable individuals are especially sensitive to threats and uncertainty [ , ] . individuals who score low on emotional stability tend to experience a number of negative emotions such as anxiety, depression, hostility, self-consciousness, and vulnerability [ ] . individuals who score high on emotional stability can be described as self-confident, calm, and relaxed [ ] . these psychological characteristics suggest that messages containing rules and policies aiming at providing structures and formalized procedures are positively accepted by a motivational system that is normally inhibited by uncertainty and unpredictability [ , ] . however, enacting self-isolation and keeping social distancing for long periods of time can result in increased stress and negative emotions for emotionally unstable individuals, than for more emotionally stable individuals. this could possibly motivate the former to break rules as an attempt to protect their psychological wellbeing [ ] . as such, while individuals who score low on emotional stability can respond to authorities' messages in different ways, we assume that the opportunity of feeling secure by complying with rules and policies will not be perceived as such if it results in increased risk of anxiety and depression. accordingly, such messages are not processed fluently and effectively which leads to a tendency for those lower in emotional stability to violate authorities' rules and behavioral guidelines. hypothesis : there is a positive association between emotional stability and the tendency of people to comply with covid- transmission mitigation behavioral guidelines. openness to experience is a personality trait that characterizes someone who values creativity, innovation, and intellectual stimulation [ ] . individuals who score high on openness to experience can show active imagination, creativity, preference for variety, and intellectual curiosity. individuals who score low on openness to experience can be described as conventional, narrow in interests, and unanalytical. these psychological characteristics suggest that open individuals can perceive the self-isolation and social distancing rules as an opportunity to cultivate their curiosity and imagination. the lockdown can create the conditions (e.g., by increasing time for themselves) to engage in activities that promote absorption, self-examination, and creative solutions [ ] . accordingly, they have little interest in escaping a situation that allows to satisfy their needs for intellectual stimulation and cognition [ ] . hypothesis : there is a positive association between openness to experience and the tendency of people to comply with covid- transmission mitigation behavioral guidelines. agreeable individuals value communal goals and interpersonal harmony [ ] . people who score high on agreeableness have strong cooperative values and a preference for positive interpersonal relationships [ , ] . people who score low on agreeableness can be described as manipulative, self-centered, suspicious, and aggressive [ , , ] . because agreeableness may lead one to be particularly empathetic, individuals at the high end of this personality construct tend to show great concern for the welfare of others [ ] . accordingly, they are likely to be very motivated to comply with rules and behavioral guidelines that present self-isolation and social distancing as a way to protect themselves and those around them. hypothesis : there is a positive association between agreeableness and the tendency of people to comply with covid- transmission mitigation behavioral guidelines. conscientious individuals value achievement, order, hard work, and efficiency [ , ] . individuals high on conscientiousness are described as careful and diligent as opposed to easy going and disorderly [ ] . the psychological characteristics of conscientious individuals suggest that violation of rules and behavioral guidelines aiming at controlling social mobility to limit the spread of the virus is not consistent with their tendency and motivation to show selfdiscipline, act dutifully, and achieve efficiency [ , ] . hypothesis : there is a positive association between conscientiousness and the tendency of people to comply with covid- transmission mitigation behavioral guidelines. our sample is drawn from japanese citizens aged to years old. the data was collected between the th and th of march . a sample of , individuals responded to the survey. a quota sampling approach was adopted to match the sample distribution to the japanese population in terms of gender, age, and employment status. after excluding individuals who did not respond to any of the items measuring our variables of interests, missing values, and individuals who responded with "don't know" to any of our variables of interest, we were left with a sample of , individuals. further information on the study is available at https:// www.openicpsr.org/openicpsr/project/ /version/v /view. it is also worth-noting that this research does not require an ethics committee approval because it is a secondary analysis of anonymous data. dependent variable. adoption of transmission mitigation behavioral guidelines. the measure of our outcome variable is measured using policy statements that assess the extent to which individuals adopt the transmission mitigation behavioral guidelines. the data includes behavioral guidelines developed to prevent the spread of the virus, such as respondents' tendency to "always wear a surgical-style mask when going out", "stockpile surgical-style masks", "avoid large gatherings", and "participate in virtual events using online tools" (see s appendix for the full scale items). for each policy, respondents selected the extent to which they adopted the policy on a -point scale; -very true, -true, -neither, -not true, and -not at all. we reversed the scale so that a higher score corresponds to a more likelihood of compliance with the transmission mitigation behavioral guidelines. internal consistency analysis of the measure returned a cronbach's alpha value of . . independent variables. personality traits. we use a short scale, very well-established in personality research, to assess individuals' psychological traits, specifically the ten item personality inventory (tipi) [ , p. , , ] . the tipi is comprised of items, each consisting of a pair of traits (see s appendix). for consistency of interpretation, we reverse some responses, such that the higher the value, the higher the level of extraversion, openness to experience, agreeableness, conscientiousness, and emotional stability. the cronbach's alpha value of each of the big five ranged from . to . , which is a limitation that we consider below. control variables. we control for the effects of a number of covariates. specifically, we control for the influences of gender ( -male, -female) because research shows that gender is related to various psychological traits [ ] . further, as socio-economic conditions could have an effect on both personality traits, and individual behaviors [ ] , we control for the dummies of individuals' annual household income, with the first dummy corresponding to having "less than , k japanese yen", and the highest dummy corresponding to "more than , k jpy" (see s appendix for further details). following prior research on the relationship between the big five and education [ ] , we also account for the influence of education by controlling for whether respondents are university or college graduates. furthermore, as age captures various factors that could influence individuals' personality traits [ , ] , we control for age categories as dummies. we also control for marital status ( -married, -unmarried) because marital status might confound the effects of the big five on different behaviors [ , ] . in addition, having a partner might impact certain behavioral guidelines, such as gathering with friends. furthermore, because the sources of information used by individuals may affect the tendency of people to comply with the covid- transmission mitigation behavioral guidelines, we control for the sources of information, such as "tv news programs", "information sent by the ministry of health, labor and welfare", and "information sent by local (prefecture) government" (see s appendix for further details). all our sample is drawn from japan, and therefore location is automatically controlled for. we use stata mp version for the analyses. table presents the correlations between the variables (see s table in s appendix for further details). our sample consists entirely of japanese citizens. approximately % of the sample are males and % are females. in terms of marital status, approximately % of the sample are married and % are not married. the sample includes various age groups ranging from the age of to the age of years old. table presents the results of a number of ols models examining the influence of personality traits on the compliance with covid- transmission mitigation behavioral guidelines. specifically, model examines the effect of personality traits on the compliance with covid- transmission mitigation behavioral guidelines without any controls. we find support for all our hypotheses apart from extraversion which supports a significant positive effect on compliance with covid- transmission mitigation behavioral guidelines. model adds our control variables, and again we find support for our hypotheses. importantly, when adding controls in model , we now find that extraversion negatively influences the tendency of people to comply with covid- transmission mitigation behavioral guidelines, meanwhile agreeableness, conscientiousness, and openness to experience positively influence the tendency of people to big five personality traits and covid- behavioral guidelines while we are cautious about causality issues given the cross-sectional nature of our data, we emphasize that covid- transmission mitigation behavioral guidelines are a result of an exogenous shock (i.e. the sudden outbreak of covid- ). as dunning [ ] explains, exogenous shocks constitute natural experiments in which subjects are-as-if-randomly assigned to different levels of a treatment and therefore may allow researchers to uncover causal relationships. therefore, causality issues are reduced. however, despite our inclusion of a number of key controls, omitted variables might still bias the estimates of our model parameters. one way to deal with these potential biases is the use of multilevel modeling [ , ] . as such, we perform an additional multi-level analysis to overcome the aforementioned issues of omitted variable bias. the rationale for applying a multilevel estimator is the fact that for a global phenomenon as the covid- pandemic, government communications have often been aimed at certain specific societal groups, including different age groups [ ] , and household characteristics [ ] . for instance, older people are asked to be more cautious compared to younger ones [ ] . therefore, multilevel models can be used to capture variations at both levels; individuals at the first level, as well as age and household annual income groups at the second level. hence, for robustness reasons, we re-estimate our models using the multilevel estimator we find similar results to the ols analysis; with and without the control variables (see s appendix). because our large sample size increases our power to detect statistical significance of even small effects, we also consider the substantive importance of our results in terms of effect size, using the odds ratio. specifically, our findings indicate that the highest odds ratio is for conscientiousness, with people high in conscientiousness % more likely to adopt covid- transmission mitigation behavioral guidelines compared to people low in conscientiousness, followed by % for openness to experience, and % for agreeableness (i.e. these percentages are calculated based on the odds ratios computed based on a unit increase/decrease on the scale items used). we also found that people high in extraversion are % less likely to adopt covid- transmission mitigation behavioral guidelines compared to introverts (see fig ) . it is worth mentioning that our outcome is assessed using scale items and therefore the linear coefficients estimated might overestimate/underestimate the effect size of our independent variables [ , ] . therefore, we have calculated the effect sizes based on odds ratios estimated through ordinal logit models (see also fig for linear effect sizes) . in this respect, we emphasize that in the case of an ordinal outcome such as the scale item being used, the interpretation is not read as a contrast between extremes as in the binary outcome case, but as a contrast for each unit change. in other words, on a scale demarcated as , , , , as in the case of our compliance measure, an or of . , for instance, entails a % increase in the odds of the dependent variable for each unit change in the independent variable (e.g. moving from to , or to , or to , or to on the scale demarcated). for robustness, we re-test our hypotheses after splitting our sample into males and females. we find consistent results across both samples for agreeableness, conscientiousness, and openness to experience. however, extraversion shows a negative influence on the adoption of covid- transmission mitigation behavioral guidelines only for the male sample, but not for the female sample. the covid- pandemic has resulted in the introduction of an unprecedented number of governmental policy measures intended to contain the health crisis and mitigate its effects on the economy [ ] . however, as of mid- , most governments are still struggling to contain the outbreak of covid- . in this paper, we argue that the effectiveness of governmental messaging, in terms of its influence on behavioral change of individual citizens, is dependent on individual differences in personality traits. there are a number of key implications of our findings, which translate into actionable insights for government policy makers and those who implement policies. a first key implication is that governments need to tailor messaging towards different personality traits. at the top of the list in this regard is conscientiousness. in essence, using a sample of , individuals from japan, we find that conscientiousness increases the likelihood of adopting covid- transmission mitigation behavioral guidelines by %. in fact, identifying individuals low in conscientiousness can be helpful in knowing the communities where transmission mitigation behavioral guidelines are least likely to be adopted. though we do not find consistent patterns for other personality traits, we find tentative evidence of the role of extraversion, agreeableness, and openness to experience in the adoption covid- transmission mitigation behavioral guidelines, with the highest effect size detected for openness to experience, followed by agreeableness, and then extraversion. we emphasize that these effect sizes are not deterministic. personality influences imply probabilistic propensities rather than hard-wired patterns of covid- guidelines compliance behavior. thus, our suggestion that the influence of our independent variables on the tendency of people to comply with covid- transmission mitigation behavioral guidelines should not be confounded with determinism. that said, when dealing with a societal-level communication task such as that required for pandemic-mitigation guidelines, understanding these probabilistic propensities is highly valuable, even if they are not deterministic per se. our study provides several contributions. to begin with, the value of our findings can be seen in the example of efforts to increase the number of people who comply with covid- transmission mitigation behavioral guidelines. this can be accomplished by implementing initiatives that can help trigger some personality traits, including relatively static ones [ , ] . for instance, since our findings show that conscientiousness considerably increases the likelihood that people adopt covid- transmission mitigation behavioral guidelines, governments are encouraged to boost citizens' sense of belonging and obligation to their communities-which has been suggested to develop conscientiousness [ , ] . moreover, because our findings show that openness to experience, especially for males, positively influences the tendency of people to adopt transmission mitigation behavioral guidelines, promoting online inductive reasoning training can be beneficial for developing openness to experience [ ] and therefore the adoption of transmission mitigation behavioral guidelines. in addition, as our results indicate that agreeableness positively influences the adoption of transmission mitigation behavioral guidelines, especially for females, governments are urged to promote training on balancing criticism and empathy to trigger higher levels of agreeableness [ ] and hence higher adoption of behavioral guidelines. further, researchers argue that contact tracing is of significant importance to contain the spread of the virus [ ] . yet, many countries are still struggling to develop effective ways of tracing. given our findings, we have three suggestions. first, countries can trace groups that are less likely to have developed high levels of conscientiousness, openness to experience, and agreeableness. one quite feasible way of doing this is through sending out short surveys on personality traits using social network platforms, such as facebook, twitter, and linkedin. based on those surveys, governments and organizations can provide different covid- messages. another way is through occupational categorizing, for instance, entrepreneurs are known for their high levels of conscientiousness, and openness to experience, unlike full-time employees [ , ] . hence, tracing certain occupational groups (i.e. entrepreneurs and fulltime employees) might be informative in this respect (indeed, we empirically examined this suggestion and found that fulltime employees are less likely to comply with covid- transmission mitigation behavioral guidelines compared to entrepreneurs, part-time employees, and unemployed individuals). as a result, governments can send different messages to different occupational groups and therefore increase the likelihood that those occupational groups comply with the announced covid- transmission mitigation behavioral guidelines. second, assessing individuals' personalities could be beneficial to identify people who tend to violate the transmission mitigation behavioral guidelines. for instance, using the tipi which is an "ultra-short scale" [ , p. ], countries can collect information about the people who tend not to adopt the covid- transmission mitigation behavioral guidelines. further, recent research shows that digital footprints, such as their facebook likes or tweets, can predict people's personality traits [ ] . thus, observing individuals' digital footprints could inform about their personalities, and therefore help us identify the people who are least likely to adopt the transmission mitigation behavioral guidelines. that said, we recognise that the privacy implications of such initiatives would also have to be balanced with their potential effectiveness. in sum, with our study, we respond to the question of davidai, day [ , p. ] on who complies with covid- transmission mitigation behavioral guidelines. based on our findings, we provide one plausible answer, that is: those who are high in conscientiousness, introverts, and agreeable people as well as individuals who are high in openness to experience. we also provide insights for covid- media campaigns. we demonstrate the potential importance of tailoring campaigns to people's psychological characteristics-which may help provide an explanation for why the significant resources that have been expended on campaigns to encourage transmission mitigation behaviors have yielded sometimes little effect. this research has some limitations. first, the tipi that is used to measure the big five might be inferior to other scales, given its internal-consistency issues [ ] . however, as park, wiernik [ , p. ] explain, different big-five factor models are recommended based on "specific studies, research questions, and contexts". as the tipi is characterized by having a high level of content validity and is highly urged in situations "when brevity is a priority" [ , p. ], such as the outbreak of the deadly pandemic, we see its relevance to our study. meanwhile, future research is urged to retest our hypotheses using other scales. second, although our findings can be insightful to many countries, our study applies to japan. countries have implemented to a great extent the same covid- transmission mitigation behavioral guidelines, yet there have been some differences. even proximate countries showed different reactions to covid- . for example, sweden has implemented very few behavioral guidelines to face the pandemic unlike its neighboring finland which has implemented stricter quarantine conditions. therefore, further research focusing on other countries is urged. third, the small amount of variance explained by the big five ( %) suggests that the big five personality traits alone do not completely predict compliance with covid- transmission mitigation behavioral guidelines. rather, they may play a role in one of the many mechanisms explaining compliance with covid- transmission mitigation behavioral guidelines. therefore, it is important for future research to examine different interactive effects of the big five with other factors on compliance with covid- transmission mitigation behavioral guidelines [ ] . over years ago, science magazine published an article that put down some lessons from the spanish flu pandemic [ ] . as bavel, baicker [ ] explain, the paper demonstrates that three main factors contribute to the outspread of a pandemic: ( ) individuals do not appreciate the risks they undertake, ( ) people are resistant to shutting themselves up in strict isolation as a means to contain the outbreak of a pandemic, and ( ) people in many instances act as a continuing danger to others and themselves unconsciously. therefore, "how individuals respond to advice on how best to prevent transmission will be as important as government actions, if not more important" [ , p. ] . a century later, in the midst of another pandemic, we hope the present paper helps provide some assistance in this regard. who director-general's opening remarks at the media briefing on covid- - using social and behavioural science to support 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many emerging or re-emerging pathogens, cases in humans arise from a mixture of introductions (via zoonotic spillover from animal reservoirs or geographic spillover from endemic regions) and secondary human-to-human transmission. interventions aiming to reduce incidence of these infections can be focused on preventing spillover or reducing human-to-human transmission, or sometimes both at once, and typically are governed by resource constraints that require policymakers to make choices. despite increasing emphasis on using mathematical models to inform disease control policies, little attention has been paid to guiding rational disease control at the animal-human interface. methods: we introduce a modeling framework to analyze the impacts of different disease control policies, focusing on pathogens exhibiting subcritical transmission among humans (i.e. pathogens that cannot establish sustained human-to-human transmission). we quantify the relative effectiveness of measures to reduce spillover (e.g. reducing contact with animal hosts), human-to-human transmission (e.g. case isolation), or both at once (e.g. vaccination), across a range of epidemiological contexts. results: we provide guidelines for choosing which mode of control to prioritize in different epidemiological scenarios and considering different levels of resource and relative costs. we contextualize our analysis with current zoonotic pathogens and other subcritical pathogens, such as post-elimination measles, and control policies that have been applied. conclusions: our work provides a model-based, theoretical foundation to understand and guide policy for subcritical zoonoses, integrating across disciplinary and species boundaries in a manner consistent with one health principles. zoonotic pathogens are a major threat to global health, both through their on-going contributions to disease burden and their potential contributions to the emergence of novel pandemic pathogens [ ] . zoonotic spillover is defined as transmission of a pathogen from an animal host to a susceptible human and is the source of diseases from monkeypox to plague to leishmaniasis. risk of zoonotic spillover is driven by many ecological, epidemiological, and behavioral factors across scales [ ] [ ] [ ] . the combination of animal ecology, human behavior, and environmental conditions can lead to cross-species transmission and, thus, requires a onehealth perspective to evaluate and respond to outbreaks of disease. beyond the complexity of the zoonotic spillover process, zoonotic pathogens differ greatly with respect to their efficiency of human-to-human transmission [ , ] . transmissibility between humans is described by the reproductive number, r , which is defined as the average number of secondary cases caused by a single infected individual in an entirely susceptible population [ ] . some zoonotic pathogens face preexisting immunity in the population, and are governed by the effective reproductive number, r eff , which is the average number of secondary cases in a population with both susceptible and immune individuals [ ] [ ] [ ] . for simplicity, we will use r throughout this study to refer to r or r eff , in either case representing the efficiency of human-to-human transmission before further control measures are considered. it is useful to classify zoonoses by their transmissibility among humans, as captured by their r value [ ] . for pathogens with r = , like west nile virus or rabies virus, transmission only occurs through spillover, and the pathogen is unable to transmit between humans. when r is between and , the pathogen is subcritical and causes self-limiting outbreaks, as for monkeypox virus, nipah virus, or some avian influenza viruses. supercritical pathogens with r > , such as pandemic influenza or ebola virus, can cause epidemics or pandemics in the human population. subcritical zoonoses have been understudied by infectious disease modelers, likely because they do not align with dominant modeling frameworks, they require integration of animal and human dynamics, and they presently lack pandemic potential [ ] . modeling effort on these systems has been particularly sparse for questions of disease control and its economic components, and the interplay between spillover and human-to-human transmission in driving the epidemiology of subcritical pathogens. some improvements have been made in the last decade, especially in methods for estimating r for subcritical pathogens [ ] [ ] [ ] [ ] [ ] , but there is still a lack of theory to guide control efforts [ ] . this paper aims to address this gap. we note that our findings extend directly to non-zoonotic pathogens such as postelimination measles, where r < due to herd immunity, and geographic importation plays the role of spillover. our findings also relate to the on-going covid- pandemic caused by sars-cov- , where r < in some settings due to social distancing, contact tracing, quarantine and isolation, and other measures, and again geographic importation acts like spillover to introduce new cases. our work also applies equally to pathogens that transmit directly or via arthropod vectors. control measures for subcritical zoonoses can be classified into three functional groups according to the modes of transmission they aim to reduce: prevention of spillover, reduction of human-to-human transmission, and control of both spillover and human-to-human transmission jointly (table ) . because subcritical pathogens cannot cause epidemics and every outbreak is triggered by a spillover event, public health policy may naturally focus on spillover prevention. however as r rises toward , an increasing proportion of cases are caused by human-to-human transmission (fig. ) . this leads to open questions about how to target control measures. should control be targeted at animal-tohuman transmission, human-to-human transmission, or both? furthermore, for pathogens that spill over infrequently, implementing controls that focus on human-tohuman transmission when there are no active outbreaks does not seem cost effective. would a reactive strategy which switches from preventing zoonotic spillover to reducing human-to-human transmission be more effective? this decision space gets more complicated when economic costs of control are considered, especially because measures to reduce different types of transmission may differ in cost. similarly, there are often known host or environmental factors that influence spillover risk. epidemiological risk factor studies can define these factors so high-risk groups can be identified. for example, individuals in contact with dromedary camels and hunting or handling bushmeat are at higher risk for transmission of middle east respiratory syndrome (mers) coronavirus and simian retroviruses, respectively [ , ] . can targeted reduction of spillover in these high-risk groups be an effective control measure for subcritical pathogens? this study presents a general theory to build intuition and give evidence-based guidelines for effective control of subcritical zoonoses (or other subcritical pathogens). our framework reveals general principles to aid policymakers faced with difficult decisions and resource constraints and can be adapted to specific pathogens and settings to guide concrete decisions and support allocation of finite resources. for a subcritical zoonosis, the total incidence of infection in the human population arises from a mixture of primary and secondary cases. we assume that zoonotic spillover events (primary cases) occur at some characteristic total rate λ z in a population of interest, e.g. λ z might represent spillover events per year in a given administrative region. each human case is then capable of transmitting the infection to cause secondary cases, with the reproductive number r denoting the expected number of secondary cases per infected human. it is possible to model the stochastic dynamics of transmission in the human population using a branching process [ ] [ ] [ ] or similar formulation. for the present analysis, it is sufficient to focus on the expected dynamics of these models. the first generation of transmission (i.e. those infected by the index case) will have r cases, on average. each of these cases will infect another r cases, so the second generation will have r cases, and so on. thus the mean number of cases in each minor outbreak, including the primary case that triggers the outbreak, is given by a geometric series, and for r < [ ] : the expected total incidence rate i is then given by the product of the spillover rate and the mean number of cases associated with each spillover event: proportion of cases infected by human sources as shown above (eq. ), when r < , the expected number of cases that result from each introduction is /( -r). because there is one primary case per introduction, the proportion of cases that are primary is given by the reciprocal of this quantity and is equal to ( -r). thus, for zoonotic pathogens with r < , the expected proportion of cases infected by humans is r. we consider the effect on total incidence of control measures that reduce spillover rates, human-to-human transmission, or both. let c z be the factor by which control measures reduce spillover rates, and c r be the factor by which control measures reduce the reproductive number in the human population. when these reduction factors equal , there is no impact on transmission; when they equal , that mode of transmission is halted completely. the total incidence under control, i c , is then: for control measures that affect both modes of transmission equally, such as protective vaccination of humans, c z = c r = c and this expression simplifies accordingly. in settings where it is necessary to choose between measures to reduce zoonotic spillover (via c z ) and measures to reduce human-to-human transmission (via c r ), we can compare the total incidence when each measure a human-to-human transmission has been reported in nosocomial settings but is rare fig. the expected source of infection for cases is determined by the reproductive number for human-to-human transmission is in place. the point where the two strategies are equivalent is given by: since the zoonotic spillover rate enters both sides linearly, the preferred strategy in a given context is governed by the reproductive number. rearranging these expressions, we can find the value of the reproductive number where the two strategies are equivalent: when r > r switch , the strategy to reduce human-tohuman transmission will yield a greater reduction in incidence. to incorporate the influence of differing cost, we consider how the effectiveness of control measures varies with effort using a simple model for the principle of diminishing returns on investment (fig. ). this corresponds to many public health settings where heterogeneity in the structure, accessibility and compliance of populations means that the incremental cost of expanding coverage rises as coverage rises. we model this phenomenon by setting the effectiveness of control measures to be a declining exponential function of resources invested, r. to reflect the different costs of different control strategies, we introduce a factor α to scale the return on investment for reducing spillover relative to reducing human-to-human transmission: substituting these expressions into eq. and solving for the value of the reproductive number r switch at which the strategies are equivalent, we find: r switch is the value of r above which control measures should be targeted at human-to-human transmission, for a given level of resource investment. the curves in fig. are generated by plotting c z (or equivalently, − e −αr ) versus r switch parametrically as a function of r, for different values of the relative cost α (which are shown as different line types). for a given reduction factor (c) describing the effectiveness of control, the greatest reduction in incidence is obtained from control measures such as vaccination that simultaneously reduce both zoonotic spillover and human-to-human transmission. when this is not possible and when resources are constraining, it may be desirable to implement control measures in a reactive manner. here we analyze the impact of control policies that focus on reducing spillover as a default but switch their focus to reducing human-to-human transmission when an outbreak has been detected. we assume that the switch occurs after k generations of transmission among humans, reflecting inevitable delays in case identification and policy implementation. if control is imposed after the first generation of human-to-human transmission has occurred (k = ), then the first generation will have expected size r and subsequent generations will have expected size c r r. thus, the expected number of cases in the minor outbreak will be: in the supplement we show that the general form, for a delay of k generations, will be: thus the total incidence under reactive control strategy, with reduction factors c r and c z , is: this expression was used to plot the green curves in fig. with c r = c z . for most zoonotic pathogens, zoonotic spillover risk is not fixed across the population due to variation in ecological, epidemiological, and behavioral factors. to explore how heterogeneous spillover risk might influence the choice of disease control strategy, we analyze a model with two defined groups with different risk of zoonotic infection. we define p as the proportion of the population in the group with higher risk of zoonotic spillover. let λ h be the spillover rate for the high-risk group and λ l be the spillover rate for the low risk group. then the total spillover rate λ z can be written as pλ h + ( − p)λ l . thus, in the absence of control measures, the incidence is given by: analysis of control measures for subcritical zoonoses with risk groups we now consider the effect of different control measures when there are defined high-risk and low-risk spillover groups. like before, we can apply a general spillover reduction term, c λ , that applies to both risk groups to reduce the two spillover rates equally. the total incidence is then: in settings with defined risk groups, interventions that target the high-risk group are an attractive strategy for reducing overall incidence. to model control measures targeted at the high-risk spillover group, we define c h to fig. impacts of different control measures on incidence of a zoonotic infection with initial value of r (i.e. before control) between and . panel a illustrates the effects of control on the total incidence expected in a focal population, whereas panel b shows the proportional reduction in expected incidence when compared to the incidence level without control (black line). in a, the black line shows how the expected total incidence increases nonlinearly with r, for a fixed rate of zoonotic spillover. colored lines show the total incidence that would result from interventions that cause % reductions in spillover transmission (red), human-to-human transmission (blue), or both types of transmission (purple). green lines show the incidence resulting from a reactive intervention strategy, where effort is focused on reducing spillover transmission but is shifted to reducing human-to-human transmission once an outbreak is detected. the three green lines show the total incidence resulting when control is shifted after one, two, or three generations of transmission among humans, respectively from top to bottom be the factor by which control measures reduce spillover rates in the high-risk group. the total incidence under such a targeted control policy is then: we assume that targeted control makes more efficient use of resources, in proportion to the size of the highrisk group. thus to calculate the effect of targeted control in our cost-benefit analyses, we multiply the resources invested by a factor /p. the reduction factor c h is thus a function of resources invested, r, the factor α that reflects the relative cost of reducing spillover versus reducing human-to-human transmission, and the proportion of high-risk individuals in the population, p: different combinations of targeted spillover reduction, universal spillover reduction, and efforts to reduce r give rise to incidence expressions similar to eqs. ( ) and ( ) . table s contains the full list of equations that were used to plot the curves in figs. and . our analysis of control measures for subcritical zoonoses is guided by strikingly simple predictions, derived from basic theory for outbreak dynamics, about the expected proportion of all human cases infected by other humans versus by animals ( fig. ; eq. ). the relative importance of these transmission routes in any system is governed by the efficiency of human-to-human transmission, as quantified by r. for subcritical zoonoses with r < , the expected number of cases that result from each introduction (including the primary case) is /( -r), and thus the proportion of cases infected by humans is r. when r > , endemic circulation of the pathogen in the human population is possible. averaging over many introductions, secondary cases from successful outbreaks greatly outweigh the primary cases, including instances where introductions go extinct, and effectively all cases are from human sources. for a given rate of zoonotic spillover, the expected total incidence level depends strongly on the prevailing value of r, with expected outbreak sizes rising sharply as r approaches (fig. a) . accordingly, disease control interventions exhibit marked differences in effectiveness as a function of r, in both absolute and proportional terms (fig. a,b) . because the total incidence scales linearly with the spillover rate (eq. ), measures that reduce spillover transmission have a fixed proportional impact, regardless of r (fig. b) . measures to reduce human-tohuman transmission have limited impact when r is low, compared to measures reducing zoonotic spillover, but this situation is reversed dramatically as r approaches (fig. ) . when comparing measures that reduce either type of transmission by % (i.e. comparing c z = . to c r = . ), spillover-reducing measures are preferred for r values up to . , then measures reducing human-tohuman transmission are preferred above this point (eq. , fig. a) . the most effective control measures are those, like vaccination, that reduce both routes of transmission by a given amount. when vaccines are not available, as is initially the case for many emerging pathogens, a reactive strategy that targets spillover then switches to human-to-human transmission once an outbreak is detected can be almost as effective, even if the switch is delayed for several generations of transmission (fig. a,b) . we then considered how various control strategies perform under different scenarios of resource investment, where resources govern the effectiveness of control measures via our assumption of diminishing returns on investment (fig. ) . two findings stood out. first, control measures that focus strictly on reducing human-tohuman transmission will never reduce incidence to zero (fig. ) . even with very high resource investment, when human-to-human transmission is halted entirely, primary cases are undiminished. however, at lower resource levels, measures to reduce human-to-human transmission can be cost-effective, depending on the epidemiological context (fig. ) . in low transmissibility settings, investing resources into reducing human-tohuman transmission is only barely better than doing nothing. as r increases, though, we see a growing range of resource levels where reducing r is more effective than reducing spillover. when r = . , this difference is large and persists throughout almost the full range of incidence reductionyet only spillover reduction can drive incidence to zero (fig. ) . unsurprisingly, if it is possible to reduce both modes of transmission at the same cost as reducing one, then this is always the most cost-effective strategy. notably, though, the reactive strategy is nearly as cost-effective, given the costs of reducing cross-species transmission and human-to-human transmission are equal. for most emerging zoonoses a vaccine is unavailable, and in many settings reactive measures may not be practical due to logistical challenges, unavoidable delays, or shortcomings in surveillance. in these settings a choice must be made between reducing zoonotic spillover or reducing human-to-human transmission, and we can determine which strategy would be most effective for a given r value. the preferred strategy depends on the level of resources available, which we quantify here by the proportional reduction in spillover that is achievable if all resources are devoted to spillover control (fig. ) . the curved solid line marks the boundary between optimal strategies, assuming it is equally expensive to implement spillover reduction or human-to-human transmission reduction (i.e. α = ). this line corresponds to eq. for r switch , plotted parametrically as a function of resource investment (i.e. with zero investment and c z = at the bottom, and infinite investment and c z = at fig. impacts of control measures with varying resource investments on incidence of a zoonotic infection with r between and . each panel shows a different r (before control) value. the black lines show the incidence under no control. colored lines show the change in total incidence that would result from increasing investment for interventions that cause reductions in spillover transmission (red), human-to-human transmission (blue), or both types of transmission (purple). the green line shows the incidence for increasing investment resulting from a reactive intervention strategy, where effort is focused on reducing spillover transmission but is shifted to reducing human-to-human transmission once an outbreak is detected (detection after two generations of transmission is shown). controls measures targeting spillover transmission are assumed to be equally costly as measures targeting human-to-human transmission, i.e. α = fig. policy guidance whether incidence will be reduced more by focusing on reducing spillover transmission or human-to-human transmission, for different values of r (before control) and the reduction in spillover that is achievable given resource constraints. the solid line shows the boundary between preferred strategies when costs of the two types of control are equal, as defined by eq. ( ). the dashed and dotted lines show how the boundary shifts due to differences in relative cost (each line is labeled by the relative cost of reducing spillover by a given proportion compared to the cost of reducing r by the same proportion) the top). when r is low or resource levels are high (fig. -shaded in orange), it is preferable to cut off zoonoses at the source by focusing control efforts on reducing cross-species spillover. as r approaches , it becomes more effective to reduce human-to-human transmission, as a diminishing fraction of cases are attributed to spillover. yet in order to drive total incidence to zero, in the limit of high resource investment, it is necessary to focus on spillover reduction. if the costs of the strategies are not equal, the tradeoff line shifts (fig. , dotted and dashed lines) . the greater the cost of reducing spillover transmission relative to reducing human-to-human transmission, the more the tradeoff curve moves to the left, indicating that targeting human-to-human transmission would be a better use of resources for lower r valuesthough spillover reduction always becomes preferable as we aim to push incidence levels toward zero (figs. and ) . conversely, if reducing spillover transmission is substantially cheaper than reducing human-to-human spread, then spillover reduction remains the preferred strategy for values of r approaching (fig. ) . in many settings, there are identifiable groups at elevated risk for zoonotic spillover risk, and these high-risk groups present an attractive focus for targeted control measures. to incorporate a risk structure for spillover in our model, we assumed that the high-risk group composed a fixed proportion (here p= . ) of the population, and varied the rate ratio of zoonotic infection (λ h / λ l ) between the high-and low-risk groups. under no control, total incidence grows nonlinearly with increasing r, as in fig. a , and also rises as the relative risk of spillover in the high-risk group increases (fig. a) . the latter effect is a simple reflection of increased total spillover in the population, as we treat λ l as constant. considering different control strategies, we find that the broad hierarchy of strategies as described above is remarkably robust to heterogeneities in spillover risk, while the epidemiological parameters shape the potential benefit of targeted control. we first observe that untargeted control policies, such as general awareness campaigns aimed at reducing spillover in the whole population or human-to-human transmission, are unaffected by the defined risk groups (fig. b & c) . in contrast, a targeted strategy to reduce spillover, such as improved biosafety protocols among people who have high-risk contacts with animals, will have varying impact depending on the risk ratio (fig. d ), but as with universal spillover reduction (fig. b) , this impact does not exhibit any dependence on r. we also note that the overall incidence reduction appears lower for targeted control than for universal spillover control, but this is because this plot assumes equal reduction factors (c = . ) for all control measures; under this assumption, control measures are inevitably more impactful when applied to the whole population versus a high-risk group of just % of the population. considering mixed strategies that combine targeted control of the high-risk spillover group with general control of human-to-human transmission (fig. e-h) , we see that the benefits of targeted control for total incidence reduction are greater for higher risk ratios, but this difference diminishes as r approaches and human-to-human transmission dominates the epidemiology. as in fig. b , the benefits of including human-to-human transmission controls depend on the delay before initiation. for longer delays the curves resemble the targeted spillover control in fig. d for low values of r, since when r is low many transmission chains do not last long enough to be affected by reduced human-to-human transmission. in contrast, under joint programs with no delay (fig. e) , the benefits of control are seen immediately as r increases. finally, we consider targeted control measures under different resource scenarios, to explore the possible benefits of efficiently reducing spillover in the high-risk group. again, we see a tradeoff between strategies preferred at modest resource levels and those preferred when resources are not limiting (fig. ) . among strategies that only reduce spillover transmission (red and orange lines in fig. ) , targeted control shows considerable benefits at low resource levels, particularly for high risk ratios and higher values of r. yet targeted strategies are less effective at high resource levels, since they do not reduce spillover in the low-risk group, and hence can never reduce incidence to zero. a similar pattern is found for mixed strategies, where targeted joint or reactive approaches (i.e. high-risk spillover reduction followed by a switch to reducing human-to-human transmission once an outbreak is underway) are the most effective control policies at low resource levels, particularly when r > . and the risk ratio is high, but are incapable of reducing incidence to zero even at high levels of investment. in many other epidemiological settings, such as when r is . or lower and when risk ratios are near , any benefits to targeted control are imperceptible and tend to be outweighed by the disadvantages of allowing spillover to the low-risk group to continue unchecked. implementing efficient, cost-effective control measures is crucial for the control of emerging infectious disease, both to reduce the disease burden of human cases and to minimize the opportunities for pathogen adaptation, international spread, or other adverse events. however, for subcritical pathogens that exhibit low transmissibility among humans, it is not obvious whether control efforts should focus on reducing primary cases arising from spillover from external reservoirs or reducing secondary cases arising from human-to-human transmission. using a simple mathematical model, we developed a theoretical framework to guide decisions about how to target resources under scenarios with different pathogen transmissibility and risk group structure. we focused on the relative impacts achievable in resource-constrained settings, as well as the maximum benefits that could be obtained when resource investment was high. our work is framed in the context of zoonotic infections, where introductions arise via cross-species spillover from animal reservoirs, but our findings translate fully to other scenarios where outbreaks of subcritical pathogens are seeded by introductions from outside. this includes vaccine-preventable diseases such as measles in postelimination settings where herd immunity has reduced r below , or pathogens such as methicillin-resistant staphylococcus aureus (mrsa) in hospitals that exhibit inefficient nosocomial transmission [ , , ] . geographic importation from endemic regions serves as 'spillover' for measles or covid- , introducing the pathogen into areas where it was previously eliminated or brought under control. similarly, community introduction of mrsa into hospitals serves as the spillover mechanism prior to transmission within the hospital. we found that the optimal focus of control measures for subcritical pathogens depends primarily on the human-to-human transmissibility of the pathogen, as fig. impacts of different control measures on the total incidence of a zoonotic infection with r (before control) between and with a varying ratio of high and low spillover rates. panel a shows how total incidence increases with r for varying ratios of high-to-low zoonotic spillover. panels b-e illustrate proportional reduction in incidence for controls that would cause % reductions in all spillover transmission (b), human-to-human transmission (c), spillover transmission into the high-risk group (d), or jointly high-risk spillover and human-to-human transmission (e). panels f-h show the proportional reduction in incidence given a reactive strategy that first targets high-risk spillover and then switches to reducing human-to-human transmission after , , or generations of transmission, respectively. note that longer delays cause the results to resemble panel d over increasing ranges of r values, since at low r many transmission chains don't last multiple generations. the proportion of high-risk individuals in the population was set to . summarized by the reproductive number r (fig. ) . for pathogens with the lowest transmissibility among humans (r near zero; e.g. h n avian influenza), measures to reduce zoonotic spillover are most effective. thus for these zoonoses, strategies such as awareness campaigns to reduce contact with reservoir host animals or animals found dead, infection control in live animal markets, culling infected reservoir populations, and removing rodents from homes (table ) will be most effective in reducing human cases. for pathogens with greater transmissibility among humans (e.g. postelimination measles, sars-cov- , or ebola), reducing human-to-human transmission becomes more effective. in such scenarios, preferred control methods will include providing personal protective equipment in high-risk settings such as hospitals, awareness campaigns to reduce unprotected contact with sick individuals, and strengthened surveillance for improved case tracking and faster case isolation. of course, the strongest control strategies would act to reduce zoonotic spillover and human-to-human transmission at the same time, as with a protective vaccine. where this option is not available (or is cost-prohibitive to deploy widely in advance of an outbreak), we found that a reactive strategy could achieve nearly the same effect without substantially greater investment. such a strategy would have a baseline emphasis on reducing zoonotic spillover, but when a spillover or subsequent outbreak is discovered, the fig. impacts of different control measures with varying resource investment on the total incidence of a zoonotic infection with r (before control) between and with different ratios of high-to-low spillover rates. columns (left to right) show increasing values of r. rows (top to bottom) represent an increasing ratio of spillover rates in high-risk versus low-risk groups (λ h /λ l ). the black lines indicate total incidence under no control. colored lines represent the reduction in incidence for increasing resource investment. these scenarios were explored earlier in fig. but now include the added comparison of targeted versus universal spillover control for all strategies emphasis would shift locally to reducing human-tohuman transmission. strategies could include an awareness campaign that focuses on reducing interactions with known animal hosts, such as not touching dead animals in the forest, shifting to increased contact precautions and active surveillance to detect human cases quickly to reduce human-to-human transmission once an outbreak is detected [ ] . unsurprisingly, many existing control policies designed by public health professionals align broadly with the recommendations of our model. for pathogens with low r such as h n avian influenza, our work advises an emphasis on preventing spillover. this is consistent with current public health control measures for h n avian influenza, such as market disinfection or cessation of live poultry trade, which focus on reducing contact with birds and lowering risk of cross-species transmission [ ] [ ] [ ] . in contrast, lassa virus has a higher r value estimated near . and, thus, has a higher expected proportion of cases which arise from human-to-human transmission. public health policy for lassa fever has recently focused on preventing nosocomial transmission between humans [ ] [ ] [ ] . in some settings, r changes through time due to shifts in population immunity or other factors, and priorities for disease control should change accordingly. for example, r for monkeypox has increased over the decades since the cessation of widespread smallpox vaccination around [ , ] , and the historic emphasis on spillover transmission should be re-examined in light of changing circumstances. similarly, r for measles has risen as childhood vaccination rates have dropped [ , ] . public health systems frequently deal with resource constraints, in terms of finances and human or institutional capacity [ ] . exploring the effects of resource investment on the impacts of control on overall human incidence, our work illustrates potential trade-offs between higher cost effectiveness at low investment versus the ability to reduce incidence to zero at high investment (fig. ) . at low investment levels, the best simple strategies are those which follow the priorities laid out above, i.e. focusing on spillover if r is low, or on human-to-human transmission if r is higher. however, as resource levels increase, the limitations of these simple priorities become clear, because strategies that omit the reduction of spillover cannot ever reduce human incidence to zero as they do not decrease the number of primary cases. therefore, it is necessary to incorporate spillover reduction in any policy hoping to drive incidence to zero. when all types of interventions are assumed to be available with the same cost, then joint approaches that reduce both animal-to-human transmission and human-to-human transmission are most effective for a given resource level. when resources do not permit reduction of both transmission modes simultaneously, practitioners must decide which transmission mode is more important to control. our analysis provides guidance as to which transmission method is best to control as a function of resource investment and r, accounting for possible differences in cost (fig. ) . while further work is needed to characterize the cost-efficacy curves for control measures in particular systems, in order to implement this approach, this analysis provides a foundation for rational cost-benefit analysis to support disease control policy. zoonotic spillover risk is heterogeneous in the human population, since some groups have more frequent or riskier exposures to zoonotic reservoirs due to cultural or occupational factors [ ] . our analysis demonstrated that targeted spillover control in these high-risk groups offers the potential for markedly greater reductions in incidence, relative to control efforts spread across the entire population, when resources are limited. however, these targeted strategies are limited in impact as investment levels rise, since they don't reduce the spillover rate in the low-risk group so they can never drive incidence to zero. if there is negligible risk in the low-risk group or if the low-risk group receives low-intensity control as a side benefit of the targeted control (for instance, via an awareness campaign focused on the highrisk group but available to all), then the targeted control strategy would remain the most efficient option. ultimately, the desirability of targeting the high-risk spillover group depends on the epidemiological context (r value), resource level, and risk ratio between the risk groups. it is important to recognize that there are often substantial challenges in identifying and quantifying risk factors for spillover, to support a rational decision about targeting. for zoonoses that spill over very infrequently and unpredictably, such as ebolaviruses, coronaviruses including sars-cov- and mers, or some hantaviruses, the necessary data are hard to acquire and uncontrolled variation among spillover events can obscure patterns. in settings where the majority of individuals engage in potentially high-risk activities, yet spillover events are sporadic due to variation at other levels (e.g. in infection prevalence in the animal reservoir), it can be difficult to ascertain how the magnitude of risk is split across specific risk factors [ ] . for example, in populations which nutritionally or economically rely on bushmeat, the majority of individuals can be exposed to multiple animal species through multiple modes of contact (e.g. hunting, food preparation, and cooking), which all present a potential risk of transmission [ ] . the resulting difficulties in determining risk factors, and identifying distinct high-risk groups, can further complicate the implementation of targeted control measures. several caveats should be borne in mind in interpreting our analysis, which point to opportunities for further research. for the sake of clarity, our model is based on expected incidence levels under different scenarios, but stochastic variation can be large so individual outbreaks could differ substantially from our predictions. we also assumed stationarity (i.e. no changes in the model parameters through time), ignoring behavior change of affected populations or on-the-ground factors that can impede control measures [ ] . we did not account for superspreading, or for variation in transmissibility across spatial or social contexts, both of which can have dramatic effects in the early phase of outbreaks [ , ] . our analysis incorporated heterogeneities in spillover risk but did not address different risk groups for ongoing human-to-human transmission. such a scenario could arise due to age-structured mixing or susceptibility, or from other risk factors such as occupational exposure in health-care settings, and could have important effects on outbreak dynamics [ , ] . factors giving rise to immune compromise, such as human immunodeficiency virus (hiv) infection, are another potential source of heterogeneity in both modes of transmission [ , ] . the existence of distinct risk groups for human-to-human transmission would offer another important opportunity for targeted control measures and warrants further investigation. all of the above complexities could be addressed via more complex analytic methods, such as multitype branching processes, or via stochastic simulation analyses. our cost-benefit model is theoretical in nature and aims for simplicity rather than realism. we used a phenomenological model to represent diminishing returns on investment, but we do not properly account for complexities in scaling up control measures in space or time. for the reactive strategy, we assumed a clean and immediate switch between reducing spillover and reducing human-to-human transmission with no overlap and no lapse in control. in real-world settings, ramping up (or terminating) control measures is inevitably more complicated and a reactive strategy would likely entail delays and changing effectiveness through time. we also assumed there is no additional cost associated with switching strategies, but this is unlikely to be true due to the resources involved in initiating any program. while our theoretical analysis enabled a first exploration of the general cost-effectiveness of subcritical disease control, more intensive case studies are needed for specific pathogens. subcritical zoonotic pathogens exist at the animalhuman interface, and little policy guidance exists on the most effective ways to implement controls. in this study we present a framework to think systematically about controlling subcritical zoonoses, considering the relative importance of reducing animal-to-human spillover versus human-to-human transmission. our work shows how the relative effectiveness of these strategies depends on epidemiological context and highlights a trade-off between cost-effectiveness at low resource levels and the potential to reduce incidence to zero as investment increases. our findings illustrate core principles for evidence-based control of subcritical zoonoses and provide a foundation for integrative studies of particular systems to carry these ideas toward 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democratic republic of the congo invasion dynamics in spatially heterogeneous environments characterizing the transmission potential of zoonotic infections from minor outbreaks detecting differential transmissibilities that affect the size of self-limited outbreaks hiv- /parasite co-infection and the emergence of new parasite strains antiretroviral drugs for tuberculosis control in the era of hiv publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors would like to acknowledge seth blumberg for early input on the theory of the paper. received: january accepted: july key: cord- - d rq qj authors: patel, jay title: transmission routes of sars-cov- date: - - journal: j dent sci doi: . /j.jds. . . sha: doc_id: cord_uid: d rq qj nan however, the authors make inaccurate references to the established transmission routes of sars-cov- . the authors state that the novel coronavirus is spread via aerosols and the faecal-oral route, in spite of a largely undeveloped evidence-base in support of these pathways. in their most recent scientific brief, the world health organisation suggest heightening infection prevention and control measures around contact and respiratory droplet transmission. indeed, aerosol-generating procedures (agps) are implied in facilitating airborne transmission but limited evidence is available to support this for sars-cov- . there is an urgent need to develop the evidence-base for the risk associated with agps, particularly when planning the return to routine dental practice. the authors imply confirmation of the faecal-oral route and reference a paper by meng and colleagues however this seems to have been misinterpreted. i concur with the plausibility of this pathway, owing to recent findings of viral rna detection in stool samples and enteric symptoms experienced by several cohorts of covid- patients. , in the absence of any reports of faecal-oral transmission, this remains a hypothesis, albeit highly probable. although the suggested infection control measures for oral healthcare settings seem practical, a thorough awareness of transmission routes is pre-requisite to devising effective advice. none. oral healthcare during the covid- pandemic modes of transmission of virus causing covid- : implications for ipc precaution recommendations coronavirus disease (covid- ): emerging and future challenges for dental and oral medicine covid- : faecaleoral transmission? toothbrushes and covid- . br dent j please cite this article as: patel j, transmission routes of sars-cov- none. available online at www.sciencedirect.com key: cord- -pk d hs authors: olu, olushayo oluseun; waya, joy luba lomole; maleghemi, sylvester; rumunu, john; ameh, david; wamala, joseph francis title: moving from rhetoric to action: how africa can use scientific evidence to halt the covid- pandemic date: - - journal: infect dis poverty doi: . /s - - - sha: doc_id: cord_uid: pk d hs the ongoing pandemic of the coronavirus disease has spread rapidly to all countries of the world. africa is particularly predisposed to an escalation of the pandemic and its negative impact given its weak economy and health systems. in addition, inadequate access to the social determinants of health such as water and sanitation and socio-cultural attributes may constrain the implementation of critical preventive measures such as hand washing and social distancing on the continent. given these facts, the continent needs to focus on targeted and high impact prevention and control strategies and interventions which could break the chain of transmission quickly. we conclude that the available body of scientific evidence on the coronavirus disease holds the key to the development of such strategies and interventions. going forward, we recommend that the african research community should scale up research to provide scientific evidence for a better characterization of the epidemiology, transmission dynamics, prevention and control of the virus on the continent. the ongoing pandemic of the coronavirus disease (covid- ) has severely impacted global health, economy and politics in different patterns in various continents. the disease which is caused by the severe acute respiratory syndrome coronavirus (sars-cov- ) was declared a public health event of international concern on th january [ ] and a pandemic on th march [ ] . as of th august , confirmed cases and deaths of the disease had been reported from all countries, areas and territories of the world [ ] . africa reported its first case in egypt on th february through an importation and by th august , all african countries had reported confirmed cases and deaths [ , ] . local community transmission has been established in most of these african countries. while africa remains one of the least affected regions, recent developments and data from within the continent and other regions particularly europe and america show that the numbers of cases and deaths can grow exponentially and overwhelm even the best of systems in a relatively short time if effective prevention and control measures are not instituted on time [ , ] . the fear, anxiety and panic induced by the rapid spread of the pandemic prompted several african countries to take drastic actions some of which are not necessarily based on scientific evidence. some countries closed their air, sea and land borders and imposed total national or partial sub-national lockdowns in a bid to prevent importation and minimize local transmission. given the weak health system in most african countries, mounting timely and robust responses to the covid- pandemic will be a big challenge hence the need to focus on targeted and high impact prevention and control interventions that could break the chain of transmission quickly. this becomes more pertinent given the african context where inadequate access to water, sanitation and the extended family system renders the implementation of critical preventive measures such as hand washing and social distancing challenging. this is further compounded by the global shortage of required human and material resources, which is more glaring in africa. due to the rapid spread and impact of the disease on human health, trade and travel, several research (mostly preliminary) have been conducted and published to characterize the virus and the dynamics of its transmission, prevention and control. while some of these publications have shown varying findings, conclusions and recommendations, many key and consistent evidences on the characteristics of the virus, its transmission, prevention and control are now emerging. this body of knowledge is critical to inform the development of timely, effective and context-specific prevention and control strategies in africa. in this article, we review the relevant scientific literatures on the covid- pandemic, and synthesize the relevant evidence that could potentially change the game in africa's fight against the disease; finally we propose strategic recommendations for prevention and control of covid- transmission in the africa continent specifically. the initial characteristics of covid- cases suggest that the disease is zoonotic [ ] . however, recent scientific evidence demonstrates that the current transmission pattern globally is from human-to-human. the virus is similar to the severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) viruses with susceptibility and severity associated with older age group [ , ] , male gender [ , ] and underlying medical conditions such as poor immune functions, chronic diseases and surgery [ ] . with a basic reproduction rate ranging from . to . [ , ] and fatality rate from . to % [ , ] it is more transmissible but less fatal compared to sars and mers [ , ] . as is the case with most influenza viruses, the transmission of sars-cov- significantly reduces with an increase in temperature and humidity [ , ] , however, this advantage may be offset by the high transmissibility of the virus. three main routes of transmission have been identified among humans namely ingestion or inhalation of contaminated droplets released into the air when a patient sneezes, coughs or talks, contact with surfaces which have been contaminated by infected persons and the inhalation of aerosols generated during some medical procedures [ , ] . a few studies have also suggested faeco-oral transmission of the virus [ , ] . a recent study concluded that the virus remains viable and infectious in aerosols for a few hours and up to a few days on surfaces, particularly on stainless steel and plastics [ ] . while distinct signs and symptoms such as fever, dry cough, runny nose, difficulty in breathing, etc. have been associated with the disease, recent evidence suggests a high proportion of covid- cases are infectious but undocumented either because they have mild or no symptoms but yet continue to transmit the disease [ ] . this could contribute to the high transmissibility and rapid geographic spread of the virus. based on the lessons learnt from responding to the outbreak in china, prevention and control strategies have been proposed and are in use at various levels. in the absence of a vaccine, infection prevention and control measures that include measures to reduce or prevent exposure to the virus such as identification of suspected cases through syndromic screening at points of entry into countries, public places, health facilities, prevention of shedding of virus into the environment through respiratory hygiene have been recommended as prevention and control strategies in the general population [ ] . others include proper sanitation and waste management, social distancing to prevent contact with infected persons, avoidance of touching potentially contaminated surfaces, eyes, nose and mouth with contaminated hands and hand washing with soap and water or hand sanitizers which contain at least % alcohol [ ] . available evidence suggests that social distancing may have a dramatic effect on the transmission of sars-cov- and other respiratory infections, [ ] but there may be renewed virus transmission following relaxation of such measures due to the large proportion of susceptible people that would still be in the population [ ] . there is a convergent view on the important role of face masks in reducing the transmission of covid- by protecting healthy persons who come into contact with an infected individual and by preventing infected persons from shedding the droplets into the environment [ , ] . the use of face masks has also been associated with lower levels of anxiety and depression among the general population and health care workers which further supports its importance in prevention and control of the disease [ ] [ ] [ ] . at the individual case level, timely diagnosis, isolation and supportive management of confirmed cases, identification and follow-up of their contacts, prevention of nosocomial transmission through strong infection prevention and control methods and use of personal protective equipment are recommended [ ] . there is no known cure for the disease currently but several clinical trials involving various therapies are ongoing. who recommends that all laboratory confirmed cases should be isolated and managed in health facility settings but where this is not possible priority should be given to cases with the probability of poor outcomes such as those aged above years and with underlying medical conditions which put them at higher risk [ ] . recommendations for covid- strategy development specific for the africa continent putting the above scientific evidences on the characteristics and dynamics of covid- transmission, prevention and control into perspective against the backdrop of the social, cultural and economic context in africa, we deduce several lessons which could guide african countries to better prepare for and respond to the covid- pandemic on the continent. while the mostly hot and humid african weather and largely younger population may be deterrent factors for wide transmission of the disease, any advantage conferred by this is offset by the high transmissibility of the disease. this is more so given the high population density, larger families and large vulnerable populations such as refugees, internally displaced persons (idps), people living with the human immunodeficiency virus (hiv), tuberculosis (tb) and malnutrition thus emphasis in african countries should be on prevention of the spread of infection, especially to these vulnerable groups. in this regard, african countries should invest in identifying, developing and implementing tailor-made prevention strategies to protect at risk populations from infection [ ] . syndromic surveillance, laboratory testing and contact tracing at the community level given the high proportion of undocumented and asymptomatic cases of covid- , the use of syndromic surveillance for disease detection at points of entry may not be very effective [ ] . while syndromic surveillance may offer some level of reassurance to governments and the general population, the cost in terms of the human and financial resources associated with conducting it may offset its benefits. african countries should rather invest in active search for cases and their contacts at the community and household levels particularly the asymptomatic contacts and transmitters through scaling up testing of all persons who may have been exposed to the virus but remain asymptomatic. to achieve this, covid- testing strategies which prioritize massive testing of various categories of persons based on the transmission scenario should be developed. additionally, efforts should be made to increase testing capacity and timeliness by decentralizing testing to the sub-national levels. the evidence that the virus survives much longer on surfaces such as stainless steel and plastic as compared to respiratory droplets have far reaching implications for prevention and control of the virus at the population level. first, risk communication messages should emphasize the high risk constituted by surfaces such as doorknobs, stainless steel handrails, disposable plastics etc. and encourage people to refrain from unnecessary touching of such surfaces. second, regular disinfection of such surfaces at the household and community level is advised and should be included in risk communication messages and during community engagement sessions [ ] . third, in the light of new findings on asymptomatic transmission of covid- and recommendations on the usage of face masks by healthy individuals, african countries should define clear policies on the use of face masks. such policies should ensure that face masks are available to those who need them particularly the frontline healthcare workers, caregivers and vulnerable groups, address the issue of shortage of masks and other supplies which is already a challenge in many african countries and importantly provide clear guidance to the general population on the pros and cons, safe use, donning and doffing of face masks. furthermore, african scientists should pursue urgent researches into the use of locally available material for the production of face masks which are suitable to the african context [ , ] . while available scientific evidence shows that the social distancing which is the ultimate aim of the current lockdowns and population movement restriction measures instituted by several african countries may reduce transmission of the virus in the short term, this strategy alone may not be enough to break the chain of transmission [ ] . since there is already widespread community transmission in many of these countries, population confinement may result in a change in the transmission pattern from the community to the household level [ ] . furthermore, african countries may not be able to sustain such lockdowns for a long time given their socioeconomic context thus they should focus on making the best use of the small window of opportunity that they offer. first, clear objectives should be set for lockdowns which should be to reduce transmission through the scale up of preparedness and response interventions and to control the outbreak in areas of transmission. these objectives should be communicated clearly to the general population to forestall community resistance to lockdowns which is being experienced in some of the african countries. second, the definition of areas where to impose confinement should be guided by the epidemiology and pattern of transmission of the disease. third, the lockdowns should be accompanied by intensive risk communication, active case search at the community and household levels, massive testing, contact tracing and isolation. fourth, adequate preparation should be made to ensure that confined populations have access to basic services such as food, water, healthcare etc. during lockdowns in order to reduce community resistance and ensure adherence. fifth, appropriate strategies to prevent a second wave of the pandemic following the lifting of the lockdown measures should be developed and implemented [ ] . given the weak health systems in most of the infected african countries, institutional management of all laboratory confirmed cases may not be a feasible option. on the other hand, home management of such cases is constrained by several challenges due to the large household size, poor housing and high population density in many african countries. countries should therefore develop context-specific case management strategies which should classify cases according to their risk and health needs, identify places such as health facilities and non-health facilities such as repurposed hostels, schools, hotels or stadia where the various categories of cases will be isolated, define and identify the minimum package of resources such as health workers, medicines, medical equipment and other logistics which are needed to effectively manage the anticipated caseloads. such strategies should be based on the prevailing transmission scenario in the country. the covid- pandemic has overwhelmed even strong health systems in europe and america. a review and analysis of the impact of the - ebola outbreaks in west africa on health systems revealed that there was a significant reduction in access to routine health services and this led to substantially increased mortality from preventable diseases such as malaria, measles, hiv, aids and tb. african countries should learn from this experience and implement available guidance from who to ensure that essential health services are maintained during the covid- pandemic particularly during lockdowns to reduce excess mortality from other preventable diseases [ ] [ ] [ ] . key to maintenance of essential services during the covid- pandemic is the protection of health care workers from acquiring covid- infection; this can be achieved by providing african health workers with the necessary equipment, information and training on how to protect themselves [ ] . management of covid- outbreaks in the situation of population displacement such as refugee and idps camps and in prisons and urban slums which are common in africa is a major challenge. other high-risk situations include in large-scale industries which employ a large number of semi-skilled workers [ ] . the high transmissibility of the virus, overcrowding and inadequate access to social services such as water and sanitation will rapidly facilitate transmission of the virus and constrain implementation of preventive measures such as social distancing in such situations. african countries should, therefore, invest in the development of special public health strategies for prevention and control of outbreaks in such settings [ ] . establishment of covid- information and testing centres near such areas is recommended to improve rapid access of the high-risk populations to covid- prevention and control services [ ] . importantly, the lessons from the rapid spread of the virus in china, italy, iran, republic of korea and america should be a wake-up call for african countries to rapidly scale up risk communication, community engagement, and participation. the scientific evidence described above and outcomes of anthropological studies on covid- should be used as the basis for development of evidence-based and context specific risk communication messages. such risk communication messages should be focused on achieving behavioural change and tailor-made to address the several sociocultural myths, stigma, misconceptions and rumours associated with the virus, its transmission, prevention and control. african countries need to act early and decisively to avert excess morbidity and mortality due to covid- and the associated impact it could have on their economy, public health and health system. this could be achieved by using the available global scientific evidence to inform the development and implementation of context-specific covid- prevention and control strategies. given that there is currently no known cure or vaccine for the disease, such strategies should prioritize prevention and other appropriate interventions in a balanced manner. the african research community should scale up research to provide scientific information for better characterization of the epidemiology, transmission dynamics, prevention and control of the sars-cov- and other viruses on the continent. furthermore, african countries should use the opportunity of the covid- preparedness and response to systematically strengthen their health system capacity for broader and longer-term epidemic preparedness and response by using platforms such as the national action plans for health security. finally, given the chronic outlook of this pandemic, african countries should explore opportunities to mainstream ongoing covid- response interventions into existing healthcare programmes to ensure cost-effectiveness and sustainability in the long-term. detail/ - - -statement-on-the-secondmeeting-of-the-international-health-regulations accessed world health organization. who director-general's opening remarks at the media briefing on covid world health organization. coronavirus disease (covid- ) situation dashboard world health organization regional office for africa. covid- in the world health organization african region world health organization regional office for eastern mediterranean world health organization. coronavirus disease (covid- ) situation report − lessons from italy's response to coronavirus, havard business review chinese center for disease control and prevention. environmental samples from the south china seafood market in wuhan epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia the incubation period of -ncov infections among travellers from wuhan. china euro surveill updated understanding of the outbreak of novel coronavirus ( -ncov) in wuhan modelling the epidemic trend of the novel coronavirus outbreak in china breaking down of healthcare system: mathematical modelling for controlling the novel coronavirus ( -ncov) outbreak in wuhan transmission dynamics of novel coronavirus ( -ncov) a mathematical model for simulating the phase-based transmissibility of a novel coronavirus high temperature and high humidity reduce the transmission of covid- accessed the efects of temperature and relative humidity on the viability of the sars coronavirus epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (covid- ) during the early outbreak period: a scoping review modes of transmission of virus causing covid- : implications for ipc precaution recommendations. scientific brief air, surface environmental, and personal protective equipment contamination by severe acute respiratory ryndrome coronavirus (sars-cov- ) from a symptomatic patient aerosol and surface stability of sars-cov- as compared with sars-cov- substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov ) how we know ending social distancing will lead to more deaths public health interventions and epidemic intensity during the influenza pandemic rational use of face masks in the covid- pandemic the-use-of-masks-in-the-community-during-home-care-andin-healthcare-settings-in-the-context-of-the-novel-coronavirus-( -ncov)-outbreak is returning to work during the covid- pandemic stressful? a study on immediate mental health status and psychoneuroimmunity prevention measures of chinese workforce immediate psychological responses and associated factors during the initial stage of the coronavirus disease (covid- ) epidemic among the general population in china a longitudinal study on the mental health of general population during the covid- epidemic in china disinfection measures for pneumonia foci infected by novel coronavirus in home care for patients with covid- presenting with mild symptoms and management of their contacts: interim guidance covid- control in low-income settings and displaced populations: what can realistically be done? effectiveness of airport screening at detecting travellers infected with novel coronavirus ( -ncov) the covid- pandemic in the us: a clinical update what's the way out? potential exit strategies from the covid- lockdown the health impact of the - ebola outbreak effects of response to - ebola outbreak on deaths from malaria, hiv/aids, and tuberculosis covid- : operational guidance for maintaining essential health services during an outbreak interim guidance coverage of health information by different sources in communities: implication for covid- epidemic response characterize health and economic vulnerabilities of workers to control the emergence of covid- in an industrial zone in vietnam we thank the global research community which has worked tirelessly to provide scientific evidence for better understanding and management of covid- . we acknowledge the support provided by victoria awuor jura in the proof reading and copy-editing of the final version of the manuscript. the authors alone are responsible for the views expressed in this article, which do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated. authors' contributions ooo conceived and wrote the first draft of the manuscript. all authors read and provided significant inputs into all drafts of the manuscript, agreed to be accountable for all aspects of the work and approved the final draft of the manuscript for publication. all the authors are members of the covid- preparedness and response team of who country office, south sudan. no funding was received for this manuscript.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. received: april accepted: august key: cord- -ibohbjfb authors: odih, erkison e.; afolayan, ayorinde o.; akintayo, ifeoluwa; okeke, iruka n. title: could water and sanitation shortfalls exacerbate sars-cov- transmission risks? date: - - journal: am j trop med hyg doi: . /ajtmh. - sha: doc_id: cord_uid: ibohbjfb sars-cov- , the etiologic agent of covid- , is shed in stool. sars coronaviruses have been detected in wastewater during outbreaks in china, europe, and the united states. in this perspective, we outline the risk fecal shedding poses at locations without safely managed sanitation, as in most of nigeria where we work. we believe that feco-oral transmission could occur if community transmission becomes high and sustained in densely populated cities without proper sanitation in nigeria and many other african and asian settings. in the absence of basic sanitation, or where existing sanitation is not safely managed, groundwater, which is often drawn up from wells and boreholes for drinking and household use, can become contaminated with enteric bacteria and viruses from fecal matter. endemic and epidemic transmission of multiple feco-oral pathogens via this route continues to be documented in areas without safely managed sanitation, and, therefore, the risk of sars-cov- transmission needs to be evaluated, tracked, and forestalled in such settings. we suggest that fecal matter from treatment facilities and recovered patients should be carefully and properly disposed. furthermore, environmental surveillance of sars-cov- in wastewater and accumulated human waste, as well as efforts to mitigate the virus’ entry into unprotected household water sources, should be a priority part of the covid- response in settings without safely managed sanitation for the duration of the pandemic. every effort must be deployed to limit continued spread of the etiologic agent of the covid- pandemic. mounting evidence shows that sars-cov- is amplified in the gastrointestinal tracts of infected people, excreted in stool, and detectable in wastewater at high levels [ ] [ ] [ ] (rimoldi et al., ; medrxiv preprint doi: https://doi.org/ . / . . . ). we are concerned that, in areas without safely managed sanitation, drinking and household water supplies could become contaminated with the virus. this potential risk of feco-oral transmission is highest in densely populated urban centers. sars-cov- has largely been transmitted via respiratory droplets and fomites from infected persons to the respiratory systems of susceptible individuals. however, the virus replicates in gut enterocytes and is detected in stool from patients with severe or mild covid- , as well as from presymptomatic and asymptomatic individuals. , recovered covid- patients may continue to shed virus for as long as days after symptoms have ceased, even after they test negative by conventional respiratory tests. , , considerable concern has been expressed in the literature that the feco-oral transmission potential for sars-cov- places endoscopists, caregivers of diapered children who shed the virus, and fecal transplant recipients at high risk of contracting the infection. for intestinal sars-cov- to transmit via fecal matter, it would have to be viable when shed and persist in the environment until a count greater than an oral infective dose is ingested by a susceptible individual. the cycle could potentially be shortcut by direct dissemination of fecal matter inadvertently from person-to-person or by pests like flies and cockroaches, or it could be broken if wastewater or domestic water treatment inactivates sars-cov- . because wastewater treatment eradicates sars-cov- and most of the worst affected countries have robust water purification systems, community feco-oral transmission has been less extensively discussed. feco-orally transmitted pathogens are endemic in nigeria, which is among the top five countries worldwide contributing to diarrhea-derived under-five mortality. a principal reason why the burden from feco-oral pathogens is so high is that for most nigerians, sewage systems are nonfunctional, incompletely functional, or nonexistent. of six major northern nigeria cities conducting polio virus environmental surveillance, only abuja operates a sewage plant. in lagos, there are multiple sewage treatment plants, but their performance is suboptimal, and they therefore pose a risk of enteric pathogen transmission to surrounding areas. , sewage handling capacity has not grown in tandem with the explosive and continued growth of this megacity so that coverage does not extend to all residents. this situation prevails in many african urban centers and in some south asian settings: between % and % of african city dwellers are not connected to sewerage and instead use a range of autonomous solutions or resort to open defecation. as a result, fecal matter can be deposited into the open environment, pour from toilets unconnected to sewerage into surface water, or be buried underground in soakaways and pits from where, if these receptacles are not adequately protected, it can seep into shallow wells used for irrigation, drinking, and household purposes. , [ ] [ ] [ ] according to the who/unicef, million people in africa and asia do not have access to safe water, and diarrheal disease is a major cause of illness and death in those populations. in recent years, surveillance of household water at a number of african and asian locations has revealed frequently found indicators of recent fecal contamination, such as escherichia coli, or outright pathogens, including enteric viruses. in each case, links have been made to human or animal open defecation, proximal latrines, or improperly processed wastewater. [ ] [ ] [ ] in those settings, even pathogens known not to persist or thrive in the environment are among those recovered from contaminated household water or causing outbreaks. , although there are as yet no reports of transmission of sars-cov- via sewage or fecal matter in settings without safely managed sanitation, or recovery from household water, these examples demonstrate that feco-oral transmission by endemic pathogenic organisms is commonplace in these settings. there is now convincing evidence, from countries with adequate sanitation, that sars-cov- is present in feces, around toilets, and in wastewater. , , both sars-cov and sars-cov- nucleic acid have been detected in wastewater during outbreaks. , , replicable virus is less commonly reported, although it is less commonly sought, and has been found. in laboratory studies, wang et al. found that sars-cov, the agent of the sars epidemic, remains viable in water for days at °c but for only days at °c, suggesting that survival in tropical regions may be inadequate to sustain viability in stored water. however, coronaviruses are protected by organic matter, and this will greatly affect their survival under real-world conditions. sars-cov- rna has been detected in substantial concentrations in wastewater and downstream water bodies. rimoldi et al. reported that sars-cov- is susceptible to wastewater treatment and that viral infectiveness in wastewater is negligible; viral rna was amplified in untreated but not treated wastewater. zhang and coworkers in another preprint, however, found the china cdc-recommended sodium hypochlorite treatment of wastewater to be ineffective for the removal of sars-cov- rna. these studies await peer review, and further investigation is needed to clarify risks. as noted by lodder and de roda husman, early finding of a covid- case in the united states with no known exposure to an infected case suggests that a form other than human-tohuman respiratory transmission of covid- may be possible. additional evidence comes from a recently published systematic review from wuhan, which spotlighted a small number of patients with diarrhea but no respiratory symptoms. however, most patients in this pandemic who could have had the opportunity to be infected feco-orally to date have also been exposed to respiratory droplets or fomites; thus, the magnitude of the risk is challenging to gauge. fecooral transmission nonetheless remains a valid, if untested, hypothesis. , , , , [ ] [ ] [ ] [ ] our review of the evidence suggests that the risk of this mode of transmission in communities without basic sanitation may be high. unfortunately, countries without effective sanitation and water purification are also those least likely to have the wherewithal to detect live virus in environmental samples (detection of viral nucleic acid does not infer infectivity) and therefore measure this risk. , as at the time of writing, most african and asian cities without basic or safely managed sanitation had reported relatively few covid- cases. however, case numbers are increasing, and, as they rise, the viral load in untreated fecal waste pools could escalate. this is particularly true of urban settings experiencing rapid rises in case numbers such as lagos and kano, two nigerian megacities. as at may , , the nigerian centre for disease control had confirmed , and cases in these states, respectively, together representing . % of the number of cases nationally. because of occupancy pressures on isolation facilities, most nigerian cities have erected makeshift isolation and treatment facilities for patients who have tested positive, to supplement the few facilities that were available at the start of the pandemic. these new facilities often lie outside hospitals that manage their own wastewater. the same pressures on treatment facilities mean that sars-cov- -infected persons in nigeria are discharged as soon as two consecutive respiratory swabs test negative: symptom free but likely shedding the virus when they return to their communities. other factors could additionally combine to alter the risk of feco-oral sars-cov- transmission. in kathmandu, nepal, where salmonella enterica typhi and paratyphi have been shown to leach into the municipal water system, breaches occur more heavily during the rains. we note that african countries on the upswing of their covid- epidemics are just beginning the rainy season. rainy season sewage overflows can overwhelm even properly managed wastewater plants, leading to heightened enteric virus transmission. on the other hand, it is possible that only very high counts of sars-cov- would yield orally infectious doses. thus, feco-oral transmission may only occur when the epidemic reaches an as yet unknown threshold. either way, those at risk within those settings are poor urban communities and informal settlements, which have the worst sanitation options and access to health care. individuals could become infected even if they were able to implement physical distancing recommendations, which themselves are a challenge, and need to be decisively protected from fecal sars-cov- . possible options for halting feco-oral sars-cov- transmission are disinfection of known open defecation sites, intensifying handwashing messages, encouraging boiling or chemical treatment of household water, and explicitly treating waste from isolation and treatment facilities. safer sewage management should be instituted or reinstituted, as priority where possible. these include ensuring that standard operating procedures are followed, and there are no interruptions in sewage decontamination, as well as quality assurance to ensure that decontamination goals are met. stalled or slowed sanitation projects should be expedited, and new ones could be explored. individuals who have to work in or close to wastewater handling facilities, particularly those operating suboptimally, should be informed of their risk and provided with protection where feasible. in those situations, as research from the sars outbreak demonstrated, aerosolized virus poses a risk for respiratory transmission in addition to any feco-oral risk that may exist. , on the positive side, fecal shedding of sars-cov- can be exploited for community surveillance of wastewater or human waste using similar methods that would be required for risk evaluation. , enteric pathogen, polio, and antimicrobial resistance environmental surveillance could be leveraged, where these have been initiated, , , but sites with no access to sewerage, typically not used for surveillance, must also be included. in high-risk settings, waste and wastewaterbased epidemiology could help balance sampling biases inherent in case-and contact-tracing-based human testing for covid- and consequently predict prevalence. , it would also preemptively identify epidemic foci and ascertain the exact risk of community transmission via the fecal-oral route. indeed, it could represent a dedicated strategy to protect the poor and marginalized in whom outbreaks in this pandemic have typically been detected with significant lags. although sanitation shortfalls risk sars-cov- feco-oral transmission much is focused on the current emergency, the potential risk from feco-oral sars-cov transmission should motivate and even initiate concrete steps toward lasting wastewater and sewage systems wherever possible. this would leave a post-covid- development legacy that could impact disease transmission, extend the value of other disease control strategies, and improve the quality of life in the long term. sars-cov- productively infects human gut enterocytes the presence of sars-cov- rna in the feces of covid- patients characteristics of pediatric sars-cov- infection and potential evidence for persistent fecal viral shedding who, . modes of transmission of virus causing covid- : implications for ipc precaution recommendations: scientific brief prolonged presence of sars-cov- viral 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transmission of the severe acute respiratory syndrome virus environmental transmission of sars at amoy gardens leveraging africa's preparedness towards the next phase of the covid- pandemic global monitoring of antimicrobial resistance based on metagenomics analyses of urban sewage pathogen surveillance in the informal settlement, kibera, kenya, using a metagenomics approach letter to the editor: wastewater-based epidemiology can overcome representativeness and stigma issues related to covid- the moment to see the poor impact of rotavirus vaccination varies by level of access to piped water and sewerage: an analysis of childhood clinic visits for diarrhea in peru sanitation shortfalls risk sars-cov- feco-oral transmission key: cord- -gyvvcnuf authors: fallahi, hamid reza; keyhan, seied omid; zandian, dana; kim, seong-gon; cheshmi, behzad title: being a front-line dentist during the covid- pandemic: a literature review date: - - journal: maxillofac plast reconstr surg doi: . /s - - - sha: doc_id: cord_uid: gyvvcnuf coronavirus is an enveloped virus with positive-sense single-stranded rna. coronavirus infection in humans mainly affects the upper respiratory tract and to a lesser extent the gastrointestinal tract. clinical symptoms of coronavirus infections can range from relatively mild (similar to the common cold) to severe (bronchitis, pneumonia, and renal involvement). the disease caused by the novel coronavirus ( -ncov) was called covid- by the world health organization in february . face-to-face communication and consistent exposure to body fluids such as blood and saliva predispose dental care workers at serious risk for -ncov infection. as demonstrated by the recent coronavirus outbreak, information is not enough. during dental practice, blood and saliva can be scattered. accordingly, dental practice can be a potential risk for dental staff, and there is a high risk of cross-infection. this article addresses all information collected to date on the virus, in accordance with the guidelines of international health care institutions, and provides a comprehensive protocol for managing possible exposure to patients or those suspected of having coronavirus. since the first reported case in wuhan, china, in december , coronavirus disease- has widely spread to japan, korea, iran, and many european countries [ ] . the world health organization (who) declared a pandemic in march . as saliva is a main tool of spread, dentists are in danger of contracting covid- . although the exact nature of this disease must be clarified in detailed studies, current knowledge of coronavirus infection should be shared without any restrictions. this article was written by an iranian team of oral and maxillofacial surgeons. as iran has many covid- patients, they have significant experience with this disease. maxillofacial plastic and reconstructive surgery is an open-access journal, and this type of important information can be shared via our publication platform without restrictions. coronaviruses are enveloped viruses with a positivesense single-stranded rna genome. their helical symmetry nucleocapsid is approximately - kb in size, making it the largest investigated genome among rna viruses [ , ] . coronaviruses have a fundamental resemblance in their organization and genome expression [ ] . previously, it was thought that coronaviruses only cause enzootic infections in a number of animals, including certain birds and mammals, but recent findings indicate that a variety of these viruses, including antigenic groups ( e and nl ), antigenic groups (oc ), and hku , can infect humans [ , ] . these viruses often lead to upper respiratory tract infection, frequently resulting in common cold symptoms. three specific strains of these viruses that are of zoonotic origin, including severe acute respiratory syndrome coronavirus (sars-cov), middle east respiratory syndrome coronavirus (mers-cov), and novel coronavirus ( -ncov), have recently caused lethal infections in humans [ , , ] . coronavirus infections in humans mainly affect the upper respiratory tract and to a lesser extent the gastrointestinal tract. manifestations of coronavirus infections can range from relatively mild (similar to the common cold) to severe (bronchitis, pneumonia, and renal involvement) [ ] (table ) . the ability to infect humans is mainly due to the infection of peridomestic animals, which are considered intermediate hosts, nurturing recombination and mutation events as well as the development of genetic diversity among coronaviruses [ ] . studies have suggested that the spike glycoprotein (s glycoprotein) plays an important role in host range restriction by attaching virions to the host cell membrane [ ] . generally, coronaviruses primarily replicate in the respiratory and intestinal epithelial cells and subsequently cause cytopathic alterations [ ] . since december , numerous unexplained cases of pneumonia have been reported in china. the disease caused by -ncov was called covid- by the who in february [ ] . limiting the exposure of suspicious cases to the rest of society could be an effective strategy in the early outbreak phases. however, the subsequent worldwide virus spread and person-to-person transmission made the situation more complex and uncontrollable [ ] . no detailed studies have been conducted to expound the pathogenicity of -ncov on a molecular scale. however, exploratory data established via whole-genome sequencing and subsequent bioinformatics analyses revealed that -ncov is phylogenetically related to sars-cov that was isolated for the first time in chinese horseshoe bats between and [ ] [ ] [ ] . to a large extent, the clinical similarities of -ncov infection with sars-cov infection are substantial. the incubation period of -ncov has been estimated to be - days, and it has been shown that asymptomatic individuals may also be involved in the spread of this virus [ ] [ ] [ ] . since the possibility of the transmission from asymptomatic carriers has been raised currently, checking body temperature only may not be enough to screen asymptomatic carriers. according to a recent report, temperature-based screening in the airport can detect only % of -ncov carriers and the others were found during the self-isolation period after immigration [ ] . to suppress the disease spread, a wide range of laboratory tests for immigrants and general population seems to be necessary. however, the infection rate from asymptomatic carriers has not been clarified until now. the primary non-specific reported symptoms of -ncov infection at the prodromal phase are malaise, fever, and dry cough. the most commonly reported signs and symptoms are fever ( %), cough ( %), dyspnea ( %), and myalgia or fatigue ( %) [ , ] . unlike patients with other human coronavirus infections (such as sars-cov), upper respiratory tract and intestinal manifestations such as sore throat, rhinorrhea, and diarrhea in those with -ncov infection are infrequent [ , , ] (fig. ). the patient mean age is generally between and years. studies have shown that males are more likely to have this infection [ , , ] . the lack of serious illness in youngsters is a characteristic of sars-cov infection, which is similarly observed in -ncov infection [ ] . increased exposures to -ncov due to occupational requirements, for instance health care workers, maybe another factor contributing to the higher risk of infection. following the outbreak, the full -ncov genomic sequence was released in public databases [ ] . this facilitates the way for further pcr assays for virus detection. the who recommendations for outpatient cases and patients with more critical conditions respectively include rapid collection and nucleic acid amplification testing (naat) of respiratory samples including nasopharyngeal and oropharyngeal swabs as well as sputum and/or endotracheal aspirate or bronchoalveolar lavage [ ] . table presents recommended instructions that all practitioners in the field of dental care, including dentists, assistants, and others, should consider when treating patients or those suspected of having coronavirus. protocol figure shows a protocol that can organize our approach to managing suspected or infected patients. the purpose of this protocol is to protect the entire dental care team, prevent any cross-infection in the office, inform health authorities active in the field of controlling and managing the disease, and ultimately provide the optimal medical and dental care for patients affected by the virus according to the cdc and the ada guidelines. the two main routes known for -ncov transmission include ( ) direct transmission (through coughing, sneezing, and inhalation of droplets) and ( ) contact transmission (through contact with nasal, oral, and ocular mucosa) [ ] . typical clinical manifestations of covid- do not comprise ocular symptoms. however, conjunctival sample analysis has revealed that the transmission of -ncov is not limited to the respiratory tract route [ ] , but ocular exposure is also an effective method of virus transmission [ ] . moreover, studies have revealed that via direct/indirect contact or course and/or droplets, respiratory viruses such as -ncov may be transmitted from human to human. studies have also shown direct and indirect transmission of -ncov through saliva [ ] . for a comprehensive understanding of the transmission dynamics of -ncov, it is also important to know that this virus is also transmissible through asymptomatic patients [ ] . the remarkable feature of -ncov is that its rna is detectable via quantitative reverse transcriptase polymerase chain reaction (qrt-pcr) in stool samples after the first week of infection [ ] . however, the aerosol and fecal-oral transmission routes, which carry more public concern, still need further investigation and confirmation [ ] (fig. ) . new evidence suggests that -ncov may be transmitted directly from human to human via respiratory secretion containing droplets [ , ] . virus transmission through contact and fomites is also likely [ , ] . to et al. [ ] reported that using the viral culture [ ] . since -ncov effectively uses ace receptor for cell invasion, it can promote human-tohuman transmission [ ] . ace + cells are abundantly present all over the respiratory tract. ace + epithelial cells present in the salivary glands were considered one of the main targets of sars coronavirus infection. similarly, -ncov may also use the same mechanism to induce infection, although definitive judgment regarding this issue needs further study [ ] . due to close face-to-face contact with patients and frequent utilization of sharp devices, dental personnel are repeatedly exposed to respiratory tract secretions, blood, saliva, and other contaminated body fluids and are always at risk for -ncov infection. -ncov transmission in dental settings occurs through four major routes: ( ) direct exposure to respiratory secretions containing droplets, blood, saliva, or other patient materials; ( ) indirect contact with contaminated surfaces and/or instruments; ( ) inhalation of suspending airborne viruses; and ( ) mucosal (nasal, oral, and conjunctival) contact with infection-containing droplets and aerosols that are propelled by coughing and talking without a mask [ ] [ ] [ ] [ ] [ ] (fig. ) . the most important concern in dental clinics is the transmission of -ncov via droplets and aerosol because, despite all of the precautions taken, it is almost impossible to reduce droplet and aerosol production to zero during dental procedures [ ] . dental handpieces utilize high-speed gas to rotate with running water, which leads to the generation of a considerable amount of droplets and aerosol mixed with patients' saliva and/ or blood [ ] . therefore, it can be deduced that -ncov is capable of transmitting through dental practice; this transmission can be from patients to clinic staff or other patients at the clinic [ ] . research has shown that coronaviruses can remain on metal, glass, and plastic surfaces for several days [ , ] . therefore, as surfaces in dental clinics serve as venues for droplets and aerosol mixed with patients' saliva and/ or blood, they can effectively help spread infection. coronaviruses can actively maintain their virulence at room temperature from h up to days. their activity at % humidity was significantly higher than %. therefore, in the dental environment, it seems that keeping surfaces clean and dry will play a significant role in preventing -ncov transmission [ ] . table standard precautions based on cdc and ada guidelines for dentists on the coronavirus disease [ ] [ ] [ ] postponing following the announcement of disease outbreak by international or local authorities, dentists can play a significant role in disrupting the transmission chain, thereby reducing the incidence of the disease by simply postponing all non-emergency dental care for all patients. where to treat all dental care should be provided in an outpatient dental setting with a minimum of six air changes per hour, such as a hospital with dental care services or customized clinics equipped for covid- patients. primary non-specific reported symptoms of -ncov infection at the prodromal phase are malaise, fever, and dry cough. the most commonly reported signs and symptoms are fever ( %), cough ( %), dyspnea ( %), and myalgia or fatigue ( %). they also may have traveled to one of the countries considered disease hotspots in the prior days or have encountered people from those countries or people who have traveled to those countries. some patients may be asymptomatic or have unexpected symptoms such as diarrhea. since it is not possible to know the etiology of each patient's illness, it is crucial to follow the guidelines and precautions at all times during the disease outbreak. be alert, identify patients with respiratory illnesses, and provide them a disposable surgical face mask. isolate them in a room with the door closed. limit their direct contact with others. isolated patients must wear masks outside their room. isolate suspected patients before and during care to minimize their direct contact with other patients and staff and immediately report any cases to local and state public health authorities. to prevent -ncov transmission, dental practices should adhere to the infection control protocol, including hand hygiene, providing tissues and no-touch receptacles, and providing face masks for coughing patients. dental health care personnel should wear white coats, gowns, head caps, goggles, face shields, masks, latex gloves, and impermeable shoe covers to prevent exposure. disposable masks should be substituted between patients or even during treatment if they get wet. since covid- recommendations may change rapidly with increasing information about the disease, the ada recommends checking for updates on the cdc's coronavirus infection control web page for health care professionals. the cdc strongly recommends that all health care staff, including dentists and personnel, should receive the flu vaccine and that staff with influenza must not report to work. since the fecal-oral route is considered one of the -ncov transmission routes, attention to hand hygiene before, during, and after dental practice is important. dentists should exercise extreme caution to avoid contact with their own facial mucosal surfaces including their eyes, mouth, and nose. since transmission of airborne droplet is considered one of the main routes of infection spread, application of personal protective equipment such as masks, protective goggles, gowns, helmet, gloves, caps, face shields, and shoe covers is strongly recommended for all health care personnel. covid- patients should not be treated in a regular dental care setting without special considerations. unexpected circumstances may occur when the dentist cannot delay treatment or refer the patient to the appropriate medical institution. under such circumstances, special protective clothing such as hazardous materials (hazmat) suits are required. if hazmat suits are not available, white coats, gowns, head caps, protective eyewear, face shields, masks, latex gloves, and virus-proof shoe covers should be used [ ] . the effect of chlorhexidine, which is commonly used for pre-procedural mouth washing in dental practice, has not yet been demonstrated to be capable of eliminating -ncov. however, oxidative agents containing mouth rinses with % hydrogen peroxide or . % povidone-iodine are recommended. pre-procedural use of mouthwash, especially in cases of inability to use a rubber dam, can significantly reduce the microbial load of oral cavity fluids [ ] . using rubber dams due to the creation of a barrier in the oral cavity effectively reduces the generation of droplets and aerosol mixed with patient saliva and/or blood in m diameter of the surgical field by % [ ] . following the placement of the dam, extra high-volume suction is also required for maximum prevention of aerosol and spatter from spreading [ ] . if it is not possible to use rubber dams for any reason, manual tools such as carisolvs or hand scalers are preferable. throughout the covid- pandemic, the use of any dental handpieces that do not have an anti-retraction function should be avoided. for emergency treatment, anti-retraction handpieces designed with anti-retractive valves can play an effective role in preventing the diffusion and dispersion of droplets and aerosol [ , ] . since there is still little information available regarding -ncov, relatively similar genetic features between -ncov and sars-cov indicate that the novel coronavirus can be vulnerable to disinfectants such as sodium hypochlorite ( ppm or . % for surfaces and , ppm or % for blood spills), . % hydrogen peroxide, - % ethanol, and phenolic and quaternary ammonium compounds if utilized in accordance with the manufacturer's instructions. studies show that other biocidal agents such as . - . % benzalkonium chloride or . % chlorhexidine digluconate probably have lower efficiency. in addition to the type of disinfectant, paying attention to other factors such as the duration of use, dilution rate, and especially the expiration time following the preparation of the solution according to the manufacturer's instructions is also crucial. prior to any inappropriate accumulation, dental office waste should be routinely transported to the institution's temporary storage facility. reusable tools and equipment must be properly pre-treated, cleaned, sterilized, and properly stored until the next use. dental waste resulting from the treatment of suspected or confirmed -ncov patients is considered medically infectious waste that must be strictly disposed of in accordance with the official instructions using double-layer yellow medical waste package bags and "gooseneck" ligation. following the announcement of the disease outbreak by international or local authorities, dentists can play a significant role in disrupting the transmission chain, thereby reducing the incidence of disease by simply postponing all non-emergency dental care for all patients. dental professionals must be fully aware of -ncov spreading modalities, how to identify patients with this infection, and, most importantly, self-protection considerations. the effect of chlorhexidine, which is commonly used for preprocedural mouth washing in dental practice, has not yet been demonstrated to be capable of eliminating -ncov. however, the prescription of oxidative agents containing mouth rinses such as % hydrogen peroxide or . % povidone is recommended. a higher rate of virus exposure because of occupational commitments in health care workers is considered a key factor associated with the increased risk of infection. yen my et al asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus (sars-cov- ): facts and myths homology-based identification of a mutation in the coronavirus rnadependent rna polymerase 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overview and comparison with other emerging viruses transmission of blood-borne pathogens in us dental health care settings: update aerosols and splatter in dentistry: a brief review of the literature and infection control implications transmission routes of -ncov and controls in dental practice transmission of sars and mers coronaviruses and influenza virus in healthcare settings: the possible role of dry surface contamination transmission routes of -ncov and controls in dental practice office of state administration of traditional chinese medicine. notice on the issuance of a program for the diagnosis and treatment of novel coronavirus ( -ncov) infected pneumonia (trial version ) the efficacy of rubber dam isolation in reducing atmospheric bacterial contamination severe acute respiratory syndrome and dentistry: a retrospective view publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations maxillofacial plastic and reconstructive surgery prof. esmaeil yazdi passed away due to coronavirus infection few days ago. he was one of the iranian society of omfs founder years ago. the authors send sincere condolence to his family and colleagues. the authors also appreciate his great contribution on the progress of maxillofacial surgery. the article was written by hrf and bc. dz collected the data. illustrations were drawn by sok and bc. sok and ksg corrected the article and performed the critical review. the authors read and approved the final manuscript. not applicable.availability of data and materials not applicable.ethics approval and consent to participate not applicable. consent for publication not applicable. the authors declare that the authors have no competing interests as defined by nature research or other interests that might be perceived to influence the results and/or discussion reported in this paper. key: cord- -dq xu c authors: poutanen, susan m.; mcgeer, allison j. title: transmission and control of sars date: journal: curr infect dis rep doi: . /s - - - sha: doc_id: cord_uid: dq xu c severe acute respiratory syndrome (sars) was first recognized in china in november and was subsequently associated with a worldwide outbreak involving people, of whom died. the outbreak was declared contained on july , , after the last human chain of transmission of sars had been broken. whether outbreaks of sars will return is debatable, but no one disagrees that it is important to be prepared for this possibility. this article presents an overview of the transmission and control of sars based on the current state of knowledge derived from published studies of the outbreak and on our own personal experience. severe acute respiratory syndrome (sars) was recognized in march as a global threat after first appearing in china in november [ ] . an outbreak followed, spanning countries and involving people, of whom died [ ] . health care workers represented % of cases overall and up to % in some countries. on july , the world health organization declared the outbreak contained [ ] . since then, in september and december , two isolated cases have been reported in researchers in singapore and taiwan working in laboratories culturing sars-associated coronavirus (cov), the newly discovered coronavirus identified as the cause of sars [ , ] . in addition, four isolated cases with relatively mild symptoms and no evidence of secondary transmission have been identified in individuals in china in december and january [ , ] . increasing evidence suggests that sars-cov originated from interspecies transmission of a sars-cov-related virus from animals to humans, with the himalayan palm civet being one of the most likely animals involved [ ••, •, ] . genotypic analysis of sars-cov strains from the recent outbreak reveals that genotypes from persons affected early in the outbreak are more similar to animal sars-cov-related viruses than genotypes from persons affected in the middle and later parts of the outbreak. the genotype changes are consistent with positive selective pressures resulting eventually in stabilization and emergence of a predominant genotype [ ••] . genotypic analysis of the virus involved in one of the recent isolated cases of sars identified in china reveals that it is much more closely related to the sars-cov-related virus of palm civets than any human sars-cov detected in the previous outbreak [ ••] . this finding, with seroprevalence data revealing that a small proportion ( . %) of healthy persons in hong kong had been exposed to sars-cov-related viruses at least years before the recent sars outbreak [ •] , suggests that occasional human infection with animal sars-cov-related viruses may have occurred undetected for years before the outbreak and may continue to occur. unlike the outbreak sars-cov virus, animal sars-cov-related viruses may not have the same propensity to cause severe human disease and may not be able to be transmitted from human to human. further investigation is needed to understand the circumstances that permitted the selective adaptation and purification processes that resulted in the evolution of the sars-cov outbreak strains. whether sars outbreaks will return is debatable [ ] [ ] [ ] . the most likely source of individual human cases is research laboratories that work with live sars-cov. however, appropriate biosafety measures should minimize this risk, and awareness of this risk should permit early detection of cases and implementation of control measures so that transmission, if it occurs, should be limited. the most likely source of outbreaks is the replication of the event(s) that resulted in the evolution of the sars-cov outbreak virus from animal sars-cov-related virus. the existence of human or animal reservoirs of the outbreak sars-cov virus has been postulated, but is extremely unlikely [ ] . although it is unclear whether new outbreaks of sars will occur, it is important to be prepared for the possibility that they will. indeed, much research is ongoing, optimizing diagnostic tests, treatments, and vaccination directed at sars, and vigilant surveillance is being completed worldwide. part of this preparation includes understanding the timing and modes of transmission of sars, and the strategies that allowed for the effective control of the outbreak. during the outbreak, it was evident that sars was readily transmissible from person to person, especially in health severe acute respiratory syndrome (sars) was first recognized in china in november and was subsequently associated with a worldwide outbreak involving people, of whom died. the outbreak was declared contained on july , , after the last human chain of transmission of sars had been broken. whether outbreaks of sars will return is debatable, but no one disagrees that it is important to be prepared for this possibility. this article presents an overview of the transmission and control of sars based on the current state of knowledge derived from published studies of the outbreak and on our own personal experience. care facilities. however, how transmissible, for what period, and by which modes was unclear. since the outbreak, much effort has been placed on better understanding these issues. the incubation period of sars is to days, with a mean of to days [ •] . outliers include a small proportion (< %) of cases with incubation period as short as day and as long as days [ •] . there is no evidence of communicability before symptom onset, and transmission is infrequent during the first few days of illness. risk for transmission appears to be greatest in patients who are most severely ill and peaks during the second week of illness, corresponding with the timing of peak viral load [ •, ] . most countries considered sars patients to be potentially infectious until days after resolution of fever and signs of clinical improvement, and isolation precautions were not discontinued until this occurred. there is no evidence of transmission from anyone treated in this manner, and it is possible that isolation for a shorter time period would be sufficient. despite the absence of transmission, sars-cov viral rna remained detectable in respiratory secretions and stool and urine specimens for more than days in some patients [ ] . this may be explained by the fact that viral rna does not necessarily correlate with the presence of viable virus; indeed, positive viral cultures were noted predominantly in the first weeks of illness, with no positive cultures after the third week of illness [ ] . there is no evidence of relapse of sars-cov infections. sars-cov has been detected in respiratory specimens, stool, and to a lesser extent, in blood, urine, and conjunctival secretions [ ] . respiratory droplet and direct contact are the primary modes of sars transmission. evidence for this includes studies in hong kong and toronto, canada that show an increased risk for sars in health care workers who entered the room of a patient with sars, with increasing risk in those with closer proximity to the patient and those remaining in the room for a longer duration, suggesting that transmission is enhanced by close, prolonged contact [ •, •] in addition, an increased risk in household members of patients with sars has been shown in those who had close, prolonged contact with the index person, and in particular, in those who shared a bed, reported being within meter of the index person, and dined together [ •] . increasing risk was noted as the duration of time the symptomatic index patient spent at home increased. exposure to respiratory secretions appears to pose a particular risk, with higher risks for sars noted in health care workers who assisted with intubation, suctioned before intubation, manipulated oxygen masks, or were present during noninvasive ventilation of a sars patient for more than minutes [ •, •] , in addition to higher risks being noted in household members of sars patients who were coughed at by the index person within meter [ •] . a summary of the results of these studies is outlined in table . whether exposure to fecal material poses a particular risk has not been as well-documented. however, given the high proportion of stool samples positive for sars-cov by molecular tests (up to % in some studies), one can propose that transmission through stool is likely [ •] . although no study has documented the role of fecal-oral transmission, fecal droplet transmission was thought to have played a significant role in the amoy gardens community outbreak in hong kong. fecal droplets were thought to have resulted from unsealed floor drain traps that permitted an open connection to the soil stack. widespread transmission of these droplets was thought to have resulted from the temporary shutdown of the flush water system, powerful room exhaust fans, and a building layout permitting exhausted droplets to re-enter the building at other locations [ ] . the extent to which fomites play a role in the transmission of sars through indirect contact also is unclear. although there is no evidence to suggest that fomites played a significant role in the recent outbreak, the fact that sars-cov is able to survive up to days at room temperature on several inanimate surfaces suggests that this mode of transmission is possible [ ] . evidence to support this includes a study in hong kong in which self-reported inconsistent hand hygiene practices were associated with an increased risk for sars among health care workers who reported no contact with patients (odds ratio = . [ . - . ]; p = . ) [ • ]. in addition, in the amoy gardens outbreak, lack of household disinfection was associated with an increased risk in household members of patients with sars [ • ]. in addition to droplet and contact transmission, limited evidence suggests that airborne transmission may occur on occasion. the studies that suggested this possibility describe specific sars clusters in which the pattern of transmission for a subset of individuals cannot be explained by droplet or contact transmission. for example, in a study assessing medical students exposed to a single patient, four students who were not within the -feet droplet risk zone [ ] from the patient acquired sars [ •] . in an investigation of a nosocomial outbreak in toronto, one health care worker who had not worked in the index patient's room acquired sars [ •]. on a flight carrying a symptomatic person with sars, % of the persons who became ill were seated more then feet away from the index patient [ ] . although all of these examples are consistent with possible airborne transmission, alternate explanations implicating indirect contact transmission or unrecognized exposures also are possible. in addition, one can postulate that an enhanced droplet transmission mechanism exists in which droplets are capable of being transmitted beyond the traditional -feet radius from the index patient but are incapable of traditional airborne transmission. particularly worrisome during the outbreak were reported scenarios in which transmission occurred despite the use of droplet, contact, and airborne precautions. for example, a nurse who was wearing an n respirator, two sets of gowns and gloves, safety glasses, a face shield, hair cover, and shoe covers acquired sars after providing bagvalve-mask ventilation to a patient with sars [ ] . in addition, at least two health care workers using n equivalent respirators, gown, gloves, and safety glasses, with or without a face shield, acquired sars after assisting in the provision of noninvasive ventilation and a difficult intubation of a patient with sars complicated by copious frothy secretions [ ] . common factors in these scenarios include being involved in a procedure that has the potential to generate aerosols (eg, noninvasive ventilation, intubation) that is being performed on severely ill patients and requires close contact with the patient in the context of using n or n equivalent respirators that were not fittested. potential explanations for the through-precautions transmission seen in these scenarios include the possibility of unrecognized breaches in precautions, contamination upon removal of precautions, or an airborne viral load high enough to overwhelm the non-fit-tested n or n equivalent respirators used. whether n respirators require fit-testing in order to be effective in reducing airborne transmission has not been studied in the clinical setting. although the united states has supported fit-testing for all n respirators since , other countries such as canada have only done so in response to sars and specifically in response to the through-precautions transmission scenarios described earlier [ ] . further study is needed to definitely determine the role of fit-testing in preventing air-borne transmission and to better understand the mechanisms responsible for through-precautions transmission. based on analyses of the outbreaks in hong kong and singapore, the basic reproduction number for sars, r o , defined as the expected number of secondary infectious cases generated by an average infectious case in an entirely susceptible population, is estimated between . and . [ , ] . this is consistent with an infectious disease spread by contact or droplet transmission [ •] . the relatively fast decrease in the effective reproduction number, r t , to less than noted after implementation of control measures, is suggestive of an infectious disease with relatively low efficiency in transmission that is readily controlled [ ] . data from recent seroprevalence studies support this showing that in typical situations relatively few people with exposure to patients with confirmed sars-cov infection actually became infected. for example, typical attack rates among health care workers in hospital settings who used no protection or inconsistent protection ranged from % to . % [ ] [ ] [ ] [ ] . typical attack rates in household settings ranged from . % to % [ •, ] . typical attack rates on flights were % to . % [ , ] , and no significant transmission was seen with casual contact in the community setting [ ] . however, notable exceptions to this typical transmissibility are so-called superspreading events, in which transmission of sars-cov was shown to be highly efficient, with attack rates as high as % on one flight [ ] and % [ ] and % [ •] in some hospital settings. for example, in guangzhou, the index patient was shown to transmit sars to other individuals, with an associated large cluster of secondary infections giving rise to the outbreak in guangzhou [ ] . in singapore, multiple superspreading events were described at the beginning of the outbreak, with one individual responsible for at least other cases of sars through direct contact [ ] . in canada, superspreading events also were described in the index hospital in toronto, with one patient directly responsible for other cases of sars and with attack rates among exposed staff as high as % [ ] . it has been proposed that the presence of a superspreading event was likely the dominant factor influencing which countries were significantly involved in the recent worldwide outbreak [ • ]. there is a limited understanding of what causes superspreading events, but it is generally believed that a combination of host, environment, and virus interactions is involved. host factors, such as age, underlying illness, and increased severity of sars symptoms may be associated with increased viral shedding, permitting more efficient transmission. shen et al. [ •] have shown that cases associated with superspreading in beijing were more likely to be older patients with high case fatality rates. increased opportunity for exposure through increased interaction with patients (such as that which typically occurs in hospitals settings) may further aid transmission. this is confirmed in the study by shen et al. [ •] , which showed that superspreading patients in beijing were more likely to have higher numbers of close contacts than were patients unassociated with superspreading. although association with aerosol-generating procedures was not seen in beijing, it has been proposed as an alternate explanation that may further facilitate transmission in superspreading events. inadequate infection control precautions also may be partly responsible, and after the implementation of control measures in beijing, superspreading events were greatly reduced [ •] . whether strain variations in sars-cov or coinfections with other organisms might play a role in these situations has not been fully assessed. superspreading events are not unique to sars but also have been described with other diseases such as ebola, rubella, and measles [ •, ] . additional investigation is needed to further understand the role of various determinants of superspreading events in sars. control of sars depends on the rapid identification of cases and early implementation of control measures such as isolating the patient, using appropriate personal protective equipment, contact tracing, and possibly implementing quarantine. community measures, such as travel restriction and airport screening, also were implemented in the recent outbreak and may play a role in the event of a larger outbreak. implicit in these measures is the need to educate health care workers in addition to the general public. a general paradigm shift regarding how one approaches potentially infectious persons is needed given the ongoing threat of emerging infectious diseases such as sars. in order to identify cases early in the course of a patient's illness, implementation of surveillance programs is needed at the hospital and community level. given the uncertainty as to whether sars will return and the costs associated with implementing surveillance programs, surveillance efforts ideally would not be restricted to sars but would be incorporated into general surveillance efforts for other potentially communicable infectious diseases, which are already in place in most institutions and community settings. surveillance for sars is complicated because clinical features alone cannot distinguish sars from other respiratory infections or from the many possible explanations for fever and pulmonary infiltrates in patients with multiple comorbidities. surveillance is further complicated because adequately sensitive rapid diagnostic tests are unavailable early in the disease [ ] . thus, surveillance for sars should rely on screening for patients who have compatible clinical features in the context of potential sars-cov exposure. epidemiologic risks to consider include: exposure to settings where sars activity is suspected or documented; a person with an epidemiologic link to a cluster of persons with unexplained respiratory illness, especially when such a cluster occurs within a single health care facility setting; a health care worker with direct patient-care responsibilities; or a laboratory worker in a laboratory that contains live sars-cov [ ••] . upon identification of possible cases of sars on the basis of these clinical and epidemiologic factors, appropriate infection control precautions should be initiated and laboratory testing for sars and alternative diagnoses that might explain the illness should be completed. infection control precautions should be continued until sars has been ruled out or alternative diagnoses have been identified that fully explain the patient's symptoms. updated infection control practice recommendations for use with patients with possible or confirmed sars are available [ ••] . as evidence accumulates regarding the effectiveness of infection control measures used in the recent outbreak, revisions of these recommendations are being made. a summary of some of the most informative studies regarding effectiveness of specific infection control precautions is presented here and outlined in table . seto et al. [ • ] completed a case-control study involving health care workers, of whom acquired sars, from five hong kong hospitals. they noted that the risk for acquiring sars after direct care of a patient with sars was significantly reduced with the use of n respirators or surgical masks and gowns, and hand-washing. multivariate analysis revealed masks (n respirators or surgical masks) to be the only significant protective measure. the authors contend the fact that surgical masks and n respirators were effective, with the finding that % of noninfected staff did not use masks of any type, supports that transmission is not typically airborne. loeb et al. [ • ] completed a retrospective cohort study among nurses, eight of whom acquired sars after working in one of two toronto critical care units with sars patients. they noted that the consistent use of n respirators was significantly more protective than was not wearing a mask. the consistent use of surgical masks also reduced the risk, but not significantly. n respirators appeared to reduce the risk more than did surgical masks, but not significantly. the use of gowns and gloves was not shown to significantly reduce the risk for sars. lau et al. [ • ] completed a case-control study involving heath care workers with sars and matched controls from hong kong. they noted that transmission of sars occurred despite almost all of the study respondents using n respirators or masks when providing direct care for patients with sars, suggesting that masks were not sufficient to prevent transmission of sars. the use of gloves, gowns, goggles, and caps was significantly associated with a reduced risk for acquiring sars, but the high degree of collinearity in the use of these precautions made it difficult to ascertain which measure was most important. other findings included an increased risk for sars among health care workers who perceived there to be an inadequate supply of personal protection equip-ment and among those who received less than hours of sars infection control training. based on these studies and on the fact that the patterns of transmission of sars suggest droplet and contact modes of transmission, one can suppose that isolating patients with sars and implementing droplet precautions using surgical masks and contact precautions for all persons interacting with them are likely sufficient to prevent the transmission of sars from these patients to others. however, despite the lack of definitive studies showing an involvement in transmission through fomites, routine environmental cleaning and disinfection also should be completed; % sodium hypochlorite, % ethanol, and % phenol have all been shown to inactivate sars-cov within minutes [ ] . in addition, because of potential for possible airborne transmission associated with aerosolgenerating procedures and because airborne transmission cannot be ruled out altogether in some cases occurring in the recent outbreak, the use of n respirators and negative pressure rooms (when available) is likely prudent until further studies better define the role of possible airborne transmission. whether n respirators require fit-testing needs further study, as described earlier. in addition to the protective measures described earlier, given the reported cases of through-precautions transmissions, additional measures to reduce the opportunity of transmission also should be enforced. these include minimizing the number of health care workers and visitors permitted in the patient's room, minimizing the time spent by health care workers and visitors in the room and specifically minimizing the time spent in close contact with the patient, keeping to the side of the patient (out of direct droplet range), only having the most experienced personnel perform procedures on the patient, providing adequate medication to suppress cough and vomiting with the goal to minimize droplets produced from the patient, and avoiding transporting patients with sars when possible. furthermore, ensuring an adequate supply of protective equipment and providing intense training with regard to its appropriate use is important, as documented by lau et al. [ •] . an additional component to controlling the spread of sars is tracing all close contacts of symptomatic sars patients, isolating those who are symptomatic, and quarantining those who are asymptomatic for the -day incubation period after their exposure. such measures were instituted in many of the countries involved in the recent outbreak, including china, taiwan, hong kong, singapore, and canada. however, given the limited understanding of transmission that existed at the beginning of the outbreak, in some areas of the world close and remote contacts of symptomatic and asymptomatic patients with sars were quarantined, as opposed to limiting quarantine to only close contacts of symptomatic patients with sars, who are now appreciated as being the only contacts that have significant risk for acquiring the disease. in taiwan, by the end of the epidemic, , people had been placed in quarantine, with failure to comply punishable by fines of $ to $ and incarceration of up to years [ ] . in beijing, approximately , residents were quarantined in their homes or quarantine sites [ •] . these numbers would be lower had quarantine been limited to only close contacts of symptomatic cases. in beijing, by limiting quarantine in this way, the number of persons quarantined would have been reduced by approximately % [ •] . typically, quarantined persons were asked to stay where they were quarantined, wear surgical masks when near others, take their temperature two to three times a day, and seek medical attention promptly if they developed fever (≥ ° c) or other symptoms compatible with sars. phone calls or visits from public health officials occurred regularly to check on the status of quarantined persons. the use of quarantine as a strategy in the control of infectious diseases is controversial given the ethical and legal issues regarding its negative associated impact on civil liberties. in addition, the effectiveness of quarantine has been questioned because of the difficulty of tracing all atrisk contacts and ensuring observance of the rules of quarantine in all quarantined persons. as a strategy in the control of sars specifically, one could argue that the effectiveness of quarantine should be further questioned given the lack of evidence of transmission during the incubation period before the onset of symptoms. however, the role of quarantine is not only to prevent transmission dur-ing the incubation period, should that be associated with a particular infection, but it also can facilitate early detection and management of symptomatic cases by enforcing compliance with reporting the onset of symptoms. in beijing, the effectiveness of quarantine is supported by the fact that no secondary transmission to relatives or other contacts was detected from any person who had sars while quarantined [ •] . analysis has shown that restricting quarantine in beijing to only those who had close contact with an actively ill patient with sars would not have compromised its effectiveness [ •] . the decision to implement quarantine needs to be made in conjunction with local public health authorities. in the event that the recognition of sars is delayed and an outbreak ensues that is not readily controllable using the aforementioned strategies alone, other additional control strategies should be considered in order to expedite control of the disease. central to this is the designation and coordination of an interdisciplinary outbreak team with excellent communication capabilities. decisions need to be made regarding implementation of more drastic control measures, such as hospital-wide screening and visitor restriction, closing hospitals, removing exposed or symptomatic groups to designated hospitals, or managing exposed or symptomatic cohorts in place. all of these strategies were used in different circumstances in singapore with positive effect [ ] . additional control measures to consider include airport screening and travel restrictions, although the usefulness of these strategies in terms of their contribution to the control of infectious diseases has not been systematically studied. sars has opened the world's eyes to the existence of emerging infectious diseases that have the capability of causing worldwide outbreaks within a relatively short span of time. given the threat of the return of sars and the ongoing threat of other emerging infectious diseases, it is prudent to consider a general paradigm shift regarding the approach to potentially infectious persons. implicit in this is the need to educate health care workers in addition to the general public. health care "new normal" directives implemented in ontario, canada that suggest addressing all patients presenting with respiratory illness as potentially infectious until proven otherwise and that reinforce that ill health care workers should stay at home until they are well are an example of the implementation of this paradigm shift [ ] . in addition, "healthy habits" posters directed at the general public and created by the us centers for disease control and prevention (cdc) in atlanta, georgia are an excellent example of the kind of basic health hygiene education that should be reinforced [ ] . in so doing, the goal is to change the way that infectious diseases are managed in health care and by the public, in order to increase the emphasis on the prevention of transmission of such diseases, with the ultimate goal of possibly averting a worldwide outbreak of the next newly emerged infectious disease. sars is a newly recognized infectious disease that caused a worldwide outbreak affecting people in countries from november through july . studies have shown that transmission occurs primarily through droplet and contact, but airborne transmission cannot be ruled out. superspreading events, although the exception to the rule, play a significant role in propagating transmission, especially in hospital settings. control depends on the identification of cases and early implementation of isolation and appropriate personal protective measures, contact tracing, and possibly the implementation of quarantine for asymptomatic contacts. these were the measures that permitted the control of the worldwide to outbreak and will hopefully prevent another outbreak from becoming as widespread, should sars re-emerge. papers of particular interest, published recently, have been highlighted as: • of importance •• of major importance world health organization: who issues a global alert about cases of atypical pneumonia world health organization: summary of probable sars cases with onset of illness from world health organization: sars: breaking the chains of transmission world health organization: severe acute respiratory syndrome (sars) in singapore--update world health organization: sars case in laboratory worker in taiwan world health organization: update --review of probable and laboratory-confirmed sars cases in southern china world health organization: new case of laboratory-confirmed sars in guangdong this is an excellent description of the molecular evolution of sars-cov based on the sars outbreak in china isolation and characterization of viruses related to the sars coronavirus from animals in southern china this is the first report of the isolation and characterization of sars-cov-related viruses from animals in southern china prevalence of igg antibody to sarsassociated coronavirus in animal traders--guangdong province, china this seroprevalence study determined that a small proportion of healthy persons in hong kong had been exposed to sars-covrelated viruses at least years before the recent sars outbreak sars--one year later why sars will not return: a polemic the big question now: will it be back? science • world health organization: consensus document on the epidemiology of severe acute respiratory syndrome (sars) this is an excellent summary of the understanding of the epidemiology of sars clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study detection of sars coronavirus in patients with suspected sars interpretation of diagnostic laboratory tests for severe acute respiratory syndrome: the toronto experience cluster of sars among medical students exposed to single patient this is a retrospective cohort study analyzing risks for transmission of sars among medical students exposed exclusively to the first sars patient in the prince of wales hospital in hong kong before his illness was recognized illness in intensive care staff after brief exposure to severe acute respiratory syndrome this is a retrospective analysis studying the risk for transmission of sars among intensive care staff after a brief unexpected exposure to a patient with sars in probable secondary infections in households of sars patients in hong kong this is a retrospective analysis describing risk factors for secondary infection occurring in households and household members of patients with sars in hong kong this is a retrospective cohort analysis describing risk factors for transmission of sars among nurses who worked in two critical care units with sars patients in toronto first data on stability and resistance of sars coronavirus compiled by members of who laboratory network sars transmission among hospital workers in hong kong this is a case-control study of hospital workers with sars and matched controls assessing risk factors for transmission of sars in hong kong guideline for isolation precautions in hospitals transmission of the severe acute respiratory syndrome on aircraft possible sars coronavirus transmission during cardiopulmonary resuscitation cluster of severe acute respiratory syndrome cases among protected health-care workers transmission dynamics and control of severe acute respiratory syndrome transmission dynamics of the etiological agent of sars in hong kong: impact of public health interventions lack of sars transmission among healthcare workers, united states lack of sars transmission among public hospital workers sars infection among health care workers in beijing, china healthcare worker seroconversion in sars outbreak secondary household transmission of sars introduction of sars in france sars transmission, risk factors, and prevention in hong kong investigation of a nosocomial outbreak of severe acute respiratory syndrome (sars) in toronto, canada this is a description of the risks associated with four superspreading sars events occurring in beijing epidemiology and cause of severe acute respiratory syndrome (sars) in guangdong, people's republic of china severe acute respiratory syndrome combining clinical and epidemiologic features for early recognition of sars this is an excellent description of a strategic framework for the early recognition of sars public health guidance for community-level preparedness and response to severe acute respiratory syndrome (sars). supplement i: infection control in heathcare effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (sars) this is a case-control study of noninfected and infected staff members from five hong kong hospitals with documented exposures to index patients with sars use of quarantine to prevent transmission of severe acute respiratory syndrome--taiwan efficiency of quarantine during an epidemic of severe acute respiratory syndrome this is a description of the efficiency effectiveness of quarantine during the sars outbreak in beijing sars transmission and hospital containment new normal" directives to healthcare facilities centers for disease control and prevention: healthy habits to stop germs at home, work and school key: cord- -ex z b authors: tupper, p.; colijn, c. title: covid- 's unfortunate events in schools: mitigating classroom clusters in the context of variable transmission date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: ex z b widespread school closures occurred during the covid- pandemic. because closures are costly and damaging, many jurisdictions have since reopened schools with control measures in place. early evidence indicated that schools were low risk and children were unlikely to be very infectious, but it is becoming clear that children and youth can acquire and transmit covid- in school settings and that transmission clusters and outbreaks can be large. we describe the contrasting literature on school transmission, and argue that the apparent discrepancy can be reconciled by heterogeneity, or ``overdispersion'' in transmission, with many exposures yielding little to no risk of onward transmission, but some unfortunate exposures causing sizeable onward transmission. in addition, respiratory viral loads are as high in children and youth as in adults, pre- and asymptomatic transmission occur, and the possibility of aerosol transmission has been established. we use a stochastic individual-based model to find the implications of these combined observations for cluster sizes and control measures. we consider both individual and environment/activity contributions to the transmission rate, as both are known to contribute to variability in transmission. we find that even small heterogeneities in these contributions result in highly variable transmission cluster sizes in the classroom setting, with clusters ranging from to individuals in a class of . none of the mitigation protocols we modeled, initiated by a positive test in a symptomatic individual, are able to prevent large transmission clusters unless the transmission rate is low (in which case large clusters do not occur in any case). among the measures we modeled, only rapid universal monitoring (for example by regular, onsite, pooled testing) accomplished this prevention. we suggest approaches and the rationale for mitigating these ``unfortunate events'', even if they are expected to be rare. coronavirus disease (covid- ) is a global pandemic caused by sars-cov- , a newly emerged respiratory virus. while covid- can be severe especially among the elderly, its impact on children and youth is relatively mild, with a very low fatality rate among children aged - years [ ] and low levels of hospitalization and severe illness compared to adults. children also comprise a lower portion of reported cases than they do of the general population in many settings, though they can get covid- and can (at low rates) suffer complications [ ] . to control the pandemic, many jurisdictions implemented widespread distancing measures including school closures, and partly as a result, despite the pandemic's global reach with over m cases worldwide [ ] at the time of writing, there remains considerable uncertainty about in contrast to the literature cited above, there have been reports of larger outbreaks and broader transmission among school-age children, particularly in jurisdictions with more community transmission at the time. in georgia, usa, an overnight camp attended by residents had a large outbreak resulting in % positivity among the tested attendees [ ] . the overall attack rate was % among those age - years and % overall, despite efforts to follow most components of the centre for disease control's risk reduction recommendations (though masks were not worn by campers and there was "vigorous singing and cheering"). % of cases for whom there was symptom data reported not having had symptoms. in israel, all school classes reopened on may , with hygiene, face masks, health checks and distancing measures in place. a high school registered two unlinked cases ten days later; subsequently, school-wide testing found students and staff members who tested positive for covid- with an additional relatives and friends ultimately infected as well [ ] . cases were most concentrated in - th grades with - % of those year groups infected), compared to . - . % among th- th grade students. nearly half of the - th grade cases were asymptomatic. classes were crowded and due to a heat wave, air conditioning was used and students were exempted from wearing masks. the age distribution of covid- cases in jerusalem also shifted, reflecting a higher portion of [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] year olds [ ] . in trois rivières, québec, despite physical distancing and other measures, of students in an elementary class contracted covid- after a student was infected in the community [ ] . also in québec, confirmed cases were found at a day camp [ ] , and subsequently caused nearly secondary cases among mainly siblings, family and friends [ ] . an outbreak in a chilean high school began shortly after the first case in chile was detected (march , ) [ ] ; by march there were two confirmed cases in the school, which was then placed in quarantine. by april , school community members had been confirmed positive and there had been one death. serology in early may found antibody positivity rates of . % among students and . % among staff (compared to much lower baseline rates in the community) [ ] . as of sept. , , covid- cases were linked to an outbreak in a canadian elementary school [ ] . a survey of school outbreaks in germany [ ] found of them between the th of january and the st of august, comprising only ( . %) of all the outbreaks in the country in that period. there were a total of cases involved, almost half of which were adults ( years or older). most of the outbreaks ( / ) had or fewer cases, though the largest had . there was no data available on the number of exposures without transmission, as an outbreak was defined by there being more than one case detected. at the population level, children have been infected with covid- , though at lower rates than adults. in the eu/eea and uk (as of july ), only % of reported cases were among those under (who comprise approximately % of the population) [ , ] . in a large spanish study, seroprevalence in children was under . % compared to . % among adults [ ] . in a large icelandic study of those at high risk, . % of children under and . % of those over tested positive [ ] . a swiss population-level study found only of children aged - year who tested positive for antibodies, suggesting a lower rate than other age groups, and did not find a lower rate in those aged - years than in the general population [ ] . in the united states (where children comprise approximately % of the population overall), as of october , , . % of overall covid- cases were in children (typically - or years) with high variability by state [ ] . states reported > % of cases among children aged - year ( - in tennessee) and two states reported under % of cases among children (typically - years in those states); in the united states schools have been closed for most of the pandemic thus far [ ] . in sweden, where elementary schools remained open, a study in may of individuals found that . % of children and teenagers and . % of adults aged - had antibodies; the relatively higher rate in children may suggest transmission in schools [ ] . recently, an analysis of over , contacts of , index cases in two states in india found enhanced transmission in similar-aged pairs, an effect that was strongest for those aged - and over [ ] . the two main public health concerns with respect to the transmission covid- among children in . 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. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . schools are i) are we endangering children, teachers and staff and families by having children together in the classroom setting? and ii) does the presence of children in the classroom accelerate the spread of the virus through the broader community? the evidence above leaves the situation unclear. large outbreaks are possible and children can transmit covid- to each other [ ] , suggesting sufficiently high transmission rates for clusters to arise. on the other hand, there are many documented cases where there is exposure with little or no transmission, suggesting that frequently transmission is very low. this apparent inconsistency matches what we know about other covid- transmission data: at one choir practice an individual infected / participants [ ] ; at another there appears to be no transmission [ ] . occasionally multiple infections occur on a single flight [ ] ; but the majority of potential exposures on planes lead to no transmission [ ] . these considerations point to covid- transmission being highly heterogeneous, or "overdispersed", a phenomenon with a building body of evidence [ , [ ] [ ] [ ] . here we use stochastic individual-based simulations to explore the implications of the above observations for control of transmission clusters in classrooms. we consider two sources of transmission heterogeneity: individual variation in infectiousness and variability in how effective a particular environment/activity combination is for transmitting covid- . we include the potential for pre-and a-symptomatic transmission and for transmission outside of an identified set of close contacts (via aerosols and/or mixing outside of the group). we explore intervention protocols in the context of this heterogeneity, comparing interventions focusing on groups of close contacts to those intervening at the whole class level, and to those using wider regular testing. we use crowdsourced data available through covidÉcoles québec [ ] to inform our underlying simulation framework. they collect reports of known covid- exposures or clusters in educational settings, along with the date, a date of last update, and the number of reported cases. in figure we show the distribution of cluster sizes along with the type of school the cluster occurred in. the majority of exposures have led to no additional reported cases, which is indicated by clusters of size in this data set. however, there is a tail of larger clusters. this data is consistent with a model of transmission where infectiousness is variable and the distribution of secondary cases is overdispersed. we model two contributing factors that are known to affect transmission [ ] : the individual and the classroom/activity combination. individuals vary extensively in viral load both over their course of infection and from individual to individual. in addition, talking, singing, shouting activities in crowded conditions in poor ventilation are associated with large reported outbreaks and with data on aerosol and droplet generation. we therefore model index cases of varying infectiousness arriving in classrooms whose additional contribution to transmission is variable, stratifying the simulations according to the individual and environment risks. we model covid- progression in an individual as having the states susceptible (s), exposed (e), presymptomatic (p), symptomatic (sym), and recovered (r). individuals start in the susceptible state and then transition to the exposed state when they are infected. exposed individuals are not able to infect others. individuals transition from the exposed state to the presymptomatic state at which point they are able to infect others, but have no symptoms. individuals may either transition from presymptomatic to symptomatic states (showing symptoms while remaining infectious) or directly to the recovered state without ever showing symptoms. symptomatic people eventually enter the recovered state, where they are . 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. cluster sizes in québec schools whose exposure was on or before oct. , , as of oct. , . the inset shows only those with or more cases; the main plot shows all exposures. most exposures have not led to detected clusters; % of the exposures have led to at least one additional detected case, and % to at least two additional detected cases. no longer infectious. presymptomatic or symptomatic individuals infect susceptibles at constant rate β when they are together, where β may depend on the individuals involved, their exact state, their proximity and the environment. individuals stay in the exposed state for the duration of the latent period, after which they become presymptomatic. latent periods are modeled as gamma-distributed with mean µ and standard deviation σ . for each presymptomatic individual a gamma-distributed presymptomatic infectious period (pip) and a gamma-distributed infectious periods are generated (with means and standard deviations (µ p , σ p ) and (µ i , σ i ) respectively). with probability α they never show symptoms (and are asymptomatic); otherwise symptoms appear after the pip. rather than assuming that all students in the class are equally likely to transmit the infection to each other, we model individual and contact group effects. we assume that the n class students are broken into smaller groups of n group students. we start with a base rate β of transmission which represents the rate of transmission of from one infectious individual to another in the same group. our default value for β is . transmissions per contact per hour ( . in environments with increased transmission). another source of variability is in the infectiousness of individuals. as discussed in the introduction, some evidence indicates that certain individuals are superspreaders and so have atypically large β compared to others. the most important instance of this is when the index case has high β. in order to capture this, we model the index case as having a separate transmission rate β = f index β where f index = or , depending on whether the index case has the same infectiousness or a higher infectiousness than others. we also model reduced infectiousness of asymptomatic individuals. their transmission rate is f asymp β where we choose f asymp = . . we explore the impact of these assumptions in the supporting information. the final effect modifying transmission rate is to decrease it when the infectious person and the susceptible person are in different contact groups. the effect is to multiply β by f aero = . . we model the effect of these different heterogeneities multiplicatively, so that if, for example, the index case is asymptomatic, the rate of transmission to a susceptible in another group is f index f asymp f aero β. we note that our maximum value of β (when both the environment and the infectiousness of the index case are most conducive to transmission) is . transmissions per contact per hour. this is considerably . 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 october , . smaller than the estimates of index β for widely-reported outbreaks in adults [ ] , by up to a factor of for some events. table lists the parameter values used in our simulations and provides supporting citations. we run our simulations twice: once with the index case is symptomatic, and once when the index case is asymptomatic, because this turns out to be a crucial factor in determining cluster size. we model transmission in both an elementary school and a high school environment, taking the structures from that in british columbia when schools opened in september . for the elementary school, n class = students who spend hours a day together, from monday to friday. all students except the index case are susceptible. the index case turns infectious at the beginning of the day on monday. we assume that students are in contact groups of n group = . we simulate for days, and in most simulations all students are recovered before the end of that period. for the high school, morning and afternoon are structured differently. in the morning n class = students in groups of size n group = meet for . hours monday through friday. in the afternoon n class = students meet in a distanced way for . hours on tuesday and friday only. we model the distancing using contact groups of size . we assume there is no overlap between the morning and afternoon classes except for the index case. table summarizes these classroom settings. we consider four different protocols for what interventions are implemented when students become symptomatic or receive a positive test result. in each protocol students who become symptomatic immediately stop attending school and therefore cannot infect other students. (we do not model infection . 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 october , . in the home environment, which is of course an important real-life practical consideration.) every student who is symptomatic is tested and learns their results t delay = days later. the value of the parameter t delay is important for the interventions, as the larger it is the more time pre-or asymptomatic students (who were infected by the index case, but remain in the class) have to infect their classmates. the protocols differ in which interventions are used after a student tests positive. in the baseline protocol no further action is taken. symptomatic student are remain home and cannot infect other students, but the class continues to operate so that any other presymptomatic or asymptomatic students may infect others. in the contact protocol as soon as a symptomatic student receives a positive test result all the other students in their group are isolated (sent home from the class) and no longer able to infect other students. it is possible for any number of groups to be isolated, and under this protocol those decisions are made independently. in the two groups is an outbreak protocol, as in the contact model, groups with a student receiving a positive test are isolated, but when two or more groups are detected, an outbreak is declared and all students go into isolation, preventing any further transmission. in the whole class protocol, when a symptomatic student receives a positive test result, all students are isolated and further transmission is prevented. for each of the protocols we consider three different performance metrics. total cluster size is the number of students who are ultimately infected in class (or in both classes in the high school), including the index case. total disrupted is the total number of students who are either asked to isolate or are tested. a student is included if they became symptomatic and had to isolate, if they were a member of a group that was asked to isolate, or when their class was asked to isolate (or be tested). we did not explicitly simulate the number of new clusters that a cluster seeds through out-of-class social contacts (siblings, parents, teacher-teacher contact, after-school activities and so on). a measure of the risk of such "bridging" interactions is asymptomatic student-days, the total number of student-days where a student is infectious, but not asked to isolate. for the different protocols this number depends on the exact policy used. under a lax policy we assume that asymptomatic or presympomatic students are never told to isolate, and this number is just the total number of student-days of infectiousness without symptoms. under a strict policy we assume that when a group or class is shut down all students in the group isolate until they recover or receive a negative test result. for four different combinations of class room β and index case infectiousness we computed runs of the simulation for both a symptomatic and an asymptomatic index case. we show the distributions of our measures total cluster size, total disrupted, and asymptomatic student-days for a single introduced case in . 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. . 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 october , . an elementary school in our model. see the supporting information for the corresponding results for the high school model. figure shows the distribution of total cluster size. the first row shows results for when both the transmission in the class is low (β = . transmissions per contact per hour) and the index case has the same transmission rate as others (f index = ). cluster size is small with a symptomatic index case (no transmission % of the time), but ranges from - individuals (median= ) if the index is asymptomatic. this is because asymptomatic individuals have more time to expose others before recovering. none of the protocols make a large difference to the cluster size in this setting. if the index case has a higher infectiousness (f index = ) but the room is still low risk (β = . transmissions per contact per hour) (second row), again the cluster sizes are very small with a symptomatic index case (no transmission % of the time), though the tail of rare events is longer. when the index case is asymptomatic, in the baseline protocol the median cluster size is and even in the whole class protocol, the median is reduced to . this pattern continues; with a highly infectious index case in a higher-risk room (fourth row): in the baseline protocol in which the main intervention is that symptomatic individuals do not attend, cluster sizes range from to over students in a single classroom (median= , sympt. index; median= , asymp. index) . the whole class protocol reduces the mean cluster size from . to . in the aysmptomatic case, whereas the group and two group protocols reduce it to . and . students, respectively. over all the scenarios the whole class protocol reduced cluster sizes roughly in half, with the contact and two group protocols doing a little worse. figure shows the distribution of total disrupted for the four scenarios. the whole class model is the most disruptive, as expected. when transmission is low in the class and the index case is low risk, simply sending symptomatic individuals home accomplishes good cluster control and is least disruptive. in most transmission risk scenarios in which the index case is symptomatic, the median cluster sizes are small; however, there are rare high sizes in the long upper tail (for example, up to students even with a low-risk classroom and medium-risk, symptomatic index case). these clusters can linger, eventually requiring each group to suffer disruption. in contrast, the whole-class model disrupts the whole class at the first positive test, leading to high levels of disruption and surprisingly weak control of larger clusters. this is particularly true when the index case is symptomatic. figure shows the distribution of asymptomatic student-days in our four scenarios. by this measure, the effectiveness of the whole-class intervention is strong, particularly in the most unfortunate scenarios (high transmission index case and environment, and asymptomatic index). here, the median numbers of asymptomatic student-days are reduced from . to . in the lax case and . in the strict case. in the low-transmission scenarios the whole-class intervention does remove the long tail (up to student-days of potential infectiousness in the other protocols, compared to a maximum of less than student-days in the whole-class model). particularly in the "strict" case, the whole-class protocol achieves a dramatic reduction in the force of infection that can arise from a cluster, both in the median and in the variability, compared to the baseline protocol in which only symptomatic individuals cease attending. we note, however, that the two-group protocol (in which there is a whole-class-level intervention once two different contact groups have detected covid- cases) achieves nearly the same level of reduction of the potential force of infection from the cluster, with less overall disruption. we obtain qualitatively similar results for high schools, in which the model is more complex -see figures a through a in the supporting information. however, because of the reduced duration of attendance in the high school configurations we modeled, the cluster sizes are smaller and less variable than they are in the elementary school model. the extent of disruption is higher due to larger numbers of overall contacts. importantly the much lower cluster sizes in the high school setting versus the elementary point setting is due to how extensively the high school schedule has been restructured in response to the pandemic. we illustrate this by showing results on cluster size for a high school with pre-covid structure: four . hour classes every day with largely different students in each. see figure a . . 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 october , . . 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 october , . total disrupted: the total numbers of students who are either asked to isolate or must be tested, in the different protocols, according to the index and classroom's transmission risk and whether the index case is asymptomatic. a student is included if they became symptomatic and had to isolate, if they were a member of a group that was asked to isolate or when their class was asked to isolate (or be tested). . 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 october , . asymptomatic student-days: the number of student-days on which a student is infectious but not yet told to isolate. left: index case is symptomatic. right: index case is asymptomatic. lax: only symptomatic students are ever told to isolate. strict: all student in a shut down group or class are told to isolate. . 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 october , . ; the mitigation protocols in figure a make a disappointing impact on the total cluster size; variation is driven much more by the transmission rate and whether the index case is asymptomatic. while the whole-class model in which testing (even asymptomatic) class members is used to identify infections rapidly reduces the number of student-days when infections go undetected, none of the protocols reduces the cluster sizes so greatly that they would be a reliable approach for in-class clusters in the unfortunate event where a highly infectious index arrives in a moderate-risk room. fundamentally, this is because too much transmission can occur in the pre-infectious period if the index is symptomatic, and/or too much occurs before the first case has symptoms (if the index is asymptomatic). in most of our scenarios the index case directly infects most of the students who become infected, and so the amount of time the index case spends in class is key. if they are symptomatic, then the period of time they have to infect others is just the pre-infectious period, with an average of or days. but if they are asymptomatic they have the entire time until someone they infect becomes symptomatic to infect others. without closing schools down entirely, if we want to prevent large clusters from occurring altogether, this leaves approaches to detect potential index cases before they show symptoms. pooled testing, wastewater monitoring and airflow monitoring have all been proposed with this aim [ , ] . we simulated introduced cases and resulting transmission under the baseline of no regular testing (with the same baseline as above, symptomatic individuals going home) and compared this to weekly or every three day testing or environmental monitoring covering all individuals in the class. the results for the total cluster size are shown in figure . regular pooled or otherwise universal testing dramatically reduces the sizes of even the most unfortunate clusters (infectious index, higher-risk room), for example from a median of to a median size of if the index is asymptomatic. but even with regular pooled or otherwise universal testing, testing in a matter of hours (e.g. onsite) has a substantially greater impact than testing at a centralized laboratory (if that takes days including shipping time). data on covid- transmission in schools is consistent with overdispersed transmission in which many exposures -even a large majority -do not lead to clusters or outbreaks, but some do. overdispersion in transmission is known in respiratory infectious disease and in covid- in particular [ , , [ ] [ ] [ ] . sars-cov- viral loads are reported to vary by over orders of magnitude, with meta-analysis not finding significant differences in variability or viral load between children and adults [ ] , and with variation over the infectious period. activities and symptoms both affect droplet production, and ventilation and distancing affect whether droplets or aerosols containing virions are likely to reach an individual. our model structure captures this complexity using two components contributing to the transmission rate: host variability and a contribution from the environment and activity. in this framework, even relatively low variation in transmissibility between individuals, combined with even lower variation in the environment/activity's contribution, explains widely variable cluster sizes. our study has some limitations. we have not extended our simulations beyond the classroom (or high school classrooms) to simulate how each cluster may spread outwards via siblings, parents, teachers and their contacts, other household interactions, friendship groups and the broader community. these factors are complex and other models have explored them [ ] [ ] [ ] [ ] [ ] , some also finding that extensive testing or successful test and trace systems are required to avoid schools amplifying covid- transmission. we focused instead on how heterogeneity in transmission, arising from individual and environment effects, impacts the ability of mitigation measures to detect and control in-class transmission. we have a simple model of contact in which a known, fixed group of contacts are at highest risk from a given index case. this does not reflect the complex interactions in a classroom setting, but additional mixing or errors in identifying precise who an index case was in close contact with can be modeled in the same way that we . 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. cluster sizes are greatly reduced with regular universal (e.g. pooled) testing, particularly when that testing is performed on site (in the model, in hours, compared to an assumed -day time to result for tests processed off site). left: index case symptomatic. right: index case asymptomatic. the baseline scenario shows the cluster sizes without regular testing, compared to weekly (middle row) or every days (top row). regular testing reduces the median cluster size from or (index symptomatic, asymptomatic) to if testing is done offsite, or if it is performed rapidly on site. the fraction of clusters of size > is reduced from % to % (or % for rapid onsite testing) if the index is asymptomatic, and from % to just - % if the index is symptomatic. . 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 october , . have modeled increased contribution of aerosol transmission (i.e. a risk of transmission outside the identified group of close contacts). there remain many unknowns about the timing and nature of covid- transmission and we have used a simple model with constant infectiousness over time and with variability in the pre-infectious, infectious and symptomatic periods consistent with current knowledge of covid- transmission. in the particular context of schools, we find that interventions triggered by positive tests from symptomatic individuals are relatively ineffective in mitigating "unfortunate events" -high-transmission index cases in moderate (or higher)-transmission environments-even if everyone in the class is isolated upon the first positive test. there is growing evidence that large clusters can happen in schools and that children can transmit covid- [ , ] . this calls for preventive measures beyond protocols centred on symptomatic testing. up to autumn , school closures were the primary mechanism for preventing school transmission, and more broadly, widespread social distancing and non pharmaceutical interventions were the widely used and widely effective in controlling community transmission throughout spring [ ] [ ] [ ] . if, instead, we are to maintain open schools, it is necessary to prevent large school transmission clusters, even if they are expected to be rare. the expected benefit of preventing large transmission clusters will naturally depend on the state of covid- transmission in the community, with larger clusters likely to be amplified and spread onwards where community transmission is ongoing. such settings will also have more school exposures, and the chance of an unfortunate high-transmission introduction to a school is correspondingly higher, creating a viscious cycle. our analysis and modeling suggest three approaches to prevention. first, reducing community transmission can play a large role; if exposures themselves are rare, the waiting time before a high-transmission introduction is likely to be much longer than if community transmission leads to frequent exposures. in a jurisdiction with . % prevalence, where % of cases are symptomatic and not attending (or have been alerted to their exposure), the probability that a high school with staff and students has at least one case attending is still %. the more introductions happen in schools, the sooner we can expect to be unlucky. this may account for reports of large school clusters in israel, sweden, chile [ ] and some larger clusters in québec [ ] , while countries with low overall levels found very low risk of transmission from children in the same period [ ] . second, testing can be used not only to mitigate one cluster in (e.g.) a classroom, but to prevent the next. we comment on two testing frameworks: testing triggered by detection of a symptomatic individual, and regular testing or monitoring to detect any covid- in any individual, regardless of symptoms or known exposure (e.g. pooled testing). rapid regular universal monitoring is far superior in preventing large clusters to testing that is initiated upon detection of a symptomatic case, even if a whole class is then tested soon afterward. finally, steps should be taken to control the environment's contribution to the variation in transmission rates (and therefore to cluster sizes). indoor, crowded, loud, poorly ventilated environments with singing, eating and dining are recognized to be comparatively high risk [ , ] . however, data could now be gathered prospectively with a focus on schools: when there are exposures in classroom settings, these could be linked to data on the room size, ventilation, whether windows were open, numbers of students in the class and classroom organization, and then further linked to follow-up on cluster size. less is known about what may lead an individual to have a high viral load and to generate high volumes of infectious droplets or aerosols, though symptomaticity (especially coughing) creates more droplets while talking, singing and breathing produce aerosols whether an individual is symptomatic or not [ ] . here too, data collection linking individual-level information with transmission via contact tracing and follow-up could aid in identifying risk and preventing high-risk introductions. our results have focused on classroom settings in schools but could apply to other settings in which people spend multiple hours per day with the same group of approximately - others, and have closest contact with a subset of these individuals. the fact that our results for the case of bc high schools (one in-person class per day with a hybrid class some afternoons) are very similar to the simpler contact . 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 october , . structure in elementary schools indicates that the specific details of the contact patterns are less important for the cluster sizes and roles of mitigation than the variation in transmission. accordingly, many workplaces may be well represented by our model and conclusions. pt was supported by an nserc (canada) discovery grant. cc was supported by genome bc grant cov- and by the canada research chairs program of the federal government of canada. we thank covidÉcoles québec for the data on cluster sizes in québec schools. . 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 october , . ; https://doi.org/ . / . . . doi: medrxiv preprint results for high schools. here we provide the same results for high schools as we did for elementary schools in the main text. for each of the conditions and protocols, figure a shows total number of infected students in the clusters, figure a shows the number of students disrupted, and figure a shows the number of asymptomatic student-days. the effect of the protocols are more modest than in the elementary schools, thought this is in large part because the high school structure we consider is already quite good at restricting transmission. the key feature is that transmission is low in the afternoon class because of social distancing (and it only meeting two days a week). the morning class is somewhat larger than the elementary school class, but only meets for half the time. for purposes of illustration we also compare our high school model with a model corresponding to a pre-covid structure in which students go to different classes every day for . hours. figure a shows the difference in cluster size between the two high school structures. alternative parameter choices. figure a shows the total cluster sizes under different assumptions for the pre-infectious period (pip) which was mean days (standard deviation day) in the main text, the relative infectiousness of asymptomatic individuals ( . times that of symptomatic individuals in the main text) and the extent to which exposure is focused in the identified group of close contacts of an individual. (we took equal numbers of simulations with each of the assumptions on β and the infectiousness of the index case that we used in the main text.) aerosol transmission and extended mixing in the classroom would both serve to expose individuals who would not be identified as among the close contacts. if ( ) the pip is short, ( ) if individuals without symptoms transmit much less than those with symptoms and ( ) there is very limited aerosol transmission and very limited mixing outside a known group of close contacts within the classroom, then cluster sizes remain small (though nonzero) no matter the intervention protocol. assumptions ( )-( ) are all strong and optimistic assumptions, and are not supported by data in adults or by viral load data from asymptomatic individuals. however, if these assumptions did hold in children then school transmission should be rare and would likely involve a high fraction of transmission among teachers and other adult staff when it did occur. in figure a we progress from top to bottom panels, first assuming all three and then allowing for a longer pip, higher asymptomatic transmission and finally higher mixing/aerosol. . 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. high school total cluster sizes are smaller and less variable than those in elementary schools because high schools are operating with one full in-person class every day and another, smaller and distanced, class two afternoons per week. however, if the index case is asymptomatic and high-risk, even this protocal can allow a cluster of infections. . 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. . 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. . 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. comparison of total number of infected students in a pre-covid high school structure versus the modified plan we have studied here. . 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. results in the main text correspond to the fourth panel whose parameters we believe are best representative of current data. . 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. (which was not certified by peer review) the copyright holder for this preprint this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint assessing the age specificity of infection fatality rates for covid- : systematic review, meta-analysis, and public policy implications covid- in children and teens coronavirus resource center european centre for disease prevention and control. covid- in children and the role of school settings in covid- transmission report on ombudspersons and commissioners for children's challenges and responses to covid- covid- , school closures, and child poverty: a social crisis in the making covid- and the re-opening of schools: a policy maker's dilemma covid- impacts on child and youth anxiety and depression: challenges and opportunities the long-term health consequences of child physical abuse, emotional abuse, and neglect: a systematic review and meta-analysis no evidence of secondary transmission of covid- from children attending school in ireland transmission of sars-cov- in australian educational settings: a prospective cohort study cluster of covid- in northern france: a retrospective closed cohort study sars-cov- infection in primary schools in northern france: a retrospective cohort study in an area of high transmission children are unlikely to be the main drivers of the covid- pandemic -a systematic review south korean schools close after kindergartner tests positive for coronavirus sars-cov- transmission and infection among attendees of an overnight camp -georgia a large covid- outbreak in a high school days after schools' reopening, israel almost an entire class of students caught coronavirus at a trois-rivières school cases of covid- confirmed at boucherville day camp. cbc news nearly secondary cases of covid- linked to boucherville day camp, bringing total cases to sars-cov- antibody prevalence in blood in a large school community subject to a covid- outbreak: a cross-sectional study keep cautious, kids': student with covid- at winnipeg's john pritchard school speaks out surveillance of covid- school outbreaks being young in europe today -demographic trends prevalence of sars-cov- in spain (ene-covid): a nationwide, population-based seroepidemiological study spread of sars-cov- in the icelandic population seroprevalence of anti-sars-cov- igg antibodies in geneva, switzerland (serocov-pop): a population-based study how sweden wasted a 'rare opportunity' to study coronavirus in schools epidemiology and transmission dynamics of covid- in two indian states high sars-cov- attack rate following exposure at a choir practice flight-associated transmission of severe acute respiratory syndrome coronavirus corroborated by whole-genome sequencing nearly , people have been exposed to the coronavirus on flights, the cdc says. the washington post full genome viral sequences inform patterns of sars-cov- spread into and within israel wrong person, place and time: viral load and contact network structure predict sars-cov- transmission and super-spreading events heterogeneity in transmissibility and shedding sars-cov- via droplets and aerosols event-specific interventions to minimize covid- transmission estimating the time interval between transmission generations when negative values occur in the serial interval data: using covid- as an example evidence for transmission of covid- prior to symptom onset cluster of coronavirus disease (covid- ) in the french alps pooled tests can be used in dorms, community. the straits times pooled sample testing and screening testing for covid- heterogeneities in the transmission of infectious agents: implications for the design of control programs superspreading and the effect of individual variation on disease emergence estimating the overdispersion in covid- transmission using outbreak sizes outside china schools are not islands: balancing covid- risk and educational benefits using structural and temporal countermeasures covid school modelling: looking at the impact of different test, trace and isolation protocols expected impact of reopening schools after lockdown on covid- epidemic inÎle-de-france model-based projections for covid- outbreak size and student-days lost to closure in ontario childcare centres and primary schools determining the optimal strategy for reopening schools, the impact of test and trace interventions, and the risk of occurrence of a second covid- epidemic wave in the uk: a modelling study covid- , children, and schools: overlooked and at risk the effectiveness of eight nonpharmaceutical interventions against covid- in countries infectious diseases of humans: dynamics and control evaluating the effectiveness of social distancing interventions to delay or flatten the epidemic curve of coronavirus disease key: cord- -q g authors: schutzer‐weissmann, j.; magee, d.j.; farquhar‐smith, p. title: severe acute respiratory syndrome coronavirus (sars‐cov‐ ) infection risk during elective peri‐operative care: a narrative review date: - - journal: anaesthesia doi: . /anae. sha: doc_id: cord_uid: q g the protection of healthcare workers from the risk of nosocomial severe acute respiratory syndrome coronavirus (sars‐cov‐ ) infection is a paramount concern. sars‐cov‐ is likely to remain endemic and measures to protect healthcare workers against nosocomial infection will need to be maintained. this review aims to inform the assessment and management of the risk of sars‐cov‐ transmission to healthcare workers involved in elective peri‐operative care. in the absence of data specifically related to the risk of sars‐cov‐ transmission in the peri‐operative setting, we explore the evidence‐base that exists regarding modes of viral transmission, historical evidence for the risk associated with aerosol‐generating procedures and contemporaneous data from the covid‐ pandemic. we identify a significant lack of data regarding the risk of transmission in the management of elective surgical patients, highlighting the urgent need for further research. widely reported and is an issue of great concern to clinicians and policy-makers. community surveillance in the uk suggests an increased incidence of sars-cov- infection among patient-facing healthcare workers [ ] . of confirmed covid- cases in china, . % were healthcare workers and higher proportions have been reported in italy and spain [ ] . up to may , healthcare worker deaths had been reported in the uk [ ] . whilst none of these were anaesthetists or intensivists, / ( . %) healthcare workers performing or involved in tracheal intubation of patients with confirmed or suspected covid- subsequently reported laboratory-confirmed sars-cov- infection [ ] . more than % of all severe acute respiratory syndrome (sars) cases were healthcare workers [ ] and nosocomial sars infection was prominent among healthcare workers looking after patients who required respiratory support [ ] . following the sars epidemic, the world health organization (who) published a list of aerosol-generating procedures [ ] , a concept originally developed to protect against transmission of tuberculosis, an obligate airborne pathogen [ ] . the who subsequently commissioned a systematic review of the evidence for the association between aerosol-generating procedures and nosocomial sars coronavirus- (sars-cov- ) transmission [ ] . this incorporated retrospective observational studies, five case-control and five cohort studies. given its genesis, the evidence is inevitably associative and imprecise. nonetheless, there was a consistent and strong signal (pooled odds ratio . ) that tracheal intubation was associated with an increased risk of transmission of sars-cov- to healthcare workers. understandably, this has been given considerable weight by policy-makers during the current pandemic [ ] [ ] [ ] . the possibility that this increased risk may, in part, be due to airborne transmission has informed not only the use of personal protective equipment (ppe) but also procedural modifications of the peri-operative pathway. guidance continues to evolve [ ] and, although not all are explicitly advised in national or international guidelines, these have included: tracheal intubation and extubation in the operating theatre to avoid contamination of anaesthetic rooms; an 'aerosol clearance time' defined in terms of room ventilation during which no one should enter, and some suggest even leave, the room following an aerosol-generating procedure; avoiding manual (bag-mask) ventilation before tracheal intubation; and, by inference, avoiding intra-operative positive pressure ventilation via supraglottic airway devices. these may be associated with adverse consequences or resource cost, some of which are outlined in table . this article is protected by copyright. all rights reserved unlike sars-cov- , sars-cov- is likely to become an endemic threat. healthcare systems face the challenge of increasing activity to accommodate the backlog that has built up due to service disruption [ ] whilst protecting patients and staff from nosocomial infection. however, there is limited evidence concerning transmission risk in the elective peri-operative setting. here, we review the evidence from sars and contemporaneous data from covid- to inform assessment and management of the risk of sars-cov- transmission to healthcare workers involved in elective peri-operative care. according to the who, sars-cov- is predominantly transmitted by contact with infected respiratory fluids or exposure to infected respiratory droplets [ ] . environmental contamination is widespread [ , ] and this can be mitigated by hand hygiene, gloves, aprons and environmental decontamination. exposure to infective droplets emitted by coughing may be mitigated by wearing a fluid-resistant surgical mask [ ] . airborne transmission is via aerosols, particles "that remain infectious when suspended in air over long distance and time" [ ] and may, therefore, transmit infection further than the two-metre range of larger droplets [ , ] . aerosol deposition is also an important source of surface contamination [ ] . airborne viral transmission is complex, uncertain and controversial [ ] . respiratory bioaerosols are generated by wind shear forces arising from the passage of air over infected mucosa in the respiratory tract. the number and size distribution of aerosols and their viral content vary according to the site and force of generation, environmental conditions and the degree of viral shedding at the site of aerosol generation. the infectivity of aerosols depends upon the aerosol viral load, where they deposit in the respiratory tract and tissue tropic factors (such as, in the case of sars-cov- , cellular angiotensinconverting enzyme- (ace- ) receptor expression) [ ] . airborne viral spread has been demonstrated in animal models [ ] and healthy human volunteers [ ] and epidemiological studies suggest that this is a transmission route in other viruses [ , ] . sars-cov- infects and replicates in both lower respiratory tract and nasopharynx [ ] . under experimental conditions, the persistence of viable sars-cov- in aerosols for up to h has been demonstrated [ ] . sars-cov- ribonucleic acid (rna) has been detected in air samples from clinical environments [ ] . other studies were unable to detect sars-cov- in air samples but swabs from air outlets were positive [ ] . it is important to note that presence of detectable sars-cov- rna does not necessarily imply the presence of viable virus and there are no reports to date of viable sars-cov- isolated from air samples this article is protected by copyright. all rights reserved collected in the clinical environment. there is no direct evidence of sars-cov- airborne transmission but there is epidemiological evidence that airborne sars-cov- transmission may have occurred, both in the community and in the healthcare environment. for example, modelling of airflow dynamics correlated with the sars-cov- transmission dynamics in an apartment block, where spread by contact or respiratory droplet was unlikely [ ] . similarly, the transmission of sars-cov- to medical students who were not in direct contact with an infected patient correlated with airflow modelling [ ] . in both cases, defective engineering created environmental conditions that may have contributed to these events (in the first, faulty drain seals allowing faecal aerosols to be drawn into the air conditioning; in the second, imbalance between ventilation inflow and outflow) and they are not necessarily representative of normal transmission dynamics [ , ] . whilst the predominant route of sars-cov- transmission may be contact/droplet-mediated, environmental conditions -including those associated with aerosol-generating procedures -may promote 'opportunistic' airborne transmission [ ] . aerosol-mediated airborne transmission has been a source of great anxiety among healthcare workers. national guidelines recommend 'airborne precautions' [ ] for those involved in aerosol-generating procedures but contact/droplet precautions for most other clinical activity [ , , ] . the who list of aerosol-generating procedures is based on epidemiological evidence of transmission to healthcare workers caring for sars patients [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . this evidence is related to the risk of transmission whilst caring for patients with respiratory failure and critical appraisal of how this sars data applies to the risk of sars-cov- transmission in the elective peri-operative environment is necessary. table summarises the raw data from the who-commissioned systematic review by tran et al. [ ] related to transmission risk associated with tracheal intubation. tracheal intubation has been highlighted here because it is the most relevant aerosol-generating procedure in the context of elective peri-operative care. other procedures, such as extubation, rely on this evidence by extension. moreover, it is notable as an example of the methodology that tracheal intubation is a discrete and identifiable event and was common among sars patients. it is therefore liable to proxy assumptions: for example, if the majority of sars patients had developed appendicitis, such methodology might identify appendicectomy as an aerosol-generating procedure. this article is protected by copyright. all rights reserved the studies were limited by heterogeneous populations, poorly-defined and variable exposure, and recall bias. across eight studies, there were infections associated with tracheal intubation among a population of healthcare workers. the number of healthcare workers exposed to tracheal intubation is relatively small compared with those who were not, such as non-clinical staff. across all studies, patients transmitted sars-cov- to healthcare workers. in the second-largest study, the healthcare workers who developed sars all looked after seven -and looked after only four -of the sars patients whose tracheas were intubated [ ] . in the largest case-control study caring for a "superspreading patient" (no definition offered in the paper) was associated with healthcare worker infection, and in multivariate analysis, this association was stronger than tracheal intubation [ ] . this evidence, therefore, rests on a small number of infections associated with a yet smaller number of highly infectious patients, among a heterogeneous population of healthcare workers, matched in some cases according to profession, in others by presence during rather than performance of the procedures under investigation. all identify other measures of proximity or contact with patients which are associated with increased transmission risk of a comparable order of magnitude to that of being involved in tracheal intubation. the authors discuss the "difficulty in identifying the specific part of a given procedure, which may be complex and involve several manoeuvres, that imparts the greatest risk of transmission." they "acknowledge that the findings presented may have been influenced by direct and indirect contact transmission" and conclude that their "findings serve to highlight the lack of precision in the definition for aerosol generating procedures" [ ] . a recent systematic review led by health protection scotland appraised the evidence base for the who list of aerosol-generating procedures [ ] . they only identified four additional reports relating to transmission risk during tracheal intubation. three are case reports and in each of these they found that "the multiple factors that could have led to infection transmission in this case make it very difficult, if not impossible to identify the most high risk elements." the other study that they singled out [ ] was included in the who systematic review. health protection scotland could only identify "weak evidence for an increased risk of respiratory infection transmission" from performing tracheal intubation. this article is protected by copyright. all rights reserved there is a consistent and strong signal throughout these studies that involvement in tracheal intubation of sars patients with respiratory failure was associated with an increased risk of viral transmission. in a recent international study, . % healthcare workers involved in tracheal intubation during the covid- pandemic reported lab-confirmed sars-cov- infection or hospitalisation or self-isolation due to covid- symptoms [ ] . how the risk of infection associated with tracheal intubation is mediated, however, is not clear. the elective peri-operative environment is different from the acute settings from which this evidence is drawn. the preconditions and purpose of tracheal intubation for elective surgery are different from emergent/urgent tracheal intubation for respiratory failure. pre-admission measures such as selfisolation, symptomatic screening and viral rna testing prior to admission aim to reduce the risk that patients undergoing elective surgery are infected with sars-cov- and the risk of healthcare worker exposure to the virus in the elective peri-operative environment. however, it is important to note that these measures do not eliminate these risks. in order to provide effective and efficient protection to healthcare workers in this environment, it is imperative to consider how and why involvement in tracheal intubation and related airway procedures is associated with increased risk of viral transmission. coughing is the common denominator of a number of defined aerosol-generating procedures, including tracheal intubation, extubation and bronchoscopy. indeed, the tuberculosis guidelines which introduced the term refers to 'cough-inducing and aerosol-generating procedures' [ ] . the recent reiteration [ ] that tracheal intubation is aerosol-generating was based on simulated tracheal intubation of a 'coughing' manikin [ ] . modelling studies confirm that the risk of airborne transmission depends upon cough frequency [ ] . air sampling demonstrates increased bio-aerosol concentrations during coughing on bronchoscope insertion [ ] . coughing is not a procedure but its exclusion from discussions of aerosol-generating procedures may also reflect the misconception that it does not produce aerosols, which originates from early studies that were technically insensitive to smaller particles [ ] . any respiratory activity, including breathing, produces aerosols and more recent studies have demonstrated that coughing produces large numbers of both droplets and aerosols [ , ] . the dichotomy between droplets that deposit within a short distance and aerosols that travel further may be an over-simplification [ , ] . this article is protected by copyright. all rights reserved h n avian influenza viral titres in air samples taken during tracheal intubation were not significantly higher than background levels in intensive care units [ ] although this study may have been underpowered to detect this difference [ ] . another study found no link between influenza aerosols in sampled air and aerosol-generating procedures [ ] . in canada, use of muscle relaxants for tracheal intubation was increased during the second sars outbreak which may have contributed to the decrease in healthcare worker infections [ ] and support the notion that coughing is the prime aerosol (and/or droplet) generator. the studies upon which the who list of aerosol-generating procedures is based do not provide any direct evidence that tracheal intubation itself increases the risk of sars transmission. rather, this data implies that proximity and time in proximity to desaturation after induction of anaesthesia can be minimised by effective pre-oxygenation [ , ] and measures which facilitate apnoeic oxygenation (for example, maintaining airway patency, minimising air entrainment via mask leak and head-up position [ ] ). recent guidance supports the judicious use of supraglottic airway devices [ ] . some have advocated against the use of supraglottic airway devices in favour of cuffed tracheal tubes on the basis that there may be a lower risk of an aerosol leak during positive pressure ventilation [ ] . there is evidence that, when used appropriately, this is not the case. the mean oropharyngeal leak pressure of the i-gel® (intersurgical, wokingham, uk) is cmh o in non-paralysed patients and cmh o in paralysed patients [ ] . the leak fraction with i-gel® was no higher when ventilating with peak pressures below cmh o compared with cuffed tracheal tube [ ] . several tests of leak have been shown to be sensitive and reliable in clinical settings [ ] . the risk of aerosol generation may be greater on insertion or removal where poor seal or coughing may facilitate generation and dispersal of aerosols. therefore, perhaps more important than leak fraction is the primary failure rate where supraglottic airway devices do not achieve an adequate seal on insertion. for i-gel® this has been estimated to be - % [ ] but in this regard, supraglottic airway devices with an inflatable cuff may be more reliable [ ] . an 'aerosol clearance time' -waiting for a period of time for room ventilation defined in terms of air changes -has been recommended [ , ] . uk national guidance from public health england advocates (as 'pragmatic') minutes in a room with to air changes per hour following an aerosol-generating procedure [ ] . this corresponds to approximately four air changes and a clearance of - %. this is similar to the three to five air changes recommended by the australian and new zealand college of this article is protected by copyright. all rights reserved anaesthetists [ ] . there is evidence to support this where there has been extensive aerosol generation, e.g. intensive care rooms [ ] or bronchoscopy suites [ ] . if aerosols are generated by associated respiratory activities rather than the act of tracheal intubation or extubation itself, requiring an aerosol clearance time following these procedures but not in other situations, for example in a recovery ward where patients are breathing and coughing, may seem logically inconsistent: in both environments, patients generate potentially infectious aerosols by breathing and coughing. there are, however, arguments for maintaining aerosol clearance times in the elective perioperative environment. foremost is the precautionary principle: there is epidemiological evidence that tracheal intubation and other airway manoeuvres are consistently associated with an increased viral transmission risk and there may be elements of these procedures which increase risk that we do not appreciate. current uk guidelines do not recommend airborne precautions for healthcare workers where aerosolgenerating procedures are not taking place, for example in recovery wards, outpatient suites or general practice consultation rooms [ ] . other international authorities, however, advise airborne precautions for all healthcare workers coming into close proximity to an 'open' airway and not just after aerosolgenerating procedures [ ] and this would include healthcare workers in recovery wards and many outpatient and community healthcare environments. this guidance is supported by the evidence presented here which emphasises the importance of proximity to patients' airways over the procedure itself. a further example of this might be a recent study of anaesthetists who performed awake spinal anaesthesia (not an aerosol-generating procedure) on sars-cov- positive patients which found that only / ( . %) who used aerosol precaution ppe subsequently tested positive for sars-cov- compared to / ( . %) who used droplet precaution ppe [ ] . this may have implications for other regional anaesthetic techniques, a subject which has been recently reviewed by uppal et al. [ ] . the focus on aerosol-generating procedures may also risk neglecting other practices to reduce transmission that are equally important. these control measures include frequent handwashing [ ] , double-gloving during tracheal intubation [ ] , surface cleaning of anaesthetic machines, monitors and other equipment in the immediate vicinity after tracheal intubation [ ] and patient use of fluid-resistant surgical mask following extubation [ ] . basic infection control practices are often poorly observed [ ] . sampling studies consistently identify extensive surface contamination warranting greater emphasis on this element of infection control [ , ] . evidence-based guidance [ ] includes simple, inexpensive this article is protected by copyright. all rights reserved measures such as placing alcohol-gel dispensers near anaesthetists which have been shown to dramatically increase hand decontamination [ ] . strict adherence to standard infection control precautions and frequent, thorough surface cleaning may reduce contact transmission [ ] . one product of the sars experience was the concept of the aerosol-generating procedure. this epidemiological evidence, graded as very low quality, provides useful guidance in the management of symptomatic acutely unwell patients. in the elective peri-operative and other healthcare settings, however, restricting airborne precautions to healthcare workers undertaking aerosol-generating procedures may under-estimate risks to those who are in close proximity to patients but not involved in these procedures. the emphasis on aerosol-generating procedures also potentially risks neglecting the primary barriers to covid- transmission of contact precautions and hand washing. the limitations of this review reflect the limitations of the data. there is very limited evidence related to the risk of sars-cov- transmission in the elective peri-operative environment. the mechanism of infection transmission and the factors that influence it is 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summary of the raw data incorporated by tran et al. [ ] of evidence relating aerosol-generating procedures to sars-cov- infection among healthcare workers.*p < . ; or, odds ration; rr, relative risk; na, not available; ecg, electrocardiograph ma et al. [ ] this study is based on the same dataset used by liu et al. [ ] . the exposure definition used is different: it reports a risk estimate for exposure to a composite of four procedures (intubation, tracheotomy, airway care, and cardiac resuscitation). to avoid duplication and false comparison, its data is not presented here. healthcare workers exposed to confirmed sars-cov- wong et al. [ ] not applicable to tracheal intubation but reports a cohort of medical students exposed to a single inpatient; key: cord- - vjfkfd authors: peng, shanbi; chen, qikun; liu, enbin title: the role of computational fluid dynamics tools on investigation of pathogen transmission: prevention and control date: - - journal: sci total environ doi: . /j.scitotenv. . sha: doc_id: cord_uid: vjfkfd transmission mechanics of infectious pathogen in various environments are of great complexity and has always been attracting many researchers' attention. as a cost-effective and powerful method, computational fluid dynamics (cfd) plays an important role in numerically solving environmental fluid mechanics. besides, with the development of computer science, an increasing number of researchers start to analyze pathogen transmission by using cfd methods. inspired by the impact of covid- , this review summarizes research works of pathogen transmission based on cfd methods with different models and algorithms. defining the pathogen as the particle or gaseous in cfd simulation is a common method and epidemic models are used in some investigations to rise the authenticity of calculation. although it is not so difficult to describe the physical characteristics of pathogens, how to describe the biological characteristics of it is still a big challenge in the cfd simulation. a series of investigations which analyzed pathogen transmission in different environments (hospital, teaching building, etc) demonstrated the effect of airflow on pathogen transmission and emphasized the importance of reasonable ventilation. finally, this review presented three advanced methods: lbm method, porous media method, and web-based forecasting method. although cfd methods mentioned in this review may not alleviate the current pandemic situation, it helps researchers realize the transmission mechanisms of pathogens like viruses and bacteria and provides guidelines for reducing infection risk in epidemic or pandemic situations. volume, contact angle and environmental temperature were analyzed and the lifetime of droplets under those conditions was investigated. the evaporation of droplets will also be affected by the dust in the air, and this factor should be also considered in the future. different from other particles, pathogens are much smaller and their diameters are generally no more than nm and their motion is largely affected by flowing air, hence it is difficult to analyze their trajectories directly in the atmospheric environment. with the development of computer science, a new method based on computation fluid dynamics (cfd) can be used to solve this problem and it has been already well developed over the years. [ ] and in the next decades, an increasing number of investigations about air pollution, atmosphere environment and pathogen transmission can be found. as mentioned above, the droplet can bring the pathogen into the airflow and hence cause infectious diseases due to the spread of it. normally the droplet with pathogens is generated by coughing or sneezing from the infected and the procedure of droplets generated by sneezing is shown in fig. : the impact of covid- is global and the pandemic situation is closely related to the health of every individual. it does not mean that there is no way to prevent or control it effective vaccines are unavailable though. understanding the transmission of infections such as covid- in various media is of great importance. in this review, the principles of different cfd algorithms are described concisely and intuitively; theories and applications of cfd in investigations of pathogen transmission are summarized. the objective of this research work is to indicate the important role of cfd method in analyzing pathogen transmission. through summarizing various applications of cfd method, the transmission mechanism of pathogens and prevention methods are also concluded in this work. three steps are necessary for numerical analysis by using cfd tools: ( ) generating the mesh model with high quality is the key to ensure the accuracy of calculation; ( ) boundary conditions are required to define variables at the boundary. ( ) different algorithms that can be selected in cfd determine the way of iteration. this work carried out in this section is to summarize the feature of cfd from three aspects: simplification, algorithms diversity and maneuverability. different from experimental methods, the cfd method based on mathematical models that can be operated on computers is effective and cost-saving. in numerical simulations, the pathogens are carried by small particles like solid particles or droplets can be defined by calculation models. although the biological properties of the pathogen are complicated and various, the shape feature of the pathogen carrier is relatively simple to describe. in cfd, those particles can be defined as spheres, tetrahedrons, hexahedrons and even by the shape factor, then the pathogen transmission in different environmental fluids can be solved by utilizing multiphase models. moreover, the transport species model can be also applied to simulations of it. in this model, the infectious pathogen in the air is defined as the pollutant source with a constant concentration (generally measured by the field experiment). characteristics of fourier heat transfer law used to describe the heat exchange: fick law used to describe the mass exchange: (j j is the source diffusion relative to coordinates, d is the diffusion coefficient between two sources) () reynolds transportation law calculates the source quantity in control volume at time "t", which can be described as: introducing the continuous equation: and guass law (divergence law) then, the improved transportation can be written as: combining the balance equation of forces: then, the equation can be written as the form shown below: considering the acceleration caused by forces except the drag force and solving the particle motion in each step by iterative calculation: besides, the volume of fluent (vof) model performs well in simulating pathogen transmission, especially in the gas-liquid interface. in a control volume, the total value of each phase equals % and there are three situations in vof: if the volume fraction of "q" phase is  ,then: ( ) α  , no "q" phase in this cell; ( ) α  , the cell is full of "q" phase; ( ) < α < , interface between "q" phase and other phases can be found in the cell. the momentum equation and the energy equation of vof are determined and shared by each phase. the momentum equation mainly depends on characteristics and volume fraction of each phase and it can be written as below: energy equation of vof can be written as: j o u r n a l p r e -p r o o f k eff is effective thermal conductivity; j j,q is diffusion flux of "j" phase in "q" phase while the h j,q represents the enthalpy of it; s h is the volume of the heating source defined by users. the energy was defined as a variable relating to the average quality in vof: ( ) resistance characteristics in all directions are assumed the same, and the equation can be written as: generally, the inertia resistance coefficient c and viscous coefficient   are needed as the parameter of the boundary condition. taking the medical mask as an example and the way of obtaining these parameters are shown in fig. : the pressure difference (p -p ) between both ends of material from the mask as shown in fig. j o u r n a l p r e -p r o o f can be measured under a velocity input (v i ). the relationship between pressure difference and the input velocity can be described by the equation as: then the coefficient c and   can be calculated in the case of density  and thickness n  are known. some of investigations about transport species model and multiphase model are listed in tab several algorithms are mainly used in recent as summarized in table. . although the mechanism of pathogen transmission in the fluid is complex, the motion of pathogens still follows the hydrodynamics law and can be solved by mathematics models of cfd algorithms. for example, the lbm method can be used to solve pathogen transmission in small-scale while fdm method can be applied on the large-scale transmission of the pathogen. cfd tools are in high compatibility and their computing files can be transferred in a variety of software. in general, the structure of cfd software consists of three parts: pre-processing, solver and post-processing and fig. below shows some options of each part. pathogen transmission in the environment is a complex process. for the sake of the accurate simulation result, the calculation model and parameters of the simulation are necessary. furthermore, epidemic models should be taken into account in numerical simulations. by using experimental methods to get the data that is required in the boundary condition is important, besides, experimental data are also needed to validate the simulation result. this section summarizes various epidemic models that should be used in the simulation. moreover, experimental methods which can be applied to analyzing pathogen transmission are presented in this section as well. although some of the experiments summarized were not used in combination with cfd methods, they can provide valuable references for similar studies by using numerical simulations. poussou, et.al [ ] investigated the effects of moving people on pollutant diffusion and airflow. by combining the piv experiment technology, they used cfd method with a second-order upwind scheme to simulate the airflow. the re-normalization group (rng) k-ε was used in simulation in order to solve the turbulence with the good performance of accuracy, efficiency and robustness; in gao and niu [ ] study, rng k-ε model including the effect of low-reynolds-number is used to solve the airflow and the diffusion of tracer gas which can represent the contaminant transmission are calculated by the equation below: where t,  and  are time, air density and tracer gas concentration respectively. unsteady flow is a big challenge in accurate simulation as zhang, et.al [ ] indicated. flow in the environmental channel is always unsteady, and it hence increases the complexity of simulation on pathogen transmissions. how to treat an unsteady flow as the steady flow in practice is still a difficulty. by defining the wave in hydraulic calculation can effectively simplify the disturbance in unsteady flow. capillary wave [ ] can reflect the disturbance brought by some factors to surface of fluid which can be written as: ( ) for shallow waves: ( ) for deep waves: ku [ ] presented a "waveform" method to model unsteady flow in blood which reflects the relationship between time and volumetric flow rate: fig. volumetric flow rate mantha, et.al [ ] used this method in the simulation of biological flows and found the relationship between wall shear stress and the location of the aneurysm; nanduri, et.al [ ] also used "waveform" to solve the unsteady laminar flow and the objective of this study is to build a human body surface model to simulate the airflow around the body. although this method is useful for analyzing particle transportation in biological flows, it is not suitable for simulating unsteady flow in the atmosphere due to greater disturbance. more, in order to simplify the model for analyzing the airflow in building, axley [ ] presented a multi-zone model which allows users to calculate the hourly rate of airflow between various rooms and dols and walton et.al [ ] improved this model by providing the equation of mass conversion as: based on the dispersal theory which is not limited to the wall-mixed region, multi-zone model parameters should also be considered as well. airflow caused by temperature difference will affect pathogen transmission. chen, et.al [ ] simulated the three cases by combing the multi-zone model and two-way air flow effect in order to demonstrate the effect of temperature difference on air quality of indoor. it can be found from one of the cases they studied, the airflow generated by the temperature difference between bathroom and corridor can transport infectious pathogens, and hence the door of infected zoom should be closed as they suggested. closing doors and windows in a room is not equivalent to obtaining a closed space. the crack of the door and windows is always ignored by researchers when simulating the airflow or pathogen spreading in the building or a single room. by using multi-zone method in cfd simulation, yang, et.al [ ] analyzed the effect of stack and wind effect on contaminating dispersion and found that these factors will cause the contamination horizontally or vertically spread. their research also indicated that the pollutant gas can be transported through cracks of doors and windows and may cause infectious disease. because of the great effectiveness, multi-zone method was widely used in many cases which can be found in wu ( ) where s is the susceptible people in an area, i is the number of infectious people and p represents the pulmonary ventilation rate of susceptible people. zhu, et.al [ ] investigated the potential risk of infection in public transportation by using wells-riley model in cfd simulations. it was proved in their study that the closer to the operating exhaust in the bus the infected person is, the smaller the infection risk bringing to others is. besides, this study indicated that the ventilation system of most of buses is not effective because there is only one single exhaust was located in the middle of the cabin or the back wall. yan, et.al [ ] studied the transmission of coughing particles in the breathing zone of people. in their investigation, the method that combines the wells-riley model and the lagrange model in cfd was used. it was illustrated from this study that the location of releasing particles will affect the particle travel distance. based on the well-riley model, this research work has also presented a quantifiable approach to assess the infection risk of passengers. these studies are helpful for improving the design of the vehicle ventilation system and hence reduce the infection risk though, they did not consider the effect of altitude on airflow patterns in vehicles. the wells-riley model can also be applied to building simulation. niu based on physical characteristics like aerodynamics of respiration droplets, chaudhuri, et.al [ ] proposed a numerical model for the early state of covid- pandemic by integrated the chemical mechanism and pandemic evolution equations. the " " this work derived by using the theory of collision rate represents the lifetime of the droplet. it can be written as: some investigations based on these models are listed below in tab. : more, hathway [ ] combined the cfd method and sir model in order to analyze pathogen transmission in hospital space and asanuma and kazuhide ito [ ] predicted the exposure risk of the population in the hospital by using cfd with considering the sir model. from these investigations, it can be found that this epidemic model is well performed in simulating the spread of infectious diseases. however, the number of researches that applied these models to cfd simulation is still a small amount due to the complexity of modelling and calculation in simulating the airflow or particle transport among a crowd of people. in cfd simulation, not only the mesh model is crucial but also the parameter of simulation is of great importance to let users obtain the results they require. generally, the boundary condition such as velocity, pressure, turbulence intensity can be measured from experiments. in recent, micro-particles experiments and tracer gas experiments are most used in investigations of airborne transmission. romano, et.al [ ] simulated the airflow pattern and concentration of airborne particles in an operating theater (ot) by using cfd method. they also conducted an experiment in order to verify the accuracy of simulation results and in their experiment, a six-way aerosol distributor was used to convey the generated aerosol particles; opc (optical particles counter) equipped with a dilution system was used to measure the particle concentration; a rotating vane anemometer and a thermo-anemometer were used to measure the velocity and temperature respectively. they also validated the simulation result by comparing the data measured from the experiment and found that the experimental and numerical data were well coincided (error is less than % for temperature and % for velocity). the value of mean absolute percentage error for particle concentration is % though, the experimental curve and the numerical curve are similar in changing trends. therefore, experiments involving particle-fluid flow are more suitable for qualitative analysis, because it is hard to accurately control conditions such as temperature, pressure, stable velocity of flow. zhou, et.al [ ] established a model which can be used to predict the distribution of negative ions produced by the air ionizer and the efficiency of this device. in their experiment, an emission system consisting of a compressor and nebulizer was used to compress the filtered air and aerosolize the j o u r n a l p r e -p r o o f bacteria; an ion counter was used to test the emission concentration. in order to present their experiment clearly, the installed experimental system is shown below in fig. : fig. the detailed experimental setup [ ] the objective of the experiment carried out in this work was to measure the susceptibility besides, it was proved that the bacterial load in the shower air will increase while turning on the shower spray. the effect of droplet velocity and distribution on aerosolized bacterial groups was not given this study, more, the parameter of shower such as water temperature, nuzzle structures should be also considered in the experiment as well. choi, et.al [ ] classified the airborne particle according to their optical properties by using experimental methods. ink-jet aerosol generator (ijag) was used to generate, dry the airborne particle, the light-scattering signal was used to estimate the correlation value in the classification analysis of airborne particles. the correlation value proposed in this work is helpful for particle detection and classification though, how to apply this method to detect other airborne pathogens with more complicated biological characteristics is required to be furthered. mei ( ) conveyed air from experiment needs to be filtered; ( ) particles should be uniformly delivered. j o u r n a l p r e -p r o o f experiments to analyzed the particle are useful for understanding the motion law of it. however, it is difficult to massively measure the characteristic of nano-scale particles. the tracer gas method is also a common method in analyzing the pollution diffusion and airflow patterns. tracer gas can be mixed with air without any changes and it can be easily detected because of special physical characteristics. helium, nitrogen, argon and carbon dioxide are always chosen to carry out the experiment as a tracer gas. gao, et.al [ ] combined the use of experiment and cfd method to study airborne transmission in different flats of a high-rise building and to verify their simulation, the data of tracer gas experiment from denmark aalborg university [ ] is used. the analysis of this work is comprehensive by illustrating the transmission mechanism of the airborne virus and how to control virus transmission in a high building based on this investigation is needed to be furthered. to investigate airborne transmission between horizontal adjacent units, wu, et.al [ ] analyzed influence factors of transmission route especially the contribution of wind force and thermal buoyancy force and found from the result that the wind force is the main driving force to affect the inter-unit dispersion. the experiment conducted in this work is conducted in a slab-type building in hongkong, sf was used as the tracer gas and injected by the air samples; co was used to calculate the ventilation rate and monitored by tsi q-trak and co sensor. although the spread risk may be overestimated in the analysis because the crack of the door and windows can cause the pathogens aerosol deposit, this work still provides a valuable study in identifying the possible transmission route of the airborne. ai, et.al [ ] used a tracer gas (no ) experiment to examine the characteristics of airborne transmission of the exhaled droplet between two people in an experimental room. two manikins were used to represent an exposed people and an infected people; air velocity was measured by the swema omnidirectional anemometer; pt sensor was used to monitor the air temperature; to test the tracer gas concentration, a faster concentration meter (fmc) and innova multi-gas sampler and monitor are used. this work has indicated an interaction between exhaled gas and supply flow and analyzed the impact of these factors on infection risk for an exposed person facing an infectious person. although the experiment carried out in this work was based on a steady-state condition without taking the impact factor of time into consideration, it provided an effective method for researches afterward. ( ) culturing and filtering the suitable bacteria; ( ) aerosolizing the bacteria particles and conveying into measuring environment; ( ) analyzing the airborne transmission of e. coli by using pcr. and the flow chart given by them is shown below in fig. : fig. experiment process of tracing bacteria [ ] it will be more persuasive if this process can be carried out in an experiment of researches by using the tracer gas method or particle experiment. however, it will also increase the risk in conducting experiments if the bacteria or virus are highly infectious. overall, both the particle experiment and tracer gas experiment can help people understand the process of pathogen transmission, moreover, it provides crucial information for cfd users. on the one hand, the information including experimental data can be used as boundary conditions in cfd simulation; on the other hand, the results of the experiment can be quantitively or qualitatively verified to ensure the accuracy of cfd simulation. therefore, designing an effective experiment in analyzing pathogen transmission is necessary, it makes the simulation result more convincing. j o u r n a l p r e -p r o o f transmission of pathogens can be different in various spaces and when the epidemic outbreaks caused by infectious pathogens, hospitals will become a high-risk place and may lead to a second infection. how to control the pathogen in hospitals by using an effective ventilation system becomes a great concern. kao et.al [ ] [ ] they used the tracer gas no to replace the viral gas emitted from the patient and simulated three cases under different volumes of supplied air and exhausted air, the simulation results presented the diffusion process of tracer gas as in fig. : fig. the simulation of tracer gas diffusion [ ] in the same year, this research group studied a similar topic by using the tracer gas and cfd method. in this analysis, the stack effect of high rise building on airflow is considered and the simulation model is based on the general hospital k in korea as shown in fig. . fig. the prince of wales hospital and the simulation model of it [ ] they have simulated the spread of tracer gas in the wards of both on the lower floor ( f) and higher floor ( f) to demonstrate the stack effect. some of the simulation results are shown as shown in fig. : figure. simulation results of the tracer gas transmission in wards of different floors [ ] j o u r n a l p r e -p r o o f these researches above mainly investigated pathogen transmission inside the hospital and they are meaningful in protecting patients and hospital staff. however, not only pathogen transmission inside the hospital is dangerous, but the pollutant emission from the hospital is also a great concern for public health. chang et.al [ ] by using cfd modeled the atmospheric environment out the hospital and simulated the spread of the viral (sars) gas emitted from the hospital. the mesh model of simulation is shown in fig. : fig. mesh model of simulation [ ] this model was generated by tetrahedral grids; the wind velocity as a boundary parameter was measured by the hot-film probe and anemometry equipment; wind directions were considered in the calculation. moreover, in order to verify this model, tracer gas was used in the experiment model with a : scale. the simulation result below in fig. respectively shows the concentration contour of pollutant gas at both the height of the roof chimney (right) and . m (left) above the ground. fig. diffusion of pollutant gas emitted from hospital [ ] by the simulation results, they indicated that both the maximum concentration and mean concentration of pollutant gas in small and would not affect residents' health. however, when a large number of sars patients were arranged in the hospital, it is still a bit risky for people who actives in the high-concentration area on the ground level. research works above were mainly focused on the airflow pattern or impact of ventilation on pathogen transmission. however, cross-infection frequently happened in hospitals and should be paid attention to in case studies of pathogen transmission. based on eulerian-lagrangian method, a case study proposed by wang, et.al [ ] has illustrated that the sneezing process from a virus carrier is ventilation is easier to be controlled, hence, it is necessary to ensure safety when emitted the viral gas from the exhausted system from the hospital. without professional medical equipment, the buildings with high population density such as residential buildings, commercial buildings and campus buildings are in higher infection risk. yang, et.al [ ] studied natural ventilation in teaching buildings by using cfd method. in their investigation, phoenics with rans model was used to simulate the ventilation; the simple algorithm was used to calculate and presto scheme was used to staggered the pressure interpolation; the wind profile at inlet boundary of the simulation was determined by the equation of ashrae [ ] as: . () ref u y y uh     ( ) through the simulation, they indicated that the ventilation of the teaching building with a "line-type" corridor is better than that of the inside corridor; they have also presented an optimization design for better ventilation in teaching buildings by determining the best wind angle. moreover, cuce, et.al [ ] studied the natural ventilation in school buildings based on its working principles and limitation of passive ventilation; in a crowded room, the concentration of volatile organic substances generated by human skin oil is high, xiong, et.al it can be observed from simulations that particles will spread in flushing because of the turbulence generated by the high speed of flowing water. more, it was obtained that %~ % of particles can reach above the toilet seat. the research of this work is meaningful and it was indicated that before flushing, laying down the lid is useful for preventing the virus transmission. more, washing the seat of the toilet is necessary because the floating virus may deposit on the surface of it. this research group has also analyzed the movement of a virus-laden particle in the process of urinal flushing [ ] . without the prevention, over % of particles can escape from the urinal and the particle can reach the highest position of . m at only . s . so it is mandatory to wear a mask in public to reduce infection risk. furthering this study about virus transmission in the squat toilet by applying the method j o u r n a l p r e -p r o o f proposed in this work is important because, in many places such as china, the use of the squat toilet is higher than that of the sitting toilet in public. some investigations of cfd simulations of ventilation or pathogen transmission in the building environment are summarized below in tab. : it can be obtained from these investigations: ( ) ventilation is one of the most effective methods to control the pathogens transmission and the reasonable arrangement of the ventilation system is necessary. ( ) the effect of the stack effect should be considered when analyzing the ventilation in high-rise buildings. ( ) rooms with infected patients need to be diluted with plenty of fresh air. traffic vehicles are also dangerous when there are infectious patients. under the high personnel density and weak ventilation system, it is difficult to control the pathogen such as the airborne virus. according to this problem, more and more researchers investigated airflow in various kinds of vehicles by using cfd methods. ( ) two particles collisions are mainly considered; ( ) the velocity distribution of each particle exists independently; ( ) the external force does not affect the dynamic behavior of the local collision. there are various models that can be used in the simulation of lbm and these models can be defined by the layout of lattice, some models which are in common use are shown in fig. ( d) and face masks have been used to prevent virus transmission and it is necessary for the epidemic situation. li [ ] simulated the aerodynamic behavior of a gas mask which consists of two filter layers. fig. : fig. grid model of the gas mask (left) and the flow field of simulation (right) [ ] this research indicated that the design of the mask such as the hole properties is important: larger hole area and greater hole distribution lead to a lower pressure drop, a smaller dead zone, and so on. theoretical analysis was mainly studied in this work and it has also provided a reference in designing a sufficient mask. dbouk, et.al [ ] analyzed the role of the mask in preventing the droplet transmission by utilizing openfoam with a combination of the use of turbulence model and porous model. in the simulation model, the mask fitting to the face was considered which is shown as in fig. : turbulent flow in the atmosphere is unsteady due to the changing weather and it is difficult to measure the airborne transmission in the atmospheric environment directly. although aerodynamics models of airborne transmission based on cfd method have been greatly developed, it is still a big challenge for applying them to the large-scale environment. seo, et.al [ ] presented a method based on meteorological information from web-system that can help for solving this problem. this research group analyzed the relationship between foot-and-mouth disease (fmd) spread and hourly wind in anseong. moreover, they collected the infection data and built a model by using the gis method. then, they used a code division multiple access (cdma) to send the weather data to a weather data acquisition server (wdas) in every minutes and interlock the data with geographical information. the openfoam code was used to simulate the spread of the airborne virus the simulation result can well describe the virus transmission. the process of the cfd simulation based on web-based forecasting system can be described as below in fig. : fig. detailed process of cfd simulation based on web-based forecasting system the web-based forecasting system has been widely used in various cases such as flooding (li, j o u r n a l p r e -p r o o f et.al [ ] ), tourism demand (song, et.al [ ] ), monitoring of marine pollution (kulawiak, et.al [ ] ), etc. however, there are few studies about pathogen transmission based on combing the web-based forecasting system and cfd method. hence, more databases of pathogen transmission and meteorological information are needed to develop the web-based forecasting system in the analysis of pathogen transmission. from investigations summarized in this review, it can be found that ventilation is one of the most effective methods to control pathogen transmission in the air. different environments require different ventilation systems, the building environment such as teaching building and residential building and the natural ventilation method is the main way to dilute the concentration of the pathogen. however, in high-risk zones such as hospitals, not only the reasonable ventilation of indoor is required, but also the infectious risk due to emission needs to be considered. besides, pathogen transmission in j o u r n a l p r e -p r o o f journal pre-proof different vehicles is distinct, a proper strategy of ventilation is necessary for transportation especially the airplane and high-speed train with an enclosed environment. this review also presented some advanced methods for cfd application on pathogen transmission according to recent investigations as: ( ) lbm simulation allows researchers to investigate pathogen transmission from the mesoscale level; ( ) based on the porous media model, researchers can better analyze the transport of pathogens in complex media, such as medical masks, human organs, etc. ( ) web-based forecasting system can be combined with the cfd method to analyze the transmission of infectious pathogens in the atmospheric 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web-based forecasting system for the airborne spread of livestock infectious disease using computational fluid dynamics a web-based flood forecasting system for shuangpai region developing a web-based tourism demand forecasting system interactive visualization of marine pollution monitoring and forecasting data via a web-based gis the authors are grateful for the research support received from applied basic the authors declared that they have no conflicts of interest to this work as: we declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.j o u r n a l p r e -p r o o f key: cord- -j dik f authors: zhang, x. sophie; duchaine, caroline title: sars-cov- and health care worker protection in low-risk settings: a review of modes of transmission and a novel airborne model involving inhalable particles date: - - journal: clin microbiol rev doi: . /cmr. - sha: doc_id: cord_uid: j dik f since the beginning of the covid- pandemic, there has been intense debate over sars-cov- ’s mode of transmission and appropriate personal protective equipment for health care workers in low-risk settings. the objective of this review is to identify and appraise the available evidence (clinical trials and laboratory studies on masks and respirators, epidemiological studies, and air sampling studies), clarify key concepts and necessary conditions for airborne transmission, and shed light on knowledge gaps in the field. we find that, except for aerosol-generating procedures, the overall data in support of airborne transmission—taken in its traditional definition (long-distance and respirable aerosols)—are weak, based predominantly on indirect and experimental rather than clinical or epidemiological evidence. consequently, we propose a revised and broader definition of “airborne,” going beyond the current droplet and aerosol dichotomy and involving short-range inhalable particles, supported by data targeting the nose as the main viral receptor site. this new model better explains clinical observations, especially in the context of close and prolonged contacts between health care workers and patients, and reconciles seemingly contradictory data in the sars-cov- literature. the model also carries important implications for personal protective equipment and environmental controls, such as ventilation, in health care settings. however, further studies, especially clinical trials, are needed to complete the picture. t he world is facing a devastating new infectious disease, with only preliminary scientific data to guide policy. disagreement with the world health organization's stance on personal protective equipment (ppe), guideline changes over time (e.g., european cdc, france) , and inconsistent data on the effectiveness of medical masks have left health care workers (hcws) wondering if they are sufficiently protected. the general consensus is that sars-cov- predominantly transmits through droplets and contact (although precise mechanisms for both modes of transmission are yet to be fully understood), but the airborne debate is still raging. this review attempts to summarize current cumulative data on sars-cov- 's modes of transmission and identify gaps in research while offering preliminary answers to the question on everyone's mind: is the airborne route significant and should we modify our covid- ppe recommendations for frontline workers in low-risk settings? this review starts by investigating the differences between droplets and aerosols and goes over prerequisites for clinically significant airborne transmission. it then appraises the evidence in support of the airborne hypothesis: trials and experiments on masks, epidemiological studies, data on sars-cov- , air sampling findings, and aerosol studies. the focus is on low-risk health care settings, in the absence of aerosolgenerating procedures (agps), with a special look at long-term-care facilities where major outbreaks occurred. national and international guidelines are compared, and alternative hypotheses for sars-cov- 's contagiousness are explored, such as presymptomatic transmission, as well as fomite and fecal routes. possible mechanisms behind high hcw infection rates are described, and the limits of the precautionary principle are addressed. finally, a revised model of inhalable particles is proposed to support ppe recommendations and guide future research. determining sars-cov- 's main mode of transmission is essential as it informs clinical guidelines for patient management, prevention practices, and hcw protection. while infectious disease precautions in health care settings are transmission-based (either airborne or droplet), in reality, the distinction is not clear-cut; instead, they are two ends of a spectrum. in the literature, respiratory droplets are usually defined as larger particles (diameter Ͼ m) sometimes visible to the human eye, produced during spitting, sneezing, and coughing. these droplets are thought to be the main mode of transmission of covid- ( ), and they typically travel to m before landing on surrounding surfaces. however, they may be propelled further in the presence of ventilation ( ) or forceful ejection (e.g., a violent sneeze) ( ) and under certain environmental conditions (e.g., cool and humid) ( ) . the sars-cov- virus is also thought to be transmitted by direct contact person to person (e.g., exchange of saliva or a handshake) or by indirect contact through intermediate objects (e.g., sharing of cups, doorknobs). generally, contact transmissions occur when contaminated hands are brought to the face and touch mucous membranes (eyes, nose, and mouth). the fate of smaller droplets may be desiccation (evaporation of the liquid) and formation of particles called droplet nuclei, or aerosols, which can contain infectious agents but also secretions, cells, surfactant, and any other product contained in the original droplet. traditionally, aerosols are defined as particles of Ͻ m that can remain airborne for prolonged periods (several minutes or even hours) and travel long distances with air currents (several meters away). with the potential for direct entry into the lungs, they are the primary mode of transmission for tuberculosis, measles, and varicella. in other communicable diseases, such as influenza, aerosols are considered opportunistic and play a role that is of variable importance depending on the context ( ) . conversely, in the field of industrial hygiene, occupational exposure of different body regions to harmful airborne agents is classified into three overlapping categories, according to the median size of penetrating particles ( ): m for nose and mouth (inhalable), m for trachea and bronchi (thoracic), and m for alveoli and air exchange regions (respirable). this aerosol classification was recently reviewed and elegantly illustrated by milton ( ) . in this model, the concept of aerosol inhalability is defined as the fraction of particles capable of penetrating into the head airways or below, upon inhalation: it excludes larger droplets with ballistic behavior (since inhalation requires suspension in the air) but includes particles that are larger than the traditional -m definition of aerosols. throughout our review, this more nuanced conceptualization of airborne transmission will be explored, and the larger inhalable aerosols will be contrasted to the smaller respirable aerosols from the classic airborne model. finally, some procedures, such as intubation, are known to generate aerosols, while others, such as nebulizer therapy, are associated with an uncertain risk of aerosolization ( ) . n s (or similar respiratory protection devices) are unequivocally recommended for hcws working in high-risk settings with agps, although controversy still remains around which interventions constitute an agp. the design protocol for the n , and the origin of the name, is based on its efficiency at capturing % of the most penetrating size range ( . m) of respirable aerosols ( ) . by default, respirators are therefore capable of blocking the entire spectrum of airborne particles. medical masks, on the other hand, are designed to block droplets and do not undergo aerosol-filtering tests; they are therefore not considered to provide respiratory protection against airborne transmission. given that substantial disagreement persists on the importance of natural aerosol generation by covid- patients, and consequently, the necessary level of respiratory protection in non-agp contexts, our review will focus on transmission and ppe in low-risk health care settings. natural respiratory activities such as breathing, talking, and coughing can generate a broad range of particle sizes, from submicron aerosols to large droplets ( ) ( ) ( ) ( ) ( ) . for the viral aerosols to constitute a clinically significant risk of airborne infection, three conditions are required: viral load (the concentration of infectious particles), infectivity (the ability of a virion to infect a host cell), and tropism (the specificity of a virus for a particular host cell type or tissue). since the amount of sars-cov- virus required to infect a host is unknown, and likely varies from one individual to another (preprint article [ ] ), it is hard to determine whether typical respiratory activity generates sufficient quantities of infectious aerosols for airborne transmission. in a light-scattering study, stadnytskyi et al. estimated that min of loud speaking generated at least , virion-containing droplet nuclei that remain airborne for more than min ( ) . however, the calculations were based on several theoretical assumptions and data from sputum load was incorrectly applied to saliva, likely overestimating aerosol viral loads. in this model, the probability that a hypothetical speech-generated droplet nucleus of m contains a sars-cov- virion is only . %, after aerosolization and desiccation. furthermore, in a mathematical modeling study on viral aerosol emissions, an individual with a high viral load was estimated to emit only modest amounts of virus with regular breathing ( , copies/ m ) compared to coughing ( . million copies/m ) ( ). accordingly, the authors conclude that the infectious risk posed by a typical covid- patient is low, especially if symptoms are mild, and only a few individuals with high viral load pose a significant risk. these authors suggest that strict respiratory protection may be needed in the case of prolonged exposure to high emitters in poorly ventilated closed environments. notwithstanding, evidence of aerosol generation during natural respiratory activity or the presence of viral rna in the air are not sufficient to prove that the virus remains infectious once airborne. not all viruses are equally stable in the air, and further aerodynamic and environmental factors may inactivate viruses during aerosolization ( ) . therefore, upon detecting sars-cov- aerosols, infectivity must then be demonstrated. evaluation of infectivity is usually done with viral cultures: researchers were able to culture rhinovirus ( ) and influenza ( ) from the fine particles emitted naturally by infected participants, and only recent yet unpublished research has started to achieve the same for sars-cov- . however, it is important to note that culture methods vary between viruses and false-negative results due to the low sensitivity of commonly used sars-cov- cultures could have possibly underestimated infectivity from air samples until now. for instance, clinical samples (e.g., nasopharyngeal swabs) that yield positive cultures typically have low pcr cycle threshold (c t ) values of Ͻ (samira mubareka, university of toronto, unpublished data), while c t values for environmental samples (including air samples) are often Ͼ . finally, since particles penetrate and deposit in different parts of the respiratory tract depending on size, knowledge of target locations for infection (e.g., viral tropism) can hint at typical size range and mode of transmission. sars-cov- 's main entry into host cells is through ace receptors, which seem to be largely expressed in the nose ( , ) . importantly, the highest and most consistent signs of viral infectivity have been observed for nasal cells, with a gradient along the respiratory tract characterized by a marked reduction in infectivity in the distal bronchioles and alveoli. this may suggest that lower airways are not targets for infection and that transmission via respirable aerosols is not predominant. interestingly, the typical patchy bilateral pneumonia found in covid- patients is postulated to be caused by oropharyngeal microaspirations rather than direct viral seeding in the lungs, possibly accounting for the increased risk with age and comorbidities ( ) . different types of studies suggest airborne transmission, but their levels of evidence are variable. in this review, given the focus on health care settings and hcw protection, studies are appraised according to clinical relevance: hard outcomes (e.g., morbidity) are markers of higher levels of evidence, while surrogate outcomes (e.g., pathophysiological mechanisms, modeling, and laboratory results) are considered lower levels of evidence, independent of method or design quality (table ) . the term "mask," as used here, comprises medical masks, surgical masks, procedural masks, fluid-resistant masks, and face masks worn by hcws. the term "respirator" is used interchangeably with n , which is the equivalent of ffp (european standard filtering facepiece) and kf (korean filter) respirators. in the absence of clinical trials on sars-cov- , trials on other viruses with similar infection patterns (i.e., documented droplet and suspected airborne transmission) are the best available alternatives. recent systematic and narrative reviews comparing the effectiveness of respirators versus masks against common viral respiratory infections (including coronaviruses and influenza viruses such as h n ) come to similar conclusions: both devices offer comparable protection in health care settings ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . a few reviews ( ) ( ) ( ) favor respirators, on the basis of two randomized controlled trials (rcts) conducted by the same lead authors, macintyre et al. (table ) ( , ) . individually and in combination (meta-analysis) ( ), these two rcts report superiority of continuous n use over mask use for a single self-reported outcome: clinical respiratory illness (cri), defined as two or more respiratory symptoms or one respiratory symptom and a systemic symptom. no difference is found for other more rigorous outcomes: influenza-like illness (ili; defined as fever and one respiratory symptom), laboratory-confirmed viral respiratory infection (lvi), or laboratory-confirmed influenza (lci). the difference between the self-reported outcome and the laboratory results could be explained by detection bias in the absence of participant blinding and universal testing: higher symptom reporting rates in the medical mask group, rather than true infection, could have skewed cri results in favor of respirators. furthermore, selection bias is suspected to have occurred during allocation, given the surprisingly uneven distribution of major confounding variables such as agps, age, and handwashing, between the n and mask groups. the other two rcts ( , ) included in the reviews had more robust methodologies and lesser risk of bias (e.g., comparable groups, test results for all participants, and longer follow-up periods). the studies did not find any significant differences between respirators and masks for clinical and laboratory outcomes, in both low and high-risk settings. a recent systematic review of observational studies suggests that "n respirators might be more strongly associated with protection from viral transmission than surgical masks" ( ) . regrettably, of studies, not a single one directly compared respirators to masks, and nine of them looked at sars or mers rather than sars-cov- . the lone covid- study only compared n s to no masks and did not include medical masks at all ( ) . the researchers drew their conclusions by comparing the pooled results for n studies with the pooled results for mask studies, obtaining a p value for interaction by mask type that was borderline significant after partial adjustment. however, the difference between the two groups was not statistically significant (overlapping confidence intervals) and the very high heterogeneity (i ϭ %) could have undermined the validity of the meta-analysis. also, the presence of agps was unknown in of studies: since all the studies were done in a hospital setting where agps frequently occur, and n s are known to be superior in high-risk settings, failure to adjust for agps will skew the results in favor of n s. finally, all studies were observational and many did not control for important confounding factors, leading the authors themselves to rate the overall certainty for mask data as low. since many trials studied airborne viruses (e.g., influenza) and included exposure to agps, it may seem surprising that the vast majority of reviews, past and present, did not find respirators to be superior to masks. a possible explanation is that, while not designed to filter very fine particles, the medical mask might nonetheless be effective in blocking the low levels of aerosols produced in most health care contexts. a few case reports seem to support this hypothesis. for example, in a study of two severely ill covid- patients who were not initially isolated, contact tracing identified hcws, of whom only tested positive ( ) . all infected hcws had close and prolonged contact without wearing the mask or ocular protection and had been present during agps. on the other hand, all of the hcws who used droplet and contact precautions did not get infected, leading the authors to conclude that there was no evidence of airborne transmission. similarly, two studies reported on and intensive care hcws exposed to an intubated and mechanically ventilated covid- patient: and % wore surgical masks, respectively, and the others wore n s, yet none were infected according to clinical and laboratoryconfirmed results ( , ) . furthermore, a covid- patient who stayed h in an open cubicle of a general ward, coughed frequently, and received high-flow oxygen at liters/min, did not infect any of the staff members and patients, of which and , respectively, had close contacts wearing either n s or masks ( ) . finally, strict contact and droplet precautions, as well as the use of masks rather than respirators, completely prevented nosocomial transmission from three community-infected hcws to coworkers and patients in an italian hospital ( ) . as for the effectiveness of medical masks as source control (blocking particles emitted by infected individuals), clinical trials are scarce ( ) ( ) ( ) , and they suggest a reduction of clinical but not laboratory-confirmed viral illnesses. therefore, we must turn to lower levels of evidence (e.g., laboratory studies) for further guidance. the ability of protection devices to control either source emission (e.g., infected individuals) or exposure prevention (e.g., hcws) has been the subject of several laboratory studies, whose findings are summarized in table . the majority show high filtration capacity for both masks and respirators. the latter, however, are known to provide better protection against fine particles (Ͻ m) because of a far superior fit factor. interestingly, source control with masks may be superior to exposure prevention by either respirators or masks. although these studies provide relevant information on the theoretical performances of protection devices, the experimental generation process and particle sizes may not resemble natural respiratory activity. also, many studies suffer from major limitations and inconsistencies in design: the use of different respiratory viruses with distinct behaviors, the lack of information on the size distribution of particles tested, the use of nonstandardized test particles (e.g., in contrast to standard respirator testing protocols), selection bias for ballistic behavior (petri dish sampling) rather than aerosols (air sampling), and confounding biases (e.g., fit factor and variable cough intensities). more importantly, many laboratory studies fail to account for crucial clinical and behavioral factors. for example, studies have reported lower adherence to n respirators compared to medical masks, due to higher rates of adverse events ( , , ) . in one study on the tolerability of respirators in hcws, the probability of discontinuing respirator use during an -h work shift was around to %, despite regular -or -min breaks every h ( ) . other studies show that one of the most challenging steps in donning and doffing is n use, which can result in a higher risk of contamination ( , ) . in addition, an important, yet overlooked factor is the fitting of the device on the face (or the degree of leakage of particles around the edges). the fit factor varies between mask models and is typically very high for respirators, which is probably its main advantage. however, a poorly fitted respirator could perform no better than a loosely fitting mask ( ) . seals used in some laboratory studies are poor surrogates for actual fitting on a hcw. finally, during exposure to covid- patients, hcws are instructed to wear ocular protection in addition to masks, and yet very few studies examine the combined effects of overall ppe. some experiments have shown that masks integrated with visors ( ) and face shields individually ( ) are protective not only against droplets but also aerosols (but efficiency decreases with exposure time). the vast majority of epidemiological studies that analyze sars-cov- outbreak patterns (case identification, contact tracing, epidemiological curves, and basic reproduction number or r estimates), undertaken in a variety of contexts, including health care facilities ( ) ( ) ( ) ( ) ( ) , homes ( ) , churches ( ), fitness facilities ( ), call centers ( ), airplanes ( ) , and company conferences and tour groups ( ) , are in agreement: contact and droplets were the probable modes of transmission. rather than long-range propagation and frequent mass outbreaks typical of airborne patterns, the distribution of infected individuals was strongly correlated with close encounters and secondary attack rates were estimated be very low, around % ( ) . rather than high r estimates typical of airborne viral pathogens such as chickenpox ( to ) ( ) and measles ( to ) ( ), community reproduction numbers fell between and ( , ) and were easily lowered by droplet and contact precautions ( ) . moreover, the who's largescale epidemiological analysis of , covid- patients did not confirm any cases of long-range airborne transmission ( ) . in health care settings, the use of medical masks appears to be sufficiently protective of hcws exposed to covid- patients, as mentioned previously. several epidemiological reports from hospitals around the world even show little or no nosocomial transmission in the absence of recommended ppe (i.e., no n s or masks during agps or improper mask use during close contact). combining the findings of six studies, out of a cumulative total of hcws exposed to covid- patients without proper protection, only hcws were infected. all five workers either did not wear any mask or used a mask intermittently during an agp or prolonged exposure (Ͼ min) ( ) ( ) ( ) ( ) ( ) ( ) . these low levels of transmission from nonisolated covid- patients to nonequipped hcws are not suggestive of significant airborne transmission and support the effectiveness of basic pci measures beyond ppe. nonetheless, some epidemiological evidence is compatible with short-range airborne transmission. the washington choir outbreak is known for linking aerosolization from loud vocalization (i.e., singing) to rapid spread; however, the index case was symptomatic rather than asymptomatic as reported by the media ( ), and multiple opportunities for droplet or fomite transmission were revealed in the published investigation ( ) . in turn, the well-known outbreak at the guangzhou restaurant has been the subject of controversy: based on epidemiological data, one research team determined that droplets, expelled further than usual by air conditioning, were the probable source of transmission from an index patient to two neighboring tables ( ); a second team, based on computer modeling and a tracer gas (a surrogate for exhaled particles), ruled in favor of airborne transmission (preprint article [ ] ). moreover, a recently published study analyzed an outbreak involving two groups who rode separate buses to attend a -participant worship event ( ) . while no transmission occurred on bus , passengers on bus were infected, some of whom were sitting up to m away from the index case. seven other participants who did not ride on the buses were infected, all of whom reported close contact with the index case during the outdoor event. since proximity to source was not correlated with infection risk in the bus, but window and door seats seemed to be protective, the researchers hypothesized that bus 's closed environment and air recirculation enabled airborne transmission to occur. furthermore, the widely studied diamond princess cruise ship outbreak is still up for debate. based on epidemiological data showing exclusive in-room transmission following imposed quarantine, as well as no correlation between infection patterns and central ventilation system, one research team concluded that close contacts and fomites were the main transmission routes (preprint article [ ] ). in support of this view, an environmental study failed to detect any virus in air samples despite widespread positive surface sampling; however, passengers had disembarked at the time of sampling ( ) . conversely, a modelization study simulating the cruise ship outbreak found that the epidemic models which best predicted the empirical data suggested predominant short-range and long-range airborne transmission (preprint article [ ] ). finally, two studies ( , ) analyzed the impacts of public health policies on the epidemiological curves of highly impacted regions: the first compared wuhan, italy, and new york city (nyc) while the second compared u.s. states. according to the authors, mask-wearing but not social distancing (quarantine, stay-at-home, and lockdown) policies were effective in curtailing covid- outbreaks, suggesting that the main route of transmission is airborne rather than contact and droplets. however, the studies have come under criticism for not accounting for major confounding biases, such as differences between the three regions in terms of timing of lockdown (at Ͼ , confirmed cases in italy and nyc [ , ] compared to confirmed cases in wuhan [ ] ), public health policy (e.g., contact tracing efficiency, testing criteria, and access), and population demographics ( ) . in addition, using the date of governmentmandated mask-wearing as the start point for regression slopes is misleading, since the impacts of any new policy on epidemiological curves are delayed and nonlinear, especially given uneven compliance to mask-wearing, typically around % in the united states. ( ) , but variable between states, compared to over % in asia ( ) . if we further scrutinize nyc (as well as other states), it appears that the number of daily new cases, hospital admissions, and deaths started to fall before the mask-wearing order ( ) , thus warranting an alternative explanation for the decline, such as an increasing proportion of immune individuals or the adoption of more aggressive testing. moreover, researchers could not explain why certain states managed to control their outbreaks without mask-wearing policies and others did not show a decline in new or cumulated cases after facemask adoption. beyond the airborne versus droplet debate, there is consensus among epidemiologists: prolonged short-range exposure is the main risk factor. interestingly, the revised airborne model presented in the conclusions: proposed model (below), involving inhalable aerosols, can accurately explain epidemiological observations as well as the dynamics of several contentious outbreaks. despite some caveats, sars-cov- studies may be useful to understand sars-cov- , given that they share around % of their genomic sequence ( ) . a well-studied outbreak at amoy gardens in hong kong, a high-rise housing estate where Ͼ tenants were confirmed infected despite little contact between them, was studied by different teams ( , ) . the majority agree on airborne transmission of sars-cov- , originating from the aerosolization of feces and urine through hydraulic action (i.e., toilet flushing) of an index patient who presented with diarrhea and high viral load in excrements. this particular outbreak involved primarily environmental and engineering factors such as unsealed floor drain traps, bathroom fans causing negative pressure, bathroom fixtures contributing to drain overload or backflow, and the specific configuration of the exhaust system, which contributed to drawing aerosolized sewer droplets from the plumbing system back into the bathrooms and spreading them throughout the building ( ) . the involvement of respiratory aerosols was not hypothesized. more relevant to health care settings is a hong kong hospital outbreak study on medical students exposed to an index sars patient: proximity with the patient was the main risk factor, but the duration of contact did not appear to be associated with transmission. the researchers conclude that the mode of transmission was probably through droplets and contact, but airborne transmission could not be excluded, especially given the presence of a potential agp ( -min nebulizer therapy four times a day) ( ) . furthermore, in a canadian study, air samples were collected from sars patient rooms in low-risk and high-risk settings, as well as four adjacent nursing support areas: of the wet air samples and none of the dry air samples were pcr positive ( ) . the two positive samples were both from the room of a single recovering sars patient where agps did not appear to be performed. subsequent viral culture; however, turned out negative. as for protection devices, a case-control study in five hong kong hospitals showed no difference in infection rates between hcws wearing a mask or a respirator, when exposed to sars patients ( ) . other observational studies ( ) ( ) ( ) done in high-risk settings (including agps) suggest possible n superiority, but the studies either did not adequately compare the two equipment types or did not obtain statistically significant results. other lower levels of evidence for sars-cov- come to similar conclusions regarding ppe. no nosocomial transmission was found in hcws from eight u.s. hospitals, despite several of them not wearing any masks and % of them being exposed to agps ( ) . furthermore, no nosocomial transmission was found in vietnamese hcws exposed for weeks to hospitalized cases, wearing only medical masks ( ) . however, given the differences between sars-cov- and sars-cov- (e.g., peak viral load, asymptomatic transmission rates, and mortality rates), direct extrapolations from one virus to the other must be made with caution. similarly to the current pandemic, the significance of airborne transmission for the previous sars remains uncertain to this day, as the prerequisites (viral load, infectivity, and tropism) are not clearly met. unfortunately, sars-cov- seems to suffer from the same lack of rigorous clinical trials as its contemporary cousin. data from air and no-touch surface sampling studies (tables and ) conducted in covid- patient rooms and health care facilities are often cited to support airborne transmission. unfortunately, interstudy comparisons are complicated by the diversity of methodological approaches. for instance, positive air samples correlate with patient features (e.g., viral load and symptom intensity and duration), ventilation parameters, and cleaning procedures, but these elements are not always mentioned or detailed. moreover, large variations are reported in terms of total volume of air collected (Ͻ liters to up to , liters), flow rates ( . to liters/min), sampling duration, and technique (gelatin versus polycarbonate filtration, dry cyclonic sampling versus condensation sampling). furthermore, the sampling of no-touch surfaces, defined as areas typically out of reach of human contact or droplets and therefore assumed to be contaminated by aerosols only, is often poorly described and not always comparable to air samples. given that each design is associated with its own set of advantages and limitations (e.g., longer duration of air sampling may increase detection probability but decrease infectivity), there is no easy conclusion to be drawn when comparing studies. the majority of published and unpublished studies detected viral rna in the air and on no-touch surfaces (table ), but some did not (table ) . unfortunately, few positive studies included viral cultures. the main limitations of these studies were the lack of information on particle sizes and concentrations, unknown or suboptimal air sampler location, unknown time interval between aerosol production and collection (air or surface), and possible false negatives (e.g., negative pressure, open windows, and insufficient sampling volume or duration). for the studies that calculated viral concentrations from the environmental samples, various protocols, target genes (e.g., orf ab/ rdrp, e, n, and s), and chemistry detection technology, should caution against direct comparisons. most studies were carried out in both low-and high-risk areas, and frequently in intensive care units (icus) where agps commonly occur and ventilation is optimized. many studies, however, did not specify the general risk level and did not indicate if agps were carried out during sampling. therefore, positive air and no-touch surface samples could not be clearly associated with an emission source (i.e., natural aerosolization versus agps) or risk factors (e.g., ventilation rate). this makes the results hard to generalize to most low-risk health care settings, such as long-term-care facilities. negative results from air sampling studies in home and commercial settings ( , ) , in the definite absence of agps, also add to the uncertainty. it is worth noting that when researchers modelized aerosol emission during normal breathing, the observed concentrations of airborne particles were low, frequently under the detection limit for most air sampling approaches ( ) . this could explain the negative results of many studies (table ) . nonetheless, air and no-touch surface sampling studies support the presence of natural and/or intervention-generated aerosols in covid- health care facilities. however, the infectivity of these aerosols and their significance as a transmission route, beyond the mere detection of viral particles, remain uncertain. indeed, a better understanding of viral resistance to airborne stress is key to estimating infectious risk. three published studies ( ) ( ) ( ) included viral cultures from air samples, all of which were negative; however, the santarpia et al. study ( ) observed indirect signs of viral replication in two of their samples, including a mild cytopathic effect upon microscopic inspection after to days. on the other hand, in two unpublished studies, santarpia sars-cov- and health care worker protection clinical microbiology reviews et al. ( ) and lednicky et al. ( ) succeeded in obtaining positive cultures. the former used innovative methods such as detection of viral rna in supernatant and western blotting to yield interesting results. however, data scrutiny is impeded by the absence of c t values in the manuscript. in turn, the latter study would benefit from a thorough peer review process given that its methodology is not clearly detailed, and total and culturable viral counts seem implausible, since they are orders of magnitude higher than previously reported in the literature. the use of a condensation-based air sampler could perhaps explain the unusual results. the fact that few research teams have attempted to culture the virus, and many of those who have did not succeed, could imply that sars-cov- aerosols are scarce or weakly infectious. however, multiple other factors could be at play. viral cultures must be done in biosafety level facilities and are therefore not easily accessible to some research teams. even when culturing is possible, viral shedding dynamics may be unpredictable or intermittent, leading to failed detection within the time frame of air sampling ( ) . furthermore, the sampling process of aerosols, in itself, may induce substantial damage to viruses and alter their integrity and, consequently, their infectivity ( ) . finally, current culture techniques may not be optimal for the low viral concentration found in air samples. increased sensitivity could be achieved with a bioassay or alternative methods such as electron microscopy, detection of viral proteins, and rt-qpcr in culture lysis and supernatants ( ) . lastly, studies involving the in vitro generation of sars-cov- aerosols with jet collison nebulizers have been widely cited in support of airborne transmission. using this method, the well-known van doremalen et al. letter measured infectious titers per liter of air in a simulated aerosolized environment and showed stability of the sars-cov- virus in aerosols for up to h, with a half-life of . h ( ). another similar study made headlines because the aerosols produced were stable for up to h ( ) . as with all in vitro models for bioaerosols, while they provide precious information on virus properties in aerosol state, including relative stability (which seems to be high) and comparative viral behavior, it is uncertain whether the mechanically produced sars-cov- aerosols exhibit the same properties as naturally generated ones. therefore, such experimental studies are generally considered of low applicability to clinical settings. tragic outbreaks in long-term-care facilities (ltcs) have plagued many countries in europe ( ) and north america ( ) , with astonishing death tolls. some facilities report % resident infection rates, high hcw infection rates, as well as faulty ventilation systems ( ), triggering intense debate over potential airborne transmission. while aerosols could have contributed in cases involving inadequate ventilation ( ) , other explanations are also conceivable. some have justified the devastating statistics by pointing to higher viral loads ( ) or longer infection periods ( ) in the elderly, two phenomena likely attributable to the weakening of the immune system with age. notwithstanding, ltcs are fundamentally vulnerable to covid- because of an array of predisposing risk factors ( , ) . unlike the general adult population, covid-infected residents in ltcs are not always capable of communicating their symptoms and frequently have atypical clinical presentations, such as diarrhea, delirium, or falls ( ) . on the other hand, between and % ( , ) of them are asymptomatic or presymptomatic at the time of their positive test. these geriatric features complicate and delay case detection. the typical patient profile also leads to poor compliance with infection prevention and control (ipc) practices: most residents have neurocognitive disorders and behavioral symptoms, but some also have mental health disorders or intellectual disability, which means isolation, mask-wearing, and hand hygiene are often impossible. rates of resident noncompliance can reach almost % in certain special care units (e.g., wandering ward). moreover, a majority of residents with severe loss of functional autonomy requiring several hours of proximity care per day (e.g., personal hygiene and bath, urinary and bowel elimination, feeding, and medication administration), means close and sustained contact between hcws and infected patients (without source control for the most part) and consequently, higher infection risk on both sides ( ) . structural and administrative impediments also come into play. some ltcs have high bed occupancy rates and tight physical spaces (e.g., shared bedrooms and bathrooms), where distancing becomes a challenge and cross-contamination an inevitability ( ) . with high population density and limited space, it is very difficult to efficiently segregate patients into zones according to infectious status, leading to mixed units and high infection rates. moreover, some facilities have defective ventilation systems ( ) , while others have no mechanical ventilation at all, and must rely on opening windows for air exchange. most importantly, many already understaffed ltcs were hard hit by pandemic-related absenteeism and had to resort to mobilizing staff between units and facilities or calling on lesser-trained external staff to fill in; this element exaggerated all the other risk factors because it hindered the detection and isolation of suspected cases, the deployment of covid- units with dedicated staff, the optimal application of ipc practices, and the overall quality of care ( ) . unfortunately, despite ltcs being at the epicenter of many regions' epidemic, data are still lacking. studies on transmission modes specific to this geriatric subgroup, where various clinical, administrative, and environmental factors intersect, would be very revealing. most authorities agree with the who recommendations for droplet and contact precautions with covid- patients. in the united kingdom ( ), canada ( ), france ( ) , switzerland ( ), spain ( ), portugal ( ) , and australia ( ), medical masks are indicated in most situations and respirators are required only in high-risk settings involving agps. recently, the who has acknowledged that "short-range aerosol transmission, particularly in specific indoor locations, such as crowded and inadequately ventilated spaces over a prolonged period of time with infected persons cannot be ruled out" but specifies that the significance of covid- airborne transmission has not been convincingly demonstrated and requires further research ( ) . while the european society of intensive care medicine and society of critical care medicine ( ) is also in line with who ppe recommendations, the european centre for disease prevention and control began by recommending respirators at all times, but backtracked in recent updates and now states that both equipment types are appropriate outside of agps ( ) , in agreeance with the infectious diseases society of america (idsa) ( ) . on the other hand, the united states ( ), south korea ( ), singapore ( ) , and china ( ) recommend respirators for routine care. the u.s. cdc states that hcws should wear an n , but a facemask is a suitable alternative if a respirator is not available. in summary, most western countries have adopted similar guidelines in line with who recommendations, but comparisons with countries in other parts of the world were not possible due to language barriers. surprising attack rates have been reported. possible explanations include the high presymptomatic contagion of certain individuals ( ) , as well as the many asymptomatic or paucisymptomatic cases ( ) who seem to have similar viral loads to their symptomatic counterparts ( ) . furthermore, unlike sars-cov- which reached peak viral load (and therefore contagion) at day to from the start of symptoms ( ), viral load seems to peak right before the advent of symptoms ( ) . given these data, certain researchers estimate that % of transmission happens in the presymptomatic phase ( ) . finally, nasopharyngeal viral load appears to be much (up to , times) higher than that of the first sars ( ) . we are therefore faced with a very contagious virus that can silently infect a large number of people. moreover, another possible mode of transmission that remains to be elucidated is through fomites. few studies look at sars-cov- survival on surfaces. a widely cited experiment showed that the virus could subsist between h (on copper) and h (on plastic) ( ) . however, the study took place under experimental conditions (laboratory surface inoculation, at a stable temperature of to °c) which do not represent droplet deposition on surfaces in clinical contexts nor the variations of typical indoor environments. nonetheless, the potentially prolonged stability of coronaviruses on surfaces ( ) , as well as the extensive environmental contamination reported by many surface sample studies in health care settings ( , ( ) ( ) ( ) ( ) , needs to be confirmed by future research, including viral cultures for infectivity. possible fecal transmission is also worth considering. a significant proportion of patients declare gastrointestinal symptoms before respiratory symptoms, and it is even a predominant form of presentation in some individuals ( ) . in addition, severe covid- cases appear to have more gastrointestinal symptoms than mild or moderate cases ( ) . a meta-analysis of over , patients reported % pcr-positive stool samples, of which % remained positive even after nasopharyngeal pcr had turned negative ( ) . endoscopic studies also found rna in the esophagi, stomachs, duodena, and recta of patients with severe gastrointestinal symptoms ( ) . finally, two studies showed the toilet was among the most contaminated areas in indoor settings ( , ) : interestingly, the patient who's toilet air sample was positive had a negative exhaled breath sample, warranting the consideration that detectable airborne sars-cov- could originate from fecal rather than respiratory aerosols. as with air, a limited number of studies have been able to culture infectious viruses from stools ( , ) , supporting infectivity. in theory, fecal transmission could occur through different routes, including contact (e.g., while changing incontinence briefs), short-range aerosolization (i.e., inhalation), or long-range aerosolization due to toilet flushing ( ) . the latter was well established in the sars-cov- amoy gardens outbreak and was recently considered the main mode of transmission in a sars-cov- outbreak involving a high-rise building in china, where the nine infected cases lived in three vertically aligned flats connected by drainage pipes in the master bathrooms ( ) . hcws constitute a high-risk population for infection ( ) . however, the contribution of nosocomial transmission was perhaps overestimated at the beginning of the pandemic, since recent genome-sequencing studies have highlighted the importance of community-acquired infection among hcws ( ) . for instance, with epidemiological and genomic data on hcws and patients at hospitals in the netherlands, researchers linked these infections with three different clusters, two of which showed local circulation in the community ( ) . within each cluster, "identical or near-identical sequences in health care workers at the same hospital, and between patients and health care workers at the same hospital, were found, but no consistent link was noted among health care workers on the same ward or between health care workers and patients on the same ward." the authors therefore concluded that the patterns observed were consistent with multiple introductions into the hospitals through community-acquired infections. similarly, studies are pointing to community transmission dynamics and public policies (e.g., universal mask-wearing) as the main drivers of hcws infection ( ) ( ) ( ) . nonetheless, given that hcws can both infect patients and get infected from patients, workplace practices deserve a closer look. in the presence of a contagious virus and extensive environmental contamination in health care settings, any breach in protection, as small as it may be, can lead to infection. hcws who work regularly with covid- patients, especially those in close contact (e.g., patient attendants, nurse aides) can hardly maintain constant and perfect compliance with ipc practices. besides, risk exposure not only occurs with patients during ppe violations but also with other staff members in shared areas without ppe (e.g., cafeterias and changing rooms). unfortunately, few studies looked at ppe compliance during the covid- pandemic: one study reported very poor adherence to mask recommendations due to lack of use (almost %) or improper use ( ) . before the pandemic, cornerstone practices such as hand hygiene were already poorly applied according to several studies in a variety of hospital departments (including icus) across different countries ( ) ( ) ( ) . a drastic change in a short lapse of time appears improbable, especially in long-term-care facilities where the culture and philosophy are one of "home setting" rather than health care setting. moreover, hcws appear to have a false perception of their own compliance with hygiene practices: a mers-cov study showed an absence of correlation between staff's self-assessment and their observed behavior ( ) . the researchers mention that most hcws understood the importance of hand hygiene but did not consistently apply it. even so, proper ppe use does not only depend on individual compliance and technique; it is a multidimensional issue with organizational, systemic, and political ramifications ( ) . more importantly, ppe is neither the only nor the best way to protect hcws. in fact, when it comes to protection from occupational hazards, ppe is the last and least effective measure in the niosh hierarchy of controls ( ) (see fig. b ). for the current pandemic and future ones, our priority should therefore be elimination strategies (e.g., decreasing bed occupancy rates, source control), engineering controls (e.g., segregated red zones and proper ventilation), and administrative controls (e.g., dedicated staff, adequate training, and strict enforcement of ipc regulations), ending with ppe ( ) . unfortunately, we have seen, around the globe, many health care systems fail to meet the structural, human, and material challenges brought on by covid- , and some hcws have paid the price for our collective unpreparedness. one final potential source for hcw infection could be the combination of risk factors for aerosol accumulation in certain exceptional circumstances, such as an overcrowded and underventilated long-term-care facility ( ) , or makeshift hospitals such as we have seen built around the world ( ) . while the vast majority of home and hospital environments are probably safe ( ) , some care homes are located in old substandard infrastructure which relies on natural ventilation and does not allow for optimization of air exchange. it is plausible that under these specific conditions, normally minimal levels of infectious respirable aerosols could reach a threshold where classic airborne transmission becomes significant. while we wait for future research to confirm this scenario, we must strive to control what we can, eliminating physical, environmental, and administrative risk factors to protect frontline workers ( ) . drawing the line between precaution and excess is a fundamentally subjective process. many experts agree that current droplet and contact precautions are adequate in low-risk settings. however, some prefer to exercise precaution by recommending respiratory protection with critically ill patients (e.g., severe desaturation or tachypnea), arguing that these clinical features predict progression to agps such as intubation ( ) . others consider that the minimum precautionary practice is universal n use. finally, some argue that only drastic measures such as full head hoods and full-body suits, often seen in china, are sufficiently protective. in the presence of diverging opinions on the definition of so-called precaution, it seems reasonable to use an evidence-based approach to ppe recommendations. the bulk of evidence, until now, indicates that the medical mask is protective in low-risk settings and the respirator is required only for agps, although higher levels of evidence in the future may tip the balance the other way. long-term care facilities, where the risk level may at times be considered high despite the absence of agps, deserve special attention from researchers. lastly, one could argue that our collective but rather limited energy, time, and resources should be invested in the most impactful areas: proven practices that achieve broad consensus and transmission routes that appear to be predominant. for sars-cov- , long-winded debates on the gray zones and the applicability of the precautionary principle sometimes distract from crucial measures, such as hand hygiene, source control, and optimal ventilation ( ) , which are uncontroversial and highly effective, yet still unevenly applied in some settings such as long-term-care facilities. we are in favor of a return to core ipc principles, which should dominate the scientific conversation around covid- management. beyond the alarming statistics, several success stories around the world prove that much can be achieved quickly and efficiently with basic yet effective practices ( , ( ) ( ) ( ) , without the need to resort to elaborate theories or equipment. this article is an in-depth literature overview attempting to answer frequently asked questions about droplet and airborne transmission. although not a systematic review, it goes deeper than current narrative reviews and has important implications for ipc practices, hcw protection, and future research. however, there are several limitations. the first is the controversial distinction between droplets and aerosols, still commonly used in much of the scientific literature, although deemed arbitrary and inaccurate by many experts. natural generation of particles belonging to a broad range of size, containing various concentrations of infectious agents, is probably concurrent rather than mutually exclusive, and transmission patterns are likely on a continuum rather than dichotomous. our proposed model addresses this issue. going forward, we are in favor of adapting public health policies and ppe recommendations to include a broader industrial hygiene-inspired definition of aerosols, as presented above, in order to lessen confusion and better represent the nuanced and complex reality of sars-cov- transmission. the second major limitation is the lack of clinical studies on sars-cov- transmission and ppe effectiveness, meaning that many conclusions are drawn from lower levels of evidence, extrapolations from other viruses, and laboratory and experimental studies. the available literature, however, is mostly consistent: while airborne transmission exists under certain conditions, there is limited direct evidence of it, especially in low-risk health care settings. given the very high viral load typical of sars-cov- infections, it is surprising that, after several months of pandemic, many air samples turn out negative or weakly positive, and subsequent positive cultures remain scarce. this may be attributed to the many logistical and technical limitations associated with air sampling and viral cultures, as mentioned previously, which could underestimate airborne infectivity. we must therefore rely primarily on clinical evidence (trials on masks and epidemiological studies) to study transmission; for now, it suggests that the classic airborne route is not significant. a broader airborne model, involving the short-range inhalation route, could better explain current observations. third, only a few national and international guidelines are compared because of the lack of translated documents. a thorough search of guidelines from comparable countries across different continents would allow for an unbiased comparison but is very challenging in practice. while impatiently waiting for future studies, especially clinical trials, to dispel remaining uncertainties and provide definitive answers to the questions raised here, we would like to propose a revised model for sars-cov- transmission, involving inhalable aerosols and favorable conditions for airborne transmission (fig. ) . the premises of this model are based on cumulative data and clinical observations. in light of the positive air and no-touch surface samples found in health care facilities, respiratory sars-cov- aerosols probably occur, but many of their attributes are yet unknown; studies thus far seem to suggest these aerosols are short-range and dilute with distance ( , , ) . similarly, epidemiological studies do not support the existence of long-distance aerosol propagation: the four outbreaks most often cited as evidence of airborne transmission (the washington choir, the guangzhou restaurant, the eastern chinese bus riders, and the diamond princess cruise ship) all involved individuals who were in relatively close contact for a prolonged period of time, in an enclosed space, with the presence of enabling factors (e.g., crowdedness, air currents, and poor ventilation). indeed, these conditions seem necessary for respiratory airborne transmission to occur. fecal aerosols, on the other hand, may be more common due to toilet flushing, but further studies are needed to clarify their role and distinguish them from respiratory aerosols. worst-case scenario: no protection on either the sick patient (source) or the health care worker (exposure), emission of particles of various sizes (droplets and aerosols) during natural respiratory activity (breathing, talking, and coughing), entry of infectious inhalable aerosols, and impaction in the nose where viral receptors are abundant and infectivity is greatest. (b) best-case scenario and niosh hierarchy of controls: source control (mask-wearing by the sick patient), engineering control (optimal ventilation), and exposure control (droplet-contact ppe worn by the health care worker) to prevent short-range droplet and inhalable aerosol transmission. clinical microbiology reviews moreover, to solve the mystery of particle size, we must first acknowledge that airborne transmission is not exclusive to small aerosols: some larger particles typically classified as droplets may remain airborne, especially if suboptimal airflows contribute to their preservation in suspension and reduce their dilution ( ) . thus, inhalable aerosols are the ideal candidate to explain current findings, because they exhibit shorter travel distance and air suspension time than respirable aerosols while having greater potential for infection because of their higher probability of containing virions ( ) . furthermore, because inhalable aerosols are larger, they are more likely to deposit proximally in upper airways compared to respirable aerosols ( ) , which is in line with the robust data suggesting that nasal cells are the main portal for initial infection, with a gradient of infectivity from the proximal (nose) to the distal (lungs) respiratory tract ( , ) . therefore, transmission of short-range airborne and inhalable aerosols could explain the seemingly contradictory finding that there are viruses in the air and transmission between individuals without contact, but lack of convincing clinical evidence of classic airborne transmission (i.e., long-distance ranges and superiority of respirators). this size range could exhibit behaviors typical of both droplets and aerosols: higher viral load, airborne behavior, inhalation, and deposition in the nose. despite relatively shorter suspension time, inhalable aerosols become especially significant in the case of prolonged exposure and close proximity. in addition, they are less likely to follow air streams through leaks in the nonfitted mask, nor make it down to alveolar space, because of larger size, but rather will remain in nasal cells due to natural impaction processes. consequently, tight seals and superior filtration would not be required in most low-risk settings, as masks (with the help of face shields) could readily block these airborne particles. however, different categories of hcws may not be exposed to the same level of risk: an attendant who spends an hour feeding, bathing and positioning a patient will be at much higher risk of inhaling aerosols compared to a doctor who questions and examines a patient for min. finally, ventilation parameters (air exchange rate, flow direction, and airflow patterns) would play a role, since they could contribute to enhancing or reducing airborne suspension and transmission ( ) . this model is difficult to assess given the short-range distance and the short airborne stability, as well as the alteration of particle size during most air sampling processes (desiccation and impaction in liquid). however, we believe this novel paradigm, which departs from the outdated aerosol/droplet dichotomy, more accurately portrays the reality of naturally generated viral particles and the nuances in transmission patterns. broadening the "airborne" definition to inhalable aerosol exposure in the context of proximity care, and considering inhalation as a significant route of entry for the sars-cov- virus, could open up new paths of exploration. in summary, traditional droplets (larger particles with ballistic behavior that deposit onto surfaces), as well as our newly defined inhalable aerosols (particles that can be suspended, breathed in, and impacted at the nose, at the location of highest infectivity), could be the predominant modes of transmission of sars-cov- . classic respirable aerosols, even if present, seem unlikely to be significant in routine health care contexts, possibly due to insufficient quantity, inactivation 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hospital for severe covid- patients we thank magali-wen st-germain for the original design, creation, and development of fig. , as well as patrick lane, sceyence studios, for the final version of fig. . we thank stéphanie langevin, quoc dinh nguyen, luc trudel, and jean barbeau for their contribution in reviewing the original manuscript.both authors substantially contributed to the conception, design, analysis, and interpretation of data, as well as reviewing and approving the final version of the manuscript. we agree to be accountable for the contents.c.d. is holder of tier- canada research chair on bioaerosols. for this review article, we received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.we declare that we do not have commercial or financial relationships that could, in any way, lead to a potential conflict of interest with regard to this publication.