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Review of Aerosol Transmission of Influenza A Virus

Review of Aerosol Transmission of Influenza A Virus Review of Aerosol Transmission of Influenza A Virus Raymond Tellier*† In theory, influenza viruses can be transmitted through known human influenza viruses would seem rational. aerosols, large droplets, or direct contact with secretions Because infection with influenza A (H5N1) virus is associ- (or fomites). These 3 modes are not mutually exclusive. ated with high death rates and because healthcare workers Published findings that support the occurrence of aerosol cannot as yet be protected by vaccination, recommending transmission were reviewed to assess the importance of an enhanced level of protection, including the use of N95 this mode of transmission. Published evidence indicates respirators as part of PPE, is important. Following are a that aerosol transmission of influenza can be an important brief review of the relevant published findings that support mode of transmission, which has obvious implications for the importance of aerosol transmission of influenza and a pandemic influenza planning and in particular for recom- brief discussion on the implications of these findings on mendations about the use of N95 respirators as part of per- sonal protective equipment. pandemic preparedness. Influenza Virus Aerosols oncerns about the likely occurrence of an influenza By definition, aerosols are suspensions in air (or in a Cpandemic in the near future are increasing. The high- gas) of solid or liquid particles, small enough that they ly pathogenic strains of influenza A (H5N1) virus circulat- remain airborne for prolonged periods because of their low ing in Asia, Europe, and Africa have become the most settling velocity. For spherical particles of unit density, set- feared candidates for giving rise to a pandemic strain. tling times (for a 3-m fall) for specific diameters are 10 s Several authors have stated that large-droplet transmis- for 100 µm, 4 min for 20 µm, 17 min for 10 µm, and 62 sion is the predominant mode by which influenza virus min for 5 µm; particles with a diameter <3 µm essentially infection is acquired (1–3). As a consequence of this opin- do not settle. Settling times can be further affected by air ion, protection against infectious aerosols is often ignored turbulence (10,11). for influenza, including in the context of influenza pan- The median diameters at which particles exhibit aerosol demic preparedness. For example, the Canadian Pandemic behavior also correspond to the sizes at which they are Influenza Plan and the US Department of Health and efficiently deposited in the lower respiratory tract when Human Services Pandemic Influenza Plan (4,5) recom- inhaled. Particles of >6-µm diameter are trapped increas- mend surgical masks, not N95 respirators, as part of per- ingly in the upper respiratory tract (12); no substantial dep- sonal protective equipment (PPE) for routine patient care. osition in the lower respiratory tract occurs at >20 µm This position contradicts the knowledge on influenza virus (11,12). Many authors adopt a size cutoff of <5 µm for transmission accumulated in the past several decades. aerosols. This convenient convention is, however, some- Indeed, the relevant chapters of many reference books, what arbitrary, because the long settling time and the effi- written by recognized authorities, refer to aerosols as an cient deposition in the lower respiratory tract are properties important mode of transmission for influenza (6–9). that do not appear abruptly at a specific diameter value. In preparation for a possible pandemic caused by a Certainly, particles in the micron or submicron range will highly lethal virus such as influenza A (H5N1), making the behave as aerosols, and particles >10–20 µm will settle assumption that the role of aerosols in transmission of this rapidly, will not be deposited in the lower respiratory tract, virus will be similar to their role in the transmission of and are referred to as large droplets (10–12). Coughing or sneezing generates a substantial quantity *Hospital for Sick Children, Toronto, Ontario, Canada; and of particles, a large number of which are <5–10 µm in †University of Toronto, Toronto, Ontario, Canada Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 11, November 2006 1657 PERSPECTIVE diameter [reviewed in (10)]. In addition, particles expelled Experimental Influenza Infection by coughing or sneezing rapidly shrink in size by evapora- Experimental infection studies permit the clear separa- tion, thereby increasing the number of particles that tion of the aerosol route of transmission from transmission behave as aerosols. Particles shrunken by evaporation are by large droplets. Laboratory preparation of homogeneous referred to as droplet nuclei (10–12). This phenomenon small particle aerosols free of large droplets is readily affects particles with a diameter at emission of <20 µm, achieved (13,18). Conversely, transmission by large and complete desiccation would decrease the diameter to a droplets without accompanying aerosols can be achieved little less than half the initial diameter (10). Droplet nuclei by intranasal drop inoculation (13). are hygroscopic. When exposed to humid air (as in the Influenza infection has been documented by aerosol lungs), they will swell back. One would expect that inhaled exposure in the mouse model, the squirrel monkey model, hygroscopic particles would be retained in the lower respi- and human volunteers (12,13,17–19). Observations made ratory tract with greater efficiency, and this hypothesis has during experimental infections with human volunteers are been confirmed experimentally (11,12). Because aerosols particularly interesting and relevant. In studies conducted remain airborne, they can be carried over large distances, by Alford and colleagues (18), volunteers were exposed to which may create a potential for long-range infections. carefully titrated aerosolized influenza virus suspensions The occurrence of long-range infections is affected by sev- by inhaling 10 L of aerosol through a face mask. The diam- eral other factors. These include dilution, the infectious eter of the aerosol particles was 1 µm–3 µm. Demon- dose, the amount of infectious particles produced, the stration of infection in participants in the study was duration of shedding of the infectious agent, and the per- achieved by recovery of infectious viruses from throat sistence of the agent in the environment (11). Inferring an swabs, taken daily, or by seroconversion, i.e., development absence of aerosols because long-range infections are not of neutralizing antibodies. The use of carefully titrated frequently observed is incorrect. viral stocks enabled the determination of the minimal Humans acutely infected with influenza A virus have a infectious dose by aerosol inoculation. For volunteers who high virus titer in their respiratory secretions, which will lacked detectable neutralizing antibodies at the onset, the be aerosolized when the patient sneezes or coughs. The 50% human infectious dose (HID ) was 0.6–3.0 TCID , 50 50 viral titer measured in nasopharyngeal washes culminates if one assumes a retention of 60% of the inhaled particles on approximately day 2 or 3 after infection and can reach (18). In contrast, the HID measured when inoculation up to 10 50% tissue culture infective dose (TCID )/mL was performed by intranasal drops was 127–320 TCID 50 50 (13,14). The persistence of the infectivity of influenza (13). Additional data from experiments conducted with virus in aerosols has been studied in the laboratory. In aerosolized influenza virus (average diameter 1.5 µm) experiments that used homogeneous aerosolized influenza showed that when a dose of 3 TCID was inhaled, ≈1 virus suspensions (mean diameter 6 µm), virus infectivity TCID only was deposited in the nose (12). Since the dose (assessed by in vitro culture) at a fixed relative humidity deposited in the nose is largely below the minimal dose undergoes an exponential decay; this decay is character- required by intranasal inoculation, this would indicate that ized by very low death rate constants, provided that the rel- the preferred site of infection initiation during aerosol ative humidity was in the low range of 15%–40% (15,16). inoculation is the lower respiratory tract. Another relevant These results are consistent with those of an older study observation is that whereas the clinical symptoms initiated (admittedly performed in a more rudimentary manner) in by aerosol inoculation covered the spectrum of symptoms which infectious influenza viruses in an aerosol could be seen in natural infections, the disease observed in study demonstrated for up to 24 h by using infection in mice as participants infected experimentally by intranasal drops a detection method, provided that the relative humidity was milder, with a longer incubation time and usually no was 17%−24% (17). In all these studies, the decay of virus involvement of the lower respiratory tract (13,20). For infectivity increased rapidly at relative humidity >40%. safety reasons, this finding led to the adoption of intranasal The increased survival of influenza virus in aerosols at low drop inoculation as the standard procedure in human relative humidity has been suggested as a factor that experimental infections with influenza virus (13). accounts for the seasonality of influenza (15,16). The Additional support for the view that the lower respira- sharply increased decay of infectivity at high humidity has tory tract (which is most efficiently reached by the aerosol also been observed for other enveloped viruses (e.g., route) is the preferred site of infection is provided by stud- measles virus); in contrast, exactly the opposite relation- ies on the use of zanamivir for prophylaxis. In experimen- ship has been shown for some nonenveloped viruses (e.g., tal settings, intranasal zanamivir was protective against poliovirus) (11,15,16). experimental inoculation with influenza virus in intranasal drops (21). However, in studies on prophylaxis of natural 1658 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 11, November 2006 Aerosol Transmission of Influenza A Virus infection, intranasally applied zanamivir was not protec- inate the upper air of rooms only, large droplets would not tive (22), whereas inhaled zanamivir was protective in one have been exposed to UV, whereas aerosols, carried by study (23) and a protective effect approached statistical thermal air mixing, would have been exposed (27,28). So significance in another study (22). These experiments and in effect in this study only the aerosol route of infection observations strongly support the view that many, possibly was blocked, and this step alone achieved near complete most, natural influenza infections occur by the aerosol protection. route and that the lower respiratory tract may be the pre- The converse occurrence, blocking only the large ferred site of initiation of the infection. droplet and fomites routes in natural infections, can be inferred from the studies on the use of zanamivir for pro- Epidemiologic Observations phylaxis described previously. In experimental settings, In natural infections, the postulated modes of transmis- intranasally applied zanamivir was protective against an sion have included aerosols, large droplets, and direct con- experimental challenge with influenza by intranasal drops tact with secretions or fomites because the virus can (21). However, in studies on prophylaxis of natural dis- remain infectious on nonporous dry surfaces for <48 hours ease, intranasal zanamivir was not protective (22), which (24). Because in practice completely ruling out contribu- leads to the conclusion that natural infection can occur tions of a given mode of transmission is often difficult, the efficiently by a route other than large droplets or fomites. relative contribution of each mode is usually difficult to As noted above, inhaled zanamivir was significantly pro- establish by epidemiologic studies alone. However, a cer- tective (22,23). tain number of observations are consistent with and strong- ly suggestive of an important role for aerosol transmission Discussion and Implications for Infection in natural infections, for example the “explosive nature Control during Influenza A (H5) Pandemic and simultaneous onset [of disease] in many persons” (9), In principle, influenza viruses can be transmitted by 3 including in nosocomial outbreaks (25). The often-cited routes: aerosols, large droplets, and direct contact with outbreak described by Moser et al. on an airplane with a secretions (or with fomites). These 3 routes are not mutu- defective ventilation system is best accounted for by ally exclusive and, as noted above, may be difficult to dis- aerosol transmission (26). Even more compelling were the entangle in natural infections. observations made at the Livermore Veterans For the purpose of deciding on the use of N95 respira- Administration Hospital during the 1957–58 pandemic. tors in a pandemic, showing that aerosol transmission The study group consisted of 209 tuberculous patients con- occurs at appreciable rates is sufficient. Evidence support- fined during their hospitalization to a building with ceil- ing aerosol transmission, reviewed above, appears com- ing-mounted UV lights; 396 tuberculous patients pelling. Despite the evidence cited in support of aerosol hospitalized in other buildings that lacked these lights con- transmission, many guidelines or review articles neverthe- stituted the control group. Although the study group partic- less routinely state that “large droplets transmission is ipants remained confined to the building, they were thought to be the main mode of influenza transmission” (or attended to by the same personnel as the control group, and similar statements) without providing supporting evidence there were no restrictions on visits from the community. from either previously published studies or empirical find- Thus, it was unavoidable at some point that attending per- ings. Despite extensive searches, I have not found a study sonnel and visitors would introduce influenza virus in both that proves the notion that large-droplets transmission is groups. During the second wave of the pandemic, the con- predominant and that aerosol transmission is negligible (or trol group and the personnel sustained a robust outbreak of nonexistent). Reports on many outbreaks suggest that respiratory illness, shown retrospectively by serology to be influenza aerosols are rapidly diluted because long-range due to the pandemic strain influenza A (H2N2), whereas infections occur most spectacularly in situations of crowd- the group in the irradiated building remained symptom ing and poor ventilation (25,26). However, even if long- free. The seroconversion rate to influenza A (H2N2) was range infections do not readily occur when sufficient 19% in the control group, 18% in personnel, but only 2% ventilation exists, this does not rule out the presence at in the study group (27,28). closer range of infectious particles in the micron or submi- Whereas UV irradiation is highly effective in inactivat- cron range, against which surgical masks would offer little ing viruses in small-particle aerosols, it is ineffective for protection (29,30). Many infection control practitioners surface decontamination because of poor surface penetra- have argued that the introduction of large-droplets precau- tions. It is also ineffective for large droplets because the tions in institutions has proven sufficient to interrupt germicidal activity sharply decreases as the relative influenza outbreaks and therefore that aerosol transmission humidity increases (28). Furthermore, because the installa- appears negligible. This evidence is, unfortunately, incon- tion of UV lights was set up in such a way as to decontam- clusive because of several confounding or mitigating Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 11, November 2006 1659 PERSPECTIVE factors. First, unless precise laboratory diagnosis is be demonstrated in human tissue sections from the respira- obtained, respiratory syncytial virus outbreaks can be mis- tory tract in a distribution corresponding to that of the α- taken for influenza outbreaks (9), which would artificially 2,3 receptors in the respiratory tract (34,35). This pattern increase the perceived “effectiveness” of large-droplets of virus binding correlates well with autopsy findings, precautions against influenza. Second, serologic studies which show extensive alveolar damage (34,37), and also are often not conducted, and therefore asymptomatic infec- correlates well with the observation that recovery of the A tions are not documented (among healthcare workers a (H5N1) virus is much more difficult from nasal swabs than large fraction of influenza infections are asymptomatic or from throat swabs (37). Thus, in the respiratory system the mistaken for another disease [31]). Third, since we are in current strains of A (H5N1) appear to infect mostly (per- an interpandemic period and the viruses currently circulat- haps exclusively) the lower respiratory tract. If that is ing have been drifting from related strains for decades, we indeed the case, it in turn suggests that human cases of all have partial immunity against these viruses, immunity avian influenza were acquired by exposure to an aerosol, that is further boosted in vaccinated healthcare workers. It since large droplets would not have delivered the virus to has even been argued that after several decades of circula- the lower respiratory tract. (Another hypothesis might be tion the current human influenza viruses are undergoing gastrointestinal infection, followed by viremia and dissem- gradual attenuation (32). Finally, surgical masks (used in ination, but not all patients have gastrointestinal symptoms large-droplets precautions) do not offer reliable protection [37]). Given the strong evidence for aerosol transmission against aerosols, but they nevertheless have a partially pro- of influenza viruses in general, and the high lethality of the tective effect, which further confuses the issue (29,30). current strains of avian influenza A (H5N1) (37), recom- In contrast, the situation with a pandemic strain of mending the use of N95 respirators, not surgical masks, as influenza A (H5) would become only too clear because no part of the protective equipment seems rational. one would have any degree of immunity against such a Several infection control guidelines for influenza have virus, vaccines would not be available for months, and recently been published, some specifically aimed at the these viruses would likely be highly virulent. Even though current strains of A (H5N1), others as part of more com- efficient human-to-human transmission of the A (H5N1) prehensive pandemic plans that address the emergence not virus has not yet been observed (by any mode), transmis- only of a pandemic form of A (H5) but also of other types sion of influenza A (H5N1) by aerosols from geese to of pandemic influenza viruses. Even though to date quails has been demonstrated in the laboratory (33). Thus, human-to-human transmission of A (H5N1) remains very even in the current incarnation of A (H5N1), infection by inefficient, the high lethality of the infection and potential the virus can generate aerosols that are infectious for high- for mutations call for prudence. The use of N95 respirators ly susceptible hosts. As far as we know, 1 of the main is included in the 2004 recommendations of the Centers for blocks to efficient human-to-human transmission of Disease Control and Prevention for healthcare workers influenza A (H5N1) is the virus’s current preference for who treat patients with known or suspected avian influen- specific sialic acid receptors. The current strains still pre- za (38). The World Health Organization’s current (April fer α-2,3–linked sialic acids, which is typical of avian 2006) guidelines for avian influenza recommend the use of influenza viruses, whereas human influenza viruses bind airborne precautions when possible, including the use of preferentially to α-2,6–linked sialic acids (34–36). In all N95 respirators when entering patients’ rooms (39). likelihood, 1 of the mutations required for influenza A Currently, several pandemic plans differ considerably (H5N1) to give rise to a pandemic strain would be to in their recommendations for infection control precautions change its receptor affinity to favor the α-2,6–linked sialic and PPE. The current version of the Canadian pandemic acids. For the influenza A (H1N1) pandemic strain of plan recommends surgical masks only, disregarding data 1918, this change required only 1 or 2 amino acid substi- that support the aerosol transmission of influenza (4). The tutions (36). Once a highly transmissible strain of influen- US pandemic plans (5) and the British plans, from both the za A (H5) has arisen, it will likely spread in part by National Health Service (available from http:// www.dh. aerosols, like other human influenza viruses. gov.uk/PublicationsAndStatistics/Publications/ Recent studies have shown that whereas epithelial cells PublicationsPolicyAndGuidance/PublicationsPolicyAndG in the human respiratory tract express predominantly the uidanceArticle/fs/en?CONTENT_ID=4121735&chk=Z6k α-2,6 sialic acid receptor, cells expressing the α-2,3 recep- jQY) and the Health Protection Agency (http://www. tor were detected only occasionally in the upper respirato- hpa.org.uk/infections/topics_az/influenza/pandemic/ ry tract; however, measurable expression of α-2,3–linked pdfs/HPAPandemicplan.pdf), acknowledge the contribu- sialic acid receptors was found in some cells in the alveo- tion of aerosols in influenza but curiously recommend sur- lar epithelium and at the junction of alveolus and terminal gical masks for routine care; the use of N95 respirators is bronchiole (35). Binding of influenza A (H5N1) virus can reserved for protection during “aerosolizing procedures” 1660 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 11, November 2006 Aerosol Transmission of Influenza A Virus 11. Knight V. Viruses as agents of airborne contagion. Ann N Y Acad Sci. (5,40). These recommendations fail to recognize that 1980;353:147–56. infectious aerosols will also be generated by coughing and 12. Knight V. Airborne transmission and pulmonary deposition of respi- sneezing. The Australian Management Plan for Pandemic ratory viruses. In: Hers JF, Winkles KC, editors. Airborne transmis- Influenza (June 2005) recommends N95 respirators for sion and airborne infections. VIth International Symposium on Aerobiology. New York: Wiley; 1973. p. 175–82. healthcare workers (http://www.health.gov.au/internet/ 13. Douglas RG. Influenza in man. In: Kilbourne ED, editor. The influen- wcms/Publishing.nsf/Content/phd-pandemic-plan.htm), za viruses and influenza. 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Webster RG, Guan Y, Peiris M, Walker D, Krauss S, Zhou NN, et al. 39. World Health Organization. Avian influenza, including influenza Characterization of H5N1 influenza viruses that continue to circulate A(H5N1) in humans: WHO interim infection control guidelines for in geese in southeastern China. J Virol. 2002;76:118–26. health care facilities. 2006 [cited 2006 Jul 20]. Available from 34. van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, http://www.wpro.who.int/NR/rdonlyres/EA6D9DF3-688D-4316- Osterhaus AD, et al. H5N1 virus attachment to lower respiratory 91DF-5553E7B1DBCD/0/InfectionControlAIinhumans tract. Science. 2006;312:399. WHOInterimGuidelinesfor2.pdf 35. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian 40. Health Protection Agency. Guidance for pandemic influenza: infec- flu: influenza virus receptors in the human airway. Nature. tion control in hospitals and primary care settings. Oct 2005 [cited 2006;440:435–6. 2006 Jul 20]. Available from http://www.dh.gov.uk/assetRoot/04/ 36. Stevens J, Blixt O, Glaser L, Taubenberger JK, Palese P, Paulson JC, 12/17/54/04121754.pdf et al. Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specifici- Address for correspondence: Raymond Tellier, Division of Microbiology, ties. J Mol Biol. 2006;355:1143–55. The Hospital for Sick Children, 555 University Ave, Toronto, Ontario 37. Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, et al. M5G 1X8, Canada; email: raymond.tellier@sickkids.ca Avian influenza A (H5N1) infection in humans. N Engl J Med. 2005;353:1374–85. 38. Centers for Disease Control and Prevention. Interim recommenda- The opinions expressed by authors contributing to this journal do tions for infection control in health care facilities caring for patients not necessarily reflect the opinions of the Centers for Disease with known or suspected avian influenza. 2004 [cited 2006 Apr 12]. Control and Prevention or the institutions with which the authors Available from http://www.cdc.gov/flu/avian/pdf/infectcontrol.pdf are affiliated. Search 1662 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 11, November 2006 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Emerging Infectious Diseases Pubmed Central

Review of Aerosol Transmission of Influenza A Virus

Emerging Infectious Diseases , Volume 12 (11) – Nov 1, 2006

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Abstract

Review of Aerosol Transmission of Influenza A Virus Raymond Tellier*† In theory, influenza viruses can be transmitted through known human influenza viruses would seem rational. aerosols, large droplets, or direct contact with secretions Because infection with influenza A (H5N1) virus is associ- (or fomites). These 3 modes are not mutually exclusive. ated with high death rates and because healthcare workers Published findings that support the occurrence of aerosol cannot as yet be protected by vaccination, recommending transmission were reviewed to assess the importance of an enhanced level of protection, including the use of N95 this mode of transmission. Published evidence indicates respirators as part of PPE, is important. Following are a that aerosol transmission of influenza can be an important brief review of the relevant published findings that support mode of transmission, which has obvious implications for the importance of aerosol transmission of influenza and a pandemic influenza planning and in particular for recom- brief discussion on the implications of these findings on mendations about the use of N95 respirators as part of per- sonal protective equipment. pandemic preparedness. Influenza Virus Aerosols oncerns about the likely occurrence of an influenza By definition, aerosols are suspensions in air (or in a Cpandemic in the near future are increasing. The high- gas) of solid or liquid particles, small enough that they ly pathogenic strains of influenza A (H5N1) virus circulat- remain airborne for prolonged periods because of their low ing in Asia, Europe, and Africa have become the most settling velocity. For spherical particles of unit density, set- feared candidates for giving rise to a pandemic strain. tling times (for a 3-m fall) for specific diameters are 10 s Several authors have stated that large-droplet transmis- for 100 µm, 4 min for 20 µm, 17 min for 10 µm, and 62 sion is the predominant mode by which influenza virus min for 5 µm; particles with a diameter <3 µm essentially infection is acquired (1–3). As a consequence of this opin- do not settle. Settling times can be further affected by air ion, protection against infectious aerosols is often ignored turbulence (10,11). for influenza, including in the context of influenza pan- The median diameters at which particles exhibit aerosol demic preparedness. For example, the Canadian Pandemic behavior also correspond to the sizes at which they are Influenza Plan and the US Department of Health and efficiently deposited in the lower respiratory tract when Human Services Pandemic Influenza Plan (4,5) recom- inhaled. Particles of >6-µm diameter are trapped increas- mend surgical masks, not N95 respirators, as part of per- ingly in the upper respiratory tract (12); no substantial dep- sonal protective equipment (PPE) for routine patient care. osition in the lower respiratory tract occurs at >20 µm This position contradicts the knowledge on influenza virus (11,12). Many authors adopt a size cutoff of <5 µm for transmission accumulated in the past several decades. aerosols. This convenient convention is, however, some- Indeed, the relevant chapters of many reference books, what arbitrary, because the long settling time and the effi- written by recognized authorities, refer to aerosols as an cient deposition in the lower respiratory tract are properties important mode of transmission for influenza (6–9). that do not appear abruptly at a specific diameter value. In preparation for a possible pandemic caused by a Certainly, particles in the micron or submicron range will highly lethal virus such as influenza A (H5N1), making the behave as aerosols, and particles >10–20 µm will settle assumption that the role of aerosols in transmission of this rapidly, will not be deposited in the lower respiratory tract, virus will be similar to their role in the transmission of and are referred to as large droplets (10–12). Coughing or sneezing generates a substantial quantity *Hospital for Sick Children, Toronto, Ontario, Canada; and of particles, a large number of which are <5–10 µm in †University of Toronto, Toronto, Ontario, Canada Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 11, November 2006 1657 PERSPECTIVE diameter [reviewed in (10)]. In addition, particles expelled Experimental Influenza Infection by coughing or sneezing rapidly shrink in size by evapora- Experimental infection studies permit the clear separa- tion, thereby increasing the number of particles that tion of the aerosol route of transmission from transmission behave as aerosols. Particles shrunken by evaporation are by large droplets. Laboratory preparation of homogeneous referred to as droplet nuclei (10–12). This phenomenon small particle aerosols free of large droplets is readily affects particles with a diameter at emission of <20 µm, achieved (13,18). Conversely, transmission by large and complete desiccation would decrease the diameter to a droplets without accompanying aerosols can be achieved little less than half the initial diameter (10). Droplet nuclei by intranasal drop inoculation (13). are hygroscopic. When exposed to humid air (as in the Influenza infection has been documented by aerosol lungs), they will swell back. One would expect that inhaled exposure in the mouse model, the squirrel monkey model, hygroscopic particles would be retained in the lower respi- and human volunteers (12,13,17–19). Observations made ratory tract with greater efficiency, and this hypothesis has during experimental infections with human volunteers are been confirmed experimentally (11,12). Because aerosols particularly interesting and relevant. In studies conducted remain airborne, they can be carried over large distances, by Alford and colleagues (18), volunteers were exposed to which may create a potential for long-range infections. carefully titrated aerosolized influenza virus suspensions The occurrence of long-range infections is affected by sev- by inhaling 10 L of aerosol through a face mask. The diam- eral other factors. These include dilution, the infectious eter of the aerosol particles was 1 µm–3 µm. Demon- dose, the amount of infectious particles produced, the stration of infection in participants in the study was duration of shedding of the infectious agent, and the per- achieved by recovery of infectious viruses from throat sistence of the agent in the environment (11). Inferring an swabs, taken daily, or by seroconversion, i.e., development absence of aerosols because long-range infections are not of neutralizing antibodies. The use of carefully titrated frequently observed is incorrect. viral stocks enabled the determination of the minimal Humans acutely infected with influenza A virus have a infectious dose by aerosol inoculation. For volunteers who high virus titer in their respiratory secretions, which will lacked detectable neutralizing antibodies at the onset, the be aerosolized when the patient sneezes or coughs. The 50% human infectious dose (HID ) was 0.6–3.0 TCID , 50 50 viral titer measured in nasopharyngeal washes culminates if one assumes a retention of 60% of the inhaled particles on approximately day 2 or 3 after infection and can reach (18). In contrast, the HID measured when inoculation up to 10 50% tissue culture infective dose (TCID )/mL was performed by intranasal drops was 127–320 TCID 50 50 (13,14). The persistence of the infectivity of influenza (13). Additional data from experiments conducted with virus in aerosols has been studied in the laboratory. In aerosolized influenza virus (average diameter 1.5 µm) experiments that used homogeneous aerosolized influenza showed that when a dose of 3 TCID was inhaled, ≈1 virus suspensions (mean diameter 6 µm), virus infectivity TCID only was deposited in the nose (12). Since the dose (assessed by in vitro culture) at a fixed relative humidity deposited in the nose is largely below the minimal dose undergoes an exponential decay; this decay is character- required by intranasal inoculation, this would indicate that ized by very low death rate constants, provided that the rel- the preferred site of infection initiation during aerosol ative humidity was in the low range of 15%–40% (15,16). inoculation is the lower respiratory tract. Another relevant These results are consistent with those of an older study observation is that whereas the clinical symptoms initiated (admittedly performed in a more rudimentary manner) in by aerosol inoculation covered the spectrum of symptoms which infectious influenza viruses in an aerosol could be seen in natural infections, the disease observed in study demonstrated for up to 24 h by using infection in mice as participants infected experimentally by intranasal drops a detection method, provided that the relative humidity was milder, with a longer incubation time and usually no was 17%−24% (17). In all these studies, the decay of virus involvement of the lower respiratory tract (13,20). For infectivity increased rapidly at relative humidity >40%. safety reasons, this finding led to the adoption of intranasal The increased survival of influenza virus in aerosols at low drop inoculation as the standard procedure in human relative humidity has been suggested as a factor that experimental infections with influenza virus (13). accounts for the seasonality of influenza (15,16). The Additional support for the view that the lower respira- sharply increased decay of infectivity at high humidity has tory tract (which is most efficiently reached by the aerosol also been observed for other enveloped viruses (e.g., route) is the preferred site of infection is provided by stud- measles virus); in contrast, exactly the opposite relation- ies on the use of zanamivir for prophylaxis. In experimen- ship has been shown for some nonenveloped viruses (e.g., tal settings, intranasal zanamivir was protective against poliovirus) (11,15,16). experimental inoculation with influenza virus in intranasal drops (21). However, in studies on prophylaxis of natural 1658 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 11, November 2006 Aerosol Transmission of Influenza A Virus infection, intranasally applied zanamivir was not protec- inate the upper air of rooms only, large droplets would not tive (22), whereas inhaled zanamivir was protective in one have been exposed to UV, whereas aerosols, carried by study (23) and a protective effect approached statistical thermal air mixing, would have been exposed (27,28). So significance in another study (22). These experiments and in effect in this study only the aerosol route of infection observations strongly support the view that many, possibly was blocked, and this step alone achieved near complete most, natural influenza infections occur by the aerosol protection. route and that the lower respiratory tract may be the pre- The converse occurrence, blocking only the large ferred site of initiation of the infection. droplet and fomites routes in natural infections, can be inferred from the studies on the use of zanamivir for pro- Epidemiologic Observations phylaxis described previously. In experimental settings, In natural infections, the postulated modes of transmis- intranasally applied zanamivir was protective against an sion have included aerosols, large droplets, and direct con- experimental challenge with influenza by intranasal drops tact with secretions or fomites because the virus can (21). However, in studies on prophylaxis of natural dis- remain infectious on nonporous dry surfaces for <48 hours ease, intranasal zanamivir was not protective (22), which (24). Because in practice completely ruling out contribu- leads to the conclusion that natural infection can occur tions of a given mode of transmission is often difficult, the efficiently by a route other than large droplets or fomites. relative contribution of each mode is usually difficult to As noted above, inhaled zanamivir was significantly pro- establish by epidemiologic studies alone. However, a cer- tective (22,23). tain number of observations are consistent with and strong- ly suggestive of an important role for aerosol transmission Discussion and Implications for Infection in natural infections, for example the “explosive nature Control during Influenza A (H5) Pandemic and simultaneous onset [of disease] in many persons” (9), In principle, influenza viruses can be transmitted by 3 including in nosocomial outbreaks (25). The often-cited routes: aerosols, large droplets, and direct contact with outbreak described by Moser et al. on an airplane with a secretions (or with fomites). These 3 routes are not mutu- defective ventilation system is best accounted for by ally exclusive and, as noted above, may be difficult to dis- aerosol transmission (26). Even more compelling were the entangle in natural infections. observations made at the Livermore Veterans For the purpose of deciding on the use of N95 respira- Administration Hospital during the 1957–58 pandemic. tors in a pandemic, showing that aerosol transmission The study group consisted of 209 tuberculous patients con- occurs at appreciable rates is sufficient. Evidence support- fined during their hospitalization to a building with ceil- ing aerosol transmission, reviewed above, appears com- ing-mounted UV lights; 396 tuberculous patients pelling. Despite the evidence cited in support of aerosol hospitalized in other buildings that lacked these lights con- transmission, many guidelines or review articles neverthe- stituted the control group. Although the study group partic- less routinely state that “large droplets transmission is ipants remained confined to the building, they were thought to be the main mode of influenza transmission” (or attended to by the same personnel as the control group, and similar statements) without providing supporting evidence there were no restrictions on visits from the community. from either previously published studies or empirical find- Thus, it was unavoidable at some point that attending per- ings. Despite extensive searches, I have not found a study sonnel and visitors would introduce influenza virus in both that proves the notion that large-droplets transmission is groups. During the second wave of the pandemic, the con- predominant and that aerosol transmission is negligible (or trol group and the personnel sustained a robust outbreak of nonexistent). Reports on many outbreaks suggest that respiratory illness, shown retrospectively by serology to be influenza aerosols are rapidly diluted because long-range due to the pandemic strain influenza A (H2N2), whereas infections occur most spectacularly in situations of crowd- the group in the irradiated building remained symptom ing and poor ventilation (25,26). However, even if long- free. The seroconversion rate to influenza A (H2N2) was range infections do not readily occur when sufficient 19% in the control group, 18% in personnel, but only 2% ventilation exists, this does not rule out the presence at in the study group (27,28). closer range of infectious particles in the micron or submi- Whereas UV irradiation is highly effective in inactivat- cron range, against which surgical masks would offer little ing viruses in small-particle aerosols, it is ineffective for protection (29,30). Many infection control practitioners surface decontamination because of poor surface penetra- have argued that the introduction of large-droplets precau- tions. It is also ineffective for large droplets because the tions in institutions has proven sufficient to interrupt germicidal activity sharply decreases as the relative influenza outbreaks and therefore that aerosol transmission humidity increases (28). Furthermore, because the installa- appears negligible. This evidence is, unfortunately, incon- tion of UV lights was set up in such a way as to decontam- clusive because of several confounding or mitigating Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 11, November 2006 1659 PERSPECTIVE factors. First, unless precise laboratory diagnosis is be demonstrated in human tissue sections from the respira- obtained, respiratory syncytial virus outbreaks can be mis- tory tract in a distribution corresponding to that of the α- taken for influenza outbreaks (9), which would artificially 2,3 receptors in the respiratory tract (34,35). This pattern increase the perceived “effectiveness” of large-droplets of virus binding correlates well with autopsy findings, precautions against influenza. Second, serologic studies which show extensive alveolar damage (34,37), and also are often not conducted, and therefore asymptomatic infec- correlates well with the observation that recovery of the A tions are not documented (among healthcare workers a (H5N1) virus is much more difficult from nasal swabs than large fraction of influenza infections are asymptomatic or from throat swabs (37). Thus, in the respiratory system the mistaken for another disease [31]). Third, since we are in current strains of A (H5N1) appear to infect mostly (per- an interpandemic period and the viruses currently circulat- haps exclusively) the lower respiratory tract. If that is ing have been drifting from related strains for decades, we indeed the case, it in turn suggests that human cases of all have partial immunity against these viruses, immunity avian influenza were acquired by exposure to an aerosol, that is further boosted in vaccinated healthcare workers. It since large droplets would not have delivered the virus to has even been argued that after several decades of circula- the lower respiratory tract. (Another hypothesis might be tion the current human influenza viruses are undergoing gastrointestinal infection, followed by viremia and dissem- gradual attenuation (32). Finally, surgical masks (used in ination, but not all patients have gastrointestinal symptoms large-droplets precautions) do not offer reliable protection [37]). Given the strong evidence for aerosol transmission against aerosols, but they nevertheless have a partially pro- of influenza viruses in general, and the high lethality of the tective effect, which further confuses the issue (29,30). current strains of avian influenza A (H5N1) (37), recom- In contrast, the situation with a pandemic strain of mending the use of N95 respirators, not surgical masks, as influenza A (H5) would become only too clear because no part of the protective equipment seems rational. one would have any degree of immunity against such a Several infection control guidelines for influenza have virus, vaccines would not be available for months, and recently been published, some specifically aimed at the these viruses would likely be highly virulent. Even though current strains of A (H5N1), others as part of more com- efficient human-to-human transmission of the A (H5N1) prehensive pandemic plans that address the emergence not virus has not yet been observed (by any mode), transmis- only of a pandemic form of A (H5) but also of other types sion of influenza A (H5N1) by aerosols from geese to of pandemic influenza viruses. Even though to date quails has been demonstrated in the laboratory (33). Thus, human-to-human transmission of A (H5N1) remains very even in the current incarnation of A (H5N1), infection by inefficient, the high lethality of the infection and potential the virus can generate aerosols that are infectious for high- for mutations call for prudence. The use of N95 respirators ly susceptible hosts. As far as we know, 1 of the main is included in the 2004 recommendations of the Centers for blocks to efficient human-to-human transmission of Disease Control and Prevention for healthcare workers influenza A (H5N1) is the virus’s current preference for who treat patients with known or suspected avian influen- specific sialic acid receptors. The current strains still pre- za (38). The World Health Organization’s current (April fer α-2,3–linked sialic acids, which is typical of avian 2006) guidelines for avian influenza recommend the use of influenza viruses, whereas human influenza viruses bind airborne precautions when possible, including the use of preferentially to α-2,6–linked sialic acids (34–36). In all N95 respirators when entering patients’ rooms (39). likelihood, 1 of the mutations required for influenza A Currently, several pandemic plans differ considerably (H5N1) to give rise to a pandemic strain would be to in their recommendations for infection control precautions change its receptor affinity to favor the α-2,6–linked sialic and PPE. The current version of the Canadian pandemic acids. For the influenza A (H1N1) pandemic strain of plan recommends surgical masks only, disregarding data 1918, this change required only 1 or 2 amino acid substi- that support the aerosol transmission of influenza (4). The tutions (36). Once a highly transmissible strain of influen- US pandemic plans (5) and the British plans, from both the za A (H5) has arisen, it will likely spread in part by National Health Service (available from http:// www.dh. aerosols, like other human influenza viruses. gov.uk/PublicationsAndStatistics/Publications/ Recent studies have shown that whereas epithelial cells PublicationsPolicyAndGuidance/PublicationsPolicyAndG in the human respiratory tract express predominantly the uidanceArticle/fs/en?CONTENT_ID=4121735&chk=Z6k α-2,6 sialic acid receptor, cells expressing the α-2,3 recep- jQY) and the Health Protection Agency (http://www. tor were detected only occasionally in the upper respirato- hpa.org.uk/infections/topics_az/influenza/pandemic/ ry tract; however, measurable expression of α-2,3–linked pdfs/HPAPandemicplan.pdf), acknowledge the contribu- sialic acid receptors was found in some cells in the alveo- tion of aerosols in influenza but curiously recommend sur- lar epithelium and at the junction of alveolus and terminal gical masks for routine care; the use of N95 respirators is bronchiole (35). 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Control and Prevention or the institutions with which the authors Available from http://www.cdc.gov/flu/avian/pdf/infectcontrol.pdf are affiliated. Search 1662 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 11, November 2006

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