Sludge Watch ==> Aerosol transmission of Influenza A Virus
Maureen Reilly
maureen.reilly at sympatico.ca
Mon Nov 13 12:01:24 EST 2006
Sludgewatch Admin:
This article looks at the transport of the influenza virus and aerosols, not
just large droplets, may be a source of transmission.
We need to look at the transport and land application of sewage sludge in
our pandemic planning.
..................................................................................................................
EID Journal Home > Volume 12, Number 11–November 2006
Volume 12, Number 11–November 2006
Perspective
Review of Aerosol Transmission of Influenza A Virus
Raymond Tellier*†
*Hospital for Sick Children, Toronto, Ontario, Canada; and †University of
Toronto, Toronto, Ontario, Canada
Suggested citation for this article
Abstract
In theory, influenza viruses can be transmitted through aerosols, large
droplets, or direct contact with secretions (or fomites). These 3 modes are
not mutually exclusive. Published findings that support the occurrence of
aerosol transmission were reviewed to assess the importance of this mode of
transmission. Published evidence indicates that aerosol transmission of
influenza can be an important mode of transmission, which has obvious
implications for pandemic influenza planning and in particular for
recommendations about the use of N95 respirators as part of personal
protective equipment.
Concerns about the likely occurrence of an influenza pandemic in the near
future are increasing. The highly pathogenic strains of influenza A (H5N1)
virus circulating in Asia, Europe, and Africa have become the most feared
candidates for giving rise to a pandemic strain.
Several authors have stated that large-droplet transmission is the
predominant mode by which influenza virus infection is acquired (1–3). As a
consequence of this opinion, protection against infectious aerosols is often
ignored for influenza, including in the context of influenza pandemic
preparedness. For example, the Canadian Pandemic Influenza Plan and the US
Department of Health and Human Services Pandemic Influenza Plan (4,5)
recommend surgical masks, not N95 respirators, as part of personal
protective equipment (PPE) for routine patient care. This position
contradicts the knowledge on influenza virus transmission accumulated in the
past several decades. Indeed, the relevant chapters of many reference books,
written by recognized authorities, refer to aerosols as an important mode of
transmission for influenza (6–9).
In preparation for a possible pandemic caused by a highly lethal virus such
as influenza A (H5N1), making the assumption that the role of aerosols in
transmission of this virus will be similar to their role in the transmission
of known human influenza viruses would seem rational. Because infection with
influenza A (H5N1) virus is associated with high death rates and because
healthcare workers cannot as yet be protected by vaccination, recommending
an enhanced level of protection, including the use of N95 respirators as
part of PPE, is important. Following are a brief review of the relevant
published findings that support the importance of aerosol transmission of
influenza and a brief discussion on the implications of these findings on
pandemic preparedness.
Influenza Virus Aerosols
By definition, aerosols are suspensions in air (or in a gas) of solid or
liquid particles, small enough that they remain airborne for prolonged
periods because of their low settling velocity. For spherical particles of
unit density, settling times (for a 3-m fall) for specific diameters are 10
s for 100 μm, 4 min for 20 μm, 17 min for 10 μm, and 62 min
for 5 μm; particles with a diameter <3 μm essentially do not
settle. Settling times can be further affected by air turbulence (10,11).
The median diameters at which particles exhibit aerosol behavior also
correspond to the sizes at which they are efficiently deposited in the lower
respiratory tract when inhaled. Particles of >6-μm diameter are trapped
increasingly in the upper respiratory tract (12); no substantial deposition
in the lower respiratory tract occurs at >20 μm (11,12). Many authors
adopt a size cutoff of <5 μm for aerosols. This convenient convention
is, however, somewhat arbitrary, because the long settling time and the
efficient deposition in the lower respiratory tract are properties that do
not appear abruptly at a specific diameter value. Certainly, particles in
the micron or submicron range will behave as aerosols, and particles >10–20
μm will settle rapidly, will not be deposited in the lower respiratory
tract, and are referred to as large droplets (10–12).
Coughing or sneezing generates a substantial quantity of particles, a large
number of which are <5–10 μm in diameter [reviewed in (10)]. In
addition, particles expelled by coughing or sneezing rapidly shrink in size
by evaporation, thereby increasing the number of particles that behave as
aerosols. Particles shrunken by evaporation are referred to as droplet
nuclei (10–12). This phenomenon affects particles with a diameter at
emission of <20 μm, and complete desiccation would decrease the
diameter to a little less than half the initial diameter (10). Droplet
nuclei are hygroscopic. When exposed to humid air (as in the lungs), they
will swell back. One would expect that inhaled hygroscopic particles would
be retained in the lower respiratory tract with greater efficiency, and this
hypothesis has been confirmed experimentally (11,12). Because aerosols
remain airborne, they can be carried over large distances, which may create
a potential for long-range infections. The occurrence of long-range
infections is affected by several other factors. These include dilution, the
infectious dose, the amount of infectious particles produced, the duration
of shedding of the infectious agent, and the persistence of the agent in the
environment (11). Inferring an absence of aerosols because long-range
infections are not frequently observed is incorrect.
Humans acutely infected with influenza A virus have a high virus titer in
their respiratory secretions, which will be aerosolized when the patient
sneezes or coughs. The viral titer measured in nasopharyngeal washes
culminates on approximately day 2 or 3 after infection and can reach up to
107 50% tissue culture infective dose (TCID50)/mL (13,14). The persistence
of the infectivity of influenza virus in aerosols has been studied in the
laboratory. In experiments that used homogeneous aerosolized influenza virus
suspensions (mean diameter 6 μm), virus infectivity (assessed by in
vitro culture) at a fixed relative humidity undergoes an exponential decay;
this decay is characterized by very low death rate constants, provided that
the relative humidity was in the low range of 15%–40% (15,16). These results
are consistent with those of an older study (admittedly performed in a more
rudimentary manner) in which infectious influenza viruses in an aerosol
could be demonstrated for up to 24 h by using infection in mice as a
detection method, provided that the relative humidity was 17%-24% (17). In
all these studies, the decay of virus infectivity increased rapidly at
relative humidity >40%. The increased survival of influenza virus in
aerosols at low relative humidity has been suggested as a factor that
accounts for the seasonality of influenza (15,16). The sharply increased
decay of infectivity at high humidity has also been observed for other
enveloped viruses (e.g., measles virus); in contrast, exactly the opposite
relationship has been shown for some nonenveloped viruses (e.g., poliovirus)
(11,15,16).
Experimental Influenza Infection
Experimental infection studies permit the clear separation of the aerosol
route of transmission from transmission by large droplets. Laboratory
preparation of homogeneous small particle aerosols free of large droplets is
readily achieved (13,18). Conversely, transmission by large droplets without
accompanying aerosols can be achieved by intranasal drop inoculation (13).
Influenza infection has been documented by aerosol exposure in the mouse
model, the squirrel monkey model, and human volunteers (12,13,17–19).
Observations made during experimental infections with human volunteers are
particularly interesting and relevant. In studies conducted by Alford and
colleagues (18), volunteers were exposed to carefully titrated aerosolized
influenza virus suspensions by inhaling 10 L of aerosol through a face mask.
The diameter of the aerosol particles was 1 μm–3 μm. Demonstration
of infection in participants in the study was achieved by recovery of
infectious viruses from throat swabs, taken daily, or by seroconversion,
i.e., development of neutralizing antibodies. The use of carefully titrated
viral stocks enabled the determination of the minimal infectious dose by
aerosol inoculation. For volunteers who lacked detectable neutralizing
antibodies at the onset, the 50% human infectious dose (HID50) was 0.6–3.0
TCID50, if one assumes a retention of 60% of the inhaled particles (18). In
contrast, the HID50 measured when inoculation was performed by intranasal
drops was 127–320 TCID50 (13). Additional data from experiments conducted
with aerosolized influenza virus (average diameter 1.5 μm) showed that
when a dose of 3 TCID50 was inhaled, ≈1 TCID50 only was deposited in
the nose (12). Since the dose deposited in the nose is largely below the
minimal dose required by intranasal inoculation, this would indicate that
the preferred site of infection initiation during aerosol inoculation is the
lower respiratory tract. Another relevant observation is that whereas the
clinical symptoms initiated by aerosol inoculation covered the spectrum of
symptoms seen in natural infections, the disease observed in study
participants infected experimentally by intranasal drops was milder, with a
longer incubation time and usually no involvement of the lower respiratory
tract (13,20). For safety reasons, this finding led to the adoption of
intranasal drop inoculation as the standard procedure in human experimental
infections with influenza virus (13).
Additional support for the view that the lower respiratory tract (which is
most efficiently reached by the aerosol route) is the preferred site of
infection is provided by studies on the use of zanamivir for prophylaxis. In
experimental settings, intranasal zanamivir was protective against
experimental inoculation with influenza virus in intranasal drops (21).
However, in studies on prophylaxis of natural infection, intranasally
applied zanamivir was not protective (22), whereas inhaled zanamivir was
protective in one study (23) and a protective effect approached statistical
significance in another study (22). These experiments and observations
strongly support the view that many, possibly most, natural influenza
infections occur by the aerosol route and that the lower respiratory tract
may be the preferred site of initiation of the infection.
Epidemiologic Observations
In natural infections, the postulated modes of transmission have included
aerosols, large droplets, and direct contact with secretions or fomites
because the virus can remain infectious on nonporous dry surfaces for <48
hours (24). Because in practice completely ruling out contributions of a
given mode of transmission is often difficult, the relative contribution of
each mode is usually difficult to establish by epidemiologic studies alone.
However, a certain number of observations are consistent with and strongly
suggestive of an important role for aerosol transmission in natural
infections, for example the "explosive nature and simultaneous onset [of
disease] in many persons" (9), including in nosocomial outbreaks (25). The
often-cited outbreak described by Moser et al. on an airplane with a
defective ventilation system is best accounted for by aerosol transmission
(26). Even more compelling were the observations made at the Livermore
Veterans Administration Hospital during the 1957–58 pandemic. The study
group consisted of 209 tuberculous patients confined during their
hospitalization to a building with ceiling-mounted UV lights; 396
tuberculous patients hospitalized in other buildings that lacked these
lights constituted the control group. Although the study group participants
remained confined to the building, they were attended to by the same
personnel as the control group, and there were no restrictions on visits
from the community. Thus, it was unavoidable at some point that attending
personnel and visitors would introduce influenza virus in both groups.
During the second wave of the pandemic, the control group and the personnel
sustained a robust outbreak of respiratory illness, shown retrospectively by
serology to be due to the pandemic strain influenza A (H2N2), whereas the
group in the irradiated building remained symptom free. The seroconversion
rate to influenza A (H2N2) was 19% in the control group, 18% in personnel,
but only 2% in the study group (27,28).
Whereas UV irradiation is highly effective in inactivating viruses in
small-particle aerosols, it is ineffective for surface decontamination
because of poor surface penetrations. It is also ineffective for large
droplets because the germicidal activity sharply decreases as the relative
humidity increases (28). Furthermore, because the installation of UV lights
was set up in such a way as to decontaminate the upper air of rooms only,
large droplets would not have been exposed to UV, whereas aerosols, carried
by thermal air mixing, would have been exposed (27,28). So in effect in this
study only the aerosol route of infection was blocked, and this step alone
achieved near complete protection.
The converse occurrence, blocking only the large droplet and fomites routes
in natural infections, can be inferred from the studies on the use of
zanamivir for prophylaxis described previously. In experimental settings,
intranasally applied zanamivir was protective against an experimental
challenge with influenza by intranasal drops (21). However, in studies on
prophylaxis of natural disease, intranasal zanamivir was not protective
(22), which leads to the conclusion that natural infection can occur
efficiently by a route other than large droplets or fomites. As noted above,
inhaled zanamivir was significantly protective (22,23).
Discussion and Implications for Infection Control during Influenza A (H5)
Pandemic
In principle, influenza viruses can be transmitted by 3 routes: aerosols,
large droplets, and direct contact with secretions (or with fomites). These
3 routes are not mutually exclusive and, as noted above, may be difficult to
disentangle in natural infections.
For the purpose of deciding on the use of N95 respirators in a pandemic,
showing that aerosol transmission occurs at appreciable rates is sufficient.
Evidence supporting aerosol transmission, reviewed above, appears
compelling. Despite the evidence cited in support of aerosol transmission,
many guidelines or review articles nevertheless routinely state that "large
droplets transmission is thought to be the main mode of influenza
transmission" (or similar statements) without providing supporting evidence
from either previously published studies or empirical findings. Despite
extensive searches, I have not found a study that proves the notion that
large-droplets transmission is predominant and that aerosol transmission is
negligible (or nonexistent). Reports on many outbreaks suggest that
influenza aerosols are rapidly diluted because long-range infections occur
most spectacularly in situations of crowding and poor ventilation (25,26).
However, even if long-range infections do not readily occur when sufficient
ventilation exists, this does not rule out the presence at closer range of
infectious particles in the micron or submicron range, against which
surgical masks would offer little protection (29,30). Many infection control
practitioners have argued that the introduction of large-droplets
precautions in institutions has proven sufficient to interrupt influenza
outbreaks and therefore that aerosol transmission appears negligible. This
evidence is, unfortunately, inconclusive because of several confounding or
mitigating factors. First, unless precise laboratory diagnosis is obtained,
respiratory syncytial virus outbreaks can be mistaken for influenza
outbreaks (9), which would artificially increase the perceived
"effectiveness" of large-droplets precautions against influenza. Second,
serologic studies are often not conducted, and therefore asymptomatic
infections are not documented (among healthcare workers a large fraction of
influenza infections are asymptomatic or mistaken for another disease [31]).
Third, since we are in an interpandemic period and the viruses currently
circulating have been drifting from related strains for decades, we all have
partial immunity against these viruses, immunity that is further boosted in
vaccinated healthcare workers. It has even been argued that after several
decades of circulation the current human influenza viruses are undergoing
gradual attenuation (32). Finally, surgical masks (used in large-droplets
precautions) do not offer reliable protection against aerosols, but they
nevertheless have a partially protective effect, which further confuses the
issue (29,30).
In contrast, the situation with a pandemic strain of influenza A (H5) would
become only too clear because no one would have any degree of immunity
against such a virus, vaccines would not be available for months, and these
viruses would likely be highly virulent. Even though efficient
human-to-human transmission of the A (H5N1) virus has not yet been observed
(by any mode), transmission of influenza A (H5N1) by aerosols from geese to
quails has been demonstrated in the laboratory (33). Thus, even in the
current incarnation of A (H5N1), infection by the virus can generate
aerosols that are infectious for highly susceptible hosts. As far as we
know, 1 of the main blocks to efficient human-to-human transmission of
influenza A (H5N1) is the virus's current preference for specific sialic
acid receptors. The current strains still prefer α-2,3–linked sialic
acids, which is typical of avian influenza viruses, whereas human influenza
viruses bind preferentially to α-2,6–linked sialic acids (34–36). In
all likelihood, 1 of the mutations required for influenza A (H5N1) to give
rise to a pandemic strain would be to change its receptor affinity to favor
the α-2,6–linked sialic acids. For the influenza A (H1N1) pandemic
strain of 1918, this change required only 1 or 2 amino acid substitutions
(36). Once a highly transmissible strain of influenza A (H5) has arisen, it
will likely spread in part by aerosols, like other human influenza viruses.
Recent studies have shown that whereas epithelial cells in the human
respiratory tract express predominantly the α-2,6 sialic acid receptor,
cells expressing the α-2,3 receptor were detected only occasionally in
the upper respiratory tract; however, measurable expression of
α-2,3–linked sialic acid receptors was found in some cells in the
alveolar epithelium and at the junction of alveolus and terminal bronchiole
(35). Binding of influenza A (H5N1) virus can be demonstrated in human
tissue sections from the respiratory tract in a distribution corresponding
to that of the α-2,3 receptors in the respiratory tract (34,35). This
pattern of virus binding correlates well with autopsy findings, which show
extensive alveolar damage (34,37), and also correlates well with the
observation that recovery of the A (H5N1) virus is much more difficult from
nasal swabs than from throat swabs (37). Thus, in the respiratory system the
current strains of A (H5N1) appear to infect mostly (perhaps exclusively)
the lower respiratory tract. If that is indeed the case, it in turn suggests
that human cases of avian influenza were acquired by exposure to an aerosol,
since large droplets would not have delivered the virus to the lower
respiratory tract. (Another hypothesis might be gastrointestinal infection,
followed by viremia and dissemination, but not all patients have
gastrointestinal symptoms [37]). Given the strong evidence for aerosol
transmission of influenza viruses in general, and the high lethality of the
current strains of avian influenza A (H5N1) (37), recommending the use of
N95 respirators, not surgical masks, as part of the protective equipment
seems rational.
Several infection control guidelines for influenza have recently been
published, some specifically aimed at the current strains of A (H5N1),
others as part of more comprehensive pandemic plans that address the
emergence not only of a pandemic form of A (H5) but also of other types of
pandemic influenza viruses. Even though to date human-to-human transmission
of A (H5N1) remains very inefficient, the high lethality of the infection
and potential for mutations call for prudence. The use of N95 respirators is
included in the 2004 recommendations of the Centers for Disease Control and
Prevention for healthcare workers who treat patients with known or suspected
avian influenza (38). The World Health Organization's current (April 2006)
guidelines for avian influenza recommend the use of airborne precautions
when possible, including the use of N95 respirators when entering patients'
rooms (39).
Currently, several pandemic plans differ considerably in their
recommendations for infection control precautions and PPE. The current
version of the Canadian pandemic plan recommends surgical masks only,
disregarding data that support the aerosol transmission of influenza (4).
The US pandemic plans (5) and the British plans, from both the National
Health Service (available from
http://www.dh.gov.uk/PublicationsAndStatistics/Publications/PublicationsPolicyAndGuidance/
PublicationsPolicyAndGuidanceArticle/fs/en?CONTENT_ID=4121735&chk=Z6kjQY)
and the Health Protection Agency
(http://www.hpa.org.uk/infections/topics_az/influenza/pandemic/pdfs/HPAPandemicplan.pdf),
acknowledge the contribution of aerosols in influenza but curiously
recommend surgical masks for routine care; the use of N95 respirators is
reserved for protection during "aerosolizing procedures" (5,40). These
recommendations fail to recognize that infectious aerosols will also be
generated by coughing and sneezing. The Australian Management Plan for
Pandemic Influenza (June 2005) recommends N95 respirators for healthcare
workers
(http://www.health.gov.au/internet/wcms/Publishing.nsf/Content/phd-pandemic-plan.htm),
and in France, the Plan gouvernemental de prévention et de lutte <<Pandémie
grippale>>(January 2006) recommends FFP2 respirators (equivalent to N95
respirators) (http://www.splf.org/s/IMG/pdf/plan-grip-janvier06.pdf). Given
the scientific evidence that supports the occurrence of aerosol transmission
of influenza, carefully reexamining current recommendations for PPE
equipment would appear necessary.
Acknowledgment
The author thanks Martin Petric for his helpful review of the manuscript.
Dr Tellier is a microbiologist for the Hospital for Sick Children; senior
associate scientist, Research Institute, Hospital for Sick Children; and
associate professor, Department of Laboratory Medicine and Pathobiology,
Faculty of Medicine, University of Toronto.
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Suggested Citation for this Article
Tellier R. Review of aerosol transmission of influenza A virus. Emerg Infect
Dis [serial on the Internet]. 2006 Nov [date cited]. Available from
http://www.cdc.gov/ncidod/EID/vol12no11/06-0426.htm
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