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 [
22‐
24]. In addition, Tang et al. [
25] 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
Measles (also known as rubeola) is a febrile, rash illness caused by the measles virus, a lipid-enveloped, single-stranded, 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 [
26], including that of Riley and colleagues who used the concept of ‘quanta’ of infection [
27]. Later, two other outbreaks in outpatient clinics included retrospective airflow dynamics analysis, providing more evidence for the transmissibility of measles via the airborne route [
28,
29].
Tuberculosis
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 [
30,
31], which has been repeated more recently in a slightly different clinical context [
32]. Numerous other outbreak reports have confirmed the transmissibility of TB via the airborne route [
33‐
35], and interventions specifically targeting the airborne transmission route have proven effective in reducing TB transmission [
36].
Smallpox
Smallpox is a now eradicated, febrile, vesicular rash and disseminated illness, caused by a complex, double-stranded 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 [
37]. 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 17 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 [
38].
Emerging coronaviruses: Severe acute respiratory syndrome (SARS), middle-east respiratory syndrome (MERS)
Coronaviruses are lipid-enveloped, single-stranded positive sense RNA viruses, belong to the genus Coronavirus and include several relatively benign, seasonal, common cold viruses (229E, OC43, NL63, HKU-1). They also include two new more virulent coronaviruses: severe acute respiratory syndrome coronavirus (SARS-CoV), which emerged in the human population in 2003; and Middle-East Respiratory Syndrome coronavirus (MERS-CoV), which emerged in humans during 2012.
For SARS-CoV, several thorough epidemiological studies that include retrospective airflow tracer investigations are consistent with the hypothesis of an airborne transmission route [
39‐
41]. 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 [
42].
Although several studies compared and contrasted SARS and MERS from clinical and epidemiological angles [
43‐
45], 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 [
46‐
48]. 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 [
49].
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 [
50‐
52]. 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 4 (DPP4), the identified receptor used by the virus, in the cells of the human URT. The search for an alternate receptor was negative [
53]. 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
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 [
54‐
57]. In experimental inoculation experiments on human volunteers, aerosolized influenza viruses are infectious at a dose much lower than by nasal instillation [
58]. The likely answer is that both routes are possible and that the importance and significance of each route will vary in different situations [
16,
20,
21].
For example, tighter control of the environment may reduce or prevent airborne transmission by: 1) isolating infectious patients in a single-bed, negative pressure isolation room [
25]; 2) controlling environmental relative humidity to reduce airborne influenza survival [
59]; 3) 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) [
60]; 4) 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 [
61]. 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 influenza-infected human subjects [
62‐
66] and have detected influenza RNA in environmental air [
67‐
69]. More recently, some of these studies have shown the absence of [
70], or significantly reduced numbers of viable viruses in air-samples with high influenza RNA levels (as tested by PCR) [
66,
71,
72]. 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 air-sampling 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 [
73].
In some earlier articles that discuss the predominant mode of influenza virus transmission [
74‐
78], 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 [
79]. 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 59 published studies on interventions to reduce the spread of respiratory viruses, there were actually only two studies specifically about influenza viruses [
80]. 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 1–2 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. 38 in an outbreak on an Alaska Airlines flight [
11].
Ebola
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 2013–2016. The transmission of Ebola viruses has been reviewed in depth by Osterholm et al. (4). 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 [
81,
82] (also reviewed in [
4]). Experimental infections of Rhesus monkeys by Ebola Zaire using aerosol infection has been shown to be highly effective [
83,
84] and this experimental procedure has in fact been used as infectious challenge in Ebola vaccine studies [
85,
86]. 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 [
83,
84].
Such respiratory pathological lesions have not been reported in human autopsies of Ebola cases, but as noted by Osterholm et al. [
4], 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 [
87,
88] and aerosolization of blood or other fluids would create a significant airborne transmission hazard.