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Transmissibility and transmission of respiratory viruses

Abstract

Human respiratory virus infections lead to a spectrum of respiratory symptoms and disease severity, contributing to substantial morbidity, mortality and economic losses worldwide, as seen in the COVID-19 pandemic. Belonging to diverse families, respiratory viruses differ in how easy they spread (transmissibility) and the mechanism (modes) of transmission. Transmissibility as estimated by the basic reproduction number (R0) or secondary attack rate is heterogeneous for the same virus. Respiratory viruses can be transmitted via four major modes of transmission: direct (physical) contact, indirect contact (fomite), (large) droplets and (fine) aerosols. We know little about the relative contribution of each mode to the transmission of a particular virus in different settings, and how its variation affects transmissibility and transmission dynamics. Discussion on the particle size threshold between droplets and aerosols and the importance of aerosol transmission for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus is ongoing. Mechanistic evidence supports the efficacies of non-pharmaceutical interventions with regard to virus reduction; however, more data are needed on their effectiveness in reducing transmission. Understanding the relative contribution of different modes to transmission is crucial to inform the effectiveness of non-pharmaceutical interventions in the population. Intervening against multiple modes of transmission should be more effective than acting on a single mode.

Introduction

Human respiratory viruses include a broad range of viruses that infect cells of the respiratory tract, elicit respiratory and other symptoms, and are transmitted mainly by respiratory secretions of infected persons. Respiratory virus infections often cannot be differentiated clinically. Respiratory viruses belong to diverse virus families that differ in viral and genomic structures, populations susceptible to infection, disease severity, seasonality of circulation, transmissibility and modes of transmission. Together, they contribute to substantial morbidity1, mortality2 and concomitant economic losses3 annually worldwide. In addition, occasional pandemics cause extreme disruption to societies and economies as exemplified by the current COVID-19 pandemic. Until effective treatments or vaccines for COVID-19 are available, we have to rely heavily on population-based and individual-based public health measures to mitigate transmission. The effectiveness and the suitability of a non-pharmaceutical intervention (NPI) to mitigate transmission depends substantially on the ease of transmission (transmissibility) and the mechanism of transmission (modes of transmission) specific to that virus, as these interventions can target some but not all potential modes of transmission. Therefore, understanding how to evaluate the transmissibility and evidence supporting different modes of transmission will aid in the control of respiratory virus transmission.

Previous reviews and commentaries discussed the transmissibility of influenza virus4,5; methods for studying transmission, including animal models4,5,6,7, human models6,8 and epidemiological studies9; the mechanism and evidence for different modes of transmission4,6,7,9,10,11,12; factors affecting transmission4,5,11,13; controversies regarding the relative importance of different modes of transmission14,15; pharmaceutical interventions4 and NPIs11,16,17,18 for mitigating transmission16,17,18,19; and guidelines from public health agencies on infection prevention and control recommendations for respiratory viruses9,15. These various aspects of transmissibility and transmission have been more comprehensively studied for influenza virus4,5,6,7,10,14,17,19 than for other respiratory viruses9,11,12,15,16,18. In this Review, I will bring these discussions together to provide a broad overview of the transmissibility and modes of transmission of respiratory viruses, the approaches used to make these assessments, the viral, host and environmental determinants of transmission, and common NPIs for mitigating respiratory virus transmission, in the hope of illustrating the common approaches for studying respiratory virus transmission as well as the interconnection and differences between these discussions. I also discuss recent controversies regarding the role of aerosols in transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the difficulties in evaluating the relative contribution of each mode to the transmission of respiratory viruses.

Transmissibility

In the control of a novel pandemic, one of the most important early questions is how easily the disease will spread from an infected person to a susceptible person; that is, how transmissible the disease is. Transmissibility is determined by the infectivity of the pathogen, the contagiousness of the infected individual, the susceptibility of the exposed individual, the contact patterns between the infected individual and the exposed individual, and the environmental stress exerted on the pathogen during transmission. These will determine the scale and intensity of control measures needed to suppress transmission. In animal models, volunteer transmission studies, modelling studies and observational as well as interventional epidemiological studies, although the number of successful transmission events (that is, infection in the exposed individual) is often used as an outcome measure, these study designs answer different research questions when evaluating the transmissibility of a respiratory virus.

Evaluating transmissibility in animals and volunteers

Animal models are often used to compare the transmissibility of respiratory viruses with different naturally occurring or engineered genomic constructs to identify viral molecular determinants of increased transmissibility, or to compare the transmissibility between different modes of transmission (Box 1). For example, for influenza virus, animal transmission studies have been used to evaluate the molecular determinants of transmissibility20, the airborne transmission potential of emerging viruses21 or drug-resistant viruses22, the relative importance of droplets and aerosols to transmission23 and the anatomical site that drives the different routes of transmission24. Alternatively, volunteer transmission studies, where transmission is observed in susceptible volunteers who are exposed to other volunteers who are either experimentally or naturally infected8, may be used to provide important information on the effectiveness of interventions and the importance of presymptomatic or asymptomatic transmission in a controlled setting25. However, these studies can be challenging and expensive to conduct, and may be criticized as too artificial8.

Evaluating transmissibility in the population

Mathematical or statistical models are often used to estimate transmissibility of a respiratory virus in the population, especially during pandemics to assess the extent of transmission. With use of data from surveillance, observational and interventional epidemiological studies, or simulation from modelling studies, transmissibility is usually assessed by the estimation of the basic reproduction number (R0) or secondary attack rate (SAR) (Box 2). In addition, by comparing the two simultaneously, one can assess the role of specific populations (for example, households or schools)26 or superspreading events27 in driving community transmission.

Modes of transmission

Respiratory viruses are transmitted between individuals when the virus is released from the respiratory tract of an infected person and is transferred through the environment, leading to infection of the respiratory tract of an exposed and susceptible person. There are a number of different routes (or modes) through which transmission could occur, the chance of which is modified by viral, host and environmental factors. Although there is evidence in support of individual modes of transmission, the relative contribution of different modes to a successful transmission event, and the relative effect of each factor on each mode or multiple modes simultaneously, is often unknown.

Direct contact, indirect contact, droplet and aerosol

Respiratory viruses can be transmitted via respiratory secretions over multiple routes independently and simultaneously. Traditionally, it is believed that respiratory viruses are transmitted directly via physical contact between an infected individual (infector) and a susceptible individual (infectee), indirectly via contact with contaminated surfaces or objects (fomites) or directly through the air from one respiratory tract to another via large respiratory droplets or via fine respiratory aerosols6,7 (Fig. 1). These four major modes of transmission (direct contact, indirect contact/fomite, droplet and aerosol) are often the foci of transmission control; for example, infection prevention and control measures in health-care settings are designed specifically for each mode28. Some respiratory viruses, including influenza viruses, coronaviruses and rhinoviruses, can be recovered from faeces29,30 or infect cells in the gastrointestinal tract29, suggesting infection may spread via faeces; for example, via aerosolization during toilet flushing31. Studies have shown SARS-CoV-2 in ocular secretions32 and influenza virus infection by ocular exposure33, suggesting respiratory viruses might also be transmitted via exposure to the eyes.

Fig. 1: Major modes of transmission of respiratory viruses during short-range and long-range transmission.
figure1

During an acute respiratory virus infection, an infected individual (infector; red) may shed virus in exhaled breath droplets and aerosols, and may also contaminate their immediate bodily surfaces (for example, skin and clothes) or surrounding objects and surfaces (for example, tables) with their respiratory secretions. In general, if a susceptible individual (infectee; grey) is close to the infector, short-range transmission may occur when the infectee breathes in the virus-laden droplets or aerosols released by the infector, during direct (physical) contact with the infector or during physical contact with objects or surfaces contaminated (fomite) by the infector. If the infectee is at a distance from the infector, long-range transmission may occur when the infectee breathes in the virus-laden aerosols released by the infector or during physical contact with a fomite. However, the terminology and the defining features of each mode of respiratory virus transmission, especially regarding redefining the particle size threshold between droplets and aerosols, is under active discussion (see the section Terminology and defining features of modes of transmission).

Terminology and defining features of each mode of transmission

The lack of standardization of terminology and the defining features of each major mode of respiratory virus transmission, in particular the difficulty to differentiate between ‘droplets’ and ‘aerosols’, has caused much confusion34. Although the direct contact route traditionally refers to transmission via direct physical contact between infectors and infectees6,7,9, some consider exposure to infectious (large) droplets as an additional form of contact transmission28,35,36, sometimes using the term ‘droplet contact’ to describe transmission via droplets37 and ‘direct contact’35 or ‘close contact’36 to describe transmission via both physical contact and exposure to droplets. The WHO uses ‘direct, indirect, or close contact’ to describe ‘contact and droplet transmission’, although it is unclear whether ‘close contact’ refers to transmission via droplets alone, direct (physical) contact alone or both38,39. Some attempted to define ‘close contact transmission’ by proposing three subroutes as ‘short-range airborne’, ‘large droplets’ and ‘immediate body-surface contact’ to describe transmission in close proximity, where the last refers to an infectee in contact with the infector’s immediate contaminated bodily surfaces (for example, skin and clothes), and is to be distinguished from the (distant) fomite route, which involves delayed and less frequent touching from a greater distance40. Some use ‘airborne’ to describe transmission via droplets and aerosols as both can travel through the air9, whereas others use it to describe transmission via aerosols only6,12,28,39,41.

In the 1930s, William F. Wells, who studied air bacteriology and the transmission of respiratory tuberculosis, proposed that the particle size of exhaled respiratory droplets influences how they are transported in the air, and could be classified as ‘aerosols’ or ‘droplets’, with different implications to disease transmission42 (Box 3). Subsequently, animal studies, experimental volunteer studies and observational epidemiological studies were conducted to study the transmission of respiratory syncytial virus (RSV), rhinovirus and influenza virus in homes and health-care settings43,44. In recent years, on the basis of different aspects of particle behaviours45, various particle size cut-offs, often in the range between 5 and 20 µm, have been used to differentiate particles as ‘aerosols’ or ‘droplets’. For example, the cut-off at 5 µm used by many regulatory bodies35,38 is based on early studies of pulmonary tuberculosis that believed particles smaller than 5 µm would deposit in the pulmonary/alveolar region of the lung by settlement and initiate infection, whereas particles larger than 5 µm deposit in the nasal cavity by centrifugal force28,46,47. Other studies put similar emphasis on the region of particle deposition in the human respiratory tract, and suggested that particles smaller than 10 µm reach and deposit in the pulmonary region12,45,48,49, and particles of size between 10 and 100 µm are inspired but deposit in the head airways or tracheobronchial regions49,50. Some consider particles smaller than 20 µm important for aerosol transmission as particles of 20 µm were estimated to take 4 minutes to settle on the ground from a height of 3 m, whereas particles smaller than 3 µm practically do not settle due to regular resuspension by air currents51.

A recent workshop on the airborne transmission of SARS-CoV-2 suggested referring to ‘aerosols’ as a stable suspension of solid and/or liquid particles in air, with a particle size cut-off set to an order of magnitude larger than previously thought (that is, ~30–100 µm), and ‘droplets’ as liquid particles that are larger than aerosols52. Some argued such dichotomization based on particle size alone has not accounted for the influence of expiratory activities on particle behaviour and proposed a turbulent gas cloud model to describe exhaled particle behaviour53. The model describes exhaled air as primarily a multiphase turbulent gas cloud (‘puff’) that consists of clusters of exhaled particles mixed with ambient air, where the particles have sizes on a continuous scale and are carried forwards by the momentum of expiratory activities53. The behaviour of exhaled particles is then influenced by conditions of both the ambient and the exhaled air, such as composition, temperature, humidity and airflow, highlighting the chance of larger droplets to be propelled further away than would be expected on the basis of particle size alone53,54.

Increased concern for aerosol transmission

To many, bioaerosols (Box 3) pose particular concerns in transmission control. As bioaerosols can remain airborne for a prolonged period and travel through the air over long distances55,56,57,58,59,60, this potentiates disease transmission over long distances and therefore requires additional measures (for example, larger spatial separation between hospital beds28). Individuals with higher bioaerosol production might contribute to superspreading events61,62. Some hypothesize that the propensity of aerosol deposition in the lower respiratory tract45 might require a lower infectious dose and lead to severer disease. Volunteer challenge studies showed that influenza virus and adenovirus infection initiated by the inhalation of infectious bioaerosols required a lower infectious dose51,63,64, whereas rhinovirus might require a similar or a higher infectious dose51. Infection initiated by inhaling infectious influenza virus bioaerosols led to higher risk of fever compared with intranasal inoculation65, although some studies alternatively suggested that infection initiated by droplets leads to severer disease due to a higher infectious dose66. Alternatively, a narrower bottleneck of the minimum infectious virions required for transmission via aerosols may reduce virus diversity in the population and therefore the chance of a pandemic strain emerging67, whereas a wider bottleneck via the contact route may allow the propagation of minor variants, such as drug-resistant viruses68.

Determinants of transmission

Virus, host and environmental factors influence whether a successful transmission occurs by governing the infectivity of the respiratory virus, the contagiousness of the infector, the susceptibility of the exposed individual and the environmental stress on the virus (Fig. 2). These determinants may have different relative effects on each mode of transmission69.

Fig. 2: Viral, environmental and host determinants of respiratory virus transmission.
figure2

Virus, environmental and host factors influence whether a successful transmission occurs by governing the infectivity of the respiratory virus, the contagiousness of the infected person, the environmental stress on the virus, which affects its persistence and survival during transmission, and the susceptibility of the exposed person.

Viral determinants

The propensity for respiratory viruses to be transmitted is affected by virus stability under environmental stress70,71, which in turn is influenced by the composition and structure of the virus envelope72,73, capsid74, internal proteins and genomes75 as well as the formation of viral aggregates76. For instance, DNA viruses such as herpesviruses (for example, varicella zoster virus (VZV)) with a more densely packaged genome have a stronger capsid structure that may prevent premature release of the viral genome before infection77. RNA virus genomes such as those of influenza virus have higher mutation rates, giving rise to diverse viral genomic variants (quasispecies) in infected individuals78, which may allow faster host adaptation of a virus strain that is efficiently transmitted via respiratory droplets79. In addition to virus stability, other viral factors, such as viral protein expression and modification, also influence transmission. Viral surface and internal proteins can affect transmissibility by determining the site of infection and interacting with specific host receptors with differing binding specificity and affinity. In studies of the pandemic potential of avian influenza viruses, human adapted haemagglutinin (HA) and polymerase subunit PB2, which exhibit a preferential binding to ɑ2,6-linked sialic acids and support viral genome replication in the lower-temperature environment of the mammalian airway, respectively, conferred efficient transmission over the respiratory droplet route in ferrets80. Similarly, an optimal ratio of HA to neuraminidase (NA) was essential for efficient transmission over the respiratory droplet route20, which is hypothesized to be associated with the release of single viral particles instead of aggregates with increased NA activity81. The loss of glycosylation sites at specific HA amino acid positions also conferred transmissibility to an avian influenza virus in a mammalian model82, thereby increasing its pandemic potential.

Environmental determinants

Environmental determinants could, on one hand, affect transmissibility by influencing the survival and persistence of respiratory viruses in respiratory droplets or fomites after their release to the environment, or on the other hand, modulate transmission by modulating host factors such as viral shedding and human behaviour. These effects could differ across different transmission modes and settings, and may favour one mode over another. As demonstrated mostly for influenza virus, environmental factors that may affect virus survival include temperature, humidity, salinity, pH, the medium or materials of the contaminated objects or surfaces, ventilation, airflow and ultraviolet radiation83,84. Their effects on survival may differ between viruses85, and their effects on transmission may be assessed in animal, epidemiological or modelling studies86. Interestingly, although a higher temperature is usually associated with lower influenza virus survival, different studies have suggested that the association between influenza virus survival and relative humidity may follow a monotonic inverse or a U-shaped relationship13. For transmission, transmission risk assessment suggested non-fabric surface materials, compared with fabric surfaces, favour fomite transmission for RSV and rhinovirus but not for influenza virus in hospital rooms and aircraft cabins87. In guinea pig models, a cold and dry environment was shown to favour influenza virus transmission, with the contact route dominating at higher temperatures88. Alternatively, to explain the difference in seasonality of influenza virus circulation across regions with temperate, subtropical and tropical climates, ecological studies suggested that influenza virus transmission was favoured in a cold-and-dry climate if a lower threshold of humidity and temperature was reached; otherwise transmission was favoured in a humid-and-rainy climate when precipitation was greatest89. However, it was unclear how much was due to changes in virus survival, host susceptibility, indoor crowding or the dominant route of transmission89,90.

Host determinants

Host determinants in both infectors and infectees could affect the propensity of transmission or the preferential routes of transmission. For infectors, tissue and cellular tropism for productive virus replication in the respiratory tract determines the site of release of virus progeny. Compared with SARS-CoV, which replicates mainly in alveolar epithelium, SARS-CoV-2 replicates extensively in both bronchial and alveolar epithelia, which, together with other factors, might explain its more efficient transmission91. Host viral shedding could determine the contagiousness of the infector. However, nasal or throat viral shedding alone was inadequate to explain influenza A virus transmission in households92, suggesting the importance of other host factors (for example, variability in symptom presentation93 or lung function94) that may lead to heterogeneity in contagiousness and partially explain the presence of superspreaders and superspreading events. For SARS-CoV-2, some studies showed presymptomatic viral shedding and transmission95, and similar levels of viral shedding96 in asymptomatic and symptomatic infected individuals, demonstrating substantial ‘silent’ presymptomatic transmission or transmission from a substantial fraction of infected individuals who are asymptomatic97 is possible. Pre-existing immunity98 and vaccination history93,99 may also modulate virus shedding in infectors. For infectees, tissue-specific expression of viral receptors100 or glycosylation and glycan expression101 along the respiratory tract determines the site of infection and may affect the preferential route of infection. Interestingly, despite the aerodynamic tendency of aerosols to deposit in the lower respiratory tract102, a preferential expression of ACE2 and the observation that virus-laden aerosols deposited mostly in the nose may indicate that virus-laden aerosols may initiate SARS-CoV-2 infection in the nasal cavity100. Although host genetics is suggested to modulate infection severity upon virus exposure, less evidence is available for its role in the transmissibility and modes of transmission of respiratory viruses103. At the population level, heterogeneous social contacts and age-related mixing patterns between infected and susceptible individuals drives transmission in specific groups or favours a particular route of transmission in different settings104.

Evidence and relative importance of modes of transmission

Various approaches, including environmental sampling, experimental animal and volunteer transmission studies, and epidemiological observations (mostly from outbreak investigations), have been used to provide evidence in support of each individual mode of transmission for different respiratory viruses, although for each, some may criticize their relevance6,7. Furthermore, although attempts have been made to classify each mode as ‘obligate’, ‘preferential’ or ‘opportunistic’15,50, limited research was done to quantify the relative importance of each mode to transmission9.

Evidence supporting individual modes of transmission

There are different types of evidence in support of individual modes of transmission of common respiratory viruses in humans (Table 1). For the direct (physical) contact and the fomite routes, experimental studies demonstrated the survival of respiratory viruses on surfaces, although higher viral doses than would usually be identified in natural settings are usually used105,106. Virus genetic material, and much less often infectious viruses, were recovered from patients’ hands or naturally contaminated objects in homes, workplaces, day-care centres, nursing homes and hospitals105,106,107. Experimental animal studies68,108 and limited experimental human109,110,111 or epidemiological112 studies were able to demonstrate disease transmission via fomites in the absence of direct contact, droplets and aerosols. For the droplet and aerosol routes, collection of exhaled breath from healthy individuals suggested human expiratory activities release respiratory droplet particles in a continuum of particle size, covering droplets or aerosols, via the mouth and nose. The particle sizes and their respective concentrations depend on the expiratory activities involved and the original sites of particle generation in the respiratory tract113. Although many recognize the generation of respiratory droplets and aerosols via talking, coughing and sneezing, additionally studies have demonstrated the exhalation of aerosols during normal breathing; such generation varies considerably between individuals94,113,114. Furthermore, studies showed that exhaled particles could contain respiratory viruses115. Viral RNA (for example, influenza virus, rhinovirus and coronavirus RNA) was recovered from both exhaled breath droplets and aerosols of symptomatic infected individuals93,99,115, but infectious virus has so far been only found in aerosols and not in droplets for influenza virus93,99,116. Experimental animal studies of influenza virus108, experimental human studies of rhinovirus117 and epidemiological studies of SARS-CoV118 have demonstrated transmission via respiratory droplets (including both droplets and aerosols); however, experimental animal studies of influenza virus23,119 and SARS-CoV-2 (ref.120), experimental human studies of Coxsackie virus63 (which belongs to the same family as rhinovirus) and epidemiological studies of influenza virus121 and rhinovirus122 have demonstrated that transmission likely occurs via aerosols. Epidemiological studies observed reduced SARS-CoV transmission associated with the use of masks and respirators in health-care settings123 and reduced influenza virus transmission after disinfection of room air by ultraviolet light124, suggestive of the role of aerosols and/or droplets in the transmission. Notably, few studies have demonstrated transmission via droplets only in the absence of aerosols, direct physical contact and fomites7,62.

Table 1 Transmissibility of, modes of transmission of and transmission-based precautions for common respiratory viruses in humans

Relative importance of modes of transmission

Very few experimental human transmission or epidemiological studies have evaluated the relative importance of different modes of transmission in the same study25,117,125. In a human challenge transmission study of rhinovirus, the authors observed that droplet and aerosol routes alone were sufficient to allow rhinovirus transmission to occur, whereas transmission via fomites was not observed (in the article ‘aerosols’ probably refers to both droplets and aerosols)117. In a recent similar study of influenza virus25, by attributing its failure to achieve the targeted SAR to a higher ventilation rate when compared with an earlier proof-of-concept study126, the authors suggested aerosol transmission was more important than transmission via the large droplet and contact routes.

Alternatively, the relative importance of different modes of transmission in different circumstances may be evaluated using mathematical mechanistic models, simulations and risk analyses; for example, outbreaks in aircraft36, on cruise ships127 and in health-care settings61 or during patient care128 (for example, in households49,129). By describing the efficiency of virus transfer at each step of a transmission route and coupled with a dose–response model with reference to the minimal infectious virus dose needed to initiate infection, one may estimate the relative infection risk between routes, thereby identifying the major transmission route in a particular circumstance. Furthermore, these approaches can also inform the likely values of the impact of individual determinants130 on each route, and the potential effectiveness of route-specific interventions such as face coverings128, and allow comparison of the major transmission modes between viruses36. However, a particular challenge for this approach is to identify the minimal infectious dose required for the virus to establish infection via a specific transmission mode.

Aerosol transmission of SARS-CoV-2 and influenza virus

Historically, national and international agencies commonly consider respiratory viruses to be transmitted over the contact and/or droplet route, and exercise caution when one is considering the possibility of aerosol transmission28,131. However in recent years, more researchers have advocated the recognition of the importance of aerosol transmission12,132. The recent controversy regarding aerosol transmission of SARS-CoV-2 reflects the perspectives and long-standing challenges in evaluating the relative importance of each mode of transmission for respiratory viruses.

The report by the WHO–China Joint Mission on Coronavirus Disease 2019 (ref.133) published on 28 February 2020 stated that “airborne spread has not been reported for COVID-19 and it is not believed to be a major driver of transmission based on available evidence; however, it can be envisaged if certain aerosol-generating procedures are conducted in health-care facilities”. The initial perception was that droplets and fomites were the major routes of transmission for SARS-CoV-2. However, as more data on SARS-CoV-2 transmission became available, on 27 March, the WHO published another scientific brief specifically on the modes of SARS-CoV-2 transmission38. It described droplet transmission as transmission that occurs through infective respiratory droplets of diameter larger than 5 µm to 10 µm or fomites in the immediate environment around the infected person, and airborne transmission through infective droplet nuclei smaller than 5 µm (ref.38). Addressing the findings of SARS-CoV-2 remaining infectious in artificially generated aerosols for 3 hours or more134 and the absence of SARS-CoV-2 in a small number of air samples collected near symptomatic individuals with COVID-19 (refs135,136), the WHO continued to recommend droplet and contact precautions in the absence of aerosol-generating procedures (that is, airborne transmission was not considered to be a major route).

On 6 July 2020, a group of 239 multidisciplinary scientists published an open letter advocating the recognition of potential airborne transmission of SARS-CoV-2 (ref.132), citing the latest studies of SARS-CoV-2 as well as previous studies of influenza virus, coronaviruses and other respiratory viruses. These studies included mechanistic evidence showing generation of (non-virus-containing) aerosols from human expiratory activities113,137, infectious influenza virus in cough aerosols99,138, that exhaled droplets of 60–100 µm can be carried less than 1 m away by breathing and more than 2 m by coughing139, and survival of SARS-CoV-2 in artificially generated aerosols (the same study referenced by the WHO)134. Furthermore, these studies provided evidence of SARS-CoV-2 viral RNA140, or infectious RSV141, Middle East respiratory syndrome-related coronavirus142 and SARS-CoV-2 (ref.143) in aerosols from the air near infected individuals. They also cited epidemiological observations of outbreaks or infection clusters of SARS and COVID-19, sometimes supported by additional modelling studies, which suggested transmission occurs mainly via aerosols. These studies included the large community outbreak of SARS in Amoy Gardens in Hong Kong59; clusters of SARS-CoV-2 infections in a restaurant in Guangzhou54,144 and a shopping mall in Wenzhou145, China, and a choir in Skagit County, Washington, United States144,146,147; and a modelling study with tracer gas measurement to simulate the spread of exhaled respiratory droplets from the suspected index patient for the SARS-CoV-2 restaurant outbreak in Guangzhou148. Some argued149,150 that the current epidemiological data and clinical observations for COVID-19 do not support the letter’s claim of the importance of aerosols in SARS-CoV-2 transmission; for example, the lack of observed long-range transmission or observed increased risk of infection among health-care workers in the absence of airborne precautions150, which the authors of the open letter responded to151. On 9 July, the WHO issued a updated scientific brief39, citing some of the evidence described in the open letter132 and extensive subsequent evidence on SARS-CoV-2 transmission. Addressing studies that identified low quantities of SARS-CoV-2 RNA in the exhaled breath of infected individuals152 or in air samples collected from health-care facilities in the absence of aerosol-generating procedures140,153,154,155,156, the WHO commented these do not necessarily indicate a sufficient dose of infectious virus for transmission to occur157. Addressing outbreak reports54,147,158,159, the WHO acknowledged possible SARS-CoV-2 transmission through aerosols in indoor crowded spaces in the absence of aerosol-generating procedures, although transmission through droplets or fomites cannot be ruled out. Therefore, the WHO concluded that SARS-CoV-2 is transmitted primarily through direct, indirect or close contact with infected persons or their respiratory droplets that are expelled during coughing, sneezing, talking or singing, that transmission via fomites is likely and that transmission via aerosols is possible in indoor crowded spaces39.

This is not the first time that the same evidence base has led different scientists or regulatory bodies to different conclusions on the importance of the aerosol route of transmission, with a similar discussion for influenza virus6,10,14,160, where there is evidence both for and against the importance of aerosol transmission. In support, infectious influenza virus was detected in aerosols in exhaled breath and coughs93,99 and in the air161, infectious aerosols could initiate infection in volunteers51,64, long-range transmission followed airflow162 and epidemiological studies showed increased transmission with less ventilation121 or decreased transmission with upper air disinfection by ultraviolet light124. Additional evidence includes influenza virus survival in artificially generated aerosols163, suggestive of infectiousness in aerosols in nature; however, this work has been criticized as being too artificial6, and influenza virus RNA recovery in the air in both community settings164 and health-care settings55,56,165 (even beyond 1.5 m from the source55,56) has been criticized because infectious virus was not identified. Some argued that there is insufficient evidence of influenza virus aerosol transmission6, such as evidence for infectious virus recovery far from the source, infection initiated by inhaling air from patient rooms, transmission over long distances, association between airflow and disease spread after removal of the source patient, and effectiveness of ultraviolet irradiation in reducing transmission; moreover, aerosol transmission is argued against as outbreaks in aircraft still occur despite their being well ventilated. Some researchers have explicitly considered that transmission via the aerosol route is essentially a long-range transmission6 and have argued that influenza virus transmission is mostly observed at close range and particularly with prolonged close contact. Importantly, some researchers have argued that since the goal of recognizing the importance of aerosol transmission is to minimize the risk of transmission in health-care settings by airborne precautions15, such recognition may be counterproductive due to resource limitations, logistics challenges and low compliance6.

In summary, some researchers argued that the ability to be transmitted over long distances is a prerequisite for aerosol transmission6, as was shown for measles virus57,58, VZV166,167 and Mycobacterium tuberculosis168, the three respiratory pathogens that are widely accepted to be transmitted mainly via aerosols12. They also require evidence of transmission via aerosols in the absence of all other routes6. The latest WHO scientific brief on modes of transmission of SARS-CoV-2 also reflects the emphasis of identifying infectious virus, and not viral RNA alone, in air samples39. However, although transmission over longer distances through the air is possible for some respiratory viruses57,166, this would require large numbers of viruses to be produced at the source and could be prevented by air dilution via ventilation or virus inactivation by environmental determinants. A failure to observe long-range transmission is therefore not evidence against aerosol transmission7, as it could also be explained by low rates of virus emission at the source or by effective dilution or inactivation. The observation that influenza virus viral load in aerosols decreased substantially with increasing distance from the source, possibly because of dilution of virus concentration further from the source56,169, suggests that if aerosol transmission does occur, it will occur mostly at close range and rarely at long range170. Furthermore, transmission via the droplet route in the absence of all other routes has yet to be observed (Table 1), raising the concern of the available evidence that supports placing relatively more emphasis on droplets over aerosols.

Non-pharmaceutical interventions

At the early stage of pandemics, virus-specific pharmaceutical interventions such as vaccines and therapeutics are not available, and in resource-limited settings, such interventions are rarely readily available. Furthermore, owing to constant viral evolution, new viral strains emerge or resistance is gained such that pharmaceutical interventions can soon become outdated. Therefore, at the early stages of a pandemic, NPIs become the most important public health measures that individuals or communities can adopt to reduce respiratory virus transmission. Common NPIs include the use of personal protective equipment (PPE) or hygiene practices at the individual level, environmental disinfection or dilution at a systemic level, and social distancing measures at the community level, which reduce transmission by interfering with a single mode or multiple modes of transmission. In particular, in health-care settings, different NPIs constitute part of standard precautions or transmission-based precautions (that is, contact, droplet or airborne precautions) (Table 1), which represent different sets of practices and PPE that health-care workers adopt to lower the risk of nosocomial transmission. Although many NPIs have demonstrated mechanistically the ability to inactivate or reduce the amount of respiratory viruses in experimental or natural settings, the effectiveness of these NPIs in preventing infection at the individual level or mitigating transmission at the population level depends on a number of factors: the overall risk of transmission in a specific setting (for example, dining in restaurants versus playing sports outdoor) or population group (for example, health-care workers versus institutionalized individuals); the risk of transmission through the specific modes which the NPIs act on, and whether the virus could be transmitted via alternative modes after intervention; and individual adherence or population-wide adoption of the NPIs (Table 2).

Table 2 Mechanistic evidence and effectiveness of common non-pharmaceutical interventions

PPE and personal hygiene practices

Hand hygiene: soaps and alcohol-based hand sanitizers

Since Semmelweis first demonstrated in the 1840s that health-care workers, by adopting hand hygiene practices, reduced mortality in parturient women, hand hygiene has probably been the most widely adopted NPI for mitigating disease transmission (targeting the physical contact route) and is recommended as part of standard precautions for all patient care in health-care facilities171. Common hand hygiene practices used in health-care and community settings include handwashing with plain (non-antimicrobial) soaps or hand rub using alcohol-based hand sanitizers172 (Table 2). Alcohol-based hand sanitizers are useful in situations where sinks are not readily available, but are not recommended when hands are visibly dirty171. There is mechanistic evidence demonstrating bacterium or virus inactivation by hand hygiene173, and a number of systematic reviews of observational studies or randomized trials together suggest that hand hygiene alone is significantly associated with reducing respiratory illnesses; however, it is unclear whether hand hygiene is effective against laboratory-confirmed influenza virus infections17,18,19, possibly due to insufficiently large study sample size or weak adherence to the intervention125,174.

Face coverings: cloth masks, surgical masks, respirators, face shields and eye protection

Surgical face masks, face shields and eye protection are commonly used by health-care workers during routine patient care or when they are performing high-risk procedures as protection against splashes of bodily fluids or respiratory secretions, and respirators are commonly used as protection against aerosols15,131,175. In the community, the COVID-19 pandemic has not only led to community-wide adoption of surgical face masks; the extremely high demand has also resulted in (reusable) cloth masks being advocated as an alternative to surgical masks176. Apart from mitigating droplet and aerosol transmission, these face coverings might also reduce contact transmission by reducing the frequency of hands touching respiratory mucosa177. Mechanistically, face coverings can act either as protection against infection by reducing exposure to a virus when worn by a healthy individual or as source control by filtration93 and deflection when worn by an infected person178,179 (Table 2). On the basis of systematic reviews of observational studies123,180 and randomized trials16,18,123, many believe there is sufficient evidence supporting the effectiveness of the use of face coverings alone, or in combination with other NPIs, in reducing the risk of respiratory illness or virus transmission in health-care settings123,180 and high-risk community settings16, whereas some do not18. Mechanistic data from one study preliminarily suggest the effectiveness of surgical face masks may differ between viruses93. The relatively lower infection risk in the community compared with health-care settings, the requirement for fit testing and lower adherence argue against the use of respirators in the community181. Although surgical face masks as source control are likely applicable to most settings, as protection against infection they may have more utility in close encounters178 and crowded indoor settings; however, more research is needed. More research on the use of reusable masks, including cloth masks, in community settings either as source control or as protection is also urgently needed, including key parameters for assessment and standardization to address the diversity of materials available.

Environmental disinfection and dilution

Surface cleaning

Surface cleaning by disinfectants used in health-care settings182 or household cleaning agents183 (Table 2) mitigates transmission via the fomite route and might also block the droplet or aerosol route by reducing fomites available for resuspension due to various activities (for example, walking or door opening)184. Although supported by mechanistic evidence on virus inactivation, limited epidemiological studies have evaluated its effectiveness in reducing respiratory virus transmission17. One randomized trial in day-care nurseries suggested biweekly disinfection of toys significantly reduced the detection of adenovirus, rhinovirus and RSV, but not common cold coronaviruses, parainfluenza virus and bocavirus, in the environment; however, surface cleaning did not reduce the incidence of respiratory illness185, suggesting transmission may have occurred via routes other than the fomite route.

Air dilution by ventilation and directional airflow

Ventilation and directional airflow, although usually used to provide thermal comfort and clean air, could also help in mitigating droplet and aerosol transmission by dilution, especially indoors. Ventilation is an intentional mechanical or natural introduction of outdoor air into a building (Table 2). Natural ventilation, if properly designed, is valuable especially in resource-limited settings, but can be used only in locations where climatic conditions are favourable186. The ventilation rate is usually described as either per building or per room as the number of air changes per hour, or per occupant in the space as outdoor air rate per person. The minimal ventilation required differs depending on the level of infection risk expected or protection needed; for example, six air changes per hour in patient rooms and 12 air changes per hour in airborne-infection isolation rooms187. Separately, directional airflow provides clean air from the cleanest patient care areas to less clean patient care areas. Although limited data demonstrate reduced virus recovery in the air with increased ventilation or the presence of directional airflow122, it has been suggested there is ‘strong and sufficient’ evidence supporting the association between ventilation and airflow patterns in buildings and transmission of respiratory viruses, including SARS-CoV, influenza virus, measles virus and VZV41,188, although this may require further validation by intervention studies or randomized trials86. Furthermore, directional airflow may reduce the risk of airborne infection in vulnerable individuals or nosocomial transmission in health-care settings187,189, and also in community settings (for example, aircraft cabins190). Some suggested that for high levels of virus exposure in crowded indoor areas, increasing indoor mechanical ventilation may be less effective or less cost-effective to achieve sufficient risk reduction191, and that it might increase aerosol dispersion and infection risk for individuals further away from the source190; an uninterrupted air stream from the source to the exhaust may then have a more important role in reducing transmission192.

Air and surface disinfection by ultraviolet germicidal irradiation

Concern over aerosol and fomite transmission of SARS-CoV-2 has renewed interest in the use of ultraviolet germicidal irradiation (UVGI)193 — that is, the use of ultraviolet light in the germicidal range of wavelengths (200–320 nm) — for the disinfection of air and surfaces194. For air disinfection, upper-room UVGI and in-duct UVGI are usually used195 (Table 2). The use of UVGI to prevent airborne transmission was pioneered by Wells for the control of tuberculosis; Wells also demonstrated its use to prevent measles virus transmission in schools196. Upper-room UVGI was associated with reduced influenza virus infections among individuals with tuberculosis124. Surface disinfection with UVGI was initially used for bacterial decontamination197. Studies evaluating the inactivation of respiratory viruses on surfaces using UVGI in experimental settings198 are scarce and would be strengthened by studies using infectious virus recovery from naturally contaminated surfaces as the outcome measure. Randomized trials evaluating the effectiveness of UVGI for air or surface disinfection in reducing respiratory virus transmission are also lacking. Some proposed disinfecting surgical masks and respirators199 with UVGI to allow their reuse in resource-limited settings200. Although UVGI is not considered carcinogenic, its domestic use (for example, consumer products advertised for control of COVID-19) is cautioned against as it requires expert knowledge of the dosage required, and the efficacies of these consumer products are in doubt201.

Conclusions

The complexity of the control of respiratory virus transmission is reflected by the cross-disciplinary efforts to estimate the transmissibility of a respiratory virus, to evaluate the relative importance of modes of transmission and factors affecting transmission, to evaluate the efficacy and effectiveness of NPIs in different settings, and in turn how these translate to reduced transmissibility in the general and specific populations. Although population-based estimates of transmissibility (R0) could inform the combined effectiveness of multiple interventions in reducing transmission, the household-based estimates (SAR) in randomized trials could inform the effectiveness of individual interventions. As shown, relative transmissibility between respiratory viruses may be different depending on whether R0 or SAR is used to describe transmissibility, amid heterogeneities in estimates of the same virus (Table 1). Studies comparing the transmissibility of different respiratory viruses in parallel in the same study, perhaps in case-ascertained household studies, where study settings are more controlled, would be useful to identify which respiratory viruses are more transmissible than others.

The controversies regarding the role of aerosols in the transmission of SARS-CoV-2 and influenza virus highlight our very limited understanding on the relative importance of different modes of transmission. This includes the lack of consensus on the defining features of each mode of transmission, especially the difficulty in differentiating between droplets and aerosols; the different levels of scrutiny when evidence supporting each mode is being evaluated; the technical challenges in recovering infectious virus from the environment; the challenges in identifying the minimal infectious dose required to establish infection in susceptible or immunized individuals; and the lack of quantitative risk assessment for different modes of transmission. Given the different types of qualitative evidence available in support of individual modes of transmission (Table 1), discussion may be warranted in assigning priority or strength of evidence to these different types of evidence in support of each mode; for example, whether the demonstration of transmission via aerosols alone in the absence of other routes is essential to support the importance of the aerosol route, as suggested for measles virus57 and VZV166, but which was not done in support of the importance of the droplet route for RSV. These study designs may be possible for aerosols and fomites, but it will be more challenging to demonstrate transmission via direct contact and droplets in the absence of (close-range) aerosols. For rhinovirus, airborne precautions are not required despite the evidence of aerosol transmission in the absence of other routes63,117; in addition, as rhinovirus transmission has been demonstrated independently via direct contact202, fomite109 and aerosols63,117, efforts should be made to quantitatively evaluate the relative contribution of each mode to transmission and their determinants in different settings130. However, the relative contribution of different modes at the population level likely varies between different settings, populations and interventions in place, and at the individual level varies between individuals due to heterogeneity in contagiousness and susceptibility, which also changes over time. There is also minimal research on the modes of transmission of bocavirus and metapneumovirus (Supplementary Table 1). In general, there is a lack of studies demonstrating droplet transmission alone in the absence of other routes for all respiratory viruses (Table 1), and such studies are urgently needed to support the importance of droplets over aerosols and will have important implications for the choice of NPIs for mitigating transmission. Alternatively, aerosol transmission does not necessarily indicate a higher intrinsic transmissibility of the virus (Table 1) nor long-range transmission, as transmissibility depends on multiple factors, including the degree of presymptomatic transmission, the contagiousness of the infector, the susceptibility of the infectee, the contact patterns between them and the environmental determinants of transmission in the shared space; and long-range transmission depends on rates of virus emission at the source or effective dilution or inactivation by environmental determinants. Moving beyond deciding on the adoption of an NPI mostly on the basis of the perceived importance of a particular mode of transmission would provide an incentive for public health practitioners to recognize the importance of aerosol transmission.

For common NPIs, although we have mechanistic evidence supporting their efficacy with regard to virus reduction or inactivation, we have limited knowledge of their effectiveness in reducing transmission in the population both in health-care settings and in community settings. This may be because we do not yet know the relative contribution of different modes of transmission in a particular setting and whether the different modes can partially compensate for each other if a mode is absent174. If the latter is true, studies evaluating the effectiveness of one intervention alone, which targets a specific mode, may underestimate its potential effectiveness because a reduction in transmission via a specific mode by the NPI might be compensated by transmission via another mode174. Given effectiveness is demonstrated, the eventual adoption of NPIs would also depend on the perceived severity of the disease15, the infection risk in a particular setting175,180, the accessibility of the resources, the purpose of interventions6 and the economic or societal costs of implementing the intervention. In particular, the choice of which transmission-based precautions to adopt for a particular respiratory virus in health-care settings depends on the perceived major modes of transmission for the pathogen15, the level of caution and the resources likely available if the recommendation is made15, and therefore could differ between countries. Intervening against multiple modes of transmission would be more effective than acting against a single mode. For example, although effectiveness of the use of face masks or hand hygiene alone in mitigating community transmission of laboratory-confirmed respiratory virus infection was not demonstrated, possibly due to various experimental challenges, their combined use has been shown to be effective in reducing influenza virus transmission and should be considered203. A clear public health message accounting for these uncertainties will help to gain public confidence and support public health efforts.

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Acknowledgements

This work was supported by the Theme-based Research Scheme (project no. T11-712/19-N) from the Research Grants Council and the Collaborative Research Fund (project no. C7025-16G) from the University Grants Committee of Hong Kong. The author acknowledges B. Cowling for helpful discussions.

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Leung, N.H.L. Transmissibility and transmission of respiratory viruses. Nat Rev Microbiol (2021). https://doi.org/10.1038/s41579-021-00535-6

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