Coronavirus Disease 2019’s Challenges to Infection Control Dogma Regarding Respiratory Virus Transmission

The COVID-19 pandemic has highlighted controversies and unknowns about how respiratory pathogens spread between hosts. Traditionally, it was thought that respiratory pathogens spread between people through large droplets produced in coughs and through contact with contaminated surfaces (fomites). However, several respiratory pathogens are known to spread through small respiratory aerosols, which can float and travel in air flows, infecting people who inhale them at short and long distances from the infected person. Wang et al . review recent advances in understanding airborne transmission gained from studying the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and other respiratory pathogens. The authors suggest that airborne transmission may be the dominant form of transmission for several respiratory pathogens, including SARS-CoV-2, and that further understanding of the mechanisms underlying infection from the airborne route will better inform mitigation measures. —GKA A Review discusses the scientific basis of and factors controlling airborne transmission of respiratory viruses including coronavirus. BACKGROUND Exposure to droplets produced in the coughs and sneezes of infected individuals or contact with droplet-contaminated surfaces (fomites) have been widely perceived as the dominant transmission modes for respiratory pathogens. Airborne transmission is traditionally defined as involving the inhalation of infectious aerosols or “droplet nuclei” smaller than 5 μm and mainly at a distance of >1 to 2 m away from the infected individual, and such transmission has been thought to be relevant only for “unusual” diseases. However, there is robust evidence supporting the airborne transmission of many respiratory viruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS)–CoV, influenza virus, human rhinovirus, and respiratory syncytial virus (RSV). The limitations of traditional views of droplet, fomite, and airborne transmission were illuminated during the COVID-19 pandemic. Droplet and fomite transmission of SARS-CoV-2 alone cannot account for the numerous superspreading events and differences in transmission between indoor and outdoor environments observed during the COVID-19 pandemic. Controversy surrounding how COVID-19 is transmitted and what interventions are needed to control the pandemic has revealed a critical need to better understand the airborne transmission pathway of respiratory viruses, which will allow for better-informed strategies to mitigate the transmission of respiratory infections. ADVANCES Respiratory droplets and aerosols can be generated by various expiratory activities. Advances in aerosol measurement techniques, such as aerodynamic and scanning mobility particle sizing, have shown that the majority of exhaled aerosols are smaller than 5 μm, and a large fraction are <1 μm for most respiratory activities, including those produced during breathing, talking, and coughing. Exhaled aerosols occur in multiple size modes that are associated with different generation sites and production mechanisms in the respiratory tract. Although 5 μm has been used historically to distinguish aerosols from droplets, the size distinction between aerosols and droplets should be 100 μm, which represents the largest particle size that can remain suspended in still air for more than 5 s from a height of 1.5 m, typically reach a distance of 1 to 2 m from the emitter (depending on the velocity of airflow carrying the aerosols), and can be inhaled. Aerosols produced by an infected individual may contain infectious viruses, and studies have shown that viruses are enriched in small aerosols (<5 μm). The transport of virus-laden aerosols is affected by the physicochemical properties of aerosols themselves and environmental factors, including temperature, relative humidity, ultraviolet radiation, airflow, and ventilation. Once inhaled, virus-laden aerosols can deposit in different parts of the respiratory tract. Larger aerosols tend to be deposited in the upper airway; however, smaller aerosols, although they can also be deposited there, can penetrate deep into the alveolar region of the lungs. The strong effect of ventilation on transmission, the distinct difference between indoor and outdoor transmission, well-documented long-range transmission, the observed transmission of SARS-CoV-2 despite the use of masks and eye protection, the high frequency of indoor superspreading events of SARS-CoV-2, animal experiments, and airflow simulations provide strong and unequivocal evidence for airborne transmission. Fomite transmission of SARS-CoV-2 has been found to be far less efficient, and droplets are only dominant when individuals are within 0.2 m of each other when talking. Although both aerosols and droplets can be produced by infected individuals during expiratory activities, droplets fall quickly to the ground or surfaces within seconds, leaving an enrichment of aerosols over droplets. The airborne pathway likely contributes to the spread of other respiratory viruses whose transmission was previously characterized as droplet driven. The World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) have officially acknowledged the inhalation of virus-laden aerosols as a main transmission mode in spreading COVID-19 at both short and long ranges in 2021. OUTLOOK Airborne transmission of pathogens has been vastly underappreciated, mostly because of an insufficient understanding about the airborne behavior of aerosols and at least partially because of the misattribution of anecdotal observations. Given the lack of evidence for droplet and fomite transmission and the increasingly strong evidence for aerosols in transmitting numerous respiratory viruses, we must acknowledge that airborne transmission is much more prevalent than previously recognized. Given all that we have learned about SARS-CoV-2 infection, the aerosol transmission pathway needs to be reevaluated for all respiratory infectious diseases. Additional precautionary measures must be implemented for mitigating aerosol transmission at both short and long ranges, with particular attention to ventilation, airflows, air filtration, UV disinfection, and mask fit. These interventions are critical tools for ending the current pandemic and preventing future outbreaks. Phases involved in airborne transmission of respiratory viruses. Virus-laden aerosols (<100 I1/4m) are first generated by an infected individual through expiratory activities, through which they are exhaled and transported in the environment. They may be inhaled by a potential host to initiate a new infection, provided that they remain infectious. In contrast to droplets (>100 I1/4m), aerosols can linger in air for hours and travel beyond 1 to 2 m from the infected individual who exhales them, causing new infections at both short and long ranges. CREDIT: N. CARY/ SCIENCE The COVID-19 pandemic has revealed critical knowledge gaps in our understanding of and a need to update the traditional view of transmission pathways for respiratory viruses. The long-standing definitions of droplet and airborne transmission do not account for the mechanisms by which virus-laden respiratory droplets and aerosols travel through the air and lead to infection. In this Review, we discuss current evidence regarding the transmission of respiratory viruses by aerosols—how they are generated, transported, and deposited, as well as the factors affecting the relative contributions of droplet-spray deposition versus aerosol inhalation as modes of transmission. Improved understanding of aerosol transmission brought about by studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires a reevaluation of the major transmission pathways for other respiratory viruses, which will allow better-informed controls to reduce airborne transmission. 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Heneghan and colleagues' systematic review, funded by WHO, published in March, 2021, as a preprint, states: “The lack of recoverable viral culture samples of SARS-CoV-2 prevents firm conclusions to be drawn about airborne transmission”. 1 This conclusion, and the wide circulation of the review's findings, is concerning because of the public health implications. If an infectious virus spreads predominantly through large respiratory droplets that fall quickly, the key control measures are reducing direct contact, cleaning surfaces, physical barriers, physical distancing, use of masks within droplet distance, respiratory hygiene, and wearing high-grade protection only for so-called aerosol-generating health-care procedures. Such policies need not distinguish between indoors and outdoors, since a gravity-driven mechanism for transmission would be similar for both settings. But if an infectious virus is mainly airborne, an individual could potentially be infected when they inhale aerosols produced when an infected person exhales, speaks, shouts, sings, sneezes, or coughs. Reducing airborne transmission of virus requires measures to avoid inhalation of infectious aerosols, including ventilation, air filtration, reducing crowding and time spent indoors, use of masks whenever indoors, attention to mask quality and fit, and higher-grade protection for health-care staff and front-line workers. 2 Airborne transmission of respiratory viruses is difficult to demonstrate directly. 3 Mixed findings from studies that seek to detect viable pathogen in air are therefore insufficient grounds for concluding that a pathogen is not airborne if the totality of scientific evidence indicates otherwise. Decades of painstaking research, which did not include capturing live pathogens in the air, showed that diseases once considered to be spread by droplets are airborne. 4 Ten streams of evidence collectively support the hypothesis that SARS-CoV-2 is transmitted primarily by the airborne route. 5 First, superspreading events account for substantial SARS-CoV-2 transmission; indeed, such events may be the pandemic's primary drivers. 6 Detailed analyses of human behaviours and interactions, room sizes, ventilation, and other variables in choir concerts, cruise ships, slaughterhouses, care homes, and correctional facilities, among other settings, have shown patterns—eg, long-range transmission and overdispersion of the basic reproduction number (R0), discussed below—consistent with airborne spread of SARS-CoV-2 that cannot be adequately explained by droplets or fomites. 6 The high incidence of such events strongly suggests the dominance of aerosol transmission. Second, long-range transmission of SARS-CoV-2 between people in adjacent rooms but never in each other's presence has been documented in quarantine hotels. 7 Historically, it was possible to prove long-range transmission only in the complete absence of community transmission. 4 Third, asymptomatic or presymptomatic transmission of SARS-CoV-2 from people who are not coughing or sneezing is likely to account for at least a third, and perhaps up to 59%, of all transmission globally and is a key way SARS-CoV-2 has spread around the world, 8 supportive of a predominantly airborne mode of transmission. Direct measurements show that speaking produces thousands of aerosol particles and few large droplets, 9 which supports the airborne route. Fourth, transmission of SARS-CoV-2 is higher indoors than outdoors 10 and is substantially reduced by indoor ventilation. 5 Both observations support a predominantly airborne route of transmission. Fifth, nosocomial infections have been documented in health-care organisations, where there have been strict contact-and-droplet precautions and use of personal protective equipment (PPE) designed to protect against droplet but not aerosol exposure. 11 Sixth, viable SARS-CoV-2 has been detected in the air. In laboratory experiments, SARS-CoV-2 stayed infectious in the air for up to 3 h with a half-life of 1·1 h. 12 Viable SARS-CoV-2 was identified in air samples from rooms occupied by COVID-19 patients in the absence of aerosol-generating health-care procedures 13 and in air samples from an infected person's car. 14 Although other studies have failed to capture viable SARS-CoV-2 in air samples, this is to be expected. Sampling of airborne virus is technically challenging for several reasons, including limited effectiveness of some sampling methods for collecting fine particles, viral dehydration during collection, viral damage due to impact forces (leading to loss of viability), reaerosolisation of virus during collection, and viral retention in the sampling equipment. 3 Measles and tuberculosis, two primarily airborne diseases, have never been cultivated from room air. 15 Seventh, SARS-CoV-2 has been identified in air filters and building ducts in hospitals with COVID-19 patients; such locations could be reached only by aerosols. 16 Eighth, studies involving infected caged animals that were connected to separately caged uninfected animals via an air duct have shown transmission of SARS-CoV-2 that can be adequately explained only by aerosols. 17 Ninth, no study to our knowledge has provided strong or consistent evidence to refute the hypothesis of airborne SARS-CoV-2 transmission. Some people have avoided SARS-CoV-2 infection when they have shared air with infected people, but this situation could be explained by a combination of factors, including variation in the amount of viral shedding between infectious individuals by several orders of magnitude and different environmental (especially ventilation) conditions. 18 Individual and environmental variation means that a minority of primary cases (notably, individuals shedding high levels of virus in indoor, crowded settings with poor ventilation) account for a majority of secondary infections, which is supported by high-quality contact tracing data from several countries.19, 20 Wide variation in respiratory viral load of SARS-CoV-2 counters arguments that SARS-CoV-2 cannot be airborne because the virus has a lower R0 (estimated at around 2·5) 21 than measles (estimated at around 15), 22 especially since R0, which is an average, does not account for the fact that only a minority of infectious individuals shed high amounts of virus. Overdispersion of R0 is well documented in COVID-19. 23 Tenth, there is limited evidence to support other dominant routes of transmission—ie, respiratory droplet or fomite.9, 24 Ease of infection between people in close proximity to each other has been cited as proof of respiratory droplet transmission of SARS-CoV-2. However, close-proximity transmission in most cases along with distant infection for a few when sharing air is more likely to be explained by dilution of exhaled aerosols with distance from an infected person. 9 The flawed assumption that transmission through close proximity implies large respiratory droplets or fomites was historically used for decades to deny the airborne transmission of tuberculosis and measles.15, 25 This became medical dogma, ignoring direct measurements of aerosols and droplets which reveal flaws such as the overwhelming number of aerosols produced in respiratory activities and the arbitrary boundary in particle size of 5 μm between aerosols and droplets, instead of the correct boundary of 100 μm.15, 25 It is sometimes argued that since respiratory droplets are larger than aerosols, they must contain more viruses. However, in diseases where pathogen concentrations have been quantified by particle size, smaller aerosols showed higher pathogen concentrations than droplets when both were measured. 15 In conclusion, we propose that it is a scientific error to use lack of direct evidence of SARS-CoV-2 in some air samples to cast doubt on airborne transmission while overlooking the quality and strength of the overall evidence base. There is consistent, strong evidence that SARS-CoV-2 spreads by airborne transmission. Although other routes can contribute, we believe that the airborne route is likely to be dominant. The public health community should act accordingly and without further delay. © 2021 Ap Garo/Phanie/Science Photo Library 2021 Show more

Background Scarce data are available on what variables affect the risk of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the development of symptomatic COVID-19, and, particularly, the relationship with viral load. We aimed to analyse data from linked index cases of COVID-19 and their contacts to explore factors associated with transmission of SARS-CoV-2. Methods In this cohort study, patients were recruited as part of a randomised controlled trial done between March 17 and April 28, 2020, that aimed to assess if hydroxychloroquine reduced transmission of SARS-CoV-2. Patients with COVID-19 and their contacts were identified by use of the electronic registry of the Epidemiological Surveillance Emergency Service of Catalonia (Spain). Patients with COVID-19 included in our analysis were aged 18 years or older, not hospitalised, had quantitative PCR results available at baseline, had mild symptom onset within 5 days before enrolment, and had no reported symptoms of SARS-CoV-2 infections in their accommodation or workplace within the 14 days before enrolment. Contacts included were adults with a recent history of exposure and absence of COVID-19-like symptoms within the 7 days preceding enrolment. Viral load of contacts, measured by quantitative PCR from a nasopharyngeal swab, was assessed at enrolment, at day 14, and whenever the participant reported COVID-19-like symptoms. We assessed risk of transmission and developing symptomatic disease and incubation dynamics using regression analysis. We assessed the relationship of viral load and characteristics of cases (age, sex, number of days from reported symptom onset, and presence or absence of fever, cough, dyspnoea, rhinitis, and anosmia) and associations between risk of transmission and characteristics of the index case and contacts. Findings We identified 314 patients with COVID-19, with 282 (90%) having at least one contact (753 contacts in total), resulting in 282 clusters. 90 (32%) of 282 clusters had at least one transmission event. The secondary attack rate was 17% (125 of 753 contacts), with a variation from 12% when the index case had a viral load lower than 1 × 106 copies per mL to 24% when the index case had a viral load of 1 × 1010 copies per mL or higher (adjusted odds ratio per log10 increase in viral load 1·3, 95% CI 1·1–1·5). Increased risk of transmission was also associated with household contact (3·0, 1·59–5·65) and age of the contact (per year: 1·02, 1·01–1·04). 449 contacts had a positive PCR result at baseline. 28 (6%) of 449 contacts had symptoms at the first visit. Of 421 contacts who were asymptomatic at the first visit, 181 (43%) developed symptomatic COVID-19, with a variation from approximately 38% in contacts with an initial viral load lower than 1 × 107 copies per mL to greater than 66% for those with an initial viral load of 1 × 1010 copies per mL or higher (hazard ratio per log10 increase in viral load 1·12, 95% CI 1·05–1·20; p=0·0006). Time to onset of symptomatic disease decreased from a median of 7 days (IQR 5–10) for individuals with an initial viral load lower than 1 × 107 copies per mL to 6 days (4–8) for those with an initial viral load between 1 × 107 and 1 × 109 copies per mL, and 5 days (3–8) for those with an initial viral load higher than 1 × 109 copies per mL. Interpretation In our study, the viral load of index cases was a leading driver of SARS-CoV-2 transmission. The risk of symptomatic COVID-19 was strongly associated with the viral load of contacts at baseline and shortened the incubation time of COVID-19 in a dose-dependent manner. Funding YoMeCorono, Generalitat de Catalunya. Translations For the Catalan translation of the abstract see Supplementary Materials section. Show more