September 16, 2020

        This information was originally published  by the New England Journal of Medicine on September 8, 2020, on NEJM.org.

AUTHORS: Monica Gandhi, M.D., M.P.H., and George W. Rutherford, M.D.

As SARS-CoV-2 continues its global spread, it’s possible that one of the pillars of COVID-19 pandemic control — universal facial masking — might help reduce the severity of disease and ensure that a greater propor­tion of new infections are asymp­tomatic. If this hypothesis is borne out, universal masking could be­come a form of “variolation” that would generate immunity and thereby slow the spread of the vi­rus in the United States and else­where, as we await a vaccine.

One important reason for population-wide facial masking became apparent in March, when reports started to circulate describ­ing the high rates of SARS-CoV-2 viral shedding from the noses and mouths of patients who were presymptomatic or asymptomatic — shedding rates equivalent to those among symptomatic patients.¹ Universal facial masking seemed to be a possible way to prevent transmission from asymptomatic infected people. The Centers for Disease Control and Prevention (CDC) therefore rec­ommended on April 3 that the public wear cloth face coverings in areas with high rates of com­munity transmission — a recom­mendation that has been unevenly followed across the United States.

Past evidence related to other respiratory viruses indicates that facial masking can also protect the wearer from becoming infected, by blocking viral particles from entering the nose and mouth.² Epidemiologic investigations conduct­ed around the world — especially in Asian countries that became accustomed to population-wide masking during the 2003 SARS pandemic — have suggested that there is a strong relationship be­tween public masking and pan­demic control. Recent data from Boston demonstrate that SARS-CoV-2 infections decreased among health care workers after univer­sal masking was implemented in municipal hospitals in late March.

SARS-CoV-2 has the protean ability to cause myriad clinical manifestations, ranging from a complete lack of symptoms to pneumonia, acute respiratory dis­tress syndrome, and death. Re­cent virologic, epidemiologic, and ecologic data have led to the hy­pothesis that facial masking may also reduce the severity of disease among people who do become infected.³ This possibility is consis­tent with a long-standing theory of viral pathogenesis, which holds that the severity of disease is pro­portionate to the viral inoculum received. Since 1938, researchers have explored, primarily in animal models, the concept of the lethal dose of a virus — or the dose at which 50% of exposed hosts die (LD50). With viral infections in which host immune responses play a predominant role in viral pathogenesis, such as SARS-CoV-2, high doses of viral inoculum can overwhelm and dysregulate innate immune defenses, increasing the severity of disease. Indeed, down-regulating immunopathology is one mechanism by which dexamethasone improves outcomes in severe COVID-19 infection. As proof of concept of viral inocula influencing disease manifesta­tions, higher doses of adminis­tered virus led to more severe manifestations of COVID-19 in a Syrian hamster model of SARS-CoV-2 infection.⁴

If the viral inoculum matters in determining the severity of SARS-CoV-2 infection, an addition­al hypothesized reason for wear­ing facial masks would be to re­duce the viral inoculum to which the wearer is exposed and the subsequent clinical impact of the disease. Since masks can filter out some virus-containing drop­lets (with filtering capacity deter­mined by mask type),² masking might reduce the inoculum that an exposed person inhales. If this theory bears out, population-wide masking, with any type of mask that increases acceptability and adherence,² might contribute to increasing the proportion of SARS-CoV-2 infections that are asymp­tomatic. The typical rate of asymp­tomatic infection with SARS-CoV-2 was estimated to be 40% by the CDC in mid-July, but asymptom­atic infection rates are reported to be higher than 80% in settings with universal facial masking, which provides observational evi­dence for this hypothesis. Coun­tries that have adopted population-wide masking have fared better in terms of rates of severe COVID-related illnesses and death, which, in environments with limited test­ing, suggests a shift from sympto­matic to asymptomatic infections. Another experiment in the Syrian hamster model simulated surgi­cal masking of the animals and showed that with simulated mask­ing, hamsters were less likely to get infected, and if they did get infected, they either were asymp­tomatic or had milder symptoms than unmasked hamsters.

The most obvious way to spare society the devastating effects of COVID-19 is to promote measures to reduce both transmission and severity of illness. But SARS-CoV-2 is highly transmissible, cannot be contained by syndromic-based surveillance alone,¹ and is proving difficult to eradicate, even in re­gions that implemented strict ini­tial control measures. Efforts to increase testing and containment in the United States have been ongoing and variably successful, owing in part to the recent in­crease in demand for testing.

The hopes for vaccines are pinned not just on infection pre­vention: most vaccine trials include a secondary outcome of decreas­ing the severity of illness, since increasing the proportion of cas­es in which disease is mild or asymptomatic would be a public health victory. Universal masking seems to reduce the rate of new infections; we hypothesize that by reducing the viral inoculum, it would also increase the propor­tion of infected people who re­main asymptomatic.³

In an outbreak on a closed Ar­gentinian cruise ship, for example, where passengers were provided with surgical masks and staff with N95 masks, the rate of asymptom­atic infection was 81% (as com­pared with 20% in earlier cruise ship outbreaks without universal masking). In two recent outbreaks in U.S. food-processing plants, where all workers were issued masks each day and were required to wear them, the proportion of asymptomatic infections among the more than 500 people who became infected was 95%, with only 5% in each outbreak experi­encing mild-to-moderate symptoms.³ Case-fatality rates in coun­tries with mandatory or enforced population-wide masking have remained low, even with resur­gences of cases after lockdowns were lifted.

Variolation was a process whereby people who were suscep­tible to smallpox were inoculated with material taken from a vesi­cle of a person with smallpox, with the intent of causing a mild infection and subsequent immu­nity. Variolation was practiced only until the introduction of the variola vaccine, which ultimately eradicated smallpox. Despite con­cerns regarding safety, worldwide distribution, and eventual uptake, the world has high hopes for a highly effective SARS-CoV-2 vac­cine, and as of early September, 34 vaccine candidates were in clinical evaluation, with hundreds more in development.

While we await the results of vaccine trials, however, any pub­lic health measure that could in­crease the proportion of asymp­tomatic SARS-CoV-2 infections may both make the infection less deadly and increase population-wide immunity without severe illnesses and deaths. Reinfection with SARS-CoV-2 seems to be rare, despite more than 8 months of circulation worldwide and as sug­gested by a macaque model. The scientific community has been clarifying for some time the humoral and cell-mediated compo­nents of the adaptive immune response to SARS-CoV-2 and the inadequacy of antibody-based seroprevalence studies to estimate the level of more durable T-cell and memory B-cell immunity to SARS-CoV-2. Promising data have been emerging in recent weeks suggesting that strong cell-medi­ated immunity results from even mild or asymptomatic SARS-CoV-2 infection,⁵ so any public health strategy that could reduce the se­verity of disease should increase population-wide immunity as well.

To test our hypothesis that population-wide masking is one of those strategies, we need fur­ther studies comparing the rate of asymptomatic infection in areas with and areas without universal masking. To test the variolation hypothesis, we will need more studies comparing the strength and durability of SARS-CoV-2–specific T-cell immunity between people with asymptomatic infec­tion and those with symptomatic infection, as well as a demonstra­tion of the natural slowing of SARS-CoV-2 spread in areas with a high proportion of asymptom­atic infections.

Ultimately, combating the pan­demic will involve driving down both transmission rates and se­verity of disease. Increasing evi­dence suggests that population-wide facial masking might benefit both components of the response.

Disclosure forms provided by the au­thors are available at NEJM.org.

From the Center for AIDS Research, Division of HIV, Infectious Diseases, and Global Medi­cine, Department of Medicine (M.G.); and the Division of Infectious Disease and Global Epidemiology, Department of Epidemiolo­gy and Biostatistics (G.W.R.), University of California, San Francisco, San Francisco.

^1. Gandhi M, Yokoe DS, Havlir DV. Asymp­tomatic transmission, the Achilles’ heel of current strategies to control COVID-19. N Engl J Med 2020;382:2158-60.

^2. van der Sande M, Teunis P, Sabel R. Pro­fessional and home-made face masks reduce exposure to respiratory infections among the general population. PLoS One 2008; 3(7): e2618.

^3. Gandhi M, Beyrer C, Goosby E.  Masks do more than protect others during COVID-19: reducing the inoculum of SARS-CoV-2 to protect the wearer.  J Gen Intern Med 2020 July 31 (Epub ahead of print).

^4. Imai M, Iwatsuki-Horimoto K, Hatta M, et al. Syrian hamsters as a small animal model for SARS-CoV-2 infection and coun­termeasure development. Proc Natl Acad Sci U S A 2020; 117: 16587-95.

^5. Sekine T, Perez-Potti A, Rivera-Ballesteros O, et al. Robust T cell immunity in conva­lescent individuals with asymptomatic or mild COVID-19. Cell 2020 August 11 (Epub ahead of print).

DOI: 10.1056/NEJMp2026913

Copyright© 2020 Massachusetts Medical Society.