SARS-CoV-2: non-symptomatic cases substantially contribute to community transmission

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A new study out of the University of Chicago has found that during the initial wave of the COVID-19 outbreak in New York City, only 1 in 5 to 1 in 7 cases of the virus was symptomatic.

The research team found that non-symptomatic cases substantially contribute to community transmission, making up at least 50% of the driving force of SARS-CoV-2 infection.

The results were published on Feb. 10 in the Proceedings of the National Academy of Sciences.

When the COVID-19 epidemic arrived in the U.S., the investigators noticed that it was very difficult to estimate what proportion of people infected with SARS-CoV-2 would go on to develop symptoms, partially due to the initial challenges with testing capacity.

“Without testing capacity data, it’s very difficult to estimate the difference between cases that were unreported due to a lack of testing and cases that were actually asymptomatic,” said first author Rahul Subramanian, a Ph.D. student of epidemiology at UChicago.

“We wanted to disentangle those two things, and since New York City was one of the first cities to report the daily number of tests completed, we were able to use those numbers to estimate how many COVID-19 cases were symptomatic.”

While there are a number of existing models that use epidemiological data to estimate undetected case numbers and transmission rates, this is the first peer-reviewed model to incorporate data about daily testing capacity and changes in testing rates over time to provide a more accurate picture of what proportion of SARS-CoV-2 infections are symptomatic in a large U.S. city.

“Incorporating these data into the model showed that the proportion of individuals who are symptomatic for COVID-19 is somewhere between 13% and 18%,” said senior author Mercedes Pascual, Ph.D., the Louis Block Professor of Ecology and Evolution at UChicago.

“And regardless of uncertainty in all other parameters, we can tell that more that 50% of the transmission happening in the community is from people without symptoms – those who are asymptomatic and pre-symptomatic.”

While this data analysis does not indicate how infectious asymptomatic individuals are, nor account for the new variants of the virus currently spreading in the U.S., the model provides additional support for the importance of following public health guidelines to reduce community transmission of the virus, whether individuals show symptoms.

“Even if asymptomatic people aren’t transmitting the virus at high rates, they constitute something like 80% of all infections,” said co-author Qixin He, now an assistant professor at Perdue University.

“This proportion is quite surprising. It’s crucial that everyone – including individuals who don’t show symptoms – adhere to public health guidelines, such as mask wearing and social distancing, and that mass testing is made easily accessible to all.”

The investigators say that these results also demonstrate that public health agencies need to make their testing protocols and numbers publicly available to allow these data to be incorporated into existing transmission models.

“Making this information available is as important as reporting the number of cases,” said Pascual. “Otherwise, we have a discrepancy between the number and type of cases that are reported over time and the underlying transmission dynamics. These data are critical for epidemiological modeling.”


The asymptomatic fraction of infection is the proportion of infected persons who never develop, perceive, and report symptoms (1). Among common pathogens, the asymptomatic fraction varies widely. For example, an asymptomatic carrier state has not been documented for measles virus infection (2), whereas a significant proportion of persons with cytomegalovirus or poliovirus infection have no symptoms and are unaware of infection (3, 4).

The asymptomatic fraction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection seems to be sizable (5). The range of severity of illness associated with SARS-CoV-2 infection is noteworthy because it spans asymptomatic infection; mild illness; and severe, life-threatening illness.

Perhaps because of this broad spectrum of presentation, the topic of asymptomatic SARS-CoV-2 infection has generated some controversy (6). Imprecise use of the term “asymptomatic” is partly to blame. “Asymptomatic” should be reserved for persons who never develop symptoms, whereas “presymptomatic” is a better description of those who have no symptoms when they receive a positive test result but who eventually develop symptoms.

We know for certain who is asymptomatic only in retrospect. On the basis of our current knowledge of the natural history of coronavirus disease 2019 (COVID-19), after a person is infected with SARS-CoV-2, we must wait approximately 14 days to determine whether symptoms have developed (7). Infection without symptoms, whether presymptomatic or asymptomatic, is important because infected persons can transmit the virus to others even if they have no symptoms (8, 9).

In June 2020, we published a review of the limited data then available on the prevalence of asymptomatic SARS-CoV-2 infection (5). Since then, considerable new data have become available. The present review summarizes currently available data that might allow us to estimate the proportion of persons infected with SARS-CoV-2 who are asymptomatic.

Discussion
Symptom detection relies on the subjective reports of patients (73). For example, anosmia has turned out to be a distinctive symptom of COVID-19 (74), and we depend on patients to perceive and report a diminution, however slight, of their normal olfactory abilities. But such self-reports are influenced by many factors, including variability in the ability to recall symptoms and idiosyncratic awareness of bodily sensations.

Current data suggest that infected persons without symptoms—including both presymptomatic and asymptomatic persons—account for more than 40% of all SARS-CoV-2 transmission (75–77). The proportion of new infections caused by asymptomatic persons alone is uncertain, but when researchers in Wanzhou, China, analyzed epidemiologic data for “183 confirmed COVID-19 cases and their close contacts from five generations of transmission,” they determined that the asymptomatic cases, which made up 32.8% of infected persons, caused 19.3% of infections (78).

The 61 studies and reports that we have collected provide compelling evidence that the asymptomatic fraction of SARS-CoV-2 infection is sizable. These data enable us to make reasonable inferences about the proportion of SARS-CoV-2 infections that are asymptomatic.

Studies designed to achieve representative samples of large populations provide useful data because they may accurately reflect human populations in general. Four of the PCR-based studies are in this category, with target populations of England (10–12, 14), Iceland (16), and Indiana (23).

The proportion of persons who tested positive but had no symptoms at the time of testing ranged from 43.0% to 76.5%, with a median of 45.6% (IQR, 43.6% to 61.8%).

However, these studies fall short of providing the highest-quality evidence because they collected only cross-sectional data. As a result, we cannot distinguish between presymptomatic and asymptomatic cases.

In 14 longitudinal studies that reported information on the evolution of symptomatic status, a median of 72.3% of persons who tested positive but had no symptoms at the time of testing remained asymptomatic during a follow-up period (15, 17, 18, 20, 22, 32, 37–40, 47, 51, 53, 54).

If a similar proportion remained asymptomatic in the 4 large, representative, PCR-based studies, in which the median was 45.6%, the asymptomatic fraction of SARS-CoV-2 infection would be 33.0%.

Among the data that we have assembled here, the highest-quality evidence comes from the large-scale studies using antibody testing that were designed to achieve representative samples of nationwide populations in England (n = 365 104) (55) and Spain (n = 61 075) (56). It is remarkable that these independently conducted serosurveys yielded nearly identical proportions of asymptomatic SARS-CoV-2 infections: 32.4% in England and 33.0% in Spain.

We may infer that persons who receive positive antibody test results can be classified accurately as asymptomatic because such results are likely to occur only after the onset of symptoms, if any. In a study of 222 hospitalized patients in Wuhan, China, IgM and IgG antibodies to SARS-CoV-2 were first detected 3 and 4 days, respectively, after symptomatic onset of COVID-19 (79).

In a study of 109 health care workers and 64 hospitalized patients in Zurich, Switzerland, the severity of illness seemed to affect how quickly SARS-CoV-2 antibodies appeared (80). Patients with severe COVID-19 had detectable SARS-CoV-2 antibody titers after symptom onset, but those with mild cases “remained negative or became positive [for SARS-CoV-2 antibodies] 12 to 14 days after symptom onset” (80).

These data suggest that positive antibody test results are unlikely to occur during the period when it is uncertain whether an infected person is presymptomatic or asymptomatic.

However, serosurveys do have significant limitations for the purpose of estimating the asymptomatic fraction. Not all persons who are believed to have been infected with SARS-CoV-2 later have a positive result for SARS-CoV-2 antibodies (81). The reasons may include a false-positive result on the initial PCR test; a false-negative result on the antibody test; or the absence of detectable antibodies, perhaps because the infection was cleared without requiring adaptive immunity.

In addition, the role of mucosal immunity in clearing SARS-CoV-2 infection has not yet been fully elucidated (82), and a nasal wash to detect the IgA antibodies active in mucosal immunity is not part of standard testing practice.

Persons who clear SARS-CoV-2 infection through innate or mucosal immunity might be more likely to be asymptomatic but would not be categorized as such in a serosurvey, possibly contributing to an underestimate of the asymptomatic fraction.

Another limitation of serosurveys is the requirement that an interview or questionnaire about symptomatic status accompany the blood sample. The onus is on the study participant to accurately recall symptoms, if any, from weeks or even months earlier. In the midst of a pandemic that has transformed everyday life around the globe, it seems reasonable to hypothesize that awareness of and memory for symptoms possibly related to COVID-19 are heightened.

This might result in a greater likelihood of noticing and reporting symptoms that would otherwise be missed or ignored, thereby leading to a lower estimate of the asymptomatic fraction. For these reasons, we have evaluated serosurveys in the context of other results and found them to be concordant.

When estimates from large-scale, cross-sectional, PCR-based studies with representative samples; longitudinal PCR-based studies; and nationwide serosurveys with representative samples are combined, it seems that the asymptomatic fraction of SARS-CoV-2 infection is at least one third.

To confirm this estimate, large-scale longitudinal studies using PCR testing with representative samples of national populations would be useful. As SARS-CoV-2 vaccination campaigns are implemented worldwide, though, the window for such research may be closing.

In light of the data presented here, we believe that COVID-19 control strategies must be altered, taking into account the prevalence and transmission risk of asymptomatic SARS-CoV-2 infection.

Frequent, inexpensive, rapid home tests (83) to identify and contain presymptomatic or asymptomatic cases – along with government programs that provide financial assistance and, if necessary, housing to enable infected persons to isolate themselves (84)—may be a viable option. And as the first generation of SARS-CoV-2 vaccines is deployed, more research will be needed to determine their efficacy in preventing asymptomatic infection (85).

reference link: https://www.acpjournals.org/doi/10.7326/M20-6976


More information: Rahul Subramanian et al, Quantifying asymptomatic infection and transmission of COVID-19 in New York City using observed cases, serology, and testing capacity, PNAS March 2, 2021 118 (9) e2019716118; doi.org/10.1073/pnas.2019716118

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