Reviews3 June 2020

Prevalence of Asymptomatic SARS-CoV-2 Infection

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A Narrative Review
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    Abstract

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly throughout the world since the first cases of coronavirus disease 2019 (COVID-19) were observed in December 2019 in Wuhan, China. It has been suspected that infected persons who remain asymptomatic play a significant role in the ongoing pandemic, but their relative number and effect have been uncertain. The authors sought to review and synthesize the available evidence on asymptomatic SARS-CoV-2 infection. Asymptomatic persons seem to account for approximately 40% to 45% of SARS-CoV-2 infections, and they can transmit the virus to others for an extended period, perhaps longer than 14 days. Asymptomatic infection may be associated with subclinical lung abnormalities, as detected by computed tomography. Because of the high risk for silent spread by asymptomatic persons, it is imperative that testing programs include those without symptoms. To supplement conventional diagnostic testing, which is constrained by capacity, cost, and its one-off nature, innovative tactics for public health surveillance, such as crowdsourcing digital wearable data and monitoring sewage sludge, might be helpful.

    Key Summary Points

    • The likelihood that approximately 40% to 45% of those infected with SARS-CoV-2 will remain asymptomatic suggests that the virus might have greater potential than previously estimated to spread silently and deeply through human populations.

    • Asymptomatic persons can transmit SARS-CoV-2 to others for an extended period, perhaps longer than 14 days.

    • The absence of COVID-19 symptoms in persons infected with SARS-CoV-2 might not necessarily imply an absence of harm. More research is needed to determine the significance of subclinical lung changes visible on computed tomography scans.

    • The focus of testing programs for SARS-CoV-2 should be substantially broadened to include persons who do not have symptoms of COVID-19.

    In the early months of the coronavirus disease 2019 (COVID-19) pandemic, an iconic image has been the “proned” patient in intensive care, gasping for breath, in imminent need of artificial ventilation. This is the deadly face of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which as of 26 May 2020 had claimed more than 348 000 lives worldwide (1). But it is not the only face, because SARS-CoV-2 now seems to have a dual nature: tragically lethal in some persons and surprisingly benign in others.

    Since February 2020 (2, 3), there have been reports of persons who were infected with SARS-CoV-2 but did not develop symptoms of COVID-19. In some cases (4, 5), the viral load of such asymptomatic persons has been equal to that of symptomatic persons, suggesting similar potential for viral transmission. The prevalence of asymptomatic SARS-CoV-2 infection, however, has remained uncertain. We sought to review and synthesize the available evidence on testing for SARS-CoV-2 infection, carried out by real-time reverse transcriptase polymerase chain reaction using nasopharyngeal swabs in all studies that specified the method of testing.

    Most data from the 16 cohorts in this narrative review are not the output of large, carefully designed studies with randomly selected, representative samples. They do not generally purport to depict anything more than certain circumscribed cohorts at specific moments in time. We have not attempted to pool them for the purposes of statistical analysis. When viewed as a collection, though—as a kind of mosaic or patchwork—these data may offer potentially valuable insights into SARS-CoV-2 incidence and the highly variable effect of infection.

    The difficulty of distinguishing asymptomatic persons from those who are merely presymptomatic is a stumbling block. To be clear, the asymptomatic individual is infected with SARS-CoV-2 but will never develop symptoms of COVID-19. In contrast, the presymptomatic individual is similarly infected but eventually will develop symptoms. The simple solution to this conundrum is longitudinal testing—that is, repeated observations of the individual over time. Unfortunately, only 5 of our cohorts include longitudinal data. We must therefore acknowledge the possibility that some of the proportions of asymptomatic persons are lower than reported.

    Methods

    From 19 April through 26 May 2020, using the keywords COVID-19, SARS-CoV-2, symptoms, and asymptomatic, we periodically searched the published medical literature using the PubMed service maintained by the U.S. National Library of Medicine of the National Institutes of Health. We also searched for unpublished manuscripts using the bioRxiv and medRxiv services operated by Cold Spring Harbor Laboratory. In addition, we searched for news reports using Google and monitored relevant information shared on Twitter.

    Cohorts

    Iceland

    In the largest cohort in our set (6), researchers in Iceland used the following 2 methods to screen the general population for SARS-CoV-2 infection: an open invitation for interested parties to register online then provide biosamples at a Reykjavik location, and a text message sent to “randomly chosen Icelanders between the ages 20 and 70 years” inviting them to participate in the same manner as the first group (Table) (7–19). In all, 13 080 persons volunteered for the screening, 100 (0.8%) of whom tested positive for SARS-CoV-2. All who tested positive were aged 10 years or older. None of the 848 children younger than 10 years in the sample tested positive. Among those with positive results, 43 (43%) had no symptoms of COVID-19 at the time of testing. As the researchers note, though, “symptoms almost certainly developed later in some of them” (6).

    Table. Summary of SARS-CoV-2 Testing Studies

    Vo', Italy

    At the beginning and end of a 14-day lockdown imposed by authorities in the northern Italian town of Vo' (7), researchers collected nasopharyngeal swabs from 2812 residents during the first sampling effort and 2343 during the second; this represented 85.9% and 71.5%, respectively, of the entire population. In the first group, 30 (41.1%) of 73 persons who tested positive for SARS-CoV-2 had no symptoms. In the second, 13 (44.8%) of 29 who tested positive were asymptomatic. According to the researchers, in the roughly 2-week period between the sampling efforts, none of the asymptomatic persons developed any symptoms of COVID-19. In addition, through contact tracing, they confirmed that several new cases of SARS-CoV-2 infection that appeared during the second sampling had been caused by exposure to asymptomatic persons. In Vo' during the 14-day period studied, young children seemed to play no role in the transmission of SARS-CoV-2: “No infections were detected in either survey in 234 tested children ranging from 0 to 10 years, despite some of them living in the same household as infected people” (7).

    Diamond Princess

    On 3 February 2020, the Diamond Princess cruise ship returned to Yokohama, Japan, for quarantine (8), having transferred an ill passenger to shore in Hong Kong on 25 January who later tested positive for SARS-CoV-2. As of 16 March, 712 (19.2%) of 3711 passengers and crew had tested positive. At the time of testing, 331 (46.5%) of those with positive results were asymptomatic. Although the latter infected persons reported no symptoms, some actually had subclinical changes in their lungs. When computed tomography scans for 76 of these persons were examined, 54% showed lung opacities (20).

    An independent statistical modeling analysis (21) based on data available as of 21 February claimed to estimate—with “a Bayesian framework using Hamiltonian Monte Carlo algorithm”—the proportion of asymptomatic persons on the Diamond Princess; it arrived at a figure of 17.9%. Considering, though, that data for asymptomatic persons were available only for 15 through 20 February and that the actual proportions of asymptomatic persons among those tested on these dates were 56.7%, 54.3%, 70.7%, 73.9%, 86.1%, and 46.2%, this estimate seems puzzling. In a separate news account (22), one of the coauthors of this analysis was reported to have estimated that “40% of the general population might be able to be infected [with SARS-CoV-2] without showing any signs.”

    Boston Homeless Shelter

    After a cluster of 15 COVID-19 cases was identified over 5 days at a large homeless shelter in Boston, Massachusetts, the infected persons were removed from the shelter, and all occupants were subsequently tested over a 2-day period (9). Among 408 occupants, 147 (36.0%) tested positive for SARS-CoV-2, of whom 129 (87.8%) were asymptomatic (23). The researchers concluded that “front-door symptom screening in homeless shelter settings will likely miss a substantial number of COVID-19 cases in this high-risk population” (9).

    Los Angeles Homeless Shelter

    On 28 March, an initial case of COVID-19 was diagnosed with a positive test result at a homeless shelter in downtown Los Angeles, California (10). After a cluster of symptomatic persons was identified early in the week of 20 April, the shelter was closed to new occupants and testing was started for current occupants. As of 22 April, 43 (24.2%) of 178 completed tests were positive for SARS-CoV-2 and 27 (63.8%) of the persons who tested positive were asymptomatic.

    New York City Obstetric Patients

    Between 22 March and 4 April 2020, women who delivered infants at 2 New York City hospitals were tested for SARS-CoV-2 (11). Among 214 patients, 33 (15.4%) tested positive, 29 (87.9%) of whom were asymptomatic. The researchers note that “fever developed in 3 (10%) before postpartum discharge (median length of stay, 2 days)” (11). Two of those patients, though, were presumed to have endomyometritis, for which they were treated with antibiotics.

    U.S.S. Theodore Roosevelt

    The first case of SARS-CoV-2 infection aboard the American aircraft carrier U.S.S. Theodore Roosevelt was diagnosed on 22 March 2020 (24). As of 24 April, 4954 crew members had been tested for the virus; 856 (17.3%) tested positive (12). According to a news report, about 60% of those with positive results were asymptomatic (25). After an extended period of isolation, many of these asymptomatic persons continued to test positive for SARS-CoV-2. An internal U.S. Navy document stated, “Results of out-testing portions of the [Theodore Roosevelt] crew following 14 days of quarantine leads us to reevaluate our assessment of how the virus can remain active in an asymptomatic host” (26).

    Charles de Gaulle Aircraft Carrier

    On 8 April 2020, crew members aboard the French naval vessel Charles de Gaulle first began showing symptoms of COVID-19, 24 days after last having had contact with those outside the ship while docked on 15 March (27). On 10 April, 50 crew members received positive test results for SARS-CoV-2. The entire crew of 1760 was subsequently tested. As of 18 April, 1046 (59.4%) had tested positive, and of these, nearly 50% were asymptomatic (13).

    Japanese Citizens Evacuated From Wuhan, China

    As of 6 February 2020, a total of 565 Japanese citizens had been repatriated from Wuhan, China, on charter flights. Thirteen (2.3%) tested positive for SARS-CoV-2, of whom 4 (30.8%) were asymptomatic. As of 6 March, none of the latter persons had developed COVID-19 symptoms (2).

    Greek Citizens Evacuated From Spain, Turkey, and the United Kingdom

    From 20 through 25 March 2020, a total of 783 Greek citizens were repatriated from Spain, Turkey, and the United Kingdom on 7 flights. Forty (5.1%) tested positive for SARS-CoV-2 (14). At the time of testing, 39 (97.5%) were asymptomatic. At follow-up about 2 weeks later, 35 (87.5%) had remained asymptomatic (Lytras T. Personal communication.).

    Nursing Facility Residents in King County, Washington

    On 1 March 2020, a staff member who had worked at a 116-bed skilled-nursing facility in King County, Washington, on 26 and 28 February tested positive for SARS-CoV-2 (15). On 13 March, 76 (92.6%) of the facility's 82 current residents were tested; 23 (30.3%) tested positive. At the time of testing, 12 (52.2%) of the latter persons were asymptomatic. On 19 and 20 March, 49 residents were retested, including those who had previously received negative results and those who had tested positive but were asymptomatic or had atypical symptoms. In this second round of testing, 24 residents (49.0%) had positive results. Of these, 15 (63.5%) were asymptomatic. After a median of 4 days of follow-up, 24 (88.9%) of the 27 asymptomatic persons developed symptoms of COVID-19.

    The researchers note, “More than half of residents with positive test results were asymptomatic at the time of testing and most likely contributed to transmission. Infection-control strategies focused solely on symptomatic residents were not sufficient to prevent transmission after SARS-CoV-2 introduction into this facility” (15).

    Inmates in Arkansas, North Carolina, Ohio, and Virginia

    Widespread outbreaks of COVID-19 in the correctional facilities of several states have led to large-scale screening programs. According to research by Reuters journalists (16), as of 25 April 2020, SARS-CoV-2 test results that include data on symptom status were available for 4693 inmates in the state prison systems of Arkansas, North Carolina, Ohio, and Virginia. Among these inmates, 3277 (69.8%) tested positive, of whom 3146 (96%) had no symptoms at the time of testing.

    Rutgers University Students and Employees

    From 24 March through 7 April 2020, researchers recruited 829 students and employees at Rutgers University and 2 affiliated hospitals for SARS-CoV-2 testing (17); 546 were health care workers. In total, 41 (4.9%) tested positive. Among health care workers, 40 (7.3%) tested positive, compared with 1 (0.4%) of those in other fields. Of all who tested positive, 27 (65.9%) reported no symptoms when they were tested.

    Indiana Residents

    From 25 April through 1 May 2020, the Indiana State Department of Health and the Indiana University Richard M. Fairbanks School of Public Health tested 4611 residents of Indiana for SARS-CoV-2 (18, 28). “This number includes more than 3,600 people who were randomly selected and an additional 900 volunteers recruited through outreach to the African American and Hispanic communities to more accurately represent state demographics” (28). In total, 78 (1.7%) tested positive; 35 (44.8%) of these persons were asymptomatic.

    Argentine Cruise Ship Passengers and Crew

    In mid-March 2020, a cruise ship departed Ushuaia, Argentina, for a planned 21-day expedition (19). After the emergence of a febrile passenger on the eighth day of the cruise, the ship's itinerary was altered, and it eventually docked at Montevideo, Uruguay, on the 13th day. All 217 passengers and crew members were tested; 128 (59.0%) tested positive, of whom 104 (81.3%) were asymptomatic.

    San Francisco Residents

    During 4 days in late April 2020, “4,160 adults and children, including more than half of the residents in the 16 square blocks that make up San Francisco Census Tract 229.01” in the Mission District, were tested (29). Seventy-four (1.8%) tested positive, of whom 39 (52.7%) were asymptomatic.

    Discussion

    Despite concerns about distinguishing asymptomatic from presymptomatic persons, data from 4 of 5 of the cohorts with longitudinal reporting suggest that a small fraction of asymptomatic persons may eventually develop symptoms. In the Italian and Japanese cohorts, 0% of asymptomatic persons became symptomatic. In the Greek and New York cohorts, 10.3% of asymptomatic persons became symptomatic. In the New York cohort, the figure might be as low as 3.4% because of the presumed diagnosis of endomyometritis in 2 of the 3 women who developed fevers. The observation period in this cohort, however, was extremely brief: a median of 2 days.

    The King County cohort—in a skilled-nursing facility—is an outlier. Of 27 initially asymptomatic residents, 24 (88.9%) eventually developed symptoms and were therefore recategorized as having been presymptomatic. These persons were presumably much older and had more comorbid conditions than those in the other 4 longitudinal cohorts. In addition, they resided together in a single facility, which might have allowed for repeated exposures to infected persons. More research is needed to ascertain the effect of age and environmental factors on the natural history of COVID-19.

    The Vo' cohort seems to confirm that asymptomatic persons can indeed transmit SARS-CoV-2 to others, and the experience aboard the U.S.S. Theodore Roosevelt suggests that they might be able to transmit the virus to others for longer than 14 days. These worrisome findings could explain, in part, the rapid spread of the virus around the globe. Persons who do not feel or look ill are likely to have far more interaction with others than those who have symptoms. If asymptomatic transmission is indeed common, testing only those with symptoms would seem to be folly.

    The finding that 54% of the 76 asymptomatic persons on the Diamond Princess who were examined by computed tomography appeared to have significant subclinical abnormalities in their lungs is disturbing. Further research will be required to confirm this potentially important finding, taking into account possible confounding factors, including the age of passengers aboard the Diamond Princess. If confirmed, this finding suggests that the absence of symptoms might not necessarily mean the absence of harm. The subclinical nature of the finding raises the possibility that SARS-CoV-2 infection causes subtle deficits in lung function that might not be immediately apparent.

    Does the relatively high proportion (60.5%) of asymptomatic cases on the U.S.S. Theodore Roosevelt—whose crew members, presumably, are mostly in their 20s and 30s—suggest that asymptomatic infection is more likely in younger persons? Perhaps, but it must be noted that the proportion of asymptomatic infection (47.8%) on the Charles de Gaulle aircraft carrier seems to be only marginally higher than average. A case series from Wuhan, China, from 24 December 2019 to 24 February 2020 included data for “78 patients from 26 cluster cases of exposure to the Hunan seafood market or close contact with other patients with COVID-19” (30). Asymptomatic patients “were younger (median [interquartile range] age, 37 [26-45] years vs 56 [34-63] years; P < .001), and had a higher proportion of women (22 [66.7%] women vs 14 [31.%] [sic] women; P = .002).”

    As noted earlier, the data and studies reviewed here are imperfect in many ways. The ideal study of asymptomatic SARS-CoV-2 infection has yet to be done. What might that study look like? Most important, it must include a large, representative sample of the general population, similar to the U.S. serosurvey for which the National Institutes of Health is currently recruiting (31). In contrast to the narrowly defined cohorts here, it will be illuminating to have data that accurately reflect the population at large. In addition, longitudinal data must be collected over a sufficiently long time to distinguish between asymptomatic and presymptomatic cases.

    Closed cohorts, such as cruise ships, aircraft carriers, and correctional facilities, offer both advantages and disadvantages. Because the likelihood of viral exposure is so much greater than in other settings, the “treatment” that participants receive may be close to uniform. As a result, we may learn more about the average incidence of asymptomatic infection. But the confined environment—which ensures frequent, overlapping interaction between participants—makes it challenging to accurately trace contacts and elucidate the chain of viral transmission.

    On the basis of the 3 cohorts with representative samples—Iceland and Indiana, with data gathered through random selection of participants, and Vo', with data for nearly all residents—the asymptomatic infection rate may be as high as 40% to 45%. A conservative estimate would be 30% or higher to account for the presymptomatic admixture that has thus far not been adequately quantified. In any case, these high rates are not aligned with current testing programs that have predominantly focused on symptomatic cases. Beyond expanding testing to those without symptoms or known exposure, our inability to recognize carriers might make necessary the broad adoption of preventive strategies, such as masks.

    The 96% rate of asymptomatic infection among thousands of inmates in 4 state prison systems is remarkable. Without any longitudinal data, we cannot estimate the number of presymptomatic cases. If the missing data prove to be similar to the Italian, Japanese, Greek, and New York cohorts, though, the vast majority of these persons will remain asymptomatic. Why, then, might the asymptomatic infection rate in this setting be so anomalously high?

    One plausible factor could be cross-immunity imparted by the betacoronaviruses HCoV-OC43 and HCoV-HKU1, which has been proposed as a mitigating factor in the spread of SARS-CoV-2 (32). According to the U.S. Centers for Disease Control and Prevention, HCoV-HKU1 was active across the United States from late November 2019 through mid-February 2020 (33). In a locked-down congregate setting like a prison, it seems possible that contagious respiratory viruses could spread rapidly, so it would be interesting to do a serosurvey for antibodies to these betacoronaviruses. Still, 96% is very high. It would be prudent to review the source data carefully for errors.

    What individual differences might account for why 2 persons of the same age, sex, and health status, for example, have idiosyncratic responses to SARS-CoV-2 infection? Why does one come through with nary a symptom, while the other lies near death in intensive care? At the moment, we simply do not know. If ever there were a need for precision medicine—for deeply and thoroughly understanding the multitudinous “-omics” that shape each of us—this is it. Perhaps there will be not just 1 therapy or vaccine for SARS-CoV-2 but versions that are individualized to maximize their efficacy.

    In countries like the United States that have been hardest hit by the SARS-CoV-2 pandemic, it has been apparent for some time that the amount of testing must be significantly and rapidly increased—perhaps by an order of magnitude or more. With this new knowledge that a large proportion of those infected with SARS-CoV-2 have no symptoms, the urgency for more testing becomes even greater.

    In a perfect world, perhaps using simple, accurate, inexpensive technology that is still on the drawing board (34), we would test each person every day for SARS-CoV-2. Until that is possible, innovative surveillance tactics might provide useful data for public health officials. Self-monitoring with internet-connected thermometers and smart watches that monitor heart rate, then crowdsourcing the resulting data, has been shown to accurately predict the incidence of influenza-like illness as reported by the California Department of Public Health and the Centers for Disease Control and Prevention (35–37). Similarly, monitoring sewage sludge provided “SARS-CoV-2 RNA concentrations [that] were a seven-day leading indicator ahead of compiled COVID-19 testing data and led local hospital admissions data by three days” (38).

    The early data that we have assembled on the prevalence of asymptomatic SARS-CoV-2 infection suggest that this is a significant factor in the rapid progression of the COVID-19 pandemic. Medical practice and public health measures should be modified to address this challenge.

    References

    Comments

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    Andrew N. Cohen, Bruce Kessel7 June 2020
    Analysis should address test specificity/sensitivity, and adequate assessment of asymptomatic status

    Oran and Topol reviewed 16 studies that provide data on asymptomatic individuals who tested positive for SARS-CoV-2 by RT-PCR, and based on three representative studies concluded that 40-45% of infected individuals are asymptomatic. From this they drew several policy recommendations. However, their calculations did not take into account the tests' sensitivity or specificity. We found 20 studies that reported false negative rates of 0-52% (i.e. sensitivities of 48-100%) in SARS-CoV-2 RT-PCR tests (1). Though these tests typically have 100% analytical specificity, there are no data yet on their clinical specificity, which includes false positives due to contamination and other human error. In a review of 37 large external quality assessments of RT-PCR viral assays conducted in 2004-2019, false positive rates ranged from <0.6-8.1% (1).

    The three representative studies cited by Oran and Topol had positivity rates of 0.8-2.0%; with a false negative rate of 0-52%, false positive rates of 0.3-0.9% would yield enough false positives to account for all the asymptomatic infected individuals reported. In other words, they may not actually have been infected. They also may not have been asymptomatic. Oran and Topol noted that asymptomatic individuals—those who are infected but never develop symptoms—must be distinguished from presymptomatic individuals. This requires checking for symptoms over the period of time in which symptoms could potentially appear, that is, over the maximum reported incubation period starting from the individual's date of infection (if known) or diagnosis. Oran and Topal acknowledged that longitudinal observations were made in only 5 of the 16 studies they reviewed. However, in 4 of those 5 studies the actual or median observation periods were 2 days (obstetric patients), 7 days (nursing home), 0 to about 14 days (Italy), and about 14 days (Greek evacuees), while the maximum incubation period for COVID-19 is reported as more than 14 days (2).

    In the three representative studies specifically, there was either no effort to determine symptoms over time (Iceland, Indiana) or an insufficient effort (Italy). We want to be clear that we do not here argue that there are no asymptomatic carriers of SARS-CoV-2. Rather, we suggest that the data reviewed does not support the review's conclusion that a large proportion of infected individuals are asymptomatic.

    1. Cohen AN, Kessel B. False positives in reverse transcription PCR testing for SARS-CoV-2. medRxiv; 2020. https://www.medrxiv.org/content/10.1101/2020.04.26.20080911v2
    2. Linton NM, Kobayashi T, Yang Y, et al. Incubation period and other epidemiological characteristics of 2019 Novel Coronavirus infections with right truncation: a statistical analysis of publicly available case data. J Clin Med. 2020;9:538. [PMID: 32079150] doi:10.3390/jcm9020538
    Dr. Charles Bens7 June 2020
    Nearly Half of Coronavirus Spread May Be Traced to People Without Symptoms
    This article raises many questions, but provides very few answers. Why get you not explore the Ames Theory of priorities for nutrient use, the existing level of vitamin D3, the negative impact of sugar consumption on white blood cell strength or the overall strength of the immune system measured by the Bens Immune Biomarker Test? Previous Coronavirus exposure many have allowed the COVID-19 virus to think this person has immunity, if so why were lungs still damaged?
    Len Geiger8 June 2020
    WHO Statement

    I’d like to see the authors’ response to The World Health Organization’s recent statement, “Asymptomatic spread of coronavirus is ‘very rare.’” It seems to me that a “minimum of 30%” and “very rare” are difficult to equate and border on being mutually exclusive statements.

    CNBC article on the subject: https://www.cnbc.com/2020/06/08/asymptomatic-coronavirus-patients-arent-spreading-new-infections-who-says.html

    Muge Cevik, Isaac I Bogoch, Gail Carson, Eric D’Ortenzio, Krutika Kuppalli10 June 2020
    A problematic interpretation of a narrative review containing a dearth of poor-quality evidence resulting in an overestimate of asymptomatic infections, which might misinform policy response.

    There is a clear need to better understand the contribution of asymptomatic SARS-CoV-2 infections (those with no symptoms at all throughout the infection) in driving the current pandemic. However, there are caveats that in our opinion are pertinent when interpreting the reported findings of this review, including the lack of a clear definition of asymptomatic infection and selective inclusion of cross-sectional studies.

    In addition, there is a problematic interpretation of a narrative review containing a dearth of poor-quality evidence resulting in an overestimate of asymptomatic infections, which might misinform policy response. Of the 16 reports included in this review, four defined symptoms of COVID-19 as fever and respiratory symptoms, three had no clear symptom definition, and six were media articles proving no information about symptoms. Respiratory symptoms or fever do not cover the spectrum of COVID-19 presentations, and many individuals with non-specific or mild symptoms are misclassified as being asymptomatic. For instance, Gudbjartsson et al. reported that approximately half of the participants in their population screening had rhinorrhoea and cough despite inquiring for those not to participate (1).

    Second, cross-sectional studies cannot determine who will remain asymptomatic throughout their infection (2). For example, a study of 359 COVID-19 cases in Guangzhou found that 71 (86%) later developed symptoms (3). Oran and Topal include 9/16 cross-sectional reports, but describe them as cohorts, so it is unclear whether some patients might have developed symptoms later on. Only one report included other symptoms (malaise, rhinorrhoea, sore throat etc.) and followed individuals, with 89% of patients developing symptoms later (4).

    Third, none of the studies cited included contact tracing; therefore, we cannot comment on asymptomatic transmission based on included studies. In contrast to the author’s conclusions, recent studies assessing longitudinal characteristics of viral load and transmission have found truly asymptomatic patients have significantly lower viral loads than those who develop symptoms and transmit to fewer secondary cases (5).

    Finally, a systematic review addressed the same question using a robust methodology, excluded several of the studies that Oran and Topol included and conclude that 15-20% of SARS-CoV-2 infected people remain asymptomatic (2). There remains an immediate need to fill knowledge gaps on COVID-19; however, efforts must coalesce to conducting systematic reviews using robust and transparent methodologies, to avoid selective reporting and to provide a balanced synthesis of evidence. Academic groups should join forces to coordinate efforts, share the burden to deliver timely robust systematic reviews, avoid duplication and improve quality.

    References:

    1. Gudbjartsson DF, Helgason A, Jonsson H, Magnusson OT, Melsted P, Norddahl GL, et al. Spread of SARS-CoV-2 in the Icelandic Population. N Engl J Med. 2020.

    2. Buitrago-Garcia DC, Egli-Gany D, Counotte MJ, Hossmann S, Imeri H, Ipekci AM, et al. The role of asymptomatic SARS-CoV-2 infections: rapid living systematic review and meta-analysis. medRxiv. 2020:2020.04.25.20079103.

    3. Zhang W, Cheng W, Luo L, Ma Y, Xu C, Qin P, et al. Secondary Transmission of Coronavirus Disease from Presymptomatic Persons, China. Emerg Infect Dis. 2020;26(8).

    4. Arons MM, Hatfield KM, Reddy SC, Kimball A, James A, Jacobs JR, et al. Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility. New England Journal of Medicine. 2020;382(22):2081-90.

    5. Chau NVV, Thanh Lam V, Thanh Dung N, Yen LM, Minh NNQ, Hung LM, et al. The natural history and transmission potential of asymptomatic SARS-CoV-2 infection. Clinical Infectious Diseases. 2020.

    Daniel T. Halperin10 June 2020
    A Very Useful, also Highly Problematic Review Article

    Comment: This review is commendably useful for estimating the PROPORTION of SARS-CoV-2 carriers who are asymptomatic. However, the additional conclusion that “asymptomatic SARS-CoV-2 infection…is a significant factor in the rapid progression of COVID-19” appears to be utterly unsubstantiated (and surprising, considering this journal’s normally rigorous peer review standards). Regarding the authors’ assertion, in the abstract, that “asymptomatic persons…can transmit the virus,” only two data are presented to support this: 1) Citing an Italian study, they claim (my CAPS for emphasis) that the Italian authors: “CONFIRMED several new cases of SARS-CoV-2 infection had been caused by exposure to asymptomatic persons.” However, the (non-peer-reviewed) online paper cited merely mentions that 2 (or at most 3) of 8 persons studied “MAY have become infected from an asymptomatic carrier.” (E.g., “Subject 5 reported meeting an asymptomatic infected individual before the lockdown...”) Note the same study reported that “No infections were detected in…234 tested children [under age 11], despite…living in same household as infected people,” consistent with other evidence that children are much less likely to become infected, and even if infected are typically asymptomatic (as opposed to presymptomatic) carriers 2) (www.washingtonpost.com/opinions/2020/05/29/case-reopening-schools-this-fall/).  

    The only other evidence cited by Oran and Topal for the role of asymptomatic transmission is from one of the other 16 cohort studies they reviewed, regarding which they conclude: “More than half of [infected nursing facility] residents…were ASYMPTOMATIC at the time of testing and MOST LIKELY contributed to transmission.” In fact, the cited 3) NEJM paper explains that “7 days after their positive test, 24 of 27 asymptomatic residents (89%) had onset of symptoms and were RECATEGORIZED as presymptomatic.” Apparently Oran and Topal have confused here the very same issue (asymptomatic vs presymptomatic transmission) that they attempt to clarify at the onset of their own paper, re “To be clear, the asymptomatic individual…will NEVER develop symptoms.” I petition the journal editors to retract this paper, or at least to request that the authors modify their (perhaps unintentional but clearly misleading) conclusion regarding the contagiousness of asymptomatic SARS-CoV-2 carriers. Surely any objective expert or meticulous reader would also wonder whether  the paper’s conclusion, that asymptomatic carriers in point of fact are significant drivers of COVID-19 at the population level, is sufficiently substantiated by the "data" cited by the authors (i.e., that two or three persons in Italy reporting having had contact with asymptomatic carriers MAY thereby have become infected). This article and in particular its unsubstantiated conclusion has already been widely cited and therefore requires immediate correction.

     

     

     

    1.Lavezzo E, Franchin E, Ciavarella C, et al. Suppression of COVID-19 outbreak in the municipality of Vo, Italy. Preprint. Posted online 18 April 2020. medRxiv. doi:10.1101/2020.04.17.20053157

     2. Halperin, D T.  The case for reopening schools this fall. Washington Post, May 29, 2020. (https://www.washingtonpost.com/opinions/2020/05/29/case-reopening-schools-this-fall/)

     3.Arons MM, Hatfield KM, Reddy SC, et al; Public Health–Seattle and King County and CDC COVID-19 Investigation Team. Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility. N Engl J Med. 2020;382:2081-2090. [PMID: 32329971] doi:10.1056/NEJMoa2008457

     

     

    Daniel P. Oran and Eric J. Topol11 June 2020
    Authors' Response to Cevik, Bogoch, Carson et al

    We are puzzled by your critique. In the opening paragraphs of our review, we clearly state that most of these studies are cross-sectional in nature, taking care to label in our table the minority of longitudinal studies. We also clearly explain the ambiguity surrounding asymptomatic versus presymptomatic status.

    In our opinion, the unpublished “systematic review” preprint that you refer to, which appeared after our article was published and has not been subject to peer review, fails to adequately address the compelling data that it includes (as did we) from Vo, Italy. Not only is that a large representative sample with longitudinal data, but its findings are supported by other groups that we included. In the study, completed over 14 days, the researchers concluded that the proportion of asymptomatic individuals was 43%. In addition, none of the subjects who were asymptomatic at the beginning of the study had developed symptoms by the end.

    In the midst of a global pandemic, we believed that it would be valuable to collect all the currently available data on an ill-defined phenotype and address an important issue: whether a sizable proportion of those infected with SARS-CoV-2 will have no symptoms. As of late May 2020, when we completed our review, which was just five months after the appearance of the first cases of COVID-19, much of that data was in rough and fragmentary form. We think that we faithfully and accurately reported what we found.

    Journalism has been described as a first draft of history. In a similar way, our narrative review, which has collected the earliest available evidence, is a first draft of science. In the months and years ahead, new evidence — ideally, from well-designed, large-scale studies with representative samples — will appear, adding greater detail and clarity to our knowledge.

    We share your perspective that significant gaps remain in what we know about crucial aspects of COVID-19, including the details and frequency of SARS-CoV-2 transmission by infected individuals who have no symptoms, and the harm to the lungs and possibly other parts of the body that might be associated with asymptomatic infection.

    We are unaware of any other pathogen that can cause asymptomatic infection in a significant minority of patients — whether that is 20% or 40% — while also having a serious potential of taking lives. We look forward to collaborating with all interested investigators to expand our knowledge of SARS-CoV-2 and COVID-19.

    Zoë Hyde11 June 2020
    Comment on: Prevalence of Asymptomatic SARS-CoV-2 Infection: A Narrative Review

    To the Editor: In their recent review, Oran and Topol (1) aimed to determine the prevalence of asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and concluded 40-45% of infected persons likely remain symptom-free.

    Although the authors attempted to distinguish between pre-symptomatic cases (i.e., those yet to develop symptoms) and those who are truly asymptomatic, they base their conclusions on only three studies, two of which are cross-sectional. Furthermore, the remaining longitudinal study considered symptomatic persons to be those with fever or cough, which is an extremely limited definition.

    At least two high-quality longitudinal studies were published during the period the authors searched the literature, both reporting a considerably lower prevalence. In a study of 100 laboratory-confirmed index cases and 2,761 close contacts in Taiwan, 22 secondary cases were identified, of which only 4 (18%) were asymptomatic during 14 days of follow-up (2). Following an outbreak in a call centre in Korea, 1,143 people were tested and 97 were found to be infected with SARS-CoV-2. Of these, 4 were pre-symptomatic and 4 (1.9%) remained asymptomatic during a 14-day monitoring period (3). These findings more likely represent the prevalence of asymptomatic infection, given the rigorous testing, contact tracing, and monitoring strategy employed in both settings.

    The authors also noted an apparent high proportion of asymptomatic cases (58.4%) among crew members of the U.S.S. Theodore Roosevelt. However, in a serological study of crew and associated personnel published subsequently, only 18.5% were found to be asymptomatic (4). Oran and Topol (1) also draw attention to the persistent test positivity of crew members, writing that asymptomatic persons “might be able to transmit the virus to others for longer than 14 days.” This thankfully now seems unlikely. While shedding of viral RNA may occur for a month or more, infectious virus was never cultured after the 11th day of illness in patients in Singapore (5). Thus, with the exception of immunocompromised persons and severely ill patients, infectivity is unlikely to persist beyond the second week of illness.

    Nonetheless, the authors’ suggestion that widespread mask use may be necessary is wise. The infectious period begins approximately two days before symptom onset, and pre-symptomatic transmission accounts for a substantial fraction of cases (5). While the authors rightly call for policy changes to minimise the risk of silent transmission, their apparent overestimate of asymptomatic infection risks creating the perception that SARS-CoV-2 is less virulent than in reality.

    References

    1. Oran DP, Topol EJ. Prevalence of Asymptomatic SARS-CoV-2 Infection: A Narrative Review. Ann Intern Med. 2020. https://doi.org/10.7326/M20-3012

    2. Cheng HY, Jian SW, Liu DP, Ng TC, Huang WT, Lin HH. Contact Tracing Assessment of COVID-19 Transmission Dynamics in Taiwan and Risk at Different Exposure Periods Before and After Symptom Onset. JAMA Intern Med. 2020. https://doi.org/10.1001/jamainternmed.2020.2020

    3. Park SY, Kim YM, Yi S, et al. Coronavirus Disease Outbreak in Call Center, South Korea. Emerg Infect Dis. 2020;26(8). https://doi.org/10.3201/eid2608.201274

    4. Payne DC, Smith-Jeffcoat SE, Nowak G, et al. SARS-CoV-2 Infections and Serologic Responses from a Sample of U.S. Navy Service Members - USS Theodore Roosevelt, April 2020. MMWR Morb Mortal Wkly Rep. 2020. https://dx.doi.org/10.15585/mmwr.mm6923e4

    5. National Centre for Infectious Diseases, Chapter of Infectious Disease Physicians, Academy of Medicine Singapore. Period of Infectivity to Inform Strategies for De-isolation for COVID-19 Patients. Accessed at https://www.ams.edu.sg/view-pdf.aspx?file=media\5558_fi_168.pdf

    Daniel Oran, Eric topal15 June 2020
    Authors' response to Zoë Hyde

    The study cited by Hyde about the U.S.S. Theodore Roosevelt, which reported an asymptomatic proportion of 18.5%, included just 382 (27%) of the 1,417 crew members. The researchers describe this as a "convenience sample of persons who might have had a higher likelihood of exposure."

    The fact that 18.5% of this unrepresentative 27% were asymptomatic does not tell us anything about the remaining 73%.

    Daniel Oran, Eric Topal15 June 2020
    Authors' response to Daniel T. Halperin

    In our view, Halperin does not fairly characterize the evidence of asymptomatic transmission presented by Lavezzo et al. concerning their research in Vo', Italy. The authors state, "The presence of a significant number of asymptomatic SARS-CoV-2 infections raises questions about their ability to transmit the virus. To address this issue, we conducted an extensive contact tracing analysis of the 8 new infections."Then, after describing the various contacts of the infected individuals, the authors conclude, "These results suggest that asymptomatic infections may play a key role in the transmission of SARS-CoV-2."

    This is the complete sentence in the final paragraph of our review from which Halperin quotes: "The early data that we have assembled on the prevalence of asymptomatic SARS-CoV-2 infection suggest that this is a significant factor in the rapid progression of the COVID-19 pandemic."From our perspective, it appears that Halperin has inferred a far more extreme interpretation than our actual words are meant to convey. We stress that the data are early, not definitive. We describe them as suggestive, not conclusive.

    We believe that our review accurately portrays the source material that we have collected. Our review is a beginning, though, not an end. In the months and years to come, we expect that far more will be learned about asymptomatic SARS-CoV-2 infection. We are eager to see what research teams around the world will contribute to this important area.

    Dongsheng Han, Jinming Li16 June 2020
    Proportion of asymptomatic SARS-COV-2 infections: need convincing answers

    The existence of a substantial but unclear number of asymptomatic SARS-COV-2 patients worldwide has raised concerns among global public health authorities. This narrative review concluded that the proportion of asymptomatic patients might account for approximately 40% to 45% of SARS-CoV-2 infections based on results of 16 cohort studies from different sources. Unfortunately, however, this article did not include any of the studies from China.

    In fact, in China, the detection of asymptomatic infection is a core task for combating COVID-19 spread. Based on the studies in China that have been peer-reviewed and officially published, we found that the proportion of asymptomatic infection was no more than 20% (from 6% to 15.8%), much lower than the reported proportion (40% to 45%) in this narrative review.

    These studies in China were based on different populations, including hospitalized contacts of COVID-19 patients (Wuhan City in Hubei province: 12.2%, 34/279) [1], all infected people tracked throughout a city (Shenzhen City in Guangdong province: 6%, 25/391 [2]; Anqing city in Anhui province: 9.6%, 8/83 [3]), and asymptomatic infections in childhood cases across China (12.9%, 94/731) [4] and Wuhan city in Hubei province (15.8%, 27/171) [5]. However, due to the differences in the study setting and the included populations of all the studies, including the 16 cohorts in this narrative review, the inferred proportion of asymptomatic SARS-CoV-2 infection, whether 20% or 40%, may not be accurate. The true proportion needs to be answered by more carefully designed studies in the future.

    Nevertheless, in the context of the current research, we think that this article should supplement the knowledge we provide here in order to give readers a more objective understanding of the proportion of asymptomatic infections.

    References:

    1.Wang Y, Tong J, Qin Y, Xie T, Li J, Li J, et al. Characterization of an asymptomatic cohort of SARS-COV-2 infected individuals outside of Wuhan, China. Clin Infect Dis 2020. DOI: 10.1093/cid/ciaa629.

    2. Bi Q, Wu Y, Mei S, Ye C, Zou X, Zhang Z, et al. Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study. Lancet Infect Dis 2020. DOI: 10.1016/S1473-3099(20)30287-5.

    3. Luo SH, Liu W, Liu ZJ, Zheng XY, Hong CX, Liu ZR, et al. A confirmed asymptomatic carrier of 2019 novel coronavirus (SARS-CoV-2). Chin Med J (Engl) 2020;133(9):1123-1125.

    4. Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiology of COVID-19 Among Children in China. Pediatrics 2020: e20200702.

    5. Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. SARS-CoV-2 Infection in Children. N Engl J Med 2020. DOI: 10.1056/NEJMc2005073.

    Disclosures:

    there is no any conflicts of interest

    N.Belgin Akilli, Ramazan Koylu23 June 2020
    40-45% Asymptomatic case rate may not reflect reality.

    Dear Editor,

    The world is facing a problem that's very rare to date. Since its diagnosis in December 2019 8,860,331 people have been infected worldwide and 465,740 people have died (22 June 2020) (1). Many issues related to this disease are waiting to be clarified. Oran and Topol analyzed 16 studies on patients with positive diagnosis for Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcriptase polymerase chain reaction (RT-PCR), and suggested that the disease may be asymptomatic in 40-45% (2). Even thought he evidence level of the studies is low, we think that a remarkable point that may affectt he daily functioning of health institution sand public health professionals in pandemic conditions is mentioned.

    However, the point we want to emphasize is that the sensitivity of RT-PCR may be low due to factors such as suboptimal clinical sampling and variability in viral load and sensitivity of the manufacturer test kit (3). False negativite rate for SARS-CoV-2 was reported between 2-29% (3). In a study of 205 patients, RT-PCR sensitivity was 93% for bronchoalveolaer lavage, 72% for sputum, and 63% for nasal swabs and 32% for throat (4). This value is uncertain for asymptomatic patients. Woloshin et al. stated that determining the test sensitivity in asymptomatic individuals is an urgent priority, and even in a highly sensitive test, negative results cannot exclude the infection if the probability of pretesting is high (5). We think that the rate of asymptomatic individuals in the society may be higher due to the lack of gold standard for the diagnosis of coronavirus disease 2019 (COVID-19).

    Despite the World Health Organization's report on the contamination of asymptomatic COVID 19 cases causing confusion, we believe that asymptomatic COVID 19 cases may be more than expected in the community and that public health policies for controlling infection should be developed accordingly.

    Referances:

    1- https://covid19.who.int/

    2- Oran DP, Topol EJ. Prevalence of Asymptomatic SARS-CoV-2 Infection: A Narrative Review. Ann Intern Med. 2020. doi:10.7326/M20-3012

    3- Watson J, Whiting PF, Brush JE. Interpreting a covid-19 test result. BMJ 2020 doi: 10.1136/bmj.m1808

    4- Wang W, Xu Y, Gao R, Lu R., Han K, Wu G etal . Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 2020. doi:10.1001/jama.2020.3786. 32159775

    5- Woloshin S., Patel N, Kesselheim AS. False Negative Tests for SARS-CoV-2 Infection —Challenges and Implications NEJM 2020 doi: 10.1056/NEJMp2015897

    Eric Topol, Daniel Oran23 June 2020
    Author's Response to Han and Li

    None of the sources cited by Han and Li present data that were collected from representative samples. In contrast, three of the studies that we have included in our review are the result of representative samples, and one of these has the added benefit of longitudinal data from a 14-day period. We were impressed by the narrow range reported in these studies for the proportion of asymptomatic infected persons: between 42.2% and 44.8%. However, in the absence of longitudinal data for two of these studies, and the resulting uncertainty concerning the possible admixture of presymptomatic persons, we have suggested that 30% is a conservative estimate.

    We agree with Han and Li that carefully designed studies will be required to determine accurately the prevalence of asymptomatic SARS-CoV-2 infection in human populations.

    Wynn Bear, Mingzi Wu29 June 2020
    Binary Star Social Systems for SARS-CoV-2

    Although truth can be gleaned from lively debates and consensus is usually formed in the midst of discussions and arguments, we preferred 40-45% asymptomatic case rate since some of the comments represent the past, the author's conclusion representative now, more ongoing conclusions will on behalf of the future.

    With continuous mutation of the virus, only current data and models will be more conducive to the current work. The author even suggested that this is the early data that they have assembled and therefore manifests that public health measures should be modified to address this challenge. Actually, this unprecedented pandemic calls for unprecedented measures to achieve its ultimate defeat is too much(RE.1).

    This is a novel intervention measure be called binary star social systems for symptomatic transmission, pre-symptomatic transmission, and asymptomatic transmission, in which the whole society is divided into two or more subsystems. They are respectively with a swappable model for lockdown and free to get adequately both in economic and social benefits and isolating the virus. The details of the swappable model had been as a Letter submitted to Science (shown in RE.2)

    Along with the continuous progress of cognition to SARS-CoV-2, more and more specialist have realized that effective drugs and vaccines will be unable to rely on for a long time, and the use of creative non-pharmaceutical interventions and alternative approaches with reliable means would be a long-term task.

    Referances:

    1. Monica Gandhi, et al. Asymptomatic Transmission, the Achilles' Heel of Current Strategies to Control Covid-19. May 28, 2020, N Engl J Med 2020. DOI: 10.1056/NEJMe2009758

    2. Mingzi Wu, et al., Always Swapping Isolation will be alternative approaches for maintaining physical distancing and minimize the risk. https://science.sciencemag.org/content/368/6496/1163/tab-e-letters

    3. Edward A. Belongia, Michael T. Osterholm, COVID-19 and flu, a perfect storm. Vol. 368, Issue 6496, pp. 1163, Science 12 Jun 2020. DOI: 10.1126/science.abd2220

    4. López, L., Rodó, X. The end of social confinement and COVID-19 re-emergence risk. Nat Hum Behav (2020). https://doi.org/10.1038/s41562-020-0908-8 Disclosures: There is no any conflicts of interest

    Fan Yang, M.D.1,2* Dan Ma, M.D.2*2 July 2020
    Proportion of Asymptomatic SARS-COV-2 Carriers: The Challenge of Stepping Twice into the Same River

     

    To the Editor,

    In a recent narrative review, Oran and Topol (1) aimed to determine the prevalence of asymptomatic SARS-CoV-2 infection. They concluded that asymptomatic persons seem to account for 40% to 45% of the infections.

    What moves us to seek the proportion? Assuming that it is feasible to anticipate the scale of tricky asymptomatic carriers according to accessible symptomatic cases. Detecting and isolating these persons will prevent them from spreading the virus. This demand ignited the passion. In fact, only adopt the inferred proportion to predict existing asymptomatic carriers might fail at a greater than expected rate.

    To a large extent, the relative proportion of asymptomatic carriers and presymptomatic patients reflects the capacity of active detection, intensity of RT-PCR testing and the scope of coverage. Meanwhile, different pandemic phases are the most important heterogeneous factor in determining the true number of asymptomatic carriers.

    At the beginning of the outbreak, nucleic acid testing resources were extremely limited. Close contact tracking could incidentally catch only a small number of asymptomatic carriers (2). The overall initial data (1% asymptomatic) mirrored the dilemma (3). Evacuated citizens from the epicenters were convenient samples which could partially represent the internal situations.

    As community outbreaks continued to spread, a wider range of the population exposed to the virus. With the gradual improvement of nucleic acid testing capacity, widespread testing was carried out in some enclosed environments. As expected, poorly quantified presymptomatic admixture disturbed our view of asymptomatic carrier. Only longitudinal studies with a long enough follow-up period could effectively distinguish them. In addition, the demographic characteristics of these samples—cruise ships, nursing facilities (mainly for the elderly), obstetrics (women of childbearing age) and aircraft carriers (healthy young male dominated)—had a significant impact on the proportion of asymptomatic carriers.

    When the exponential growth of cases had been successfully reversed by lockdown and social distancing, longitudinal serial testing data showed the falling asymptomatic infection rates tracked the declining general population infection curve (4).

    At the remission period, substantially all community outbreaks had been contained. New cases persisted to tend to zero. Mass indiscriminate RT-PCR testing was employed to identify hidden asymptomatic carriers to completely interrupt chains of transmission. The results indicated the proportion of asymptomatic carriers diminished dramatically (5).

    In the setting of coexisting global pandemic and local remission, it is wise to rethink about the evidence dynamically and comprehensively rather than stick to the rigid proportion.

     

     

    References

    1. Oran DP, Topol EJ. Prevalence of Asymptomatic SARS-CoV-2 Infection: A Narrative Review. Ann Intern Med. 2020. [PMID:32491919] doi: 10.7326/M20-3012
    2. Bi Q, Wu Y, Mei S, Ye C, Zou X, Zhang Z, et al. Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study. Lancet Infect Dis. 2020. [PMID: 32353347] doi: 10.1016/S1473-3099(20)30287-5
    3. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020. [PMID: 32091533] doi: 10.1001/jama.2020.2648
    4. Treibel TA, Manisty C, Burton M, McKnight A, Lambourne J, Augusto JB, et al. COVID-19: PCR screening of asymptomatic health-care workers at London hospital. Lancet. 2020;395(10237):1608-10. [PMID: 32401714] doi: 10.1016/S0140-6736(20)31100-4
    5. Wuhan Tests Nearly 10 Million People in 19 Days, Finding Just 300 Coronavirus Infections. Associated Press. 03 June 2020. Accessed at time.com/5847226/wuhan-10-million-coronavirus-tests/ on 30 June 2020.
    Andrew N. Cohen, Bruce Kessel1 July 2020
    Problems with review: false positives; inadequate longitudinal study; overly narrow symptom definitions; poor evidence of asymptomatic transmission

    Oran and Topol have not responded to our comments submitted earlier (June 7) nor to some critical comments submitted by others. We write so that four key criticisms are not missed.

    The authors concluded that 40-45% of individuals infected with SARS-CoV-2 are asymptomatic, in the sense of never developing symptoms. The authors state, and we agree, that evidence for the asymptomatic ratio in the general population must be based on (a) cohorts that are representative of the general population, and (b) longitudinal studies that are capable of distinguishing individuals that never develop symptoms from those who are simply presymptomatic at the time of testing. Of the 16 studies covered in the review only three, according to the authors, are of representative cohorts, and of these only one is longitudinal: the study conducted in Vo', Italy (1). Accordingly, we will focus on the Vo' study.

    We previously commented, based on the authors' summary of the Vo' study, that even a low false positive rate could produce enough false positives to account for all of the individuals reported as infected and asymptomatic. We have now examined the data set posted with the Vo' preprint (1), and can provide more detail. At total of 5,220 tests were administered to 2,900 residents, with 131 positive results on samples from 80 residents. 35 residents were classified as both infected and asymptomatic; of these, 25 tested positive only once. With the reported test numbers, a false positive rate of only 0.5% would produce 25 false positive results. Since the median false positive rate in 43 external quality assessments of similar viral diagnostic tests was 2.3% (2), 25 of the 35 residents reported as infected and asymptomatic could easily have been uninfected individuals who received false positive test results.

    We, along with Cevik et al. and Hyde, raised concerns about the inadequacy of the longitudinal studies reviewed. A fully adequate longitudinal study would check for symptoms over the entire period of time in which symptoms could potentially appear. Since an individual can test positive near the beginning of the incubation period, an effective longitudinal study should monitor for symptoms over a period that includes the time from the first positive test to either the first negative test or to the length of the maximum incubation period after the first positive test, whichever comes first. The maximum incubation period for COVID-19 isn't known, but the best fit model indicates that it is over 14 days (3).

    The authors inaccurately characterized the length of time that the Vo' study monitored symptoms. They stated that tests were conducted "at the beginning and end of a 14-day lockdown" and referred to "the roughly 2-week period between the sampling efforts." In responding Cevik et al. the authors described the Vo' study as a "longitudinal...study, complete over 14 days...none of the subjects who were asymptomatic at the beginning of the study had developed symptoms by the end." These statements appear to suggest that symptoms were monitored over 14 or nearly 14 days. However, the Vo' data set shows that 10 of the 35 residents reported as infected and asymptomatic were not tested again after their initial positive test, and thus were not monitored longitudinally at all. Another 9 of the 35 residents weren't monitored until they received a negative test result or until 14 days after their first positive test. Thus a majority of the 35 residents—even assuming they were all infected—may have been presymptomatic rather than asymptomatic.

    Cevik et al. and Hyde argued that the studies reviewed did not consider all relevant symptoms when distinguishing asymptomatic individuals, and we agree. The World Health Organization (WHO) lists 10 symptoms of COVID-19 (4), but the Vo' study classified residents as symptomatic only if they had fever or cough or were hospitalized. Consider one symptom listed by WHO that the Vo' study did not ask about: the loss of taste or smell. Based on the prevalence of this symptom in individuals that tested positive for COVID-19 but did not have fever or cough (5), 8 or 9 of the 35 Vo' residents reported as infected and asymptomatic would be expected to have this symptom.

    Cevik et al., Hyde, and Halperin argued, and we agree, that the evidence for asymptomatic transmission cited by the authors is too weak to support the authors' conclusions that there is a "high risk" of spread by asymptomatic individuals, that "asymptomatic individuals can transmit SARS-CoV-2 to others for an extended period", and that transmission by asymptomatic individuals is a "significant factor in the rapid progression of the COVID-19 pandemic." The authors defended these statements by referring to the Vo' study, which suggested that two individuals may have been infected by contacts that the study identified as asymptomatic and infected, since in each case contact tracing failed to identify an alternative source of infection. However, the strength of that argument depends on how thorough and effective the contact tracing was, which in this study failed to identify any possible source of infection in 25% of the cases traced. Also, as discussed earlier, the individuals identified by the study as potential asymptomatic sources might have been uninfected false positives, or infected but not asymptomatic. These two suggested cases thus seem an inadequate basis for the authors' statements about the risk and significance of asymptomatic transmission.

    References:

    1. Lavezzo E, Franchin E, Ciavarella C, et al. Suppression of COVID-19 outbreak in the municipality of Vo, Italy. Preprint. medRxiv; 2020. https://doi.org/10.1101/2020.04.17.20053157
    2. Cohen AN, Kessel B. False positives in reverse transcription PCR testing for SARS-CoV-2. medRxiv; 2020. https://doi.org/10.1101/2020.04.26.20080911
    3. Linton NM, Kobayashi T, Yang Y, et al. Incubation period and other epidemiological characteristics of 2019 Novel Coronavirus infections with right truncation: a statistical analysis of publicly available case data. J Clin Med. 2020;9:538. [PMID: 32079150] doi:10.3390/jcm9020538
    4. World Health Organization. Coronavirus. https://www.who.int/health-topics/coronavirus#tab=tab_3 (accessed 30 June 2020)
    5. Menni C, Sudre CH, Steves CJ, Ourselin S, Spector TD. Quantifying additional COVID-19 symptoms will save lives. Lancet  2020;395(10241):e107-e108. [PMID: 32505221] doi: 10.1016/S0140-6736(20)31281-2

    Disclosures:

    No conflicts of interest.

    Mostafa M Alfishawy, MD1, Ramazan Azim Okyay, MD2, Amira Elbendary, MBBCh, MSc3, Mohanad M Elfishawi, MD429 June 2020
    Could the MMR Vaccine Offer Cross-protection for Covid-19?

    Dear Editor,

    We have read with enthusiasm the article by Daniel et al.,[1] describing the prevalence of asymptomatic SARS-CoV-2 infection. It draws our attention the interesting finding of the inmates in Arkansas, North Carolina, Ohio and Virginia, in whom 96% of the positively tested patients were asymptomatic. As the authors proposed that this high rate could be due to cross immunity by the betacoronaviruses HCoV-OC43 and HCoV-HKU1 or could be error in data collection, yet, we think that this high rate is related to the compulsory vaccines given to the inmates.

    Given the available data of children being less affected by COVID-19 with significantly lower mortality and no severe cases in 6-10 age range [2], we thought that a childhood vaccine may be also responsible for cross-protection against COVID-19 [3], with Measles, Mumps and Rubella (MMR) vaccine high in the list as a booster dose is scheduled around the age of six.

    Measles vaccine was used as a vector for other Coronaviruses such as Severe Acute Respiratory Syndrome Corona Virus (SARS-Co-V) and also in the Middle East Respiratory Syndrome Coronavirus (MERS-Co-V) where it was able to induce multifunctional T cell response in a mouse model [4].

    Interestingly, Italy suffered from measles outbreaks in the last couple of years. Physicians in Italy have one of the lowest rates of measles vaccination which may be the cause for such high infections among physicians there [5].

    Preliminary data from our  assessment of titres for vaccine-preventable diseases in patients with COVID-19 showed high titres with Measles and variable results with Rubella (data not published yet) hence we started the first study for prevention of COVID-19 with Measles, Mumps and Rubella vaccine in Healthcare workers [NCT04357028].

     References

    1. Oran DP, Topol EJ. Prevalence of Asymptomatic SARS-CoV-2 Infection: A Narrative Review [published online ahead of print, 2020 Jun 3]. Ann Intern Med. 2020;M20-3012. doi:10.7326/M20-3012
    2. Dong Y, Mo X, Hu Y, Qi X, et al. Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China. Pediatrics. 2020 Mar 16. pii: e20200702. doi: 10.1542/peds.2020-0702.
    3. Okyay R, Sahin A, Aguinada R, Tasdogan M. Why are Children Less Affected by COVID-19 ? Could there be an Overlooked Bacterial Co-Infection? EJMO. 2020; 4(1): 104-105 | DOI: 10.14744/ejmo.2020.40743
    4. Bodmer BS, Fiedler AH, Hanauer JRH, et al. Live-attenuated bivalent measles virus-derived vaccines targeting Middle East respiratory syndrome coronavirus induce robust and multifunctional T cell responses against both viruses in an appropriate mouse model. Virology. 2018;521:99–107. doi:10.1016/j.virol.2018.05.028
    5. Genovese C, Picerno IAM, Trimarchi G, et al. Vaccination coverage in healthcare workers: a multicenter cross-sectional study in Italy. J Prev Med Hyg. 2019;60(1):E12–E17. Published 2019 Mar 29. doi:10.15167/2421-4248/jpmh2019.60.1.1097

     

    Daniel Oran, Eric Topal15 July 2020
    Authors' response to Cohen and Kessel

    Cohen and Kessel write, "The authors concluded that 40-45% of individuals infected with SARS-CoV-2 are asymptomatic, in the sense of never developing symptoms."

     No, as we write in our review, "The asymptomatic infection rate may be as high as 40% to 45%. A conservative estimate would be 30% or higher to account for the presymptomatic admixture that has thus far not been adequately quantified."

     Cohen and Kessel write, "Even a low false positive rate could produce enough false positives to account for all of the individuals reported as infected and asymptomatic." The recent experience in Wuhan, where public health officials tested 9.9 million people from 14 May through 1 June, might be instructive. According to the Time Magazine account cited by Yang and Ma in these comments, just 300 positive cases were identified, all of which were asymptomatic. Even if all 300 cases were false positives, that would mean that the false positive rate was 0.003%.  We have no reason to believe that the testing performed in Vo' was significantly different from that performed in Wuhan.

     Cohen and Kessel write, "The authors inaccurately characterized the length of time that the Vo' study monitored symptoms." There was no inaccuracy in our characterization. This is a verbatim quote from the Lavezzo et al. preprint: "Notably, all asymptomatic individuals never developed symptoms, in the interval between the first and the second survey."

     We should note that in the time since we reviewed that preprint, the paper has been accepted for publication in Nature, which has posted an early version of the manuscript online. [1]

     References:

     [1] Lavezzo, E., Franchin, E., Ciavarella, C. et al. Suppression of a SARS-CoV-2 outbreak in the Italian municipality of Vo’. Nature (2020). https://doi.org/10.1038/s41586-020-2488-1

     

     

    Daniel Oran, Eric Topal15 July 2020
    Authors' Response to Yang and Ma

    In describing a SARS-CoV-2 testing effort that included 9.9 million people in Wuhan during the period 14 May through 1 June, Yang and Ma write, "The results indicated the proportion of asymptomatic carriers diminished dramatically."

    In fact, as reported in the Time Magazine account that they cited, the testing "identified just 300 positive cases, all of whom had no symptoms." That is to say, the proportion of asymptomatic carriers was 100%, which means the number had increased relative to previous estimates, not diminished.

     

    Charles Elder17 September 2020
    Helpful review, but provocative conclusions are not supported by the data

    The narrative review by D. Oran and E. Topol (1) catalogues the existing evidence regarding prevalence of asymptomatic SARS-CoV-2 infection and thus provides a useful resource for clinicians and policymakers. However, the authors draw several provocative conclusions that are not supported by the data.

    The authors accurately report that after 2 weeks of quarantine, some sailors on board the U.S.S. Theodore Roosevelt continued to test positive for SARS-CoV-2.  In their discussion the authors state that “the experience aboard the U.S.S. Theodore Roosevelt suggests that they might be able to transmit the virus for longer than 14 days.”  However, the reverse transcription polymerase chain reaction assays commonly used for COVID-19 diagnosis can remain positive for weeks after the onset of symptoms, yet this does not imply that such patients remain infectious.  To the contrary, data suggest that it would be unusual to detect infectious viral particles more than 10 days after illness onset where symptoms have resolved. (2) The author’s key summary point that “asymptomatic persons can transmit SARS-CoV-2 to others for an extended period, perhaps longer than 14 days” does not follow from the U.S.S. Theodore Roosevelt experience, and thus seems misleading.

    The authors site the Vo’, Italy data in support of the concern that transmission of SARS-CoV-2 occurs from asymptomatic individuals.  That such asymptomatic transmission can take place is widely accepted, however the extent to which this is so, and the contribution which this phenomenon makes to the spread of the pandemic, remain uncertain points.  In one analysis from Singapore, pre-symptomatic transmission was implicated in only 6.4% of cases, (3) and in any case, the article by Oran and Topol adds no new information to this discussion.  The statement in their concluding paragraph, “the early data that we have assembled on the prevalence of asymptomatic SARS-CoV-2 infection suggest that this is a significant factor in the rapid progression of the COVID-19 pandemic” likewise seems exaggerated and premature. 

    Much about the SARS-CoV-2 virus remains unknown.  The narrative review by Oran and Topol will serve as a helpful reference. However, scientists can help to balance a public environment already saturated with disinformation and media hype by modeling accurate reporting, prudence, and restraint.

    Daniel P. Oran, AM and Eric J. Topol, MD21 September 2020
    Authors' Response to Elder

    We assembled the data in our review in April and May of this year, beginning about three months after the first reports of illness caused by a novel coronavirus. The review, published on June 4, was our best effort to present and interpret those early data. In our opinion, the review scrupulously adheres to the "accurate reporting, prudence, and restraint" suggested by Elder.

    Like so much else with SARS-CoV-2, the finer points of infectiousness and asymptomatic transmission are, as of this writing, hardly settled matters.

    According to the CDC, "Recovery of replication-competent virus between 10 and 20 days after symptom onset has been documented in some persons with severe COVID-19 that, in some cases, was complicated by immunocompromised state." [1]

    An analysis of the outbreak aboard the Diamond Princess cruise ship concluded, "Asymptomatic individuals were the source for 69% (20-85%) of all infections." [2]

    References

    [1] Centers for Disease Control and Prevention. Duration of isolation & precautions for adults. Sept. 10, 2020.

    https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html

    [2] Emery JC, Russell TW, Liu Y, et al. The contribution of asymptomatic SARS-CoV-2 infections to transmission on the Diamond Princess cruise ship. eLife. Aug 24, 2020.

    https://elifesciences.org/articles/58699