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The Proportion of SARS-CoV-2 Infections That Are Asymptomatic
A Systematic Review
Daniel P. Oran, AM, and Eric J. Topol, MD
Background: Asymptomatic infection seems to be a nota
ble feature of severe acute respiratory syndrome coronavirus
2 (SARS CoV 2), the pathogen that causes coronavirus dis
ease 2019 (COVID 19), but the prevalence is uncertain.
Purpose: To estimate the proportion of persons infected
with SARS CoV 2 who never develop symptoms.
Data Sources: Searches of Google News, Google Scholar,
medRxiv, and PubMed using the keywords antibodies ,asymp
tomatic ,coronavirus ,COVID 19 ,PCR,seroprevalence ,a n d
SARS CoV 2 .
Study Selection: Observational, descriptive studies and reports
of mass screening for SARS CoV 2 that were either cross sectional
or longitudinal in design; were p ublished through 17 November
2020; and involved SARS CoV 2 nucleic acid or antibody testingof a target population, regardless of current symptomatic status,
over a de fined period.
Data Extraction: The authors collaboratively extracted data
on the study design, type of testing performed, number of
participants, criteria for determining symptomatic status, testing results, and setting.
Data Synthesis: Sixty one eligible studies and reports were
identi fied, of which 43 used polymerase chain reaction (PCR)
testing of nasopharyngeal swabs to detect current SARSCoV 2 infection and 18 used antibody testing to detect current or prior infection. In the 14 studies with longitudinaldata that reported information on the evolution of sympto
matic status, nearly three quarters of persons who tested
positive but had no symptoms at the time of testing remainedasymptomatic. The highest quality evidence comes from nationwide, representative serosurveys of England ( n365 104) and
Spain ( n61 075), which suggest that at least one third of
SARS CoV 2 infections are asymptomatic.
Limitation: For PCR based studies, data are limited to distin
guish presymptomatic from asymp tomatic infection. Heterogeneity
precluded formal quantitative syntheses.
Conclusion: Available data suggest that at least one third of
SARS CoV 2 infections are asymp tomatic. Longitudinal studies
suggest that nearly three quarters of persons who receive a positive PCR test result but have no symptoms at the time of testingwill remain asymptomatic. Control strategies for COVID 19 should
be altered, taking into account the prevalence and transmission
risk of asymptomatic SARS CoV 2 infection.
Primary Funding Source: National Institutes of Health.
Ann Intern Med. 2021;174:655-662. doi:10.7326/M20-6976 Annals.org
For author, article, and disclosure information, see end of text.
This article was published at Annals.org on 22 January 2021.
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, anasymptomatic carrier state h as not been documented for
measles virus infection (2), whereas a signi ficant propor
tion of persons with cytomegalovirus or poliovirus infection have no symptoms and are unaware of infection (3,4). The asymptomatic fraction of severe acute respiratorysyndrome coronavirus 2 (SARS CoV 2) infection seems tobe sizable (5). The range of severity of illness associatedwith SARS CoV 2 infection is noteworthy because itspans asymptomatic infection; mild illness; and severe,life threatening illness.
Perhaps because of this broad spectrum of presenta
tion, the topic of asymptomatic SARS CoV 2 infection has
generated some controversy (6). Imprecise use of theterm “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 posi
tive test result but who eventually develop symptoms. Weknow 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 14days 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 asymptomaticSARS CoV 2 infection (5). Since then, considerable new
data have become available. The present review summa
rizes currently available data that might allow us to
estimate the proportion of persons infected with SARS
CoV 2 who are asymptomatic.
METHODS
Data Sources, Search Terms, and Study Selection
Using the keywords antibodies ,asymptomatic, corona
virus,COVID 19, PCR,seroprevalence ,a n d SARS CoV 2,
we periodically searched Google News, Google Scholar,
m e d R x i v ,a n dP u b M e df o ro b s e r v a t i o n a l ,d e s c r i p t i v es t u d
ies and reports of mass screening for SARS CoV 2 that
were either cross sectional or longitudinal in design; were
published through 17 No vember 2020; and involved
SARS CoV 2 nucleic acid or antibody testing of a targetpopulation, regardless of cu rrent symptomatic status, over
ad efined period.
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Data Extraction and Quality Assessment
We recorded the total number of persons tested, the
number that tested positive, the number of positive
cases without symptoms, the criteria for determining
symptomatic status, whether the data were crosssectional or longitudinal in nature, whether randomselection techniques were used to achieve a representative sample of a target population, and whether the testing involved polymerase chain reaction (PCR) analysis ofa nasopharyngeal swab or serologic analysis of antibodies in a blood sample. For longitudinal studies that provided information on the evolution of symptomaticstatus, we recorded the proportion of persons whotested positive but had no symptoms at the time of testing and who then remained asymptomatic during a follow up period. In addition, we flagged studies that
required clari fication of ambiguous details.
Studies or reports that are based on PCR results and
include only cross sectional data do not make it possibleto distinguish between presymptomatic and asymptomatic SARS CoV 2 infection because symptomatic status isobserved on only 1 occasion, which may occur beforethe development of symptoms, if any. In contrast, we candistinguish between presymptomatic and asymptomaticinfection with either antibody based studies, in which aninterview or questionnaire gathers information aboutsymptoms reported at the time a blood sample is takenand during a prior period, or PCR based studies thatinclude longitudinal data.
In assessing quality, we put the greatest emphasis on
random selection of participants to achieve a representa
tive sample of a regional or national population, a large
number of study participants ( n>1 0 0 0 0 ) ,a n ds t u d y
designs that make it possible to distinguish between presymptomatic and asymptomatic infection. Evaluated inthis manner, the highest quality evidence comes fromlarge scale, national studies with representative samplesthat include data from either antibody or longitudinalPCR testing. In Tables 1 and2,w es h o wi nb o l d f a c et h e
details that increase a study's likelihood of providinghigher quality evidence.
Data Synthesis and Analysis
We synthesized evidence qualitatively by evaluating
study design, including whether data were collected lon
gitudinally; testing methods; number of participants;and setting. We compared the range and consistency ofestimates of the proportion of persons who tested positive but had no symptoms at the time of testing.
Role of the Funding Source
The National Institutes of Health played no role in
the design, conduct, or analysis of this review or in the
decision to submit the manuscript for publication.
RESULTS
We identi fied 61 studies or reports that met eligibility
criteria. Table 1 (10 54) summarizes data from the 43
that used PCR testing, and Table 2 (55 72) summarizes
data from the 18 that used antibody testing. Theheterogeneity of the studies in particular, disparate set
tings and populations precluded quantitative summa
ries using meta analysis. We summarize the evidence in
terms of the number of studies and the range, median,
and interquartile range (IQR) for persons who tested pos
itive but had no symptoms at the time of PCR testing orwho reported having had no symptoms before or at the
time of antibody testing. Thirty of the studies included a
list of speci fic symptoms, independent of signs, used to
determine symptomatic status (10 14, 17, 18, 22 28, 35,
36, 38, 42, 49, 51, 55 57, 60 62, 64). Many of the remaining studies used some variation of the catch all phrase“symptoms compatible with COVID 19. ”
Nucleic Acid PCR Testing
Among the 43 studies using PCR testing (10 54), the
proportion of persons who tested positive but had no
symptoms at the time of testing ranged from 6.3% to
100%, with a median of 65.9% (IQR, 42.8% to 87.0%).
Nineteen of the PCR based studies collected data on
symptoms longitudinally after testing, making it possible
to distinguish between presymptomatic and asymptom
atic infection (15, 17, 18, 20, 22, 25, 26, 27, 32, 37 40,
45, 47, 48, 51, 53, 54). The follow up period in thesestudies ranged from 2 to 70 days, with a median of 14days (IQR, 14.0 to 15.8 days). The proportion of persons
who tested positive and remained asymptomatic ranged
from 6.3% to 91.7%, with a median of 42.5% (IQR, 29.6%to 77.8%).
Of the 19 longitudinal studies, 14 provided informa
tion on the evolution of symptomatic status ( Table 3 )( 1 5 ,
17, 18, 20, 22, 32, 37 40, 47, 51, 53, 54). Among personswho tested positive but had no symptoms at the time of
testing, the proportion who remained asymptomatic dur
ing a follow up period ranged from 11.1% to 100%, witha median of 72.3% (IQR, 56.7% to 89.7%).
Of the 43 studies that used PCR testing, 24 collected
cross sectional data and reported only the symptomaticstatus at the time of testing, so we could not distinguishbetween presymptomatic and asymptomatic cases (10
14, 16, 19, 21, 23, 24, 28 31, 33 36, 41 44, 46, 49, 50,
52). In these studies, the proportion of persons whotested positive but had no symptoms at the time of test
ing ranged from 40.7% to 100%, with a median of 75.5%
(IQR, 50.3% to 86.2%).
Of the 43 studies that used PCR testing, 4 used ran
dom selection of participants to achieve a representative
sample of their target population: residents of England
(1012, 14), Iceland (16), or Indiana (23). Proportions of
persons who tested positive but had no symptoms at the
time of testing ranged from 43.0% to 76.5%, with a me
dian of 45.6% (IQR, 43.6% to 61.8%). None of the PCRtesting studies that used random selection of participants
collected longitudinal data on symptoms, so we could
not distinguish between presymptomatic and asymptomatic cases.
T h el a r g e s to ft h er e p r e s e n t a t i v ed a t as e t s ,a n dt h e
largest study identi fied in our search, was from the REACT
(Real time Assessment of Community Transmission) pro
gram. REACT has implemented nationwide nucleic acid
and antib od
y testing (discussed later) for SARS CoV 2 ofREVIEW The Proportion of SARS CoV 2 Infections That Are Asymptomatic
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persons in England aged 5 years and older in multiple
phases since May 2020 (10 12). In Table 1 ,w eh a v ec o m
bined the results of 6 phases of nucleic acid testing fromREACT, yielding data for 932 072 persons (England residents 1). At the time of testing, 1425 of 3029 persons(47.0%) who tested positive had no symptoms. The studydid not collect longitudinal data on symptoms, so we couldnot distinguish between presymptomatic and asymptomatic cases.
The second largest of the representative studies was
also from England; it included 36 061 persons testedbetween 26 April and 27 June 2020 (14). The proportionof persons who tested positive was 0.3%, identical to thatreported by REACT, but the proportion of persons whotested positive but had no symptoms at the time oftesting was 74.8%, much larger than in the REACT study.The study did not collect longitudinal data on symptoms,so we could not distinguish between presymptomaticand asymptomatic cases.
In the cross sectional study of Belgian long term care
facilities ( n= 280 427), age did not seem to affect the
proportion of persons who tested positive but had nosymptoms at the time of testing (13). The study tested138 327 staff and 142 100 residents. Median age was 42years for staff and 85 years for residents; despite this considerable difference, the proportion of those who testedpositive without symptoms was 74.0% for staff and75.3% for residents. This finding is consonant with the
finding of a longitudinal study from Vo ’, Italy, in which
more than 85% of the town's 3275 residents were tested:
Table 1. Nucleic Acid PCR Testing
Study or Report Tested, n* Longitudinal
Data*Random
Sampling*SARS-CoV-2 –
Positive, n(%)Positive, but NoSymptoms, n (%)
England residents 1 (10-12) 932 072 No Yes 3029 (0.3) 1425 (47.0)
Belgium long-term care facility residents and staff (13) 280 427 No No 8343 (3.0) 6244 (74.8)
England residents 2 (14) 36 061 No Yes 115 (0.3) 88 (76.5)
U.S. skilled-nursing facility residents (15) † 22 368 Yes No 5403 (24.2) 2194 (40.6)
Iceland residents (16) 13 080 No Yes 100 (0.8) 43 (43.0)
Vo’, Italy, residents (17) 5155 Yes No 102 (2.0) 34 (42.5)
U.S. Navy aircraft carrier crew (18) 4779 Yes No 1271 (26.6) 572 (45.0)
Arkansas, North Carolina, Ohio, and Virginia inmates (19) 4693 No No 3277 (69.8) 3146 (96.0)
San Francisco, California, residents (20) 3871 Yes No 83 (2.1) 23 (27.7)
Arkansas poultry plant employees (21) 3748 No No 481 (12.8) 455 (94.6)
Diamond Princess cruise ship passengers and crew (22) 3618 Yes No 712 (19.7) 311 (43.7)
Indiana residents (23) †‡ 3605 No Yes 47 (1.7) 18 (44.2)
South London, England, nursing home residents and staff (24) 2455 No No 160 (6.5) 115 (71.9)
U.S. Marine recruits (25) 1801 Yes No 51 (2.8) 46 (90.2)
Charles de Gaulle aircraft carrier crew (26) 1568 Yes No 1001 (63.8) 130 (13.0)
Marseille, France, long-term care facility residents (27) 1691 Yes No 226 (13.4) 46 (23.0)
King County, Washington, homeless shelter residents and staff (28) 1434 No No 29 (2.0) 21 (72.4)
Germany oncology clinic patients (29) 1286 No No 40 (3.1) 37 (92.5)
Pasadena, California, long-term care facilities residents and staff (30) 938 No No 631 (67.3) 257 (40.7)
Rutgers University students and employees (31) 829 No No 41 (4.9) 27 (65.9)
Greek citizens evacuated from the United Kingdom, Spain, and Turkey (32) † 783 Yes No 40 (5.1) 35 (87.5)
Boston, Massachusetts, obstetric patients (33) 757 No No 20 (2.6) 9 (45.0)
Córdoba, Colombia, residents (34) 686 No No 35 (5.1) 18 (51.4)
New York City obstetric patients 1 (35) 675 No No 70 (10.4) 55 (78.6)
Santiago, Chile, obstetric patients (36) 586 No No 37 (6.3) 16 (43.2)
Japanese citizens evacuated from Wuhan, China (37) 564 Yes No 11 (2.0) 3 (27.3)
London nursing home residents and staff (38) 518 Yes No 158 (30.5) 72 (45.6)
Indian citizens evacuated from Iran (39) 474 Yes No 48 (10.1) 44 (91.7)
Maryland long-term care facility residents (40) 426 Yes No 177 (41.5) 154 (87.0)
South India retinal surgery patients (41) 413 No No 9 (2.2) 9 (100.0)
Boston homeless shelter occupants (42) 408 No No 147 (36.0) 129 (87.8)
Seafood plant employees (43)§ 376 No No 124 (33.0) 118 (95.0)
Genoa, Italy, obstetric patients (44) 333 No No 7 (2.1) 6 (85.7)
London maternity hospital staff (45) 266 Yes No 47 (17.7) 16 (34.0)
Argentine cruise ship passengers and crew (46) 217 No No 128 (59.0) 104 (81.3)
New York City obstetric patients 2 (47) 214 Yes No 33 (15.4) 29
(87.9)
Bogotá, Colombia, airport employees (48) 212 Yes No 35 (16.5) 24 (68.6)
Porto, Portugal, obstetric patients (49) 184 No No 11 (6.0) 9 (81.8)
Los Angeles, California, homeless shelter occupants (50) 178 No No 43 (24.2) 27 (62.8)
Illinois skilled-nursing facility residents (51) 126 Yes No 33 (26.2) 13 (39.4)
Boston grocery store employees (52) 104 No No 21 (20.2) 16 (76.2)
Los Angeles skilled-nursing facility residents (53) 99 Yes No 19 (19.2) 6 (31.6)
King County nursing facility residents (54) 76 Yes No 48 (63.2) 3 (6.3)
PCR = polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
* Boldface indicates details that increase the likelihood of higher-quality evidence.
†Data clari fied via personal communication with coauthor.
‡Percentages re flect weighting by the study's authors to estimate statewide prevalence.
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“Among con firmed SARS CoV 2 infections, we did not
observe signi ficant differences in the frequency of asymp
tomatic infection between age groups ”(17).
Of the 43 studies that used PCR testing, 21 involved
high density living or working environments, such as
nursing homes and factories (13, 15, 18, 19, 21, 22, 2428, 30, 38, 40, 42, 46, 50, 51, 53, 54). The settings withthe highest proportion of persons who tested positivewithout symptoms included prisons (19) and poultryprocessing plants (21). Yet, the data seem to be insuf fi
cient to conclude that setting was a causative factor. In
the 21 studies of high density environments, the propor
tion of persons who tested positive but had no symptoms at the time of testing ranged from 6.3% to 96.0%,with a median of 62.8% (IQR, 40.6% to 87.0%). In theremaining 22 studies that did not involve such highdensity environments, the proportion ranged from27.3% to 100%, with a median of 67.2% (IQR, 43.5% to84.7%).Antibody Testing
In the 18 studies based on antibody testing ( Table 2 )
(5572), the proportion of persons who tested positive
but did not report having had symptoms ranged from
21.7% to 85.0%, with a median of 41.2% (IQR, 32.6% to48.1%).
Among the 18 antibody testing studies, 6 used ran
dom selection of participants to achieve a representativesample of their target population: residents of England
(55); Spain (56); Bavaria, Germany (59); Louisiana (60);
Maranhão, Brazil (64); or Connecticut (68). In these antibody studies with representative samples, the proportion of persons who tested positive but did not reporthaving had symptoms ranged from 21.7% to 47.3%, with
a median of 32.7% (IQR, 28.7% to 43.4%).
The 2 largest studies based on antibody testing were
nationwide serosurveys from England (55) and Spain
(56), both designed to achieve representative samples of
Table 3. Evolution of Symptomatic Status
Study Initially Tested
Positive Without
Symptoms, nRemained
Asymptomatic,
n(%)
U.S. skilled-nursing facility residents (15) 3227 2194 (68.0)
Vo’, Italy, residents (17) 34 34 (100.0)
U.S. Navy aircraft carrier crew (18) 978 572 (58.5)San Francisco, California, residents (20) 41 23 (56.1)Diamond Princess cruise ship passengers and crew (22) 410 311 (75.9)
Greek citizens evacuated from the United Kingdom, Spain, and Turkey (32)* 39 35 (89.7)
Japanese citizens evacuated from Wuhan, China (37) 6 3 (50.0)
London, England, nursing home residents and staff (38) 67 46 (68.7)Indian citizens evacuated from Iran (39) 44 44 (100.0)Maryland long-term care facility residents (40) 177 154 (87.0)
New York City obstetric patients 2 (47) 29 26 (89.7)
Illinois skilled-nursing facility residents (51) 14 13 (92.9)Los Angeles, California, skilled-nursing facility residents (53) 14 6 (42.9)King County, Washington, nursing facility residents (54) 27 3 (11.1)
* Data clari fied via personal communication with coauthor.Table 2. Antibody Testing
Study or Report Tested,
n*RandomSampling*SARS-CoV-2 –
Positive, n(%)Asymptomatic,n(%)
England residents (55) 365 104 Yes 17 576 (4.8) 5694 (32.4)
Spain residents (56) 61 075 Yes 3053 (5.0) 1008 (33.0)
Detroit, Michigan, hospital staff (57) 20 614 No 1818 (8.8) 798 (43.9)
Wuhan, China, hospital staff (58) 8553 No 424 (5.0) 148 (34.9)
Bavaria, Germany, children aged 1 –18 y (59) 4859 Yes 47 (1.0) 22 (46.8)
Louisiana residents (60) 4778 Yes 311 (6.5) 147 (47.3)
Munich, Germany, hospital staff (61) 4554 No 108 (2.4) 28 (25.9)
Cairo, Egypt, hospital staff (62) 4040 No 170 (4.2) 116 (68.2)
Health care personnel at 13 U.S. medical centers (63) 3248 No 194 (6.0) 56 (28.9)
Maranhão, Brazil, residents (64) 3156 Yes 1167 (37.0) 320 (27.4)
Ischgl, Austria, residents (65) 1473 No 622 (42.2) 529 (85.0)
Wuhan dialysis patients (66) 1027 No 99 (9.6) 50 (50.5)
Buenos Aires, Argentina, residents (67) 873 No 466 (53.4) 396 (85.0)
Connecticut residents (68) 567 Yes 23 (4.1) 5 (21.7)
Sweden nursing home staff (69) 459 No 86 (18.7) 40 (46.5)
London, England, dialysis patients (70) 356 No 129 (36.2) 52 (40.3)
Nashville, Tennessee, hospital staff (71) 249 No 19 (7.6) 8 (42.1)
London maternity unit staff (72) 200 No 29 (14.5) 10 (34.5)
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
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community dwelling persons. The English data, from the
REACT program described earlier, were collected during
3 rounds of testing from June through September 2020
and include 365 104 persons. The Spanish data were collected 27 April to 11 May 2020 and include 61 075 persons. The proportion of persons who tested positive butdid not report having had symptoms was 32.4% inEngland and 33.0% in Spain.
DISCUSSION
Symptom detection relies on the subjective reports
of patients (73). For example, anosmia has turned out tobe a distinctive symptom of COVID 19 (74), and wedepend on patients to perceive and report a diminution,however slight, of their normal olfactory abilities. Butsuch self reports are in fluenced by many factors, includ
ing 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 asymp
tomatic persons account for more than 40% of all
SARS CoV 2 transmission (75 77). The proportion of
new infections caused by asymptomatic persons aloneis uncertain, but when researchers in Wanzhou, China,analyzed epidemiologic data for “183 con firmed 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, caused19.3% of infections (78).
The 61 studies and reports that we have collected
provide compelling evidence that the asymptomaticfraction of SARS CoV 2 infection is sizable. These dataenable 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 theymay accurately re flect 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 testedpositive but had no symptoms at the time of testingranged from 43.0% to 76.5%, with a median of 45.6%(IQR, 43.6% to 61.8%). However, these studies fall shortof providing the highest quality evidence because theycollected only cross sectional data. As a result, we cannotdistinguish 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, inwhich 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 stud
ies using antibody testing that were designed to achieverepresentative samples of nationwide populations inEngland (n = 365 104) (55) and Spain ( n= 61 075) (56). It is
remarkable that these independently conducted serosur
veys yielded nearly identic al proportions of asymptomatic
SARS CoV 2 infections: 32.4% in England and 33.0% inSpain.
We may infer that persons who receive positive anti
body test results can be classi fied accurately as asymp
tomatic because such results are likely to occur only afterthe onset of symptoms, if any. In a study of 222 hospital
ized patients in Wuhan, China, IgM and IgG antibodies
to SARS CoV 2 were first detected 3 and 4 days, respec
tively, after symptomatic onset of COVID 19 (79). In astudy 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 de
tectable 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 duringthe period when it is uncertain whether an infected per
son is presymptomatic or asymptomatic.
However, serosurveys do have signi ficant limitations
for the purpose of estimating the asymptomatic fraction.
Not all persons who are believed to have been infected
withSA
RS CoV 2 later have a positive result for SARS
CoV 2 antibodies (81). The reasons may include a falsepositive result on the initial PCR test; a false negative
result on the antibody test; or the absence of detectableantibodies, perhaps because the infection was cleared
without requiring adaptive immunity. In addition, the
role of mucosal immunity in clearing SARS CoV 2 infec
tion has not yet been fully elucidated (82), and a nasal
wash to detect the IgA antibodies active in mucosal im
munity is not part of standard testing practice. Persons
who clear SARS CoV 2 infection through innate or muco
sal 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 asymp
tomatic fraction.
Another limitation of serosurveys is the requirement
that an interview or questionnaire about symptomaticstatus 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 pan
demic that has transformed everyday life around the
globe, it seems reasonable to hypothesize that aware
ness of and memory for symptoms possibly related to
COVID 19 are heightened. This might result in a greater
likelihood of noticing and reporting symptoms thatwould otherwise be missed or ignored, thereby leading
to a lower estimate of the asymptomatic fraction. For
these reasons, we have evaluated serosurveys in the con
text 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 con firm this estimate, large scaleThe Proportion of SARS CoV 2 Infections That Are Asymptomatic REVIEW
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longitudinal studies using PCR testing with representa
tive samples of national populations would be useful. AsSARS CoV 2 vaccination campaigns are implementedworldwide, though, the window for such research maybe closing.
In light of the data presented here, we believe that
COVID 19 control strategies must be altered, taking intoaccount the prevalence and transmission risk of asymptomatic SARS CoV 2 infection. Frequent, inexpensive,rapid home tests (83) to identify and contain presympto
matic or asymptomatic cases along with government pro
grams 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 beneeded to determine their ef ficacy in preventing asymp
tomatic infection (85).
From Scripps Research Translational Institute, La Jolla,
California (D.P.O., E.J.T.).
Grant Support: By grant UL1TR002550 from the National
Institutes of Health.
Disclosures: Authors have disclosed no con flicts of interest.
Forms can be viewed at www.acponline.org/authors/icmje/Con flictOfInterestForms.do?msNum M20 6976.
Reproducible Research Statement: Study protocol and statisti
cal code: Not applicable. Data set: All of the data on which the
authors based their analysis have been published with thisreview.
Corresponding Author: Eric J. Topol, MD, Scripps Research
Translational Institute, 3344 North Torrey Pines Court, 3rdFloor, La Jolla, CA 92037; e mail, [email protected].
Current author addresses and author contributions are avail
able at Annals.org.
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Current Author Addresses: Mr. Oran and Dr. Topol: Scripps
Research Translational Institute, 3344 North Torrey Pines Court,
3rd Floor, La Jolla, CA 92037.Author Contributions: Conception and design: D.P. Oran, E J.
Topol.Analysis and interpretation of the data: D.P. Oran, E.J. Topol.Drafting of the article: D.P. Oran, E.J. Topol.Critical revision of the article for important intellectual content:D.P. Oran, E.J. Topol.Final approval of the article: D.P. Oran, E J. Topol.Statistical expertise: D.P. Oran.Obtaining of funding: E.J. Topol.Administrative, technical, or logistic support: D.P. Oran, E J.
Topol.
Collection and assembly of data: D.P. Oran, E.J. Topol.
Annals.org Annals of Internal Medicine •Vol. 174 No. 5 •May 2021
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