Covid: asymptomatic cases, a review

 

A recent systematic review documented the high proportion of patients with SARS-CoV-2 infection who are asymptomatic (see covid asymptomatic system review AIM2021 in dropbox, or doi:10.7326/M20-6976)

 

Details: 

-- 61 studies were identified, 43 using PCR testing of nasopharyngeal swabs, 18 using antibody testing

-- 14 studies had longitudinal data that reported the evolution of symptoms

    --it is  very important to differentiate those truly “asymptomatic” from those who are ”presymptomatic”, since clinical  SARS-CoV-2 infections are typically asymptomatic in the beginning but those infected later develop symptoms.  “Asymptomatic” refers to people who remain without symptoms for at least 14 days

 

Results: 

-- PCR studies:

    -- 19 studies had longitudinal data on symptoms, with 14 providing information on the evolution of whether they subsequently developed symptoms

    -- proportion of persons who tested positive and remained asymptomatic ranged from 11.1% to 100%, median 72.3% (interquartile range, IQR 56.7%-89.7%) [the interquartile range is the middle 50% of values, ranging from the 25^th to the 75^th percentile]

    -- 4 of the studies (England, Iceland, and Indiana) had representative population samples and found that 43.0% to 76.5% of people had no symptoms at the time of testing, with median of 45.6% (IQR 43.6% to 61.8%).

        -- unfortunately, these studies did not have longitudinal followup, so unclear if these were asymptomatic or presymptomatic

        --but, from the data above from the 14 studies, a median of 72.3% who tested positive by PCR who were asymptomatic at testing and remained so, would suggest that about 72.3% of the 45.6% who had no symptoms at time of testing might remain asymptomatic (ie, about 33%)

 

-- antibody testing:

    -- 18 studies, 6 used random selection of participants to achieve a representative sample

        -- proportion of persons who tested positive but did not report having had symptoms ranged from 21.7% to 47.3% with a median of 32.7% (IQR 28.7%-43.4%)

    -- the highest quality data came from the 2 largest studies in England (365,104) people and Spain (61,075 people) which found that asymptomatic SARS-CoV-2  infection rate was 32.4% in England and 33.0% in Spain [pretty strikingly similar numbers…]

  

 

Commentary:

-- this systematic review did not include a meta-analysis since the studies were so disparate that the authors felt they could not elicit a quantitative summary (as done in meta-analyses), and instead provided a range of results

-- other blogs have reviewed some of the articles on asymptomatic infections: eg see http://gmodestmedblogs.blogspot.com/2020/08/covid-asymptomatic-people-have-high.html , which also found that some asymptomatic patients have very high viral loads and therefore might have quite transmissible virus. (other studies have found lower viral loads in some patients with mild infections)

--another blog reviewed an Antarctic cruise ship which had pretty impressive epidemiologic data, and found lots of asymptomatic SARS-CoV-2 (81%!!) and pretty clear asymptomatic transmission: see http://gmodestmedblogs.blogspot.com/2020/06/covid-asymptomatic-infections-and-viral.html

-- a Chinese study also found a 33% rate of asymptomatic infections

-- a recent nursing home study noted high levels of asymptomatic infections, on the order of 60-80%, and noted the recent decrease in cases of covid is perhaps best explained by herd immunity (see http://gmodestmedblogs.blogspot.com/2021/05/covid-herd-immunity-in-nursing-homes.html )

 

Limitations:

-- as with any systematic review (or meta-analysis for that matter), they are including studies that have very different populations, different outcomes measured, different times that these outcomes were measured (and the disease may change over time because of different prevalences, mutations, treatments, or even human biases that might evolve over time). Therefore, the summary data may obscure how disparate the studies were and challenge the accuracy of the analysis. It is notable, however, how consistently high the number of asymptomatic patients were over the diverse studies.

-- there are issues/concerns regarding the antibody test:

    -- these likely reflect older infections, so a positive antibody without symptoms is highly suggestive of an asymptomatic infection

    -- but, some patients who have clinical SARS-CoV-2 infections never develop detectable antibodies, perhaps because the infection was without an adaptive immune response. There also may be a role in mucosal immunity in clearing infection, though IgA antibodies are not routinely assessed

        -- a Swiss study, for example, found that antibodies remain negative or became positive 12 to 14 days after symptom onset

    -- this lack of antibodies, especially common in those with milder infections (and probably also in those who are asymptomatic) would likely underestimate asymptomatic disease. the above data suggests that the percentage of  those with asymptomatic disease ascertained by antibody testing may be lower than by PCR testing

    -- defining symptoms of Covid in those with positive antibody tests may not be so accurate:

        -- this may require recall of symptoms many months prior, and minor symptoms may not be remembered, falsely raising the reported % of asymptomatic infections

        -- but, the contrary might also happen, where patients might have mild symptoms from another viral upper respiratory infection and misidentified as covid infection because of heightened covid awareness. And falsely lowering the reported % of asymptomatic infections

--this study does not address transmissibility of infection from those with asymptomatic infection, which has been reported as noted above, though hard to know the rate, given the lack of large-scale community data on asymptomatic infections and longitudinal followup

 

So, this study does add some numbers to the incidence of asymptomatic disease, suggesting (as we knew) that it is quite common, with some clear implications:

--our estimates of covid cases clearly underestimates the true number, since asymptomatics typically are not counted

--the lack of clear numbers of asymptomatic infections blunts our ability to determine what is “herd immunity” in different populations . herd immunity may be different with different SARS-CoV-2 variants, some of which may be more transmissible and require a higher population immunity by prior infection (including asymptomatic) plus vaccination rates to achieve sufficient population immunity to progressively decrease infection prevalence

--this asymptomatic cohort can continue to be a source of viral transmission (and this may well happen in those vaccinated, though not clear in the literature). Which does suggest that mask wearing may still be useful in those vaccinated but in higher risk situations (indoors, closed windows/doors) and in higher risk people (comorbidities, or older age). Though it is clear that vaccination is the primary way to decrease our current scourge: see http://gmodestmedblogs.blogspot.com/2021/05/covid-herd-immunity-in-nursing-homes.html

 

geoff

 

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