COVID: asymptomatic patient immune/inflammatory responses

A study of a small group of persistently asymptomatic SARS-CoV-2 patients in China found that they had median duration of viral shedding by PCR longer than those who were symptomatic, and lower cytokine levels and long-term antibody responses, many becoming IgG seronegative (see covid asx clinical immunol naturemed2020 in dropbox, or https://www.nature.com/articles/s41591-020-0965-6.pdf)

 

Details:

-- 37 asymptomatic individuals in the Wanzhou District in China were diagnosed with PCR-confirmed SARS-CoV-2 infection, but without symptoms in the preceding 14 days and during hospitalization

-- these individuals were found through extensive PCR screening of 2088 close contacts under quarantine

-- median age 41, 22 of the 37 were female

-- no statistically significant differences in comorbidities: 30% had some comorbidity, with hypertension 16%, cardiovascular disease 3%, diabetes 6%, chronic kidney disease 1%, liver disease 5%

-- labs in asymptomatic patients: LFTs abnormal in 32%, temperature 36.5°C, heart rate 82, mean arterial pressure 95 mmHg, lymphocyte count 1.7, platelets 211K, pro-time 13, d-dimer 0.4, creatinine 60 µmol/L (normal), LDH 154, calcitonin 0.02, ferritin 22, CRP 1.5, hypersensitive troponin-I 0.005 (there were a few individuals with abnormal results, but the medians above were all normal)

-- chest CT found groundglass opacities in 11 of the 37 (30%), stripe shadows/diffuse consolidation in 10 (27%) and 43% had no abnormalities. However 5 individuals developed focal groundglass opacities or stripe shadows within 5 days of hospital admission

-- 28 had a confirmed history of contact with a PCR-confirmed patient with Covid-19, and 9 were from the Wuhan area

    -- of those who had positive PCR results, 60 had no symptoms in the preceding 14 days and were transferred to a governmental hospital for centralized isolation

    -- 17 were excluded from mild or atypical symptoms, 6 develop symptoms 4-17 days after admission: leaving 37 people, excluding these 2 groups

-- these 37 patients were compared to 37 sex, age, and comorbidity-matched mildly symptomatic patients for comparison of antibody and cytokine measurements

-- they were also compared to 37 sex and age-matched control groups with negative PCR for cytokine comparisons

 

Results:

-- the initial PCR Ct values (inverse of viral load) was similar in asymptomatic and symptomatic patients, in the 32 range

-- median duration of viral shedding was 19 days, vs 14 days in the symptomatic group, p=0.028 (viral shedding was defined as interval from 1^st to last positive nasopharyngeal swab for PCR, with a range of 6 to 45 days) [though, importantly, viral shedding by PCR does not imply transmissibility]

-- acute phase (3-4 weeks after exposure):

    -- virus-specific IgG levels in the asymptomatic group 81% vs in 84% of symptomatic patients (though the levels were much higher in the symptomatic group); 62% and 78% respectively had detectable IgM

-- early convalescent phase (8 weeks after hospital discharge):

    -- IgG antibody levels: levels still higher in symptomatic people though there were reductions in 93% (by a median of 71%) of asymptomatic vs 97% (by a median of 76%) of symptomatic patients

        -- 40% of asymptomatic people became seronegative for IgG, vs 13% of symptomatic ones

    -- neutralizing antibodies: 81% had reduction in asymptomatic patients (median reduction of 8%), vs 62% of symptomatic patients (median reduction of 12%)

--asymptomatic patients also had lower levels of 18 pro-and anti-inflammatory cytokines, especially in 5 of those tested, including IL-6 (ie, asymptomatic patients had a muted inflammatory response)

 

Commentary:

-- there is a paucity of data on the characteristics of asymptomatic SARS-CoV-2 patients, despite the fact that these individuals may be able to spread the virus efficiently and may be a continuing vector for the continuation of the pandemic

-- the data on the prevalence of asymptomatic patients varies tremendously from study to study. In this time period in Wanzhou, a total of 178 patients with confirmed SARS-CoV-2 infections were found, so these 37 represented 21% of the group. this all suggests:

    -- there really needs to be large studies of the prevalence of asymptomatic patients with SARS-CoV-2 infection in the general population, in different situations with different prevalences of Covid-19 disease.

    -- one issue is how reliable the SARS-CoV-2 PCR is for these patients. We do know that there are large numbers of false negative tests in those symptomatic varying by times after the onset of symptoms (see http://gmodestmedblogs.blogspot.com/2020/05/covid-false-negative-pcr-results-over.html). What about in the group who never have symptoms? is there consistent variability in the test by the number of days after exposure? most people will not know a specific date of exposure: how does that affect the false negative rate? At what point do they have live, potentially transmissible virus?? for how long?? Should we use antibody testing (which, depending on the test, may also be quite unreliable: see http://gmodestmedblogs.blogspot.com/2020/04/covid-antibody-testing-and-concerns.html )

    -- and we do know there is quite a variability of transmissibility: about 80% of secondary infections are from about 20% of infected people (superspreaders). what makes them different? are some asymptomatic people superspreaders??

    -- and, are those picked up by SARS-CoV-2 PCR different from those who have negative tests but are found through different testing?? (ie, are they still transmissable even if there is a false negative PCR test, perhaps by viral culture?)

-- the data in the study does suggest that those who were asymptomatic had weaker immune response to SARS-CoV-2 infection, raising questions of even short-term immunity to reinfection, and reinforcing the WHO declamation that positive antibody testing does not necessarily imply protection from reinfection (see http://gmodestmedblogs.blogspot.com/2020/05/covid-who-dont-trust-antibody-testing.html ).  

    -- though, of note, a good percentage of totally asymptomatic patients did have some lab or radiologic abnormalities consistent with infection (ie, the virus did have some effect even if the patients were asymptomatic). but, how were these asymptomatic patients different from those who had completely normal testing? 

-- studies from SARS and MERS have found detectable circulating antibodies for >2 years and >34 months, respectively

    -- this study found decreasing levels of IgG and neutralizing antibody levels for SARS-CoV-2 within 2-3 months

    -- we just don’t know which of our measurements of immune response might confer clinical immunity. Perhaps T-cell responses may be more durable and effective (as noted in http://gmodestmedblogs.blogspot.com/2020/06/covid-potential-new-vaccine-and.html )??

--it was also notable that there was such a muted inflammatory response in asymptomatic patients. this is in line with the concept that SARS-CoV-2 infection initiates a significant inflammatory response in many symptomatic Covid-19 patients, and this response itself (not necessarily the virus) may lead to bad clinical outcomes. and perhaps early initiation of strong anti-inflammatory meds may decrease progression to these bad outcomes?? and even later initiation may well help (eg, the UK dexamethasone study showing decreased mortality in very sick patients, though i cannot comment much now until it is published...)

so, another study adding some information and raising even more questions:

--how common is asymptomatic SARS-CoV-2 infection? and what is the best test to assess it, knowing the potentially very high false negative rates of PCR and the potential unreliability of antibody tests. and we have even less information about these tests in asymptomatics 

    --this is a hard issue, given lack of a gold standard. should we be doing viral cultures to see if the virus is viable (at least in the lab)? and at least see which of our other easier tests (PCR, antibody) are the best predictors??

    --or should we be testing T-cell responses??

--but given the persistence of this pandemic and highly likely subsequent waves (in the absence of an effective vaccine), understanding the prevalence and infectivity of asymptomatic patients seems like a really important goal...

geoff

 

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