A study evaluating asymptomatic adults for COVID-19 would add another 16m to the total number of SARS-CoV-2 infections in the US, at least up to September 2020. Investigators assessed 61,910 adults who reported feeling well when they applied for life insurance. A total of 4,094, or 6.6%, had a positive serum or plasma antibody test for SARS-CoV-2 infection.
The finding would "double the number who have been infected with COVID-19 compared to the number of clinically diagnosed cases," lead author Dr Robert L Stout, chief scientific officer at Clinical Reference Laboratory Inc in Lenexa, Kansas is quoted in Medscape Medical News as saying.
"As of September, the scope of the pandemic was about double the number of reported cases," Stout added. "It is not like measles, where it is easily identified. Quite simply, for the asymptomatic patient they think that everything is fine and continue to go about their normal activities. Some practice recommended CDC guidelines in public places, while some may not."
Once investigators evaluated the national convenience sample in September 2020, they extrapolated to the number of US adults, based on census data.
The cross-sectional study included age, sex, state of residence, and antibody status. The mean age of people in the study was 39 years. Of the 4094 positive cases, 54% were men.
The seroprevalence rate was slightly higher among women, 6.9%, compared with 6.4% among men.
The lowest SARS-CoV-2 seroprevalence rate was 2.8% among asymptomatic people older than 70. In contrast, the youngest cohort up to age 30 years had the highest rate, at 9.8%.
"The seroprevalence rates varied widely by state," noted Stout and co-author Dr Steven Rigatti, owner and founder of Rigatti Risk Analytics. The highest SARS-CoV-2 seroprevalence rate in September 2020 was 14.4% in New York, followed by 12% in Louisiana, and 10% in Nevada. States with the lowest rates included Oregon with 1.5%, Maine with 0.6%, and Alaska with 0%.
"Our estimate implied more than twice the number of infections than cases reported to the US Centres for Disease Control and Prevention," the researchers note, "suggesting a more widespread pandemic."
Potential limitations of the study include self-reporting of health – all people reported feeling well – and evaluation of blood tests submitted for clinical evaluation vs a random sample of the overall population.
"Overall, it is difficult to interpret the findings, as the sample for the study was a convenience sample of individuals applying for life insurance," Dr Neeraj Sood said in the report.
The numbers might even be higher. "People applying for life insurance tend to be more educated, richer, and probably more risk-averse. So the findings from this study do not generalize to the general population and probably represent a lower bound of true seroprevalence in the general population," said Sood, director of the COVID Initiative at the University of Southern California Schaeffer Centre in Los Angeles.
Sood was the lead author of a study in May 2020 evaluating the seroprevalence of SARS-CoV-2 among adults in Los Angeles County.
Seroprevalence of SARS-CoV-2 Antibodies in the US Adult Asymptomatic Population as of September 30, 2020
Robert L Stout; Steven J Rigatti
Published in JAMA Network Open on 16 March 2021
Because severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be asymptomatic or minimally symptomatic, counts of officially reported cases may substantially underestimate the overall burden of infection in the United States.1 Viral serologic testing may provide a more accurate estimate of cumulative disease prevalence. This cross-sectional study assesses the seroprevalence of SARS-CoV-2 in a nationwide, self-reported well population.
In September 2020, a national adult convenience sample of 61 910 self-reported well life insurance applicants was evaluated for the presence of antibody to nucleocapsid protein with an immunoassay intended for qualitative detection of antibodies to SARS-CoV-2 in human serum and plasma (Elecsys Anti–SARS-CoV-2; Roche Diagnostics) at the Clinical Reference Laboratory in Lenexa, Kansas. This test has a reported sensitivity and specificity of 99.5% and 99.8%, respectfully.2 Applicants’ age, sex, state of residence, and antibody status were recorded and all personal data were removed. The Western Institutional Review Board reviewed the study under the Common Rule and applicable guidance and deemed it to be exempt because it uses deidentified study samples for epidemiologic investigation. All participants signed disclosures indicating that results may be used for research purposes. The study conforms to the recommendations of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
To estimate the total burden of SARS-CoV-2 infections in the United States, the 2019 estimated US Census population was multiplied by the proportion of the US population between the ages of 16 and 80 years (75.5%), the selected adult portion of the total population. Then, the state-specific proportion of positive test results was applied from our sample. Confidence limits were estimated by generating 5000 bootstrap samples and recalculating the total number of US cases. The χ2 test and unpaired, 2-tailed t test were used to test for differences between seropositive and seronegative groups as appropriate, with a significance level of 99%. All statistical analyses were performed using R version 3.6.13 and RStudio version 1.2.1335 software (R Foundation for Statistical Computing).4
A total of 61 910 participants were tested for antibodies to SARS-CoV-2. Among the 4094 seropositive participants, 2215 (54%) were male. The median age of male participants was 39 years (interquartile range [IQR], 31-50 years); for female participants the median age was 39 years (IQR, 31-49 years). Among the 57 816 seronegative participants, 32 377 (56%) were male with a median age of 42 years (IQR, 34-54 years); for the 27 173 seronegative female participants the median age was 41 years (IQR, 33-53 years). The differences in age and sex were both significant (2-sided P < .001 for age; 2-sided P = .005 for sex). The seroprevalance rate was slightly higher for female than male participants (6.9% compared with 6.4%) and was associated with age; those older than 70 years had the lowest seroprevalence rate (2.8%), and those younger than 30 years (9.8%) had the highest seroprevalence rate (9.8%) (Table 1).
The seroprevalence rate varied widely by state (Table 2). On the basis of this sample, it was estimated that 15.9 million (bootstrap 95% CI, 15.5-16.5 million) asymptomatic or undiagnosed SARS-CoV-2 infections had occurred in the United States as of September 30, 2020.
Other studies of SARS-CoV-2 serologic testing have found a higher implied cumulative prevalence.5 This difference may be due to unintended bias when testing samples submitted for clinical testing compared with the generally well insurance population. Our estimate implied more than twice the number of infections than cases reported to Centers for Disease Control and Prevention,6 suggesting a more widespread pandemic. Limitations of the study include self-reported health status (well) and an imbalanced representation of the US population by age, sex, and residence location. Even with these limitations, the study validates the need for ongoing population-wide surveillance.
The findings of this cross-sectional study suggest that, based on a sample from an otherwise healthy population, the overall number of SARS-CoV-2 infections in the US may be substantially higher than estimates based on public health case reporting.
Full Medscape report (Open access)
JAMA Network Open (Restricted access)