Seroprevalence of SARS-CoV-2 antibodies in US adult asymptomatic population

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Introduction

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.

Methods

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

Results

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.

Discussion

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.

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Article Information

Accepted for Publication: January 21, 2021.

Published: March 16, 2021. doi:10.1001/jamanetworkopen.2021.1552

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2021 Stout RL et al. JAMA Network Open.

Corresponding Author: Robert L. Stout, PhD, Clinical Reference Laboratory Inc, 8433 Quivira Rd, Lenexa, KS 66215 (Robert.Stout@crlcorp.com).

Author Contributions: Drs Stout and Rigatti had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Stout.

Acquisition, analysis, or interpretation of data: Both authors.

Drafting of the manuscript: Rigatti.

Critical revision of the manuscript for important intellectual content: Both authors.

Statistical analysis: Both authors.

Administrative, technical, or material support: Rigatti.

Conflict of Interest Disclosures: Dr Rigatti reported receiving personal fees from Clinical Reference Laboratories, Inc for consultation services, including manuscript preparation and data analysis during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was funded by Clinical Reference Laboratory, Lenexa, Kansas.

Role of the Funder/Sponsor: Clinical Reference Laboratory had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.

Kronbichler  A, Kresse  D, Yoon  S, Lee  KH, Effenberger  M, Shin  JI.  Asymptomatic patients as a source of COVID-19 infections: a systematic review and meta-analysis.   Int J Infect Dis. 2020;98:180-186. doi:10.1016/j.ijid.2020.06.052PubMedGoogle ScholarCrossref
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Roche Diagnostics. Elecsys Anti-SARS-CoV-2. Package insert 2020-07, version 4.0; material numbers 09203095190 and 09203079190. Accessed July 2020. https://diagnostics.roche.com/us/en/products/params/elecsys-anti-sars-cov-2.html
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R Core Team. R: a language and environment for statistical computing, version 3.6.0. R Foundation for Statistical Computing. 2019. Accessed April 2019. https://www.R-project.org/
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RStudio Team. RStudio: integrated development for R. RStudio, PBC, version 4.0.0. 2020. Accessed April 2020. https://rstudio.com/
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Bajema KL, Wiegand RE, Cuffe K, et al.  Estimated SARS-CoV-2 seroprevalence in the US as of September 2020.   JAMA Intern Med. Published online November 24, 2020. doi:10.1001/jamainternmed.2020.7976
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Centers for Disease Control and Prevention. Nationally Notifiable Diseases Surveillance System. Coronavirus disease 2019 (SARS-COV-2). Accessed January 10, 2021. https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html

Source: Seroprevalence of SARS-CoV-2 antibodies in US adult asymptomatic population



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