Diagnostic Utility of SARS-CoV-2 Nucleocapsid Antigenemia: A Meta-analysis

Abstract

Background: Studies of the diagnostic performance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid antigen in blood (antigenemia) have reached variable conclusions. The potential utility of antigenemia measurements as a clinical diagnostic test needs clarification.

Methods: We performed a systematic review of Pubmed, Embase, and Scopus through July 15, 2023, and requested source data from corresponding authors.

Results: Summary sensitivity from 16 studies (4543 cases) sampled at ≤14 days of symptoms was 0.83 (0.75-0.89), and specificity was 0.98 (0.87-1.00) from 6 studies (792 reverse transcription polymerase chain reaction-negative controls). Summary sensitivity and specificity for paired respiratory specimens with cycle threshold values ≤33 were 0.91 (0.85-0.95) and 0.56 (0.39-0.73) from 10 studies (612 individuals). Source data from 1779 cases reveal that >70% have antigenemia 2 weeks following symptom onset, which persists in <10% at 28 days. The available studies suffer from heterogeneity, and Omicron-era data are scarce.

Conclusions: Nucleocapsid antigenemia currently has limited utility due to limitations of existing studies and lack of Omicron-era data. Improved study designs targeting potential clinical uses in screening, surveillance, and complex clinical decision-making-especially in immunocompromised patients-are needed.

Keywords: SARS-CoV-2; antigenemia; nucleocapsid.

Figure 1.

Meta-analyses of nucleocapsid antigenemia as a diagnostic marker of acute COVID-19 based on clinical diagnosis using an index text cutoff of 2.97 pg/mL. Studies are grouped according to the assay used (Quanterix Simoa, COV-QUANTO, and other assays). A, Sensitivity using the authors’ definition of acute COVID-19. B, Sensitivity only for those cases with ≤14 days of symptoms. C, Specificity for SARS-CoV-2-negative individuals. Abbreviations: COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 2.

Meta-analysis of nucleocapsid antigenemia as a diagnostic indicator of nasal swab RT-PCR Ct value ≤33. Univariate models for (A) sensitivity and (B) specificity, and (C) summary ROC curve using a bivariate model. Abbreviations: Ct, cycle threshold; ROC, receiver operating characteristics; RT-PCR, reverse transcription polymerase chain reaction.

Figure 3.

Timeline of studies identified in our review superimposed on variant trends retrieved from GISAID.org. The relative frequency of each variant is depicted as a fraction of the sequenced isolates. Studies that did not indicate specimen collection dates were omitted.

Figure 4.

Antigenemia kinetics. A, Antigenemia levels vs days since symptom onset for source data from 10 studies. All measurements below the threshold value were plotted at 2.97 pg/mL. An exponential fit to the log₁₀ of antigenemia level vs day of symptoms was performed. A-inset axes, Details of 28-day kinetics following COVID-19 symptom onset. The line and shaded region represent the mean and standard deviation of the log₁₀ of the antigenemia level. B, Proportion of patients represented in source data with antigenemia >2.97 pg/mL as a function of days of symptoms. For data where more precise symptom durations were provided, values were rounded down to the nearest integer. The shaded region represents the 95% CI calculated for each time point using the formula for standard error. The number below indicates the total number of cases in the aggregate data set at each time point. Abbreviation: COVID-19, coronavirus disease 2019.