Diagnostic Value of Nucleocapsid Protein in Blood for SARS-CoV-2 Infection

• Published in: Clinical chemistry (Baltimore, Md.) Vol. 68; no. 1; pp. 240 - 248
• Main Authors: Zhang, Yu, Ong, Chui Mei, Yun, Cassandra, Mo, Weike, Whitman, Jeffery D, Lynch, Kara L, Wu, Alan H B
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-01-2022
• Subjects: Antibodies; Antibodies, Viral - blood; Antigens; Biomarkers; Blood; Coronavirus Nucleocapsid Proteins - blood; Coronaviruses; Correlation; COVID-19; COVID-19 - diagnosis; COVID-19 Testing - methods; Diagnostic systems; Disease transmission; Electronic health records; Electronic medical records; Evidence-based Medicine and Test Utilization (TUO); Humans; Immune response; Infections; Medical diagnosis; Nucleocapsid Proteins; Nucleocapsids; Pandemics; Phosphoproteins - blood; Proteins; Respiratory diseases; Respiratory system; Retrospective Studies; Ribonucleic acid; RNA; RNA, Viral; SARS-CoV-2; Sensitivity; Sensitivity and Specificity; Severe acute respiratory syndrome coronavirus 2; Viral diseases; United States; COVID-19; SARS-CoV-2; serum nucleocapsid protein; biomarker
• ISSN: 0009-9147; 1530-8561
• DOI: 10.1093/clinchem/hvab148

Abstract
Background
Biomarkers have been widely explored for coronavirus disease 2019 diagnosis. Both viral RNA or antigens (Ag) in the respiratory system and antibodies (Ab) in blood are used to identify active infection, transmission risk, and immune response but have limitations. This study investigated the diagnostic utility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein (N-Ag) in serum.
Methods
We retrospectively studied 208 randomly selected cases with SARS-CoV-2 infection confirmed by viral RNA test in swabs. N-Ag concentrations were measured in remnant serum samples, compared to viral RNA or Ab results, and correlated to electronic health records for clinical value evaluation.
Results
Serum N-Ag was detected during active infection as early as day 2 from symptom onset with a diagnostic sensitivity of 81.5%. Within 1 week of symptom onset, the diagnostic sensitivity and specificity reached 90.9% (95% CI, 85.1%–94.6%) and 98.3% (95% CI, 91.1%–99.9%), respectively. Moreover, serum N-Ag concentration closely correlated to disease severity, reflected by highest level of care, medical interventions, chest imaging, and the length of hospital stays. Longitudinal analysis revealed the simultaneous increase of Abs and decline of N-Ag.
Conclusions
Serum N-Ag is a biomarker for SARS-CoV-2 acute infection with high diagnostic sensitivity and specificity compared to viral RNA in the respiratory system. There is a correlation between serum N-Ag concentrations and disease severity and an inverse relationship of N-Ag and Abs. The diagnostic value of serum N-Ag, as well as technical and practical advantages it could offer, may meet unsatisfied diagnostic and prognostic needs during the pandemic.