Plasma SARS-CoV-2 nucleocapsid antigen levels are associated with progression to severe disease in hospitalized COVID-19
Katherine D. Wick,
Aleksandra Leligdowicz,
Andrew Willmore,
Sidney A. Carrillo,
Rajani Ghale,
Alejandra Jauregui,
Suzanna S. Chak,
Viet Nguyen,
Deanna Lee,
Chayse Jones,
Robin Dewar,
H. Clifford Lane,
Kirsten N. Kangelaris,
Carolyn M. Hendrickson,
Kathleen D. Liu,
Pratik Sinha,
David J. Erle,
Charles R. Langelier,
Matthew F. Krummell,
Prescott G. Woodruff,
Carolyn S. Calfee,
Michael A. Matthay,
the COMET Consortium
Affiliations
Katherine D. Wick
Cardiovascular Research Institute, University of California San Francisco
Aleksandra Leligdowicz
Cardiovascular Research Institute, University of California San Francisco
Andrew Willmore
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco
Sidney A. Carrillo
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco
Rajani Ghale
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco
Alejandra Jauregui
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco
Suzanna S. Chak
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco
Viet Nguyen
Cardiovascular Research Institute, University of California San Francisco
Deanna Lee
Cardiovascular Research Institute, University of California San Francisco
Chayse Jones
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco
Robin Dewar
Virus Isolation and Serology Laboratory, Applied and Developmental Directorate, Frederick National Laboratory
H. Clifford Lane
Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Kirsten N. Kangelaris
Department of Hospital Medicine, University of California San Francisco
Carolyn M. Hendrickson
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California San Francisco
Kathleen D. Liu
Division of Nephrology, Department of Medicine, University of California San Francisco School of Medicine
Pratik Sinha
Department of Anesthesia, Division of Critical Care, Washington University
David J. Erle
Cardiovascular Research Institute, University of California San Francisco
Charles R. Langelier
Division of Infectious Diseases, University of California San Francisco
Matthew F. Krummell
ImmunoX Initiative, University of California San Francisco
Prescott G. Woodruff
Cardiovascular Research Institute, University of California San Francisco
Carolyn S. Calfee
Cardiovascular Research Institute, University of California San Francisco
Michael A. Matthay
Cardiovascular Research Institute, University of California San Francisco
Abstract Background Studies quantifying SARS-CoV-2 have focused on upper respiratory tract or plasma viral RNA with inconsistent association with clinical outcomes. The association between plasma viral antigen levels and clinical outcomes has not been previously studied. Our aim was to investigate the relationship between plasma SARS-CoV-2 nucleocapsid antigen (N-antigen) concentration and both markers of host response and clinical outcomes. Methods SARS-CoV-2 N-antigen concentrations were measured in the first study plasma sample (D0), collected within 72 h of hospital admission, from 256 subjects admitted between March 2020 and August 2021 in a prospective observational cohort of hospitalized patients with COVID-19. The rank correlations between plasma N-antigen and plasma biomarkers of tissue damage, coagulation, and inflammation were assessed. Multiple ordinal regression was used to test the association between enrollment N-antigen plasma concentration and the primary outcome of clinical deterioration at one week as measured by a modified World Health Organization (WHO) ordinal scale. Multiple logistic regression was used to test the association between enrollment plasma N-antigen concentration and the secondary outcomes of ICU admission, mechanical ventilation at 28 days, and death at 28 days. The prognostic discrimination of an externally derived “high antigen” cutoff of N-antigen ≥ 1000 pg/mL was also tested. Results N-antigen on D0 was detectable in 84% of study participants. Plasma N-antigen levels significantly correlated with RAGE (r = 0.61), IL-10 (r = 0.59), and IP-10 (r = 0.59, adjusted p = 0.01 for all correlations). For the primary outcome of clinical status at one week, each 500 pg/mL increase in plasma N-antigen level was associated with an adjusted OR of 1.05 (95% CI 1.03–1.08) for worse WHO ordinal status. D0 plasma N-antigen ≥ 1000 pg/mL was 77% sensitive and 59% specific (AUROC 0.68) with a positive predictive value of 23% and a negative predictive value of 93% for a worse WHO ordinal scale at day 7 compared to baseline. D0 N-antigen concentration was independently associated with ICU admission and 28-day mechanical ventilation, but not with death at 28 days. Conclusions Plasma N-antigen levels are readily measured and provide important insight into the pathogenesis and prognosis of COVID-19. The measurement of N-antigen levels early in-hospital course may improve risk stratification, especially for identifying patients who are unlikely to progress to severe disease.
