TY - JOUR
T1 - Plasma SARS-CoV-2 nucleocapsid antigen levels are associated with progression to severe disease in hospitalized COVID-19
AU - the COMET Consortium
AU - Wick, Katherine D.
AU - Leligdowicz, Aleksandra
AU - Willmore, Andrew
AU - Carrillo, Sidney A.
AU - Ghale, Rajani
AU - Jauregui, Alejandra
AU - Chak, Suzanna S.
AU - Nguyen, Viet
AU - Lee, Deanna
AU - Jones, Chayse
AU - Dewar, Robin
AU - Lane, H. Clifford
AU - Kangelaris, Kirsten N.
AU - Hendrickson, Carolyn M.
AU - Liu, Kathleen D.
AU - Sinha, Pratik
AU - Erle, David J.
AU - Langelier, Charles R.
AU - Krummell, Matthew F.
AU - Woodruff, Prescott G.
AU - Calfee, Carolyn S.
AU - Matthay, Michael A.
AU - Abe-Jones, Yumiko
AU - Beagle, Alexander
AU - Bhide, Sharvari
AU - Fragiadakis, Gabriela K.
AU - Gonzalez, Ana
AU - Jamdar, Omid
AU - Jones, Norman
AU - Lea, Tasha
AU - Leroux, Carolyn
AU - Milush, Jeff
AU - Pierce, Logan
AU - Prasad, Priya
AU - Rashid, Sadeed
AU - Rodriguez, Nicklaus
AU - Sigman, Austin
AU - Ward, Alyssa
AU - Wilson, Michael
N1 - Funding Information:
This project was funded in part by the National Institutes of Health (U19AI077439, supporting the UCSF component of the NIAID Immunophenotyping Assessment in a COVID-19 Cohort [IMPACC] Network), and in part by Genentech (TSK-020586).
Funding Information:
We thank the members of the COMET consortium. The names and affiliations of those members not listed as authors are provided in Additional file 1. We also thank Drs. Benoit Fatou, Kinga Smolen, Hanno Steen, Patrick van Zalm, and Arthur Viode from the IMPACC Proteomics Core for sharing their data on the mass spectrometric detection. COMET consortium members and affiliations Yumiko Abe-Jones: Division of Hospital Medicine, University of California, San Francisco, California. Alexander Beagle: Department of Medicine, University of California, San Francisco, CA, USA. Sharvari Bhide: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California San Francisco. Gabriela K. Fragiadakis: Department of Medicine, Division of Rheumatology, University of California, San Francisco, CA 94143, USA, CoLabs, University of California, San Francisco, CA 94143, USA, Bakar ImmunoX Initiative, University of California, San Francisco, CA 94143, USA. Ana Gonzalez: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California San Francisco. Omid Jamdar: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. Norman Jones: Core Immunology Laboratory. Division of Experimental Medicine, University of California San Francisco, California, USA. Tasha Lea: Department of Pathology, University of California, San Francisco, CA, USA. Carolyn Leroux: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, USA. Jeff Milush: Core Immunology Laboratory. Division of Experimental Medicine, University of California San Francisco, California, USA.Logan Pierce: Division of Hospital Medicine, University of California, San Francisco, California. Priya Prasad: Division of Hospital Medicine, University of California, San Francisco, California. Sadeed Rashid: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. Nicklaus Rodriguez: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. Austin Sigman: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, USA. Luz Torres Altamirano: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. Alyssa Ward: Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, California, USA. Michael Wilson: Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85137925897&partnerID=8YFLogxK
U2 - 10.1186/s13054-022-04153-3
DO - 10.1186/s13054-022-04153-3
M3 - Article
C2 - 36104754
AN - SCOPUS:85137925897
SN - 1364-8535
VL - 26
JO - Critical Care
JF - Critical Care
IS - 1
M1 - 278
ER -