An immune-based biomarker signature is associated with mortality in COVID-19 patients

• Published in: JCI insight Vol. 6; no. 1
• Main Authors: Abers, Michael S, Delmonte, Ottavia M, Ricotta, Emily E, Fintzi, Jonathan, Fink, Danielle L, de Jesus, Adriana A Almeida, Zarember, Kol A, Alehashemi, Sara, Oikonomou, Vasileios, Desai, Jigar V, Canna, Scott W, Shakoory, Bita, Dobbs, Kerry, Imberti, Luisa, Sottini, Alessandra, Quiros-Roldan, Eugenia, Castelli, Francesco, Rossi, Camillo, Brugnoni, Duilio, Biondi, Andrea, Bettini, Laura Rachele, D'Angio', Mariella, Bonfanti, Paolo, Castagnoli, Riccardo, Montagna, Daniela, Licari, Amelia, Marseglia, Gian Luigi, Gliniewicz, Emily F, Shaw, Elana, Kahle, Dana E, Rastegar, Andre T, Stack, Michael, Myint-Hpu, Katherine, Levinson, Susan L, DiNubile, Mark J, Chertow, Daniel W, Burbelo, Peter D, Cohen, Jeffrey I, Calvo, Katherine R, Tsang, John S, Su, Helen C, Gallin, John I, Kuhns, Douglas B, Goldbach-Mansky, Raphaela, Lionakis, Michail S, Notarangelo, Luigi D
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 11-01-2021; American Society for Clinical investigation
• Subjects: Adrenal Cortex Hormones - therapeutic use; Adult; Aged; Anti-Bacterial Agents - therapeutic use; Antibodies, Monoclonal, Humanized - therapeutic use; Antiviral Agents - therapeutic use; Azithromycin - therapeutic use; Biomarkers; Calgranulin B - genetics; Calgranulin B - immunology; Case-Control Studies; Chemokine CCL2 - genetics; Chemokine CCL2 - immunology; Chemokine CXCL9 - genetics; Chemokine CXCL9 - immunology; COVID-19; COVID-19 - genetics; COVID-19 - immunology; COVID-19 - mortality; COVID-19 - therapy; Enzyme Inhibitors - therapeutic use; Female; Ferritins - genetics; Ferritins - immunology; Gene Expression Profiling; Humans; Hydroxychloroquine - therapeutic use; Immunologic Factors - therapeutic use; Immunology; Interferon Type I - genetics; Interferon Type I - immunology; Interferon-gamma - genetics; Interferon-gamma - immunology; Interleukin-1 Receptor-Like 1 Protein - genetics; Interleukin-1 Receptor-Like 1 Protein - immunology; Interleukin-10 - genetics; Interleukin-10 - immunology; Interleukin-15 - genetics; Interleukin-15 - immunology; Interleukin-2 - genetics; Interleukin-2 - immunology; Interleukin-6 - genetics; Interleukin-6 - immunology; Lactoferrin - genetics; Lactoferrin - immunology; Lipocalin-2 - genetics; Lipocalin-2 - immunology; Male; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - immunology; Middle Aged; Multivariate Analysis; NF-kappa B - genetics; NF-kappa B - immunology; Prognosis; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - immunology; SARS-CoV-2; Severity of Illness Index; Vascular Endothelial Growth Factor Receptor-1 - genetics; Vascular Endothelial Growth Factor Receptor-1 - immunology; COVID-19; Immunology; Cytokines; Chemokines
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.144455

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.