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

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.

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.