Immunological Biomarkers of Fatal COVID-19: A Study of 868 Patients

Martín-Sánchez, Esperanza; Garcés, Juan José; Maia, Catarina; Inogés, Susana; López-Díaz de Cerio, Ascensión; Carmona-Torre, Francisco; Marin-Oto, Marta; Alegre, Félix; Molano, Elvira; Fernandez-Alonso, Mirian; Perez, Cristina; Botta, Cirino; Zabaleta, Aintzane; Alcaide, Ana Belen; Landecho, Manuel F.; Rua, Marta; Pérez-Warnisher, Teresa; Blanco, Laura; Sarvide, Sarai; Vilas-Zornoza, Amaia; Alignani, Diego; Moreno, Cristina; Pineda, Iñigo; Sogbe, Miguel; Argemi, Josepmaria; Paiva, Bruno; Yuste, José Ramón

Information on the immunopathobiology of coronavirus disease 2019 (COVID-19) is rapidly increasing; however, there remains a need to identify immune features predictive of fatal outcome. This large-scale study characterized immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection using multidimensional flow cytometry, with the aim of identifying high-risk immune biomarkers. Holistic and unbiased analyses of 17 immune cell-types were conducted on 1,075 peripheral blood samples obtained from 868 COVID-19 patients and on samples from 24 patients presenting with non-SARS-CoV-2 infections and 36 healthy donors. Immune profiles of COVID-19 patients were significantly different from those of age-matched healthy donors but generally similar to those of patients with non-SARS-CoV-2 infections. Unsupervised clustering analysis revealed three immunotypes during SARS-CoV-2 infection; immunotype 1 (14% of patients) was characterized by significantly lower percentages of all immune cell-types except neutrophils and circulating plasma cells, and was significantly associated with severe disease. Reduced B-cell percentage was most strongly associated with risk of death. On multivariate analysis incorporating age and comorbidities, B-cell and non-classical monocyte percentages were independent prognostic factors for survival in training (n=513) and validation (n=355) cohorts. Therefore, reduced percentages of B-cells and non-classical monocytes are high-risk immune biomarkers for risk-stratification of COVID-19 patients.