Immunological Biomarkers of Fatal COVID-19: A Study of 868 Patients
Esperanza Martín‐Sánchez, Juan‐José Garcés, Catarina Maia, Susana Inogés, Ascensión López-Dı́az de Cerio, Francisco Carmona-Torre, Marta Marín‐Oto, Félix Alegre, Elvira Molano, Mirian Fernández-Alonso, Cristina Pérez, Cirino Botta, Aintzane Zabaleta, Ana B. Alcaide, Manuel F. Landecho, Marta Covela Rúa, Teresa Pérez-Warnisher, Laura Blanco, Sarai Sarvide, Amaia Vilas‐Zornoza, Diego Alignani, Cristina Moreno, Iñigo Pineda, Miguel Sogbe, Josepmaria Argemí, Bruno Paiva, José Ramón Yuste
Abstract
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.