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

• Main Authors: Esperanza Martín-Sánchez, Juan José Garcés, Catarina Maia, Susana Inogés, Ascensión López-Díaz de Cerio, Francisco Carmona-Torre, Marta Marin-Oto, Félix Alegre, Elvira Molano, Mirian Fernandez-Alonso, Cristina Perez, Cirino Botta, Aintzane Zabaleta, Ana Belen Alcaide, Manuel F. Landecho, Marta Rua, Teresa Pérez-Warnisher, Laura Blanco, Sarai Sarvide, Amaia Vilas-Zornoza, Diego Alignani, Cristina Moreno, Iñigo Pineda, Miguel Sogbe, Josepmaria Argemi, Bruno Paiva, José Ramón Yuste
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-05-01
• Series: Frontiers in Immunology
• Subjects: COVID-19; SARS-CoV-2; flow cytometry; lymphopenia; outcome; survival
• Online Access: https://www.frontiersin.org/articles/10.3389/fimmu.2021.659018/full

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.