• Thibault Dupont, Sophie Caillat-Zucman, Véronique Fremeaux-Bacchi, Florence Morin, Etienne Lengliné, Michael Darmon, Régis Peffault de Latour, Lara Zafrani, Elie Azoulay, and Guillaume Dumas.
• Medical Intensive Care Unit, Saint Louis Hospital, Assistance Publique Hôpitaux de Paris (APHP), Université de Paris, Paris, France.
• Chest. 2021 May 1; 159 (5): 1884-1893.

BackgroundSevere acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causes direct lung damage, overwhelming endothelial activation, and inflammatory reaction, leading to acute respiratory failure and multi-organ dysfunction. Ongoing clinical trials are evaluating targeted therapies to hinder this exaggerated inflammatory response. Critically ill coronavirus disease 2019 (COVID-19) patients have shown heterogeneous severity trajectories, suggesting that response to therapies is likely to vary across patients.Research QuestionAre critically ill COVID-19 patients biologically and immunologically dissociable based on profiling of currently evaluated therapeutic targets?Study Design And MethodsWe did a single-center, prospective study in an ICU department in France. Ninety-six critically ill adult patients admitted with a documented SARS-CoV-2 infection were enrolled. We conducted principal components analysis and hierarchical clustering on a vast array of immunologic variables measured on the day of ICU admission.ResultsWe found that patients were distributed in three clusters bearing distinct immunologic features and associated with different ICU outcomes. Cluster 1 had a "humoral immunodeficiency" phenotype with predominant B-lymphocyte defect, relative hypogammaglobulinemia, and moderate inflammation. Cluster 2 had a "hyperinflammatory" phenotype, with high cytokine levels (IL-6, IL-1β, IL-8, tumor necrosis factor-alpha [TNF⍺]) associated with CD4+ and CD8+ T-lymphocyte defects. Cluster 3 had a "complement-dependent" phenotype with terminal complement activation markers (elevated C3 and sC5b-9).InterpretationPatients with severe COVID-19 exhibiting cytokine release marks, complement activation, or B-lymphocyte defects are distinct from each other. Such immunologic variability argues in favor of targeting different mediators in different groups of patients and could serve as a basis for patient identification and clinical trial eligibility.Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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