Identification of Distinct Immunophenotypes in Critically Ill Coronavirus Disease 2019 Patients

BACKGROUND: Severe 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 QUESTION: Are critically ill COVID-19 patients biologically and immunologically dissociable based on profiling of currently evaluated therapeutic targets? STUDY DESIGN AND METHODS: We 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. RESULTS: We 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 cyto-kine levels (IL-6, IL-1 beta, IL-8, tumor necrosis factor-alpha [TNF alpha]) associated with CD4+ and CD8+T-lymphocyte defects. Cluster 3 had a complement-dependent phenotypewith terminal complement activation markers (elevated C3 and sC5b-9). INTERPRETATION: Patients 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.

Automated summary

A prospective study conducted in France on critically ill COVID-19 patients revealed three distinct clusters based on immunologic features, each associated with different outcomes in the ICU. The variability in immune responses suggests the need to target different mediators in different patient groups, providing a basis for individualized treatment and clinical trial eligibility.