Abstract
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 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).
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.
Keywords: critical care; immunology; inflammation; respiratory failure.
【저자키워드】 immunology, Inflammation, Critical care, respiratory failure., 【초록키워드】 COVID-19, coronavirus disease, immunology, SARS-CoV-2, Necrosis, Coronavirus disease 2019, clinical trial, therapy, Critical care, Respiratory failure, severe COVID-19, multi-organ dysfunction, IL-6, SARS-COV-2 infection, severity, Prospective Study, Infection, immunodeficiency, Acute respiratory failure, complement, cytokine, ICU, SC5b-9, Complement activation, outcomes, Severe acute respiratory syndrome, tumor necrosis factor, Critically ill, therapeutic, Patient, ICU admission, Clustering, Cluster, IL-8, France, phenotype, respiratory, group, targeted therapy, Critical, moderate, patients, severe acute respiratory syndrome-coronavirus-2, Hypogammaglobulinemia, marker, IL-1β, principal components, COVID-19 patient, Profiling, hierarchical clustering, critically ill COVID-19 patients, lung damage, mediators, tumor necrosis, response to therapies, Trajectories, Hierarchical, endothelial, Activation, tumor necrosis factor-alpha, patient identification, Variability, favor, single-center, eligibility, CD4+, heterogeneous, inflammatory reaction, cytokine release, principal components analysis, CD8+, exaggerated inflammatory response, variable, feature, enrolled, shown, evaluated, elevated, conducted, cause, predominant, exhibiting, cytokine level, immunologically, 【제목키워드】 immunophenotype, identification, Ill,