Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing COVID-19 pandemic have caused ~33 million cases and over 585,000 deaths in the United States alone. Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths being Black/African-American (AA) patients in some areas, yet targeted studies to delineate features of disease severity within this demographic are scant. Our multi-omics single-cell analyses of immune profiles from airways and matching blood samples of Black/AA patients revealed pronounced pulmonary neutrophilia and low viral burden as a hallmark of severe disease, where neutrophil phenotypes display advanced features of cytokine release syndrome and acute respiratory distress syndrome (ARDS). Cell-cell communication and trajectory analysis reveal a subset of circulating S100A12⁺/CXCR4⁺ mature neutrophils that infiltrate the lung via the IL-8/CXCR2 axis. Recruited neutrophils progress toward a transcriptionally active and pathogenic state characterized by exacerbated production of IL-8, IL-1β, IL-6, and CCL3/4 along with elevated levels of neutrophil elastase and myeloperoxidase. Inflammatory monocytes recruited via neutrophil-derived CCL3/4 also produce elevated neutrophil chemotactic factor IL-8, potentiating the sustained neutrophilia in the airways. The IL-8/CXCR2 axis emerges as a potential therapeutic target to reduce pathogenic neutrophilia and constrain ARDS in severe COVID-19.