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Abstract: BACKGROUND: Severe immunopathology may drive the deleterious manifestations observed in the advanced stages of coronavirus disease 2019 (COVID-19) but are poorly understood. OBJECTIVE: To phenotype leukocyte subpopulations and the cytokine milieu in the lungs and blood of critically ill patients with COVID-19 acute respiratory distress syndrome (ARDS). METHODS: We consecutively included patients <72 hours after intubation following informed consent from next of kin. Bronchoalveolar lavage fluid (BALF) was evaluated by microscopy and BALF and blood was assessed by 10-colored flow cytometry and a multiplex cytokine panel. RESULTS: Four mechanically ventilated patients (40-75 yr.) with moderate to severe COVID-19 ARDS were included. Immature neutrophils dominated in both blood and lungs, while CD4 and CD8 T cell lymphopenia were observed in the two compartments. However, T regulatory cells and Th17 cells were found in higher fractions in the lung. Lung CD4 and CD8 T cells and macrophages expressed an even higher upregulation of activation markers than in blood. A wide range of cytokines were expressed at high levels both in blood and in the lungs, most notably IL-1RA, IL-6, IL-8, IP-10, and MCP-1, consistent with hyperinflammation. CONCLUSION: COVID-19 ARDS exhibits a distinct immunologic profile in the lungs with a depleted and exhausted CD4 and CD8 T cell population that resides within a heavily hyperinflammatory milieu. TRIAL REGISTRATION: clinicaltrials.gov/ct2/show/NCT04354584.