Rationale: Uncontrolled inflammatory innate response and impaired adaptive immune response are associated with clinical severity in patients with coronavirus disease (COVID-19).

Objectives: To compare the immunopathology of COVID-19 acute respiratory distress syndrome (ARDS) with that of non–COVID-19 ARDS, and to identify biomarkers associated with mortality in patients with COVID-19 ARDS.

Methods: Prospective observational monocenter study. Immunocompetent patients diagnosed with RT-PCR–confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and ARDS admitted between March 8 and March 30, 2020, were included and compared with patients with non–COVID-19 ARDS. The primary clinical endpoint of the study was mortality at Day 28. Flow cytometry analyses and serum cytokine measurements were performed at Days 1–2 and 4–6 of ICU admission.

Measurements and Main Results: As compared with patients with non–COVID-19 ARDS (n = 36), those with COVID-19 (n = 38) were not significantly different regarding age, sex, and Sequential Organ Failure Assessment and Simplified Acute Physiology Score II scores but exhibited a higher Day-28 mortality (34% vs. 11%, P = 0.030). Patients with COVID-19 showed profound and sustained T CD4⁺ (P = 0.002), CD8⁺ (P < 0.0001), and B (P < 0.0001) lymphopenia, higher HLA-DR expression on monocytes (P < 0.001) and higher serum concentrations of EGF (epithelial growth factor), GM-CSF, IL-10, CCL2/MCP-1, CCL3/MIP-1a, CXCL10/IP-10, CCL5/RANTES, and CCL20/MIP-3a. After adjusting on age and Sequential Organ Failure Assessment, serum CXCL10/IP-10 (P = 0.047) and GM-CSF (P = 0.050) were higher and nasopharyngeal RT-PCR cycle threshold values lower (P = 0.010) in patients with COVID-19 who were dead at Day 28.

Conclusions: Profound global lymphopenia and a “chemokine signature” were observed in COVID-19 ARDS. Increased serum concentrations of CXCL10/IP-10 and GM-CSF, together with higher nasopharyngeal SARS-CoV-2 viral load, were associated with Day-28 mortality.