The dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome
Mathieu Blot, Jean‐Baptiste Bour, Jean‐Pierre Quenot, Abderrahmane Bourredjem, Maxime Nguyen, Julien Guy, Serge Monier, Marjolaine Georges, Audrey Large, Auguste Dargent, A Guilhem, S. Mouriès-Martin, Jérémy Barben, Bélaïd Bouhemad, Pierre‐Emmanuel Charles, P. Chavanet, Christine Binquet, Lionel Piroth, for the LYMPHONIE study group, Pascal Andreu, François Aptel, Marie Labruyère, Sébastien Prin, Guillaume Beltramo, Philippe Bonniaud, P. Bielefeld, Hervé Devilliers, Bernard Bonnotte, Marielle Buisson, Alain Putot
Abstract
BACKGROUND: Although immune modulation is a promising therapeutic avenue in coronavirus disease 2019 (COVID-19), the most relevant targets remain to be found. COVID-19 has peculiar characteristics and outcomes, suggesting a unique immunopathogenesis. METHODS: Thirty-six immunocompetent non-COVID-19 and 27 COVID-19 patients with severe pneumonia were prospectively enrolled in a single center, most requiring intensive care. Clinical and biological characteristics (including T cell phenotype and function and plasma concentrations of 30 cytokines) and outcomes were compared. RESULTS: At similar baseline respiratory severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (15 [7-22] vs. 4 (0-15) days; p = 0.0049). COVID-19 patients had lower levels of most classical inflammatory cytokines (G-CSF, CCL20, IL-1β, IL-2, IL-6, IL-8, IL-15, TNF-α, TGF-β), but higher plasma concentrations of CXCL10, GM-CSF and CCL5, compared to non-COVID-19 patients. COVID-19 patients displayed similar T-cell exhaustion to non-COVID-19 patients, but with a more unbalanced inflammatory/anti-inflammatory cytokine response (IL-6/IL-10 and TNF-α/IL-10 ratios). Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariate regression analysis confirmed that GM-CSF, CXCL10 and IL-10 levels were independently associated with the duration of mechanical ventilation. CONCLUSION: We identified a unique cytokine response, with higher plasma GM-CSF and CXCL10 in COVID-19 patients that were independently associated with the longer duration of mechanical ventilation. These cytokines could represent the dysregulated immune response in severe COVID-19, as well as promising therapeutic targets. ClinicalTrials.gov: NCT03505281.