Dysregulated host response in SARS-CoV-2 induced critical illness

Tiwari-Heckler, Shilpa; Rauber, Conrad; Longhi, Maria Serena; Zörnig, Inka; Schnitzler, Paul; Jäger, Dirk; Giese, Thomas; Merle, Uta

BACKGROUND: Impaired immune response has been described to be the cause of the development of COVID-19 related respiratory failure. Further studies are needed to understand the immunopathogenesis and to enable an improved stratification of patients that are at risk for critical illness. METHODS: 32 severely ill hospitalized COVID19 patients were recruited in our center at the University Hospital Heidelberg. We performed a comprehensive analysis of immune phenotype, cytokine and chemokine profiling and leukocyte transcripts in severe COVID-19 patients comparing critically ill patients requiring mechanical ventilation and high flow oxygen therapy and non-critically ill patient receiving low flow oxygen therapy. RESULTS: Critically ill patients exhibited low levels of CD8 T cells and myeloid dendritic cells. We noted a pronounced CCR6 (+) TH17 phenotype in CD4 central memory cells and elevated circulating levels of IL-17 in the critical group. Gene expression of leukocytes derived from critically ill patients was characterized by an upregulation of proinflammatory cytokines and reduction of IFN-responsive genes upon stimulation with toll-like receptor 7/8 agonist. When correlating clinical improvement and immune kinetics, we found that CD8 T cell subsets and myeloid dendritic cells significantly increased after disconnection from the ventilator. CONCLUSION: Critical illness was characterized by a TH17-mediated response and dysfunctional IFN-associated response, indicating an impaired capacity to mount antiviral responses during SARS-CoV-2 severe infection.