Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients.

Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49–14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08–18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 –a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention. Author summary: We examined the immune abnormalities linked to critical illness and death in COVID-19 patients on ICU, performing immunophenotyping of viral antigen-specific and unconventional T cell responses, together with studies of neutralizing antibodies, and serum proteins. We compared these findings to a parallel set of patients with severe influenza. From this screen we identified mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19. MAIT cell activation correlated with several other mortality-associated immunologic measures including elevated levels of cytokines and chemokines, such as GM-CSF and CXCL10. MAIT cell activation is also a predictor of disease severity in influenza. Single-cell RNA-sequencing revealed a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 –a feature not observed in severe influenza. Overall we observed key potential biomarkers and targetable pathways in critical viral illness, many shared between influenza and COVID-19 and some unique to each infection. [ABSTRACT FROM AUTHOR]